Anti-adalimumab antibodies in rheumatoid arthritis patients are associated with interleukin-10 gene polymorphisms.

Inadequate response to tumor necrosis factor (TNF )–blocking therapy in rheumatoid arthritis (RA) may result from the formation of antibodies against these drugs (1). Previous studies have shown that polymorphisms in the promoter region of the gene for interleukin-10 (IL-10), a cytokine with a key role in antibody formation, are associated with the formation of antibodies that inhibit recombinant factor VIII (FVIII) in hemophilia (2) and with the development of autoantibodies against nicotinic acetylcholine receptor (nAChR) in myasthenia gravis (MG) (3). We hypothesized that polymorphisms in IL10 are also associated with the formation of antibodies against anti-TNF agents. To test this hypothesis, the presence of antiadalimumab antibodies was determined in a prospective study of 192 white patients with RA according to the criteria of the American College of Rheumatology (formerly, the American Rheumatism Association) (4). Patients had been treated with adalimumab (40 mg subcutaneously/every other week) in combination with methotrexate (mean dosage 20 mg/week), and the presence of antibodies was determined 28 weeks after initiation of treatment with adalimumab (1). Three singlenucleotide polymorphisms (SNPs) in the promoter region of the IL-10 gene (rs1800871 at 819, rs1800896 at 1082, and rs6703630 at 2849) were typed using TaqMan technology (Applied Biosystems, Foster City, CA), and odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. The study was approved by the local Medical Ethics Committee. Anti-adalimumab antibodies were present in 25 of the 192 patients (13%) and were associated with nonresponse according to the European League Against Rheumatism criteria (5) after 28 weeks of treatment with adalimumab (OR 4.05 [95% CI 1.69–9.73], P 0.001) (43 of the patients [22%] did not exhibit treatment response). Furthermore, the 1082 AA genotype was strongly associated with a significantly lower frequency of anti-adalimumab antibodies (OR 0.05 [95% CI 0.003–0.86], P 0.001) (Table 1). However, we did not find an association between the AA genotype and response to adalimumab (P 0.35). Four haplotypes were inferred using Phase 2.0 (http:// www.stat.washington.edu/stephens/software.html) with an average probability of certainty in haplotype inference of 99%. Carriage of the GAT haplotype (alleles at positions 2849, 1082, and 819) showed a significant negative association with anti-adalimumab antibodies (P 0.004), and carriage of the AGC haplotype showed a positive association with antiadalimumab antibodies (P 0.041). Unlike haplotype GAC (P 0.860), a positive trend toward carriage of haplotype GGC was found (P 0.063). Based on microsatellite SNP haplotypes reported in a Dutch population (6), our observations are consistent with the reported association of the G8 microsatellite allele with formation of antibodies to recombinant FVIII in hemophilia (2) and to nAChR in MG (3). In conclusion, our results indicate that IL10 polymorphisms are associated with increased formation of antibodies against adalimumab in RA patients. Additional studies utilizing larger groups of patients are needed to confirm our findings. Dr. Tak has received consulting fees and/or honoraria from Abbott, Amgen, Centocor, Schering-Plough, UCB, and Wyeth (less than $10,000 each).