Scolaris Content Display Scolaris Content Display

Cochrane Database of Systematic Reviews Protocol - Overview

Biologics for rheumatoid arthritis: an overview of Cochrane reviews

Authors' declarations of interest

Version published: 08 July 2009 Version history

https://doi.org/10.1002/14651858.CD007848

This is not the most recent version

view the current version 07 October 2009
Collapse all Expand all

Abstract

This is a protocol for a Cochrane Review (Overview). The objectives are as follows:

To compare the efficacy and safety of biologic DMARDs in adults with rheumatoid arthritis.

Background

Description of the condition

Rheumatoid arthritis (RA) is a systematic inflammatory disease characterized by inflammation of synovial lining of the joints, tendons and periarticular structures (Harris 1990). RA has a prevalence of 0.5‐1.0% in the Western countries (Kvien 2004). Untreated, RA leads to joint destruction, functional limitation and severe disability (Odegard 2005; Yelin 2007) and has a significant impact on health‐related quality of life (HRQoL) (Kvien 2005; Lubeck 2004).

The systemic and joint inflammation in RA is mediated by activation of T‐cells (Cope 2008), B‐cells, macrophages (Szekanecz 2007), and other immune cells (Woolley 2003). These interactions lead to expression of chemokines, metalloproteinase and inflammatory cytokines such as tumor necrosis factor‐alpha (TNF‐alpha) and various interleukins (IL) (Brennan 2008; Choy 2001). Interaction of lymphocytes and inflammatory cytokines with host cells such as fibroblasts, osteoclasts and chondrocytes leads to bone and cartilage destruction, a hallmark of RA (Brennan 2008; Connell 2006).

Treatment options for rheumatoid arthritis include use of non‐steroidal anti‐inflammatory drugs (NSAIDs), corticosteroids, traditional disease‐modifying anti‐rheumatic drugs (DMARDs) (methotrexate, sulfasalazine, hydroxychloroquine) and biologic DMARDs.  DMARDs help to improve not only pain and function in patients with RA as well as improves the long‐term outcomes including radiographic progression (Finckh 2006; Pincus 2002) and disability (Cash 1994; Strand 2008).

Description of the interventions

The introduction of biologic DMARDs has revolutionized the management of rheumatoid arthritis (RA).  These medications are commonly used for patients with suboptimal response or intolerance to traditional DMARDs such as methotrexate (MTX).  Many are used in combination with MTX in patients with suboptimal response to MTX.  These include three tumor necrosis factor inhibitors (Scott 2006) ‐ infliximab (REMICADE, approved 1998 in the U.S.) (FDA 1998), etanercept (ENBREL, approved 1998) (FDA 1998a), adalimumab (HUMIRA, approved, 2002) (FDA 2002); anti‐IL1 therapy ‐ anakinra (KINERET, approved 2001) (FDA 2001); anti‐CD28 therapy ‐ abatacept (ORENCIA, approved 2005) (FDA 2006); and anti‐B‐cell therapy ‐ rituximab (RITUXAN/MABTHERA, approved 1997) (FDA 1997). These biologic DMARDs have been approved for use in RA patients in Europe, Canada, Australia and many countries internationally, although the indications for use differ slightly between countries.

How the intervention might work

The mechanism of action of biologic DMARDs is summarized in the individual Cochrane systematic reviews and will not be repeated here for brevity. Furst et al. summarized the specifics regarding the use of each biologic DMARD in their consensus statement as follows (Furst 2008):

1.  Anti‐TNFs are used in conjunction with another DMARD, usually methotrexate (MTX), for the treatment of RA. These drugs are also effective for the treatment of RA in MTX‐naive patients and have been used successfully with other DMARDs, including sulfasalazine and leflunomide.

 

2. Anakinra is recommended for the treatment of active RA after an adequate trial of another conventional DMARD, for example, MTX. It may be used alone or with MTX. The safety of anakinra has also been studied with other DMARDs. In Europe, the anakinra label requires its use with MTX.

 

3. Abatacept is recommended for treatment of active RA, alone or with background DMARDs, in patients with an inadequate response to MTX or another effective DMARD (in the USA). Monotherapy is only approved in the USA in patients with an inadequate response to one or more TNF blocking agent. Abatacept has been approved in Europe for treatment of active RA in patients who have an inadequate response to another non‐biological DMARD, including a failure of at least one TNF blocking agent.

 

4. Rituximab is approved in the USA for the treatment of moderate‐to‐severe RA in patients who have had an inadequate response to at least one TNF blocking agent or have at least moderate disease activity despite MTX therapy. It may be used alone or in combination with MTX. It may also be used when TNF inhibitors are not suitable.

Why it is important to do this overview

The biologic DMARDs are very effective in treating RA, however there is a lack of head‐to‐head comparison studies. Thus, it is prudent to perform indirect comparison analyses enabling the clinician to be fully informed about efficacy using rigorous methods including a multitude of therapies in the same review (Kristensen 2007).  This umbrella review aims to systematically review the existing updated Cochrane systematic reviews of Biologic DMARDs for RA. This will help clinicians and patients in making treatment choices.

Objectives

To compare the efficacy and safety of biologic DMARDs in adults with rheumatoid arthritis.

Methods

Criteria for considering reviews for inclusion

Completed and updated Cochrane reviews of biologic DMARDs for RA.

Search methods for identification of reviews

We will search the Cochrane Database of Systematic Reviews using the search term “Rheumatoid arthritis” as title, abstract or keyword under the search function in the Cochrane Library.  We will review these titles for systematic reviews of infliximab, etanercept, adalimumab, anakinra, abatacept and rituximab.

Types of Studies

Cochrane systematic reviews of randomized controlled trials of biologic DMARDs including infliximab, etanercept, adalimumab, anakinra, abatacept and rituximab in patients with RA.

Types of Participants

Adults 18 years or older, with RA meeting the 1987 American College of Rheumatology Classification criteria for RA (Arnett 1988)

Types of Interventions

Infliximab, etanercept, adalimumab, anakinra, abatacept or rituximab used in standard, approved‐doses.

Types of Outcome Measures

Primary Outcomes

  1. Binary: ACR50 defined as 50% improvement in both tender and swollen joint counts and 50% improvement in three of the five following five variables: patient global assessment, physician global assessments, pain scores, Health Assessment Questionnaire (HAQ) score, and acute phase reactants (Erythrocyte Sedimentation Rate (ESR) or C‐Reactive Protein (CRP) (Felson 1995; Chung 2006).

Secondary Outcomes

  1. Continuous: changes in either Disease Activity Score (DAS), a composite index of tender and swollen joint counts, patient global assessment and ESR (van der Heijde 1993) or DAS28 score (Prevoo 1995)

  2. Proportion achieving a "good state": (a) good European League Against Rheumatism (EULAR) response ‐ defined by a decrease in the DAS or DAS 28 of > 1.2 from baseline with a final DAS < 2.4 (or DAS 28 < 3.2) (Fransen 2005; van Gestel 1996); (b) low disease activity defined by DAS < 2.4 or DAS28 < 3.2 (Fransen 2005; van Gestel 1996); (c) remission defined as DAS < 1.6 or DAS28 < 2.6 (Fransen 2005; Prevoo 1996)

  3. Quality of Life, measured by Short‐Form‐36 *(SF‐36) (i.e. continuous data, 8 domains; and two summary score, physical and mental component summary) and function mesured by HAQ score or modified HAQ calculated as score changes (Fries 1980; Pincus 1983) and the proportion achieving minimally clinically important difference on HAQ >/= 0.22 (Wells 1993)

  4. Radiographic progression, as measured by Larsen/Sharp/modified Sharp scores ( Larsen 1977; Sharp 1971; van der Heijde 1989).

  5. Number and type of adverse effects (AEs)

  6. Withdrawals: (i) Total, (ii) due to lack of efficacy, (iii) due to adverse events

  7. Death

  8. ACR20 and ACR70 defined as 20% and 70% improvement in variables defined above under primary outcome (Felson 1995)

We realize that randomized controlled trials included in this umbrella review are limited in their ability to assess safety. We will search U.S. Food and Drug Administration (FDA) web site for labels and warnings and other similar regulatory agency's web sites to summarize warnings related to each of the biologic DMARDs.

Data collection and analysis

Selection of reviews

We will include all completed and updated Cochrane Database of Systematic Reviews of biologic DMARDs for RA, if they have been updated by 03/15/2009. Systematic reviews of observational studies will not be included. If a review is incomplete and/or not updated recently, the authors of the review will be contacted and requested to provide data and/or to update the review.

Search reviews (titles and abstracts) will be reviewed by two authors (JS and RC) and relevant reviews will be identified. A full text of the review will be obtained and reviewed by both authors (JS and RC). A review will be included if it contains at least one RCT, has clinically relevant outcomes, and included clear inclusion and exclusion criteria for studies.

Data extraction and management

We will import the data directly from the relevant Cochrane reviews using GRADEprofiler software (version 3.2, GRADE working group 2004‐2007). If required data are not available in the review, the two authors will review the original RCT reports. In that case, the data will be extracted independently by two authors (JS and RC) and disagreements will be resolved by discussion.

We will only include studies using standard dosing regimens of these biologic DMARDs. Specifically, the studies with the following doses: infliximab: 3 mg/kg intravenous every 8 weeks after initial dosing at 0, 2 and 6 weeks; etanercept: 25 mg subcutaneous twice weekly; adalimumab: 40 mg subcutaneous every 2 weeks; rituximab, two 1000 mg IV doses 2 weeks apart; abatacept every 4 weeks intravenously at 500mg dose in patients <60 kg, 750 mg in patients 60‐100 kg and 1000 mg in patients >100 kg, after the initial dosing regimen of baseline, 2 and 4‐week infusions; Anakinra 100mg subcutaneous every day.

Assessment of methodological quality of included reviews

The methodological quality of the included studies will be obtained from each included study by two authors (JS and RC) independently.

Quality of included reviews

The methodological quality of the included reviews will be assessed by two authors independently using the 'assessment of multiple systematic reviews' (AMSTAR) instrument (Shea 2007). The AMSTAR instrument assesses the quality of systematic reviews using the following criteria:

1. Was an a priori design provided?

2. Was there duplicate study selection and data extraction?

3. Was a comprehensive literature search performed?

4. Was the status of publication (i.e. grey literature) used as an inclusion criterion?

5. Was a list of studies (included and excluded) provided?

6. Were the characteristics of the included studies provided?

7. Was the scientific quality of the included studies assessed and documented?

8. Was the scientific quality of the included studies used appropriately in formulating conclusions?

9. Were the methods used to combine the findings of studies appropriate?

10. Was the likelihood of publication bias assessed?

11. Was the conflict of interest stated?

Quality of evidence in included reviews

Two review authors will independently (JS and RC) assess the overall quality of the evidence for each study/outcome using the GRADE approach (Atkins 2004). The GRADE approach specifies four levels of quality:

  • high quality for randomized trials; or double‐upgraded observational studies.

  • Moderate quality for downgraded randomized trials; or upgraded observational studies.

  • low quality for double‐downgraded randomized trials; or observational studies and

  • very low quality for triple‐downgraded randomized trials; or downgraded observational studies; or case series/case reports.

Review authors can downgrade randomized trial evidence by one or two levels depending on the presence of five factors:

  • Serious (‐1) or very serious (‐2) limitation to study quality

  • Important inconsistency (‐1)

  • Some (‐1) or major (‐2) uncertainty about directness

  • Imprecise or sparse data (‐1)

  • High probability of reporting bias (‐1).

Data synthesis

Statistical Analyses

For the dichotomous outcomes (e.g. the number of patients achieving more than 50% symptomatic improvement), we will perform meta‐analysis combining trials of various drugs versus placebo to obtain the mutually independent estimates using risk ratios (RR) as effect measure. On the other hand, continuous data (e.g. DAS) will be handled as the standardized mean difference ‐ anticipating the included studies will use different versions of DAS). For the safety data we anticipate that the events are rather rare (Sweeting 2004); thus these safety data will be analyzed via the Peto one‐step odds ratio method (Bradburn 2007).

In the absence of randomized trials making head to head comparisons, an indirect comparison is possible using a common comparator (Song 2003).

For the particular case of only two subgroups the difference between the subgroups can be estimated, and the statistical significance determined, using a simple procedure described by Bucher (Bucher 1997). The test can be performed using the test for differences between subgroups, as implemented in RevMan. A simple approach for a significance test that can be used to investigate differences between two or more subgroups is implemented in RevMan for fixed‐effect analyses based on the inverse‐variance method. The procedure is based on the test for heterogeneity chi‐squared statistics that appear in the bottom left hand corner of the forest plots (O’Connor 2008). If confidence intervals for the results of individual studies have poor overlap, this generally indicates the presence of statistical heterogeneity. Methods have been developed for quantifying inconsistency across studies that move the focus away from testing whether heterogeneity is present to assessing its impact on the meta‐analysis (Higgins 2002). A useful statistic for quantifying inconsistency is the I2 value (Higgins 2003); we will use the random‐effects model as the default option.

The primary analysis in this systematic review will be the comparison of the different drugs’ efficacy (i.e. ACR50); subsequently we will use the number needed to treat (NNT) for clinical interpretation (Osiri 2003), using the Visual Rx with the pooled number of responders within the available studies as the control event rate, respectively (Cates 2009; O’Connor 2008).

Sub‐group analyses/Planned Comparisons

We plan to perform the following analyses:

  1. Comparison of the six biologic DMARDs with regards to efficacy and safety

  2. Background methotrexate vs. no methotrexate

  3. RA disease duration ‐ categorized as early RA defined as duration of less than 2 years (Boers 2001) vs. established RA, duration 2 to10 years vs. late RA defined as >10 years (Barlow 1999)

  4. Anti‐TNF biologic DMARDs vs. other biologic DMARDs

  5. Use in patients who have methotrexate‐failure vs. biologic‐failure

  6. DMARD‐naïve vs. not naïve

  7. Single biologic DAMRD agent vs. combination biologic therapy

  8. Treatment duration with biologic DMARD: Short (6 months), intermediate duration (6 to 12 months) or long‐duration (>1 year)