Background One of the causes of insufficient response to biological drugs is the production of anti-drug antibodies (ADA) (1). These antibodies can decrease the effectiveness of treatment by altering bioavailability or by neutralizing the drug. In addition, they may contribute to hypersensitivity reactions. Some ADA are directed against IgG allotypes, which are protein polymorphisms able to induce an immune response in incompatible subjects. Infliximab (INX) and adalimumab (ADM) have the G1m17,1 allotypes, while about 50% of the Europeans are homozygous for the incompatible G1m3,n allotypes. Therefore, the allotypes could contribute to ADA and, in this way, explain the recently described loss of efficiency of INX in allotype-incompatible RA patients (2).

Objectives We aimed to analyze the usefulness of IgG1 allotypes as biomarker of the development of ADA against INX and ADM.

Methods The presence of ADA was determined in 252 consecutive patients with inflammatory arthritis in the Hospital La Paz (116 with rheumatoid arthritis (RA), 74 with ankylosing spondylitis (AS), 26 with psoriatic arthritis, 17 with non-radiographic spondylitis, 11 with spondylitis and inflammatory bowel disease, 3 with uveitis and 5 with other arthropathies). Patients were assessed during INX treatment (151), or with ADM (82), or sequentially during treatment with INX and ADM (19). ADA were determined by two-site bridging ELISA as described (1). Allotypes of IgG1 were determined by genotyping 2 SNPs, rs1071803 (for allotype G1m17/G1m3) and rs11621259 (for allotype G1m1/null) with the SNaPshot Multiplex kit (Applied Biosystems) as reported (2).

Results Patients with compatible allotypes (carriers of G1m17,1) showed a larger frequency of ADA (33% vs. 20%, p=0.02) and a trend toward higher titers of these antibodies (18.0x10³ vs. 8.3x10³ AU, ns) than patients with incompatible allotypes (homozygous for G1m3,n). This association was clearer in patients treated with INX (41% vs. 25%, p=0.03) than in those treated with ADM (18% vs. 12%, ns). ADA were more frequent in patients treated with INX than in those treated with ADM, as already known. Multivariate analysis showed that the frequency of ADA was increased in patients with RA compared to other diseases (OR =7.6, p<0.0001), and decreased in older patients (OR =0.65 per 10 years, p<0.001). Other factors, such as sex, having AS against other diseases, and treatment with methotrexate or corticosteroids, were not associated with ADA.

Conclusions Patients with compatible allotypes showed more frequently ADA than patients with incompatible allotypes, showing for the first time this association in patients treated with INX and reinforcing the previously reported association for ADM (3). These results suggest a genetic factor in linkage with the allotype, but different from it, that will predispose to ADA.

1. Pascual-Salcedo D, et al. Rheumatology (Oxford). 2011;50:1445

2. Montes A, et al. Arthritis Res Ther. 2015;17:63

3. Bartelds GM, et al. Arthritis Res Ther. 2010;12:R221

Acknowledgement Funding was provided by the Instituto de Salud Carlos III (Spain) through grants PI12/01909, PI15/01651 and RD12/009/008, which are partially financed by the European Regional Development Fund of the EU.

Disclosure of Interest None declared