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

Linda Hartman; Linda A Rasch; Samina A Turk; Marieke M Ter Wee; Pit J S M Kerstens; Conny J van der Laken; Michael T Nurmohamed; Dirkjan van Schaardenburg; Lilian H D van Tuyl; Alexandre E Voskuyl; Maarten Boers; Willem F Lems

doi:10.1093/rheumatology/keac582

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

Rheumatology (Oxford). 2023 Jun 1;62(6):2098-2105. doi: 10.1093/rheumatology/keac582.

Authors

Affiliations

¹ Amsterdam Rheumatology and Immunology Center, Amsterdam University Medical Centers, Vrije Universiteit, Amsterdam, The Netherlands.
² Department of Epidemiology and Data Science, Amsterdam University Medical Centers, Vrije Universiteit, Amsterdam, The Netherlands.
³ Amsterdam Rheumatology and Immunology Center, Reade, Amsterdam, The Netherlands.
⁴ Department of Rheumatology, Dijklander Ziekenhuis, Hoorn, The Netherlands.
⁵ Amsterdam Rheumatology and Immunology Center, Amsterdam University Medical Centers, Universiteit van Amsterdam, Amsterdam, The Netherlands.
⁶ Netherlands Institute for Health Services Research, Utrecht, The Netherlands.

Abstract

Objective: The aim of this study was to investigate the effect of treat-to-target combination therapy with intensification at 13 weeks in early RA.

Methods: Early RA patients were classified as being at high or low risk of worsening RA based on disease activity and prognostic factors. High-risk patients received COBRA-light (prednisolone 30 mg/day tapered to 7.5 mg/day, MTX increasing to 25 mg/week), and low-risk patients received 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 patients: prednisolone 60 mg/day tapered to 7.5 mg/day, addition of SSZ (2 g/day) and HCQ (400 mg/day); low-risk patients: prednisolone 30 mg/day tapered to 7.5 mg/day] or continuation.

Results: In the high-risk group (n = 150), 110 patients (73%) reached the target at 13 weeks, and 9 dropped out. Non-responders were randomized to intensification (n = 15) or continuation (n = 16), and after 26 weeks, 12 (80%) vs 7 (44%) of these, respectively, reached the target [difference: 36%, (95% CI 2%, 71%); P = 0.04]. In the 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, respectively, reached the target.Adverse event rates were higher in the high-risk group, and higher in the intensification subgroup of that group. 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 for drawing conclusions. In routine practice, adherence to early intensification based on strict targets is difficult.

Trial registration: Netherlands Trial Register (NTR), NL4393, https://www.trialregister.nl/.

Keywords: DMARDs; RA; epidemiology; immunosuppressants; study design.

Publication types

Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Antirheumatic Agents* / adverse effects
Arthritis, Rheumatoid* / chemically induced
Arthritis, Rheumatoid* / drug therapy
Drug Therapy, Combination
Humans
Methotrexate
Prednisolone / therapeutic use
Sulfasalazine / therapeutic use
Treatment Outcome

Substances

Antirheumatic Agents
Sulfasalazine
Methotrexate
Prednisolone

Associated data

NTR/NL4393