Link Between Antidrug Antibodies, Nonresponse to bMARDs in Patients With RA

An association between antidrug antibodies and nonresponse to biologic disease-modifying antirheumatic drugs (bMARDs) in patients with rheumatoid arthritis (RA) is insinuated in a prospective cohort study, according to Rheumatology.

Monitoring antidrug antibodies could be contemplated in the treatment of these patients, especially nonresponders to biologic RA drugs. Conflicting data exist on the association of bDMARDs in RA. The researchers’ objective was to analyze the link of antidrug antibodies with response to treatment for RA.

bDMARDs are often initiated as a second-line treatment for RA. But the retention rate is low, with only 40% to 60% of patients maintaining treatment after 2 years.

“There is still debate regarding the adverse clinical implications of antidrug antibodies for the response to treatment, which has been clearly demonstrated only for adalimumab ,” emphasized the authors.

This was a cohort study that analyzed data from the Anti-Biopharmaceutical Immunization: Prediction and Analysis of Clinical Relevance to Minimize the Risk of Immunization in Rheumatoid Arthritis Patients (ABI-RA) multicentric, open, prospective study of patients with RA from 27 recruiting centers in 4 European countries consisting of France, Italy, the Netherlands, and the United Kingdom. Eligible patients were aged 18 or older, had an RA diagnosis, and were starting a new bDMARD. Recruitment stretched from March 3, 2014, to June 21, 2016. The study reached completion in June 2018, and data were analyzed in June 2022.

Patients were treated with a novel bDMARD: adalimumab, infliximab (grouped as anti-tumor necrosis factor [TNF] monoclonal antibodies [mAbs]), etanercept, tocilizumab, and rituximab, according to the decision of the treating physician.

The primary outcome of this study was the link of antidrug antibody positivity with the European Alliance of Associations for Rheumatology (EULAR) response to treatment at month 12. The secondary end points were the EULAR response at month 6 and visits from month 6 to months 15 to 18.

Out of the 254 patients recruited, 230 (mean [SD] age, 54.3 [13.7] years; females, n = 177) were evaluated. Antidrug antibody positivity was 38.2% in patients who were treated with anti-TNF mAbs, 6.1% with etanercept, 50.0% with rituximab, and 20.0% with tocilizumab at month 12.

There was an inverse link between antidrug antibody positivity (odds ratio [OR], 0.19; 95% CI, 0.09-0.38; P < .001) aimed against all biologic drugs and EULAR response at month 12. Evaluating all the visits starting at month 6 using generalized estimating equation models confirmed the inverse link between antidrug antibody positivity and EULAR response (OR, 0.35; 95% CI, 0.18-0.65; P < .001).

There was a significantly higher drug concentration of anti-TNF mAbs in patients with antidrug antibody-negative vs antidrug antibody-positive status (mean difference, −9.6 mg/L; P < .001). Drug concentrations of etanercept (mean difference , 0.70 mg/L; P = .005) and adalimumab (mean difference, 1.8 mg/L; P = .01) were worse in nonresponders vs responders. Methotrexate comedication at baseline was inversely linked with antidrug antibodies (OR, 0.50; 95% CI, 0.25-1.00; P = .05).

In the current study, no association was found between the observed anti-rituximab antidrug antibodies and treatment response. Also, the study confirmed the high incidence of antidrug antibodies against multiple bDMARDs and the inverse link of antidrug antibodies with EULAR response.

Moreover, this study emphasized the association between antidrug antibodies and lower drug concentration of anti-TNF mAbs and lower concentration with nonresponse of adalimumab and etanercept.

Using the GEE model, an inverse association was shown for the first time between antidrug antibodies directed against tocilizumab and treatment response. These antibodies weren’t as prevalent than those against anti-TNF mAbs, but in the 20% of patients with antidrug antibody-positive status who were treated with tocilizumab, the antibodies were linked with treatment response.

The current study discovered an inverse association between antidrug antibodies against 3 bDMARDs and response to treatment. Even though the study did not find a definitive role for therapeutic drug monitoring, it provided arguments for an inverse association between clinical outcome and the presence of antidrug antibodies. The inverse association between methotrexate at baseline and the presence of antidrug antibodies against bDMARDs was also confirmed.

This study had some limitations, including that the study was not powered to show a link for each drug class. Despite this, the ORs in all analyses with individual drug classes displayed similar results or patterns.

“Monitoring of antidrug antibodies could be considered in the personalized management of patients with RA, particularly nonresponders,” concluded the authors.

Reference

Bitoun S, Hässler S, Ternant D, et al. Response to biologic drugs in patients with rheumatoid arthritis and antidrug antibodies. JAMA Netw Open. Published online July 12, 2023. doi:10.1001/jamanetworkopen.2023.23098