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. 2023 Jul 3;6(7):e2323098.
doi: 10.1001/jamanetworkopen.2023.23098.

Response to Biologic Drugs in Patients With Rheumatoid Arthritis and Antidrug Antibodies

Samuel Bitoun  1 , Signe Hässler  2   3   4 , David Ternant  5 , Natacha Szely  6 , Aude Gleizes  7   8   9 , Christophe Richez  10 , Martin Soubrier  11 , Jérome Avouac  12 , Olivier Brocq  13 , Jérémie Sellam  14 , Niek de Vries  15 , Tom W J Huizinga  16 , Elizabeth C Jury  17 , Jessica J Manson  18 , Claudia Mauri  19 , Andrea Matucci  20 , Salima Hacein Bey Abina  7   8 , Denis Mulleman  5 , Marc Pallardy  6 , Philippe Broët  2 , Xavier Mariette  1 ; ABIRISK Consortium
Collaborators, Affiliations

Response to Biologic Drugs in Patients With Rheumatoid Arthritis and Antidrug Antibodies

Samuel Bitoun et al. JAMA Netw Open. .

Abstract

Importance: There are conflicting data on the association of antidrug antibodies with response to biologic disease-modifying antirheumatic drugs (bDMARDs) in rheumatoid arthritis (RA).

Objective: To analyze the association of antidrug antibodies with response to treatment for RA.

Design, setting, and participants: This cohort study analyzed data from the ABI-RA (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 4 European countries (France, Italy, the Netherlands, and the UK). Eligible patients were 18 years or older, had RA diagnosis, and were initiating a new bDMARD. Recruitment spanned from March 3, 2014, to June 21, 2016. The study was completed in June 2018, and data were analyzed in June 2022.

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

Main outcomes and measures: The primary outcome was the association of antidrug antibody positivity with EULAR (European Alliance of Associations for Rheumatology; formerly, European League Against Rheumatism) response to treatment at month 12 assessed through univariate logistic regression. The secondary end points were the EULAR response at month 6 and at visits from month 6 to months 15 to 18 using generalized estimating equation models. Detection of antidrug antibody serum levels was performed 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.

Results: Of the 254 patients recruited, 230 (mean [SD] age, 54.3 [13.7] years; 177 females [77.0%]) were analyzed. 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) directed against all biologic drugs and EULAR response at month 12. Analyzing all the visits starting at month 6 using generalized estimating equation models confirmed the inverse association between antidrug antibody positivity and EULAR response (OR, 0.35; 95% CI, 0.18-0.65; P < .001). A similar association 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 vs responders. Methotrexate comedication at baseline was inversely associated with antidrug antibodies (OR, 0.50; 95% CI, 0.25-1.00; P = .05).

Conclusions and relevance: Results of this prospective cohort study suggest an association between antidrug antibodies and nonresponse to bDMARDs in patients with RA. Monitoring antidrug antibodies could be considered in the treatment of these patients, particularly nonresponders to biologic RA drugs.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Ternant reported receiving lecture fees on behalf of his institution from Novartis, Lundbeck, Boerhinger-Ingelheim, and AstraZeneca during the conduct of the study. Prof Richez reported receiving personal fees from Biogen, AbbVie, Pfizer, and Amgen and nonfinancial support from Biogen during the conduct of the study as well as personal fees from Lilly, Galapagos, and Bristol-Myers Squibb and nonfinancial support from Lilly outside the submitted work. Dr Soubrier reported receiving personal fees from Pfizer and Fresenius Kabi and nonfinancial support from Biogen France outside the submitted work. Prof Avouac reported receiving personal fees from Lilly, Pfizer, Galapagos, Sanofi, Chugai, Nordic, Novartis, Sandoz, Fresenius Kabi, and Biogen as well as nonfinancial support from Bristol-Myers Squibb and AbbVie outside the submitted work. Prof Sellam reported receiving personal fees from AbbVie, MSD, Pfizer, Lilly, Fresenius Kabi, Galapagos, Bristol-Myers Squibb, UCB, Chugai, Janssen, and Novartis and grants from Pfizer outside the submitted work. Prof de Vries reported receiving grants from the Innovative Medicines Initiative Joint Undertaking during the conduct of the study. Prof Jury reported receiving grants from European Union Innovative Medicines Initiative during the conduct of the study. Prof Matucci reported receiving personal fees from Pfizer and AbbVie during the conduct of the study. Prof Mulleman reported receiving grants from Cooperation in Science and Technology Association Action Chair of CA21147—European Network on Optimising Treatment with Therapeutic Antibodies in Chronic Inflammatory Diseases (ENOTTA), grants from French Higher Education and Research Ministry, and personal fees from Celltrion Healthcare Invitation outside the submitted work. Dr Mariette reported receiving personal fees from AstraZeneca, Bristol Myers Squibb, Galapagos, GlaxoSmithKline, Novartis, and Pfizer outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Response to Treatment and Antidrug Antibody Status at Month 12
Response rate in unclassified patients for antidrug antibody status is presented in eTable 1 in Supplement 1. bDMARD indicates biologic disease–modifying antirheumatic drug; mAb, monoclonal antibody; TNF, tumor necrosis factor.
Figure 2.
Figure 2.. Association of Response to Treatment With Antidrug Antibody Positivity
Etanercept was excluded from the univariate generalized estimating equation (GEE) models as an individual drug and in all biologic disease–modifying antirheumatic drugs (bDMARDs) (n = 120) because there were no patients with antidrug antibody positivity after month 1. Multiple test corrections were not performed for panels B and C as these are secondary end points. BMI indicates body mass index; DAS28-CRP, 28-item Disease Activity Score using C-reactive protein; mAbs, monoclonal antibodies; OR, odds ratio; RF, rheumatoid factor; TNF, tumor necrosis factor.
Figure 3.
Figure 3.. Drug Concentration Between Antidrug Antibody–Positive vs Antidrug Antibody–Negative Status and Between Responders vs Nonresponders
Serum drug concentrations were measured using enzyme-linked immunosorbent assay, and antidrug antibody status was determined using Meso Scale Discovery. Multiple test corrections were not performed as these are secondary end points. EULAR indicates European Alliance of Association for Rheumatology.
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