TNF, CTLA4-Ig Treatment Associated with Higher Discontinuation Rates in RA

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Patients receiving TNF, JAK, and CTLA4-Ig all demonstrated higher discontinuation rates due to ineffectiveness when compared to aIL-6R treatment.

Patients with rheumatoid arthritis (RA) treated with tumor necrosis factor inhibitors (TNF) and cytotoxic T lymphocyte-associated antigen-4-Ig (CTLA4-Ig) had higher overall drug discontinuation rates, except for non-toxicity and remission, when compared with those receiving anti-interleukin-6 receptor antibodies (aIL-6R) treatment, according to a study published in Rheumatic and Musculoskeletal Diseases.1

“Drug retention is considered a good index of drugs’ safety, effectiveness, and tolerability in observational studies, even when treatment selection and discontinuation may be influenced by variables such as differences in physician care and patient characteristics,” wrote lead investigator Kosuke Ebina, MD, PhD, associated with the Department of Musculoskeletal Regenerative Medicine, Osaka University Faculty of Medicine Graduate School of Medicine, Japan, and colleagues. “However, multicenter studies and the national health insurance system in our country may mitigate these potential deviations.”

Previous research has criticized the use of randomized controlled trials for recruiting patients who are not fully representative of real-world settings, such as younger patients and those with fewer comorbidities. Therefore, cohort-based observational studies have been favored for evaluating the efficacy of biologic disease-modifying antirheumatic drugs (bDMARDs).2

The retention rates of bDMARD and Janus kinase inhibitor (JAK) treatment were evaluated in a multicenter, observational study conducted in Japan. Investigators were interested in understanding factors affecting retention using a real-world cohort of patients with RA enrolled in the Kansai Consortium for Well-being of Rheumatic Disease Patients (ANSWER) registry.

The study included 6666 treatment courses, of which 55.4% of patients were bDMARD-naïve or JAK-naïve. Most (n = 3577) received TNF, followed by aIL-6R (n = 1497), CTLA4-Ig (n = 1139), and JAK (n = 453). Discontinuation was subcategorized by ineffectiveness, non-toxic reasons, toxic adverse events, and remission. Cox proportional hazards modelling was used to evaluate the hazard ratios (HRs) of treatment discontinuation.

Patients in the TNF cohort (HR = 1.93, 95% confidence interval [CI]: 1.69 to 2.19), the JAK cohort (HR = 1.29, 95% CI: 1.03 to 1.63), and the CTLA4-Ig cohort (HR = 1.42, 95% CI: 1.20 to 1.67) all demonstrated a higher discontinuation rate due to ineffectiveness when compared with those in the aIL-6R treatment group. However, aIL-6R (HR = 1.27, 95% CI: 1.03 to 1.57) and TNF (HR = 1.28, 95% CI: 1.05 to 1.56) were linked to higher discontinuation due to toxic adverse events when compared with CTLA4-Ig.

In patients receiving TNF, concomitant glucocorticoid treatment at baseline was associated with higher rates of discontinuation due to ineffectiveness (HR = 1.24, 95% CI: 1.09 to 1.41) and toxic adverse events (HR = 1.29, 95% CI: 1.07 to 1.55). Concomitant glucocorticoid use was also linked to higher discontinuation due to toxic adverse events in the JAK cohort (HR = 2.30, 95% CI: 1.23 to 4.28).

Investigators noted the discontinuation of treatment was based on the decisions of individual physicians, not standardized criteria, which may have limited the study. Additionally, the initial doses of each treatment were based on manufacturer recommendations and dosage adjustments during the study were difficult to collect. Other differences between agents, such as intravenous vs subcutaneous, or original vs biosimilar bDMARDs, could not be obtained. Information on comorbidities, disease duration, and disease activity were missing at baseline in some patients. Lastly, the results may have been hindered by the relatively small number of patients in the JAK cohort. However, the study was strengthened by including “difficult-to-treat” patients with RA who may have been excluded in randomized controlled trials.

“Considering the drug retention differences due to effectiveness and safety, this study might affect the initial selection of biological disease-modifying antirheumatic drugs and JAK as well as the concomitant use of oral glucocorticoids in clinical practice,” investigators concluded.


  1. Ebina K, Etani Y, Maeda Y, et al. Drug retention of biologics and Janus kinase inhibitors in patients with rheumatoid arthritis: the ANSWER cohort study. RMD Open. 2023;9(3):e003160. doi:10.1136/rmdopen-2023-003160
  2. Wolfe F, Michaud K, Dewitt EM. Why results of clinical trials and observational studies of Antitumour necrosis factor (anti-TNF) therapy differ: methodological and interpretive issues. Ann Rheum Dis 2004;63:ii13–7. doi:10.1136/ard.2004.028530