Link Between Antidrug Antibodies and bDMARDs Nonresponse in Patients With RA

Prospective cohort study results suggest a link between antidrug antibodies and nonresponse to biologic disease-modifying antirheumatic drugs (bDMARDs) in patients with rheumatoid arthritis (RA), according to JAMA Network Open.

Supervising antidrug antibodies could be considered in the treatment of these patients, especially those who don’t respond to biologic RA drugs.

There are conflicting data on the link of antidrug antibodies with response to bDMARDs in RA, so researchers aimed to analyze the link of antidrug antibodies with response to treatment for RA.

bDMARDS are recommended as a second-line treatment for RA, but the retention rate is low, with between 40% and 60% of patients maintaining treatment after 2 years. Antidrug antibodies are one of the factors linked with the ineffectiveness of these treatments, and these antibodies directed against biologic drugs might play a part in diminished drug concentration and bDMARD effectiveness loss.

This study evaluated data from the Anti-Biopharmaceutical Immunization: Prediction and Analysis of Clinical Relevance to Minimize the Risk of Immunization in Rheumatoid Arthritis Patients multicentric, open, prospective study of patients with RA from 27 recruiting centers in France, Italy, the Netherlands, and the United Kingdom. Eligible patients were 18 years old or older, had RA diagnosis, and were starting a new bDMARD. Recruitment was from March 3, 2014, to June 21, 2016. The study was finished in June 2019, and data were analyzed in June 2022.

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

The primary outcome was the association of antidrug antibody positivity with European Alliance of Associations for Rheumatology (EULAR) response to treatment at month 12 reviewed through univariate logistic regression.

Identification of antidrug antibody serum levels was conducted at months 1, 3, 6, 12, and 15 to 18 using electrochemiluminescence (Meso Scale Discovery) and drug concentration for anti-TNF mAbs, and etanercept in the serum was measured using enzyme-linked immunosorbent assay.

A total of 230 patients (mean [SD] age, 54.3 [13.7] years; 77.0% female) were evaluated. At month 12, 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. There was an inverse association 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.

Analyzing all the visits starting at month 6 using generalized estimating equation models established the inverse association between antidrug antibody positivity and EULAR response (OR, 0.35; 95% CI, 0.18-0.65; P < .001). A similar link was found for tocilizumab alone (OR, 0.18; 95% CI, 0.04-0.83; P = .03). In the multivariable analysis, antidrug antibodies, body mass index, and rheumatoid factor were independently inversely associated with response to treatment.

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; 95% CI, −12.4 to −6.9 mg/L; P < 001). Drug concentrations of etanercept (mean difference, 0.70; 95% CI, 0.2-1.2 mg/L; P = .005) and adalimumab (mean difference, 1.8; 95% CI, 0.4-3.2 mg/L; P = .01) were lower in nonresponders over responders. Methotrexate comedication at baseline was inversely linked with antidrug antibodies (OR, 0.50; 95% CI, 0.25-1.00; P = .05).

Using the generalized estimating equation model, the researchers demonstrated for the first time an inverse association between antidrug antibodies aimed against tocilizumab and treatment response. These antibodies were less prevalent than those against anti-TNF mAbs, but in the 20% of patients with antidrug antibody-positive status who were treated with tocilizumab, they were linked with response to treatment.

This study established the high incidence of antidrug antibodies against several bDMARDs and the inverse association of antidrug antibodies with EULAR response and found no link between the frequently seen anti-rituximab antidrug antibodies and response to treatment.

It also emphasized the link between antidrug antibodies and lower drug concentration of anti-TNF mAbs and lower concentration with nonresponse of adalimumab and etanercept.

This study has some limitations. First, it showed an association when all biologic drugs were analyzed together, but the study was not powered to demonstrate a link for each drug class. But, the ORs in all analyses with individual drug classes showed similar results or patterns. Second, there was a considerable proportion of patients in the unclassified category since the researchers defined these patients firmly as those lacking 1 or more antidrug antibody measurements for the analysis of response at month 12.

“In this prospective cohort study of patients with RA, response to biologic drugs was inversely associated with antidrug antibody positivity. Monitoring of antidrug antibodies could be considered in the personalized management of patients with RA, particularly nonresponders,” concluded the researchers.

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