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Systemic pharmacological treatments for chronic plaque psoriasis: a network meta‐analysis

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Background

Psoriasis is an immune‐mediated disease for which some people have a genetic predisposition. The condition manifests in inflammatory effects on either the skin or joints, or both, and it has a major impact on quality of life. Although there is currently no cure for psoriasis, various treatment strategies allow sustained control of disease signs and symptoms. Several randomised controlled trials (RCTs) have compared the efficacy of the different systemic treatments in psoriasis against placebo. However, the relative benefit of these treatments remains unclear due to the limited number of trials comparing them directly head‐to‐head, which is why we chose to conduct a network meta‐analysis.

Objectives

To compare the efficacy and safety of non‐biological systemic agents, small molecules, and biologics for people with moderate‐to‐severe psoriasis using a network meta‐analysis, and to provide a ranking of these treatments according to their efficacy and safety.

Search methods

For this living systematic review we updated our searches of the following databases monthly to September 2020: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase. We searched two trials registers to the same date. We checked the reference lists of included studies and relevant systematic reviews for further references to eligible RCTs.

Selection criteria

Randomised controlled trials (RCTs) of systemic treatments in adults (over 18 years of age) with moderate‐to‐severe plaque psoriasis or psoriatic arthritis whose skin had been clinically diagnosed with moderate‐to‐severe psoriasis, at any stage of treatment, in comparison to placebo or another active agent. The primary outcomes of this review were: the proportion of participants who achieved clear or almost clear skin, that is, at least Psoriasis Area and Severity Index (PASI) 90 at induction phase (from 8 to 24 weeks after the randomisation), and the proportion of participants with serious adverse events (SAEs) at induction phase. We did not evaluate differences in specific adverse events.

Data collection and analysis

Several groups of two review authors independently undertook study selection, data extraction, 'Risk of bias' assessment, and analyses. We synthesised the data using pair‐wise and network meta‐analysis (NMA) to compare the treatments of interest and rank them according to their effectiveness (as measured by the PASI 90 score) and acceptability (the inverse of serious adverse events).

We assessed the certainty of the body of evidence from the NMA for the two primary outcomes and all comparisons, according to CINeMA, as either very low, low, moderate, or high. We contacted study authors when data were unclear or missing.

We used the surface under the cumulative ranking curve (SUCRA) to infer on treatment hierarchy: 0% (treatment is the worst for effectiveness or safety) to 100% (treatment is the best for effectiveness or safety).

Main results

We included 158 studies (18 new studies for the update) in our review (57,831 randomised participants, 67.2% men, mainly recruited from hospitals). The overall average age was 45 years; the overall mean PASI score at baseline was 20 (range: 9.5 to 39). Most of these studies were placebo‐controlled (58%), 30% were head‐to‐head studies, and 11% were multi‐armed studies with both an active comparator and a placebo. We have assessed a total of 20 treatments. In all, 133 trials were multicentric (two to 231 centres). All but two of the outcomes included in this review were limited to the induction phase (assessment from 8 to 24 weeks after randomisation). We assessed many studies (53/158) as being at high risk of bias; 25 were at an unclear risk, and 80 at low risk. Most studies (123/158) declared funding by a pharmaceutical company, and 22 studies did not report their source of funding.

Network meta‐analysis at class level showed that all of the interventions (non‐biological systemic agents, small molecules, and biological treatments) were significantly more effective than placebo in reaching PASI 90.

At class level, in reaching PASI 90, the biologic treatments anti‐IL17, anti‐IL12/23, anti‐IL23, and anti‐TNF alpha were significantly more effective than the small molecules and the non‐biological systemic agents.

At drug level, infliximab, ixekizumab, secukinumab, brodalumab, risankizumab and guselkumab were significantly more effective in reaching PASI 90 than ustekinumab and three anti‐TNF alpha agents: adalimumab, certolizumab, and etanercept. Ustekinumab and adalimumab were significantly more effective in reaching PASI 90 than etanercept; ustekinumab was more effective than certolizumab, and the clinical effectiveness of ustekinumab and adalimumab was similar. There was no significant difference between tofacitinib or apremilast and three non‐biological drugs: fumaric acid esters (FAEs), ciclosporin and methotrexate.

Network meta‐analysis also showed that infliximab, ixekizumab, risankizumab, bimekizumab, secukinumab, guselkumab, and brodalumab outperformed other drugs when compared to placebo in reaching PASI 90. The clinical effectiveness of these drugs was similar, except for ixekizumab which had a better chance of reaching PASI 90 compared with secukinumab, guselkumab and brodalumab. The clinical effectiveness of these seven drugs was: infliximab (versus placebo): risk ratio (RR) 50.29, 95% confidence interval (CI) 20.96 to 120.67, SUCRA = 93.6; high‐certainty evidence; ixekizumab (versus placebo): RR 32.48, 95% CI 27.13 to 38.87; SUCRA = 90.5; high‐certainty evidence; risankizumab (versus placebo): RR 28.76, 95% CI 23.96 to 34.54; SUCRA = 84.6; high‐certainty evidence; bimekizumab (versus placebo): RR 58.64, 95% CI 3.72 to 923.86; SUCRA = 81.4; high‐certainty evidence; secukinumab (versus placebo): RR 25.79, 95% CI 21.61 to 30.78; SUCRA = 76.2; high‐certainty evidence; guselkumab (versus placebo): RR 25.52, 95% CI 21.25 to 30.64; SUCRA = 75; high‐certainty evidence; and brodalumab (versus placebo): RR 23.55, 95% CI 19.48 to 28.48; SUCRA = 68.4; moderate‐certainty evidence. Conservative interpretation is warranted for the results for bimekizumab (as well as mirikizumab, tyrosine kinase 2 inhibitor, acitretin, ciclosporin, fumaric acid esters, and methotrexate), as these drugs, in the NMA, have been evaluated in few trials.

We found no significant difference between any of the interventions and the placebo for the risk of SAEs. Nevertheless, the SAE analyses were based on a very low number of events with low to moderate certainty for all the comparisons. Thus, the results have to be viewed with caution and we cannot be sure of the ranking.

For other efficacy outcomes (PASI 75 and Physician Global Assessment (PGA) 0/1) the results were similar to the results for PASI 90.

Information on quality of life was often poorly reported and was absent for several of the interventions.

Authors' conclusions

Our review shows that compared to placebo, the biologics infliximab, ixekizumab, risankizumab, bimekizumab, secukinumab, guselkumab and brodalumab were the most effective treatments for achieving PASI 90 in people with moderate‐to‐severe psoriasis on the basis of moderate‐ to high‐certainty evidence. This NMA evidence is limited to induction therapy (outcomes were measured from 8 to 24 weeks after randomisation) and is not sufficient for evaluation of longer‐term outcomes in this chronic disease. Moreover, we found low numbers of studies for some of the interventions, and the young age (mean age of 45 years) and high level of disease severity (PASI 20 at baseline) may not be typical of patients seen in daily clinical practice.

Another major concern is that short‐term trials provide scanty and sometimes poorly‐reported safety data and thus do not provide useful evidence to create a reliable risk profile of treatments. We found no significant difference in the assessed interventions and placebo in terms of SAEs, and the evidence for all the interventions was of low to moderate quality. In order to provide long‐term information on the safety of the treatments included in this review, it will also be necessary to evaluate non‐randomised studies and postmarketing reports released from regulatory agencies.

In terms of future research, randomised trials directly comparing active agents are necessary once high‐quality evidence of benefit against placebo is established, including head‐to‐head trials amongst and between non‐biological systemic agents and small molecules, and between biological agents (anti‐IL17 versus anti‐IL23, anti‐IL23 versus anti‐IL12/23, anti‐TNF alpha versus anti‐IL12/23). Future trials should also undertake systematic subgroup analyses (e.g. assessing biological‐naïve participants, baseline psoriasis severity, presence of psoriatic arthritis, etc.). Finally, outcome measure harmonisation is needed in psoriasis trials, and researchers should look at the medium‐ and long‐term benefit and safety of the interventions and the comparative safety of different agents.

Editorial note: This is a living systematic review. Living systematic reviews offer a new approach to review updating, in which the review is continually updated, incorporating relevant new evidence as it becomes available. Please refer to the Cochrane Database of Systematic Reviews for the current status of this review.

PICOs

Population
Intervention
Comparison
Outcome

The PICO model is widely used and taught in evidence-based health care as a strategy for formulating questions and search strategies and for characterizing clinical studies or meta-analyses. PICO stands for four different potential components of a clinical question: Patient, Population or Problem; Intervention; Comparison; Outcome.

See more on using PICO in the Cochrane Handbook.

Which medicines, taken by mouth or injected, work best to treat a skin condition called plaque psoriasis?

Key messages

‐ After six months of treatment, medicines called 'biologics' seem to work best to clear patches of psoriasis on the skin.

‐ Longer studies are needed to assess the benefits and potential harms of longer treatment with medicines that are injected or taken by mouth to treat psoriasis.

‐ More studies are needed that compare these types of medicines directly against each other.

What is psoriasis?

Psoriasis is an immune condition that affects the skin, and sometimes the joints. Psoriasis speeds up the production of new skin cells, which build up to form raised patches on the skin known as 'plaques'. Plaques can also be flaky, scaly, itchy, and appear red on white skin, and as darker patches on darker skin tones. Plaque psoriasis is the most common form of psoriasis.

How is psoriasis treated?

Treatments for psoriasis depend on how bad the symptoms are. Around 10% to 20% of people with moderate or severe psoriasis will need to take medicines that affect their immune system, to help control the psoriasis. These medicines are called systemic treatments, because they affect the whole body. These are usually taken by mouth (oral) or injected.

Why did we do this Cochrane Review?

There are three different types of systemic medicines to treat psoriasis:

‐ 'biologics' ‐ proteins, such as antibodies, that affect biological targets called interleukins and cytokines (parts of the immune system that affect how cells behave);
‐ small molecules ‐ organic compounds that affect immune cells; examples include apremilast and tofacitinib; and
‐ non‐biologic medicines ‐ medicines that have been in use for a long time to treat psoriasis, such as methotrexate, ciclosporin and retinoids.

We wanted to find out about the benefits and potential harms of taking systemic medicines to treat psoriasis, and to see if some medicines work better than others.

What did we do?

We searched for studies that tested systemic medicines to treat plaque psoriasis.

How up to date is this review?

We include evidence up to September 2020.

What did we find?

We found 158 studies, including 18 new studies, since our last search. The studies tested 20 different medicines, covering 57,831 people with psoriasis (average age 45 years) and lasted from 2 to 6 months. Of 132 studies that reported their source of funding, a pharmaceutical company provided funding for 123 studies and nine were funded by non‐commercial organisations or academic institutions.

Most studies compared the systemic medicine against a placebo (a 'dummy' treatment that does not contain any medicine but looks identical to the medicine being tested). They used a common measurement scale called the PASI (psoriasis area and severity index) to compare how well each medicine cleared psoriasis plaques from the skin, looking for a 90% improvement (called 'PASI 90'). Few studies reported on participants' well‐being.

We compared all the medicines with each other using a mathematical method called a network meta‐analysis.

What are the main results of our review?

All the medicines tested worked better than a placebo to treat psoriasis (measured as a 90% improvement in PASI).

Biologic medicines (that targeted interleukins 17, 23 and 12/23, and the cytokine TNF‐alpha) treated psoriasis better than the small‐molecule and non‐biologic medicines.

Compared with placebo, seven biologic medicines worked best to treat psoriasis, with little difference between them:

‐ infliximab (targets TNF‐alpha);

‐ ixekizumab, bimekizumab, secukinumab and brodalumab (target interleukin‐17); and

‐ risankizumab and guselkumab (target interleukin‐23).

We found no significant difference in the numbers of serious unwanted effects for all systemic medicines tested when compared with a placebo. However, the studies did not consistently report results about safety, such as serious unwanted effects. We therefore could not create a reliable risk profile of systemic medicines.

Limitations of the evidence

We are confident in our results for the seven biologic medicines that worked best to treat psoriasis. We are less confident in our results for serious unwanted effects, because of the low number of unwanted effects reported.

We are also less confident in the results for the non‐biologic medicines because of concerns about how some of the studies were conducted. Further research is likely to change these results.

We did not find many studies for some of the 20 medicines included in our review. Participants in the studies often had severe psoriasis at the start of the study, so our results may not be useful for people whose psoriasis is less severe. Our findings relate only to treatment with systemic medicines for up to six months at most.

Editorial note: This is a living systematic review. Living systematic reviews offer a new approach to review updating, in which the review is continually updated, incorporating relevant new evidence as it becomes available. Please refer to the Cochrane Database of Systematic Reviews for the current status of this review.

Authors' conclusions

Implications for practice

In terms of achieving PASI 90 with induction therapy (evaluation from 8 to 24 weeks after the randomisation), we found the following results, based on network meta‐analysis.

  • At class level, all of the assessed interventions (non‐biological systemic agents, small molecules, and biological treatments) showed significant superiority compared with placebo;

  • At class level, the biologic treatments anti‐IL17, anti‐IL12/23, anti‐IL23, and anti‐TNF alpha showed significant superiority compared with small molecules and non‐biological systemic agents;

  • At drug level, infliximab, ixekizumab, secukinumab, brodalumab, risankizumab and guselkumab were significantly more effective in reaching PASI 90 than ustekinumab and three anti‐TNF alpha agents: adalimumab, certolizumab, and etanercept. Ustekinumab and adalimumab were significantly more effective in reaching PASI 90 than etanercept; ustekinumab was more effective than certolizumab, and the clinical effectiveness for ustekinumab and adalimumab was similar.

  • When compared with placebo, the following biological agents are the most effective treatments (in SUCRA rank order)  for reaching PASI 90: infliximab (high‐certainty evidence), ixekizumab (high‐certainty evidence), risankizumab (high‐certainty evidence), bimekizumab (high‐certainty evidence), secukinumab (high‐certainty evidence), guselkumab (high‐certainty evidence), and brodalumab (moderate‐certainty evidence). The clinical effectiveness of these seven drugs was similar when compared against each other, except for ixekizumab, which had a better chance of reaching PASI 90 compared with secukinumab, guselkumab and brodalumab.

  • There was no significant difference between tofacitinib or apremilast and three non‐biological drugs: fumaric acid esters (FAEs), ciclosporin and methotrexate.

For the other efficacy outcomes (PASI 75 and PGA0/1), the results were similar to the results for PASI 90.

For serious adverse events, there was no significant difference between any of the assessed interventions and placebo. Nonetheless, analyses of SAE events were based on a very low number of events with low‐to‐moderate certainty for all the comparisons. The findings therefore have to be viewed with caution. Considering both efficacy (PASI 90 outcome) and acceptability (SAE outcome), highly‐effective treatments also had more SAEs than the other treatments: risankizumab and bimekizumab appeared to be the better compromise between efficacy and acceptability.

Information on quality of life was not well reported and was absent for several of the interventions.

Conservative interpretation is warranted for the results for bimekizumab, mirikizumab, tyrosine kinase 2 inhibitor, acitretin, ciclosporin, fumaric acid esters, and methotrexate, as these drugs in the NMA have only been evaluated in few trials.

The evidence is limited to a selected trial population (participants were young (mean age of 45 years), had a high level of disease severity (with an overall mean score of PASI 20 at baseline, and were long‐time sufferers), and had few major comorbidities), and the NMA evidence was limited to the induction treatment phase (all results were measured from 8 to 24 weeks after randomisation), which is not relevant enough for a chronic disease, which would require long‐term treatment.

Our main results (i.e. superiority of efficacy of the biologic treatments anti‐IL17, anti‐IL12/23, anti‐IL23, and anti‐TNF alpha compared with small molecules and the non‐biological systemic agents) do not reflect the 'real life' management of patients in Europe or Canada, as an example. Currently, biological treatments may be positioned as third‐line therapies by regulatory bodies, with mandatory reimbursement criteria that patients must meet before being considered for these treatments (moderate‐to‐severe disease after failure, intolerance or contraindication to non‐biological systemic agents). Recently, the same restrictions were applied to apremilast. Such decisions were based on the lack of long‐term safety knowledge but also taking into account economic consideration. In this review, we found insufficient evidence to evaluate long‐term safety, and we did not address economic considerations, so the question of the choice of first‐line treatment for moderate‐to‐severe psoriasis is still debated.

The first choice in non‐biological systemic agents is still in question, as the limited number of trials assessing non‐biological systemic agents did not allow us to draw robust conclusions; this is also true for some small‐molecule treatments and biological treatments.

Implications for research

From a clinical point of view, we need drugs that can be administered long‐term to provide continuous effective control, because continued remission after successful treatment is as important as successful induction of remission. Moreover, treatment should be easy to use, well accepted by patients, have minimal drug‐to‐drug interactions, and should have minimal monitoring requirements, because convenience is also an important issue when dealing with chronic diseases that require prolonged treatments. Finally, the cost of the drug should be affordable by most patients and by any national health service.

Specific questions and issues in the management of psoriasis still remain unmet:

  • Which non‐biological systemic agents have the best benefit/risk balance?

  • Which patients are candidates for small molecule treatment?

  • Which treatments work for subgroups of patients (age, psoriasis severity, previous treatment, psoriatic arthritis, race and ethnicity)?

  • Which treatments offer the best combination of safety and efficacy in patients with major comorbidities (e.g. hepatitis B/C, latent tuberculosis, HIV, and renal, cardiac, and hepatic impairment) as well as pregnancy?

  • Adjustment of therapy for patients with stable low disease activity;

  • Add‐on therapy or switching for patients who failed with a systemic treatment;

  • Long‐term safety data for all the treatments.

1. Future trials need to ensure the following.

  • Participants: enough information about participants is needed to enable systematic subgroup analyses for biological‐naïve patients (or non‐biological systemic‐agent‐naïve); future trials also need to provide an adequate description of data on other important potential effect modifiers such as previous systemic treatments, whether participants are overweight/obese, the duration of a participant's psoriasis, baseline psoriasis severity (efficacy differences could be expected for patients with PASI at 10 and patients with PASI at 40); race and ethnicity, and presence of psoriatic arthritis.

  • Interventions: high‐quality trials assessing the efficacy of non‐biological systemic agents are still needed.

  • Comparators: once the benefit of a treatment has been established against placebo, only head‐to‐head trials would be helpful to provide physicians with efficacy estimates between the different biologics, with stronger evidence than indirect comparisons. Head‐to‐head comparisons are lacking between the non‐biological systemic agents and small molecules and against each other. More head‐to‐head comparisons between biological agents are also needed (anti‐IL17 versus anti‐IL23, anti‐IL23 versus anti‐IL12/23, anti‐TNF alpha versus anti‐IL12/23).

  • Outcomes: outcome measure harmonisation is needed for psoriasis, as has been done for eczema by the COMET (Core Outcome Measures in Effectiveness Trials) Initiative.

  • Timingassessment strategy: all of the trials included in this review were limited to the induction phase (from 8 to 24 weeks). Long‐term efficacy data are critical for chronic diseases. Placebo‐controlled long‐term trials would not be ethical, due to the suffering it would entail for the people in the placebo group. However, long‐term studies comparing different drugs would be ethical and informative. Such long‐term trials could also assess the adjustment of therapy for patients with stable cleared psoriasis.

2. New trial designs are needed, such as pragmatic trials that permit dose adjustment once in remission, switching, and additional treatments (i.e. adding two or more systemic treatments) as in normal clinical practice. All of this unmet medical need evidence would improve the management of the condition.

3. Finally, evidence‐based decision‐making and management of chronic plaque psoriasis require both efficacy AND safety data. As we already know, the limitations of network meta‐analysis and of randomised clinical trials (included in these meta‐analyses) mean we cannot reliably interpret the significance of rare events, given their current design. These studies are designed to detect differences in the severity of psoriasis in response to therapy over short periods of treatment, and are often underpowered and of insufficient duration to detect rare or long‐term adverse events. One way to counter this is to include observational cohort studies/registries in a network observational meta‐analysis.

Background

Please refer to our glossary (see Table 1).

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Table 1. Glossary

Term

Definition

Antagonist

A substance that interferes with or inhibits the physiological action of another.

Antigen

A molecule capable of inducing an immune response

Anti‐TNF alpha

A pharmaceutical drug that suppresses the physiologic response to tumour necrosis factor (TNF)

Biological agent

Therapeutic agents consisting of immune molecules such as soluble receptors, recombinant cytokines, and monoclonal antibodies that target effector molecules or cells of the immune system

Biosimilar

Biological agent highly similar to another already‐approved biological medicine

CD6

Cluster of differentiation (CD) 6 is a protein encoded by the CD6 gene

Cheilitis

An inflammation of the lips

Chimeric protein

A chimeric protein can be made by combining two different genes

Complex cyclophilin‐ciclosporin

Cyclophilins are a family of proteins that bind to ciclosporin, an immunosuppressant agent

Creatinine

A compound that is produced by metabolism of creatine and excreted in the urine

Cyclic adenosine monophosphate

It is a second messenger important in many biological processes

Cytokines

Small proteins produced by a broad range of cells that are important in cell signalling; they are immunomodulating agents

Dendritic cells

Antigen‐presenting cells of the immune system

Dermis

It is a layer of the skin

Epitope

It is a part of an antigen

Erythematous

Redness of the skin

Folic acid

B vitamin

Humanised antibody

Antibodies from non‐human species whose protein sequences have been modified to increase their similarity to antibody variants produced naturally in humans

IL‐17A

A pro‐inflammatory cytokine

IL‐23R

A cytokine receptor

Immune‐mediated

A group of diseases that are characterised by common inflammatory pathways leading to inflammation, and which may result from a dysregulation of the normal immune response

Immunogenicity

This is the ability of a particular substance, such as an antigen or epitope, to provoke an immune response in the body of a human or animal

Immunoglobulin 1 Fc

An antibody

Interferon (IFN)‐c

A protein released by cells, usually in response to a pathogen

Interleukin

A kind of cytokine

Janus kinase (JAK) inhibitors

A pharmaceutical drug that inhibits the activity of one or more of the Janus kinase family of enzymes

Keratinocytes

Epidermal cells that constitute 95% of the epidermis

Lymphocyte

A subtype of a white blood cell

Lymphoid organ

Part of the body that defends the body against invading pathogens that cause infections or the spread of tumours

Metalloproteinases

A protease enzyme

Monoclonal antibodies

Antibodies that are made by identical immune cells that are all clones of a unique parent cell

Murine sequence

Mouse genomic sequencing

Neutrophils

Type of white blood cell involved in the innate immune system

p40

Subunit beta of interleukin 12 and 23

Periumbilical

Around the navel

Pharmacological treatments

Drugs

Phase I

First‐in‐man studies

Phase II

Studies to assess how well the drug works, as well as to continue phase I safety assessments in a larger group of volunteers and participants

Phase III

Randomised controlled multicenter trials on large patient groups and are aimed at being the definitive assessment of how effective the drug is

Phase IV

Post‐marketing trials involve the safety surveillance

Phosphodiesterase 4 inhibitors

A pharmaceutical drug used to block the degradative action of phosphodiesterase 4

Progressive multifocal leukoencephalopathy

A rare viral neurological disease characterised by progressive damage of the white matter of the brain at multiple locations

Receptor

A protein molecule that receives chemical signals from outside a cell

Small molecules

Chemically manufactured molecules (or SMOLs for short)

Sphingosine 1‐phosphate receptor agonists

A class of protein‐coupled receptors that are targets of the lipid signalling molecule Sphingosine‐1‐phosphate

T cells/CD4 T cells

A type of white blood cell that is of key importance to the immune system

Th1 and Tc1 cells

A type of T cell

Th17 and Tc17 cells

A type of T cell

TNF‐alpha

A protein that is part of the inflammatory response

Tumour necrosis factor antagonists

Class of biological agents

Umbilic

Navel

Xerosis

Dry skin

Description of the condition

Psoriasis is an immune‐mediated disease for which a person can have genetic susceptibility, manifesting in chronic inflammatory effects on either the skin or joints, or both, with a prevalence ranging from 2.2% (USA) to 8.5% (Norway) (Boehncke 2015; Parisi 2013; Stern 2004). The causes of psoriasis are not fully understood. There appears to be interaction between environmental factors and genetic susceptibility. Genome‐wide (or whole genome) association trials found several candidate genes relating to psoriasis (Capon 2017; Elder 2010). Various environmental factors, including stress, injury, and infections, are suspected of triggering or aggravating the evolution of psoriasis. An inflammatory immune response involving dendritic cells, T cells, keratinocytes, neutrophils, and the cytokines released from immune cells initiates the pathophysiological process (Jariwala 2007; Lowes 2008; Wilson 2007; Zheng 2007).

Diagnosis is made based on clinical findings; skin biopsy is rarely used to diagnose the disease (Boehncke 2015). Several clinical types of psoriasis exist: plaque, pustular, inverse, and erythrodermic. Plaque psoriasis is the most common form, affecting 90% of people with psoriasis (Griffiths 2007). Plaque psoriasis typically appears as raised erythematous and well‐demarcated areas of inflamed skin covered with silvery‐white, scaly skin (Griffiths 2007). The location of the plaques is usually symmetrical on the elbows, knees, scalp, lower back, and the periumbilical region. For 5% to 25% of people with psoriatic rheumatic disease, their skin is also involved (Helliwell 2005; Zachariae 2003).

Severity

Chronicity characterises the natural history of plaque psoriasis; this means that severity varies over time, from minor localised patches to complete body coverage. The severity of the disease usually fluctuates around the same level for a particular person (Nijsten 2007), but for each person with this disease the evolution and duration of remission is unpredictable. The psoriasis is declared clear when there are no lesions.

More than a dozen outcome instruments are used to assess the severity of psoriasis and the efficacy of different treatments for psoriasis (Naldi 2010; Spuls 2010); the Psoriasis Area and Severity Index (PASI) score is one of these instruments (Schmitt 2005). The PASI combines the assessment of the severity of lesions and the area affected into a single score in the range of 0 (no disease) to 72 (maximal disease). Recent clinical trials evaluating biological therapies that have received secondary marketing authorisation by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) used PASI 75, i.e. a 75% improvement in the PASI score, and more recently PASI 90, i.e. 90% improvement in the PASI score, as primary end points. PASI score has substantial limitations, such as low‐response distribution, no consensus on interpretability, and low responsiveness in mild disease (Spuls 2010). However, PASI 90 is a stringent outcome, as patients reaching PASI 90 are almost clear.

Impact and quality of life

Disease severity alone does not determine the burden of psoriasis. Multiple studies have described an impairment of the quality of life (QoL); others have focused on an evaluation of the stigma people experience; and others have studied the impact on psychosocial life (Kimball 2005).

Impairment of QoL in people with psoriasis, when measured with the 36‐item Short Form Health Survey (SF‐36) questionnaire, is higher than that of people with hypertension, diabetes, or depression (Rapp 1999).

Many tools exist to measure the QoL of people with psoriasis and other skin disorders. These measures may be categorised as psoriasis‐specific (Psoriasis Index of Quality of Life (PSORIQoL), Psoriasis Disability Index (PDI)); skin‐specific (Dermatology Life Quality Index (DLQI), Skindex (a quality‐of‐life measure for people with skin disease)); and generic QoL measures (SF‐36). However, methodological weaknesses exist in the use of QoL questionnaires, and there is poor reporting of QoL outcomes in randomised clinical trials (Le Cleach 2008). Several case‐control studies reported a higher risk of metabolic syndrome and cardiovascular comorbidities (Kremers 2007; Naldi 2005).

Description of the intervention

There is currently no cure for psoriasis, but various treatments can help to control the symptoms; thus, long‐term treatment is usually needed. In daily practice, a treatment strategy needs to be defined, and this usually involves an induction therapy, e.g. the period of time of the initial therapy intended to induce remission of the disease, and a maintenance therapy, e.g. to maintain the remission of the disease.

The therapeutic approach to psoriasis includes topical treatments as a single strategy and a first‐line therapy in the management of minor forms (Mason 2013). Nevertheless, about 20% to 30% of people with psoriasis have a moderate‐to‐severe form requiring a second‐line therapy including phototherapy and non‐biological systemic agents, such as ciclosporin, methotrexate, or acitretin. Among the systemic agents, the choice of drug is not clear. The NICE 2012 clinical guidelines in the UK proposed methotrexate as the first choice of systemic agent. Biological agents, such as the tumour necrosis factor (TNF) antagonists (infliximab, etanercept, adalimumab); the monoclonal antibody ustekinumab that targets interleukin‐12 and ‐23 (IL‐12/‐23); anti‐IL17 drugs (secukinumab or ixekizumab); and new small molecules (apremilast) are more recent systemic therapies (Boehncke 2015). Many healthcare systems have developed elaborate psoriasis treatment algorithms to address the high cost of newer therapies. Indeed, in Europe and in Canada, there are mandatory reimbursement criteria that patients must meet before being considered for these treatments, due to their high costs (Nast 2015b), such as presenting a moderate‐to‐severe psoriasis after failure, intolerance or contraindication to at least two non‐biological systemic agents (French criteria).

Non‐biological systemic treatments

The oldest oral pharmacological treatments licensed for psoriasis are ciclosporin, methotrexate, acitretin (which is the retinoid of choice for psoriasis), and fumaric acid esters (FAEs) which are licensed for psoriasis in Germany and used off‐licence in other countries (Atwan 2015).

Randomised controlled trials against placebo for both induction and maintenance therapies have demonstrated the efficacy of ciclosporin for psoriasis (Bigby 2004; Christophers 1992; Ellis 1991; Flytström 2008; Koo 1998; Heydendael 2003; Ho 1999; Mahrle 1995; Meffert 1997; Mrowietz 1995; Shupack 1997). In 2008, Saurat and colleagues conducted the only randomised trial comparing the efficacy of methotrexate versus placebo (CHAMPION 2008). Randomised trials against placebo have demonstrated the efficacy of derivatives of vitamin A, the retinoids, in the treatment of plaque psoriasis (Pettit 1979). Fumaric acid esters are an alternative therapy for people with psoriasis, even though the mechanisms of action are not completely understood (Ormerod 2004). A Cochrane Review on FAEs for psoriasis was published in 2015 (Atwan 2015).

Small molecules or target therapies affect molecules inside immune cells. Recently, small molecule drugs have been developed and show potential to treat people with psoriasis not responding to non‐biological treatments. These small molecule drugs include apremilast (Papp 2012c), tofacitinib (Bachelez 2015), and BMS‐986165 (Papp 2018). Tofacitinib and BMS‐986165 had not been approved for psoriasis at the time our analyses were done.

Biological therapies

Biological therapies use substances made from living organisms, or synthetic versions, to target the immune system. In the 20th century, the development of biological treatments expanded the therapeutic spectrum of systemic treatments for psoriasis. All of the biologics have to be given by infusion or subcutaneous injection, and all have had at least one evaluation of their effectiveness against placebo: etanercept (Leonardi 2003), infliximab (Chaudhari 2001), adalimumab (REVEAL 2008), certolizumab (Reich 2012a), ustekinumab (Lebwohl 2010), secukinumab (Reich 2015), ixekizumab (Leonardi 2012), brodalumab (Papp 2012a), bimekizumab (BE ABLE 1 2018), guselkumab (Gordon X‐PLORE 2015), mirikizumab (NCT03482011), tildrakizumab (Papp 2015), and risankizumab (NCT02672852). Bimekizumab and mirikizumab had not been approved for psoriasis at the time our analyses were done.

How the intervention might work

Dysregulation of the immune system is a critical event in psoriasis, and the evolving knowledge of the role of the immune system in the disease has had an impact on treatment development. Indeed, psoriatic plaque shows marked infiltration by activated T cells, especially CD4+ cells in the dermis. The activated T cells produce several important cytokines, namely, interferon (IFN)‐c, TNF alpha (by Th1 and Tc1 cells), IL‐17A, and IL‐23R (by Th17 and Tc17 cells) (Boehncke 2015).

Non‐biological systemic treatments

Ciclosporin

Ciclosporin is an immunosuppressive agent (a drug that reduces the efficacy of the immune system); it acts by inhibiting the initial phase of the activation of CD4+ T cells, which leads to a block on the synthesis of interleukin 2 by the complex cyclophilin‐ciclosporin, thus preventing T cell proliferation that is key to the pathogenesis of psoriasis (see above) (Ho 1996). This immunosuppression is rapid and reversible. Ciclosporin rapidly reduces the severity of the lesions (over one to three months), but the continuation of treatment is difficult after two years because of the development of adverse effects, such as elevated creatinine levels (Maza 2011). A dose of 5.0 mg/kg/day ciclosporin was significantly more effective than 2.5 mg/kg/day ciclosporin for induction of the remission of psoriasis; however, elevated creatinine was significantly more likely with 5.0 mg/kg/day ciclosporin than with 2.5 mg/kg/day ciclosporin (Christophers 1992).

Methotrexate

Methotrexate is an antimetabolite (an inhibitor of a chemical that is part of normal metabolism), which acts as an antagonist of folic acid (Montaudie 2011). Low doses of methotrexate exert anti‐inflammatory and immunomodulatory activities (Montaudie 2011). The efficacy of methotrexate cannot be assessed earlier than three months; its long‐term safety profile is good. In clinical practice, methotrexate is administered orally at 15 to 25 mg/week (Montaudie 2011).

Retinoids

Retinoids, including acitretin, are involved in the growth and differentiation of skin tissue; they bind to nuclear receptors that belong to the large family of steroid hormone receptors (Sbidian 2011). Retinoids modulate many types of proteins, including epidermal structural proteins, metalloproteinases, and cytokines (Sbidian 2011). The efficacy of retinoids is evaluated after two to three months of treatment, but skin side effects (e.g. xerosis, cheilitis) may limit the ability to increase the dose. Treatment with retinoids is best avoided in women of childbearing age because of risks to a developing foetus and the necessity of using contraception two years after discontinuation of treatment (Sbidian 2011). People receiving 50 mg/day to 75 mg/day acitretin have significantly improved psoriasis compared with those receiving 10 mg/day to 25 mg/day acitretin (Goldfarb 1988).

FAEs

Fumaric acid esters (FAEs) are chemical compounds derived from the unsaturated dicarboxylic acid (Atwan 2015). Oral preparations of FAEs in psoriasis were developed containing dimethyl fumarate (DMF) and salts of monoethyl fumarate (MEF) as main compounds (Atwan 2015). FAEs produce anti‐inflammatory effects by preventing the proliferation of T cells (Atwan 2015).

FAEs are an effective therapy in people with psoriasis (50% to 70% achieve PASI 75 improvement within four months of treatment). Tolerance is limited by gastrointestinal side effects and flushing of the skin (Atwan 2015). Several case‐series described rare adverse events, such as progressive multifocal leukoencephalopathy (Balak 2016). In clinical practice, FAEs are administered orally. People receive this after a gradual dose incrementation the equivalent of 720 mg of DMF a day.

Small molecules

Small molecule drugs modulate pro‐inflammatory cytokines and selectively inhibit signalling pathways: phosphodiesterase 4 inhibitors (apremilast), Janus kinase (JAK) inhibitors (tofacitinib), or sphingosine 1‐phosphate receptor agonists (ponesimod) (Torres 2015).

Apremilast

Apremilast belongs to the phosphodiesterase 4 (PDE4) inhibitors family (Torres 2015). By increasing cyclic adenosine monophosphate (cAMP) levels, PDE4 inhibitors reduce production of pro‐inflammatory TNF alpha and IFNγ in people with psoriasis. Apremilast has been approved for psoriasis; its efficacy seems to be higher than non‐biological systemic therapy, but no randomised controlled trials (RCTs) assessing apremilast versus methotrexate or ciclosporin have been published. However, some RCTs assessing apremilast versus methotrexate are ongoing (CTRI/2019/01/017362; CTRI/2019/07/020274). The safety of the drug should be detailed in the near future with phase 4 studies. In clinical practice, apremilast is administered orally at 30 mg twice a day (Torres 2015).

Tofacitinib

Tofacitinib is a Janus kinase (JAK) inhibitor (Torres 2015). JAK inhibitors target the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway, which is pivotal for the downstream signalling of inflammatory cytokines involved in psoriasis. Tofacitinib had not been approved for psoriasis at the time our analyses were done (Torres 2015).

BMS‐986165

BMS‐986165 is a potent oral tyrosine kinase 2 (TYK2) inhibitor that binds to the pseudokinase domain of the enzyme and is functionally more selective than other tyrosine kinase inhibitors. Tyrosine kinase 2 (TYK2) is an intracellular signalling enzyme which activates signal transducer and activator of transcription (STAT)–dependent gene expression and functional responses of interleukin‐12, interleukin‐23, and type I and III interferon receptors. These cytokine pathways are involved in the pathologic processes associated with psoriasis, and are distinct from responses driven by Janus kinase (JAK) 1 (JAK1), JAK1 and JAK3 in combination, JAK2, as previously described. BMS‐986165 had not been approved for psoriasis at the time our analyses were done.

Biological therapies

Biological therapies have been developed in recent years and first target and prevent T cell proliferation and then target cytokines involved in psoriasis physiopathology (e.g. anti‐TNF alpha, anti‐IL12/23, anti‐IL23, anti‐IL17).

Anti‐TNF alpha

Two monoclonal antibodies against tumour necrosis factor alpha (TNF‐α) (infliximab, adalimumab) and one recombinant TNF‐α receptor (etanercept) have been developed to inhibit TNF‐α signalling, thus preventing its inflammatory effects, and are approved for psoriasis (Gisondi 2004). A third, certolizumab, is being assessed for psoriasis in phase 3 trials.

  • Etanercept is a recombinant TNF‐α receptor and weakly immunogenic (provokes only a mild immune response). Its efficacy is assessed at three months. A 50 mg dose of etanercept is administered subcutaneously twice weekly for three months during the induction phase (remission of the psoriasis flare) with 50 mg administered weekly as maintenance therapy (Gisondi 2004).

  • Infliximab is a chimeric antibody that neutralises the action of TNF‐α. Its efficacy is evaluated after six to eight weeks of treatment. A dose of 5.0 mg/kg infliximab is given as an intravenous (IV) induction regimen at 0, 2, and 6 weeks followed by a maintenance regimen of 5.0 mg/kg every 8 weeks. The presence of a murine sequence at recognition sites can lead to the development of anti‐infliximab antibodies that may impair the therapeutic effect (Gisondi 2004).

  • Adalimumab is a fully humanised antibody with very low immunogenicity. Its efficacy is estimated after eight and 12 weeks of treatment. One dose of 80 mg is administered subcutaneously, followed one week later by a 40 mg subcutaneous dose, which is administered every two weeks (Mossner 2009). Those receiving TNF‐α blockers are potentially exposed to a greater risk of infection and require regular monitoring (Tubach 2009).

  • Certolizumab is an anti‐TNF alpha with a unique structure that does not contain an Fc (fragment crystallisable) portion as adalimumab or infliximab does, based on the human immunoglobulin G1 Fc. Certolizumab therefore does not display Fc‐mediated effects (improving solubility, increasing drug stability, and decreasing immunogenicity) (Campanati 2017). Treatment starts with a 400‐mg dose given as two injections, followed by a further 400‐mg dose two and four weeks later. After this, depending on the condition being treated, patients should continue with 200 mg or 400 mg, given as one or two injections every two or four weeks.

Anti‐IL12/23, Anti‐IL23, Anti‐IL17

Additional monoclonal antibodies have been developed against pro‐inflammatory cytokines: IL‐12, IL‐23, and IL‐17 inhibit the inflammatory pathway at a different point to the anti‐TNF alpha antibodies (Dong 2017).

  • Interleukin‐12 and IL‐23 share a common domain, p40, which is the target of ustekinumab (which the FDA approved in 2009) (Savage 2015). A 45 mg subcutaneous dose is administered initially (90 mg if body weight is over 100 kg), then 45 mg (or 90 mg) subcutaneously four weeks later, and thereafter 45 mg (or 90 mg) subcutaneously every 12 weeks (Savage 2015). Interleukin‐23 plays an essential role in skin inflammation in psoriasis leading to the development of agents that selectively target the IL‐23p19 subunit (Dong 2017). Drugs targeting the p19 subunit of IL‐23 are guselkumab (a fully human IgG1k monoclonal IL‐23 antagonist), tildrakizumab (a humanised IgG1k monoclonal antibody), risankizumab (high‐affinity humanised IgG1 monoclonal antibody), and mirikizumab (Dong 2017). In July 2017, the FDA approved guselkumab for psoriasis. Guselkumab is given as a 100 mg subcutaneous injection every eight weeks, following two starter doses at week 0 and week 4. More recently both tildrakizumab and risankizumab were approved. The recommended dose for tildrakizumab is one 100 mg injection, followed by a further dose after 4 weeks and then an injection every 12 weeks. The dose may be increased to 200 mg in certain patients, for example those badly affected by the disease or with bodyweight over 90 kg. The recommended dose for risankizumab is 150 mg, administered by two subcutaneous injections every 12 weeks following two initiation doses at week 0 and 4. Mirikizumab had not been approved for psoriasis at the time our analyses were done.

  • Interleukin‐17 inhibitors include secukinumab (a recombinant fully human anti‐IL17A IgG1k monoclonal antibody), ixekizumab (a humanised anti‐IL17 immunoglobulin G4 monoclonal antibody), brodalumab (a human IgG2 monoclonal antibody that decreases the downstream effect of IL‐17 by antagonising the IL‐17RA receptor), and bimekizumab (a humanised monoclonal IgG1 antibody that potently and selectively neutralises the biological function of both human IL‐17A and IL‐17F) (Dong 2017). The recommended dosage for secukinumab is 300 mg administered subcutaneously at weeks 0, 1, 2, 3, and 4, and then every 4 weeks thereafter. Ixekizumab is administered at 160 mg (2 x 80 mg injections) at weeks 0, 2, 4, 6, 8, 10, and 12, and then every four weeks thereafter (Dong 2017). The recommended dose for brodalumab is 210 mg given once a week for the first three weeks and then every two weeks. Bimekizumab had not been approved for psoriasis at the time our analyses were done.

Why it is important to do this review

To determine the treatment pathway in psoriasis, the efficacy and safety of each systemic treatment must be determined relative to other therapies. Several RCTs have compared against placebo the efficacy of the different systemic treatments for psoriasis. However, there are few trials comparing non‐biological systemic therapies head‐to‐head, systemic therapies against biological therapies, or biological therapies head‐to‐head. Several previous meta‐analyses or indirect comparison meta‐analyses have been published (Bansback 2009; Brimhall 2008; Gómez‐García 2017; Gospodarevskaya 2009; Lin 2012; Loveman 2009; Nast 2015a; Nelson 2008; Reich 2008; Reich 2012b; Schmitt 2008; Signorovitch 2010; Signorovitch 2015; Spuls 1997; Strober 2006; Tan 2011; Turner 2009; Woolacott 2006). However, the number of studies included in these publications was low, the searches were not exhaustive, and several trials have been published since their search dates. Also, the publications did not evaluate some systemic treatments.

A network meta‐analysis enables the best use of the direct and indirect information available to determine the relative efficacy of treatments. In other words, a network meta‐analysis will help to highlight the missing key comparisons that are needed to inform clinical practice.

Following the publication of the 2019 update of this review, we are maintaining it as a living systematic review. This means we are continually running the searches and rapidly incorporating any newly‐identified evidence into the review. We believe a living systematic review approach is appropriate for this review, for three reasons. Firstly, the review addresses an important health issue. The high prevalence of psoriasis (1% to 3% of the world population); the major impact on quality of life for many individuals; the cardiovascular comorbidities associated with significant mortality; the many therapeutic options; and the high costs of these new systemic treatments are reasons, among others, to help physicians in determining which treatment is best suited to a patient. Secondly, an important level of uncertainty remains in the existing evidence in the field of psoriasis, despite searches including the current update (up to 8 September 2020) identifying a total of 158 studies for inclusion in the review. Few head‐to‐head trials have compared systemic treatments against each other. Once the benefit of a treatment has been established against placebo using high quality of evidence, head‐to‐head trials would be helpful to provide physicians with efficacy estimates between the different biological treatments based on stronger evidence than indirect comparisons. Further head‐to‐head trials are needed to accurately rank drugs according to their risk/benefit ratio. Thirdly, we are aware of ongoing trials in this area of research that will be important to incorporate, and we expect that future research will have an impact on the conclusions. For instance, new molecules have emerged constantly (e.g. in 2017, four new biological treatments for psoriasis emerged).

The plans for this review were published as a protocol 'Systemic pharmacological treatments for chronic plaque psoriasis' (Sbidian 2015). This review is an update of 'Systemic pharmacological treatments for chronic plaque psoriasis: a network meta‐analysis' (Sbidian 2017; Sbidian 2020).

Objectives

To compare the efficacy and safety of non‐biological systemic agents (acitretin, ciclosporin, fumaric acid esters, methotrexate), small molecules (apremilast, tofacitinib, BMS‐986165), anti‐TNF alpha (etanercept, infliximab, adalimumab, certolizumab), anti‐IL12/23 (ustekinumab), anti‐IL17 (secukinumab, ixekizumab, brodalumab, bimekizumab), and anti‐IL23 (guselkumab, tildrakizumab, risankizumab, mirikizumab) for people with moderate‐to‐severe psoriasis using a network meta‐analysis, and to provide a ranking of these treatments according to their efficacy and safety.

A secondary objective is to maintain the currency of the evidence, using a living systematic review approach.

Methods

Criteria for considering studies for this review

Types of studies

We included randomised controlled trials (RCTs).

Phase I trials were not eligible because participants, outcomes, dosages, and schema of administration of interventions are too different from phase II, III, and IV studies. Cross‐over trials were not eligible (because of the unpredictable evolution of psoriasis and risk of carry‐over bias). Non‐randomised studies, including follow‐up studies, were not eligible.

Types of participants

We considered trials that included adults (over 18 years of age) with moderate‐to‐severe plaque psoriasis (i.e. needed systemic treatment) or psoriatic arthritis whose skin had been clinically diagnosed with moderate‐to‐severe psoriasis and who were at any stage of treatment.

Types of interventions

We considered trials that assessed systemic treatments, irrespective of the dose and duration of treatment, compared with placebo or with an active comparator.

Systemic treatments included the following:

  • Non‐biological treatments

    • FAEs

    • Acitretin

    • Ciclosporin

    • Methotrexate

  • Small molecules

    • Apremilast

    • Tofacitinib

    • BMS‐986165

  • Anti‐TNF alpha

    • Infliximab

    • Etanercept

    • Adalimumab

    • Certolizumab

  • Anti‐IL12/23

    • Ustekinumab

  • Anti‐IL17

    • Secukinumab

    • Brodalumab

    • Ixekizumab

    • Bimekizumab

  • Anti‐IL23

    • Tildrakizumab

    • Guselkumab

    • Risankizumab

    • Mirikizumab

We were interested to compare both the different drugs (n = 20) and the different classes of drugs (n = 6).

Active comparators include the following:

  • any of the aforementioned systemic treatments; or

  • additional treatment not of primary interest but used for the network synthesis, such as topical treatment or phototherapy.

In multi‐arm trials, study groups assessing drugs other than those mentioned above were not eligible. In cases of multi‐dose trials, we grouped together all of the different dose groups as a single arm and performed sensitivity analysis at dose level.

In our Background section, we have referred to ongoing Cochrane Reviews that address some of the systemic treatments administered to adults with plaque psoriasis. We considered these treatments in our review, and we have liaised with each of these teams to harmonise our protocols. However, the Cochrane Review on FAEs, published in 2015, included people with all types of psoriasis and not only plaque‐type psoriasis (Atwan 2015).

In the 'Data collection and analysis > Assessment of heterogeneity' section, details on what was planned to assess the transitivity assumption for studies, participants and intervention are available.

Adaptive criteria for considering studies for this review

As a living systematic review, we are continually identifying new evidence for interventions already in the network of trials but also for novel interventions. To provide an update and a useful network of interventions for physicians, we need first to identify new interventions but also, to drop old interventions, which are no longer of interest.

To achieve these goals, we have created a research community in psoriasis, including international experts in the field who will help to provide information of new 'eligible' drugs.

Once a year, a list of all systemic drugs used for psoriasis is proposed by the scientific steering committee to the international experts’ group, including:

‐ Drugs already involved in the network

‐ Marketed drugs, identified using the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) websites (www.accessdata.fda.gov/scripts/cder/drugsatfda and www.ema.europa.eu/ema, respectively).

‐ Drugs under development, identified using the World Health Organization International Clinical Trials Registry Platform (ICTRP) (apps.who.int/trialsearch/) and ISRCTN registry (www.isrctn.com)

The international experts’ group select from this list all the systemic drugs needed for the future network. They also add relevant new interventions not proposed in the list. They provide a rationale for all proposed network changes (adding or removing interventions). The international experts' group is necessary also to determine which drugs have to be deleted from the network, with clinical practice and market authorisation being different in each country.

It is sufficient to update the interventions network once a year, as we are including phase II and III RCTs. Indeed, the timing between the phase I and the phase II/III for a promising intervention is over one year.

Types of outcome measures

Psoriasis is a chronic disease; treatments are symptomatic, often with a return to baseline after discontinuation. In the absence of an existing defined core outcome set (Spuls 2016), we chose the most relevant outcomes for patients (COMET). The Psoriasis Area and Severity Index score (PASI) 75 is the most common outcome measure used. However, confronted with a debilitating and a socially and psychologically highly visible disease, a completely 'clear or almost clear' skin is a more stringent test in the induction phase (i.e. psoriasis flare clearing phase).

Primary outcomes

  • The proportion of participants who achieved clear or almost clear skin, that is, at least PASI 90 at induction phase.

  • The proportion of participants with serious adverse events (SAEs) at induction phase. We used the definition of severe adverse events from the International Conference of Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, which includes death, life‐threatening events, initial or prolonged hospitalisation, and adverse events requiring intervention to prevent permanent impairment or damage.

Secondary outcomes

  • Proportion of participants who achieve PASI 75 at induction phase.

  • Proportion of participants who achieve a Physician Global Assessment (PGA) value of 0 or 1 at induction phase.

  • Quality of life measured by a specific scale. Available validated scales are the Dermatology Life Quality Index (DLQI), Skindex, Psoriasis Disability Index (PDI), or Psoriasis Symptom Inventory (PSI) at induction phase.

  • The proportions of participants with adverse events (AEs) at induction phase ('AE outcome' did not include SAE).

  • Proportion of participants who achieve PASI 75 at 52 weeks.

  • Proportion of participants who achieve PASI 90 at 52 weeks.

We defined the induction phase as an evaluation from 8 to 24 weeks after the randomisation. In case of multiple time points, we chose the longest one.

To avoid selection of good responders of participants entering into long‐term extension, we selected participants who have been randomised since the induction phase.

We did not include studies that had timings outside of the time ranges stated in our outcomes in our review or analyses. We did not evaluate specific adverse events, just the proportion of participants with at least one adverse event and at least one serious adverse event at induction phase.

Search methods for identification of studies

We aimed to identify all relevant RCTs, regardless of language or publication status (published, unpublished, in press, or in progress).

Electronic searches

For this living systematic review we revised our search strategies in line with advice from the Cochrane Living Evidence Network. Details of the search strategies used in the earlier published version of this review are available in Sbidian 2020.

Since September 2019 the Cochrane Skin Information Specialist has searched the following databases monthly up to 8 September 2020:

  • the Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 9) in the Cochrane Library using the strategy in Appendix 1;

  • MEDLINE (via Ovid) using the strategy in Appendix 2; and

  • Embase (via Ovid) using the strategy in Appendix 3.

Trials registers

We (SA and ES for this update) searched the following trials registers up to 25 September 2020 with the following search terms: psoriasis AND one by one, each drug name listed in Types of interventions:

Retractions and errata

We undertook a search to identify retraction statements or errata related to our included studies in MEDLINE and Embase on 11 November 2020. We retrieved no new relevant records.

Searching other resources

References from other studies

We checked the bibliographies of included studies and relevant systematic reviews for further references to relevant trials.

Unpublished literature

We contact corresponding authors of ongoing studies as we identify them, and ask them to advise us when trial results are available, or to share early or unpublished data. We also contact pharmaceutical companies to attempt to identify unpublished and ongoing trials (see Table 2).

Open in table viewer
Table 2. Investigators contacted

Contact

Requested Information

Contacted

Reply

Missing data

Akcali 2014

Prof. Akcali

Outcomes: PASI 90, PASI 75, PGA 0/1, QoL scale, AEs & SAEs

8 and 21 November 2016

No response

Al‐Hamamy 2014

Prof. Al‐Hamamy

Outcomes: PASI 75, PGA 0/1, QoL scale, AEs and SAEs

8 and 21 November 2016

No response

Asahina 2010

Prof. Asahina

Outcome: PASI 90

8 November 2016

Asahina 2010 detailed report

Asahina 2016

Prof. Asahina Pfizer

Outcomes: AEs and SAEs

3 and 12 January 2017

Additional data to the publication not provided

Asawanonda 2006

Prof. Asawanonda

Outcomes: PASI 75, PGA 0/1, AEs and SAEs

21 November 2016

15 December 2016

Asawanonda 2006 sent detailed report for PASI 75 and AEs. PGA was not collected during this study

Bissonnette 2015

Prof. Bisonnette Innovaderm Recherches Inc.

Outcomes: PASI 90, PGA 0/1, AEs

8 and 21 November 2016

Additional data to the publication not provided

FEATURE 2015

Dr Blauvelt

Novartis

Outcome: QoL scale

8 and 21 November 2016

Additional data to the publication not provided

Caproni 2009

Prof. Fabri

Outcomes: PASI 90, PASI 75, PGA 0/1, QoL scale, AEs and SAEs

8 and 21 November 2016

Caproni 2009 sent detailed report for PASI 90 and SAEs. Other outcomes (PGA, QoL and AEs) not collected during this study.

Dogra 2013

Prof. Dogra

Outcomes: PGA 0/1, QoL scale, AEs and SAEs

8 and 21 November 2016

No response

Dogra 2012

Prof. Dogra

Outcomes: PGA 0/1, QoL scale, AEs and SAEs

8 November 2016

PGA & QoL scale not collected during this study. AEs and SAEs not provided per arm

Fallah Arani 2011

Dr Fallah Arani

Outcomes: PASI 90, PGA 0/1 and QoL scale

8 and 21 November 2016

Outcomes not collected during this study

Flytström 2008

Prof. Flytström

Outcomes: PGA 0/1

12 and 19 January 2017

Additional data to the publication not provided

Gisondi 2008

Prof. Gisondi

Outcomes: PASI 90, PGA 0/1, QoL scale, AEs and SAEs

8 November 2016

Gisondi 2008 sent detailed report for the requested outcomes except for QoL (not assessed during the study)

Gordon 2006

Prof. Gordon

Outcomes: PGA0/1, AEs

3 and 12 January 2017

No response

Gottlieb 2012

Prof. Gottlieb

Abbvie

Outcomes: PASI 90 & QoL scale

8 November 2016

Gottlieb 2012 sent detailed report for the requested outcomes

Gottlieb 2011

Prof. Gottlieb

Amgen

Outcomes: PASI 90, PGA 0/1, QoL scale, AEs and SAEs

8 November 2016

Gottlieb 2011 sent detailed report for the requested outcomes

ACCEPT 2010

Prof. Griffiths

Janssen

Outcome: QoL scale

16 December 2016

QoL was not collected during this study

Krueger 2016a

Pfizer

Outcomes: PASI 90, QoL scale

3 and 12 January 2017

No response

AMAGINE‐2 2015

Prof. Lebwohl

Valeant Pharmaceuticals NA LLC

Outcomes: PASI 90 and QoL scale

8 and 21 November 2016

AMAGINE‐2 2015 sent detailed report for PASI 90; individual scores and median difference from baseline of QoL were not available

AMAGINE‐3 2015

Prof. Lebwohl

Valeant Pharmaceuticals NA LLC

Outcomes: PASI 90 and QoL scale

8 and 21 November 2016

AMAGINE‐3 2015 sent detailed report for PASI 90, individual scores and median difference from baseline of QoL were not available

Leonardi 2012

Prof. Leonardi

Outcomes: QoL scale and AEs

8 and 21 November 2016

No response

Mahajan 2010

Prof. Kaur

Outcomes: PASI 90, PGA 0/1, QoL scale, AEs and SAEs

8 and 21 November 2016

No response

REVEAL 2008

Prof. Menter

Outcome: PGA 0/1

8 and 21 November 2016

No response

EXPRESS‐II 2007

Prof. Menter

Outcome: PGA 0/1

8 and 21 November 2016

No response

BRIDGE 2017

Prof. Mrowietz

Outcome: QoL scale

3 and 12 January 2017

Additional data to the publication not provided

Ortonne 2013

Prof. Paul

Novartis

Outcome: PASI 90

3 January 2017

Additional data to the publication not provided

Papp 2013a

Prof. Papp

Outcome: QoL scale

22 November 2016 13 December 2016

Additional data to the publication not provided

AMAGINE‐1 2016

Prof. Papp

Outcome: QoL scale

22 November 2016 13 December 2016

Additional data to the publication not provided

Papp 2005

Prof. Papp

Outcome: QoL scale, AEs and SAEs

22 November 2016 13 December 2016

Additional data to the publication not provided

Papp 2012b

Prof. Papp

Outcome: QoL scale

22 November 2016 13 December 2016

Additional data to the publication not provided

Papp 2013b

Prof. Papp

Outcome: PASI 90, PGA0/1, QoL scale

3 January 2017

Additional data to the publication not provided

JUNCTURE 2015

Prof. Paul

Novartis

Outcome: QoL scale

15 December 2016, 2 January 2017

Additional data to the publication not provided

Reich 2015

Prof. Reich

Novartis

Outcomes: PGA 0/1 and QoL scale

8 November 2016, 16 December 2016

Additional data to the publication not provided

LIBERATE 2017

Prof. Reich PelotonAdvantage

Outcome: QoL scale

4 January 2017

Additional data to the publication not provided

Rich 2013

Prof. Rich

Outcome: QoL scale

22 November 2016, 13 December 2016

No response

PRESTA 2010

Prof. Sterry

Outcomes: PASI 90 and QoL scale

8 and 21 November 2016

No response

Strober 2011

Prof. Strober

Abbvie

Outcome: QoL scale

8 November 2016

Strober sent detailed report for the requested outcomes

CLEAR 2015

Prof. Thaçi

Novartis

Outcome: QoL scale

8 and 21 November 2016

Additional data to the publication not provided

Torii 2010

Prof. Torii

Outcomes: PASI 90 and PGA0/1

21 November 2016

Torii sent detailed report for the requested outcomes

Tyring 2006

Prof. Tyring

Outcomes: PGA 0/1 and QoL scale

8 and 21 November 2016

No response

Van Bezooijen 2016

Dr van Bezooijen

Outcomes: PASI 90, adverse effects

4 and 12 January 2017

Additional data to the publication not provided

Van de Kerkhof 2008

Prof. van der Kherkhof Pfizer

Outcome: AEs

8 and 21 November 2016

Additional data to the publication not provided

LOTUS 2013

No contact

Outcome: PASI 90

No

Authors' email not found

CLARITY 2018

Prof Bagel

Outcome: QoL Scale

24 June 2019

Email response 01 July 2019

Dear Dr. Sbidian,

It is a pleasure to e‐meet you – i am the medical director assigned to the CLARITY trial for Novartis, and I am responding on behalf of Dr. Bagel to your request of data.

Thanks for your interest in the CLARITY: we published the 16w data and we are currently working on the final manuscript.

The 52w manuscript will include updated PROs and clinical outcomes – unfortunately, those data are embargoed until the final manuscript is release.

Once published, we’d be happy to re‐connect to see how the CLARITY data will support your meta‐analysis.

Please feel free to reach out directly to me if you need any further assistance.

Best regards,

Elisa Muscianisi

ADACCESS 2018

Prof Blauvelt

Outcome: QoL Scale

24 June and 1st July 2019

Email response: 2 July 2019

'Cc’ing the person who should be able to help you.'

EGALITY 2017

Prof Gerdes

Outcomes: QoL Scale, AEs, SAEs

24 June 2019

Email response 27 June 2019

Dear Dr. Sbidian,

On behalf of SANDOZ Global Medical Affairs team, I wanted to thank you for your interest to the EGALITY study and for considering it for your ongoing meta‐analysis.

I’m also happy to share with you on behalf of the authors and the team who worked on the study, the requested information that you can find here attached

We would highly appreciate if you can keep us informed when the meta‐analysis will be published, meanwhile, please feel free to revert back to us in case you would need any further information

Thank you and have a nice afternoon

Best regards

Sohaib

Dr. med. Sohaib HACHAICHI

Global Medical Affairs Manager

Immunology

Ikonomidis 2017

Prof Ikonomidis

Outcomes: PASI 90, 75, PGA0/1, QoL Scale, AES, SAEs

24 June and 1st July 2019

No response

Jin 2017

Prof Zhao

Outcomes: PASI 90, PGA0/1, QoL Scale

24 June and 1st July 2019

No response

VIP Trial 2018

Prof Gelfand

Outcome: PASI 90

24 June

Email response 24 June 2019

"Yes we can do this.

I propose that we have this data approved for release to you by September 30 2019"

We will add the new data for the next update (living review).

SIGNATURE 2019

No contact

Outcomes: PASI 90, PGA0/1, AES, SAEs

24 June 2019

We will contact the authors when the article is published

NCT02581345

Dr Caminis

Outcome: QoL Scal

24 June 2019

Authors' email not found (SHIRE pharmaceutics). We will contact the authors when the article is published

AURIEL‐PsO 2020

Sponsors and collaborators: Fresenius Kabi SwissBioSim GmbH Merck KGaA, Darmstadt, Germany

Outcomes: QoL Scale, AEs

24 June 2019

No contact; We will contact the authors when the article is published

NCT02850965

Sponsors: Boehringer Ingelheim

Outcomes: PASI 90, QoL Scale, AEs

24 June 2019

No contact. We will contact the authors when the article is published

ORION 2020

Pr Ferris

Outcome: DLQI

24 June and 2nd July 2019

No response

POLARIS 2020

Janssen‐Cilag G.m.b.H, Germany Clinical Tria

Outcome: PGA0/1

24 June 2019

No contact. We will contact the authors when the article is published

SustaIMM 2019

Sponsors and collaborators: AbbVie Boehringer Ingelheim

Outcome: DLQI

24 June 2019

No contact. We will contact the authors when the article is published

Papp 2017a

Prof. Papp

Outcome: DLQI

24 June 2019

Email answer 24 June 2019

"I am not at liberty to release results that are not in the public domain.

Regards,

k"

BE ABLE 1 2018

Prof. Papp

Outcome: DLQI

24 June 2019

Email answer 24 June 2019

"I am not at liberty to release results that are not in the public domain.

Regards,

k"

Papp 2017b

Prof. Papp

Outcome: DLQI

24 June 2019

Email answer 24 June 2019

"I am not at liberty to release results that are not in the public domain.

Regards,

k"

Papp 2018

Prof. Papp

Outcome: DLQI

24 June 2019

Email answer 24 June 2019

"I am not at liberty to release results that are not in the public domain.

Regards,

k"

IXORA‐S 2017

Prof. Reich

Outcome: DLQI

24 June and 1st July 2019

E‐mails not received (email: [email protected]; [email protected])

TRANSFIGURE 2016

Prof. Reich

Outcomes: PGA0/1, DLQI

24 June and 1st July 2019

E‐mails not received (email: [email protected]; [email protected])

PRIME 2017

Prof. Sticherling

Outcome: DLQI

24 June and 1st July 2019

Email answer 02 July 2019

"Dear Dr. Sbidian,
thank you very much for your mail.
We are currently checking the data for your table to respond in due time.
Yours,
Michael Sticherling"

CIMPACT 2018

Prof. Lebwohl

Outcome: DLQI

24 June and 1st July 2019

No response

Lee 2016

Outcomes: PASI 90, DLQI

24 June and 1st July 2019

No response

NCT02672852

Sponsors and collaborators: AbbVie Boehringer Ingelheim

Outcome: DLQI

24 June 2019

No contact. We will contact the authors when the article is published

NCT02134210

Barbara K Finck, M.D.; Coherus Biosciences, Inc

Outcome: DLQI

24 June 2019

No contact. We will contact the authors when the article is published

Yu 2019

Prof. Shi

Outcomes: PGA 0/1, DLQI

12 August 2020, 8 September 2020

No response

von Stebut CARIMA 2019

Prof. von Stebut

Outcomes: PASI 90, 75, IGA 0/1, QoL Scale

12 August 2020, 8 September 2020

No response

Hodge 2017 PsOsim

Prof. Hodge

Outcomes: PASI 90, PGA 0/1, QoL Scale

12 August 2020, 8 September 2020

No response

Reich 2019

Prof. Reich

Outcome: DLQI

12 August 2020, 8 September 2020

Email answer 8 September 2020:

"

Dear Dr. Sbidian

Thank you for your interest in the mirikizumab data. The team is currently working to determine what we are allowed to share, given that this data has not been published. I have just a few questions. If we do not provide the specified information, would mirikizumab then not be included at all in the NMA? Are percentages of patients with prior phototherapy and prior topical therapy needed for the modeling? If we cannot provide mean DLQI, but we are able to provide number/% patients on prior phototherapy and topic therapy, would mirikizumab still be included in the NMA for PASI outcomes?

Thank you!
Bridget Charbonneau"

NCT02187172 Gelfand VIP‐U 2020

Prof. Gelfand

Outcome: QoL Scale

12 August 2020

Email answer 17 August 2020

NCT02187172 Gelfand VIP‐U 2020 sent detailed report for the requested outcome.

NCT02313922 Liu 2019

Prof. Liu

Outcome: QoL Scale

12 August 2020

Email answer 13 August 2020

Liu 2019 sent detailed report for the requested outcome.

Reich ECLIPSE 2019

Prof. Reich

Outcomes: QoL Scale, AEs, SAEs

12 August 2020, 8 September 2020

Email answer 11 September 2020:

"Dear Authors:

I am contacting you on behalf of the ECLIPSE authors and the Janssen team. Prof. Reich has shared with us your request for additional ECLIPSE data to be included in a meta‐analysis. The authors would like to learn more about what data are being presented and what conclusions are being made in this meta‐analysis.

For example, which other biologics are being compared and at what timepoints are these comparisons? ECLIPSE was not a placebo‐controlled trial and the primary endpoint was 48 weeks, which was much later than most other studies.

That being said, the authors would first like to have these questions answered and to also have a better understanding of the proposed methodology and the goal of your meta‐analysis. Thank you.

Best regards,

Kristin M. Sharples, PhD

Scientific Communications, Dermatology
Medical Affairs"

Gottlieb IXORA‐R 2019

Prof. Blauvelt

Outcomes: PASI 90, 75, PGA 0/1, DLQI

12 August 2020

Email answer 13 August 2020

Gottlieb IXORA‐R 2019 sent detailed report for the requested outcomes except for PASI 75 and DLQI (not disclosed yet).

NCT02748863

Sponsors: Novartis

Outcome: DLQI

12 August 2020

Email answer 25 August 2020

"

Le critère principal d’évaluation de l’étude repose à la fois sur le score PASI 75 et sur l’IGA mod 2011. L’Indice de Qualité de Vie (DLQI) correspond bien à un des critères d’évaluation secondaires.

Les résultats de l’étude ALLURE (NCT02748863) n’ont pas encore été intégralement publiés dans la littérature scientifique.

Toutefois, nous vous prions de bien vouloir trouver ci‐joints le protocole de l’étude et les premiers résultats disponibles sur le site internet clinicaltrials.gov. Ces premiers résultats incluent des données sur les caractéristiques des patients, notamment leur âge, leur sexe ainsi que leur origine ethnique.

Je mets en copie de cet email la responsable médicale dermatologie de Cosentyx pour votre région, Mme Emeline Desreumaux ([email protected], +33667445036), n’hésitez pas à la contacter directement pour plus d’information sur nos études cliniques.

Sophie Baratin"

NCT03051217

Sponsors: UCB pharma

Outcomes: AEs, SAEs

12 August 2020, 8 September 2020

No contact. We will contact the authors when the article is published

NCT03066609

Sponsors: Novartis

Outcome: QoL Scale

12 August 2020, 8 September 2020

No contact. We will contact the authors when the article is published

NCT03055494 ObePso‐S

Sponsors: Novartis

Outcomes: PASI 75, PGA 1/0, QoL Scale, AEs, SAEs

8 September 2020

No contact. We will contact the authors when the article is published

Warren IMMerge, 2020

Prof. Warren

Outcome: QoL Scale

8 September 2020

No response

NCT03482011 OASIS‐1

Sponsors: Eli Lilly and Company

Outcome: DLQI

21 October 2020

Awaiting classification studies

Chow 2015

Prof. Chow

outcomes: PASI 90, PASI 75, PGA 0/1, QoL scale, AEs and SAEs

8 November 2016, 16 December 2016

No response

Gurel 2015

Prof. Gurel

Study's protocol and outcomes: PASI 90, PASI 75, PGA 0/1, QoL scale, AEs and SAEs

17 and 24 January 2017

Gurel 2015 sent detailed report for the requested outcomes. Finally Gurel study was classified in the included studies section.

Han 2007

No contact

Outcomes: PASI 90, PASI 75, PGA 0/1, QoL scale, AEs and SAEs

No

Authors' email not found

Krishna 2016

Prof. Krishna

Asking for study protocol and efficacy/safety results

5 and 12 January 2017

11 February 2020

No response

DRKS00000716

Prof. Jacobi

Asking for study protocol and efficacy/safety results

12 and 19 January 2017

No response

CTRI/2015/05/005830

Prof. Shah

Asking for study protocol and efficacy/safety results

12 and 19 January 2017

11 February 2020

No response

NCT01088165

Prof. Holzer

Asking for study protocol and efficacy/safety results

3 and 24 June 2019

11 February 2020

No response

NCT02655705

Prof. Youn

Asking for study protocol and efficacy/safety results

3 and 24 June 2019

11 February 2020

No response

CTRI /2017/09/009850

Prof. Mease

Asking for study protocol and efficacy/safety results

17 Ausgut 2020, 8 September 2020

No response

EUCTR2010‐020168‐39‐DE

Prof. Anderson

Asking for study protocol and efficacy/safety results

17 August 2020, 8 September 2020

No response

EUCTR2015‐005279‐25‐DE

Prof. Philipp

Asking for study protocol and efficacy/safety results

17 August 2020, 8 September 2020

No response

EUCTR2017‐001615‐36‐DE

Prof. Gerdes

Asking for study protocol and efficacy/safety results

17 August 2020, 8 September 2020

Email answer 8 September 2020: "

Dear Dr. Afach,

Thank you for your request. Unfortunately the information is still confidential.

BR

Sascha Gerdes"

Ikonomidis 2019

Prof. Ikonomidis

Asking for study protocol and efficacy/safety results

17 August 2020, 8 September 2020

No response

Makavos 2020

Dr. Ikonomidis

Asking for study protocol and efficacy/safety results

30 October 2020

Abstracts

Mrowietz 2005

Prof. Mrowietz

Study's protocol and outcomes: PASI 90, PASI 75, PGA 0/1, QoL scale, AEs and SAEs

16 December 2016, 3 January 2017

Additional data to the publication not provided. Finally Mrowietz study was classified in the 'Awaiting classification' section.

Ongoing studies

CTRI/2016/10/007345

Dr Piyush Agarwal, general manager

Glenmark Pharmaceuticals Ltd

[email protected]

[email protected]

Asking for study protocol and efficacy/safety results

11 February 2020

No response

NCT01558310a

Dr Yamauchi, Dr Patnaik, Director, Clinical Science Institute

Asking for study protocol and efficacy/safety results

5 January 2017

Email response: Dear Dr Sbidian,
"Thank you for your kind email, forwarded to me by Dr Paul Yamauchi, MD,PhD. Our " Study to Evaluate the Effectiveness of STELARA ™ (USTEKINUMAB) in the Treatment of Scalp Psoriasis (NCT 01558310)” completed enrolment in December 2016 and the last subject will complete in December 2017, as such we do not have the final data analysis. What is you absolute cut‐ off for publication data ? Would an interim analysis report be acceptable? Best regards, Rickie Patnaik Director, Clinical Science Institute"

Will be included when published

EUCTR2013‐004918‐18‐NL

Prof. Spuls

Asking for study protocol and efficacy/safety results

5 January 2017

Email response

"The study is currently ongoing and has not yet been analysed. Therefore, we are not able to provide data on efficacy or safety.
We can provide you with the study protocol. Will this be helpful?
Kind regards, Phyllis Spuls and Celine Busard "

Will be included when published

NCT02701205

Prof Hongzhong Jin

Asking for study protocol and efficacy/safety results

3 June 2019

11 February 2020

Email response "This is the mail system at host mta‐8_BSR. Your message could not be delivered to one or more recipients."

AE: adverse events; PASI: Psoriasis Area and Severity Index; PGA: Physician Global Assessment; QoL: quality of life; SAE: serious adverse events

Once a year, we manually check additional sources (regulatory agencies and pharmaceutical company trial registries).

We searched reviews submitted to the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for drug registration (using www.accessdata.fda.gov/scripts/cder/drugsatfda and www.ema.europa.eu/ema) up to 8 September 2020.

Adverse events

We did not perform a separate search for rare or delayed adverse events of the target interventions. However, we examined data on adverse events from the included studies we identified.

Annual review of search methods for this living systematic review

Once a year we revisit our search methods, and if necessary, update the search strategies by adding or removing intervention terms. This ensures the strategies reflect any terminology changes in the topic area, or changes to search terms available in the databases we search.

Data collection and analysis

Selection of studies

We conducted the selection process through Covidence (Covidence 2019), a web tool allowing dual screening of search results based on titles and abstracts, and then full text by independent review authors. Thus, two review authors (from SA, ES, LLC for this update) independently examined each title and abstract to exclude irrelevant reports. These authors independently examined full‐text articles to determine eligibility. We contacted study authors for clarification when necessary and discussed disagreements to reach consensus. We list excluded studies and document the primary reason for exclusion.

As this is a living systematic review, we immediately screened any new citations retrieved by the monthly searches.

Data extraction and management

Two review authors (SA, ES for this update) extracted the data from published and unpublished reports independently, using a standardised form. We pilot‐tested this form (Data Extraction Form) on a set of included trials. We extracted the data to populate the 'Characteristics of included studies' tables in Review Manager 5 (RevMan) (Revman 2020).

We extracted the data from the reports of the US FDA when available, and if not from the US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov), and finally from the published reports.

Outcome data

We extracted arm‐level data from each included trial; hence, the total number of participants randomised to each intervention. For binary outcomes, we also extracted the number of participants (if available) who:

  • reached PASI 90, PASI 75, or PGA 0/1 during the induction phase;

  • reached PASI 90, PASI 75 during the maintenance phase (at week 52); and

  • had at least one SAE/one AE during the induction phase.

For quality of life, we extracted from each included trial the mean change score of the study‐specific scale from baseline to follow‐up.

For assessment of quality of life, we recorded all specific quality‐of‐life (QoL) scales (Dermatology Life Quality Index (DLQI), Skindex, Psoriasis Disability Index (PDI), and Psoriasis Symptom Inventory (PSI)).

Data on potential effect modifiers

We extracted baseline demographic and clinical characteristics of participants that may have acted as effect modifiers (age, sex, body weight, duration of psoriasis, severity of psoriasis at baseline, previous psoriasis treatment). Two review authors (SA, ES) checked and entered the data into the Review Manager 5 (Revman 2020) computer software. We contacted the authors of the trials to request missing data, including missing data for outcomes (see Table 2).

Assessment of risk of bias in included studies

We used Cochrane's 'Risk of bias' (RoB) tool to assess the risks of bias. Two review authors (LLC and SA for this update) independently assessed the risk of bias, and one author (ES for this update) resolved any disagreements. For each of the following domains and according to the general principles in section 8.4 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2017), we judged the following 'Risk of bias' domains as 'low', 'high', or 'unclear'.

  • Selection bias (random sequence generation and allocation concealment items)

    • Was the allocation sequence adequately generated? We considered randomisation adequate (low risk of bias) if the allocation sequence was generated from a table of random numbers or was computer‐generated. We considered randomisation inadequate (high risk of bias) if sequences could be related to prognosis. We considered randomisation unclear if the paper stated that the trial was randomised, but did not describe the method.

    • Was allocation adequately concealed? We deemed allocation concealment as adequate if the report stated that it was undertaken by means of sequentially pre‐numbered sealed opaque envelopes or by a centralised system. We considered a double‐blind double‐dummy process as being at low risk of bias even if the paper did not describe the method of allocation concealment.

  • Performance and detection bias (blinding of participants,and blinding of outcome assessor items)

    • Was knowledge of the allocated intervention adequately prevented during the study? We evaluated the risk of bias separately for personnel and participants, outcomes assessors, and each outcome.

  • Attrition bias (incomplete outcome data item)

    • Were incomplete outcome data adequately addressed? We examined if there was imbalance across intervention groups in numbers or reasons for missing data, type of measure undertaken to handle missing data, and whether the analysis was carried out on an intention‐to‐treat (ITT) basis. We assessed the use of strategies to handle missing data.

  • Reporting bias (selective outcome reporting item)

    • Were reports of the study free of suggestion of selective outcome reporting? We evaluated if each outcome was measured, analysed, and reported. We compared outcomes specified in protocols (if available on the FDA website or ClinicalTrials.gov) and in material and methods with outcomes presented in the Results section. We considered reporting bias inadequate if one specified outcome in the protocols was lacking in the main report.

  • Other risk of bias

    • We did not address the 'Other risk of bias' item as we did not highlight particular circumstances leading to other risk of bias from particular trial designs, contamination between the experimental and control groups, and particular clinical settings.

Overall risk of bias

To summarise the quality of evidence and to interpret the network results, we used these six RoB criteria (random sequence generation, allocation concealment, blinding of participants, blinding of outcome assessor, incomplete outcome data, and selective outcome reporting) in order to classify each trial.

We would classify the trial as having low risk of bias if we rated none of the domains above as high risk of bias and two or fewer as unclear risk.

We would classify the trial as having moderate risk of bias if we rated one domain as high risk of bias, one or fewer domains as unclear risk, or no domains as high risk of bias, but three or fewer were rated as unclear risk.

All other cases were assumed to pertain to high risk of bias.

Measures of treatment effect

For each pair‐wise comparison and each dichotomous outcome at each time point, we used risk ratios (RRs) with 95% confidence intervals (CIs) as a measure of treatment effect. For continuous variables (e.g. quality‐of‐life scale), we used the standardised mean difference (SMD) with a 95% CI.

For every treatment, we estimated the ranking probabilities of being at each possible rank for all outcomes. We inferred on treatment hierarchy using the surface under the cumulative ranking curve (SUCRA) (Salanti 2011). SUCRA was expressed as a percentage between 0 (when it is certain a treatment is the worst) to 100% (when it is certain a treatment is the best). The advantage of SUCRA compared to other ranking measures is that it takes into account the entire distribution of the relative effects. (For more information on SUCRA, see Chaimani 2017b; Chaimani 2017c; Veroniki 2018). It should be noted, though, that ranking measures might be of limited value in the presence of large uncertainty in the results and therefore they should always be reported along with the relative effects.

Unit of analysis issues

The primary unit of analysis was the participant. We did not consider studies with non‐standard design features that would lead to clustering (e.g. cross‐over trials).

We treated comparisons from trials with multiple intervention groups as independent two‐arm studies in the pair‐wise meta‐analyses. In this analysis, different comparisons were analysed separately and therefore no study participants were double‐counted. At the network meta‐analysis stage, we properly accounted for the within‐trial correlation.

Dealing with missing data

We extracted, when possible, both the number of randomised and analysed participants in each study arm. We contacted trial authors or sponsors by email to request missing outcome data (numbers of events and numbers of participants for important dichotomous clinical outcomes) when these were not available in study reports that were less than 10 years old (See Table 2). For the main analysis, we assumed that any participant with missing outcome data did not experience clearance (for efficacy outcomes) or did not experience AEs (for safety outcomes), whatever the group. In a sensitivity analysis, we also synthesised the data ignoring the missing participants (complete case analysis), assuming that they were missing at random (Mavridis 2014).

Assessment of heterogeneity

We undertook meta‐analyses only if we judged participants, interventions, comparisons, and outcomes to be sufficiently similar (section 10.10 of the Cochrane Handbook for Systematic Reviews of Interventions) (Deeks 2021). Potential sources of heterogeneity included participants' baseline characteristics (weight, previous systemic treatment or not, treatment doses, co‐interventions, and duration of treatment). When enough data were available, we investigated the distributions of these characteristics across studies and treatment comparisons. The latter allows assessing transitivity, i.e. whether there were important differences between the trials evaluating different comparisons other than the treatments being compared (Salanti 2014). To further reassure the plausibility of the transitivity assumption, we only included in our analyses trials not involving co‐interventions. To better reassure the plausibility of transitivity, we excluded from the main analysis trials including biological‐naïve participants, but assessing efficacy of a biological agent. Indeed, response to biologics is different depending on treatment status (systemic‐naïve or not).

In the classical meta‐analyses, we assessed statistical heterogeneity by visual inspection of the forest plots and using the Q‐test and the I2 statistic. We interpreted the I2 statistic according to the following thresholds (section 9.5.2 of the Cochrane Handbook for Systematic Reviews of Interventions; Deeks 2021): 0% to 40% might not be important; 30% to 60% may represent moderate heterogeneity; 50% to 90% may represent substantial heterogeneity; 75% to 100% represents considerable heterogeneity.

In the network meta‐analysis, the assessment of statistical heterogeneity in the entire network was based on the estimated heterogeneity variance parameter (τ2) estimated from the network meta‐analysis models (Jackson 2014). We also estimated the prediction intervals to assess how much the estimated heterogeneity affects the relative effects with respect to the additional uncertainly anticipated in future studies (Riley 2011). Where feasible, we would have investigated the possible sources of heterogeneity in subgroup analyses and meta‐regression.

Although we restricted the risk of important heterogeneity in our data by considering eligible only studies without co‐interventions, we investigated differences in heterogeneity across the different analyses. Specifically, we observed whether splitting the nodes of the network and analysing each drug and each dose separately reduced the heterogeneity estimate. We also ran a series of sensitivity analyses (see Sensitivity analysis), and we monitored whether heterogeneity became smaller or larger compared to the primary analysis.

Assessment of reporting biases

To assess reporting biases, we used an adaptation of the funnel plot by subtracting from each study‐specific effect size the mean of meta‐analysis of the study‐specific comparison, which we plotted against the study standard error (Chaimani 2013). We employed this 'comparison‐adjusted funnel plot' for all comparisons of an active treatment against placebo. When we detected substantial funnel plot asymmetry for the two primary outcomes, we investigated the presence of small‐study effects in the network meta‐regression (Chaimani 2012).

Data synthesis

Pairwise meta‐analysis

We conducted pair‐wise meta‐analyses to synthesise trials comparing one of the treatments against placebo or two treatments against each other. We performed pair‐wise meta‐analyses for all outcomes and comparisons, provided that at least two studies were available, using a random‐effects model.

Network meta‐analysis

We then employed network meta‐analysis (NMA) for all outcomes and comparisons, to estimate the relative effects for all possible comparisons between any pair of treatments within a frequentist framework. We provided a graphical depiction of the evidence network for all outcomes to illustrate the network geometry (Chaimani 2017a). We ran network meta‐analysis using the approach of multivariate meta‐analysis, which treats the different comparisons that appear in studies as different outcomes (White 2012).

We focused on confidence intervals as a finding of uncertainty, as confidence intervals were sufficiently narrow to rule out an important magnitude of effect.

We assessed inconsistency (i.e. the possible disagreement between the different pieces of evidence) locally and globally. Specifically, we used the loop‐specific approach (Bucher 1997) and the side‐splitting method (Dias 2010). We also fitted the design by treatment interaction model to evaluate the presence of inconsistency in the entire network (Higgins 2012).

We conducted pair‐wise meta‐analyses using Review Manager 5 (Revman 2020), and we performed all other analyses in Stata 14 using the 'network' (www.stata-journal.com/article.html?article=st0410) and 'network graphs' packages (www.stata-journal.com/article.html?article=st0411).

As this is a living systematic review, whenever we found new evidence (i.e. studies, data or information) meeting the review inclusion criteria, we extracted the data and assessed risks of bias. For trials identified as completed in clinical trial registries but without posted results or those identified only by a conference proceeding, and for missing outcome data, trained review authors contacted trialists to request complete results. Every six months, we incorporated each newly‐identified trial in the network. We performed one network for each outcome (PASI‐90, SAEs, PASI‐75, PGA, QoL and AEs). We re‐analysed the data every six months using the standard approaches outlined in this Data synthesis section, as well as the CiNeMa process. We checked the assumptions of the NMA each time we updated the analysis.

Subgroup analysis and investigation of heterogeneity

We had planned to undertake subgroup analyses and meta‐regressions to investigate potential sources of heterogeneity or inconsistency (such as weight of participants, duration of psoriasis, baseline severity, previous systemic treatments) during the induction phase, but we found no heterogeneity or inconsistency.

Sensitivity analysis

To assess the robustness of our results, we performed the following sensitivity analyses for the two primary outcomes:

  • running the analysis at dose‐level, considering that each different drug dose is a different intervention;

  • excluding trials at high risk of bias;

  • excluding trials with a total sample size smaller than 50 randomised participants;

  • analysing only the observed participants and assuming that missing participants are missing at random;

  • analysing only the studies with a short‐term assessment from 8 to 16 weeks (to better reassure the plausibility of the transitivity assumption);

  • including all trials irrespective of the previous systemic‐treatments received by the participants;

  • lastly, we assessed SAEs after excluding flares of psoriasis.

We undertook this analysis because it has recently been reported that after excluding cases of worsening psoriasis, the risk of occurrence of SAEs is higher in the biologic (especially for anti‐TNF agents) than in the placebo arm (Afach 2021).

Summary of findings and assessment of the certainty of the evidence

We did not include 'Summary of findings' (SoF) tables because the format of an SoF table does not allow us to present a summary of comparisons across the different drugs. The SoF tables in the last version of the review only focused on the comparisons against placebo. 

We assessed the confidence of the evidence estimates from network meta‐analysis, based on the CINeMA approach which is based on the contributions of the direct comparisons to the estimation in the network meta‐analysis (CINeMA 2017; Salanti 2014). CINeMA (Confidence in Network Meta‐Analysis) is a web application that simplifies the evaluation of confidence in the findings from network meta‐analysis.

It is based on six domains: within‐study bias (referring to the impact of risk of bias in the included studies), across‐studies bias (publication or reporting bias), indirectness (relevance to the research question and transitivity), imprecision (comparing the range of treatment effects included in the 95% confidence interval with the range of equivalence), heterogeneity (predictive intervals), and incoherence (if estimates from direct and indirect evidence disagree) (Salanti 2014).

The confidence in each NMA RRAB between two given drugs A and B was evaluated for six domains. The software required some input in each domain in order to recommend whether there were 'major concerns', 'some concerns' or 'no concerns' for the particular domain.

Thus, threshold values and evaluation rules to be decided were finalised through discussions. After determining these rules, the remaining synthesis of confidence in the evidence can be automatically calculated via CINeMA web app; hence one review author finally input all the data and got the results.

  • Within‐trial bias: we estimated it as the weighted average of the overall risk of bias of all the trials contributing information to the estimation of RRAB.

  • Reporting bias: also known as 'publication bias'. We assessed publication bias by considering the comprehensive search strategy that we performed and the risk of publication bias in the specific field. The comparison‐adjusted funnel plots that test the presence of small‐study effects in the network assisted our judgement.

  • Indirectness: since the included studies matched the clinical question of the review, we had 'no concern' about any of the evaluated RRAB.

  • Imprecision: this was rated based on whether the 95% CI of RR was allowing recommendations to be made. We set the margin of equivalent effects (where none of the drugs is favoured) to between RR 0.95 and 1.05. These values were motivated by the fact that assuming 3% response rate (reaching PASI 90) for placebo, then an RRAB of 1.05 indicated a response for drug A higher than those obtained with placebo, which we considered as clinically meaningful. Then, the degree of overlap between the 95% CI of RRAB and the margin of equivalent effects suggests the judgement.

  • Heterogeneity: this was evaluated by monitoring the agreement between confidence intervals (CIs) and prediction intervals (PIs). CINeMA judges whether the two intervals and their overlap with the margin of equivalent effects provide similar conclusions.

  • Incoherence: this was evaluated by monitoring the level of disagreement between confidence intervals (CIs) of the direct and indirect RRAB and their overlap with the margin of equivalent effects.

After the judgement for all the six domains, we summarised the overall confidence in evidence for each RR between any two drugs into high, moderate, low and very low. Starting with high confidence, we downgraded by one level for each ‘major concern’ in any of the six domains; then by two‐thirds of a level down for ‘some concerns’ in ‘within‐study bias’; one‐third of a level down for each ‘some concerns’ in any of the other five domains. To obtain the final level, we rounded the number of downgrades to their nearest integer.

For each drug, we calculated the percentage of the four levels based on all comparisons including that drug, for efficacy and safety.

Results

Description of studies

Results of the search

Recent monthly Electronic searches of databases and trials registers for this living systematic review have identified an additional 1657 references for potentially eligible studies. We have also re‐examined 53 studies from the previous version of this review identified as ongoing (42 studies reported in 44 references) or awaiting classification (11 reported in 18 references). We have therefore screened a total of 1719 references for this update.

After reviewing the titles and abstracts, we discarded 1555 references. We examined the full text of the remaining 164 references. Seventeen studies (reported in 18 references) did not meet the inclusion criteria and were excluded (see Characteristics of excluded studies). Twenty‐eight trials (reported in 38 references) were identified as studies awaiting classification (see Characteristics of studies awaiting classification). We identified 29 studies (reported in 34 references) as ongoing (see Characteristics of ongoing studies). We identified 18 new included studies (reported in 34 references) for this update. We also identified 40 references which related to studies previously included in this review.

Combining the 18 new included studies with the 140 previously identified in earlier versions of this review, we have a total of 158 studies reported in 347 references.

For a further summary of our screening process, see the study flow diagram (Figure 1).


tudy flow diagram

tudy flow diagram

Included studies

Trial design

All trials used a parallel‐group design. The mean sample size was 365 (range: 10 to 1881). In all, 133 trials were multicentric (2 to 231 centres) and 18 were single‐centre trials (Akcali 2014; Al‐Hamamy 2014; Asawanonda 2006; Chaudhari 2001; Chladek 2005; Dogra 2012; Dogra 2013; Dubertret 1989; Ellis 1991; VIP‐U Trial 2020; Gisondi 2008; Gurel 2015; Hunter 1963; Ikonomidis 2017; Khatri 2016; Mahajan 2010; Shehzad 2004; Van Bezooijen 2016); for seven trials, single‐centre or multicentric status was not clear (Caproni 2009; Engst 1994; Goldfarb 1988; Jin 2017; Olsen 1989; Yilmaz 2002; Yu 2019). Most of the trials recruited participants from a hospital setting, but some also from physicians' offices. The trials took place worldwide (n = 65, 42%), in Europe (n = 35, 22%), in North America (n = 28, 18%), in Asia (n = 25, 16%), or in the Middle East (n = 1, 0.7%). The location was not stated for four trials (Caproni 2009; Engst 1994; Goldfarb 1988; Olsen 1989).

In total, 78 trials out of 158 were multi‐arm; 53 multi‐arm trials assessed the same experimental drug at multiple dose levels; 14 assessed at least two different drugs; 11 assessed both the same experimental drug at multiple dose levels and different drugs. In total, eight trials assessed biosimilars versus original drugs for adalimumab (ADACCESS 2018; AURIEL‐PsO 2020; PsOsim 2017; NCT02581345; NCT02850965; Papp 2017a) and etanercept (EGALITY 2017; NCT02134210).

In total, 16 trials (Al‐Hamamy 2014; Asawanonda 2006; Bissonnette 2013; Gottlieb 2012; Gurel 2015; Lowe 1991; Mahajan 2010; NCT02313922; Ruzicka 1990; Saurat 1988; Shehzad 2004; Sommerburg 1993; Tanew 1991; Van Bezooijen 2016; Yilmaz 2002; Yu 2019) had a co‐intervention, mainly with phototherapy. Only 14 studies were carried out before the year 2000 (Dubertret 1989; Ellis 1991; Engst 1994; Goldfarb 1988; Hunter 1963; Laburte 1994; Lowe 1991; Meffert 1997; Nugteren‐Huying 1990; Olsen 1989; Ruzicka 1990; Saurat 1988; Sommerburg 1993; Tanew 1991).

Characteristics of the participants

This review includes 158 trials (18 new trials for the updated review), with a total of 57,831 randomised participants. We summarise the characteristics of the participants in the Characteristics of included studies. The participants were reported to be between 27 and 56.5 years old, with an overall mean age of 45; there were more men (38,877) than women (18,487). Age and gender were unreported for, respectively, 1643 and 467 participants (15 and 8 studies). The overall mean weight was 85.4 kg (range: 64 to 100.5 kg), and the overall mean Psoriasis Area and Severity Index (PASI) score at baseline was 20 (range: 9.5 to 39). The duration of psoriasis was 18 years (range 7 to 21.5).

Characteristics of the comparisons
Trials with two parallel arms (the different dose groups were grouped together in one 'arm')

Intervention versus placebo: 92 trials compared systemic treatments with placebo

  • Twenty‐two trials compared non‐biological systemic treatments versus placebo

  • Thirteen trials compared small molecule treatments versus placebo

  • Fifty‐seven trials compared biological treatments versus placebo

Intervention versus active comparators: 48 trials compared systemic treatments with systemic treatments

Trials with three parallel arms (the different dose groups were grouped together in one 'arm')

18 trials compared systemic treatments with systemic treatments and placebo.

In total, the dataset consisted of 158 studies, which provide information on 194 direct comparisons between 36 different drug dosages, 20 different drugs, six different drug classes, and placebo. For the sensitivity analyses, the different drug doses were divided into approved dosages versus other dosages:

  • methotrexate, taken orally, ≥ 15 or < 15 mg a week;

  • ciclosporin, taken orally, ≥ 3 or < 3 mg/Kg a day;

  • acitretin, taken orally, ≥ 35 or < 35 mg a day;

  • apremilast, taken orally, 30 mg twice a day or other dosages;

  • tofacitinib, taken orally, 20 mg a day or other dosages;

  • etanercept, subcutaneous (S/C), 25 mg twice a week or etanercept 50 mg twice a week;

  • infliximab, intravenous, 5 mg/kg at week 0, 2, and 4 then every 6 weeks, or other dosages;

  • adalimumab, S/C, 80 mg at week 0, 40 mg at week 1 then 40 mg every other week or other dosages;

  • certolizumab, S/C, 400 mg at week 0, 2, 4 then 400 mg every other week, or other dosages;

  • secukinumab, S/C, 300 mg at week 0, 1, 2, 3, and 4 then every 4 weeks, or other dosages;

  • ixekizumab, S/C, 160 mg at week 0 then 80 mg every other week until week 12 then 80 mg monthly, or other dosages;

  • brodalumab, S/C, 210 mg at week 0, 1, 2, then every other week, or other dosages;

  • guselkumab, S/C, 100 mg at week 0 and 4 then every 8 weeks, or other dosages;

  • tildrakizumab, S/C, 100 mg at week 0 and 4 then every 12 weeks, or other dosages;

  • risankizumab, S/C, 150 mg (2 x 75 mg injections) at week 0, week 4 and every 12 weeks thereafter, or other dosages.

FAEs (taken orally), BMS‐986165 (taken orally), ustekinumab (S/C 45 mg or 90 mg according to the weight), bimekizumab (S/C) and mirikizumab (S/C) were grouped in one dosage, whatever the dosages.

For each study, we provide details of the dosage in Characteristics of included studies.

Characteristics of the outcomes

For the efficacy outcomes during induction therapy (less than 24 weeks), out of the 158 trials, 125 reported PASI 90, 114 reported on Physician Global Assessment (PGA) 0/1, 137 reported PASI 75, and 57 trials reported assessment of change in quality of life. Fifty‐eight studies used the dermatology‐specific instrument Dermatology Life Quality Index (DLQI); six studies used other specific skin instruments (Skindex and PSS). For all of these studies, the investigators provided citations to reports indicating that the tools had been previously validated. For efficacy outcomes during maintenance phase (52 weeks), 11 trials reported PASI 90 at one year (VOYAGE‐1 2016; UltIMMa‐1 2018; UltIMMa‐2 2018; IXORA‐P 2018; NCT03482011; Ohtsuki 2017; Ohtsuki 2018; JUNCTURE 2015; ECLIPSE 2019; CLEAR 2015; IMMerge 2021) and 11 reported PASI 75 at one year (VOYAGE‐1 2016; UltIMMa‐1 2018; UltIMMa‐2 2018; IXORA‐P 2018; NCT03482011; Ohtsuki 2017; Ohtsuki 2018; JUNCTURE 2015; ECLIPSE 2019; CLEAR 2015; Zhang 2017).

Out of 158 trials, 116 reported the number of participants with adverse events (different from the number of adverse events), and 131 reported the number of serious adverse events.

These outcomes were evaluated between 8 and 24 weeks: eight weeks (five studies), 10 weeks (seven studies), 12 weeks (72 studies), 13 weeks (two studies), 15 weeks (one study), 16 weeks (49 studies), 24 weeks (15 studies) and 26 weeks (two studies). Timing of assessment was unknown or not clearly defined for four studies (Engst 1994; Hunter 1963; Saurat 1988; Shehzad 2004); one study had only a timing of assessment at 52 weeks (IXORA‐P 2018).

Funding

In all, 132 studies declared a source of funding: 123 studies declared a pharmaceutical company funding, nine studies declared a unique institutional funding (Chladek 2005; PIECE 2016; Flytström 2008; Heydendael 2003; Ikonomidis 2017; VIP Trial 2018; NCT02313922; Reich 2020; Yu 2019), four studies had no funding source (Akcali 2014; Asawanonda 2006; Fallah Arani 2011; Gurel 2015), and 22 studies did not report the source of funding (Al‐Hamamy 2014; Caproni 2009; Dogra 2012; Dogra 2013; Dubertret 1989; Engst 1994; Gisondi 2008; Hunter 1963; Jin 2017; Laburte 1994; Mahajan 2010; Meffert 1997; Nugteren‐Huying 1990; Piskin 2003; Ruzicka 1990; Sandhu 2003; Saurat 1988; Shehzad 2004; Sommerburg 1993; Torii 2010; Yang 2012; Yilmaz 2002).

Excluded studies

We have excluded a total of 411 studies in 425 references throughout the course of this review.

For this update, we excluded 17 studies (reported in 18 references). The reasons for exclusion were: in five studies (six references) the participants did not present with moderate‐to‐severe psoriasis,  one study had ineligible outcomes, one study did not assess psoriasis, three studies assessed the same intervention with two different administration routes (pen versus syringe), two studies had ineligible interventions, one study was a phase 1 trial, one study was not a controlled trial, and three studies were withdrawn. We detail all the reasons for exclusion in Characteristics of excluded studies and our study flow diagram at Figure 1.

We excluded seven previously included studies (total of 17 references) from the previous review because the interventions no longer meet the inclusion criteria for the review (ponesimod (Vaclavkova 2014 ‐ development of the drug for psoriasis stopped), alefacept (Ellis 2001; Jacobe 2008; Krueger 2002a; Lebwohl 2003; Yan 2011 ‐ not used anymore for psoriasis), itolizumab (Krupashankar 2014 ‐ not approved)). We excluded 166 for other reasons.

For seven studies with three arms, one arm was not included, as the intervention was not included in our search:

  • Saurat 1988: acitretin versus placebo versus etretinate (etretinate arm was not included);

  • Shehzad 2004: PUVA (psoralen and ultraviolet A) therapy versus methotrexate (methotrexate only was included);

  • Gottlieb 2011; Strober 2011: briakinumab versus etanercept versus placebo (briakinumab arm was not included);

  • Gisondi 2008: etanercept versus acitretin versus etanercept plus acitretin (etanercept plus acitretin arm was not included);

  • Al‐Hamamy 2014: narrowband ultraviolet B phototherapy plus methotrexate versus narrowband ultraviolet B alone and methotrexate alone (arm with methotrexate alone was not included);

  • VIP Trial 2018: adalimumab versus narrowband ultraviolet B phototherapy versus placebo (arm with narrowband ultraviolet B phototherapy was not included);

  • Lee 2016: etanercept versus acitretin versus etanercept plus acitretin (arm with etanercept plus acitretin was not included).

Thaçi 2002 compared two different dosages of ciclosporin (a fixed dosage of 200 mg/day and a dosage corresponding to 2.5 mg/kg/day), and we were unable to classify the fixed dosage group either in the ciclosporin ≥ 3 mg/kg/day group or in the ciclosporin < 3 mg/day group for the subgroup meta‐analysis.

In an earlier version of this review (Sbidian 2017), we excluded a number of studies having reviewed the full text, but without creating Characteristics of excluded studies tables (n = 203). The main reason for exclusion of these studies was that the participants did not present with moderate‐to‐severe psoriasis.

Studies awaiting classification

We classified 28 trials reported in 38 references as studies awaiting classification. More details are available in Studies awaiting classification and Table 2. Most of the awaiting studies compare a biological treatment versus another biological treatment or versus non‐biological treatment or versus placebo (n = 21). One study assessed a small molecule, and six assessed non‐biological systemic treatments.

Ongoing studies

We classified 29 trials (reported in 34 references) as ongoing studies. More details are available in Characteristics of ongoing studies and Table 2. Most of the ongoing studies compare a biological treatment versus another biological treatment or versus placebo (n = 21). Six ongoing studies assessed apremilast or oral tyrosine kinase 2 (TYK2) inhibitor, and two assessed non‐biological systemic treatments.

Risk of bias in included studies

Figure 2 and Figure 3 summarise 'Risk of bias' assessments. For overall risk of bias across studies, 80 (51%) trials were at low risk of bias. We categorised a third of the studies (53/158, 33.5%) as being at high risk of bias. We categorised the remaining 25 studies as being at unclear risk of bias. Further details of these assessments are available in the 'Risk of bias' table corresponding to each trial in the Characteristics of included studies.


'Risk of bias' summary: review authors' judgements about each 'Risk of bias' item for each included study

'Risk of bias' summary: review authors' judgements about each 'Risk of bias' item for each included study


'Risk of bias' graph: review authors' judgements about each 'Risk of bias' item presented as percentages across all included studies

'Risk of bias' graph: review authors' judgements about each 'Risk of bias' item presented as percentages across all included studies

Allocation

In 55 trials the method of sequence generation was not described at all, or was at best unclear. The remaining studies (n = 103) described the method used to generate the allocation sequence in sufficient detail, and we therefore judged this domain as low risk of bias for these studies. For allocation concealment, most studies (n = 93) received a judgement of low risk of bias. We considered the risk unclear for the 65 remaining trials because of the absence of reporting of the method used to guarantee concealment.

Blinding

Blinding of participants and personnel was achieved in 105 studies, whereas 43 studies were at high risk of performance bias. The remaining 10 studies were at unclear risk of performance bias. Blinding of outcome assessment was reported clearly in only 111 of the 158 included studies, whereas 26 studies were at high risk of detection bias. The risk of detection bias was unclear in the remaining 21 studies.

Incomplete outcome data

In more than two‐thirds of the trials (105/158) incomplete outcome data appeared to have been adequately addressed, and any missing outcome data were reasonably well‐balanced across intervention groups, with similar reasons for missing data across the groups. However, in 18 studies the reporting of missing outcome data was largely inadequate because of one or more of the following reasons: the high number of withdrawn participants, an imbalance between groups in the number of withdrawn participants, an imbalance in reasons for missing outcomes, or no intention‐to‐treat (ITT) analysis provided. In 35 studies, this domain was as at unclear risk of bias because the following were not reported: the number of participants, reasons for discontinuation, or missing data imputation.

Selective reporting

We considered 14 trials to be at high risk of selective outcome reporting because results for outcomes detailed in the Methods section were not reported in the Results section (Akcali 2014; Engst 1994; Hunter 1963; AMAGINE‐2 2015; AMAGINE‐3 2015; BRIDGE 2017; Nakagawa 2016; Papp 2013b; Papp 2005; LIBERATE 2017; Shehzad 2004; VIP‐U Trial 2020; PsOsim 2017; CARIMA 2019). In all, we considered 98 studies to be at low risk of bias for this domain, as outcome details in the trial register and in the Methods section were reported in the Results section. For other trials (n = 46), we considered the risk of bias as unclear, because we did not find these trials in any register.

Other potential sources of bias

As detailed in the Methods section, we did not address the 'Other risk of bias' item as we did not highlight particular circumstances leading to other risk of bias from particular trial designs, contamination between the experimental and control groups, and particular clinical settings.

Effects of interventions

Eight trials provided no usable or retrievable data and did not contribute further to the results of this review (Akcali 2014; Chladek 2005; Engst 1994; Ikonomidis 2017; Lowe 1991; Olsen 1989; Piskin 2003; Shehzad 2004; see Table 2). The main reason we could not use their data was that these studies addressed none of our outcomes.

Sixteen studies, involving 1667 participants (2.9% of the participants in this review), had a co‐intervention and did not contribute further to the results of this review, as we could not assess the specific intervention effect (Al‐Hamamy 2014; Asawanonda 2006; Bissonnette 2013; Gottlieb 2012; Gurel 2015; Lowe 1991; Mahajan 2010; NCT02313922; Ruzicka 1990; Saurat 1988; Shehzad 2004; Sommerburg 1993; Tanew 1991; Van Bezooijen 2016; Yilmaz 2002; Yu 2019).

Eight trials assessed biosimilars versus original drugs for adalimumab (ADACCESS 2018; NCT02581345; AURIEL‐PsO 2020; NCT02850965; Papp 2017a; PsOsim 2017) and etanercept (EGALITY 2017; NCT02134210). These were non‐inferiority trials, assessing the same dosage and same administration schema of biosimilar and original drug.

In total, 28 studies, involving 5209 participants, were not included in the classical or network meta‐analysis (reasons are mentioned above). The interventions of the 28 studies concerned the following:

We included a total of 130 studies, involving 50,081 participants (86.6% participants of this review), in the classical or network meta‐analysis for at least one of the outcomes.

One study had only long‐term outcome assessments (IXORA‐P 2018).

Ten studies, involving 2132 participants (4.3% of the participants in this review) included biological‐naïve participants when assessing efficacy of a biological agent, and did not contribute further to the results of the main analysis, as we could not assume the plausibility of transitivity. Indeed, response to biologics is different depending on treatment status (systemic‐naïve or not). However, these studies were included in the sensitivity analysis (Barker 2011; Caproni 2009; Gisondi 2008; Lee 2016; NCT03255382; NCT03331835; Reich 2020; CHAMPION 2008; PRIME 2017; POLARIS 2020).

Figure 4 and Figure 5 show the network diagrams for all of the outcomes included in the review. The size of the nodes is proportional to the total number of participants allocated to each class‐level (Figure 4) and drug‐level (Figure 5) intervention, with the thickness of the lines proportional to the number of trials evaluating each direct comparison.


Network plot for all the outcomes at class level The size of the nodes is proportional to the total number of participants allocated to each intervention and the thickness of the lines proportional to the number of studies evaluating each direct comparison.AE: adverse events; PASI: Psoriasis Area and Severity Index; PGA: Physician Global Assessment; QoL: quality of life; SAE: serious adverse events; SAE without worsening of psoriasis correspond to SAE after exclusion of flares of psoriasis

Network plot for all the outcomes at class level

The size of the nodes is proportional to the total number of participants allocated to each intervention and the thickness of the lines proportional to the number of studies evaluating each direct comparison.

AE: adverse events; PASI: Psoriasis Area and Severity Index; PGA: Physician Global Assessment; QoL: quality of life; SAE: serious adverse events; SAE without worsening of psoriasis correspond to SAE after exclusion of flares of psoriasis


Network plot for all the outcomes at drug level The size of the nodes is proportional to the total number of participants allocated to each intervention and the thickness of the lines proportional to the number of studies evaluating each direct comparison.ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumabAE: adverse events; PASI: Psoriasis Area and Severity Index; PGA: Physician Global Assessment; QoL: quality of life; SAE: serious adverse events; SAE without worsening of psoriasis correspond to SAE after exclusion of flares of psoriasis

Network plot for all the outcomes at drug level

The size of the nodes is proportional to the total number of participants allocated to each intervention and the thickness of the lines proportional to the number of studies evaluating each direct comparison.

ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumab

AE: adverse events; PASI: Psoriasis Area and Severity Index; PGA: Physician Global Assessment; QoL: quality of life; SAE: serious adverse events; SAE without worsening of psoriasis correspond to SAE after exclusion of flares of psoriasis

Figure 6 shows the network meta‐analysis estimates of all of the outcomes for each comparison at class level.


Relative effects of the class‐level intervention as estimated from the network meta‐analysis model Outcomes were all measured at the induction phase (assessment from 8 to 24 weeks after randomisation). Drugs are reported in order of primary benefit ranking. Each cell contains the risk ratio (RR) (for dichotomous outcomes: PASI 90, serious adverse events, PASI 75, PGA 0/1, adverse events) or the standardised mean difference (SMD) (for the quality‐of‐life outcome), plus the 95% confidence interval, of the class level in the respective column versus the class level in the respective row. RRs larger than 1 for the lower triangle and smaller than 1 (or SMDs smaller than zero) for the upper triangle favour the treatment on the left. Significant results are highlighted in grey.AE: adverse events; PASI: Psoriasis Area and Severity Index; PGA: Physician's Global Assessment; QoL: quality of life; SAE: serious adverse events; SAE without worsening of psoriasis correspond to SAE after exclusion of flares of psoriasis; AIL12/23: anti‐IL12/23; AIL17: anti‐IL17; AIL23: anti‐IL23, ATA: anti‐TNF alpha; CSA: non‐biological conventional systemic agents; PBO: placebo; SM: small molecules

Relative effects of the class‐level intervention as estimated from the network meta‐analysis model

Outcomes were all measured at the induction phase (assessment from 8 to 24 weeks after randomisation). Drugs are reported in order of primary benefit ranking. Each cell contains the risk ratio (RR) (for dichotomous outcomes: PASI 90, serious adverse events, PASI 75, PGA 0/1, adverse events) or the standardised mean difference (SMD) (for the quality‐of‐life outcome), plus the 95% confidence interval, of the class level in the respective column versus the class level in the respective row. RRs larger than 1 for the lower triangle and smaller than 1 (or SMDs smaller than zero) for the upper triangle favour the treatment on the left. Significant results are highlighted in grey.

AE: adverse events; PASI: Psoriasis Area and Severity Index; PGA: Physician's Global Assessment; QoL: quality of life; SAE: serious adverse events; SAE without worsening of psoriasis correspond to SAE after exclusion of flares of psoriasis; AIL12/23: anti‐IL12/23; AIL17: anti‐IL17; AIL23: anti‐IL23, ATA: anti‐TNF alpha; CSA: non‐biological conventional systemic agents; PBO: placebo; SM: small molecules

Figure 7, Figure 8 and Figure 9 show the network meta‐analysis estimates of all the outcomes for each comparison at drug level.


Relative effects of the intervention as estimated from the network meta‐analysis model for Psoriasis Area and Severity Index (PASI) 90 and serious adverse events (AEs) Outcomes were all measured at the induction phase (assessment from 8 to 24 weeks after randomisation). Drugs are reported in order of primary benefit ranking. Each cell contains the risk ratio (RR) and 95% confidence interval for the two primary outcomes (PASI 90 and SAEs) of the intervention in the respective column versus the comparator in the respective row. RRs larger than 1 for the lower triangle and smaller than 1 for the upper triangle favour the treatment on the left. Certainty of evidence was assessed for each comparison using CINeMA and classified in high (highlighted in green), moderate (in blue), low (in yellow) and very‐low (in red).ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumab

Relative effects of the intervention as estimated from the network meta‐analysis model for Psoriasis Area and Severity Index (PASI) 90 and serious adverse events (AEs)

Outcomes were all measured at the induction phase (assessment from 8 to 24 weeks after randomisation). Drugs are reported in order of primary benefit ranking. Each cell contains the risk ratio (RR) and 95% confidence interval for the two primary outcomes (PASI 90 and SAEs) of the intervention in the respective column versus the comparator in the respective row. RRs larger than 1 for the lower triangle and smaller than 1 for the upper triangle favour the treatment on the left. Certainty of evidence was assessed for each comparison using CINeMA and classified in high (highlighted in green), moderate (in blue), low (in yellow) and very‐low (in red).

ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumab


Relative effects of the intervention as estimated from the network meta‐analysis model for Psoriasis Area and Severity Index (PASI 75) and adverse events (AEs) Outcomes were all measured at the induction phase (assessment from 8 to 24 weeks after randomisation). Drugs are reported in order of primary benefit ranking. Each cell contains the Risk Ratio (RR) and 95% confidence interval for the two secondary outcomes (PASI 75 and adverse events) of the intervention in the respective column versus the comparator in the respective row. RRs larger than 1 for the lower triangle and smaller than 1 for the upper triangle favour the treatment on the left. Significant results are are highlighted in grey.ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumab

Relative effects of the intervention as estimated from the network meta‐analysis model for Psoriasis Area and Severity Index (PASI 75) and adverse events (AEs)

Outcomes were all measured at the induction phase (assessment from 8 to 24 weeks after randomisation). Drugs are reported in order of primary benefit ranking. Each cell contains the Risk Ratio (RR) and 95% confidence interval for the two secondary outcomes (PASI 75 and adverse events) of the intervention in the respective column versus the comparator in the respective row. RRs larger than 1 for the lower triangle and smaller than 1 for the upper triangle favour the treatment on the left. Significant results are are highlighted in grey.

ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumab


Relative effects of the intervention as estimated from the network meta‐analysis model for Physician's Global Assessment (PGA 0/1) and quality of life (QoL) Outcomes were all measured at the induction phase (assessment from 8 to 24 weeks after randomisation). Drugs are reported in order of primary benefit ranking. Each cell contains the risk ratio (RR) and 95% confidence interval (PGA 0/1) or standardized mean difference (quality of life) of the intervention in the respective column versus the comparator in the respective row. RRs larger than 1 for the lower triangle and smaller than 1 (or SMDs smaller than zero) for the upper triangle favour the treatment on the left. Significant results are are highlighted in grey.ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumab

Relative effects of the intervention as estimated from the network meta‐analysis model for Physician's Global Assessment (PGA 0/1) and quality of life (QoL)

Outcomes were all measured at the induction phase (assessment from 8 to 24 weeks after randomisation). Drugs are reported in order of primary benefit ranking. Each cell contains the risk ratio (RR) and 95% confidence interval (PGA 0/1) or standardized mean difference (quality of life) of the intervention in the respective column versus the comparator in the respective row. RRs larger than 1 for the lower triangle and smaller than 1 (or SMDs smaller than zero) for the upper triangle favour the treatment on the left. Significant results are are highlighted in grey.

ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumab

Figure 10, Figure 11 and Figure 12 show all of the relative effects from the network meta‐analyses against placebo with their 95% confidence and prediction intervals at class and drug level.


Interval plot. Network meta‐analysis estimates of class‐level versus placebo for all the outcomes Outcomes were all measured at the induction phase (assessment from 8 to 24 weeks after randomisation).AE: adverse events; CI: confidence interval; PGA: Physician Global Assessment; PrI: predictive interval; QoL: Specific quality of life scale; RR: risk ratio; SAE: serious adverse events; SAE without worsening of psoriasis correspond to SAE after exclusion of flares of psoriasis; SMD: standardised mean difference; AIL12/23: anti‐IL12/23; AIL17: anti‐IL17; AIL23: anti‐IL23, ATA: anti‐TNF alpha

Interval plot. Network meta‐analysis estimates of class‐level versus placebo for all the outcomes

Outcomes were all measured at the induction phase (assessment from 8 to 24 weeks after randomisation).

AE: adverse events; CI: confidence interval; PGA: Physician Global Assessment; PrI: predictive interval; QoL: Specific quality of life scale; RR: risk ratio; SAE: serious adverse events; SAE without worsening of psoriasis correspond to SAE after exclusion of flares of psoriasis; SMD: standardised mean difference; AIL12/23: anti‐IL12/23; AIL17: anti‐IL17; AIL23: anti‐IL23, ATA: anti‐TNF alpha


Interval plot. Network meta‐analysis estimates of the interventions versus placebo for the primary outcomes CI: confidence interval; PrI: predictive interval; RR: risk ratio; SAE: serious adverse eventsACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumab

Interval plot. Network meta‐analysis estimates of the interventions versus placebo for the primary outcomes

CI: confidence interval; PrI: predictive interval; RR: risk ratio; SAE: serious adverse events

ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumab


Interval plot. Network meta‐analysis estimates of the interventions versus placebo for the secondary outcomes Outcomes were all measured at the induction phase (assessment from 8 to 24 weeks after randomisation).AE: adverse events; CI: confidence interval; PGA: Physician Global Assessment; PrI: predictive interval; QoL: Specific quality of life scale; RR: risk ratio; SMD: standardised mean differenceACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumab

Interval plot. Network meta‐analysis estimates of the interventions versus placebo for the secondary outcomes

Outcomes were all measured at the induction phase (assessment from 8 to 24 weeks after randomisation).

AE: adverse events; CI: confidence interval; PGA: Physician Global Assessment; PrI: predictive interval; QoL: Specific quality of life scale; RR: risk ratio; SMD: standardised mean difference

ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumab

Figure 13 shows a two‐dimensional ranking plot based on surface under the cumulative ranking curve (SUCRA) values for benefit (PASI 90) and acceptability (serious adverse events) at class and drug level. The different colours represent different groups of interventions considering their performance on both outcomes simultaneously. Interventions belonging to the same group were assumed to have a similar performance when the two primary outcomes were considered jointly (Chaimani 2013).


Ranking plot. Ranking plot representing simultaneously the efficacy (x axis, PASI 90) and the acceptability (y axis, serious adverse events) of all the interventions (class and drug levels) for patients with moderate‐to‐severe psoriasis. Optimal treatment should be characterised by both high efficacy and acceptability and should be in the right upper corner of this graph.Outcomes were measured at the induction phase (assessment from 8 to 24 weeks after randomisation).The different colours represent different groups of interventions considering their performance on both outcomes simultaneously. Interventions belonging to the same group are assumed having a similar performance when the two primary outcomes are considered jointlyACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumabPASI: Psoriasis Area and Severity Index; SAE: serious adverse events; SUCRA: surface under the cumulative ranking curve

Ranking plot. Ranking plot representing simultaneously the efficacy (x axis, PASI 90) and the acceptability (y axis, serious adverse events) of all the interventions (class and drug levels) for patients with moderate‐to‐severe psoriasis. Optimal treatment should be characterised by both high efficacy and acceptability and should be in the right upper corner of this graph.

Outcomes were measured at the induction phase (assessment from 8 to 24 weeks after randomisation).

The different colours represent different groups of interventions considering their performance on both outcomes simultaneously. Interventions belonging to the same group are assumed having a similar performance when the two primary outcomes are considered jointly

ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumab

PASI: Psoriasis Area and Severity Index; SAE: serious adverse events; SUCRA: surface under the cumulative ranking curve

Figure 14 and Figure 15 show the ranking for all the outcomes at class and drug level, respectively.


Ranking for all the outcomes at class level AIL12/23: anti‐IL12/23; AIL17: anti‐IL17; AIL23: anti‐IL23, ATA: anti‐TNF alpha; CSA: non‐biological conventional systemic agents; PBO: placebo; SM: small moleculesAE: adverse events; PASI: Psoriasis Area and Severity Index; PGA: Physician Global Assessment; QoL: quality of life; SAE: serious adverse events; SAE without worsening of psoriasis correspond to SAE after exclusion of flares of psoriasis

Ranking for all the outcomes at class level

AIL12/23: anti‐IL12/23; AIL17: anti‐IL17; AIL23: anti‐IL23, ATA: anti‐TNF alpha; CSA: non‐biological conventional systemic agents; PBO: placebo; SM: small molecules

AE: adverse events; PASI: Psoriasis Area and Severity Index; PGA: Physician Global Assessment; QoL: quality of life; SAE: serious adverse events; SAE without worsening of psoriasis correspond to SAE after exclusion of flares of psoriasis


Ranking for all the outcomes at drug level ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumabAE: adverse events; PASI: Psoriasis Area and Severity Index; PGA: Physician Global Assessment; QoL: quality of life; SAE: serious adverse events

Ranking for all the outcomes at drug level

ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumab

AE: adverse events; PASI: Psoriasis Area and Severity Index; PGA: Physician Global Assessment; QoL: quality of life; SAE: serious adverse events

Since this review does not include ‘Summary of findings' (SoF) tables, we present Figure 7 instead. Figure 7 includes all comparison results for the two main outcomes, but also absolute effects and assessment of the certainty of evidence using CiNeMa.

1. Primary outcomes

1.1 The proportion of participants who achieved clear or almost clear skin, e.g. PASI 90
DIRECT EVIDENCE

We report treatment estimates for pair‐wise meta‐analyses at class and drug level in Analysis 1.1; Analysis 1.2; Analysis 1.3; Analysis 1.4; Analysis 1.5; Analysis 1.6; Analysis 1.7; Analysis 1.8; Analysis 1.9; and Analysis 1.10, respectively.

In terms of reaching PASI 90, anti‐IL17 treatments (secukinumab, ixekizumab, brodalumab, and bimekizumab) were more effective than placebo (risk ratio at class level (RR) 30.68, 95% confidence interval (CI) 22.96 to 41.00). These findings were also confirmed for anti‐IL23 (guselkumab, tildrakizumab, risankizumab, and mirikizumab) (class‐level RR 20.23, 95% CI 14.76 to 27.73); anti‐IL12/23 (ustekinumab) (RR 19.77, 95% CI 13.25 to 29.52); anti‐TNF alpha (infliximab, etanercept, adalimumab, and certolizumab) (class‐level RR 13.65, 95% CI 10.71 to 17.40); and small molecules (apremilast, tofacitinib, and oral tyrosine kinase 2 (TYK2) inhibitor) (class‐level RR 7.09, 95% CI 5.05 to 9.95). Both infliximab and adalimumab were more effective than methotrexate (respectively: RR 2.86, 95% CI 2.15 to 3.80; and RR 3.73, 95% CI 2.25 to 6.19), and secukinumab was more effective than FAEs (RR 8.31, 95% CI 4.23 to 16.35). Ustekinumab, secukinumab, ixekizumab, tildrakizumab and certolizumab were more effective than etanercept. Secukinumab, ixekizumab, brodalumab, and risankizumab were more effective than ustekinumab. Guselkumab and risankizumab were more effective than adalimumab. Secukinumab and ixekizumab were more effective than guselkumab. No significant difference was observed between rizankizumab and secukinumab, or between etanercept and tofacitinib, or between etanercept and apremilast for this outcome (reaching PASI 90).

NETWORK META‐ANALYSES

The PASI 90 outcome was available in 109 trials, involving 47,230 participants (94.3% of the participants in the meta‐analysis). For two trials (Nugteren‐Huying 1990; Sandhu 2003) the number of randomised participants was not available, but we added these trials in the complete‐case sensitivity analyses. This outcome was reported in eight trials out of 99 (Asahina 2016; Bissonnette 2015; Dogra 2012; Dogra 2013; Khatri 2016; SCULPTURE 2015; SIGNATURE 2019; PRISTINE 2013), comparing different dosages of the same drug in each case. We added these trials to the sensitivity analysis at dose level. This outcome was reported in 10 trials out of 109 with biological‐naïve participants and were added to the sensitivity analysis for all trials, whatever previous treatments received by the participants (Barker 2011; Caproni 2009; Gisondi 2008; Lee 2016; NCT03255382; NCT03331835; Reich 2020; CHAMPION 2008; PRIME 2017; POLARIS 2020).

Sixty‐six trials, involving 23,721 participants, were placebo‐controlled trials; 23 studies, involving 7133 participants, were head‐to‐head comparisons; and 20 studies, involving 16,376 participants, had both a placebo and at least two active treatments arms.

PASI 90 was not reported for the remaining 21 trials including IXORA‐P 2018 (only long‐term assessment outcomes), and we were not able to obtain missing information from the trial authors (Table 2).

See Figure 4; Figure 5; Figure 6; Figure 7; Figure 10; Figure 11; Figure 14; Figure 15.

Table 3 summarises the main results of both the direct and indirect evidence and the network meta‐analysis for PASI 90. The summary relative effects from the network meta‐analysis are presented in league tables for both class‐level (Figure 6) and drug‐level (Figure 7) analyses.

Open in table viewer
Table 3. Direct and indirect evidences and network meta‐analysis results summary table for PASI 90

Network meta‐analysis

Direct evidence

Indirect evidence

Comparisons*

RR

LCI

UCI

RR

LCI

UCI

RR

LCI

UCI

Adalimumab versus placebo

17.81

14.82

21.40

15.16

11.50

19.96

20.43

15.85

26.32

Apremilast versus placebo

7.73

4.51

13.24

6.95

3.38

14.33

10.25

2.53

41.52

Bimekizumab versus placebo

58.64

3.72

923.86

Brodalumab versus placebo

23.55

19.48

28.48

26.32

16.77

41.33

20.11

10.91

37.07

Certolizumab versus placebo

13.42

9.76

18.44

19.77

8.29

47.12

8.10

2.70

24.32

Ciclosporin versus placebo

7.04

1.32

37.50

Etanercept versus placebo

10.76

9.03

12.82

11.52

8.82

15.03

9.98

7.53

13.24

FAEs versus placebo

4.36

2.01

9.46

4.47

2.01

9.95

2.93

0.13

67.39

Guselkumab versus placebo

25.52

21.25

30.64

28.92

20.59

40.62

24.12

19.29

30.16

Infliximab versus placebo

50.29

20.96

120.67

42.64

16.08

113.09

99.51

13.69

723.56

Ixekizumab versus placebo

32.48

27.13

38.87

30.54

21.37

43.65

33.20

26.88

41.01

Mirikizumab versus placebo

10.96

5.46

22.00

Methotrexate versus placebo

6.97

1.42

34.34

5.85

0.73

46.93

8.94

0.75

106.67

Risankizumab versus placebo

28.76

23.96

34.54

31.96

22.80

44.79

27.97

22.95

34.09

Secukinumab versus placebo

25.79

21.61

30.78

27.55

19.28

39.36

25.33

20.83

30.82

Tildrakizumab versus placebo

18.73

14.21

24.69

17.25

8.26

36.02

20.88

8.17

53.40

Tofacitinib versus placebo

8.89

7.09

11.13

6.94

4.69

10.27

14.50

7.39

28.42

Tyrosine kinase 2 inhibitor versus placebo

13.99

1.99

98.10

Ustekinumab versus placebo

18.46

15.51

21.98

17.90

13.65

23.48

18.73

15.36

22.83

Guselkumab versus adalimumab

1.43

1.32

1.56

1.45

1.32

1.59

1.32

1.04

1.66

Risankizumab versus adalimumab

1.62

1.44

1.81

1.53

1.33

1.75

1.83

1.49

2.25

Etanercept versus apremilast

1.39

0.82

2.38

1.39

0.71

2.71

1.40

0.59

3.31

Ustekinumab versus brodalumab

0.78

0.72

0.86

0.79

0.72

0.86

0.56

0.26

.22

Etanercept versus certolizumab

0.80

0.61

1.06

0.83

0.62

1.11

0.55

0.22

1.38

Methotrexate versus ciclosporin

0.99

0.60

1.64

0.99

0.60

1.64

46.01

0.00

.

Infliximab versus etanercept

4.67

1.93

11.34

9.20

1.28

66.37

3.94

1.46

10.62

Ixekizumab versus etanercept

3.02

2.69

3.38

2.91

2.53

3.34

3.26

2.68

3.98

Secukinumab versus etanercept

2.40

2.12

2.72

2.33

1.86

2.93

2.43

2.09

2.82

Tildrakizumab versus etanercept

1.74

1.39

2.18

1.77

1.40

2.24

1.43

0.61

3.35

Tofacitinib versus etanercept

0.83

0.69

0.99

0.88

0.73

1.08

0.58

0.37

0.91

Ustekinumab versus etanercept

1.72

1.52

1.94

1.80

1.45

2.24

1.68

1.45

1.94

Ixekizumab versus guselkumab

1.27

1.17

1.39

1.29

1.18

1.42

1.16

0.93

1.45

Methotrexate versus FAEs

1.60

0.32

8.06

2.00

0.19

20.90

1.31

0.14

12.18

Secukinumab versus risankizumab

0.90

0.81

0.99

0.89

0.77

1.03

0.90

0.79

1.04

Ustekinumab versus ixekizumab

0.57

0.50

0.64

0.58

0.47

0.71

0.56

0.49

0.65

Ustekinumab versus risankizumab

0.64

0.58

0.71

0.60

0.52

0.70

0.67

0.59

0.77

Ustekinumab versus secukinumab

0.72

0.67

0.76

0.72

0.67

0.77

0.72

0.61

0.84

FAES: fumaric acid esters; LCI: low confidence interval; RR: risk ratio; UCI: upper confidence interval; vs: versus,

*The comparisons listed in this table were included in at least one direct‐evidence analysis.

All of the interventions appeared superior to placebo in terms of reaching PASI 90. At class level (Figure 6), anti‐IL17 treatment was associated with a better chance of reaching PASI 90 compared to all of the interventions: versus anti‐IL23 (RR 1.26, 95% CI 1.04 to 1.53): versus anti‐IL12/23 (RR 1.53, 95% CI 1.28 to 1.82); versus anti‐TNF alpha (RR 2.21, 95% CI 1.83 to 2.67); versus small molecules (RR 3.31, 95% CI 2.34 to 4.69); versus non‐biological systemic agents (RR 6.49, 95% CI 2.72 to 15.50). In terms of reaching PASI 90, all of the biologic interventions (anti‐IL17, anti‐IL12/23, anti‐IL23, anti‐TNF alpha) appeared significantly superior to the small molecule class of treatments and the non‐biological systemic class of treatments.

Results of comparisons between each of the drugs are available in Figure 7. There was no significant difference between infliximab, ixekizumab, bimekizumab, and risankizumab in terms of reaching PASI 90. Anti‐IL17 drugs (ixekizumab, secukinumab and brodalumab) and anti‐IL23 drugs (risankizumab and guselkumab) except tildrakizumab were significantly more likely to reach PASI 90 than ustekinumab and three anti‐TNF alpha agents: adalimumab, certolizumab and etanercept. Ustekinumab was superior to certolizumab (RR 1.38, 95% CI 1.02 to 1.86). Adalimumab and ustekinumab were superior to etanercept (RR 1.66, 95% CI 1.44 to 1.91 and RR 1.72, 95% CI 1.52 to 1.94, respectively). No significant difference was shown between tofacitinib or apremilast and two non‐biological drugs: ciclosporin and methotrexate. We assessed the certainty of evidence for each comparison using CINeMA and classified as high (highlighted in green), moderate (in blue), low (in yellow) and very low (in red) (Figure 7).

Ranking class‐level analysis (Figure 10; Figure 14; Table 4)

Open in table viewer
Table 4. Ranking findings for all outcomes at class level

Class‐level
interventions

SUCRA
PASI 90

Rank
PASI 90

SUCRA
SAE

Rank
SAE

SUCRA

SAE

excluded

flare of psoriasis

Rank

SAE

excluded

flare of psoriasis

SUCRA
PASI 75

Rank
PASI 75

SUCRA
AE

Rank
AE

SUCRA
PGA

Rank
PGA

SUCRA
QoL

Rank
QoL

Anti‐IL17

99.9

1

22.6

7

24.7

7

99.5

1

24.7

6

99.9

1

73.4

3

Anti‐IL23

82.9

2

77.7

1

77.2

1

81.1

2

88.3

2

81.8

2

85.5

1

Anti‐IL12/23

67.2

3

43.9

5

29.2

6

69.4

3

57.5

3

68.3

3

75.8

2

Anti‐TNF alpha

49.8

4

51.5

3

37.4

5

50

4

52.6

4

50

4

44.5

5

Small molecules

32.3

5

50.4

4

72.5

2

33.3

5

5.7

7

30.5

5

20.4

6

Non‐biological

treatments

18

6

74.2

2

52.6

4

16.7

6

28.8

5

19.5

6

50.2

4

Placebo

0

7

29.7

6

56.3

3

0

7

92.4

1

0

7

0.1

7

AE: adverse events; FAEs: fumaric acid esters; PGA: Physician Global Assessment; QoL: Specific quality of life scale; SAE: serious adverse events

Anti‐IL17 class had a better chance of reaching PASI 90 using SUCRA (versus placebo: RR 30.30, 95% CI 24.43 to 37.57; SUCRA = 99.9), followed by anti‐IL23 (versus placebo: RR 23.96, 95% CI 19.35 to 29.68; SUCRA = 82.9), anti‐IL12/23 (versus placebo: RR 19.82, 95% CI 15.77 to 24.92; SUCRA = 67.2), then anti‐TNF alpha (versus placebo: RR 13.69, 95% CI 11.24 to 16.68; SUCRA = 49.8). The heterogeneity τ for this network overall was 0.05, which we considered to be low.

Ranking drug‐level analysis (Figure 11; Figure 15; Table 5)

Open in table viewer
Table 5. Ranking findings for all outcomes at drug level

Drug

SUCRA
PASI 90

Rank
PASI 90

SUCRA
SAE

Rank
SAE

SUCRA

SAE

excluded

flare of psoriasis

Rank

SAE

excluded

flare of psoriasis

SUCRA
PASI 75

Rank
PASI 75

SUCRA
AE

Rank
AE

SUCRA
PGA

Rank
PGA

SUCRA
QoL

Rank
QoL

Infliximab

93.6

1

29.3

20

56.6

7

94.8

1

33.7

15

83.6

2

65.7

6

Ixekizumab

90.5

2

29.8

19

39.3

17

90.3

2

34.4

13

87.9

1

91.7

2

Risankizumab

84.6

3

68.1

3

75

2

84.2

3

71.9

6

81

4

95.3

1

Bimekizumab

81.4

4

83

2

83.3

1

79.8

4

4.7

20

74.2

6

Secukinumab

76.2

5

34.8

17

34.3

18

77.2

5

35.9

12

81

3

69.9

4

Guselkumab

75

6

44.4

12

39.5

16

73.1

6

75.3

5

61.4

8

59.2

7

Brodalumab

68.4

7

34.3

18

42.7

14

72.5

7

44.7

11

78.8

5

12.7

13

Tildrakizumab

56.5

8

52.7

9

22.4

19

58.7

9

95.2

1

46.5

12

69.5

5

Ustekinumab

56.1

9

46.5

11

43.7

13

60.8

8

60.6

8

57.8

9

73.5

3

Adalimumab

52.9

10

36.9

15

41.7

15

52.2

11

68.8

7

43.6

13

36.3

12

Tyrosine kinase 2 inhibitor

48.2

11

59.7

5

63.6

4

45.7

13

21.3

18

46.7

11

Certolizumab

41.4

12

58.8

6

16.2

20

49.6

2

78.2

3

52.4

10

37.5

11

Mirikizumab

34.1

3

62.5

4

67.1

3

55.7

10

78.2

4

67.7

7

Etanercept

33.1

4

53.7

8

48.3

12

38.9

14

53.1

10

32.3

15

42.3

9

Ciclosporin

26.5

15

35.4

16

51.5

9

24.2

16

22.7

17

30.1

16

Methotrexate

25.6

16

83.8

1

51.4

10

15.3

18

60.5

9

33.7

14

44.1

8

Tofacitinib

24.2

17

42.4

13

57.8

6

31.1

15

34

14

20.6

17

42.1

10

Apremilast

21.1

18

51.3

10

62

5

22

17

15.7

19

13

18

10.1

14

FAEs

10.4

19

55.4

7

50.9

11

9.6

20

25.6

16

7.8

19

Placebo

0.1

20

37.1

14

52.5

8

1.4

21

85.4

2

0

20

0.2

15

Acitretine

12.8

19

AE: adverse events; FAEs: fumaric acid esters; PASI: Psoriasis Area and Severity Index; PGA: Physician Global Assessment; QoL: specific quality of life scale; SAE: serious adverse events; SUCRA: Surface Under the Cumulative Ranking

At drug‐level, using SUCRA, infliximab had a better chance of reaching PASI 90 at drug level (versus placebo: RR 50.29, 95% CI 20.96 to 120.67; SUCRA = 93.6; high‐certainty evidence), followed by ixekizumab (versus placebo: RR 32.48, 95% CI 27.13 to 38.87; SUCRA = 90.5; high‐certainty evidence), risankizumab (versus placebo: RR 28.76, 95% CI 23.96 to 34.54; SUCRA = 84.6; high‐certainty evidence), bimekizumab (versus placebo: RR 58.64, 95% CI 3.72 to 923.86; SUCRA = 81.4; high‐certainty evidence), secukinumab (versus placebo: RR 25.79, 95% CI 21.61 to 30.78; SUCRA = 76.2; high‐certainty evidence), guselkumab (versus placebo: RR 25.52, 95% CI 21.25 to 30.64; SUCRA = 75; high‐certainty evidence), then brodalumab (versus placebo: RR 23.55, 95% CI 19.48 to 28.48; SUCRA = 68.4; moderate‐certainty evidence). The heterogeneity τ for this network overall was 0, which we considered to be low.

1.2 The proportion of participants with serious adverse events
DIRECT EVIDENCE

We report treatment estimates for pair‐wise meta‐analyses at class and drug level in Analysis 2.1; Analysis 2.2; Analysis 2.3; Analysis 2.4; Analysis 2.5; Analysis 2.6; Analysis 2.7; Analysis 2.8; Analysis 2.9; and Analysis 2.10, respectively.

We found no significant differences between FAEs, etanercept, adalimumab, certolizumab, ustekinumab, secukinumab, ixekizumab, brodalumab, bimekizumab, guselkumab, tildrakizumab, risankizumab, mirikizumab, apremilast, tofacitinib, oral tyrosine kinase 2 (TYK2) inhibitor, and placebo in the number of participants with serious adverse events (SAEs). The risk of SAEs was significantly lower for participants on methotrexate compared to placebo (RR 0.16, 95% CI 0.03 to 0.88). The risk of SAEs was significantly higher for participants on infliximab compared to methotrexate (RR 2.41, 95% CI 1.04 to 5.59).

There were zero SAEs in the following trials: Fallah Arani 2011 (comparing methotrexate with FAEs); Flytström 2008 (comparing ciclosporin with methotrexate); Heydendael 2003 (comparing ciclosporin with methotrexate); Gisondi 2008; (comparing etanercept with acitretin); Bagel 2012 (comparing etanercept with placebo); Caproni 2009 (comparing etanercept with acitretin); Chaudhari 2001 (comparing inflixizimab with placebo); Jin 2017 (comparing tofacitinib with placebo); Yu 2019 (comparing etanercept with methotrexate); and Hunter 1963 (comparing methotrexate with placebo).

NETWORK META‐ANALYSES

The SAE outcome was available in 114 trials, involving 47,754 participants (95.4% of the participants in the meta‐analysis). For one trial (PRESTA 2010); the number of randomised participants was not available. We added this trial to the complete‐cases sensitivity analyses. This outcome was reported in eight trials out of 114 (Asahina 2016; Bissonnette 2015; Khatri 2016; Laburte 1994; SCULPTURE 2015; Ortonne 2013; PRISTINE 2013; PRESTA 2010), comparing different dosages of the same drug in each case. We added these studies to the sensitivity analysis at dose level. This outcome was reported in 10 trials out of 114 with biological‐naïve participants and were added to the sensitivity analysis for all trials, whatever previous treatments received by the participants (Barker 2011; Caproni 2009; Gisondi 2008; Lee 2016; NCT03255382; NCT03331835; Reich 2020; CHAMPION 2008; PRIME 2017; POLARIS 2020). Sixty‐nine trials, involving 23,337 participants, were placebo‐controlled trials; 23, involving 7885 participants, were head‐to‐head comparisons, and 22, involving 16,532 participants, had both a placebo and at least two active treatments arms.

SAEs were not reported for the 16 remaining trials, and we were not able to obtain missing information from the trial authors (Table 2).

See Figure 4; Figure 5; Figure 6; Figure 7; Figure 10; Figure 11; Figure 14; Figure 15.

Table 6 summarises the main results of both direct and indirect evidence and the network meta‐analysis for SAEs. We present the summary relative effects from the network meta‐analysis in league tables for both class‐level (Figure 6) and drug‐level (Figure 7) analyses. We found no significant difference between any of the interventions and the placebo for the risk of SAE. This result was verified after excluding flares of psoriasis as SAEs (Figure 6). We assessed the certainty of evidence for each comparison using CINeMA and classified as high (highlighted in green), moderate (in blue), low (in yellow) and very‐low (in red) (Figure 7).

Open in table viewer
Table 6. Direct and indirect evidence and network meta‐analysis results summary table for serious adverse events

Network meta‐analysis

Direct evidence

Indirect evidence

Comparisons*

RR

LCI

UCI

RR

LCI

UCI

RR

LCI

UCI

Adalimumab versus placebo

1.01

0.66

1.56

1.19

0.74

1.92

0.57

0.23

1.42

Apremilast versus placebo

0.86

0.49

1.52

0.86

0.47

1.56

1.00

0.04

26.68

Bimekizumab versus placebo

0.20

0.01

3.20

Brodalumab versus placebo

1.05

0.62

1.79

0.93

0.52

1.67

2.66

0.39

18.12

Certolizumab versus placebo

0.75

0.30

1.84

0.62

0.25

1.54

33.70

0.52

2180.73

Ciclosporin versus placebo

1.28

0.15

11.01

5.69

0.32

101.52

0.19

0.01

4.90

Etanercept versus placebo

0.85

0.58

1.26

0.72

0.45

1.14

1.36

0.63

2.93

Fumaric ester acids versus placebo

0.78

0.29

2.09

0.83

0.30

2.28

0.28

0.00

19.72

Guselkumab versus placebo

0.94

0.55

1.59

1.04

0.48

2.23

0.84

0.37

1.92

Infliximab versus placebo

1.16

0.56

2.39

1.20

0.56

2.54

0.78

0.05

12.25

Ixekizumab versus placebo

1.10

0.69

1.74

1.08

0.58

2.01

1.13

0.49

2.62

Mirikizumab versus placebo

0.65

0.17

2.51

Methotrexate versus placebo

0.33

0.07

1.59

0.14

0.02

0.94

2.22

0.13

37.63

Risankizumab versus placebo

0.71

0.45

1.13

0.45

0.23

0.89

1.04

0.56

1.95

Secukinumab versus placebo

1.03

0.70

1.52

1.10

0.67

1.81

0.93

0.49

1.77

Tildrakizumab versus placebo

0.83

0.37

1.86

0.99

0.37

2.60

0.46

0.06

3.68

Tofacitinib versus placebo

0.96

0.54

1.71

1.07

0.55

2.09

0.48

0.06

Ustekinumab versus placebo

0.92

0.64

1.33

0.98

0.60

1.59

0.84

0.47

Guselkumab versus adalimumab

0.93

0.53

1.63

0.91

0.44

1.89

0.95

0.37

2.43

Risankizumab versus adalimumab

0.70

0.40

1.22

1.12

0.46

2.75

0.54

0.27

1.06

Etanercept versus apremilast

0.99

0.51

1.92

0.68

0.14

3.40

1.07

0.52

2.22

Ustekinumab versus brodalumab

0.87

0.49

1.57

0.75

0.32

1.75

1.07

0.39

2.88

Etanercept versus certolizumab

1.14

0.43

3.02

2.28

0.33

15.76

0.81

0.23

2.90

Methotrexate versus Ciclosporin

0.26

0.03

2.18

1.02

0.06

16.18

0.03

0.00

0.98

Infliximab versus Etanercept

1.36

0.60

3.05

0.92

0.06

14.05

1.41

0.60

3.31

Ixekizumab versus Etanercept

1.28

0.77

2.13

1.03

0.53

2.03

1.72

0.78

3.79

Secukinumab versus Etanercept

1.21

0.72

2.03

1.60

0.47

5.47

1.13

0.63

2.03

Tildrakizumab versus Etanercept

0.97

0.43

2.18

0.70

0.26

1.89

1.94

0.45

8.28

Todacitinib versus Etanercept

1.12

0.60

2.10

0.87

0.33

2.30

1.37

0.59

3.18

Ustekinumab versus Etanercept

1.08

0.65

1.78

1.25

0.37

4.25

1.05

0.60

1.82

Methotrexate versus Fumaric ester acids

0.42

0.07

2.48

1.00

0.02

49.21

0.34

0.05

2.46

Ixekizumab versus guselkumab

1.17

0.67

2.04

1.20

0.54

2.64

1.13

0.49

2.62

Ustekinumab versus Ixekizumab

0.84

0.47

1.49

0.16

0.01

3.42

0.89

0.50

1.60

Secukinumab versus Risankizumab

1.45

0.86

2.45

0.67

0.24

1.84

1.89

1.05

3.41

Ustekinumab versus Risankizumab

1.29

0.80

2.10

1.82

0.92

3.60

0.93

0.47

1.82

Ustekinumab versus secukinumab

0.89

0.58

1.37

0.79

0.42

1.49

0.99

0.55

1.79

FAES: fumaric acid esters; LCI: low confidence interval; RR: risk ratio; UCI: upper confidence interval

*The comparisons listed in this table were included in at least one direct‐evidence analysis.

Ranking class‐level analysis (Figure 10; Figure 14; Table 4)

Anti‐IL23 had the highest SUCRA at class level in terms of serious adverse events (versus placebo: RR 0.78, 95% CI 0.58 to 1.06; SUCRA = 77.7), followed by non‐biological systemic treatments (versus placebo: RR 0.69, 95% CI 0.30 to 1.58; SUCRA = 74.2), anti‐TNF (versus placebo: RR 0.91, 95% CI 0.71 to 1.17; SUCRA = 51.5), and then small molecules (versus placebo: RR 0.91, 95% CI 0.62 to 1.34; SUCRA = 50.4). The heterogeneity τ for this network overall was 0, which we considered to be low.

Ranking drug‐level analysis (Figure 11; Figure 15; Table 5)

Methotrexate had the highest SUCRA at drug level in terms of serious adverse events (versus placebo: RR 0.33, 95% CI 0.07 to 1.59; SUCRA = 83.8; low‐certainty evidence), followed by bimekizumab (versus placebo: RR 0.20, 95% CI 0.01 to 3.20; SUCRA = 83; moderate‐certainty evidence), risankizumab (versus placebo: RR 0.71, 95% CI 0.45 to 1.13; SUCRA = 68.1; moderate‐certainty evidence), mirikizumab (versus placebo: RR 0.65, 95% CI 0.17 to 2.51; SUCRA = 62.5; moderate‐certainty evidence), and oral tyrosine kinase 2 inhibitor (versus placebo: RR 0.61, 95% CI 0.06 to 5.79; SUCRA = 59.7; moderate‐certainty evidence). However, no significant difference was observed between drugs and placebo. The heterogeneity τ for this network overall was 0.02, which we considered to be low. After excluding worsening of psoriasis as a SAE, ranking analysis was quite similar except for methotrexate which dropped from the 1st to the 10th rank. At the opposite end, placebo rose from the 14th to the 8th rank.

1.3 Relationship between PASI 90 and serious adverse events

See Figure 13.

These findings for both efficacy (PASI 90) and acceptability (serious adverse events) were combined together in a bivariate ranking plot, where serious adverse events were transformed into acceptability by using the inverse values of the corresponding RRs so that higher values indicate higher acceptability (due to lower SAEs): accordingly, the ideal treatment (highest performance = best efficacy + best acceptability) should appear in the upper right corner of the plot.

At class level, the highly‐effective treatment (anti‐IL17) had serious adverse events. However, the anti‐IL23 treatment group was the class with the better compromise between efficacy and acceptability.

At drug level, risankizumab and bimekizumab might be the overall best treatments, considering both outcomes jointly. This result has to be considered with caution for bimekizumab, as only one trial was available for this drug.

2. Secondary outcomes

2.1 Proportion of participants who achieve PASI 75
DIRECT EVIDENCE

We report treatment estimates for pair‐wise meta‐analyses at class and drug level in Analysis 3.1; Analysis 3.2; Analysis 3.3; Analysis 3.4; Analysis 3.5; Analysis 3.6; Analysis 3.7; Analysis 3.8; Analysis 3.9; and Analysis 3.10, respectively.

NETWORK META‐ANALYSES

PASI 75 outcome was available in 119 trials, involving 48,224 participants (96.3% of the participants in this review). For one trial (PRESTA 2010), the number of randomised participants was not available. We added these trials to the complete‐case analyses. This outcome was reported in 12 trials out of 119 (Asahina 2016; Bissonnette 2015; Dogra 2012; Dogra 2013; Dubertret 1989; Khatri 2016; Laburte 1994; SCULPTURE 2015; SIGNATURE 2019; Ortonne 2013; PRISTINE 2013; PRESTA 2010), comparing different dosages of the same drug in each case. We added these trials to the sensitivity analysis at dose level. This outcome was reported in 10 trials out of 119 with biological‐naïve participants and were added to the sensitivity analysis for all trials, whatever the previous treatments received by the participants (Barker 2011; Caproni 2009; Gisondi 2008; Lee 2016; NCT03255382; NCT03331835; Reich 2020; CHAMPION 2008; PRIME 2017; POLARIS 2020). Seventy‐two trials, involving 24,502 participants, were placebo‐controlled trials; 25 trials, involving 7190 participants, were head‐to‐head comparisons; and 22 trials, involving 16,532 participants, had both a placebo and at least two active treatments arms. PASI 75 was not reported for the 11 remaining trials, and we were not able to obtain missing information from the trial authors (Table 2).

See Figure 4; Figure 5; Figure 6; Figure 8; Figure 10; Figure 12; Figure 14; Figure 15

We present the summary relative effects from the network meta‐analysis in league tables for both class‐level (Figure 6) and drug‐level (Figure 8) analyses. All of the interventions appeared superior to placebo in terms of reaching PASI 75. At class level, the anti‐IL17 class of drugs was associated with a higher chance of reaching PASI 75 compared to the other classes, except for anti‐IL23 (Figure 6). All of the interventions (anti‐IL17, anti‐IL23, anti‐IL12/23, anti‐TNF alpha) appeared significantly superior to the small molecule class and the non‐biological systemic class, and the small molecules appeared significantly superior to the non‐biological systemic agents. Results of comparisons between each of the drugs are available in Figure 8.

Ranking class‐level analysis (Figure 10; Figure 14; Table 4)

Ranking analysis performed with SUCRA strongly suggested that anti‐IL17 had a better chance of reaching PASI 75 at class level (versus placebo: RR 14.11, 95% CI 12.31 to 16.17; SUCRA = 99.9), followed by anti‐IL23 (versus placebo: RR 12.33, 95% CI 10.78 to 14.11; SUCRA = 82.9), anti‐IL12/23 (versus placebo: RR 11.52, 95% CI 10.03 to 13.24; SUCRA = 67.2), then anti‐TNF alpha (versus placebo: RR 9.01 95% CI 8.02 to 10.12; SUCRA = 49.8). The heterogeneity τ for this network overall was 0.03, which we considered to be low.

Ranking drug‐level analysis (Figure 12; Figure 15; Table 5)

Ranking analysis performed with SUCRA strongly suggested that infliximab had the higher chance of reaching PASI 75 at drug level (versus placebo: RR 18.02, 95% CI 11.92 to 27.22; SUCRA = 94.8), followed by ixekizumab (versus placebo: RR 14.54, 95% CI 12.59 to 16.79; SUCRA = 90.3), risankizumab (versus placebo: RR 13.44, 95% CI 11.87 to 15.22; SUCRA = 84.2), bimekizumab (versus placebo: RR 17.06, 95% CI 4.38 to 66.49; SUCRA = 79.8), then secukinumab (versus placebo: RR 12.71, 95% CI 11.12 to 14.52; SUCRA = 77.2). The heterogeneity τ for this network overall was 0, which we considered to be low.

2.2 Proportion of participants who achieve a Physician Global Assessment (PGA) value of 0 or 1
DIRECT EVIDENCE

We report treatment estimates for pair‐wise meta‐analyses at class and drug level in Analysis 4.1; Analysis 4.2; Analysis 4.3; Analysis 4.4; Analysis 4.5; Analysis 4.6; Analysis 4.7; Analysis 4.8; Analysis 4.9; and Analysis 4.10, respectively.

NETWORK META‐ANALYSES

The PGA 0/1 outcome was available in 104 trials, involving 46,091 participants (92.0% of the participants in this review). For three other studies (Nugteren‐Huying 1990; Sandhu 2003; PRESTA 2010), the number of randomised participants was not available. We added these trials to the complete‐case analyses. This outcome was reported in seven trials out of 104 (Asahina 2016; Bissonnette 2015; Khatri 2016; SCULPTURE 2015; Ortonne 2013; PRISTINE 2013; PRESTA 2010), comparing different dosages of the same drug. We added these trials to the sensitivity analysis at dose level. This outcome was reported in 10 trials out of 104 with biological‐naïve participants and were added to the sensitivity analysis for all trials, whatever the previous treatments received by the participants (Barker 2011; Caproni 2009; Gisondi 2008; Lee 2016; NCT03255382; NCT03331835; Reich 2020; CHAMPION 2008; PRIME 2017; POLARIS 2020). Sixty‐three trials, involving 22,218 participants, were placebo‐controlled trials; 19 trials, involving 7341 participants, were head‐to‐head comparisons; and 22 trials, involving 16,532 participants, had both a placebo and at least two active treatments arms. PGA 0/1 was not reported for the 26 remaining trials, and we were not able to obtain missing information from the trial authors (Table 2).

See Figure 4; Figure 5; Figure 6; Figure 9; Figure 10; Figure 12; Figure 14; Figure 15.

We present the summary relative effects as estimated from the network meta‐analysis in league tables at class level (Figure 6) and drug level (Figure 9). At class level, all of the interventions appeared superior to placebo in terms of reaching PGA 0/1, and anti‐IL17 monoclonal antibodies were associated with a better chance for this outcome compared to the other drug classes (Figure 6). These differences were statistically significant. All of the interventions (anti‐IL17, anti‐IL23, anti‐IL12/23, anti‐TNF alpha) appeared significantly superior to the small molecule and the non‐biological systemic class of treatments. We found no significant difference between small molecule and non‐biological systemic agents. Results of comparisons between each of the drugs are available in Figure 9.

Ranking class‐level analysis (Figure 10; Figure 14; Table 4)

Ranking analysis performed with SUCRA strongly suggested that anti‐IL17 had a better chance of reaching PGA0/1 at class level (versus placebo: RR 15.33, 95% CI 12.93 to 18.18; SUCRA = 99.9), followed by anti‐IL23 (versus placebo: RR 12.15, 95% CI 10.32 to 14.32; SUCRA = 81.8), anti‐IL12/23 (versus placebo: RR 10.82, 95% CI 9.11 to 12.84; SUCRA = 68.3), then anti‐TNF alpha (versus placebo: RR 8.39, 95% CI 7.42 to 9.72; SUCRA = 50). The heterogeneity τ for this network overall was 0.5, which we considered to be low.

Ranking drug‐level analysis (Figure 12; Figure 15; Table 5)

Ranking analysis performed with SUCRA strongly suggested that ixekizumab had a better chance of reaching PGA0/1 at drug level (versus placebo: RR 15.38, 95% CI 12.60 to 18.77; SUCRA = 87.9), followed by infliximab (versus placebo: RR 15.34, 95% CI 9.22 to 25.54; SUCRA = 83.6), secukinumab (versus placebo: RR 14.17, 95% CI 11.44 to 17.56; SUCRA = 81), risankizumab (versus placebo: RR 14.17, 95% CI 11.71 to 17.13; SUCRA = 81), brodalumab (versus placebo: RR 13.84, 95% CI 10.49 to 18.26; SUCRA =78.8), then bimekizumab (versus placebo: RR 15.35, 95% CI 3.82 to 61.69; SUCRA = 74.2). The heterogeneity τ for this network overall was 0.03, which we considered to be low.

Focusing on efficacy outcomes (PASI 90, PASI 75, and PGA 0/1), the results were similar at class level (Figure 10; Table 4) and at drug level (Figure 11; Figure 12; Table 5).

2.3 Mean difference of quality of life measured by a specific scale
DIRECT EVIDENCE

We report treatment estimates for pair‐wise meta‐analyses at class and drug level in Analysis 5.1; Analysis 5.2; Analysis 5.3; Analysis 5.4; Analysis 5.5; Analysis 5.6; Analysis 5.7; Analysis 5.8; Analysis 5.9; and Analysis 5.10, respectively.

NETWORK META‐ANALYSES

The quality‐of‐life outcome was available in 68 trials, involving 30,619 participants (61.1% of the participants in this review). This outcome was also reported in seven trials (out of 68) (Asahina 2016; Bissonnette 2015; Khatri 2016; SCULPTURE 2015; SIGNATURE 2019; Ortonne 2013; PRISTINE 2013), comparing different dosages of the same drug. We added these trials to the sensitivity analyses at dose level. This outcome was reported in 10 trials out of 68 with biological‐naïve participants and were added to the sensitivity analysis for all trials, whatever the previous treatments received by the participants (Barker 2011; Caproni 2009; Gisondi 2008; Lee 2016; NCT03255382; NCT03331835; Reich 2020; CHAMPION 2008; PRIME 2017; POLARIS 2020). The quality‐of‐life outcome was not reported for the 62 remaining trials, and we were not able to obtain missing information from the trial authors (Table 2). Forty‐one trials, involving 16,663 participants, were placebo‐controlled trials; 13, involving 3986 participants, were head‐to‐head comparisons; and 14, involving 9970 participants, had both a placebo and at least two active treatments arms.

See Figure 4; Figure 5; Figure 6; Figure 9; Figure 10; Figure 12; Figure 14; Figure 15.

We present the summary relative effects from the network meta‐analysis in league tables for both class‐level (Figure 6) and drug‐level (Figure 9) analyses. All classes of treatments appeared superior to placebo in terms of showing significant improvement on a quality‐of‐life scale. Anti‐IL23, anti‐IL12/23, anti‐IL17 and anti‐TNF agents were associated with a higher chance of improving quality of life compared to small molecules (Figure 6). These differences were statistically significant for all of the classes. No significant difference was shown between the different biological agents except for anti‐IL23 and anti‐TNF alpha (anti‐IL23 was more favourable than anti‐TNF alpha). There were no significant differences between the small molecules and the non‐biological agents. Results of comparisons between each of the drugs are available in Figure 9.

Ranking class‐level analysis (Figure 10; Figure 14Table 4)

Ranking analysis performed with SUCRA strongly suggested that anti‐IL23 had a better chance of improving quality of life at class level (versus placebo: standardised mean difference (SMD) −1.41, 95% confidence interval (CI) −1.64 to −1.17; SUCRA = 85.5), followed by anti‐IL12/23 (versus placebo: SMD −1.33, 95% CI −1.61 to −1.06; SUCRA = 75.8), and anti‐IL17 (versus placebo: SMD −1.31, 95% CI −1.61 to −1.01; SUCRA = 73.4). The heterogeneity τ for this network overall was 0.13, which we considered to be low.

Ranking drug‐level analysis (Figure 12; Figure 15Table 5)

Ranking analysis for quality of life performed with SUCRA strongly suggested that risankizumab was the best treatment at drug level (versus placebo: SMD −1.77, 95% CI −2.14 to −1.40; SUCRA = 95.3), followed by ixekizumab (versus placebo: SMD −1.67, 95% CI −1.97 to −1.38; SUCRA = 91.7), ustekinumab (versus placebo: SMD −1.39, 95% CI −1.61 to −1.17; SUCRA = 73.5), secukinumab (versus placebo: SMD −1.41, 95% CI −2.11 to −0.70; SUCRA = 69.9), then tildrakizumab (versus placebo: SMD −1.35, 95% CI −1.67 to −1.03; SUCRA = 69.5). The heterogeneity τ for this network overall was 0.07, which we considered to be low. Moreover, five interventions (acitretin, ciclosporin, oral tyrosine kinase 2 inhibitor, bimekizumab and mirikizumab) were not included in the ranking at drug level, due to no available data.

In total, information on quality of life was poorly reported and lacking for almost half of the population included in the NMA, so has to be considered with caution.

2.4 The proportions of participants with adverse events
DIRECT EVIDENCE

We report treatment estimates for pair‐wise meta‐analyses at class and drug level in Analysis 6.1; Analysis 6.2; Analysis 6.3; Analysis 6.4; Analysis 6.5; Analysis 6.6; Analysis 6.7; Analysis 6.8; Analysis 6.9; and Analysis 6.10 respectively.

NETWORK META‐ANALYSES

Adverse events (AEs) outcome was available in 105 trials, involving 45,677 participants (91.2% of the participants in this review). AEs were not reported for the 25 remaining trials, and we were not able to obtain missing information from the trial authors (Table 2). This outcome was also reported in six trials (Asahina 2016; Bissonnette 2015; Khatri 2016; SCULPTURE 2015; Ortonne 2013; PRISTINE 2013), comparing different dosages of the same drug, and were added to the sensitivity analyses at dose level. This outcome was reported in 10 trials out of 105 with biological‐naïve participants and were added to the sensitivity analysis for all trials, whatever the previous treatments received by the participants (Barker 2011; Caproni 2009; Gisondi 2008; Lee 2016; NCT03255382; NCT03331835; Reich 2020; CHAMPION 2008; PRIME 2017; POLARIS 2020). Sixty‐three trials, involving 22,325 participants, were placebo‐controlled trials; 20, involving 6820 participants, were head‐to‐head comparisons; and 22, involving 16,532 participants, had both a placebo and at least two active treatments arms.

See Figure 4; Figure 5; Figure 6; Figure 8; Figure 10; Figure 12; Figure 14; Figure 15

We present the summary relative effects from the network meta‐analysis in league tables for both class‐level (Figure 6) and drug‐level (Figure 8) analyses. At class level, all of the classes of treatments had a more significant risk of AEs compared to placebo, except anti‐IL23. Significant associations were found: anti‐IL17 had a higher risk of AEs compared with anti‐IL23 and anti‐IL12/23; anti‐IL23 also had a lower risk of AEs compared with anti‐TNF and small molecules (Figure 6). Results of comparisons between each of the drugs are available in Figure 8.

Ranking class‐level analysis (Figure 10; Figure 14Table 4)

Placebo had the highest SUCRA (SUCRA 92.4) at class‐level for all adverse events, followed by anti‐IL23 (versus placebo: RR 1.01, 95% CI 0.95 to 1.07; SUCRA = 88.3), anti‐IL12/23 (versus placebo: RR 1.07, 95% CI 1.01 to 1.14; SUCRA = 57.5), then anti‐TNF agents (versus placebo: RR 1.08, 95% CI 1.03 to 1.13; SUCRA = 52.6). The heterogeneity τ for this network overall was 0.01, which we considered to be low.

Ranking drug‐level analysis (Figure 12; Figure 15; Table 5)

Tildrakizumab had the highest SUCRA at drug‐level for all adverse events (versus placebo: RR 0.93, 95% CI 0.82 to 1.04; SUCRA = 95.2), followed by placebo (SUCRA = 85.4), certolizumab (versus placebo: RR 1.01, 95% CI 0.89 to 1.15; SUCRA = 78.2), then mirikizumab (versus placebo: RR 0.99, 95% CI 0.81 to 1.22; SUCRA = 78.2). The heterogeneity τ for this network overall was 0, which we considered to be low.

2.5. Proportion of participants who achieve PASI 90 at 52 weeks
DIRECT EVIDENCE

We report treatment estimates for pair‐wise meta‐analyses at drug level in Analysis 7.1; Analysis 7.2; and Analysis 7.3.

Eight head‐to‐head comparisons compared two different biologics; three compared two different dosages of secukinumab, guselkumab, and apremilast respectively; and one compared a biologic with placebo. We produced one meta‐analysis for the comparison risankizumab versus ustekinumab. For reaching PASI 90 at 52 weeks, risankizumab was more effective than ustekinumab (RR 1.73, 95% CI 1.46 to 2.05). Secukinumab was more effective than ustekinumab to reach PASI 90 at 52 weeks (RR 1.23, 95% CI 1.15 to 1.31); guselkumab was more effective than adalimumab to reach PASI 90 at 52 weeks (RR 1.59, 95% CI 1.40 to 1.81); ixekizumab every other week was more effective than ixekizumab every four weeks to reach PASI 90 at 52 weeks (RR 1.06, 95% CI 1.01 to 1.11); guselkumab was more effective than secukinumab to reach PASI 90 at 52 weeks (RR 0.83, 95% CI 0.78 to 0.89); risankizumab was more effective than secukinumab to reach PASI 90 at 52 weeks (RR 1.52, 95% CI 1.31 to 1.76); and ixekizumab was more effective than ustekinumab to reach PASI 90 at 52 weeks (RR 1.30, 95% CI 1.11 to 1.52; 1 study).

2.6. Proportion of participants who achieve PASI 75 at 52 weeks
DIRECT EVIDENCE

We report treatment estimates for pair‐wise meta‐analyses at drug level in Analysis 8.1; and Analysis 8.2.

Eight head‐to‐head comparisons compared two different biologics; four compared two different dosages of secukinumab, guselkumab, apremilast and tofacitinib respectively. We produced one meta‐analysis for the comparison risankizumab versus ustekinumab. For reaching PASI 75 at 52 weeks, risankizumab was more effective than ustekinumab (RR 1.26, 95% CI 1.12 to 1.41). Secukinumab was more effective than ustekinumab to reach PASI 75 at 52 weeks (RR 1.13, 95%CI 1.04 to 1.22); guselkumab was more effective than adalimumab to reach PASI 75 at 52 weeks (RR 1.40, 95% CI 1.28 to 1.54); ixekizumab every other week was more effective than ixekizumab every four weeks to reach PASI 75 at 52 weeks (RR 1.14, 95% CI 1.07 to 1.22); secukinumab was more effective than guselkumab to reach PASI 75 at 52 weeks (RR 1.14, 95% CI 1.08 to 1.21); risankizumab was more effective than secukinumab to reach PASI 75 at 52 weeks (RR 1.28, 95% CI 1.14 to 1.44); and ixekizumab was more effective than ustekinumab to reach PASI 75 at 52 weeks (RR 1.16, 95% CI 1.05 to 1.29).

We did not conduct network meta‐analyses, given the low number of studies for this outcome.

3. Assessment of heterogeneity and inconsistency

We did not identify important heterogeneity either in direct meta‐analyses or in network meta‐analysis. The common outcome‐specified network heterogeneity and the prediction intervals suggested the presence of low heterogeneity for all outcomes. We investigated differences in heterogeneity between class‐ and drug‐level analysis, and we also investigated differences in heterogeneity between primary and sensitivity analyses for the primary outcomes (see: 4. subgroup and sensitivity analyses). The results were very similar.

The distribution of some participant characteristics (age, sex ratio, weight, severity of psoriasis) did not give an indication of important differences in these characteristics across comparisons (see Figure 16; Figure 17).


Distributions of age (on the left, mean age in years in the y axis) and PASI score at baseline (on the right, mean PASI in the y axis) ratio of participants across comparisons (x axis) ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumab

Distributions of age (on the left, mean age in years in the y axis) and PASI score at baseline (on the right, mean PASI in the y axis) ratio of participants across comparisons (x axis)

ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumab


Distributions of sex (on the left, percentage of males in the y axis) and weight (on the right, mean weight in kilograms in the y axis) of participants across comparisons (x axis) ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumab

Distributions of sex (on the left, percentage of males in the y axis) and weight (on the right, mean weight in kilograms in the y axis) of participants across comparisons (x axis)

ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumab

At drug‐level analysis, the global test for inconsistency was not significant for any of the outcomes. We detail results of a global test for inconsistency at drug level in Figure 18 and Figure 19 for PASI 90 and SAEs, respectively. The loop‐specific and side‐splitting approaches did not indicate inconsistency for the two primary outcomes (Figure 20; Figure 21). There are a handful of loops and comparisons with statistically significant inconsistency for secondary outcomes (PASI 75 and adverse events), but it does not exceed the expected level of inconsistency that has been suggested by empirical evidence (Veroniki 2013), which is about 10% of the total number of loops.


Side‐splitting approach and design‐by‐treatment interaction model for inconsistency for Psoriasis Area and Severity Index (PASI) 90 ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumab

Side‐splitting approach and design‐by‐treatment interaction model for inconsistency for Psoriasis Area and Severity Index (PASI) 90

ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumab


Side‐splitting approach and design‐by‐treatment interaction model for inconsistency for serious adverse events (SAEs) ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumab

Side‐splitting approach and design‐by‐treatment interaction model for inconsistency for serious adverse events (SAEs)

ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumab


Inconsistency plots for all the outcomes at class level Inconsistency factor (IF) is calculated as the risk ratio (RR)/standardised mean difference (SMD) for direct evidence over the RR/SMD for indirect evidence in the loop with its 95% confidence interval (CI). IF value close to 0 indicates the absence of evidence for disagreement between direct and indirect evidence.AIL12/23: anti‐IL12/23; AIL17: anti‐IL17; AIL23: anti‐IL23, ATA: anti‐TNF alpha; CSA: non‐biological conventional systemic agents; PBO: placebo; SM: small molecules

Inconsistency plots for all the outcomes at class level

Inconsistency factor (IF) is calculated as the risk ratio (RR)/standardised mean difference (SMD) for direct evidence over the RR/SMD for indirect evidence in the loop with its 95% confidence interval (CI). IF value close to 0 indicates the absence of evidence for disagreement between direct and indirect evidence.

AIL12/23: anti‐IL12/23; AIL17: anti‐IL17; AIL23: anti‐IL23, ATA: anti‐TNF alpha; CSA: non‐biological conventional systemic agents; PBO: placebo; SM: small molecules


Inconsistency plots for all the outcomes at drug level Inconsistency factor (IF) is calculated as the risk ratio (RR)/standardised mean difference (SMD) for direct evidence over the RR/SMD for indirect evidence in the loop with its 95% confidence interval (CI). IF value close to 0 indicates the absence of evidence for disagreement between direct and indirectACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumab

Inconsistency plots for all the outcomes at drug level

Inconsistency factor (IF) is calculated as the risk ratio (RR)/standardised mean difference (SMD) for direct evidence over the RR/SMD for indirect evidence in the loop with its 95% confidence interval (CI). IF value close to 0 indicates the absence of evidence for disagreement between direct and indirect

ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumab

4. Subgroup and sensitivity analyses

As we found no heterogeneity, we did not perform subgroup analyses. From a clinical point of view, it could nevertheless be interesting to have specific efficacy/safety data depending on participants' comorbidities or psoriasis characteristics. However, we did not have enough data for any of the aforementioned characteristics, and were therefore unable to run subgroup analyses and meta‐regressions to investigate their potential effects on the results.

Results of the sensitivity analyses involving the following were similar to those of the main analysis for the two primary outcomes:

  • excluding studies with fewer than 50 participants (Figure 22) (the heterogeneity τ for this subgroup network was 0 and 0.02 for PASI 90 and SAEs respectively, which we considered to be low);

  • completers (Figure 23) (the heterogeneity τ for this subgroup network was 0 and 0.02 for PASI 90 and SAEs respectively, which we considered to be low);

  • analyses at dose level splitting approved dosages versus other dosages for each drug (Figure 24) (the heterogeneity τ for this subgroup network was 0 for PASI 90 and SAEs, which we considered to be low);

  • excluding studies at high risk of bias (Figure 25) (the heterogeneity τ for this subgroup network was 0 for PASI 90 and 0.03 for SAEs, which we considered to be low);

  • analysing only the studies with a short‐term assessment from 8 to 16 weeks (Figure 26): the heterogeneity τ for this subgroup network was 0 for PASI 90 and 0.02 for SAEs, which we considered to be low.

  • analysing including trials with systemic‐treatment‐naïve participants (Figure 27): the heterogeneity τ for this subgroup network was 0 for PASI 90 and SAEs, which we considered to be low.


Sensitivity analyses ‐ Interval plot. Network meta‐analysis results for primary outcomes (PASI 90 and serious adverse events, left and right forest plot respectively) for trials with at least 50 participants. ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumabCI: confidence interval; PASI: Psoriasis Area and Severity Index; RR: risk ratio

Sensitivity analyses ‐ Interval plot. Network meta‐analysis results for primary outcomes (PASI 90 and serious adverse events, left and right forest plot respectively) for trials with at least 50 participants.

ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumab

CI: confidence interval; PASI: Psoriasis Area and Severity Index; RR: risk ratio


Sensitivity analyses ‐ Interval plot. Network meta‐analysis results for primary outcomes (PASI 90 and serious adverse events, left and right forest plot respectively) for the completers. Outcomes were measured at the induction phase (assessment from 8 to 24 weeks after randomisation).ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumabCI: confidence interval; PASI: Psoriasis Area and Severity Index; RR: risk ratio

Sensitivity analyses ‐ Interval plot. Network meta‐analysis results for primary outcomes (PASI 90 and serious adverse events, left and right forest plot respectively) for the completers.

Outcomes were measured at the induction phase (assessment from 8 to 24 weeks after randomisation).

ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumab

CI: confidence interval; PASI: Psoriasis Area and Severity Index; RR: risk ratio


Sensitivity analyses ‐ Interval plot. Network meta‐analysis results for primary outcomes (PASI 90 and serious adverse events, left and right forest plot respectively) for all the interventions depending on the doses: approved dosages versus other dosages Outcomes were measured at the induction phase (assessment from 8 to 24 weeks after randomisation).MTX_AMM/Other: methotrexate ≥ 15 mg per week/ < 15 mg per week; CICLO_AMM/Other: ciclosporin ≥ 3 mg/kg/day/<3 mg/kg/day; ACI_AMM/Other: acitretin ≥ 35 mg per day/<35 mg per day; FUM: fumaric acid esters all dosages; APRE_AMM/Other: apremilast 30 mg twice daily/other dosages; TOFA_AMM/Other: tofacitinib 20 mg per day/Other dosages; ETA_AMM/Other: etanercept 50 mg twice a week/Other dosage; IFX_AMM/Other: infliximab 5 mg/kg week 0, 2, 4 every 6 weeks/Other dosages; ADA_AMM/Other: adalimumab 80 mg Week 0, 40 mg Week 1 then 40 mg every other week/Other dosages; CERTO_AMM/Other: certolizumab 400 mg at week 0,2,4 then 400 mg every other week or other dosages/Other dosages; USK 45/90: ustekinumab 45/90 mg; SECU_AMM/Other: secukinumab 300 mg at week 0, 1, 2, 3, and 4 then every 4 weeks or other dosages/other dosages; IXE_AMM/Other: ixekizumab 160 mg at Week then 80 mg every other weeks until week 12 then 80 mg monthly or other dosages; TILDRA_AMM/Other: tildrakizumab 100 mg at week 0 and 4 then every 12 weeks/Other dosages; GUSEL 100: guselkumab 100 mg per injection; BRODA_AMM/Other: brodalumab 210 mg at week 0, 1, 2 then every other weeks/other dosages; RISAN_AMM/Other: risankizumab, S/C, 150 mg (two 75 mg injections) at Week 0, Week 4 and every 12 weeks thereafter/other dosages; TYK2 (Oral Tyrosine kinase 2 inhibitor), MIRI (mirikizumab) and BIME (bimekizumab) (S/C) were grouped in one dosage whatever the dosages.CI: confidence interval; PASI: Psoriasis Area and Severity Index; RR: risk ratio; AMM: 'approved dosage'

Sensitivity analyses ‐ Interval plot. Network meta‐analysis results for primary outcomes (PASI 90 and serious adverse events, left and right forest plot respectively) for all the interventions depending on the doses: approved dosages versus other dosages

Outcomes were measured at the induction phase (assessment from 8 to 24 weeks after randomisation).

MTX_AMM/Other: methotrexate ≥ 15 mg per week/ < 15 mg per week; CICLO_AMM/Other: ciclosporin ≥ 3 mg/kg/day/<3 mg/kg/day; ACI_AMM/Other: acitretin ≥ 35 mg per day/<35 mg per day; FUM: fumaric acid esters all dosages; APRE_AMM/Other: apremilast 30 mg twice daily/other dosages; TOFA_AMM/Other: tofacitinib 20 mg per day/Other dosages; ETA_AMM/Other: etanercept 50 mg twice a week/Other dosage; IFX_AMM/Other: infliximab 5 mg/kg week 0, 2, 4 every 6 weeks/Other dosages; ADA_AMM/Other: adalimumab 80 mg Week 0, 40 mg Week 1 then 40 mg every other week/Other dosages; CERTO_AMM/Other: certolizumab 400 mg at week 0,2,4 then 400 mg every other week or other dosages/Other dosages; USK 45/90: ustekinumab 45/90 mg; SECU_AMM/Other: secukinumab 300 mg at week 0, 1, 2, 3, and 4 then every 4 weeks or other dosages/other dosages; IXE_AMM/Other: ixekizumab 160 mg at Week then 80 mg every other weeks until week 12 then 80 mg monthly or other dosages; TILDRA_AMM/Other: tildrakizumab 100 mg at week 0 and 4 then every 12 weeks/Other dosages; GUSEL 100: guselkumab 100 mg per injection; BRODA_AMM/Other: brodalumab 210 mg at week 0, 1, 2 then every other weeks/other dosages; RISAN_AMM/Other: risankizumab, S/C, 150 mg (two 75 mg injections) at Week 0, Week 4 and every 12 weeks thereafter/other dosages; TYK2 (Oral Tyrosine kinase 2 inhibitor), MIRI (mirikizumab) and BIME (bimekizumab) (S/C) were grouped in one dosage whatever the dosages.

CI: confidence interval; PASI: Psoriasis Area and Severity Index; RR: risk ratio; AMM: 'approved dosage'


Sensitivity analyses ‐ Interval plot. Network meta‐analysis results for primary outcomes (PASI 90 and serious adverse events, left and right forest plot respectively) for all the interventions excluding studies at high risk of bias. Outcomes were measured at the induction phase (assessment from 8 to 24 weeks after randomisation).ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumabCI: confidence interval; PASI: Psoriasis Area and Severity Index; RR: risk ratio

Sensitivity analyses ‐ Interval plot. Network meta‐analysis results for primary outcomes (PASI 90 and serious adverse events, left and right forest plot respectively) for all the interventions excluding studies at high risk of bias.

Outcomes were measured at the induction phase (assessment from 8 to 24 weeks after randomisation).

ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumab

CI: confidence interval; PASI: Psoriasis Area and Severity Index; RR: risk ratio


Sensitivity analyses ‐ Interval plot. Network meta‐analysis results for primary outcomes (PASI 90 and serious adverse events, left and right forest plot respectively) for all the interventions including studies with a short‐term assessment from 8 to 16 weeks. ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumabCI: confidence interval; PASI: Psoriasis Area and Severity Index; RR: risk ratio

Sensitivity analyses ‐ Interval plot. Network meta‐analysis results for primary outcomes (PASI 90 and serious adverse events, left and right forest plot respectively) for all the interventions including studies with a short‐term assessment from 8 to 16 weeks.

ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumab

CI: confidence interval; PASI: Psoriasis Area and Severity Index; RR: risk ratio


Sensitivity analyses ‐ Interval plot. Network meta‐analysis results for primary outcomes (PASI 90 and serious adverse events, left and right forest plot respectively) for all the interventions including studies with systemic treatment‐naive participants. Outcomes were measured at the induction phase (assessment from 8 to 24 weeks after randomisation).ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumabCI: confidence interval; PASI: Psoriasis Area and Severity Index; RR: risk ratio

Sensitivity analyses ‐ Interval plot. Network meta‐analysis results for primary outcomes (PASI 90 and serious adverse events, left and right forest plot respectively) for all the interventions including studies with systemic treatment‐naive participants.

Outcomes were measured at the induction phase (assessment from 8 to 24 weeks after randomisation).

ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumab

CI: confidence interval; PASI: Psoriasis Area and Severity Index; RR: risk ratio

5. Reporting bias

The comparison‐adjusted funnel plots generally appeared symmetrical, and only the graph for quality of life presented some evidence of small‐study effects which might be caused by selective outcome reporting (Figure 28). As the funnel plots were symmetrical, we did not consider running meta‐regression.


Funnel plot for network meta‐analysis of all the outcomesAE: adverse event; lnRR: Mean effect size; PASI: Psoriasis Area and Severity Index; QoL: Specific quality of life scale; RR: Risk ratio; SAE: serious adverse events; SAE without worsening of psoriasis correspond to SAE after exclusion of flares of psoriasis; SMD: standardised mean difference

Funnel plot for network meta‐analysis of all the outcomes

AE: adverse event; lnRR: Mean effect size; PASI: Psoriasis Area and Severity Index; QoL: Specific quality of life scale; RR: Risk ratio; SAE: serious adverse events; SAE without worsening of psoriasis correspond to SAE after exclusion of flares of psoriasis; SMD: standardised mean difference

6. Grading of the evidence

We present results of evaluation of certainty of evidence for the primary efficacy and safety outcomes in Table 7; Table 8 and Figure 7; Figure 29; Figure 30.

Open in table viewer
Table 7. Study Bias distribution for PASI 90 using CINeMA

Comparison

Number of studies

Within‐study bias

Reporting bias

Indirectness

Imprecision

Heterogeneity

Incoherence

Confidence rating

ADA:GUSEL

3

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

ADA:PBO

8

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

ADA:RISAN

1

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

APRE:ETA

1

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

APRE:PBO

5

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

BIME:PBO

1

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

BRODA:PBO

5

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

BRODA:USK

2

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

CERTO:ETA

1

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CERTO:PBO

5

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

CICLO:MTX

2

Major concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

ETA:IFX

1

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

ETA:IXE

2

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

ETA:PBO

14

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

ETA:SECU

1

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

ETA:TILDRA

1

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

ETA:TOFA

1

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

ETA:USK

1

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

FAEs:MTX

1

Major concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

FAEs:PBO

1

Major concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

GUSEL:IXE

1

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

GUSEL:PBO

5

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

IFX:PBO

5

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

IXE:PBO

4

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

IXE:USK

1

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

MIRI:PBO

2

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

MTX:PBO

2

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

PBO:RISAN

4

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

PBO:SECU

13

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

PBO:TILDRA

3

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

PBO:TOFA

5

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

PBO:TYK2

1

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

PBO:USK

10

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

RISAN:SECU

1

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

RISAN:USK

3

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

SECU:USK

2

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

ADA:APRE

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

ADA:BIME

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

ADA:BRODA

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

ADA:CERTO

0

No concerns

Undetected

No concerns

Some concerns

No concerns

No concerns

High

ADA:CICLO

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

ADA:ETA

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

ADA:FAEs

0

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

ADA:IFX

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

ADA:IXE

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

ADA:MIRI

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

ADA:MTX

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

ADA:SECU

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

ADA:TILDRA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

ADA:TOFA

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

ADA:TYK2

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

ADA:USK

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

APRE:BIME

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

APRE:BRODA

0

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

APRE:CERTO

0

Some concerns

Undetected

No concerns

Some concerns

Some concerns

No concerns

Low

APRE:CICLO

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

APRE:FAEs

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

APRE:GUSEL

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

APRE:IFX

0

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

APRE:IXE

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

APRE:MIRI

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

APRE:MTX

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

APRE:RISAN

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

APRE:SECU

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

APRE:TILDRA

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

APRE:TOFA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

APRE:TYK2

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

APRE:USK

0

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

BIME:BRODA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BIME:CERTO

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BIME:CICLO

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

BIME:ETA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BIME:FAEs

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

BIME:GUSEL

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BIME:IFX

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BIME:IXE

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BIME:MIRI

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BIME:MTX

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

BIME:RISAN

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BIME:SECU

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BIME:TILDRA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BIME:TOFA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BIME:TYK2

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BIME:USK

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BRODA:CERTO

0

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

BRODA:CICLO

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

BRODA:ETA

0

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

BRODA:FAEs

0

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

BRODA:GUSEL

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BRODA:IFX

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

BRODA:IXE

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

BRODA:MIRI

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

BRODA:MTX

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

BRODA:RISAN

0

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

BRODA:SECU

0

Some concerns

Undetected

No concerns

Some concerns

No concerns

No concerns

Moderate

BRODA:TILDRA

0

No concerns

Undetected

No concerns

Some concerns

No concerns

No concerns

High

BRODA:TOFA

0

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

BRODA:TYK2

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

CERTO:CICLO

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CERTO:FAEs

0

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

CERTO:GUSEL

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

CERTO:IFX

0

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

CERTO:IXE

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

CERTO:MIRI

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

CERTO:MTX

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CERTO:RISAN

0

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

CERTO:SECU

0

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

CERTO:TILDRA

0

No concerns

Undetected

No concerns

Some concerns

No concerns

No concerns

High

CERTO:TOFA

0

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

CERTO:TYK2

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

CERTO:USK

0

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

CICLO:ETA

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CICLO:FAEs

0

Major concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CICLO:GUSEL

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CICLO:IFX

0

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

CICLO:IXE

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CICLO:MIRI

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CICLO:PBO

0

Major concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

CICLO:RISAN

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CICLO:SECU

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CICLO:TILDRA

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CICLO:TOFA

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CICLO:TYK2

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CICLO:USK

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

ETA:FAEs

0

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

ETA:GUSEL

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

ETA:MIRI

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

ETA:MTX

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

ETA:RISAN

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

ETA:TYK2

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

FAEs:GUSEL

0

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

FAEs:IFX

0

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

FAEs:IXE

0

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

FAEs:MIRI

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

FAEs:RISAN

0

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

FAEs:SECU

0

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

FAEs:TILDRA

0

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

FAEs:TOFA

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

FAEs:TYK2

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

FAEs:USK

0

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

GUSEL:IFX

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

GUSEL:MIRI

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

GUSEL:MTX

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

GUSEL:RISAN

0

No concerns

Undetected

No concerns

Some concerns

No concerns

No concerns

High

GUSEL:SECU

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

GUSEL:TILDRA

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

GUSEL:TOFA

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

GUSEL:TYK2

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

GUSEL:USK

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

IFX:IXE

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

IFX:MIRI

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

IFX:MTX

0

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

IFX:RISAN

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

IFX:SECU

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

IFX:TILDRA

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

IFX:TOFA

0

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

IFX:TYK2

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

IFX:USK

0

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

IXE:MIRI

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

IXE:MTX

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

IXE:RISAN

0

No concerns

Undetected

No concerns

Some concerns

No concerns

No concerns

High

IXE:SECU

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

IXE:TILDRA

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

IXE:TOFA

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

IXE:TYK2

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

MIRI:MTX

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

MIRI:RISAN

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

MIRI:SECU

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

MIRI:TILDRA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

MIRI:TOFA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

MIRI:TYK2

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

MIRI:USK

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

MTX:RISAN

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

MTX:SECU

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

MTX:TILDRA

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

MTX:TOFA

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

MTX:TYK2

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

MTX:USK

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

RISAN:TILDRA

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

RISAN:TOFA

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

RISAN:TYK2

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

SECU:TILDRA

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

SECU:TOFA

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

SECU:TYK2

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

TILDRA:TOFA

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

TILDRA:TYK2

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

TILDRA:USK

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

TOFA:TYK2

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

TOFA:USK

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

TYK2:USK

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

Open in table viewer
Table 8. Study bias distribution for serious adverse events using CINeMA

Comparison

Number of studies

Within‐study bias

Reporting bias

Indirectness

Imprecision

Heterogeneity

Incoherence

Confidence rating

ADA:GUSEL

3

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

ADA:PBO

9

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

ADA:RISAN

1

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

APRE:ETA

1

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

APRE:PBO

7

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BIME:PBO

1

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BRODA:PBO

5

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

BRODA:USK

2

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CERTO:ETA

1

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

CERTO:PBO

4

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CICLO:MTX

2

Major concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CICLO:PBO

1

Major concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

ETA:IFX

1

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

ETA:IXE

2

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

ETA:PBO

13

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

ETA:SECU

1

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

ETA:TILDRA

1

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

ETA:TOFA

1

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

ETA:USK

1

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

FAEs:MTX

1

Major concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

FAEs:PBO

1

Major concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

GUSEL:IXE

1

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

GUSEL:PBO

5

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

IFX:PBO

6

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

IXE:PBO

4

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

IXE:USK

1

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

MIRI:PBO

2

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

MTX:PBO

2

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

PBO:RISAN

4

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

PBO:SECU

12

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

PBO:TILDRA

3

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

PBO:TOFA

7

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

PBO:TYK2

1

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

PBO:USK

11

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

RISAN:SECU

1

No concerns

Undetected

No concerns

Major concerns

No concerns

Major concerns

Low

RISAN:USK

3

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

SECU:USK

2

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

ADA:APRE

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

ADA:BIME

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

ADA:BRODA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

ADA:CERTO

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

ADA:CICLO

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

ADA:ETA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

ADA:FAEs

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

ADA:IFX

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

ADA:IXE

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

ADA:MIRI

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

ADA:MTX

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

ADA:SECU

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

ADA:TILDRA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

ADA:TOFA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

ADA:TYK2

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

ADA:USK

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

APRE:BIME

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

APRE:BRODA

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

APRE:CERTO

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

APRE:CICLO

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

APRE:FAEs

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

APRE:GUSEL

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

APRE:IFX

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

APRE:IXE

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

APRE:MIRI

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

APRE:MTX

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

APRE:RISAN

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

APRE:SECU

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

APRE:TILDRA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

APRE:TOFA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

APRE:TYK2

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

APRE:USK

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BIME:BRODA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BIME:CERTO

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BIME:CICLO

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

BIME:ETA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BIME:FAEs

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

BIME:GUSEL

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BIME:IFX

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BIME:IXE

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BIME:MIRI

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BIME:MTX

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

BIME:RISAN

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BIME:SECU

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BIME:TILDRA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BIME:TOFA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BIME:TYK2

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BIME:USK

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BRODA:CERTO

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

BRODA:CICLO

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

BRODA:ETA

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

BRODA:FAEs

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

BRODA:GUSEL

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BRODA:IFX

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

BRODA:IXE

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BRODA:MIRI

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BRODA:MTX

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

BRODA:RISAN

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

BRODA:SECU

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

BRODA:TILDRA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BRODA:TOFA

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

BRODA:TYK2

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

CERTO:CICLO

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CERTO:FAEs

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CERTO:GUSEL

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

CERTO:IFX

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

CERTO:IXE

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

CERTO:MIRI

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

CERTO:MTX

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CERTO:RISAN

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

CERTO:SECU

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

CERTO:TILDRA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

CERTO:TOFA

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CERTO:TYK2

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

CERTO:USK

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

CICLO:ETA

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CICLO:FAEs

0

Major concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CICLO:GUSEL

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CICLO:IFX

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CICLO:IXE

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CICLO:MIRI

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CICLO:RISAN

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CICLO:SECU

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CICLO:TILDRA

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CICLO:TOFA

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CICLO:TYK2

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CICLO:USK

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

ETA:FAEs

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

ETA:GUSEL

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

ETA:MIRI

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

ETA:MTX

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

ETA:RISAN

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

ETA:TYK2

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

FAEs:GUSEL

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

FAEs:IFX

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

FAEs:IXE

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

FAEs:MIRI

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

FAEs:RISAN

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

FAEs:SECU

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

FAEs:TILDRA

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

FAEs:TOFA

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

FAEs:TYK2

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

FAEs:USK

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

GUSEL:IFX

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

GUSEL:MIRI

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

GUSEL:MTX

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

GUSEL:RISAN

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

GUSEL:SECU

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

GUSEL:TILDRA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

GUSEL:TOFA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

GUSEL:TYK2

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

GUSEL:USK

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

IFX:IXE

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

IFX:MIRI

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

IFX:MTX

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

IFX:RISAN

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

IFX:SECU

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

IFX:TILDRA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

IFX:TOFA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

IFX:TYK2

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

IFX:USK

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

IXE:MIRI

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

IXE:MTX

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

IXE:RISAN

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

IXE:SECU

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

IXE:TILDRA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

IXE:TOFA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

IXE:TYK2

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

MIRI:MTX

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

MIRI:RISAN

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

MIRI:SECU

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

MIRI:TILDRA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

MIRI:TOFA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

MIRI:TYK2

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

MIRI:USK

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

MTX:RISAN

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

MTX:SECU

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

MTX:TILDRA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

MTX:TOFA

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

MTX:TYK2

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

MTX:USK

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

RISAN:TILDRA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

RISAN:TOFA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

RISAN:TYK2

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

SECU:TILDRA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

SECU:TOFA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

SECU:TYK2

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

TILDRA:TOFA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

TILDRA:TYK2

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

TILDRA:USK

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

TOFA:TYK2

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

TOFA:USK

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

TYK2:USK

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate


Certainty of evidence per drug for PASI 90 using CINeMA Each drug is presented as a bar, which indicates the composition of the 4‐level confidence of evidence from all comparisons including that drug. Green: high confidence; blue: moderate confidence; yellow: low confidence; red: very low confidence.

Certainty of evidence per drug for PASI 90 using CINeMA

Each drug is presented as a bar, which indicates the composition of the 4‐level confidence of evidence from all comparisons including that drug. Green: high confidence; blue: moderate confidence; yellow: low confidence; red: very low confidence.


Certainty of evidence per drug for Serious Adverse Events using CINeMA Each drug is presented as a bar, which indicates the composition of the 4‐level confidence of evidence from all comparisons including that drug. Green: high confidence; blue: moderate confidence; yellow: low confidence; red: very low confidence.

Certainty of evidence per drug for Serious Adverse Events using CINeMA

Each drug is presented as a bar, which indicates the composition of the 4‐level confidence of evidence from all comparisons including that drug. Green: high confidence; blue: moderate confidence; yellow: low confidence; red: very low confidence.

Table 7 and Table 8 represent for PASI 90 and SAEs respectively, the evaluation of concerns (no concern, some concerns or major concerns) for each domain assessed (within‐study bias, reporting bias, indirectness, imprecision, heterogeneity and incoherence). We detected no reporting bias, and there were no concerns that indirectness was present for any comparison for PASI 90 or SAEs. After the judgement for all the six domains, our overall confidence in the evidence for each comparisons is rated high, moderate, low and very low, as described in the Methods section. Results of overall confidence in evidence are available in Table 7, Table 8 and Figure 7.

Figure 29 and Figure 30 represent by drug the overall percentage of comparisons including that drug assessed as high, moderate, low and very‐low certainty of evidence. For PASI 90, the overall certainty of the evidence was moderate to high. None of the comparisons were assessed as very low. For methotrexate and ciclosporin certainty of evidence was low for more than 80% of comparisons including these treatments. For bimekizumab, brodalumab, certolizumab, FAEs, infliximab, and oral tyrosine kinase 2 inhibitor, certainty of evidence was moderate for most comparisons. For all other drugs, the certainty of evidence was high for most comparisons. Reasons for downgrading to moderate or low certainty were within‐study bias or imprecision, or both. For SAEs, the overall certainty of evidence was low to moderate. None of the comparisons were assessed as very low. For tofacitinib, methotrexate, FAEs, brodalumumab and ciclosporin, the certainty of evidence was low. The certainty of evidence was moderate for all other treatments. Reasons for downgrading to moderate or low certainty were within‐study bias or imprecision, or both.

Discussion

Summary of main results

Our review and meta‐analysis compares all systemic pharmacological drugs and systemic drugs undergoing phase II/III trials used for moderate‐to‐severe psoriasis in 2020.

This updated review included 158 studies, involving 57,831 randomised adult participants, which assessed most outcomes during the induction phase (from 8 to 24 weeks after randomisation). Participants in the included studies were young, with a mean age of 45 years, and had moderate‐to‐severe psoriasis with an overall mean PASI score at baseline of 20. Ninety‐two trials compared systemic treatment against placebo, 48 were head‐to‐head trials, and 18 had both an active comparator and a placebo. Sixteen trials had a co‐intervention, mainly phototherapy. Eight trials assessed biosimilars versus original drugs for adalimumab or etanercept. Finally, 123 studies declared pharmaceutical company funding, and 22 studies did not report the source of funding.

We included 130 studies (without co‐intervention and without trials in biosimilar development), involving 50,081 participants (87% of the participants in this review), in the classical or network meta‐analysis (NMA). Non‐biological systemic agents, the oldest class‐level treatment (acitretin, ciclosporin, fumaric acid esters (FAEs), methotrexate); anti‐TNF alpha treatments (etanercept, infliximab, adalimumab, certolizumab); an anti‐IL12/23 treatment (ustekinumab); anti‐IL17 treatments (secukinumab, ixekizumab, brodalumab); and anti‐IL23 (guselkumab, tildrakizumab, risankizumab) have all been approved for psoriasis, except for bimekizumab and mirikizumab. Apart from apremilast, small molecule drugs (tofacitinib, tyrosine kinase 2 inhibitor (BMS‐986165)), had not been approved for psoriasis at the time we conducted our analyses.

The following results are based on network meta‐analysis.

All of the assessed interventions appeared superior to placebo in terms of reaching Psoriasis Area and Severity Index (PASI) 90.

At class level, network meta‐analysis showed that the biologics anti‐IL17, anti‐IL23, anti‐IL12/23, and anti‐TNF alpha outperformed the small molecules and the non‐biological agents to reach PASI 90.

For reaching PASI 90, the most effective drugs when compared to placebo were (in SUCRA (surface under the cumulative ranking curve) rank order): infliximab (high‐certainty evidence), ixekizumab (high‐certainty evidence), risankizumab (high‐certainty evidence), bimekizumab (high‐certainty evidence), secukinumab (high‐certainty evidence), guselkumab (high‐certainty evidence), and brodalumab (moderate‐certainty evidence); see Figure 7. The clinical effectiveness of these drugs was similar when compared against each other, except for ixekizumab which had a better chance of reaching PASI 90 compared with secukinumab, guselkumab and brodalumab.

At drug level, infliximab, ixekizumab, secukinumab, brodalumab, risankizumab and guselkumab were significantly more effective in reaching PASI 90 than ustekinumab and three anti‐TNF alpha agents: adalimumab, certolizumab, and etanercept. Ustekinumab and adalimumab were significantly more effective in reaching PASI 90 than etanercept; ustekinumab more effective than certolizumab, and the clinical effectiveness for ustekinumab and adalimumab was similar. Only one trial assessed the efficacy of bimekizumab in this network, so the results for bimekizumab have to be interpreted with caution, as well as those for mirikizumab (two trials including a phase 2), tyrosine kinase 2 inhibitor, acitretin, ciclosporin, fumaric acid esters, and methotrexate. There was no significant difference between tofacitinib or apremilast and three non‐biological drugs: FAES, ciclosporin and methotrexate. The results were similar to PASI 90 for the other efficacy outcomes (PASI 75 and PGA 0/1).

We found no significant difference between any of the interventions and the placebo for the risk of serious adverse events (SAEs). Methotrexate (low‐certainty evidence), bimekizumab (moderate‐certainty evidence), risankizumab (moderate‐certainty evidence), mirikizumab (moderate‐certainty evidence) and oral tyrosine kinase 2 inhibitor (moderate‐certainty evidence) had the highest SUCRA at drug level for all the SAEs (see Figure 7).

There was often poor reporting of information about quality of life, and these data were absent for several of the interventions.

Finally, considering both efficacy (PASI 90 outcome) and acceptability (SAE outcome), highly‐effective treatments also had more SAEs than the other treatments, and risankizumab and bimekizumab appeared to be the better compromise between efficacy and acceptability, bearing in mind the limitations that affect interpretation of the SAE results, such as the very low number of events on which they were based.

Overall completeness and applicability of evidence

We were able to draw some conclusions on the effectiveness (and ranking) of the systemic treatment options for moderate‐to‐severe chronic plaque psoriasis during the induction phase. Long‐term efficacy and safety data are lacking. Specific details are listed below.

Participants

Participants in the included studies had a mean age of 45 years and had moderate‐to‐severe psoriasis, with an overall mean PASI score at baseline of 20 (range: 9.5 to 39) and a duration of psoriasis of 18 years (range 7 to 21.5). This young age and the high level of disease severity may not be typical of patients seen in daily clinical practice, or those who need a first‐line systemic treatment.

In addition, participants selected for randomised controlled trials (RCTs) generally have few major comorbidities. Almost all studies including one biological arm excluded patients with a history of infectious diseases or malignancies and signs of severe renal, cardiac, hepatic, demyelinating, or other disorders. This may impact the generalisability of these results for clinical practice. However, some participant characteristics (such as being overweight, imbalanced sex ratio in favour of men, presence of metabolic syndrome) were reflective of a moderate‐to‐severe psoriasis population, comparable to literature data (Wolkenstein 2009).

Interventions

Evidence on 20 active treatments included in this review was derived from 158 trials (searched for up to September 2020). We included all interventions, irrespective of the dose. Thus, we increased the number of available RCTs for each intervention and had more power to assess SAEs and adverse events (AEs). The number of studies included in the NMA was still low for the following interventions: bimekizumab, mirikizumab, tyrosine kinase 2 inhibitor, acitretin, ciclosporin, fumaric acid esters, and methotrexate, meaning we must be cautious about the conclusions drawn for these drugs. The results from the sensitivity analysis using a standard dose for each intervention was similar for PASI 90 (and SAEs) compared to the main analyses, giving us confidence in the results of the main analysis.

For drugs just approved or not yet approved for psoriasis, ongoing studies are still investigating bimekizumab, mirikizumab, brodalumab, and BMS‐986165 (Characteristics of ongoing studies).

Comparisons

Most studies included in the review were only placebo‐controlled (around 60%). Once the benefit of a treatment has been established against placebo using high‐quality evidence, only head‐to‐head trials would be helpful to provide physicians with efficacy estimates between the different biologics, based on stronger evidence than indirect comparisons.

Outcomes

Many of the trials included in this review provide evidence for the proportion of participants who reached PASI 90, PASI 75, or Physician Global Assessment (PGA) 0/1 or who experienced SAEs or AEs. We chose PASI 90 as the main efficacy outcome. The differences in PASI 90 rates must be balanced against the differences in quality‐of‐life improvements that are observed. Results for both outcomes cannot be correlated. On the other hand, patient‐reported outcome (PRO) data were scanty and poorly reported in our review. Moreover, the heterogeneity of the scales used for QOL in psoriasis trials required using the standardised mean difference (SMD) in the network. SMD shows the difference in standard deviations of the outcome, and from a clinical point of view, the interpretation of the results is difficult. It has been suggested that values 0.2, 0.5 and 0.8 might indicate small, moderate and large magnitude of the effect size (Cohen 1988). So, from a clinical point of view, the interpretation of the results was difficult: a significant result for PRO between two drugs did not mean that the result was clinically useful for the patients. Results for SAEs have to be interpreted cautiously, because RCTs do not last long enough and are not powered to be able to detect rare and severe adverse events. The results of our sensitivity analysis assessing SAEs without psoriasis flares did not differ from those of the primary outcome. We did not summarise individual SAE types or classes of SAE in this review, in part because classification differed across different data sources. This was the subject of a separate detailed assessment of types of SAE, adverse events leading to discontinuation of trial medication, and system‐organ class adverse events (Afach 2021).

Timing

All of the trials included in the NMAs assessed the efficacy of the different treatments during the induction treatment phase (from 8 to 24 weeks). Assessment of longer‐term outcomes may also be relevant for this chronic disease. The trials were designed to detect differences in the severity of psoriasis in response to therapy over short periods of treatment, and are often underpowered and of insufficient duration to detect rare or long‐term adverse events. It is therefore of interest to conduct studies taking into account the induction of remission but also the long‐term management (long‐term remission) and the long‐term safety of the drug. In order to provide long‐term information on the safety of the treatments included in this review, it will be necessary also to evaluate non‐randomised studies and postmarketing reports released from regulatory agencies.

Quality of the evidence

Overall, our confidence in the treatment estimates for PASI 90 is high or moderate for comparisons involving anti‐IL17 , anti‐IL12/23 , anti‐IL23, or anti‐TNF alpha agents, and small molecules. We judged our confidence in treatment estimates for PASI 90 as low for the comparisons involving non‐biological systemic agents; we downgraded the certainty of the evidence for risk of bias and then for imprecision. We judged our confidence in the treatment estimates for SAEs to be low certainty for one‐third of the treatment estimates, and moderate for the others; we downgraded the certainty of the evidence for imprecision and risk of bias.

Risk of bias

The risks of bias in the included studies appear to be globally low (Figure 2; Figure 3). However, some limitations should be discussed.

  • There was variation in how well the studies took measures to blind investigators and participants: a third of trials in this review were rated at high or unclear risk of performance bias (53 out of 158). This is an important point to highlight, as the outcomes used for assessing efficacy were subjective. However, the proportion of trials at high risk of blinding used in the network meta‐analyses decreased to 22% (28 out of 130).

  • The reporting of missing outcome data was largely inadequate in a few studies. Since we chose a likely scenario that any participant with missing outcome data did not experience clearance for the overall analyses, we minimised the risk of overestimating efficacy due to how we reported missing data.

  • Finally, we rated a few trials at high risk of selective outcome reporting. However, we chose a stringent definition of studies at high risk of selective outcome reporting: we considered reporting bias inadequate if one specified outcome in protocols was lacking in the main report. A large proportion of included trials did not report the patient‐reported outcomes in the main report but only in slicing publications (see Included studies). We extracted outcomes of interest both in main and slicing publications, but this disadvantaged trials that did not report all of the specified outcomes in the main report.

Indirect comparison and network meta‐analyses as standard pair‐wise meta‐analyses provide 'observational' evidence, since the treatments being compared have not been randomised across studies. However, we considered carefully the assumption underpinning the validity of indirect comparisons, to assure a sufficiently coherent evidence base (Cipriani 2013). The limitations of this review are reflected by CINeMA evaluations.

Heterogeneity (i.e. variation in effect modifiers within comparisons) and inconsistency (imbalance in effect modifiers between comparisons)

We found no evidence of heterogeneity either in direct comparisons or in the entire networks. At drug‐level analysis, the global test for inconsistency was not significant for any of the outcomes.

Imprecision

The number of studies included in the NMA was low for the following interventions (one or two studies for each interventions): bimekizumab, mirikizumab, tyrosine kinase 2 inhibitor, acitretin, ciclosporin, fumaric acid esters, and methotrexate, meaning we must be cautious about the conclusions drawn for these drugs. Indeed, it has been shown that treatment effect estimates differed according to trial sample size, with stronger effect estimates seen in small to moderately‐sized trials than in the largest trials (Dechartres 2013). Moreover, treatment effects in randomised controlled phase II trials were better than those in matched phase III trials (Liang 2019).

Indirectness or transitivity assumption

We did not find any evidence that important variables, such as age, sex, weight, and duration and severity of psoriasis, varied across comparisons (see Characteristics of included studies and Figure 16; Figure 17). However, the lack of data did not allow us to check the distributions of previous treatments across comparisons, so transitivity cannot properly be assessed statistically.

Several participant characteristics have changed in newer trials, such as participants' exclusion criteria. However, most of the included trials were conducted after 2000, minimising the variability across trial participant characteristics. The location of the trial could also create some differences between participants, as the response to treatment could be related to genetic background (Chiu 2014). To further confirm the plausibility of the transitivity assumption, we only included in our analyses trials not involving co‐interventions and not selecting participants on their previous systemic treatments, and performed several sensitivity analyses (see Quality of the evidence: Heterogeneity).

Publication bias

We assessed publication bias, considering the comprehensive search strategy we performed and the risk of publication bias in the specific field. The comparison‐adjusted funnel plot for all placebo‐controlled trials for all the outcomes did not indicate any evident risk of publication bias for the two primary outcomes (Figure 28).

Potential biases in the review process

We performed an extensive search for relevant trials. However, we did not contact pharmaceutical companies who do not have publicly available trials databases to enquiry whether they had conducted any additional relevant trials.  We consider the probability that we have missed an eligible trial is low, considering our wide search, and this view is supported by the absence of small‐study effects (testing by the comparison‐adjusted funnel plots). However, the fact that 28 studies are awaiting classification and have not yet been incorporated may be a potential source of bias.

We conducted study selection, data extraction, and 'Risk of bias' assessments in duplicate and independently, and we reached consensus by discussing any discrepancies. Some published trial reports did not provide enough details to extract outcomes and adequately assess risks of bias, especially those performed before 2000 (i.e. before the International Committee of Medical Journal Editors issued the requirement of trial registration for publication). However, we contacted the authors of the trials to request missing data, but we cannot avoid some biased assessment in the review process due to incomplete reporting of trial details or results, or both.

We had some departures from the protocol plans (see Differences between protocol and review), especially excluding from the NMA analysis trials selecting participants on their previous systemic treatments.

Thus, we added one new sensitivity analysis including all trials, irrespective of the previous systemic treatments.

We only used CINeMA to assess our confidence in the results.

Agreements and disagreements with other studies or reviews

We searched in MEDLINE Ovid (from 1946) using the strategy "Psoriasis" AND "Network Meta‐analysis" for already‐published network meta‐analyses, identifying 71 references.

We compared our findings with the six most recent network meta‐analyses (Armstrong 2020; Geng 2018; Gómez‐García 2017; Jabbar‐Lopez 2017; Loos 2018; Xu 2019). Gómez‐García 2017 included 27 trials involving 10,629 participants, assessing three anti‐TNF alpha agents (infliximab, etanercept, and adalimumab), one anti‐IL12/23 agent (ustekinumab), and one anti‐IL17 agent (secukinumab). Jabbar‐Lopez 2017 included 41 trials, involving 20,561 participants, assessing the same drugs as Gómez‐García 2017, plus ixekizumab (another anti‐IL17 agent) and methotrexate. Loos 2018 included 34 trials, involving 22,892 participants, assessing biologic treatments (infliximab, adalimumab, etanercept, ustekinumab, secukinumab, ixekizumab and brodalumab) and apremilast. Armstrong 2020 included 60 trials (the number of participants is unknown) assessing biologic treatments (infliximab, adalimumab, etanercept, certolizumab, ustekinumab, secukinumab, ixekizumab, brodalumab, risankizumab, guselkumab, and tildrakizumab), apremilast and FAEs. As Geng 2018 and Xu 2019 included systemic treatments withdrawn from the market (briakinumab and efalizumab), we did not investigate these two reviews in detail.

Compared to previous reviews, we included more interventions and consequently more trials (n = 158) and participants (n = 57,831). Regarding the overlapping period between the different NMAs, we also included more trials than the other meta‐analyses. Indeed, we performed a larger search in terms of the number of databases used, including trials registers and other resources (unpublished literature), irrespective of the date or language limitations.

Gómez‐García 2017 presented both PASI 75 and PASI 90 results. Jabbar‐Lopez 2017 chose a composite outcome: PASI 90 or Physician Global Assessment (PGA) 1. We chose PASI 90 as our primary efficacy outcome, because complete clearance seems the less subjective outcome and the most relevant for patient expectations in short‐term assessment (induction phase). The composite outcome used by Jabbar‐Lopez 2017 did not reflect complete or almost complete clearance. Indeed, PGA 1 is highly correlated with PASI 75 and not with PASI 90, which could lead to a classification bias (Robinson 2012). Loos 2018 and Armstrong 2020 presented PASI 50, 75, and 90 results.

Jabbar‐Lopez 2017 and Armstrong 2020 presented their results using the number needed to treat for an additional beneficial outcome (NNTB). Although NNTB is an easily understandable and very useful measure for patients and clinicians, it can be misleading in a network meta‐analysis, since it requires the assumption of a common average control group risk applying to all studies. This is a rather strong assumption, particularly in networks involving head‐to‐head studies without a control group, as here.

Infliximab was also the most effective drug in Gómez‐García 2017, without significant difference between infliximab and secukinumab. Infliximab was ranked in third place after ixekizumab and secukinumab in Jabbar‐Lopez 2017, without a significant difference between infliximab and secukinumab. Infliximab was ranked in third place after ixekizumab and brodalumab in Loos 2018, without a significant difference between these three drugs and secukinumab (4th rank). Risankizumab, ixekizumab, brodalumab, guselkumab, secukinumab and infliximab were the best treatment options in Armstrong 2020. Our findings were close to these results, but differed in the ranking. One hypothesis is that time of evaluation range choice (from 10 to 16 weeks in Armstrong 2020 and from 8 to 24 weeks  in our study) failed to include more Infliximab trials in Armstrong 2020. Our review also includes new agents (bimekizumab and mirikizumab for biologics).

Among the previous network meta‐analyses, Loos 2018 did not assess inconsistency, and two reported significant global and local inconsistency for PASI 75 (Gómez‐García 2017; Jabbar‐Lopez 2017).

tudy flow diagram

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Figure 1

tudy flow diagram

'Risk of bias' summary: review authors' judgements about each 'Risk of bias' item for each included study

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Figure 2

'Risk of bias' summary: review authors' judgements about each 'Risk of bias' item for each included study

'Risk of bias' graph: review authors' judgements about each 'Risk of bias' item presented as percentages across all included studies

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Figure 3

'Risk of bias' graph: review authors' judgements about each 'Risk of bias' item presented as percentages across all included studies

Network plot for all the outcomes at class level The size of the nodes is proportional to the total number of participants allocated to each intervention and the thickness of the lines proportional to the number of studies evaluating each direct comparison.AE: adverse events; PASI: Psoriasis Area and Severity Index; PGA: Physician Global Assessment; QoL: quality of life; SAE: serious adverse events; SAE without worsening of psoriasis correspond to SAE after exclusion of flares of psoriasis

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Figure 4

Network plot for all the outcomes at class level

The size of the nodes is proportional to the total number of participants allocated to each intervention and the thickness of the lines proportional to the number of studies evaluating each direct comparison.

AE: adverse events; PASI: Psoriasis Area and Severity Index; PGA: Physician Global Assessment; QoL: quality of life; SAE: serious adverse events; SAE without worsening of psoriasis correspond to SAE after exclusion of flares of psoriasis

Network plot for all the outcomes at drug level The size of the nodes is proportional to the total number of participants allocated to each intervention and the thickness of the lines proportional to the number of studies evaluating each direct comparison.ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumabAE: adverse events; PASI: Psoriasis Area and Severity Index; PGA: Physician Global Assessment; QoL: quality of life; SAE: serious adverse events; SAE without worsening of psoriasis correspond to SAE after exclusion of flares of psoriasis

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Figure 5

Network plot for all the outcomes at drug level

The size of the nodes is proportional to the total number of participants allocated to each intervention and the thickness of the lines proportional to the number of studies evaluating each direct comparison.

ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumab

AE: adverse events; PASI: Psoriasis Area and Severity Index; PGA: Physician Global Assessment; QoL: quality of life; SAE: serious adverse events; SAE without worsening of psoriasis correspond to SAE after exclusion of flares of psoriasis

Relative effects of the class‐level intervention as estimated from the network meta‐analysis model Outcomes were all measured at the induction phase (assessment from 8 to 24 weeks after randomisation). Drugs are reported in order of primary benefit ranking. Each cell contains the risk ratio (RR) (for dichotomous outcomes: PASI 90, serious adverse events, PASI 75, PGA 0/1, adverse events) or the standardised mean difference (SMD) (for the quality‐of‐life outcome), plus the 95% confidence interval, of the class level in the respective column versus the class level in the respective row. RRs larger than 1 for the lower triangle and smaller than 1 (or SMDs smaller than zero) for the upper triangle favour the treatment on the left. Significant results are highlighted in grey.AE: adverse events; PASI: Psoriasis Area and Severity Index; PGA: Physician's Global Assessment; QoL: quality of life; SAE: serious adverse events; SAE without worsening of psoriasis correspond to SAE after exclusion of flares of psoriasis; AIL12/23: anti‐IL12/23; AIL17: anti‐IL17; AIL23: anti‐IL23, ATA: anti‐TNF alpha; CSA: non‐biological conventional systemic agents; PBO: placebo; SM: small molecules

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Figure 6

Relative effects of the class‐level intervention as estimated from the network meta‐analysis model

Outcomes were all measured at the induction phase (assessment from 8 to 24 weeks after randomisation). Drugs are reported in order of primary benefit ranking. Each cell contains the risk ratio (RR) (for dichotomous outcomes: PASI 90, serious adverse events, PASI 75, PGA 0/1, adverse events) or the standardised mean difference (SMD) (for the quality‐of‐life outcome), plus the 95% confidence interval, of the class level in the respective column versus the class level in the respective row. RRs larger than 1 for the lower triangle and smaller than 1 (or SMDs smaller than zero) for the upper triangle favour the treatment on the left. Significant results are highlighted in grey.

AE: adverse events; PASI: Psoriasis Area and Severity Index; PGA: Physician's Global Assessment; QoL: quality of life; SAE: serious adverse events; SAE without worsening of psoriasis correspond to SAE after exclusion of flares of psoriasis; AIL12/23: anti‐IL12/23; AIL17: anti‐IL17; AIL23: anti‐IL23, ATA: anti‐TNF alpha; CSA: non‐biological conventional systemic agents; PBO: placebo; SM: small molecules

Relative effects of the intervention as estimated from the network meta‐analysis model for Psoriasis Area and Severity Index (PASI) 90 and serious adverse events (AEs) Outcomes were all measured at the induction phase (assessment from 8 to 24 weeks after randomisation). Drugs are reported in order of primary benefit ranking. Each cell contains the risk ratio (RR) and 95% confidence interval for the two primary outcomes (PASI 90 and SAEs) of the intervention in the respective column versus the comparator in the respective row. RRs larger than 1 for the lower triangle and smaller than 1 for the upper triangle favour the treatment on the left. Certainty of evidence was assessed for each comparison using CINeMA and classified in high (highlighted in green), moderate (in blue), low (in yellow) and very‐low (in red).ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumab

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Figure 7

Relative effects of the intervention as estimated from the network meta‐analysis model for Psoriasis Area and Severity Index (PASI) 90 and serious adverse events (AEs)

Outcomes were all measured at the induction phase (assessment from 8 to 24 weeks after randomisation). Drugs are reported in order of primary benefit ranking. Each cell contains the risk ratio (RR) and 95% confidence interval for the two primary outcomes (PASI 90 and SAEs) of the intervention in the respective column versus the comparator in the respective row. RRs larger than 1 for the lower triangle and smaller than 1 for the upper triangle favour the treatment on the left. Certainty of evidence was assessed for each comparison using CINeMA and classified in high (highlighted in green), moderate (in blue), low (in yellow) and very‐low (in red).

ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumab

Relative effects of the intervention as estimated from the network meta‐analysis model for Psoriasis Area and Severity Index (PASI 75) and adverse events (AEs) Outcomes were all measured at the induction phase (assessment from 8 to 24 weeks after randomisation). Drugs are reported in order of primary benefit ranking. Each cell contains the Risk Ratio (RR) and 95% confidence interval for the two secondary outcomes (PASI 75 and adverse events) of the intervention in the respective column versus the comparator in the respective row. RRs larger than 1 for the lower triangle and smaller than 1 for the upper triangle favour the treatment on the left. Significant results are are highlighted in grey.ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumab

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Figure 8

Relative effects of the intervention as estimated from the network meta‐analysis model for Psoriasis Area and Severity Index (PASI 75) and adverse events (AEs)

Outcomes were all measured at the induction phase (assessment from 8 to 24 weeks after randomisation). Drugs are reported in order of primary benefit ranking. Each cell contains the Risk Ratio (RR) and 95% confidence interval for the two secondary outcomes (PASI 75 and adverse events) of the intervention in the respective column versus the comparator in the respective row. RRs larger than 1 for the lower triangle and smaller than 1 for the upper triangle favour the treatment on the left. Significant results are are highlighted in grey.

ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumab

Relative effects of the intervention as estimated from the network meta‐analysis model for Physician's Global Assessment (PGA 0/1) and quality of life (QoL) Outcomes were all measured at the induction phase (assessment from 8 to 24 weeks after randomisation). Drugs are reported in order of primary benefit ranking. Each cell contains the risk ratio (RR) and 95% confidence interval (PGA 0/1) or standardized mean difference (quality of life) of the intervention in the respective column versus the comparator in the respective row. RRs larger than 1 for the lower triangle and smaller than 1 (or SMDs smaller than zero) for the upper triangle favour the treatment on the left. Significant results are are highlighted in grey.ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumab

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Figure 9

Relative effects of the intervention as estimated from the network meta‐analysis model for Physician's Global Assessment (PGA 0/1) and quality of life (QoL)

Outcomes were all measured at the induction phase (assessment from 8 to 24 weeks after randomisation). Drugs are reported in order of primary benefit ranking. Each cell contains the risk ratio (RR) and 95% confidence interval (PGA 0/1) or standardized mean difference (quality of life) of the intervention in the respective column versus the comparator in the respective row. RRs larger than 1 for the lower triangle and smaller than 1 (or SMDs smaller than zero) for the upper triangle favour the treatment on the left. Significant results are are highlighted in grey.

ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumab

Interval plot. Network meta‐analysis estimates of class‐level versus placebo for all the outcomes Outcomes were all measured at the induction phase (assessment from 8 to 24 weeks after randomisation).AE: adverse events; CI: confidence interval; PGA: Physician Global Assessment; PrI: predictive interval; QoL: Specific quality of life scale; RR: risk ratio; SAE: serious adverse events; SAE without worsening of psoriasis correspond to SAE after exclusion of flares of psoriasis; SMD: standardised mean difference; AIL12/23: anti‐IL12/23; AIL17: anti‐IL17; AIL23: anti‐IL23, ATA: anti‐TNF alpha

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Figure 10

Interval plot. Network meta‐analysis estimates of class‐level versus placebo for all the outcomes

Outcomes were all measured at the induction phase (assessment from 8 to 24 weeks after randomisation).

AE: adverse events; CI: confidence interval; PGA: Physician Global Assessment; PrI: predictive interval; QoL: Specific quality of life scale; RR: risk ratio; SAE: serious adverse events; SAE without worsening of psoriasis correspond to SAE after exclusion of flares of psoriasis; SMD: standardised mean difference; AIL12/23: anti‐IL12/23; AIL17: anti‐IL17; AIL23: anti‐IL23, ATA: anti‐TNF alpha

Interval plot. Network meta‐analysis estimates of the interventions versus placebo for the primary outcomes CI: confidence interval; PrI: predictive interval; RR: risk ratio; SAE: serious adverse eventsACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumab

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Figure 11

Interval plot. Network meta‐analysis estimates of the interventions versus placebo for the primary outcomes

CI: confidence interval; PrI: predictive interval; RR: risk ratio; SAE: serious adverse events

ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumab

Interval plot. Network meta‐analysis estimates of the interventions versus placebo for the secondary outcomes Outcomes were all measured at the induction phase (assessment from 8 to 24 weeks after randomisation).AE: adverse events; CI: confidence interval; PGA: Physician Global Assessment; PrI: predictive interval; QoL: Specific quality of life scale; RR: risk ratio; SMD: standardised mean differenceACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumab

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Figure 12

Interval plot. Network meta‐analysis estimates of the interventions versus placebo for the secondary outcomes

Outcomes were all measured at the induction phase (assessment from 8 to 24 weeks after randomisation).

AE: adverse events; CI: confidence interval; PGA: Physician Global Assessment; PrI: predictive interval; QoL: Specific quality of life scale; RR: risk ratio; SMD: standardised mean difference

ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumab

Ranking plot. Ranking plot representing simultaneously the efficacy (x axis, PASI 90) and the acceptability (y axis, serious adverse events) of all the interventions (class and drug levels) for patients with moderate‐to‐severe psoriasis. Optimal treatment should be characterised by both high efficacy and acceptability and should be in the right upper corner of this graph.Outcomes were measured at the induction phase (assessment from 8 to 24 weeks after randomisation).The different colours represent different groups of interventions considering their performance on both outcomes simultaneously. Interventions belonging to the same group are assumed having a similar performance when the two primary outcomes are considered jointlyACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumabPASI: Psoriasis Area and Severity Index; SAE: serious adverse events; SUCRA: surface under the cumulative ranking curve

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Figure 13

Ranking plot. Ranking plot representing simultaneously the efficacy (x axis, PASI 90) and the acceptability (y axis, serious adverse events) of all the interventions (class and drug levels) for patients with moderate‐to‐severe psoriasis. Optimal treatment should be characterised by both high efficacy and acceptability and should be in the right upper corner of this graph.

Outcomes were measured at the induction phase (assessment from 8 to 24 weeks after randomisation).

The different colours represent different groups of interventions considering their performance on both outcomes simultaneously. Interventions belonging to the same group are assumed having a similar performance when the two primary outcomes are considered jointly

ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumab

PASI: Psoriasis Area and Severity Index; SAE: serious adverse events; SUCRA: surface under the cumulative ranking curve

Ranking for all the outcomes at class level AIL12/23: anti‐IL12/23; AIL17: anti‐IL17; AIL23: anti‐IL23, ATA: anti‐TNF alpha; CSA: non‐biological conventional systemic agents; PBO: placebo; SM: small moleculesAE: adverse events; PASI: Psoriasis Area and Severity Index; PGA: Physician Global Assessment; QoL: quality of life; SAE: serious adverse events; SAE without worsening of psoriasis correspond to SAE after exclusion of flares of psoriasis

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Figure 14

Ranking for all the outcomes at class level

AIL12/23: anti‐IL12/23; AIL17: anti‐IL17; AIL23: anti‐IL23, ATA: anti‐TNF alpha; CSA: non‐biological conventional systemic agents; PBO: placebo; SM: small molecules

AE: adverse events; PASI: Psoriasis Area and Severity Index; PGA: Physician Global Assessment; QoL: quality of life; SAE: serious adverse events; SAE without worsening of psoriasis correspond to SAE after exclusion of flares of psoriasis

Ranking for all the outcomes at drug level ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumabAE: adverse events; PASI: Psoriasis Area and Severity Index; PGA: Physician Global Assessment; QoL: quality of life; SAE: serious adverse events

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Figure 15

Ranking for all the outcomes at drug level

ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumab

AE: adverse events; PASI: Psoriasis Area and Severity Index; PGA: Physician Global Assessment; QoL: quality of life; SAE: serious adverse events

Distributions of age (on the left, mean age in years in the y axis) and PASI score at baseline (on the right, mean PASI in the y axis) ratio of participants across comparisons (x axis) ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumab

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Figure 16

Distributions of age (on the left, mean age in years in the y axis) and PASI score at baseline (on the right, mean PASI in the y axis) ratio of participants across comparisons (x axis)

ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumab

Distributions of sex (on the left, percentage of males in the y axis) and weight (on the right, mean weight in kilograms in the y axis) of participants across comparisons (x axis) ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumab

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Figure 17

Distributions of sex (on the left, percentage of males in the y axis) and weight (on the right, mean weight in kilograms in the y axis) of participants across comparisons (x axis)

ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumab

Side‐splitting approach and design‐by‐treatment interaction model for inconsistency for Psoriasis Area and Severity Index (PASI) 90 ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumab

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Figure 18

Side‐splitting approach and design‐by‐treatment interaction model for inconsistency for Psoriasis Area and Severity Index (PASI) 90

ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumab

Side‐splitting approach and design‐by‐treatment interaction model for inconsistency for serious adverse events (SAEs) ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumab

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Figure 19

Side‐splitting approach and design‐by‐treatment interaction model for inconsistency for serious adverse events (SAEs)

ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumab

Inconsistency plots for all the outcomes at class level Inconsistency factor (IF) is calculated as the risk ratio (RR)/standardised mean difference (SMD) for direct evidence over the RR/SMD for indirect evidence in the loop with its 95% confidence interval (CI). IF value close to 0 indicates the absence of evidence for disagreement between direct and indirect evidence.AIL12/23: anti‐IL12/23; AIL17: anti‐IL17; AIL23: anti‐IL23, ATA: anti‐TNF alpha; CSA: non‐biological conventional systemic agents; PBO: placebo; SM: small molecules

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Figure 20

Inconsistency plots for all the outcomes at class level

Inconsistency factor (IF) is calculated as the risk ratio (RR)/standardised mean difference (SMD) for direct evidence over the RR/SMD for indirect evidence in the loop with its 95% confidence interval (CI). IF value close to 0 indicates the absence of evidence for disagreement between direct and indirect evidence.

AIL12/23: anti‐IL12/23; AIL17: anti‐IL17; AIL23: anti‐IL23, ATA: anti‐TNF alpha; CSA: non‐biological conventional systemic agents; PBO: placebo; SM: small molecules

Inconsistency plots for all the outcomes at drug level Inconsistency factor (IF) is calculated as the risk ratio (RR)/standardised mean difference (SMD) for direct evidence over the RR/SMD for indirect evidence in the loop with its 95% confidence interval (CI). IF value close to 0 indicates the absence of evidence for disagreement between direct and indirectACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumab

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Figure 21

Inconsistency plots for all the outcomes at drug level

Inconsistency factor (IF) is calculated as the risk ratio (RR)/standardised mean difference (SMD) for direct evidence over the RR/SMD for indirect evidence in the loop with its 95% confidence interval (CI). IF value close to 0 indicates the absence of evidence for disagreement between direct and indirect

ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumab

Sensitivity analyses ‐ Interval plot. Network meta‐analysis results for primary outcomes (PASI 90 and serious adverse events, left and right forest plot respectively) for trials with at least 50 participants. ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumabCI: confidence interval; PASI: Psoriasis Area and Severity Index; RR: risk ratio

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Figure 22

Sensitivity analyses ‐ Interval plot. Network meta‐analysis results for primary outcomes (PASI 90 and serious adverse events, left and right forest plot respectively) for trials with at least 50 participants.

ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumab

CI: confidence interval; PASI: Psoriasis Area and Severity Index; RR: risk ratio

Sensitivity analyses ‐ Interval plot. Network meta‐analysis results for primary outcomes (PASI 90 and serious adverse events, left and right forest plot respectively) for the completers. Outcomes were measured at the induction phase (assessment from 8 to 24 weeks after randomisation).ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumabCI: confidence interval; PASI: Psoriasis Area and Severity Index; RR: risk ratio

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Figure 23

Sensitivity analyses ‐ Interval plot. Network meta‐analysis results for primary outcomes (PASI 90 and serious adverse events, left and right forest plot respectively) for the completers.

Outcomes were measured at the induction phase (assessment from 8 to 24 weeks after randomisation).

ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumab

CI: confidence interval; PASI: Psoriasis Area and Severity Index; RR: risk ratio

Sensitivity analyses ‐ Interval plot. Network meta‐analysis results for primary outcomes (PASI 90 and serious adverse events, left and right forest plot respectively) for all the interventions depending on the doses: approved dosages versus other dosages Outcomes were measured at the induction phase (assessment from 8 to 24 weeks after randomisation).MTX_AMM/Other: methotrexate ≥ 15 mg per week/ < 15 mg per week; CICLO_AMM/Other: ciclosporin ≥ 3 mg/kg/day/<3 mg/kg/day; ACI_AMM/Other: acitretin ≥ 35 mg per day/<35 mg per day; FUM: fumaric acid esters all dosages; APRE_AMM/Other: apremilast 30 mg twice daily/other dosages; TOFA_AMM/Other: tofacitinib 20 mg per day/Other dosages; ETA_AMM/Other: etanercept 50 mg twice a week/Other dosage; IFX_AMM/Other: infliximab 5 mg/kg week 0, 2, 4 every 6 weeks/Other dosages; ADA_AMM/Other: adalimumab 80 mg Week 0, 40 mg Week 1 then 40 mg every other week/Other dosages; CERTO_AMM/Other: certolizumab 400 mg at week 0,2,4 then 400 mg every other week or other dosages/Other dosages; USK 45/90: ustekinumab 45/90 mg; SECU_AMM/Other: secukinumab 300 mg at week 0, 1, 2, 3, and 4 then every 4 weeks or other dosages/other dosages; IXE_AMM/Other: ixekizumab 160 mg at Week then 80 mg every other weeks until week 12 then 80 mg monthly or other dosages; TILDRA_AMM/Other: tildrakizumab 100 mg at week 0 and 4 then every 12 weeks/Other dosages; GUSEL 100: guselkumab 100 mg per injection; BRODA_AMM/Other: brodalumab 210 mg at week 0, 1, 2 then every other weeks/other dosages; RISAN_AMM/Other: risankizumab, S/C, 150 mg (two 75 mg injections) at Week 0, Week 4 and every 12 weeks thereafter/other dosages; TYK2 (Oral Tyrosine kinase 2 inhibitor), MIRI (mirikizumab) and BIME (bimekizumab) (S/C) were grouped in one dosage whatever the dosages.CI: confidence interval; PASI: Psoriasis Area and Severity Index; RR: risk ratio; AMM: 'approved dosage'

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Figure 24

Sensitivity analyses ‐ Interval plot. Network meta‐analysis results for primary outcomes (PASI 90 and serious adverse events, left and right forest plot respectively) for all the interventions depending on the doses: approved dosages versus other dosages

Outcomes were measured at the induction phase (assessment from 8 to 24 weeks after randomisation).

MTX_AMM/Other: methotrexate ≥ 15 mg per week/ < 15 mg per week; CICLO_AMM/Other: ciclosporin ≥ 3 mg/kg/day/<3 mg/kg/day; ACI_AMM/Other: acitretin ≥ 35 mg per day/<35 mg per day; FUM: fumaric acid esters all dosages; APRE_AMM/Other: apremilast 30 mg twice daily/other dosages; TOFA_AMM/Other: tofacitinib 20 mg per day/Other dosages; ETA_AMM/Other: etanercept 50 mg twice a week/Other dosage; IFX_AMM/Other: infliximab 5 mg/kg week 0, 2, 4 every 6 weeks/Other dosages; ADA_AMM/Other: adalimumab 80 mg Week 0, 40 mg Week 1 then 40 mg every other week/Other dosages; CERTO_AMM/Other: certolizumab 400 mg at week 0,2,4 then 400 mg every other week or other dosages/Other dosages; USK 45/90: ustekinumab 45/90 mg; SECU_AMM/Other: secukinumab 300 mg at week 0, 1, 2, 3, and 4 then every 4 weeks or other dosages/other dosages; IXE_AMM/Other: ixekizumab 160 mg at Week then 80 mg every other weeks until week 12 then 80 mg monthly or other dosages; TILDRA_AMM/Other: tildrakizumab 100 mg at week 0 and 4 then every 12 weeks/Other dosages; GUSEL 100: guselkumab 100 mg per injection; BRODA_AMM/Other: brodalumab 210 mg at week 0, 1, 2 then every other weeks/other dosages; RISAN_AMM/Other: risankizumab, S/C, 150 mg (two 75 mg injections) at Week 0, Week 4 and every 12 weeks thereafter/other dosages; TYK2 (Oral Tyrosine kinase 2 inhibitor), MIRI (mirikizumab) and BIME (bimekizumab) (S/C) were grouped in one dosage whatever the dosages.

CI: confidence interval; PASI: Psoriasis Area and Severity Index; RR: risk ratio; AMM: 'approved dosage'

Sensitivity analyses ‐ Interval plot. Network meta‐analysis results for primary outcomes (PASI 90 and serious adverse events, left and right forest plot respectively) for all the interventions excluding studies at high risk of bias. Outcomes were measured at the induction phase (assessment from 8 to 24 weeks after randomisation).ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumabCI: confidence interval; PASI: Psoriasis Area and Severity Index; RR: risk ratio

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Figure 25

Sensitivity analyses ‐ Interval plot. Network meta‐analysis results for primary outcomes (PASI 90 and serious adverse events, left and right forest plot respectively) for all the interventions excluding studies at high risk of bias.

Outcomes were measured at the induction phase (assessment from 8 to 24 weeks after randomisation).

ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumab

CI: confidence interval; PASI: Psoriasis Area and Severity Index; RR: risk ratio

Sensitivity analyses ‐ Interval plot. Network meta‐analysis results for primary outcomes (PASI 90 and serious adverse events, left and right forest plot respectively) for all the interventions including studies with a short‐term assessment from 8 to 16 weeks. ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumabCI: confidence interval; PASI: Psoriasis Area and Severity Index; RR: risk ratio

Figures and Tables -
Figure 26

Sensitivity analyses ‐ Interval plot. Network meta‐analysis results for primary outcomes (PASI 90 and serious adverse events, left and right forest plot respectively) for all the interventions including studies with a short‐term assessment from 8 to 16 weeks.

ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumab

CI: confidence interval; PASI: Psoriasis Area and Severity Index; RR: risk ratio

Sensitivity analyses ‐ Interval plot. Network meta‐analysis results for primary outcomes (PASI 90 and serious adverse events, left and right forest plot respectively) for all the interventions including studies with systemic treatment‐naive participants. Outcomes were measured at the induction phase (assessment from 8 to 24 weeks after randomisation).ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumabCI: confidence interval; PASI: Psoriasis Area and Severity Index; RR: risk ratio

Figures and Tables -
Figure 27

Sensitivity analyses ‐ Interval plot. Network meta‐analysis results for primary outcomes (PASI 90 and serious adverse events, left and right forest plot respectively) for all the interventions including studies with systemic treatment‐naive participants.

Outcomes were measured at the induction phase (assessment from 8 to 24 weeks after randomisation).

ACI: acitretin; ADA: adalimumab; APRE: apremilast; BIME: bimekizumab; BRODA: brodalumab; CERTO: certolizumab; CICLO: ciclosporin; ETA: etanercept; FUM: fumaric acid; IFX: infliximab; IXE: ixekizumab; GUSEL: guselkumab; MIRI: mirikizumab; MTX: methotrexate; PBO: placebo; RISAN: risankizumab; SECU: secukinumab; TILDRA: tildrakizumab; TOFA: tofacitinib; TYK2: Oral Tyrosine kinase 2 inhibitor; USK: ustekinumab

CI: confidence interval; PASI: Psoriasis Area and Severity Index; RR: risk ratio

Funnel plot for network meta‐analysis of all the outcomesAE: adverse event; lnRR: Mean effect size; PASI: Psoriasis Area and Severity Index; QoL: Specific quality of life scale; RR: Risk ratio; SAE: serious adverse events; SAE without worsening of psoriasis correspond to SAE after exclusion of flares of psoriasis; SMD: standardised mean difference

Figures and Tables -
Figure 28

Funnel plot for network meta‐analysis of all the outcomes

AE: adverse event; lnRR: Mean effect size; PASI: Psoriasis Area and Severity Index; QoL: Specific quality of life scale; RR: Risk ratio; SAE: serious adverse events; SAE without worsening of psoriasis correspond to SAE after exclusion of flares of psoriasis; SMD: standardised mean difference

Certainty of evidence per drug for PASI 90 using CINeMA Each drug is presented as a bar, which indicates the composition of the 4‐level confidence of evidence from all comparisons including that drug. Green: high confidence; blue: moderate confidence; yellow: low confidence; red: very low confidence.

Figures and Tables -
Figure 29

Certainty of evidence per drug for PASI 90 using CINeMA

Each drug is presented as a bar, which indicates the composition of the 4‐level confidence of evidence from all comparisons including that drug. Green: high confidence; blue: moderate confidence; yellow: low confidence; red: very low confidence.

Certainty of evidence per drug for Serious Adverse Events using CINeMA Each drug is presented as a bar, which indicates the composition of the 4‐level confidence of evidence from all comparisons including that drug. Green: high confidence; blue: moderate confidence; yellow: low confidence; red: very low confidence.

Figures and Tables -
Figure 30

Certainty of evidence per drug for Serious Adverse Events using CINeMA

Each drug is presented as a bar, which indicates the composition of the 4‐level confidence of evidence from all comparisons including that drug. Green: high confidence; blue: moderate confidence; yellow: low confidence; red: very low confidence.

Comparison 1: Primary outcome ‐ PASI 90, Outcome 1: Non‐biological treatments versus placebo

Figures and Tables -
Analysis 1.1

Comparison 1: Primary outcome ‐ PASI 90, Outcome 1: Non‐biological treatments versus placebo

Comparison 1: Primary outcome ‐ PASI 90, Outcome 2: Non‐biological treatment 1 versus non‐biological treatment 2

Figures and Tables -
Analysis 1.2

Comparison 1: Primary outcome ‐ PASI 90, Outcome 2: Non‐biological treatment 1 versus non‐biological treatment 2

Comparison 1: Primary outcome ‐ PASI 90, Outcome 3: Anti‐TNF alpha versus placebo

Figures and Tables -
Analysis 1.3

Comparison 1: Primary outcome ‐ PASI 90, Outcome 3: Anti‐TNF alpha versus placebo

Comparison 1: Primary outcome ‐ PASI 90, Outcome 4: Anti‐IL12/23 versus placebo

Figures and Tables -
Analysis 1.4

Comparison 1: Primary outcome ‐ PASI 90, Outcome 4: Anti‐IL12/23 versus placebo

Comparison 1: Primary outcome ‐ PASI 90, Outcome 5: Anti‐IL17 versus placebo

Figures and Tables -
Analysis 1.5

Comparison 1: Primary outcome ‐ PASI 90, Outcome 5: Anti‐IL17 versus placebo

Comparison 1: Primary outcome ‐ PASI 90, Outcome 6: Anti‐IL23 versus placebo

Figures and Tables -
Analysis 1.6

Comparison 1: Primary outcome ‐ PASI 90, Outcome 6: Anti‐IL23 versus placebo

Comparison 1: Primary outcome ‐ PASI 90, Outcome 7: Biologic versus non‐biological treatment

Figures and Tables -
Analysis 1.7

Comparison 1: Primary outcome ‐ PASI 90, Outcome 7: Biologic versus non‐biological treatment

Comparison 1: Primary outcome ‐ PASI 90, Outcome 8: Biologic 1 versus biologic 2

Figures and Tables -
Analysis 1.8

Comparison 1: Primary outcome ‐ PASI 90, Outcome 8: Biologic 1 versus biologic 2

Comparison 1: Primary outcome ‐ PASI 90, Outcome 9: Small molecules versus placebo

Figures and Tables -
Analysis 1.9

Comparison 1: Primary outcome ‐ PASI 90, Outcome 9: Small molecules versus placebo

Comparison 1: Primary outcome ‐ PASI 90, Outcome 10: Biologic versus small molecules

Figures and Tables -
Analysis 1.10

Comparison 1: Primary outcome ‐ PASI 90, Outcome 10: Biologic versus small molecules

Comparison 2: Primary outcome ‐ serious adverse events (SAE), Outcome 1: Non‐biological treatments versus placebo

Figures and Tables -
Analysis 2.1

Comparison 2: Primary outcome ‐ serious adverse events (SAE), Outcome 1: Non‐biological treatments versus placebo

Comparison 2: Primary outcome ‐ serious adverse events (SAE), Outcome 2: Non‐biological treatment 1 versus non‐biological treatment 2

Figures and Tables -
Analysis 2.2

Comparison 2: Primary outcome ‐ serious adverse events (SAE), Outcome 2: Non‐biological treatment 1 versus non‐biological treatment 2

Comparison 2: Primary outcome ‐ serious adverse events (SAE), Outcome 3: Anti‐TNF alpha versus placebo

Figures and Tables -
Analysis 2.3

Comparison 2: Primary outcome ‐ serious adverse events (SAE), Outcome 3: Anti‐TNF alpha versus placebo

Comparison 2: Primary outcome ‐ serious adverse events (SAE), Outcome 4: Anti‐IL12/23 versus placebo

Figures and Tables -
Analysis 2.4

Comparison 2: Primary outcome ‐ serious adverse events (SAE), Outcome 4: Anti‐IL12/23 versus placebo

Comparison 2: Primary outcome ‐ serious adverse events (SAE), Outcome 5: Anti‐IL17 versus placebo

Figures and Tables -
Analysis 2.5

Comparison 2: Primary outcome ‐ serious adverse events (SAE), Outcome 5: Anti‐IL17 versus placebo

Comparison 2: Primary outcome ‐ serious adverse events (SAE), Outcome 6: Anti‐IL23 versus placebo

Figures and Tables -
Analysis 2.6

Comparison 2: Primary outcome ‐ serious adverse events (SAE), Outcome 6: Anti‐IL23 versus placebo

Comparison 2: Primary outcome ‐ serious adverse events (SAE), Outcome 7: Biologic versus non‐biological treatments

Figures and Tables -
Analysis 2.7

Comparison 2: Primary outcome ‐ serious adverse events (SAE), Outcome 7: Biologic versus non‐biological treatments

Comparison 2: Primary outcome ‐ serious adverse events (SAE), Outcome 8: Biologic 1 versus biologic 2

Figures and Tables -
Analysis 2.8

Comparison 2: Primary outcome ‐ serious adverse events (SAE), Outcome 8: Biologic 1 versus biologic 2

Comparison 2: Primary outcome ‐ serious adverse events (SAE), Outcome 9: Small molecules versus placebo

Figures and Tables -
Analysis 2.9

Comparison 2: Primary outcome ‐ serious adverse events (SAE), Outcome 9: Small molecules versus placebo

Comparison 2: Primary outcome ‐ serious adverse events (SAE), Outcome 10: Biologic versus small molecules

Figures and Tables -
Analysis 2.10

Comparison 2: Primary outcome ‐ serious adverse events (SAE), Outcome 10: Biologic versus small molecules

Comparison 3: Secondary outcome ‐ PASI 75, Outcome 1: Non‐biological treatments versus placebo

Figures and Tables -
Analysis 3.1

Comparison 3: Secondary outcome ‐ PASI 75, Outcome 1: Non‐biological treatments versus placebo

Comparison 3: Secondary outcome ‐ PASI 75, Outcome 2: Non‐biological treatment 1 versus non‐biological treatment 2

Figures and Tables -
Analysis 3.2

Comparison 3: Secondary outcome ‐ PASI 75, Outcome 2: Non‐biological treatment 1 versus non‐biological treatment 2

Comparison 3: Secondary outcome ‐ PASI 75, Outcome 3: Anti‐TNF alpha versus placebo

Figures and Tables -
Analysis 3.3

Comparison 3: Secondary outcome ‐ PASI 75, Outcome 3: Anti‐TNF alpha versus placebo

Comparison 3: Secondary outcome ‐ PASI 75, Outcome 4: Anti‐IL12/23 versus placebo

Figures and Tables -
Analysis 3.4

Comparison 3: Secondary outcome ‐ PASI 75, Outcome 4: Anti‐IL12/23 versus placebo

Comparison 3: Secondary outcome ‐ PASI 75, Outcome 5: Anti‐IL17 versus placebo

Figures and Tables -
Analysis 3.5

Comparison 3: Secondary outcome ‐ PASI 75, Outcome 5: Anti‐IL17 versus placebo

Comparison 3: Secondary outcome ‐ PASI 75, Outcome 6: Anti‐IL23 versus placebo

Figures and Tables -
Analysis 3.6

Comparison 3: Secondary outcome ‐ PASI 75, Outcome 6: Anti‐IL23 versus placebo

Comparison 3: Secondary outcome ‐ PASI 75, Outcome 7: Biologic versus non‐biological treatments

Figures and Tables -
Analysis 3.7

Comparison 3: Secondary outcome ‐ PASI 75, Outcome 7: Biologic versus non‐biological treatments

Comparison 3: Secondary outcome ‐ PASI 75, Outcome 8: Biologic 1 versus biologic 2

Figures and Tables -
Analysis 3.8

Comparison 3: Secondary outcome ‐ PASI 75, Outcome 8: Biologic 1 versus biologic 2

Comparison 3: Secondary outcome ‐ PASI 75, Outcome 9: Small molecules versus placebo

Figures and Tables -
Analysis 3.9

Comparison 3: Secondary outcome ‐ PASI 75, Outcome 9: Small molecules versus placebo

Comparison 3: Secondary outcome ‐ PASI 75, Outcome 10: Biologic versus small molecules

Figures and Tables -
Analysis 3.10

Comparison 3: Secondary outcome ‐ PASI 75, Outcome 10: Biologic versus small molecules

Comparison 4: Secondary outcome ‐ PGA 0/1, Outcome 1: Non‐biological treatment versus placebo

Figures and Tables -
Analysis 4.1

Comparison 4: Secondary outcome ‐ PGA 0/1, Outcome 1: Non‐biological treatment versus placebo

Comparison 4: Secondary outcome ‐ PGA 0/1, Outcome 2: Non‐biological treatment 1 versus non‐biological treatment 2

Figures and Tables -
Analysis 4.2

Comparison 4: Secondary outcome ‐ PGA 0/1, Outcome 2: Non‐biological treatment 1 versus non‐biological treatment 2

Comparison 4: Secondary outcome ‐ PGA 0/1, Outcome 3: Anti‐TNF alpha versus placebo

Figures and Tables -
Analysis 4.3

Comparison 4: Secondary outcome ‐ PGA 0/1, Outcome 3: Anti‐TNF alpha versus placebo

Comparison 4: Secondary outcome ‐ PGA 0/1, Outcome 4: Anti‐IL12/23 versus placebo

Figures and Tables -
Analysis 4.4

Comparison 4: Secondary outcome ‐ PGA 0/1, Outcome 4: Anti‐IL12/23 versus placebo

Comparison 4: Secondary outcome ‐ PGA 0/1, Outcome 5: Anti‐IL17 versus placebo

Figures and Tables -
Analysis 4.5

Comparison 4: Secondary outcome ‐ PGA 0/1, Outcome 5: Anti‐IL17 versus placebo

Comparison 4: Secondary outcome ‐ PGA 0/1, Outcome 6: Anti‐IL23 versus placebo

Figures and Tables -
Analysis 4.6

Comparison 4: Secondary outcome ‐ PGA 0/1, Outcome 6: Anti‐IL23 versus placebo

Comparison 4: Secondary outcome ‐ PGA 0/1, Outcome 7: Biologic versus non‐biological treatments

Figures and Tables -
Analysis 4.7

Comparison 4: Secondary outcome ‐ PGA 0/1, Outcome 7: Biologic versus non‐biological treatments

Comparison 4: Secondary outcome ‐ PGA 0/1, Outcome 8: Biologic 1 versus biologic 2

Figures and Tables -
Analysis 4.8

Comparison 4: Secondary outcome ‐ PGA 0/1, Outcome 8: Biologic 1 versus biologic 2

Comparison 4: Secondary outcome ‐ PGA 0/1, Outcome 9: Small molecules versus placebo

Figures and Tables -
Analysis 4.9

Comparison 4: Secondary outcome ‐ PGA 0/1, Outcome 9: Small molecules versus placebo

Comparison 4: Secondary outcome ‐ PGA 0/1, Outcome 10: Biologic versus small molecules

Figures and Tables -
Analysis 4.10

Comparison 4: Secondary outcome ‐ PGA 0/1, Outcome 10: Biologic versus small molecules

Comparison 5: Secondary outcome ‐ quality of life, Outcome 1: Non‐biological treatments versus placebo

Figures and Tables -
Analysis 5.1

Comparison 5: Secondary outcome ‐ quality of life, Outcome 1: Non‐biological treatments versus placebo

Comparison 5: Secondary outcome ‐ quality of life, Outcome 2: Non‐biological treatment 1 versus non‐biological treatment 2

Figures and Tables -
Analysis 5.2

Comparison 5: Secondary outcome ‐ quality of life, Outcome 2: Non‐biological treatment 1 versus non‐biological treatment 2

Comparison 5: Secondary outcome ‐ quality of life, Outcome 3: Anti‐TNF alpha versus placebo

Figures and Tables -
Analysis 5.3

Comparison 5: Secondary outcome ‐ quality of life, Outcome 3: Anti‐TNF alpha versus placebo

Comparison 5: Secondary outcome ‐ quality of life, Outcome 4: Ustekinumab versus placebo

Figures and Tables -
Analysis 5.4

Comparison 5: Secondary outcome ‐ quality of life, Outcome 4: Ustekinumab versus placebo

Comparison 5: Secondary outcome ‐ quality of life, Outcome 5: Anti‐IL17 versus placebo

Figures and Tables -
Analysis 5.5

Comparison 5: Secondary outcome ‐ quality of life, Outcome 5: Anti‐IL17 versus placebo

Comparison 5: Secondary outcome ‐ quality of life, Outcome 6: Anti‐IL23 versus placebo

Figures and Tables -
Analysis 5.6

Comparison 5: Secondary outcome ‐ quality of life, Outcome 6: Anti‐IL23 versus placebo

Comparison 5: Secondary outcome ‐ quality of life, Outcome 7: Biologic versus non‐biological treatment

Figures and Tables -
Analysis 5.7

Comparison 5: Secondary outcome ‐ quality of life, Outcome 7: Biologic versus non‐biological treatment

Comparison 5: Secondary outcome ‐ quality of life, Outcome 8: Biologic 1 versus biologic 2

Figures and Tables -
Analysis 5.8

Comparison 5: Secondary outcome ‐ quality of life, Outcome 8: Biologic 1 versus biologic 2

Comparison 5: Secondary outcome ‐ quality of life, Outcome 9: Small molecules versus placebo

Figures and Tables -
Analysis 5.9

Comparison 5: Secondary outcome ‐ quality of life, Outcome 9: Small molecules versus placebo

Comparison 5: Secondary outcome ‐ quality of life, Outcome 10: Biologic versus small molecules

Figures and Tables -
Analysis 5.10

Comparison 5: Secondary outcome ‐ quality of life, Outcome 10: Biologic versus small molecules

Comparison 6: Secondary outcome ‐ adverse events, Outcome 1: Non‐biological treatments versus placebo

Figures and Tables -
Analysis 6.1

Comparison 6: Secondary outcome ‐ adverse events, Outcome 1: Non‐biological treatments versus placebo

Comparison 6: Secondary outcome ‐ adverse events, Outcome 2: Non‐biological treatment 1 versus non‐biological treatment 2

Figures and Tables -
Analysis 6.2

Comparison 6: Secondary outcome ‐ adverse events, Outcome 2: Non‐biological treatment 1 versus non‐biological treatment 2

Comparison 6: Secondary outcome ‐ adverse events, Outcome 3: Anti‐TNF alpha versus placebo

Figures and Tables -
Analysis 6.3

Comparison 6: Secondary outcome ‐ adverse events, Outcome 3: Anti‐TNF alpha versus placebo

Comparison 6: Secondary outcome ‐ adverse events, Outcome 4: Ustekinumab versus placebo

Figures and Tables -
Analysis 6.4

Comparison 6: Secondary outcome ‐ adverse events, Outcome 4: Ustekinumab versus placebo

Comparison 6: Secondary outcome ‐ adverse events, Outcome 5: Anti‐IL17 versus placebo

Figures and Tables -
Analysis 6.5

Comparison 6: Secondary outcome ‐ adverse events, Outcome 5: Anti‐IL17 versus placebo

Comparison 6: Secondary outcome ‐ adverse events, Outcome 6: Anti‐IL23 versus placebo

Figures and Tables -
Analysis 6.6

Comparison 6: Secondary outcome ‐ adverse events, Outcome 6: Anti‐IL23 versus placebo

Comparison 6: Secondary outcome ‐ adverse events, Outcome 7: Biologic versus non‐biological treatments

Figures and Tables -
Analysis 6.7

Comparison 6: Secondary outcome ‐ adverse events, Outcome 7: Biologic versus non‐biological treatments

Comparison 6: Secondary outcome ‐ adverse events, Outcome 8: Biologic 1 versus biologic 2

Figures and Tables -
Analysis 6.8

Comparison 6: Secondary outcome ‐ adverse events, Outcome 8: Biologic 1 versus biologic 2

Comparison 6: Secondary outcome ‐ adverse events, Outcome 9: Small molecules versus placebo

Figures and Tables -
Analysis 6.9

Comparison 6: Secondary outcome ‐ adverse events, Outcome 9: Small molecules versus placebo

Comparison 6: Secondary outcome ‐ adverse events, Outcome 10: Biologic versus small molecules

Figures and Tables -
Analysis 6.10

Comparison 6: Secondary outcome ‐ adverse events, Outcome 10: Biologic versus small molecules

Comparison 7: Secondary outcome ‐ PASI 90 at 52 weeks, Outcome 1: Biologic 1 versus biologic 2

Figures and Tables -
Analysis 7.1

Comparison 7: Secondary outcome ‐ PASI 90 at 52 weeks, Outcome 1: Biologic 1 versus biologic 2

Comparison 7: Secondary outcome ‐ PASI 90 at 52 weeks, Outcome 2: Small molecule 1 versus small molecule 2

Figures and Tables -
Analysis 7.2

Comparison 7: Secondary outcome ‐ PASI 90 at 52 weeks, Outcome 2: Small molecule 1 versus small molecule 2

Comparison 7: Secondary outcome ‐ PASI 90 at 52 weeks, Outcome 3: Biologic versus placebo

Figures and Tables -
Analysis 7.3

Comparison 7: Secondary outcome ‐ PASI 90 at 52 weeks, Outcome 3: Biologic versus placebo

Comparison 8: Secondary outcome ‐ PASI 75 at 52 weeks, Outcome 1: Biologic 1 versus biologic 2

Figures and Tables -
Analysis 8.1

Comparison 8: Secondary outcome ‐ PASI 75 at 52 weeks, Outcome 1: Biologic 1 versus biologic 2

Comparison 8: Secondary outcome ‐ PASI 75 at 52 weeks, Outcome 2: Small molecules 1 versus small molecules 2

Figures and Tables -
Analysis 8.2

Comparison 8: Secondary outcome ‐ PASI 75 at 52 weeks, Outcome 2: Small molecules 1 versus small molecules 2

Table 1. Glossary

Term

Definition

Antagonist

A substance that interferes with or inhibits the physiological action of another.

Antigen

A molecule capable of inducing an immune response

Anti‐TNF alpha

A pharmaceutical drug that suppresses the physiologic response to tumour necrosis factor (TNF)

Biological agent

Therapeutic agents consisting of immune molecules such as soluble receptors, recombinant cytokines, and monoclonal antibodies that target effector molecules or cells of the immune system

Biosimilar

Biological agent highly similar to another already‐approved biological medicine

CD6

Cluster of differentiation (CD) 6 is a protein encoded by the CD6 gene

Cheilitis

An inflammation of the lips

Chimeric protein

A chimeric protein can be made by combining two different genes

Complex cyclophilin‐ciclosporin

Cyclophilins are a family of proteins that bind to ciclosporin, an immunosuppressant agent

Creatinine

A compound that is produced by metabolism of creatine and excreted in the urine

Cyclic adenosine monophosphate

It is a second messenger important in many biological processes

Cytokines

Small proteins produced by a broad range of cells that are important in cell signalling; they are immunomodulating agents

Dendritic cells

Antigen‐presenting cells of the immune system

Dermis

It is a layer of the skin

Epitope

It is a part of an antigen

Erythematous

Redness of the skin

Folic acid

B vitamin

Humanised antibody

Antibodies from non‐human species whose protein sequences have been modified to increase their similarity to antibody variants produced naturally in humans

IL‐17A

A pro‐inflammatory cytokine

IL‐23R

A cytokine receptor

Immune‐mediated

A group of diseases that are characterised by common inflammatory pathways leading to inflammation, and which may result from a dysregulation of the normal immune response

Immunogenicity

This is the ability of a particular substance, such as an antigen or epitope, to provoke an immune response in the body of a human or animal

Immunoglobulin 1 Fc

An antibody

Interferon (IFN)‐c

A protein released by cells, usually in response to a pathogen

Interleukin

A kind of cytokine

Janus kinase (JAK) inhibitors

A pharmaceutical drug that inhibits the activity of one or more of the Janus kinase family of enzymes

Keratinocytes

Epidermal cells that constitute 95% of the epidermis

Lymphocyte

A subtype of a white blood cell

Lymphoid organ

Part of the body that defends the body against invading pathogens that cause infections or the spread of tumours

Metalloproteinases

A protease enzyme

Monoclonal antibodies

Antibodies that are made by identical immune cells that are all clones of a unique parent cell

Murine sequence

Mouse genomic sequencing

Neutrophils

Type of white blood cell involved in the innate immune system

p40

Subunit beta of interleukin 12 and 23

Periumbilical

Around the navel

Pharmacological treatments

Drugs

Phase I

First‐in‐man studies

Phase II

Studies to assess how well the drug works, as well as to continue phase I safety assessments in a larger group of volunteers and participants

Phase III

Randomised controlled multicenter trials on large patient groups and are aimed at being the definitive assessment of how effective the drug is

Phase IV

Post‐marketing trials involve the safety surveillance

Phosphodiesterase 4 inhibitors

A pharmaceutical drug used to block the degradative action of phosphodiesterase 4

Progressive multifocal leukoencephalopathy

A rare viral neurological disease characterised by progressive damage of the white matter of the brain at multiple locations

Receptor

A protein molecule that receives chemical signals from outside a cell

Small molecules

Chemically manufactured molecules (or SMOLs for short)

Sphingosine 1‐phosphate receptor agonists

A class of protein‐coupled receptors that are targets of the lipid signalling molecule Sphingosine‐1‐phosphate

T cells/CD4 T cells

A type of white blood cell that is of key importance to the immune system

Th1 and Tc1 cells

A type of T cell

Th17 and Tc17 cells

A type of T cell

TNF‐alpha

A protein that is part of the inflammatory response

Tumour necrosis factor antagonists

Class of biological agents

Umbilic

Navel

Xerosis

Dry skin

Figures and Tables -
Table 1. Glossary
Table 2. Investigators contacted

Contact

Requested Information

Contacted

Reply

Missing data

Akcali 2014

Prof. Akcali

Outcomes: PASI 90, PASI 75, PGA 0/1, QoL scale, AEs & SAEs

8 and 21 November 2016

No response

Al‐Hamamy 2014

Prof. Al‐Hamamy

Outcomes: PASI 75, PGA 0/1, QoL scale, AEs and SAEs

8 and 21 November 2016

No response

Asahina 2010

Prof. Asahina

Outcome: PASI 90

8 November 2016

Asahina 2010 detailed report

Asahina 2016

Prof. Asahina Pfizer

Outcomes: AEs and SAEs

3 and 12 January 2017

Additional data to the publication not provided

Asawanonda 2006

Prof. Asawanonda

Outcomes: PASI 75, PGA 0/1, AEs and SAEs

21 November 2016

15 December 2016

Asawanonda 2006 sent detailed report for PASI 75 and AEs. PGA was not collected during this study

Bissonnette 2015

Prof. Bisonnette Innovaderm Recherches Inc.

Outcomes: PASI 90, PGA 0/1, AEs

8 and 21 November 2016

Additional data to the publication not provided

FEATURE 2015

Dr Blauvelt

Novartis

Outcome: QoL scale

8 and 21 November 2016

Additional data to the publication not provided

Caproni 2009

Prof. Fabri

Outcomes: PASI 90, PASI 75, PGA 0/1, QoL scale, AEs and SAEs

8 and 21 November 2016

Caproni 2009 sent detailed report for PASI 90 and SAEs. Other outcomes (PGA, QoL and AEs) not collected during this study.

Dogra 2013

Prof. Dogra

Outcomes: PGA 0/1, QoL scale, AEs and SAEs

8 and 21 November 2016

No response

Dogra 2012

Prof. Dogra

Outcomes: PGA 0/1, QoL scale, AEs and SAEs

8 November 2016

PGA & QoL scale not collected during this study. AEs and SAEs not provided per arm

Fallah Arani 2011

Dr Fallah Arani

Outcomes: PASI 90, PGA 0/1 and QoL scale

8 and 21 November 2016

Outcomes not collected during this study

Flytström 2008

Prof. Flytström

Outcomes: PGA 0/1

12 and 19 January 2017

Additional data to the publication not provided

Gisondi 2008

Prof. Gisondi

Outcomes: PASI 90, PGA 0/1, QoL scale, AEs and SAEs

8 November 2016

Gisondi 2008 sent detailed report for the requested outcomes except for QoL (not assessed during the study)

Gordon 2006

Prof. Gordon

Outcomes: PGA0/1, AEs

3 and 12 January 2017

No response

Gottlieb 2012

Prof. Gottlieb

Abbvie

Outcomes: PASI 90 & QoL scale

8 November 2016

Gottlieb 2012 sent detailed report for the requested outcomes

Gottlieb 2011

Prof. Gottlieb

Amgen

Outcomes: PASI 90, PGA 0/1, QoL scale, AEs and SAEs

8 November 2016

Gottlieb 2011 sent detailed report for the requested outcomes

ACCEPT 2010

Prof. Griffiths

Janssen

Outcome: QoL scale

16 December 2016

QoL was not collected during this study

Krueger 2016a

Pfizer

Outcomes: PASI 90, QoL scale

3 and 12 January 2017

No response

AMAGINE‐2 2015

Prof. Lebwohl

Valeant Pharmaceuticals NA LLC

Outcomes: PASI 90 and QoL scale

8 and 21 November 2016

AMAGINE‐2 2015 sent detailed report for PASI 90; individual scores and median difference from baseline of QoL were not available

AMAGINE‐3 2015

Prof. Lebwohl

Valeant Pharmaceuticals NA LLC

Outcomes: PASI 90 and QoL scale

8 and 21 November 2016

AMAGINE‐3 2015 sent detailed report for PASI 90, individual scores and median difference from baseline of QoL were not available

Leonardi 2012

Prof. Leonardi

Outcomes: QoL scale and AEs

8 and 21 November 2016

No response

Mahajan 2010

Prof. Kaur

Outcomes: PASI 90, PGA 0/1, QoL scale, AEs and SAEs

8 and 21 November 2016

No response

REVEAL 2008

Prof. Menter

Outcome: PGA 0/1

8 and 21 November 2016

No response

EXPRESS‐II 2007

Prof. Menter

Outcome: PGA 0/1

8 and 21 November 2016

No response

BRIDGE 2017

Prof. Mrowietz

Outcome: QoL scale

3 and 12 January 2017

Additional data to the publication not provided

Ortonne 2013

Prof. Paul

Novartis

Outcome: PASI 90

3 January 2017

Additional data to the publication not provided

Papp 2013a

Prof. Papp

Outcome: QoL scale

22 November 2016 13 December 2016

Additional data to the publication not provided

AMAGINE‐1 2016

Prof. Papp

Outcome: QoL scale

22 November 2016 13 December 2016

Additional data to the publication not provided

Papp 2005

Prof. Papp

Outcome: QoL scale, AEs and SAEs

22 November 2016 13 December 2016

Additional data to the publication not provided

Papp 2012b

Prof. Papp

Outcome: QoL scale

22 November 2016 13 December 2016

Additional data to the publication not provided

Papp 2013b

Prof. Papp

Outcome: PASI 90, PGA0/1, QoL scale

3 January 2017

Additional data to the publication not provided

JUNCTURE 2015

Prof. Paul

Novartis

Outcome: QoL scale

15 December 2016, 2 January 2017

Additional data to the publication not provided

Reich 2015

Prof. Reich

Novartis

Outcomes: PGA 0/1 and QoL scale

8 November 2016, 16 December 2016

Additional data to the publication not provided

LIBERATE 2017

Prof. Reich PelotonAdvantage

Outcome: QoL scale

4 January 2017

Additional data to the publication not provided

Rich 2013

Prof. Rich

Outcome: QoL scale

22 November 2016, 13 December 2016

No response

PRESTA 2010

Prof. Sterry

Outcomes: PASI 90 and QoL scale

8 and 21 November 2016

No response

Strober 2011

Prof. Strober

Abbvie

Outcome: QoL scale

8 November 2016

Strober sent detailed report for the requested outcomes

CLEAR 2015

Prof. Thaçi

Novartis

Outcome: QoL scale

8 and 21 November 2016

Additional data to the publication not provided

Torii 2010

Prof. Torii

Outcomes: PASI 90 and PGA0/1

21 November 2016

Torii sent detailed report for the requested outcomes

Tyring 2006

Prof. Tyring

Outcomes: PGA 0/1 and QoL scale

8 and 21 November 2016

No response

Van Bezooijen 2016

Dr van Bezooijen

Outcomes: PASI 90, adverse effects

4 and 12 January 2017

Additional data to the publication not provided

Van de Kerkhof 2008

Prof. van der Kherkhof Pfizer

Outcome: AEs

8 and 21 November 2016

Additional data to the publication not provided

LOTUS 2013

No contact

Outcome: PASI 90

No

Authors' email not found

CLARITY 2018

Prof Bagel

Outcome: QoL Scale

24 June 2019

Email response 01 July 2019

Dear Dr. Sbidian,

It is a pleasure to e‐meet you – i am the medical director assigned to the CLARITY trial for Novartis, and I am responding on behalf of Dr. Bagel to your request of data.

Thanks for your interest in the CLARITY: we published the 16w data and we are currently working on the final manuscript.

The 52w manuscript will include updated PROs and clinical outcomes – unfortunately, those data are embargoed until the final manuscript is release.

Once published, we’d be happy to re‐connect to see how the CLARITY data will support your meta‐analysis.

Please feel free to reach out directly to me if you need any further assistance.

Best regards,

Elisa Muscianisi

ADACCESS 2018

Prof Blauvelt

Outcome: QoL Scale

24 June and 1st July 2019

Email response: 2 July 2019

'Cc’ing the person who should be able to help you.'

EGALITY 2017

Prof Gerdes

Outcomes: QoL Scale, AEs, SAEs

24 June 2019

Email response 27 June 2019

Dear Dr. Sbidian,

On behalf of SANDOZ Global Medical Affairs team, I wanted to thank you for your interest to the EGALITY study and for considering it for your ongoing meta‐analysis.

I’m also happy to share with you on behalf of the authors and the team who worked on the study, the requested information that you can find here attached

We would highly appreciate if you can keep us informed when the meta‐analysis will be published, meanwhile, please feel free to revert back to us in case you would need any further information

Thank you and have a nice afternoon

Best regards

Sohaib

Dr. med. Sohaib HACHAICHI

Global Medical Affairs Manager

Immunology

Ikonomidis 2017

Prof Ikonomidis

Outcomes: PASI 90, 75, PGA0/1, QoL Scale, AES, SAEs

24 June and 1st July 2019

No response

Jin 2017

Prof Zhao

Outcomes: PASI 90, PGA0/1, QoL Scale

24 June and 1st July 2019

No response

VIP Trial 2018

Prof Gelfand

Outcome: PASI 90

24 June

Email response 24 June 2019

"Yes we can do this.

I propose that we have this data approved for release to you by September 30 2019"

We will add the new data for the next update (living review).

SIGNATURE 2019

No contact

Outcomes: PASI 90, PGA0/1, AES, SAEs

24 June 2019

We will contact the authors when the article is published

NCT02581345

Dr Caminis

Outcome: QoL Scal

24 June 2019

Authors' email not found (SHIRE pharmaceutics). We will contact the authors when the article is published

AURIEL‐PsO 2020

Sponsors and collaborators: Fresenius Kabi SwissBioSim GmbH Merck KGaA, Darmstadt, Germany

Outcomes: QoL Scale, AEs

24 June 2019

No contact; We will contact the authors when the article is published

NCT02850965

Sponsors: Boehringer Ingelheim

Outcomes: PASI 90, QoL Scale, AEs

24 June 2019

No contact. We will contact the authors when the article is published

ORION 2020

Pr Ferris

Outcome: DLQI

24 June and 2nd July 2019

No response

POLARIS 2020

Janssen‐Cilag G.m.b.H, Germany Clinical Tria

Outcome: PGA0/1

24 June 2019

No contact. We will contact the authors when the article is published

SustaIMM 2019

Sponsors and collaborators: AbbVie Boehringer Ingelheim

Outcome: DLQI

24 June 2019

No contact. We will contact the authors when the article is published

Papp 2017a

Prof. Papp

Outcome: DLQI

24 June 2019

Email answer 24 June 2019

"I am not at liberty to release results that are not in the public domain.

Regards,

k"

BE ABLE 1 2018

Prof. Papp

Outcome: DLQI

24 June 2019

Email answer 24 June 2019

"I am not at liberty to release results that are not in the public domain.

Regards,

k"

Papp 2017b

Prof. Papp

Outcome: DLQI

24 June 2019

Email answer 24 June 2019

"I am not at liberty to release results that are not in the public domain.

Regards,

k"

Papp 2018

Prof. Papp

Outcome: DLQI

24 June 2019

Email answer 24 June 2019

"I am not at liberty to release results that are not in the public domain.

Regards,

k"

IXORA‐S 2017

Prof. Reich

Outcome: DLQI

24 June and 1st July 2019

E‐mails not received (email: [email protected]; [email protected])

TRANSFIGURE 2016

Prof. Reich

Outcomes: PGA0/1, DLQI

24 June and 1st July 2019

E‐mails not received (email: [email protected]; [email protected])

PRIME 2017

Prof. Sticherling

Outcome: DLQI

24 June and 1st July 2019

Email answer 02 July 2019

"Dear Dr. Sbidian,
thank you very much for your mail.
We are currently checking the data for your table to respond in due time.
Yours,
Michael Sticherling"

CIMPACT 2018

Prof. Lebwohl

Outcome: DLQI

24 June and 1st July 2019

No response

Lee 2016

Outcomes: PASI 90, DLQI

24 June and 1st July 2019

No response

NCT02672852

Sponsors and collaborators: AbbVie Boehringer Ingelheim

Outcome: DLQI

24 June 2019

No contact. We will contact the authors when the article is published

NCT02134210

Barbara K Finck, M.D.; Coherus Biosciences, Inc

Outcome: DLQI

24 June 2019

No contact. We will contact the authors when the article is published

Yu 2019

Prof. Shi

Outcomes: PGA 0/1, DLQI

12 August 2020, 8 September 2020

No response

von Stebut CARIMA 2019

Prof. von Stebut

Outcomes: PASI 90, 75, IGA 0/1, QoL Scale

12 August 2020, 8 September 2020

No response

Hodge 2017 PsOsim

Prof. Hodge

Outcomes: PASI 90, PGA 0/1, QoL Scale

12 August 2020, 8 September 2020

No response

Reich 2019

Prof. Reich

Outcome: DLQI

12 August 2020, 8 September 2020

Email answer 8 September 2020:

"

Dear Dr. Sbidian

Thank you for your interest in the mirikizumab data. The team is currently working to determine what we are allowed to share, given that this data has not been published. I have just a few questions. If we do not provide the specified information, would mirikizumab then not be included at all in the NMA? Are percentages of patients with prior phototherapy and prior topical therapy needed for the modeling? If we cannot provide mean DLQI, but we are able to provide number/% patients on prior phototherapy and topic therapy, would mirikizumab still be included in the NMA for PASI outcomes?

Thank you!
Bridget Charbonneau"

NCT02187172 Gelfand VIP‐U 2020

Prof. Gelfand

Outcome: QoL Scale

12 August 2020

Email answer 17 August 2020

NCT02187172 Gelfand VIP‐U 2020 sent detailed report for the requested outcome.

NCT02313922 Liu 2019

Prof. Liu

Outcome: QoL Scale

12 August 2020

Email answer 13 August 2020

Liu 2019 sent detailed report for the requested outcome.

Reich ECLIPSE 2019

Prof. Reich

Outcomes: QoL Scale, AEs, SAEs

12 August 2020, 8 September 2020

Email answer 11 September 2020:

"Dear Authors:

I am contacting you on behalf of the ECLIPSE authors and the Janssen team. Prof. Reich has shared with us your request for additional ECLIPSE data to be included in a meta‐analysis. The authors would like to learn more about what data are being presented and what conclusions are being made in this meta‐analysis.

For example, which other biologics are being compared and at what timepoints are these comparisons? ECLIPSE was not a placebo‐controlled trial and the primary endpoint was 48 weeks, which was much later than most other studies.

That being said, the authors would first like to have these questions answered and to also have a better understanding of the proposed methodology and the goal of your meta‐analysis. Thank you.

Best regards,

Kristin M. Sharples, PhD

Scientific Communications, Dermatology
Medical Affairs"

Gottlieb IXORA‐R 2019

Prof. Blauvelt

Outcomes: PASI 90, 75, PGA 0/1, DLQI

12 August 2020

Email answer 13 August 2020

Gottlieb IXORA‐R 2019 sent detailed report for the requested outcomes except for PASI 75 and DLQI (not disclosed yet).

NCT02748863

Sponsors: Novartis

Outcome: DLQI

12 August 2020

Email answer 25 August 2020

"

Le critère principal d’évaluation de l’étude repose à la fois sur le score PASI 75 et sur l’IGA mod 2011. L’Indice de Qualité de Vie (DLQI) correspond bien à un des critères d’évaluation secondaires.

Les résultats de l’étude ALLURE (NCT02748863) n’ont pas encore été intégralement publiés dans la littérature scientifique.

Toutefois, nous vous prions de bien vouloir trouver ci‐joints le protocole de l’étude et les premiers résultats disponibles sur le site internet clinicaltrials.gov. Ces premiers résultats incluent des données sur les caractéristiques des patients, notamment leur âge, leur sexe ainsi que leur origine ethnique.

Je mets en copie de cet email la responsable médicale dermatologie de Cosentyx pour votre région, Mme Emeline Desreumaux ([email protected], +33667445036), n’hésitez pas à la contacter directement pour plus d’information sur nos études cliniques.

Sophie Baratin"

NCT03051217

Sponsors: UCB pharma

Outcomes: AEs, SAEs

12 August 2020, 8 September 2020

No contact. We will contact the authors when the article is published

NCT03066609

Sponsors: Novartis

Outcome: QoL Scale

12 August 2020, 8 September 2020

No contact. We will contact the authors when the article is published

NCT03055494 ObePso‐S

Sponsors: Novartis

Outcomes: PASI 75, PGA 1/0, QoL Scale, AEs, SAEs

8 September 2020

No contact. We will contact the authors when the article is published

Warren IMMerge, 2020

Prof. Warren

Outcome: QoL Scale

8 September 2020

No response

NCT03482011 OASIS‐1

Sponsors: Eli Lilly and Company

Outcome: DLQI

21 October 2020

Awaiting classification studies

Chow 2015

Prof. Chow

outcomes: PASI 90, PASI 75, PGA 0/1, QoL scale, AEs and SAEs

8 November 2016, 16 December 2016

No response

Gurel 2015

Prof. Gurel

Study's protocol and outcomes: PASI 90, PASI 75, PGA 0/1, QoL scale, AEs and SAEs

17 and 24 January 2017

Gurel 2015 sent detailed report for the requested outcomes. Finally Gurel study was classified in the included studies section.

Han 2007

No contact

Outcomes: PASI 90, PASI 75, PGA 0/1, QoL scale, AEs and SAEs

No

Authors' email not found

Krishna 2016

Prof. Krishna

Asking for study protocol and efficacy/safety results

5 and 12 January 2017

11 February 2020

No response

DRKS00000716

Prof. Jacobi

Asking for study protocol and efficacy/safety results

12 and 19 January 2017

No response

CTRI/2015/05/005830

Prof. Shah

Asking for study protocol and efficacy/safety results

12 and 19 January 2017

11 February 2020

No response

NCT01088165

Prof. Holzer

Asking for study protocol and efficacy/safety results

3 and 24 June 2019

11 February 2020

No response

NCT02655705

Prof. Youn

Asking for study protocol and efficacy/safety results

3 and 24 June 2019

11 February 2020

No response

CTRI /2017/09/009850

Prof. Mease

Asking for study protocol and efficacy/safety results

17 Ausgut 2020, 8 September 2020

No response

EUCTR2010‐020168‐39‐DE

Prof. Anderson

Asking for study protocol and efficacy/safety results

17 August 2020, 8 September 2020

No response

EUCTR2015‐005279‐25‐DE

Prof. Philipp

Asking for study protocol and efficacy/safety results

17 August 2020, 8 September 2020

No response

EUCTR2017‐001615‐36‐DE

Prof. Gerdes

Asking for study protocol and efficacy/safety results

17 August 2020, 8 September 2020

Email answer 8 September 2020: "

Dear Dr. Afach,

Thank you for your request. Unfortunately the information is still confidential.

BR

Sascha Gerdes"

Ikonomidis 2019

Prof. Ikonomidis

Asking for study protocol and efficacy/safety results

17 August 2020, 8 September 2020

No response

Makavos 2020

Dr. Ikonomidis

Asking for study protocol and efficacy/safety results

30 October 2020

Abstracts

Mrowietz 2005

Prof. Mrowietz

Study's protocol and outcomes: PASI 90, PASI 75, PGA 0/1, QoL scale, AEs and SAEs

16 December 2016, 3 January 2017

Additional data to the publication not provided. Finally Mrowietz study was classified in the 'Awaiting classification' section.

Ongoing studies

CTRI/2016/10/007345

Dr Piyush Agarwal, general manager

Glenmark Pharmaceuticals Ltd

[email protected]

[email protected]

Asking for study protocol and efficacy/safety results

11 February 2020

No response

NCT01558310a

Dr Yamauchi, Dr Patnaik, Director, Clinical Science Institute

Asking for study protocol and efficacy/safety results

5 January 2017

Email response: Dear Dr Sbidian,
"Thank you for your kind email, forwarded to me by Dr Paul Yamauchi, MD,PhD. Our " Study to Evaluate the Effectiveness of STELARA ™ (USTEKINUMAB) in the Treatment of Scalp Psoriasis (NCT 01558310)” completed enrolment in December 2016 and the last subject will complete in December 2017, as such we do not have the final data analysis. What is you absolute cut‐ off for publication data ? Would an interim analysis report be acceptable? Best regards, Rickie Patnaik Director, Clinical Science Institute"

Will be included when published

EUCTR2013‐004918‐18‐NL

Prof. Spuls

Asking for study protocol and efficacy/safety results

5 January 2017

Email response

"The study is currently ongoing and has not yet been analysed. Therefore, we are not able to provide data on efficacy or safety.
We can provide you with the study protocol. Will this be helpful?
Kind regards, Phyllis Spuls and Celine Busard "

Will be included when published

NCT02701205

Prof Hongzhong Jin

Asking for study protocol and efficacy/safety results

3 June 2019

11 February 2020

Email response "This is the mail system at host mta‐8_BSR. Your message could not be delivered to one or more recipients."

AE: adverse events; PASI: Psoriasis Area and Severity Index; PGA: Physician Global Assessment; QoL: quality of life; SAE: serious adverse events

Figures and Tables -
Table 2. Investigators contacted
Table 3. Direct and indirect evidences and network meta‐analysis results summary table for PASI 90

Network meta‐analysis

Direct evidence

Indirect evidence

Comparisons*

RR

LCI

UCI

RR

LCI

UCI

RR

LCI

UCI

Adalimumab versus placebo

17.81

14.82

21.40

15.16

11.50

19.96

20.43

15.85

26.32

Apremilast versus placebo

7.73

4.51

13.24

6.95

3.38

14.33

10.25

2.53

41.52

Bimekizumab versus placebo

58.64

3.72

923.86

Brodalumab versus placebo

23.55

19.48

28.48

26.32

16.77

41.33

20.11

10.91

37.07

Certolizumab versus placebo

13.42

9.76

18.44

19.77

8.29

47.12

8.10

2.70

24.32

Ciclosporin versus placebo

7.04

1.32

37.50

Etanercept versus placebo

10.76

9.03

12.82

11.52

8.82

15.03

9.98

7.53

13.24

FAEs versus placebo

4.36

2.01

9.46

4.47

2.01

9.95

2.93

0.13

67.39

Guselkumab versus placebo

25.52

21.25

30.64

28.92

20.59

40.62

24.12

19.29

30.16

Infliximab versus placebo

50.29

20.96

120.67

42.64

16.08

113.09

99.51

13.69

723.56

Ixekizumab versus placebo

32.48

27.13

38.87

30.54

21.37

43.65

33.20

26.88

41.01

Mirikizumab versus placebo

10.96

5.46

22.00

Methotrexate versus placebo

6.97

1.42

34.34

5.85

0.73

46.93

8.94

0.75

106.67

Risankizumab versus placebo

28.76

23.96

34.54

31.96

22.80

44.79

27.97

22.95

34.09

Secukinumab versus placebo

25.79

21.61

30.78

27.55

19.28

39.36

25.33

20.83

30.82

Tildrakizumab versus placebo

18.73

14.21

24.69

17.25

8.26

36.02

20.88

8.17

53.40

Tofacitinib versus placebo

8.89

7.09

11.13

6.94

4.69

10.27

14.50

7.39

28.42

Tyrosine kinase 2 inhibitor versus placebo

13.99

1.99

98.10

Ustekinumab versus placebo

18.46

15.51

21.98

17.90

13.65

23.48

18.73

15.36

22.83

Guselkumab versus adalimumab

1.43

1.32

1.56

1.45

1.32

1.59

1.32

1.04

1.66

Risankizumab versus adalimumab

1.62

1.44

1.81

1.53

1.33

1.75

1.83

1.49

2.25

Etanercept versus apremilast

1.39

0.82

2.38

1.39

0.71

2.71

1.40

0.59

3.31

Ustekinumab versus brodalumab

0.78

0.72

0.86

0.79

0.72

0.86

0.56

0.26

.22

Etanercept versus certolizumab

0.80

0.61

1.06

0.83

0.62

1.11

0.55

0.22

1.38

Methotrexate versus ciclosporin

0.99

0.60

1.64

0.99

0.60

1.64

46.01

0.00

.

Infliximab versus etanercept

4.67

1.93

11.34

9.20

1.28

66.37

3.94

1.46

10.62

Ixekizumab versus etanercept

3.02

2.69

3.38

2.91

2.53

3.34

3.26

2.68

3.98

Secukinumab versus etanercept

2.40

2.12

2.72

2.33

1.86

2.93

2.43

2.09

2.82

Tildrakizumab versus etanercept

1.74

1.39

2.18

1.77

1.40

2.24

1.43

0.61

3.35

Tofacitinib versus etanercept

0.83

0.69

0.99

0.88

0.73

1.08

0.58

0.37

0.91

Ustekinumab versus etanercept

1.72

1.52

1.94

1.80

1.45

2.24

1.68

1.45

1.94

Ixekizumab versus guselkumab

1.27

1.17

1.39

1.29

1.18

1.42

1.16

0.93

1.45

Methotrexate versus FAEs

1.60

0.32

8.06

2.00

0.19

20.90

1.31

0.14

12.18

Secukinumab versus risankizumab

0.90

0.81

0.99

0.89

0.77

1.03

0.90

0.79

1.04

Ustekinumab versus ixekizumab

0.57

0.50

0.64

0.58

0.47

0.71

0.56

0.49

0.65

Ustekinumab versus risankizumab

0.64

0.58

0.71

0.60

0.52

0.70

0.67

0.59

0.77

Ustekinumab versus secukinumab

0.72

0.67

0.76

0.72

0.67

0.77

0.72

0.61

0.84

FAES: fumaric acid esters; LCI: low confidence interval; RR: risk ratio; UCI: upper confidence interval; vs: versus,

*The comparisons listed in this table were included in at least one direct‐evidence analysis.

Figures and Tables -
Table 3. Direct and indirect evidences and network meta‐analysis results summary table for PASI 90
Table 4. Ranking findings for all outcomes at class level

Class‐level
interventions

SUCRA
PASI 90

Rank
PASI 90

SUCRA
SAE

Rank
SAE

SUCRA

SAE

excluded

flare of psoriasis

Rank

SAE

excluded

flare of psoriasis

SUCRA
PASI 75

Rank
PASI 75

SUCRA
AE

Rank
AE

SUCRA
PGA

Rank
PGA

SUCRA
QoL

Rank
QoL

Anti‐IL17

99.9

1

22.6

7

24.7

7

99.5

1

24.7

6

99.9

1

73.4

3

Anti‐IL23

82.9

2

77.7

1

77.2

1

81.1

2

88.3

2

81.8

2

85.5

1

Anti‐IL12/23

67.2

3

43.9

5

29.2

6

69.4

3

57.5

3

68.3

3

75.8

2

Anti‐TNF alpha

49.8

4

51.5

3

37.4

5

50

4

52.6

4

50

4

44.5

5

Small molecules

32.3

5

50.4

4

72.5

2

33.3

5

5.7

7

30.5

5

20.4

6

Non‐biological

treatments

18

6

74.2

2

52.6

4

16.7

6

28.8

5

19.5

6

50.2

4

Placebo

0

7

29.7

6

56.3

3

0

7

92.4

1

0

7

0.1

7

AE: adverse events; FAEs: fumaric acid esters; PGA: Physician Global Assessment; QoL: Specific quality of life scale; SAE: serious adverse events

Figures and Tables -
Table 4. Ranking findings for all outcomes at class level
Table 5. Ranking findings for all outcomes at drug level

Drug

SUCRA
PASI 90

Rank
PASI 90

SUCRA
SAE

Rank
SAE

SUCRA

SAE

excluded

flare of psoriasis

Rank

SAE

excluded

flare of psoriasis

SUCRA
PASI 75

Rank
PASI 75

SUCRA
AE

Rank
AE

SUCRA
PGA

Rank
PGA

SUCRA
QoL

Rank
QoL

Infliximab

93.6

1

29.3

20

56.6

7

94.8

1

33.7

15

83.6

2

65.7

6

Ixekizumab

90.5

2

29.8

19

39.3

17

90.3

2

34.4

13

87.9

1

91.7

2

Risankizumab

84.6

3

68.1

3

75

2

84.2

3

71.9

6

81

4

95.3

1

Bimekizumab

81.4

4

83

2

83.3

1

79.8

4

4.7

20

74.2

6

Secukinumab

76.2

5

34.8

17

34.3

18

77.2

5

35.9

12

81

3

69.9

4

Guselkumab

75

6

44.4

12

39.5

16

73.1

6

75.3

5

61.4

8

59.2

7

Brodalumab

68.4

7

34.3

18

42.7

14

72.5

7

44.7

11

78.8

5

12.7

13

Tildrakizumab

56.5

8

52.7

9

22.4

19

58.7

9

95.2

1

46.5

12

69.5

5

Ustekinumab

56.1

9

46.5

11

43.7

13

60.8

8

60.6

8

57.8

9

73.5

3

Adalimumab

52.9

10

36.9

15

41.7

15

52.2

11

68.8

7

43.6

13

36.3

12

Tyrosine kinase 2 inhibitor

48.2

11

59.7

5

63.6

4

45.7

13

21.3

18

46.7

11

Certolizumab

41.4

12

58.8

6

16.2

20

49.6

2

78.2

3

52.4

10

37.5

11

Mirikizumab

34.1

3

62.5

4

67.1

3

55.7

10

78.2

4

67.7

7

Etanercept

33.1

4

53.7

8

48.3

12

38.9

14

53.1

10

32.3

15

42.3

9

Ciclosporin

26.5

15

35.4

16

51.5

9

24.2

16

22.7

17

30.1

16

Methotrexate

25.6

16

83.8

1

51.4

10

15.3

18

60.5

9

33.7

14

44.1

8

Tofacitinib

24.2

17

42.4

13

57.8

6

31.1

15

34

14

20.6

17

42.1

10

Apremilast

21.1

18

51.3

10

62

5

22

17

15.7

19

13

18

10.1

14

FAEs

10.4

19

55.4

7

50.9

11

9.6

20

25.6

16

7.8

19

Placebo

0.1

20

37.1

14

52.5

8

1.4

21

85.4

2

0

20

0.2

15

Acitretine

12.8

19

AE: adverse events; FAEs: fumaric acid esters; PASI: Psoriasis Area and Severity Index; PGA: Physician Global Assessment; QoL: specific quality of life scale; SAE: serious adverse events; SUCRA: Surface Under the Cumulative Ranking

Figures and Tables -
Table 5. Ranking findings for all outcomes at drug level
Table 6. Direct and indirect evidence and network meta‐analysis results summary table for serious adverse events

Network meta‐analysis

Direct evidence

Indirect evidence

Comparisons*

RR

LCI

UCI

RR

LCI

UCI

RR

LCI

UCI

Adalimumab versus placebo

1.01

0.66

1.56

1.19

0.74

1.92

0.57

0.23

1.42

Apremilast versus placebo

0.86

0.49

1.52

0.86

0.47

1.56

1.00

0.04

26.68

Bimekizumab versus placebo

0.20

0.01

3.20

Brodalumab versus placebo

1.05

0.62

1.79

0.93

0.52

1.67

2.66

0.39

18.12

Certolizumab versus placebo

0.75

0.30

1.84

0.62

0.25

1.54

33.70

0.52

2180.73

Ciclosporin versus placebo

1.28

0.15

11.01

5.69

0.32

101.52

0.19

0.01

4.90

Etanercept versus placebo

0.85

0.58

1.26

0.72

0.45

1.14

1.36

0.63

2.93

Fumaric ester acids versus placebo

0.78

0.29

2.09

0.83

0.30

2.28

0.28

0.00

19.72

Guselkumab versus placebo

0.94

0.55

1.59

1.04

0.48

2.23

0.84

0.37

1.92

Infliximab versus placebo

1.16

0.56

2.39

1.20

0.56

2.54

0.78

0.05

12.25

Ixekizumab versus placebo

1.10

0.69

1.74

1.08

0.58

2.01

1.13

0.49

2.62

Mirikizumab versus placebo

0.65

0.17

2.51

Methotrexate versus placebo

0.33

0.07

1.59

0.14

0.02

0.94

2.22

0.13

37.63

Risankizumab versus placebo

0.71

0.45

1.13

0.45

0.23

0.89

1.04

0.56

1.95

Secukinumab versus placebo

1.03

0.70

1.52

1.10

0.67

1.81

0.93

0.49

1.77

Tildrakizumab versus placebo

0.83

0.37

1.86

0.99

0.37

2.60

0.46

0.06

3.68

Tofacitinib versus placebo

0.96

0.54

1.71

1.07

0.55

2.09

0.48

0.06

Ustekinumab versus placebo

0.92

0.64

1.33

0.98

0.60

1.59

0.84

0.47

Guselkumab versus adalimumab

0.93

0.53

1.63

0.91

0.44

1.89

0.95

0.37

2.43

Risankizumab versus adalimumab

0.70

0.40

1.22

1.12

0.46

2.75

0.54

0.27

1.06

Etanercept versus apremilast

0.99

0.51

1.92

0.68

0.14

3.40

1.07

0.52

2.22

Ustekinumab versus brodalumab

0.87

0.49

1.57

0.75

0.32

1.75

1.07

0.39

2.88

Etanercept versus certolizumab

1.14

0.43

3.02

2.28

0.33

15.76

0.81

0.23

2.90

Methotrexate versus Ciclosporin

0.26

0.03

2.18

1.02

0.06

16.18

0.03

0.00

0.98

Infliximab versus Etanercept

1.36

0.60

3.05

0.92

0.06

14.05

1.41

0.60

3.31

Ixekizumab versus Etanercept

1.28

0.77

2.13

1.03

0.53

2.03

1.72

0.78

3.79

Secukinumab versus Etanercept

1.21

0.72

2.03

1.60

0.47

5.47

1.13

0.63

2.03

Tildrakizumab versus Etanercept

0.97

0.43

2.18

0.70

0.26

1.89

1.94

0.45

8.28

Todacitinib versus Etanercept

1.12

0.60

2.10

0.87

0.33

2.30

1.37

0.59

3.18

Ustekinumab versus Etanercept

1.08

0.65

1.78

1.25

0.37

4.25

1.05

0.60

1.82

Methotrexate versus Fumaric ester acids

0.42

0.07

2.48

1.00

0.02

49.21

0.34

0.05

2.46

Ixekizumab versus guselkumab

1.17

0.67

2.04

1.20

0.54

2.64

1.13

0.49

2.62

Ustekinumab versus Ixekizumab

0.84

0.47

1.49

0.16

0.01

3.42

0.89

0.50

1.60

Secukinumab versus Risankizumab

1.45

0.86

2.45

0.67

0.24

1.84

1.89

1.05

3.41

Ustekinumab versus Risankizumab

1.29

0.80

2.10

1.82

0.92

3.60

0.93

0.47

1.82

Ustekinumab versus secukinumab

0.89

0.58

1.37

0.79

0.42

1.49

0.99

0.55

1.79

FAES: fumaric acid esters; LCI: low confidence interval; RR: risk ratio; UCI: upper confidence interval

*The comparisons listed in this table were included in at least one direct‐evidence analysis.

Figures and Tables -
Table 6. Direct and indirect evidence and network meta‐analysis results summary table for serious adverse events
Table 7. Study Bias distribution for PASI 90 using CINeMA

Comparison

Number of studies

Within‐study bias

Reporting bias

Indirectness

Imprecision

Heterogeneity

Incoherence

Confidence rating

ADA:GUSEL

3

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

ADA:PBO

8

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

ADA:RISAN

1

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

APRE:ETA

1

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

APRE:PBO

5

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

BIME:PBO

1

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

BRODA:PBO

5

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

BRODA:USK

2

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

CERTO:ETA

1

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CERTO:PBO

5

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

CICLO:MTX

2

Major concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

ETA:IFX

1

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

ETA:IXE

2

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

ETA:PBO

14

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

ETA:SECU

1

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

ETA:TILDRA

1

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

ETA:TOFA

1

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

ETA:USK

1

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

FAEs:MTX

1

Major concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

FAEs:PBO

1

Major concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

GUSEL:IXE

1

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

GUSEL:PBO

5

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

IFX:PBO

5

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

IXE:PBO

4

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

IXE:USK

1

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

MIRI:PBO

2

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

MTX:PBO

2

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

PBO:RISAN

4

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

PBO:SECU

13

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

PBO:TILDRA

3

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

PBO:TOFA

5

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

PBO:TYK2

1

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

PBO:USK

10

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

RISAN:SECU

1

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

RISAN:USK

3

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

SECU:USK

2

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

ADA:APRE

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

ADA:BIME

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

ADA:BRODA

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

ADA:CERTO

0

No concerns

Undetected

No concerns

Some concerns

No concerns

No concerns

High

ADA:CICLO

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

ADA:ETA

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

ADA:FAEs

0

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

ADA:IFX

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

ADA:IXE

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

ADA:MIRI

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

ADA:MTX

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

ADA:SECU

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

ADA:TILDRA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

ADA:TOFA

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

ADA:TYK2

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

ADA:USK

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

APRE:BIME

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

APRE:BRODA

0

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

APRE:CERTO

0

Some concerns

Undetected

No concerns

Some concerns

Some concerns

No concerns

Low

APRE:CICLO

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

APRE:FAEs

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

APRE:GUSEL

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

APRE:IFX

0

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

APRE:IXE

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

APRE:MIRI

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

APRE:MTX

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

APRE:RISAN

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

APRE:SECU

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

APRE:TILDRA

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

APRE:TOFA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

APRE:TYK2

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

APRE:USK

0

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

BIME:BRODA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BIME:CERTO

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BIME:CICLO

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

BIME:ETA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BIME:FAEs

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

BIME:GUSEL

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BIME:IFX

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BIME:IXE

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BIME:MIRI

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BIME:MTX

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

BIME:RISAN

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BIME:SECU

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BIME:TILDRA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BIME:TOFA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BIME:TYK2

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BIME:USK

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BRODA:CERTO

0

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

BRODA:CICLO

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

BRODA:ETA

0

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

BRODA:FAEs

0

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

BRODA:GUSEL

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BRODA:IFX

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

BRODA:IXE

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

BRODA:MIRI

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

BRODA:MTX

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

BRODA:RISAN

0

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

BRODA:SECU

0

Some concerns

Undetected

No concerns

Some concerns

No concerns

No concerns

Moderate

BRODA:TILDRA

0

No concerns

Undetected

No concerns

Some concerns

No concerns

No concerns

High

BRODA:TOFA

0

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

BRODA:TYK2

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

CERTO:CICLO

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CERTO:FAEs

0

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

CERTO:GUSEL

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

CERTO:IFX

0

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

CERTO:IXE

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

CERTO:MIRI

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

CERTO:MTX

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CERTO:RISAN

0

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

CERTO:SECU

0

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

CERTO:TILDRA

0

No concerns

Undetected

No concerns

Some concerns

No concerns

No concerns

High

CERTO:TOFA

0

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

CERTO:TYK2

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

CERTO:USK

0

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

CICLO:ETA

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CICLO:FAEs

0

Major concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CICLO:GUSEL

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CICLO:IFX

0

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

CICLO:IXE

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CICLO:MIRI

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CICLO:PBO

0

Major concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

CICLO:RISAN

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CICLO:SECU

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CICLO:TILDRA

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CICLO:TOFA

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CICLO:TYK2

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CICLO:USK

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

ETA:FAEs

0

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

ETA:GUSEL

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

ETA:MIRI

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

ETA:MTX

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

ETA:RISAN

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

ETA:TYK2

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

FAEs:GUSEL

0

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

FAEs:IFX

0

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

FAEs:IXE

0

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

FAEs:MIRI

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

FAEs:RISAN

0

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

FAEs:SECU

0

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

FAEs:TILDRA

0

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

FAEs:TOFA

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

FAEs:TYK2

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

FAEs:USK

0

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

GUSEL:IFX

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

GUSEL:MIRI

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

GUSEL:MTX

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

GUSEL:RISAN

0

No concerns

Undetected

No concerns

Some concerns

No concerns

No concerns

High

GUSEL:SECU

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

GUSEL:TILDRA

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

GUSEL:TOFA

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

GUSEL:TYK2

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

GUSEL:USK

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

IFX:IXE

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

IFX:MIRI

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

IFX:MTX

0

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

IFX:RISAN

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

IFX:SECU

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

IFX:TILDRA

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

IFX:TOFA

0

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

IFX:TYK2

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

IFX:USK

0

Some concerns

Undetected

No concerns

No concerns

No concerns

No concerns

Moderate

IXE:MIRI

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

IXE:MTX

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

IXE:RISAN

0

No concerns

Undetected

No concerns

Some concerns

No concerns

No concerns

High

IXE:SECU

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

IXE:TILDRA

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

IXE:TOFA

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

IXE:TYK2

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

MIRI:MTX

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

MIRI:RISAN

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

MIRI:SECU

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

MIRI:TILDRA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

MIRI:TOFA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

MIRI:TYK2

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

MIRI:USK

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

MTX:RISAN

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

MTX:SECU

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

MTX:TILDRA

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

MTX:TOFA

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

MTX:TYK2

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

MTX:USK

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

RISAN:TILDRA

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

RISAN:TOFA

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

RISAN:TYK2

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

SECU:TILDRA

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

SECU:TOFA

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

SECU:TYK2

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

TILDRA:TOFA

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

TILDRA:TYK2

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

TILDRA:USK

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

TOFA:TYK2

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

TOFA:USK

0

No concerns

Undetected

No concerns

No concerns

No concerns

No concerns

High

TYK2:USK

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

Figures and Tables -
Table 7. Study Bias distribution for PASI 90 using CINeMA
Table 8. Study bias distribution for serious adverse events using CINeMA

Comparison

Number of studies

Within‐study bias

Reporting bias

Indirectness

Imprecision

Heterogeneity

Incoherence

Confidence rating

ADA:GUSEL

3

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

ADA:PBO

9

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

ADA:RISAN

1

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

APRE:ETA

1

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

APRE:PBO

7

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BIME:PBO

1

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BRODA:PBO

5

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

BRODA:USK

2

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CERTO:ETA

1

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

CERTO:PBO

4

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CICLO:MTX

2

Major concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CICLO:PBO

1

Major concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

ETA:IFX

1

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

ETA:IXE

2

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

ETA:PBO

13

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

ETA:SECU

1

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

ETA:TILDRA

1

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

ETA:TOFA

1

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

ETA:USK

1

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

FAEs:MTX

1

Major concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

FAEs:PBO

1

Major concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

GUSEL:IXE

1

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

GUSEL:PBO

5

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

IFX:PBO

6

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

IXE:PBO

4

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

IXE:USK

1

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

MIRI:PBO

2

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

MTX:PBO

2

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

PBO:RISAN

4

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

PBO:SECU

12

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

PBO:TILDRA

3

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

PBO:TOFA

7

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

PBO:TYK2

1

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

PBO:USK

11

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

RISAN:SECU

1

No concerns

Undetected

No concerns

Major concerns

No concerns

Major concerns

Low

RISAN:USK

3

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

SECU:USK

2

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

ADA:APRE

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

ADA:BIME

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

ADA:BRODA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

ADA:CERTO

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

ADA:CICLO

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

ADA:ETA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

ADA:FAEs

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

ADA:IFX

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

ADA:IXE

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

ADA:MIRI

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

ADA:MTX

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

ADA:SECU

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

ADA:TILDRA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

ADA:TOFA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

ADA:TYK2

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

ADA:USK

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

APRE:BIME

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

APRE:BRODA

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

APRE:CERTO

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

APRE:CICLO

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

APRE:FAEs

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

APRE:GUSEL

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

APRE:IFX

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

APRE:IXE

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

APRE:MIRI

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

APRE:MTX

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

APRE:RISAN

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

APRE:SECU

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

APRE:TILDRA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

APRE:TOFA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

APRE:TYK2

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

APRE:USK

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BIME:BRODA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BIME:CERTO

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BIME:CICLO

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

BIME:ETA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BIME:FAEs

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

BIME:GUSEL

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BIME:IFX

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BIME:IXE

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BIME:MIRI

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BIME:MTX

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

BIME:RISAN

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BIME:SECU

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BIME:TILDRA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BIME:TOFA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BIME:TYK2

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BIME:USK

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BRODA:CERTO

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

BRODA:CICLO

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

BRODA:ETA

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

BRODA:FAEs

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

BRODA:GUSEL

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BRODA:IFX

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

BRODA:IXE

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BRODA:MIRI

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BRODA:MTX

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

BRODA:RISAN

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

BRODA:SECU

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

BRODA:TILDRA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

BRODA:TOFA

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

BRODA:TYK2

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

CERTO:CICLO

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CERTO:FAEs

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CERTO:GUSEL

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

CERTO:IFX

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

CERTO:IXE

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

CERTO:MIRI

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

CERTO:MTX

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CERTO:RISAN

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

CERTO:SECU

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

CERTO:TILDRA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

CERTO:TOFA

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CERTO:TYK2

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

CERTO:USK

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

CICLO:ETA

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CICLO:FAEs

0

Major concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CICLO:GUSEL

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CICLO:IFX

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CICLO:IXE

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CICLO:MIRI

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CICLO:RISAN

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CICLO:SECU

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CICLO:TILDRA

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CICLO:TOFA

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CICLO:TYK2

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

CICLO:USK

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

ETA:FAEs

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

ETA:GUSEL

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

ETA:MIRI

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

ETA:MTX

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

ETA:RISAN

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

ETA:TYK2

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

FAEs:GUSEL

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

FAEs:IFX

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

FAEs:IXE

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

FAEs:MIRI

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

FAEs:RISAN

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

FAEs:SECU

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

FAEs:TILDRA

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

FAEs:TOFA

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

FAEs:TYK2

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

FAEs:USK

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

GUSEL:IFX

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

GUSEL:MIRI

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

GUSEL:MTX

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

GUSEL:RISAN

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

GUSEL:SECU

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

GUSEL:TILDRA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

GUSEL:TOFA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

GUSEL:TYK2

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

GUSEL:USK

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

IFX:IXE

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

IFX:MIRI

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

IFX:MTX

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

IFX:RISAN

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

IFX:SECU

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

IFX:TILDRA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

IFX:TOFA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

IFX:TYK2

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

IFX:USK

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

IXE:MIRI

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

IXE:MTX

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

IXE:RISAN

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

IXE:SECU

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

IXE:TILDRA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

IXE:TOFA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

IXE:TYK2

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

MIRI:MTX

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

MIRI:RISAN

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

MIRI:SECU

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

MIRI:TILDRA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

MIRI:TOFA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

MIRI:TYK2

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

MIRI:USK

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

MTX:RISAN

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

MTX:SECU

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

MTX:TILDRA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

MTX:TOFA

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

MTX:TYK2

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

MTX:USK

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

RISAN:TILDRA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

RISAN:TOFA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

RISAN:TYK2

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

SECU:TILDRA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

SECU:TOFA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

SECU:TYK2

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

TILDRA:TOFA

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

TILDRA:TYK2

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

TILDRA:USK

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

TOFA:TYK2

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

TOFA:USK

0

Some concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Low

TYK2:USK

0

No concerns

Undetected

No concerns

Major concerns

No concerns

No concerns

Moderate

Figures and Tables -
Table 8. Study bias distribution for serious adverse events using CINeMA
Comparison 1. Primary outcome ‐ PASI 90

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1.1 Non‐biological treatments versus placebo Show forest plot

4

1022

Risk Ratio (M‐H, Random, 95% CI)

2.82 [1.02, 7.78]

1.1.1 Methotrexate versus placebo

3

318

Risk Ratio (M‐H, Random, 95% CI)

2.06 [0.53, 7.97]

1.1.2 Fumaric acid esters versus placebo

1

704

Risk Ratio (M‐H, Random, 95% CI)

4.47 [2.01, 9.95]

1.2 Non‐biological treatment 1 versus non‐biological treatment 2 Show forest plot

4

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

1.2.1 Ciclosporin versus methotrexate

2

172

Risk Ratio (M‐H, Random, 95% CI)

1.18 [0.47, 2.98]

1.2.2 Methotrexate versus fumaric acid esters

2

168

Risk Ratio (M‐H, Random, 95% CI)

3.82 [1.65, 8.85]

1.3 Anti‐TNF alpha versus placebo Show forest plot

32

11869

Risk Ratio (M‐H, Random, 95% CI)

13.65 [10.71, 17.40]

1.3.1 Etanercept versus placebo

14

5650

Risk Ratio (M‐H, Random, 95% CI)

11.68 [8.14, 16.75]

1.3.2 Adalimumab versus placebo

9

3421

Risk Ratio (M‐H, Random, 95% CI)

13.13 [8.01, 21.53]

1.3.3 Certolizumab versus placebo

5

1153

Risk Ratio (M‐H, Random, 95% CI)

19.77 [8.29, 47.12]

1.3.4 Infliximab versus placebo

5

1645

Risk Ratio (M‐H, Random, 95% CI)

27.71 [12.52, 61.30]

1.4 Anti‐IL12/23 versus placebo Show forest plot

10

4274

Risk Ratio (M‐H, Random, 95% CI)

19.77 [13.25, 29.52]

1.4.1 Ustekinumab versus placebo

10

4274

Risk Ratio (M‐H, Random, 95% CI)

19.77 [13.25, 29.52]

1.5 Anti‐IL17 versus placebo Show forest plot

22

11462

Risk Ratio (M‐H, Random, 95% CI)

30.68 [22.96, 41.00]

1.5.1 Secukinumab versus placebo

12

3835

Risk Ratio (M‐H, Random, 95% CI)

31.46 [19.46, 50.86]

1.5.2 Ixekizumab versus placebo

4

3268

Risk Ratio (M‐H, Random, 95% CI)

53.85 [15.34, 189.07]

1.5.3 Brodalumab versus placebo

5

4109

Risk Ratio (M‐H, Random, 95% CI)

26.33 [16.77, 41.33]

1.5.4 Bimekizumab versus placebo

1

250

Risk Ratio (M‐H, Random, 95% CI)

58.64 [3.72, 923.86]

1.6 Anti‐IL23 versus placebo Show forest plot

14

5881

Risk Ratio (M‐H, Random, 95% CI)

20.23 [14.76, 27.73]

1.6.1 Guselkumab versus placebo

5

1767

Risk Ratio (M‐H, Random, 95% CI)

27.79 [16.23, 47.60]

1.6.2 Tildrakizumab versus placebo

3

1903

Risk Ratio (M‐H, Random, 95% CI)

17.26 [8.27, 36.05]

1.6.3 Risankizumab versus placebo

4

1476

Risk Ratio (M‐H, Random, 95% CI)

24.00 [13.04, 44.18]

1.6.4 Mirikizumab versus placebo

2

735

Risk Ratio (M‐H, Random, 95% CI)

14.29 [3.30, 61.98]

1.7 Biologic versus non‐biological treatment Show forest plot

9

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

1.7.1 Etanercept versus acitretin

2

102

Risk Ratio (M‐H, Random, 95% CI)

4.56 [0.81, 25.79]

1.7.2 Infliximab versus methotrexate

1

868

Risk Ratio (M‐H, Random, 95% CI)

2.86 [2.15, 3.80]

1.7.3 Adalimumab versus methotrexate

1

218

Risk Ratio (M‐H, Random, 95% CI)

3.73 [2.25, 6.19]

1.7.4 Secukinumab versus fumaric acid esters

1

202

Risk Ratio (M‐H, Random, 95% CI)

8.31 [4.23, 16.35]

1.7.5 Ixekizumab versus fumaric acid esters

1

108

Risk Ratio (M‐H, Random, 95% CI)

8.60 [3.69, 20.04]

1.7.6 Ixekizumab versus methotrexate

1

108

Risk Ratio (M‐H, Random, 95% CI)

2.05 [1.43, 2.94]

1.7.7 Guselkumab versus fumaric ester acids

1

119

Risk Ratio (M‐H, Random, 95% CI)

6.02 [3.13, 11.60]

1.7.8 Risankizumab versus fumaric ester acids

1

120

Risk Ratio (M‐H, Random, 95% CI)

8.33 [3.87, 17.95]

1.7.9 Brodalumab versus fumaric acid esters

1

210

Risk Ratio (M‐H, Random, 95% CI)

3.00 [2.04, 4.42]

1.8 Biologic 1 versus biologic 2 Show forest plot

22

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

1.8.1 Ustekinumab versus etanercept

1

903

Risk Ratio (M‐H, Random, 95% CI)

1.80 [1.45, 2.24]

1.8.2 Secukinumab versus etanercept

1

980

Risk Ratio (M‐H, Random, 95% CI)

2.32 [1.85, 2.92]

1.8.3 Inliximab versus etanercept

1

48

Risk Ratio (M‐H, Random, 95% CI)

9.20 [1.28, 66.37]

1.8.4 Ixekizumab versus etanercept

2

2209

Risk Ratio (M‐H, Random, 95% CI)

2.98 [2.24, 3.98]

1.8.5 Tildrakizumab versus etanercept

1

934

Risk Ratio (M‐H, Random, 95% CI)

1.76 [1.39, 2.23]

1.8.6 Certolizumab versus etanercept

1

502

Risk Ratio (M‐H, Random, 95% CI)

1.20 [0.90, 1.61]

1.8.7 Secukinumab versus ustekinumab

2

1778

Risk Ratio (M‐H, Random, 95% CI)

1.40 [1.30, 1.50]

1.8.8 Ixekizumab versus ustekinumab

1

302

Risk Ratio (M‐H, Random, 95% CI)

1.73 [1.41, 2.12]

1.8.9 Brodalumab versus ustekinumab

2

3088

Risk Ratio (M‐H, Random, 95% CI)

1.27 [1.16, 1.39]

1.8.10 Risankizumab versus ustekinumab

3

965

Risk Ratio (M‐H, Random, 95% CI)

1.67 [1.43, 1.93]

1.8.11 Guselkumab versus adalimumab

3

1658

Risk Ratio (M‐H, Random, 95% CI)

1.43 [1.26, 1.62]

1.8.12 Risankizumab versus adalimumab

1

605

Risk Ratio (M‐H, Random, 95% CI)

1.53 [1.33, 1.75]

1.8.13 Secukinumab versus guselkumab

1

1048

Risk Ratio (M‐H, Random, 95% CI)

1.10 [1.02, 1.19]

1.8.14 Ixekizumab versus guselkumab

1

1027

Risk Ratio (M‐H, Random, 95% CI)

1.29 [1.18, 1.42]

1.8.15 Risankizumab versus secukinumab

1

327

Risk Ratio (M‐H, Random, 95% CI)

1.12 [0.97, 1.30]

1.9 Small molecules versus placebo Show forest plot

11

5388

Risk Ratio (M‐H, Random, 95% CI)

7.09 [5.05, 9.95]

1.9.1 Apremilast versus placebo

5

2029

Risk Ratio (M‐H, Random, 95% CI)

6.94 [3.37, 14.30]

1.9.2 Tofacitinib versus placebo

5

3092

Risk Ratio (M‐H, Random, 95% CI)

7.81 [4.54, 13.46]

1.9.3 TYK2 versus placebo

1

267

Risk Ratio (M‐H, Random, 95% CI)

13.99 [1.99, 98.10]

1.10 Biologic versus small molecules Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

1.10.1 Etanercept versus tofacitinib

1

998

Risk Ratio (M‐H, Random, 95% CI)

1.13 [0.93, 1.38]

1.10.2 Etanercept versus apremilast

1

166

Risk Ratio (M‐H, Random, 95% CI)

1.42 [0.72, 2.78]

Figures and Tables -
Comparison 1. Primary outcome ‐ PASI 90
Comparison 2. Primary outcome ‐ serious adverse events (SAE)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

2.1 Non‐biological treatments versus placebo Show forest plot

4

1023

Risk Ratio (M‐H, Random, 95% CI)

0.39 [0.09, 1.70]

2.1.1 Methotrexate versus placebo

3

319

Risk Ratio (M‐H, Random, 95% CI)

0.16 [0.03, 0.88]

2.1.2 Fumaric acid esters versus placebo

1

704

Risk Ratio (M‐H, Random, 95% CI)

0.83 [0.31, 2.21]

2.2 Non‐biological treatment 1 versus non‐biological treatment 2 Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

2.2.1 Methotrexate versus fumaric ester acids

1

108

Risk Ratio (M‐H, Random, 95% CI)

0.33 [0.04, 3.10]

2.3 Anti‐TNF alpha versus placebo Show forest plot

32

10454

Risk Ratio (M‐H, Random, 95% CI)

1.07 [0.77, 1.49]

2.3.1 Etanercept versus placebo

13

4265

Risk Ratio (M‐H, Random, 95% CI)

0.92 [0.53, 1.60]

2.3.2 Adalimumab versus placebo

10

3485

Risk Ratio (M‐H, Random, 95% CI)

1.15 [0.72, 1.84]

2.3.3 Certolizumab versus placebo

4

1026

Risk Ratio (M‐H, Random, 95% CI)

1.19 [0.19, 7.50]

2.3.4 Infliximab versus placebo

6

1678

Risk Ratio (M‐H, Random, 95% CI)

1.99 [0.82, 4.78]

2.4 Anti‐IL12/23 versus placebo Show forest plot

11

4596

Risk Ratio (M‐H, Random, 95% CI)

0.96 [0.59, 1.54]

2.4.1 Ustekinumab versus placebo

11

4596

Risk Ratio (M‐H, Random, 95% CI)

0.96 [0.59, 1.54]

2.5 Anti‐IL17 versus placebo Show forest plot

21

10987

Risk Ratio (M‐H, Random, 95% CI)

0.99 [0.72, 1.36]

2.5.1 Secukinumab versus placebo

11

3360

Risk Ratio (M‐H, Random, 95% CI)

0.99 [0.59, 1.66]

2.5.2 Ixekizumab versus placebo

4

3268

Risk Ratio (M‐H, Random, 95% CI)

1.16 [0.63, 2.13]

2.5.3 Brodalumab versus placebo

5

4109

Risk Ratio (M‐H, Random, 95% CI)

0.92 [0.52, 1.61]

2.5.4 Bimekizumab versus placebo

1

250

Risk Ratio (M‐H, Random, 95% CI)

0.20 [0.01, 3.16]

2.6 Anti‐IL23 versus placebo Show forest plot

14

5882

Risk Ratio (M‐H, Random, 95% CI)

0.76 [0.50, 1.16]

2.6.1 Guselkumab versus placebo

5

1767

Risk Ratio (M‐H, Random, 95% CI)

1.07 [0.50, 2.28]

2.6.2 Tildrakizumab versus placebo

3

1904

Risk Ratio (M‐H, Random, 95% CI)

1.01 [0.37, 2.77]

2.6.3 Risankizumab versus placebo

4

1476

Risk Ratio (M‐H, Random, 95% CI)

0.71 [0.24, 2.10]

2.6.4 Mirikizumab versus placebo

2

735

Risk Ratio (M‐H, Random, 95% CI)

0.65 [0.17, 2.48]

2.7 Biologic versus non‐biological treatments Show forest plot

10

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

2.7.1 Etanercept versus acitretin

3

142

Risk Ratio (M‐H, Random, 95% CI)

0.30 [0.01, 7.02]

2.7.2 Infliximab versus methotrexate

1

868

Risk Ratio (M‐H, Random, 95% CI)

2.41 [1.04, 5.59]

2.7.3 Adalimumab versus methotrexate

1

218

Risk Ratio (M‐H, Random, 95% CI)

2.04 [0.19, 22.14]

2.7.4 Secukinumab versus fumaric acid esters

1

202

Risk Ratio (M‐H, Random, 95% CI)

0.53 [0.16, 1.75]

2.7.5 Ixekizumab versus fumaric ester acids

1

108

Risk Ratio (M‐H, Random, 95% CI)

0.33 [0.04, 3.10]

2.7.6 Ixekizumab versus methotrexate

1

108

Risk Ratio (M‐H, Random, 95% CI)

1.00 [0.06, 15.58]

2.7.7 Guselkumab versus fumaric ester acids

1

119

Risk Ratio (M‐H, Random, 95% CI)

1.48 [0.26, 8.51]

2.7.8 Risankizumab versus fumaric ester acids

1

120

Risk Ratio (M‐H, Random, 95% CI)

0.50 [0.05, 5.37]

2.7.9 Brodalumab versus fumaric acid esters

1

300

Risk Ratio (M‐H, Random, 95% CI)

3.00 [0.32, 28.52]

2.8 Biologic 1 versus biologic 2 Show forest plot

21

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

2.8.1 Ustekinumab versus etanercept

1

903

Risk Ratio (M‐H, Random, 95% CI)

1.25 [0.38, 4.11]

2.8.2 Secukinumab versus etanercept

1

980

Risk Ratio (M‐H, Random, 95% CI)

1.08 [0.41, 2.82]

2.8.3 Infliximab versus etanercept

1

48

Risk Ratio (M‐H, Random, 95% CI)

0.92 [0.06, 13.87]

2.8.4 Ixekizumab versus etanercept

2

2209

Risk Ratio (M‐H, Random, 95% CI)

1.07 [0.55, 2.06]

2.8.5 Tildrakizumab versus etanercept

1

934

Risk Ratio (M‐H, Random, 95% CI)

0.72 [0.28, 1.87]

2.8.6 Certolizumab versus etanercept

1

502

Risk Ratio (M‐H, Random, 95% CI)

2.56 [0.30, 21.74]

2.8.7 Secukinumab versus ustekinumab

2

1778

Risk Ratio (M‐H, Random, 95% CI)

1.26 [0.70, 2.30]

2.8.8 Ixekizumab versus ustekinumab

1

302

Risk Ratio (M‐H, Random, 95% CI)

6.09 [0.30, 125.89]

2.8.9 Brodalumab versus ustekinumab

2

3088

Risk Ratio (M‐H, Random, 95% CI)

1.51 [0.64, 3.56]

2.8.10 Risankizumab versus ustekinumab

3

965

Risk Ratio (M‐H, Random, 95% CI)

0.57 [0.24, 1.32]

2.8.11 Guselkumab versus adalimumab

3

1658

Risk Ratio (M‐H, Random, 95% CI)

0.91 [0.45, 1.84]

2.8.12 Risankizumab versus adalimumab

1

605

Risk Ratio (M‐H, Random, 95% CI)

1.12 [0.46, 2.72]

2.8.13 Ixekizumab versus guselkumab

1

1027

Risk Ratio (M‐H, Random, 95% CI)

1.20 [0.58, 2.47]

2.8.14 Risankizumab versus secukinumab

1

327

Risk Ratio (M‐H, Random, 95% CI)

1.49 [0.54, 4.09]

2.9 Small molecules versus placebo Show forest plot

15

5982

Risk Ratio (M‐H, Random, 95% CI)

0.93 [0.61, 1.43]

2.9.1 Apremilast versus placebo

7

2593

Risk Ratio (M‐H, Random, 95% CI)

0.85 [0.48, 1.52]

2.9.2 Tofacitinib versus placebo

7

3122

Risk Ratio (M‐H, Random, 95% CI)

1.09 [0.57, 2.11]

2.9.3 TYK2 versus placebo

1

267

Risk Ratio (M‐H, Random, 95% CI)

0.61 [0.06, 5.71]

2.10 Biologic versus small molecules Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

2.10.1 Etanercept versus tofacitinib

1

998

Risk Ratio (M‐H, Random, 95% CI)

1.15 [0.46, 2.89]

2.10.2 Etanercept versus apremilast

1

166

Risk Ratio (M‐H, Random, 95% CI)

0.33 [0.04, 3.14]

Figures and Tables -
Comparison 2. Primary outcome ‐ serious adverse events (SAE)
Comparison 3. Secondary outcome ‐ PASI 75

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

3.1 Non‐biological treatments versus placebo Show forest plot

4

1025

Risk Ratio (M‐H, Random, 95% CI)

2.42 [1.74, 3.35]

3.1.1 Methotrexate versus placebo

2

283

Risk Ratio (M‐H, Random, 95% CI)

2.36 [1.19, 4.68]

3.1.2 Fumaric acid esters versus placebo

1

704

Risk Ratio (M‐H, Random, 95% CI)

2.56 [1.68, 3.89]

3.1.3 Acitretin versus placebo

1

38

Risk Ratio (M‐H, Random, 95% CI)

1.85 [0.23, 14.80]

3.2 Non‐biological treatment 1 versus non‐biological treatment 2 Show forest plot

4

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

3.2.1 Ciclosporin versus methotrexate

2

172

Risk Ratio (M‐H, Random, 95% CI)

1.37 [0.84, 2.23]

3.2.2 Methotrexate versus fumaric acid esters

2

168

Risk Ratio (M‐H, Random, 95% CI)

2.30 [0.74, 7.19]

3.3 Anti‐TNF alpha versus placebo Show forest plot

35

12078

Risk Ratio (M‐H, Random, 95% CI)

9.21 [7.78, 10.91]

3.3.1 Etanercept versus placebo

15

5762

Risk Ratio (M‐H, Random, 95% CI)

8.56 [7.07, 10.36]

3.3.2 Adalimumab versus placebo

10

3485

Risk Ratio (M‐H, Random, 95% CI)

8.25 [6.03, 11.29]

3.3.3 Certolizumab versus placebo

5

1153

Risk Ratio (M‐H, Random, 95% CI)

9.55 [6.13, 14.88]

3.3.4 Infliximab versus placebo

6

1678

Risk Ratio (M‐H, Random, 95% CI)

18.87 [8.53, 41.75]

3.4 Anti‐IL12/23 versus placebo Show forest plot

11

4596

Risk Ratio (M‐H, Random, 95% CI)

11.52 [8.75, 15.17]

3.4.1 Ustekinumab versus placebo

11

4596

Risk Ratio (M‐H, Random, 95% CI)

11.52 [8.75, 15.17]

3.5 Anti‐IL17 versus placebo Show forest plot

21

11380

Risk Ratio (M‐H, Random, 95% CI)

15.52 [12.41, 19.42]

3.5.1 Secukinumab versus placebo

11

3753

Risk Ratio (M‐H, Random, 95% CI)

16.78 [12.20, 23.08]

3.5.2 Ixekizumab versus placebo

4

3268

Risk Ratio (M‐H, Random, 95% CI)

17.44 [10.45, 29.10]

3.5.3 Brodalumab versus placebo

5

4109

Risk Ratio (M‐H, Random, 95% CI)

12.80 [8.46, 19.36]

3.5.4 Bimekizumab versus placebo

1

250

Risk Ratio (M‐H, Random, 95% CI)

17.06 [4.41, 66.09]

3.6 Anti‐IL23 versus placebo Show forest plot

14

5882

Risk Ratio (M‐H, Random, 95% CI)

11.60 [9.56, 14.06]

3.6.1 Guselkumab versus placebo

5

1767

Risk Ratio (M‐H, Random, 95% CI)

12.65 [9.24, 17.31]

3.6.2 Tildrakizumab versus placebo

3

1904

Risk Ratio (M‐H, Random, 95% CI)

11.24 [7.33, 17.23]

3.6.3 Risankizumab versus placebo

4

1476

Risk Ratio (M‐H, Random, 95% CI)

11.36 [7.95, 16.21]

3.6.4 Mirikizumab versus placebo

2

735

Risk Ratio (M‐H, Random, 95% CI)

9.87 [5.74, 16.98]

3.7 Biologic versus non‐biological treatments Show forest plot

10

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

3.7.1 Etanercept versus acitretin

3

142

Risk Ratio (M‐H, Random, 95% CI)

1.98 [1.26, 3.12]

3.7.2 Infliximab versus methotrexate

1

868

Risk Ratio (M‐H, Random, 95% CI)

1.86 [1.58, 2.19]

3.7.3 Adalimumab versus methotrexate

1

218

Risk Ratio (M‐H, Random, 95% CI)

2.25 [1.72, 2.94]

3.7.4 Secukinumab versus fumaric acid esters

1

202

Risk Ratio (M‐H, Random, 95% CI)

3.30 [2.36, 4.62]

3.7.5 Ixekizumab versus fumaric ester acids

1

108

Risk Ratio (M‐H, Random, 95% CI)

4.08 [2.46, 6.77]

3.7.6 Ixekizumab versus methotrexate

1

108

Risk Ratio (M‐H, Random, 95% CI)

1.29 [1.06, 1.56]

3.7.7 Guselkumab versus fumaric acid esters

1

118

Risk Ratio (M‐H, Random, 95% CI)

3.26 [2.13, 4.99]

3.7.8 Risankizumab versus fumaric acid esters

1

120

Risk Ratio (M‐H, Random, 95% CI)

2.95 [2.06, 4.23]

3.7.9 Brodalumab versus fumaric acid esters

1

210

Risk Ratio (M‐H, Random, 95% CI)

2.12 [1.64, 2.76]

3.8 Biologic 1 versus biologic 2 Show forest plot

21

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

3.8.1 Ustekinumab versus etanercept

1

903

Risk Ratio (M‐H, Random, 95% CI)

1.26 [1.13, 1.40]

3.8.2 Secukinumab versus etanercept

1

980

Risk Ratio (M‐H, Random, 95% CI)

1.64 [1.44, 1.88]

3.8.3 Infliximab versus etanercept

1

48

Risk Ratio (M‐H, Random, 95% CI)

2.07 [1.12, 3.81]

3.8.4 Ixekizumab versus etanercept

2

2209

Risk Ratio (M‐H, Random, 95% CI)

1.79 [1.43, 2.24]

3.8.5 Tildrakizumab versus etanercept

1

934

Risk Ratio (M‐H, Random, 95% CI)

1.32 [1.16, 1.50]

3.8.6 Certolizumab versus etanercept

1

502

Risk Ratio (M‐H, Random, 95% CI)

1.19 [1.01, 1.40]

3.8.7 Secukinumab versus ustekinumab

2

1778

Risk Ratio (M‐H, Random, 95% CI)

1.14 [1.10, 1.19]

3.8.8 Ixekizumab versus ustekinumab

1

302

Risk Ratio (M‐H, Random, 95% CI)

1.24 [1.09, 1.41]

3.8.9 Brodalumab versus ustekinumab

2

3088

Risk Ratio (M‐H, Random, 95% CI)

1.10 [1.04, 1.17]

3.8.10 Risankizumab versus ustekinumab

3

965

Risk Ratio (M‐H, Random, 95% CI)

1.23 [1.13, 1.33]

3.8.11 Guselkumab versus adalimumab

3

1658

Risk Ratio (M‐H, Random, 95% CI)

1.23 [1.14, 1.32]

3.8.12 Risankizumab versus adalimumab

1

605

Risk Ratio (M‐H, Random, 95% CI)

1.26 [1.17, 1.37]

3.8.13 Secukinumab versus guselkumab

1

1048

Risk Ratio (M‐H, Random, 95% CI)

1.03 [0.99, 1.07]

3.8.14 Risankizumab versus secukinumab

1

327

Risk Ratio (M‐H, Random, 95% CI)

1.15 [1.05, 1.26]

3.9 Small molecules versus placebo Show forest plot

14

5679

Risk Ratio (M‐H, Random, 95% CI)

4.96 [3.77, 6.51]

3.9.1 Apremilast versus placebo

6

2290

Risk Ratio (M‐H, Random, 95% CI)

3.86 [2.59, 5.74]

3.9.2 Tofacitinib versus placebo

7

3122

Risk Ratio (M‐H, Random, 95% CI)

6.14 [4.31, 8.73]

3.9.3 TYK2 versus placebo

1

267

Risk Ratio (M‐H, Random, 95% CI)

7.77 [2.59, 23.36]

3.10 Biologic versus small molecules Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

3.10.1 Etanercept versus tofacitinib

1

998

Risk Ratio (M‐H, Random, 95% CI)

1.14 [1.02, 1.28]

3.10.2 Etanercept versus apremilast

1

166

Risk Ratio (M‐H, Random, 95% CI)

1.21 [0.86, 1.71]

Figures and Tables -
Comparison 3. Secondary outcome ‐ PASI 75
Comparison 4. Secondary outcome ‐ PGA 0/1

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

4.1 Non‐biological treatment versus placebo Show forest plot

4

1023

Risk Ratio (M‐H, Random, 95% CI)

2.87 [1.97, 4.18]

4.1.1 Methotrexate versus placebo

3

319

Risk Ratio (M‐H, Random, 95% CI)

3.19 [1.66, 6.16]

4.1.2 Fumaric acid esters versus placebo

1

704

Risk Ratio (M‐H, Random, 95% CI)

2.73 [1.72, 4.32]

4.2 Non‐biological treatment 1 versus non‐biological treatment 2 Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

4.2.1 Ciclosporin versus methotrexate

1

88

Risk Ratio (M‐H, Random, 95% CI)

0.82 [0.47, 1.46]

4.2.2 Methotrexate versus fumaric acid esters

1

108

Risk Ratio (M‐H, Random, 95% CI)

3.86 [1.84, 8.09]

4.3 Anti‐TNF alpha versus placebo Show forest plot

29

10194

Risk Ratio (M‐H, Random, 95% CI)

8.89 [7.36, 10.74]

4.3.1 Etanercept versus placebo

13

5030

Risk Ratio (M‐H, Random, 95% CI)

8.11 [6.35, 10.37]

4.3.2 Adalimumab versus placebo

9

3337

Risk Ratio (M‐H, Random, 95% CI)

7.89 [6.13, 10.16]

4.3.3 Certolizumab versus placebo

5

1266

Risk Ratio (M‐H, Random, 95% CI)

27.86 [12.17, 63.79]

4.3.4 Infliximab versus placebo

3

561

Risk Ratio (M‐H, Random, 95% CI)

13.11 [6.69, 25.69]

4.4 Anti‐IL12/23 versus placebo Show forest plot

11

4596

Risk Ratio (M‐H, Random, 95% CI)

10.69 [7.63, 14.98]

4.4.1 Ustekinumab versus placebo

11

4596

Risk Ratio (M‐H, Random, 95% CI)

10.69 [7.63, 14.98]

4.5 Anti‐IL17 versus placebo Show forest plot

19

11082

Risk Ratio (M‐H, Random, 95% CI)

19.01 [14.65, 24.67]

4.5.1 Secukinumab versus placebo

9

3455

Risk Ratio (M‐H, Random, 95% CI)

21.03 [11.53, 38.33]

4.5.2 Ixekizumab versus placebo

4

3268

Risk Ratio (M‐H, Random, 95% CI)

17.46 [9.87, 30.90]

4.5.3 Brodalumab versus placebo

5

4109

Risk Ratio (M‐H, Random, 95% CI)

18.78 [13.29, 26.55]

4.5.4 Bimekizumab versus placebo

1

250

Risk Ratio (M‐H, Random, 95% CI)

15.35 [3.96, 59.49]

4.6 Anti‐IL23 versus placebo Show forest plot

14

5882

Risk Ratio (M‐H, Random, 95% CI)

11.01 [9.06, 13.38]

4.6.1 Guselkumab versus placebo

5

1767

Risk Ratio (M‐H, Random, 95% CI)

10.87 [8.11, 14.57]

4.6.2 Tildrakizumab versus placebo

3

1904

Risk Ratio (M‐H, Random, 95% CI)

10.26 [6.62, 15.91]

4.6.3 Risankizumab versus placebo

4

1476

Risk Ratio (M‐H, Random, 95% CI)

11.50 [7.95, 16.66]

4.6.4 Mirikizumab versus placebo

2

735

Risk Ratio (M‐H, Random, 95% CI)

12.26 [5.88, 25.56]

4.7 Biologic versus non‐biological treatments Show forest plot

8

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

4.7.1 Infliximab versus methotrexate

1

868

Risk Ratio (M‐H, Random, 95% CI)

1.99 [1.67, 2.37]

4.7.2 Adalimumab versus methotrexate

1

218

Risk Ratio (M‐H, Random, 95% CI)

2.44 [1.79, 3.32]

4.7.3 Secukinumab versus fumaric acid esters

1

202

Risk Ratio (M‐H, Random, 95% CI)

6.16 [3.59, 10.57]

4.7.4 Etanercept versus acitretin

2

82

Risk Ratio (M‐H, Random, 95% CI)

4.98 [1.15, 21.49]

4.7.5 Ixekizumab versus fumaric acid esters

1

108

Risk Ratio (M‐H, Random, 95% CI)

6.43 [3.19, 12.96]

4.7.6 Ixekizumab versus methotrexate

1

108

Risk Ratio (M‐H, Random, 95% CI)

1.67 [1.24, 2.23]

4.7.7 Risankizumab versus fumaric acid esters

1

120

Risk Ratio (M‐H, Random, 95% CI)

2.43 [1.75, 3.38]

4.7.8 Brodalumab versus fumaric acid esters

1

210

Risk Ratio (M‐H, Random, 95% CI)

3.24 [2.15, 4.87]

4.8 Biologic 1 versus biologic 2 Show forest plot

21

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

4.8.1 Ustekinumab versus etanercept

1

903

Risk Ratio (M‐H, Random, 95% CI)

1.40 [1.24, 1.58]

4.8.2 Secukinumab versus etanercept

1

980

Risk Ratio (M‐H, Random, 95% CI)

2.09 [1.73, 2.53]

4.8.3 Infliximab versus etanercept

1

48

Risk Ratio (M‐H, Random, 95% CI)

2.50 [1.30, 4.81]

4.8.4 Ixekizumab versus etanercept

2

2209

Risk Ratio (M‐H, Random, 95% CI)

2.01 [1.74, 2.31]

4.8.5 Tildrakizumab versus etanercept

1

934

Risk Ratio (M‐H, Random, 95% CI)

1.20 [1.05, 1.37]

4.8.6 Secukinumab versus ustekinumab

2

1778

Risk Ratio (M‐H, Random, 95% CI)

1.28 [1.19, 1.38]

4.8.7 Ixekizumab versus ustekinumab

1

302

Risk Ratio (M‐H, Random, 95% CI)

1.44 [1.24, 1.68]

4.8.8 Brodalumab versus ustekinumab

2

3088

Risk Ratio (M‐H, Random, 95% CI)

1.17 [1.07, 1.27]

4.8.9 Risankizumab versus ustekinumab

3

965

Risk Ratio (M‐H, Random, 95% CI)

1.37 [1.23, 1.52]

4.8.10 Guselkumab versus adalimumab

3

1658

Risk Ratio (M‐H, Random, 95% CI)

1.26 [1.19, 1.34]

4.8.11 Risankizumab versus adalimumab

1

605

Risk Ratio (M‐H, Random, 95% CI)

1.39 [1.25, 1.54]

4.8.12 Secukinumab versus guselkumab

1

1048

Risk Ratio (M‐H, Random, 95% CI)

1.00 [0.95, 1.05]

4.8.13 Ixekizumab versus guselkumab

1

1027

Risk Ratio (M‐H, Random, 95% CI)

1.33 [1.21, 1.46]

4.8.14 Risankizumab versus secukinumab

1

327

Risk Ratio (M‐H, Random, 95% CI)

1.23 [1.10, 1.37]

4.9 Small molecules versus placebo Show forest plot

13

5704

Risk Ratio (M‐H, Random, 95% CI)

3.92 [3.17, 4.84]

4.9.1 Apremilast versus placebo

6

2333

Risk Ratio (M‐H, Random, 95% CI)

3.52 [2.40, 5.16]

4.9.2 Tofacitinib versus placebo

6

3104

Risk Ratio (M‐H, Random, 95% CI)

4.17 [3.37, 5.17]

4.9.3 TYK2 versus placebo

1

267

Risk Ratio (M‐H, Random, 95% CI)

8.24 [2.74, 24.76]

4.10 Biologic versus small molecules Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

4.10.1 Etanercept versus tofacitinib

1

998

Risk Ratio (M‐H, Random, 95% CI)

1.15 [1.04, 1.27]

4.10.2 Etanercept versus apremilast

1

166

Risk Ratio (M‐H, Random, 95% CI)

1.33 [0.78, 2.27]

Figures and Tables -
Comparison 4. Secondary outcome ‐ PGA 0/1
Comparison 5. Secondary outcome ‐ quality of life

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

5.1 Non‐biological treatments versus placebo Show forest plot

2

283

Std. Mean Difference (IV, Random, 95% CI)

‐0.67 [‐1.40, 0.06]

5.1.1 Methotrexate versus placebo

2

283

Std. Mean Difference (IV, Random, 95% CI)

‐0.67 [‐1.40, 0.06]

5.2 Non‐biological treatment 1 versus non‐biological treatment 2 Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Subtotals only

5.2.1 Methotrexate versus fumaric acid esters

1

108

Mean Difference (IV, Fixed, 95% CI)

‐7.44 [‐9.47, ‐5.41]

5.3 Anti‐TNF alpha versus placebo Show forest plot

25

8534

Std. Mean Difference (IV, Random, 95% CI)

‐1.08 [‐1.19, ‐0.97]

5.3.1 Etanercept versus placebo

8

3246

Std. Mean Difference (IV, Random, 95% CI)

‐1.11 [‐1.34, ‐0.88]

5.3.2 Adalimumab versus placebo

9

3055

Std. Mean Difference (IV, Random, 95% CI)

‐0.98 [‐1.11, ‐0.85]

5.3.3 Certolizumab versus placebo

3

588

Std. Mean Difference (IV, Random, 95% CI)

‐1.00 [‐1.26, ‐0.74]

5.3.4 Infliximab versus placebo

5

1645

Std. Mean Difference (IV, Random, 95% CI)

‐1.29 [‐1.48, ‐1.10]

5.4 Ustekinumab versus placebo Show forest plot

9

3359

Std. Mean Difference (IV, Random, 95% CI)

‐1.35 [‐1.54, ‐1.16]

5.5 Anti‐IL17 versus placebo Show forest plot

6

3566

Std. Mean Difference (IV, Random, 95% CI)

‐1.46 [‐1.80, ‐1.13]

5.5.1 Ixekizumab versus placebo

3

3126

Std. Mean Difference (IV, Random, 95% CI)

‐1.76 [‐2.09, ‐1.43]

5.5.2 Brodalumab versus placebo

2

349

Std. Mean Difference (IV, Random, 95% CI)

‐0.96 [‐1.44, ‐0.47]

5.5.3 Secukinumab versus placebo

1

91

Std. Mean Difference (IV, Random, 95% CI)

‐1.41 [‐1.87, ‐0.94]

5.6 Anti‐IL23 versus placebo Show forest plot

8

4146

Std. Mean Difference (IV, Random, 95% CI)

‐1.46 [‐1.62, ‐1.30]

5.6.1 Guselkumab versus placebo

3

1444

Std. Mean Difference (IV, Random, 95% CI)

‐1.36 [‐1.54, ‐1.18]

5.6.2 Tildrakizumab versus placebo

3

1904

Std. Mean Difference (IV, Random, 95% CI)

‐1.36 [‐1.48, ‐1.23]

5.6.3 Risankizumab versus placebo

2

798

Std. Mean Difference (IV, Random, 95% CI)

‐1.82 [‐2.04, ‐1.60]

5.7 Biologic versus non‐biological treatment Show forest plot

5

Mean Difference (IV, Fixed, 95% CI)

Subtotals only

5.7.1 Adalimumab versus methotrexate

1

218

Mean Difference (IV, Fixed, 95% CI)

‐3.40 [‐5.75, ‐1.05]

5.7.2 Ixekizumab versus fumaric acid esters

1

108

Mean Difference (IV, Fixed, 95% CI)

‐7.71 [‐9.74, ‐5.68]

5.7.3 Ixekizumab versus methotrexate

1

108

Mean Difference (IV, Fixed, 95% CI)

‐0.27 [‐2.31, 1.77]

5.7.4 Guselkumab versus fumaric acid esters

1

119

Mean Difference (IV, Fixed, 95% CI)

‐5.80 [‐8.06, ‐3.54]

5.7.5 Risankizumab versus fumaric acid esters

1

120

Mean Difference (IV, Fixed, 95% CI)

‐7.60 [‐9.97, ‐5.23]

5.7.6 Brodalumab versus fumaric acid esters

1

210

Mean Difference (IV, Fixed, 95% CI)

‐2.57 [‐4.27, ‐0.87]

5.8 Biologic 1 versus biologic 2 Show forest plot

8

Mean Difference (IV, Fixed, 95% CI)

Subtotals only

5.8.1 Ixekizumab versus etanercept

2

2209

Mean Difference (IV, Fixed, 95% CI)

‐1.99 [‐2.39, ‐1.59]

5.8.2 Guselkumab versus adalimumab

2

1407

Mean Difference (IV, Fixed, 95% CI)

‐1.73 [‐2.50, ‐0.97]

5.8.3 Risankizumab versus ustekinumab

2

799

Mean Difference (IV, Fixed, 95% CI)

‐1.00 [‐1.50, ‐0.50]

5.8.4 Tildrakizumab versus etanercept

1

932

Mean Difference (IV, Fixed, 95% CI)

‐1.40 [‐2.20, ‐0.60]

5.8.5 Infliximab versus etanercept

1

48

Mean Difference (IV, Fixed, 95% CI)

‐1.60 [‐2.93, ‐0.27]

5.9 Small molecules versus placebo Show forest plot

9

5061

Std. Mean Difference (IV, Random, 95% CI)

‐0.79 [‐0.99, ‐0.60]

5.9.1 Apremilast versus placebo

5

2166

Std. Mean Difference (IV, Random, 95% CI)

‐0.59 [‐0.70, ‐0.47]

5.9.2 Tofacitinib versus placebo

4

2895

Std. Mean Difference (IV, Random, 95% CI)

‐1.08 [‐1.23, ‐0.93]

5.10 Biologic versus small molecules Show forest plot

1

Std. Mean Difference (IV, Random, 95% CI)

Subtotals only

5.10.1 Etanercept versus tofacitinib

1

998

Std. Mean Difference (IV, Random, 95% CI)

‐0.06 [‐0.19, 0.07]

Figures and Tables -
Comparison 5. Secondary outcome ‐ quality of life
Comparison 6. Secondary outcome ‐ adverse events

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

6.1 Non‐biological treatments versus placebo Show forest plot

4

1023

Risk Ratio (M‐H, Random, 95% CI)

1.08 [0.78, 1.50]

6.1.1 Methotrexate versus placebo

3

319

Risk Ratio (M‐H, Random, 95% CI)

0.94 [0.81, 1.10]

6.1.2 Fumaric acid esters versus placebo

1

704

Risk Ratio (M‐H, Random, 95% CI)

1.40 [1.22, 1.62]

6.2 Non‐biological treatment 1 versus non‐biological treatment 2 Show forest plot

4

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

6.2.1 Ciclosporin versus methotrexate

2

172

Risk Ratio (M‐H, Random, 95% CI)

1.10 [0.90, 1.34]

6.2.2 Methotrexate versus fumaric acid esters

2

168

Risk Ratio (M‐H, Random, 95% CI)

1.06 [0.90, 1.24]

6.3 Anti‐TNF alpha versus placebo Show forest plot

27

9856

Risk Ratio (M‐H, Random, 95% CI)

1.06 [1.02, 1.10]

6.3.1 Etanercept versus placebo

11

4225

Risk Ratio (M‐H, Random, 95% CI)

1.08 [1.00, 1.16]

6.3.2 Adalimumab versus placebo

9

3338

Risk Ratio (M‐H, Random, 95% CI)

1.05 [0.99, 1.12]

6.3.3 Certolizumab versus placebo

4

1026

Risk Ratio (M‐H, Random, 95% CI)

0.97 [0.86, 1.09]

6.3.4 Infliximab versus placebo

4

1267

Risk Ratio (M‐H, Random, 95% CI)

1.12 [0.93, 1.36]

6.4 Ustekinumab versus placebo Show forest plot

11

4596

Risk Ratio (M‐H, Random, 95% CI)

1.07 [1.01, 1.13]

6.5 Anti‐IL17 versus placebo Show forest plot

21

11333

Risk Ratio (M‐H, Random, 95% CI)

1.21 [1.11, 1.30]

6.5.1 Secukinumab versus placebo

11

3706

Risk Ratio (M‐H, Random, 95% CI)

1.20 [1.06, 1.36]

6.5.2 Ixekizumab versus placebo

4

3268

Risk Ratio (M‐H, Random, 95% CI)

1.24 [1.07, 1.45]

6.5.3 Brodalumab versus placebo

5

4109

Risk Ratio (M‐H, Random, 95% CI)

1.15 [1.00, 1.32]

6.5.4 Bimekizumab versus placebo

1

250

Risk Ratio (M‐H, Random, 95% CI)

1.70 [1.11, 2.58]

6.6 Anti‐IL23 versus placebo Show forest plot

14

5882

Risk Ratio (M‐H, Random, 95% CI)

0.93 [0.87, 1.00]

6.6.1 Guselkumab versus placebo

5

1767

Risk Ratio (M‐H, Random, 95% CI)

1.00 [0.90, 1.11]

6.6.2 Tildrakizumab versus placebo

3

1904

Risk Ratio (M‐H, Random, 95% CI)

0.86 [0.72, 1.02]

6.6.3 Risankizumab versus placebo

4

1476

Risk Ratio (M‐H, Random, 95% CI)

0.91 [0.77, 1.07]

6.6.4 Mirikizumab versus placebo

2

735

Risk Ratio (M‐H, Random, 95% CI)

0.99 [0.83, 1.19]

6.7 Biologic versus non‐biological treatments Show forest plot

9

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

6.7.1 Infliximab versus methotrexate

1

868

Risk Ratio (M‐H, Random, 95% CI)

1.08 [0.97, 1.20]

6.7.2 Adalimumab versus methotrexate

1

218

Risk Ratio (M‐H, Random, 95% CI)

0.90 [0.78, 1.05]

6.7.3 Secukinumab versus fumaric acid esters

1

202

Risk Ratio (M‐H, Random, 95% CI)

0.82 [0.71, 0.94]

6.7.4 Etanercept versus acitretin

2

82

Risk Ratio (M‐H, Random, 95% CI)

1.19 [0.72, 1.96]

6.7.5 Ixekizumab versus fumaric acid esters

1

108

Risk Ratio (M‐H, Random, 95% CI)

0.95 [0.74, 1.21]

6.7.6 Ixekizumab versus methotrexate

1

108

Risk Ratio (M‐H, Random, 95% CI)

0.97 [0.76, 1.25]

6.7.7 Guselkumab versus fumaric acid esters

1

119

Risk Ratio (M‐H, Random, 95% CI)

0.76 [0.65, 0.89]

6.7.8 Risankizumab versus fumaric acid esters

1

120

Risk Ratio (M‐H, Random, 95% CI)

0.83 [0.70, 0.99]

6.7.9 Brodalumab versus fumaric acid esters

1

210

Risk Ratio (M‐H, Random, 95% CI)

0.73 [0.62, 0.87]

6.8 Biologic 1 versus biologic 2 Show forest plot

21

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

6.8.1 Ustekinumab versus etanercept

1

903

Risk Ratio (M‐H, Random, 95% CI)

0.97 [0.89, 1.06]

6.8.2 Secukinumab versus etanercept

1

980

Risk Ratio (M‐H, Random, 95% CI)

1.00 [0.89, 1.12]

6.8.3 Ixekizumab versus etanercept

2

2209

Risk Ratio (M‐H, Random, 95% CI)

1.06 [0.97, 1.15]

6.8.4 Infliximab versus etanercept

1

48

Risk Ratio (M‐H, Random, 95% CI)

0.96 [0.86, 1.08]

6.8.5 Tildrakizumab versus etanercept

1

934

Risk Ratio (M‐H, Random, 95% CI)

0.75 [0.65, 0.86]

6.8.6 Certolizumab versus etanercept

1

502

Risk Ratio (M‐H, Random, 95% CI)

1.05 [0.86, 1.28]

6.8.7 Secukinumab versus ustekinumab

2

1778

Risk Ratio (M‐H, Random, 95% CI)

1.06 [0.98, 1.16]

6.8.8 Ixekizumab versus ustekinumab

1

302

Risk Ratio (M‐H, Random, 95% CI)

1.03 [0.93, 1.13]

6.8.9 Brodalumab versus ustekinumab

2

3088

Risk Ratio (M‐H, Random, 95% CI)

1.00 [0.93, 1.09]

6.8.10 Risankizumab versus ustekinumab

3

965

Risk Ratio (M‐H, Random, 95% CI)

0.97 [0.85, 1.11]

6.8.11 Guselkumab versus adalimumab

3

1658

Risk Ratio (M‐H, Random, 95% CI)

0.98 [0.89, 1.09]

6.8.12 Risankizumab versus adalimumab

1

605

Risk Ratio (M‐H, Random, 95% CI)

1.08 [0.82, 1.43]

6.8.13 Ixekizumab versus guselkumab

1

1027

Risk Ratio (M‐H, Random, 95% CI)

1.03 [0.92, 1.15]

6.8.14 Risankizumab versus secukinumab

1

327

Risk Ratio (M‐H, Random, 95% CI)

1.00 [0.87, 1.15]

6.9 Small molecules versus placebo Show forest plot

14

5785

Risk Ratio (M‐H, Random, 95% CI)

1.25 [1.14, 1.38]

6.9.1 Apremilast versus placebo

7

2593

Risk Ratio (M‐H, Random, 95% CI)

1.24 [1.13, 1.36]

6.9.2 Tofacitinib versus placebo

6

2925

Risk Ratio (M‐H, Random, 95% CI)

1.28 [1.01, 1.63]

6.9.3 TYK2 versus placebo

1

267

Risk Ratio (M‐H, Random, 95% CI)

1.31 [0.97, 1.77]

6.10 Biologic versus small molecules Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

6.10.1 Etanercept versus tofacitinib

1

998

Risk Ratio (M‐H, Random, 95% CI)

1.00 [0.89, 1.12]

6.10.2 Etanercept versus apremilast

1

166

Risk Ratio (M‐H, Random, 95% CI)

1.32 [1.03, 1.69]

Figures and Tables -
Comparison 6. Secondary outcome ‐ adverse events
Comparison 7. Secondary outcome ‐ PASI 90 at 52 weeks

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

7.1 Biologic 1 versus biologic 2 Show forest plot

11

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

7.1.1 Secukinumab versus ustekinumab

2

1778

Risk Ratio (M‐H, Random, 95% CI)

1.23 [1.15, 1.31]

7.1.2 Secukinumab 150 versus secukinumab 300

1

121

Risk Ratio (M‐H, Random, 95% CI)

0.83 [0.61, 1.13]

7.1.3 Guselkumab versus adalimumab

1

663

Risk Ratio (M‐H, Random, 95% CI)

1.59 [1.40, 1.81]

7.1.4 Risankizumab versus ustekinumab

2

799

Risk Ratio (M‐H, Random, 95% CI)

1.73 [1.46, 2.05]

7.1.5 Guselkumab 100 versus guselkumab 50

1

128

Risk Ratio (M‐H, Random, 95% CI)

1.03 [0.85, 1.25]

7.1.6 Ixekizumab Q2W versus Ixekizumab Q4W

1

1227

Risk Ratio (M‐H, Random, 95% CI)

1.06 [1.01, 1.11]

7.1.7 Secukinumab versus guselkumab

1

1048

Risk Ratio (M‐H, Random, 95% CI)

0.83 [0.78, 0.89]

7.1.8 Risankizumab versus secukinumab

1

327

Risk Ratio (M‐H, Random, 95% CI)

1.52 [1.31, 1.76]

7.1.9 Ixekizumab versus ustekinumab

1

302

Risk Ratio (M‐H, Random, 95% CI)

1.30 [1.11, 1.52]

7.2 Small molecule 1 versus small molecule 2 Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

7.2.1 Apremilast 30mg versus apremilast other

1

170

Risk Ratio (M‐H, Random, 95% CI)

1.25 [0.84, 1.86]

7.3 Biologic versus placebo Show forest plot

1

82

Risk Ratio (M‐H, Random, 95% CI)

0.80 [0.58, 1.12]

7.3.1 Secukinumab versus placebo

1

82

Risk Ratio (M‐H, Random, 95% CI)

0.80 [0.58, 1.12]

Figures and Tables -
Comparison 7. Secondary outcome ‐ PASI 90 at 52 weeks
Comparison 8. Secondary outcome ‐ PASI 75 at 52 weeks

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

8.1 Biologic 1 versus biologic 2 Show forest plot

11

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

8.1.1 Secukinumab versus ustekinumab

2

1778

Risk Ratio (M‐H, Random, 95% CI)

1.13 [1.04, 1.22]

8.1.2 Secukinumab 150 versus secukinumab 300

1

121

Risk Ratio (M‐H, Random, 95% CI)

0.86 [0.70, 1.06]

8.1.3 Guselkumab versus adalimumab

1

663

Risk Ratio (M‐H, Random, 95% CI)

1.40 [1.28, 1.54]

8.1.4 Risankizumab versus ustekinumab

2

799

Risk Ratio (M‐H, Random, 95% CI)

1.26 [1.12, 1.41]

8.1.5 Guselkumab 100 versus guselkumab 50

1

128

Risk Ratio (M‐H, Random, 95% CI)

0.98 [0.88, 1.09]

8.1.6 Ixekizumab Q2W versus ixekizumab Q4W

1

1227

Risk Ratio (M‐H, Random, 95% CI)

1.14 [1.07, 1.22]

8.1.7 Secukinumab versus guselkumab

1

1048

Risk Ratio (M‐H, Random, 95% CI)

1.14 [1.08, 1.21]

8.1.8 Risankizumab versus secukinumab

1

327

Risk Ratio (M‐H, Random, 95% CI)

1.28 [1.14, 1.44]

8.1.9 Ixekizumab versus ustekinumab

1

302

Risk Ratio (M‐H, Random, 95% CI)

1.16 [1.05, 1.29]

8.2 Small molecules 1 versus small molecules 2 Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

8.2.1 Tofacitinib 10 mg versus tofacitinib 20 mg

1

178

Risk Ratio (M‐H, Random, 95% CI)

0.77 [0.63, 0.95]

8.2.2 Apremilast 30 versus apremilast other

1

170

Risk Ratio (M‐H, Random, 95% CI)

1.12 [0.46, 2.78]

Figures and Tables -
Comparison 8. Secondary outcome ‐ PASI 75 at 52 weeks