Restricted cubic spline analysis of treatment duration before tocilizumab withdrawal and relapse risk in rheumatoid arthritis

Abstract

Background: Tocilizumab (TCZ), an interleukin-6 receptor inhibitor, is effective for moderate to severe rheumatoid arthritis (RA). However, maintaining remission after TCZ withdrawal remains challenging, and the treatment duration required before discontinuation to minimize relapse risk is unclear. section1-1759720X261464266 Objectives: To identify a TCZ treatment-duration threshold before withdrawal that is associated with a lower risk of relapse in patients with RA. section2-1759720X261464266 Design: This was a retrospective study including 97 patients with RA who discontinued intravenous TCZ after stable disease control. section3-1759720X261464266 Methods: We retrospectively analyzed 97 RA patients who achieved remission or low disease activity prior to TCZ withdrawal. The primary outcome was relapse within 12 months post-discontinuation. Cox proportional hazards regression identified independent predictors, while restricted cubic spline (RCS) modeling assessed non-linear associations between treatment duration and relapse risk. A simplified risk stratification tool was developed and internally validated using bootstrap resampling. section4-1759720X261464266 Results: Among 97 patients with RA who discontinued TCZ after stable disease control, most were biologic-naïve (98.9%), the mean disease duration was 72.9 ± 52.7 months, and concomitant methotrexate and hydroxychloroquine were used in 73.2% and 47.4% of patients, respectively. During the 12-month follow-up, 54 patients (55.7%) relapsed. TCZ treatment duration was an independent protective factor (adjusted HR = 0.892 per month,= 0.002), whereas anti-citrullinated protein antibody (ACPA) positivity was associated with increased relapse risk (adjusted HR = 2.122,= 0.031). RCS analysis demonstrated an L-shaped non-linear relationship, identifying an empirically derived duration threshold at approximately 200 days associated with lower relapse risk. A simplified score assigning 1 point each for ACPA positivity and TCZ duration < 200 days stratified patients into low- (0 points), intermediate- (1 point), and high-risk (2 points) groups, with relapse rates of 27.3%, 53.8%, and 91.7%, respectively; the model showed acceptable discrimination (AUC = 0.76). section5-1759720X261464266 Conclusion: Longer TCZ treatment duration and ACPA negativity were associated with a lower risk of relapse after TCZ withdrawal. An approximately 200-day treatment duration may serve as a clinically informative threshold for risk-stratified withdrawal decisions in routine practice, although disease control after withdrawal should be interpreted in the context of ongoing background therapy rather than confirmed drug-free remission. section6-1759720X261464266 Plain language summary How long should tocilizumab be used before stopping in rheumatoid arthritis? Rheumatoid arthritis is a long-term condition in which the immune system attacks the joints, causing pain, swelling, and damage. Tocilizumab is a medicine that can control the disease well, but doctors and patients often face an important question: when can it be safely stopped? In this study, we reviewed 97 patients with rheumatoid arthritis whose disease was well controlled before they stopped tocilizumab. We then followed them for 12 months to see who remained stable and who had a return of symptoms. We found that a little more than half of the patients had a relapse within 1 year after stopping treatment. Two factors were especially important. First, patients who stayed on tocilizumab for a longer time were less likely to relapse. Second, patients who had a positive anti-citrullinated protein antibody blood test were more likely to relapse. Our analysis suggested that about 200 days of treatment may be an important time point. Patients who stopped treatment before this were much more likely to have their disease come back. We also developed a simple tool based on treatment duration and antibody status that could separate patients into low-, medium-, and high-risk groups. These results suggest that stopping tocilizumab too early may increase the chance of relapse, especially in patients with a positive antibody test. This may help doctors and patients make more informed decisions about treatment withdrawal. However, because this was a single-center retrospective study, larger studies are needed to confirm these findings. plain-language-summary