JAK Inhibitor Tapering in Rheumatoid Arthritis: Implications for Patients in Sustained Remission

An increasing number of clinical trials, observational studies, and meta-analyses has demonstrated that many patients with rheumatoid arthritis (RA) in long-term remission can safely taper their biologic therapy.^1–3 Further data from a randomized double-blind sub-study of an ongoing phase 3 extension trial provide evidence that most patients in prolonged remission receiving baricitinib, a small-molecule selective Janus kinase (JAK) 1 and 2 inhibitor, may be candidates for down-titration.⁴ Patients who received baricitinib 4 mg once daily for ≥15 months who had sustained low disease activity (LDA) or remission for ≥3 months were randomly assigned to either continue the same regimen or receive a reduced baricitinib dose of  2 mg once daily. Remission and LDA were defined as a clinical disease activity index (CDAI) score ≤2.8 and <10, respectively. The majority of patients (82% of participants in both groups) were treated with concomitant methotrexate (MTX). 

At 48 weeks, researchers found that 67% of patients tapered to 2 mg baricitinib maintained LDA and 33% maintained remission. Of patients who continued to receive 4 mg baricitinib, 80% maintained LDA and 40% maintained remission. The rate of rescue with open-label baricitinib 4 mg and the addition or increase in dose of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) through 48 weeks was 10% in patients on baricitinib 4 mg and 18% in patients whose baricitinib dose was tapered to 2 mg.

Adverse events following random assignment into the sub-study occurred in 59.2% of patients receiving baricitinib 2 mg vs 66.7% in patients receiving baricitinib 4 mg. Dr Takeuchi and colleagues noted that while the majority of patients in both groups maintained their state of disease control (either LDA or remission) over time, tapering was associated with a statistically significant loss of disease control: 29% in patients continued on baricitinib 4 mg vs 43% for baricitinib 2 mg at 48 weeks (P ≤.01). Of the patients who no longer had disease control after tapering to 2 mg, 66.7% recaptured their baseline LDA or remission status at 24 weeks after returning to the 4 mg dose.

Jasvinder Singh MD, MPH, a rheumatologist at University of Alabama at Birmingham, stated in an accompanying editorial, “To me, this indicates that patients in remission with baricitinib 4 mg daily dose who have taken this medication for >1 year can attempt baricitinib dose-tapering while continuing their MTX (±glucocorticoids) regimen, with some risk (10%–20%) of loss of LDA or remission state, but two-thirds regain that state with baricitinib dose escalation. This is an important finding since patients frequently consider and try RA medication tapering or discontinuation (with and without provider knowledge).”⁵

Until recently, it was presumed that patients with RA would require lifelong treatment, given the status of RA as a chronic and incurable disease. This paradigm grew out of reluctance among patients and providers to change treatment when it is yielding good results, and from the observation that drug-free remission in RA was a rare occurrence. That paradigm has changed over the last 15 years with the introduction of biologic agents and strategies emphasizing a treat-to-target approach, which have transformed sustained drug-free remission from a rarity to an achievable goal in more than 50% of patients.^{3, 4}

As more patients achieve long-term remission, however, the possibility of over-treatment has become a concern. In some patients, the downside of biologic therapy — including high cost and risk for infection or malignancy — may outweigh the benefits.⁴ Guidelines from the American College of Rheumatology and the European League Against Rheumatism now allow for tapering biologic therapy in patients in long-term remission, but not in patients with LDA.^6,7 In a recent review, Bruno Fautrel, MD, PhD, of the Departments of Epidemiology, Rheumatology and Clinical Immunology at Pierre and Marie Curie University in Paris, France, stated that tapering strategies such as increasing the intervals between injections of biologic DMARDs or dose reduction were more effective for maintaining remission than treatment discontinuation, which is associated with a relapse rate of  56% to 87% at 1 year.¹

 “We are increasingly trying to personalize the treatment of [patients with RA] by making the best management plan for an individual,” commented Christopher Edwards BSc, MBBS, MD, FRCP of the University Hospital Southampton NHS Foundation Trust in the United Kingdom, in an interview with Rheumatology Advisor. “This makes it difficult to give advice that all patients should have biologics or JAK inhibitors decreased. For most other therapies we try to use the lowest possible effective dose to reduce the possibility of side effects. However, the patients who receive biologics or JAK inhibitors usually have the most aggressive RA and great care must be taken to ensure that the disease is adequately controlled, or damage may accrue.”

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References

1. Fautrel B.  Therapeutic strategy for rheumatoid arthritis patients who have achieved remission. Joint Bone Spine. 2018;85(6):679-685.
2. den Broeder AA, van der Maas A, van den Bemt BJF. Dose de-escalation strategies and role of therapeutic drug monitoring of biologics in RA. Rheumatology (Oxford). 2010;49(10):1801-1803.
3. Lenert A, Lenert P.  Tapering biologics in rheumatoid arthritis: a pragmatic approach for clinical practice.Clin Rheumatol. 2017;36(1):1-8.
4. Takeuchi T, Genovese MC, Haraoui B, et al. Dose reduction of baricitinib in patients with rheumatoid arthritis achieving sustained disease control: results of a prospective study. Ann Rheum Dis. 2019;78(2):171-178.
5. Singh JA. Tapering Janus kinase inhibitors in rheumatoid arthritis with low disease activity or remission: reality or dream?Ann Rheum Dis. 2019;78(2):153-154.
6. Singh JA, Saag KG, Bridges SL, et al.  2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis: ACR RA Treatment Recommendations. Arthritis Care Res. 2016;68(1):1-25.
7. Smolen JS, Landewé R, Bijlsma J, et al.  EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis. 2017;76(6):960-977.