Rheumatoid arthritis risk allele PTPRC is also associated with response to anti-tumor necrosis factor alpha therapy

Abstract

Objective: Anti-tumor necrosis factor alpha (anti-TNF) therapy is a mainstay of treatment in rheumatoid arthritis (RA). The aim of the present study was to test established RA genetic risk factors to determine whether the same alleles also influence the response to anti-TNF therapy.

Methods: A total of 1,283 RA patients receiving etanercept, infliximab, or adalimumab therapy were studied from among an international collaborative consortium of 9 different RA cohorts. The primary end point compared RA patients with a good treatment response according to the European League Against Rheumatism (EULAR) response criteria (n = 505) with RA patients considered to be nonresponders (n = 316). The secondary end point was the change from baseline in the level of disease activity according to the Disease Activity Score in 28 joints (triangle upDAS28). Clinical factors such as age, sex, and concomitant medications were tested as possible correlates of treatment response. Thirty-one single-nucleotide polymorphisms (SNPs) associated with the risk of RA were genotyped and tested for any association with treatment response, using univariate and multivariate logistic regression models.

Results: Of the 31 RA-associated risk alleles, a SNP at the PTPRC (also known as CD45) gene locus (rs10919563) was associated with the primary end point, a EULAR good response versus no response (odds ratio [OR] 0.55, P = 0.0001 in the multivariate model). Similar results were obtained using the secondary end point, the triangle upDAS28 (P = 0.0002). There was suggestive evidence of a stronger association in autoantibody-positive patients with RA (OR 0.55, 95% confidence interval [95% CI] 0.39-0.76) as compared with autoantibody-negative patients (OR 0.90, 95% CI 0.41-1.99).

Conclusion: Statistically significant associations were observed between the response to anti-TNF therapy and an RA risk allele at the PTPRC gene locus. Additional studies will be required to replicate this finding in additional patient collections.

Figures

Figure 1

Primary end point analysis. Shown are genotype counts and allele frequencies (freq.) in patients with rheumatoid arthritis (RA) according to European League Against Rheumatism (EULAR) treatment response (good response versus no response) to anti–tumor necrosis factor α (anti-TNF) therapy in each of the 9 different cohorts (left), and a forest plot of the results of association analyses of PTPRC in relation to a favorable EULAR response (right). The major allele (G allele) of PTPRC is the RA risk allele, and as the forest plot shows for each cohort and for the combined analysis (n = 821 patients), the same G allele is associated with a favorable response to anti-TNF therapy. The odds ratio (OR) point estimates and 95% confidence intervals (95% CIs) are shown for the major G allele relative to the minor A allele. For purposes of scale, the upper bound of the 95% CI for the Academic Medical Center (AMC) cohort is not shown (95% CI 0.78–10.70). ABCoN = Autoimmune Biomarkers Collaborative Network; BeSt = Treatment Strategies for Rheumatoid Arthritis (Behandelstrategieen voor Reumatoide Artritis); BRAGGSS = Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate; BRASS = Brigham Rheumatoid Arthritis Sequential Study; EIRA = Epidemiological Investigation of Rheumatoid Arthritis; eRA = Immunex Early Rheumatoid Arthritis; KI = Karolinska Institutet; JBI = Jan van Breemen Institute.

Figure 2

Secondary end point analysis. The forest plot shows the results of the association analyses of PTPRC (major G allele and minor A allele) in relation to change in the Disease Activity Score in 28 joints from baseline to followup, as a quantitative trait, in patients with rheumatoid arthritis treated with anti-TNF therapy. The beta coefficient point estimates and 95% confidence intervals are shown for each cohort as well as for the combined analysis (n = 1,283 patients). See Figure 1 for definitions.