Genetic and clinical biomarkers of tocilizumab response in patients with rheumatoid arthritis
Graphical abstract
Introduction
Rheumatoid Arthritis (RA) is characterized by inflammation of the synovial membrane that lines the joints [1]. RA has an overall prevalence of 0.24% (CI95%: 0.230.25%), which has changed little since 19902010 [2]. Patients diagnosed with RA are initially treated with disease-modifying antirheumatic drugs (DMARDs), the most important being methotrexate, leflunomide or sulfasalazine [3]. RA patients who have tried at least 2 DMARDs, for a period of 6 months, and have not achieved the therapeutic goal, are candidates to start treatment with biological therapy (BT) [3]. In the last decade, the approval of tumor necrosis factor inhibitors (TNFi) for the treatment of RA has transformed the course of this disease by achieving improved effectiveness and remission (DAS28 < 2.4) rates [4], [5]. However, interindividual variability in response to BT caused by clinical, genetic and environmental factors results in 40% of non-responders [5], [6], [7]. Increased disease activity due to failing to achieve the desired therapeutic goal causes a decrease in the quality of life in RA patients, which together with the high cost of BT drugs leads to an inefficient management of health systems resources. To overcome this resistance, drugs with different targets have been developed, such as tocilizumab (TCZ), a recombinant humanized antibody targeting soluble and membrane IL-6 receptor, which blocks cytokine activities. This cytokine is produced by lymphocytes, monocytes, synoviocytes, and fibroblasts, inducing increase in TNF, differentiation and proliferation of B cells, and synthesis of acute phase proteins, such as C-reactive protein (CRP) and Erythrocyte Sedimentation Rate (ESR). Blockade of IL-6 decreases the characteristic excessive immune response of RA [8], [9]. TCZ has demonstrated great effectiveness, achieving EULAR response rates over 80% and 3555% remission rates after 6 months [10], [11], [12]. Clinical, biochemical and genetic factors have been proposed as predictors of good response to TCZ in RA patients [10], [11], [13], [14], [15], [16]. Among clinical factors, the early administration of TCZ and an increased baseline DAS28 have shown better EULAR response and remission rates, although with conflicting results [10], [14]. Biochemical indicators of high disease activity, such as acute phase reactants (CRP and ESR) have also been proposed as predictors of good response to TCZ, although there is no consensus among all studies [10], [11], [14], [16].
Genetics plays a key role in understanding the interindividual variability in response to treatment with BT [17], [18], [19]. Since TCZ administration in the clinical practice is relatively recent, the influence of genetics on response to TCZ is scarcely investigated. To date, only one genome-wide association study (GWAS) has tried to identify gene polymorphisms involved in the response to TCZ [13]. This GWAS, recently conducted in 1683 subjects with RA from six clinical studies, has identified several single nucleotide polymorphisms (SNP) in CD69 (rs11052877), GALNT18 (rs4910008), CLEC2D (rs1560011), KCNMB1 (rs703505), ENOX1 (rs9594987) genes and rs10108210, rs703297 variants, located in chromosomes 8 and 2, respectively [13]. Currently, there is no further information on the utility of these gene markers to identify RA patients candidates to good response to TCZ in other cohorts, and it would be useful to investigate if these genetic markers are capable to identify patients who will benefit from treatment with TCZ in the clinical practice.
The aim of this study was to investigate the influence of clinical and gene factors on response to TCZ (EULAR response, remission, low disease activity (LDA) and DAS28 improvement). To achieve this, we conducted a retrospective cohort study in RA patients treated with TCZ during 6 and 18 months of therapy.
Section snippets
Study design
A retrospective cohorts study was conducted. This study was approved by the Complejo Hospitalario Universitario de Granada (CHUG) Ethics and Research Committee and was performed conform the declaration of Helsinki; patients signed an informed consent previous participation. All data were recorded without patient identifiers and maintained confidentially.
Study population
White Caucasian patients 18 years diagnosed with RA according to the ACR classification criteria [20] and treated with TCZ (8 mg/kg intravenous
Characteristics of patients
The study included 79 patients (82.3% female; 65/79) diagnosed with RA at 47 [37], [38], [39], [40] years and with 8 [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15] years of disease course (Table 1). All patients had been previously treated with DMARD, and 68.4% (54/79) had tried at least one BT. The median number of BT was 2.2 [1.03.0] during 44.5 [16.582.0] months. Patients started TCZ treatment at 53.2 ± 12.6 years old, 78.5% (62/79) administered intravenously.
Discussion
Interindividual variability in response to BT in RA patients may cause up to 40% of non-responders [5], [6], [7]. TCZ, an inhibitor of IL-6 receptor, has shown EULAR response rates over 80% and 3555% remission in three prospective, multicentre, observational studies compiling more than 1500 RA patients followed during a minimum of 6 months [10], [11], [12] and a double-blind 3-year trial of 556 RA patients treated with TCZ for 26 months [31]. Similar percentages were shown by the 79 RA
Conclusions
RA patients treated with TCZ showed better EULAR response, remission, LDA and DAS28 improvement rates in patients carrying the GALNT18 C-allele or the CD69 A-allele, particularly when a lower number of BT was administered previously. GALNT18 C-allele and CD69 A-allele may act as predictors of good response to TCZ in RA patients.
Funding
This work was partly supported by a contract for Marisa Cañadas-Garre (Técnicos de Apoyo Subprogram. CA12/00097) from Instituto de Salud Carlos III, Ministerio de Economía y Competitividad.
Conflict of interest
The authors declare that there is not conflict of interest that could be perceived as prejudicing the impartiality of the research reported and there is not any competing financial interest in relation to the work described in this article.
Acknowledgements
The authors would like to acknowledge all the patients which participated in the study, the professionals from the Complejo Hospitalario Universitario de Granada that contributed to the management of the samples, especially the nursing team from the Rheumatology Department, and to Dr. Manuela Expósito-Ruiz, for her excellent advice with statistics.
The results of this investigation are part of the doctoral thesis presented by Mar Maldonado-Montoro at the University of Granada, Programme of
References (40)
- et al.
Biological effects of interleukin-6: clinical applications in autoimmune diseases and cancers
Biochem. Pharmacol.
(2015) - et al.
A new era for the treatment of inflammatory autoimmune diseases by interleukin-6 blockade strategy
Semin. Immunol.
(2014) - et al.
Genome-wide association analysis implicates the involvement of eight loci with response to tocilizumab for the treatment of rheumatoid arthritis
Pharmacogenomics J.
(2013) - et al.
The tumor necrosis factor receptor superfamily member 1b polymorphisms predict response to anti-tnf therapy in patients with autoimmune disease: a meta-analysis
Int. Immunopharmacol.
(2015) - et al.
Tocilizumab monotherapy versus adalimumab monotherapy for treatment of rheumatoid arthritis (adacta): a randomised, double-blind, controlled phase 4 trial
Lancet (London, England)
(2013) Biopathology of the synovial membrane in psoriatic arthritis
Reumatologia Clin.
(2012)- et al.
The global burden of rheumatoid arthritis: estimates from the global burden of disease 2010 study
Ann. Rheumatic Dis.
(2014) - et al.
Eular recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update
Annals Rheumatic Dis.
(2014) - et al.
Direct comparison of treatment responses, remission rates, and drug adherence in patients with rheumatoid arthritis treated with adalimumab, etanercept, or infliximab: results from eight years of surveillance of clinical practice in the nationwide danish danbio registry
Arthritis Rheumatism
(2010) - et al.
Long-term effectiveness and safety of tnf-blocking agents in daily clinical practice: results from the dutch rheumatoid arthritis monitoring register
Rheumatology (Oxford, England)
(2011)