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Favourable effect of a 'second hit' after 13 weeks in early RA non-responders: the Amsterdam COBRA treat-to-target randomized trial.

Hartman, L., Rasch, L.A., Turk, S.A., Wee, M.M. ter, Kerstens, P.J.S.M., Laken, C.J. van der, Nurmohamed, M.T., Schaardenburg, D. van, Tuyl, L.H.D. van, Voskuyl, A.E., Boers, M., Lems, W.F. Favourable effect of a 'second hit' after 13 weeks in early RA non-responders: the Amsterdam COBRA treat-to-target randomized trial. Rheumatology: 2022, 62(6), p. 2098-2105.
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Objective
To study the effect of treat-to-target combination therapy with intensification at 13 weeks in early RA.

Methods
Early RA patients were classified as high- or low-risk based on disease activity and prognostic factors. High-risk patients received COBRA-light (prednisolone 30 mg/day tapered to 7.5 mg/day, methotrexate (MTX) increasing to 25 mg/week), low-risk patients MTX monotherapy increasing to 25 mg/week. The primary outcome (target) was DAS44 <1.6 or EULAR good response at 26 weeks. At 13 weeks, non-responders were randomized to (open-label) intensification (high-risk: prednisolone 60 mg/day tapered to 7.5 mg/day, addition of sulfasalazine (2 g/day) and hydroxychloroquine (400 mg/day); low-risk: prednisolone 30 mg/day tapered to 7.5 mg/day); or continuation.

Results
High-risk group (n = 150): 110 patients (73%) reached the target at 13 weeks, 9 dropped out. Non-responders were randomized to intensification (n = 15) or continuation (n = 16). After 26 weeks, 12 (80%) vs 7 (44%) reached the target (difference: 36%, [95%CI 2%;71%]; p = 0.04). Low-risk group (n = 40): 17 (43%) reached the target. Non-responders were randomized to intensification (n = 8) or continuation (n = 7); 4 vs 3 reached the target.Adverse event rates were higher in the high-risk group, and higher in the intensification subgroup. Serious adverse events were rare. Protocol violations were frequent and mostly led to mitigation of actual treatment intensification.

Conclusion
Initial combination therapy was very successful in high-risk RA, and early intensification was beneficial in patients not reaching the strict target. The low-risk group was too small to draw conclusions. In routine practice, adherence to early intensification based on strict targets is difficult.