JAK Inhibitor Dose TAPering Strategy Study

Rheumatoid arthritis (RA) is an autoimmune disease leading to inflammation of the synovium and joint erosions, responsible for joint damage leading to pain, functional impairment, work loss and disability. The prognosis of the disease has been greatly improved for 20 years with the use of Disease-Modifying Anti-Rheumatic Drugs (DMARDs) and especially biologic DMARDs. It is recommended to target remission when initiating a DMARD and to assess patients according to a treat-to-target approach in order to adapt therapy. Once sustained remission is achieved, a decrease in the targeted therapeutic DMARD dose should be considered, according to the recommendations, in order to reduce the risk of adverse events and medical costs. Indeed, targeted DMARDs have considerably increased medical costs linked to RA and studies assessing medical economic impact of bDMARD down-titration on medical costs highlighted the cost-utility of such strategies. JAK inhibitors, a novel class of targeted therapies have proved to be very effective in treating inflammation and preventing structural progression in RA. However, awareness has recently been raised regarding the safety of JAK inhibitor in the treatment of RA, with particular emphasis on tofacitinib. Indeed, tofacitinib seems to increase the risk of thromboembolism events, infections, neoplasia and major cardiovascular events in comparison to anti-TNF in RA, with a dose-effect. To date, we have very little data regarding the feasibility of a JAK inhibitor dose-tapering strategy. As a dose-related effect was apparent in terms of major adverse events, we assume that JAK inhibitor dose-tapering strategy might reduce the risk of serious adverse events, without increasing the risk of major flares and thus be beneficial for the patient. The aim of the study will be to compare a dose-tapering strategy versus therapy continuation in rheumatoid arthritis patients in low disease activity treated with JAK inhibitors on the risk of losing low disease activity despite rescue therapy at 12 months. 1\) The dose-tapering strategy will depend on the JAK inhibitor taken by the patient. It will be based on a 50% dose-reduction every 6 months and will comprise 2 steps: A. Treatment with baricitinib 4 mg daily: * Step 1 (after randomization): baricitinib 2mg daily. * Step 2 (in case of CDAI ≤ 10 AND CRP level below the laboratory standard; 6 months after starting step1): baricitinib 2mg every other day. B. Treatment with filgotinib 200 mg daily: * Step 1 (after randomisation): filgotinib 100 mg daily. * Step 2 (in case of CDAI ≤ 10 AND CRP level below the laboratory standard; 6 months after starting step1): filgotinib 100mg every other day. C. Treatment with tofacitinib 5 mg twice daily or tofacitinib 11mg daily: * Step 1 (after randomisation): tofacitinib 5 mg once daily. * Step 2 (in case of CDAI ≤ 10 AND CRP level below the laboratory standard; 6 months after starting step1): tofacitinib 5 mg every other day. D. Treatment with upadacitinib 15 mg daily: * Step 1 (after randomisation): upadacitinib 15 mg every other day. * Step 2 (in case of CDAI ≤ 10 AND CRP level below the laboratory standard; 6 months after starting step1): upadacitinib 15 mg every 4 days. Management of flares: 1. In case of flare, diagnosed during a scheduled visit: the management of the flare will be standardized by a rescue therapy including a glucocorticoid course and returning to the previous step of JAK inhibitor dose. If the flare is not resolved after the rescue therapy, the patient will be considered in failure of the strategy. 2. In case of flare between two scheduled visits, an additional visit will be scheduled by the clinical center to confirm the flare by the physician. If the flare is confirmed, the patient will have the standardized flare management as described above. 2\) Patients randomised to the control group will have to continue the JAK inhibitor at full dose until the end of the protocol: * In case of baricitinib: baricitinib 4mg/day. * In case of filgotinib: filgotinib 200mg/day. * In case of tofacitinib: tofacitinib 5mg twice daily or 11mg/day. * In case of upadacitinib: upadacitinib 15mg/day. Management of flares: 1. In case of flare, diagnosed during a scheduled visit: the management of the flare will be standardized by a rescue therapy with a glucocorticoid course. If the flare is not resolved after the rescue therapy, the patient will be considered in failure of the strategy. 2. In case of flare between two scheduled visits, an additional visit will be scheduled by the clinical center to confirm the flare by the physician. If the flare is confirmed, the patient will have the standardized flare management as described above. Patients with co-medication with sDMARD or glucocorticoids \< 5mg/d will have to keep a stable dose of their treatment during the 12 months of the study in both groups.