A regimen of methotrexate (MTX) and tapered prednisone was not inferior to combinations of glucocorticoids and conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) in a trial comparing approaches for inducing remission in high-risk patients with early rheumatoid arthritis (RA), according to an article published in Annals of the Rheumatic Diseases.1

Contemporary guidelines for RA advocate a “treat-to-target” strategy in which objective measurement tools are used to guide and escalate the use of RA therapies until a predetermined target of either remission or low disease activity is achieved. Guidelines also advocate for aggressive treatment in early rheumatoid arthritis (ERA) in order to preserve function and avoid erosive damage. However, the ideal dosage and combination of drugs have not been firmly established.

In the study, Patrick Verschueren, MD of the Department of Rheumatology, University Hospitals Leuven, Leuven, Belgium and colleagues set out to compare the effectiveness of different csDMARDs and glucocorticoid combinations for inducing remission in  high-risk and low-risk patients with RA at 52 weeks post-treatment in an open label, randomized, parallel assignment trial (ClinicalTrials.gov Identifier NCT01172639). High- and low-risk status was assigned based on presence of erosions, disease activity, rheumatoid factor and anticitrullinated protein antibodies. 


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High Yield Data Summary

  • Conventional DMARD combination therapy was not superior to MTX monotherapy with COBRA Slim prednisone remission induction regimen at 52-weeks in patients with markers of poor RA prognosis

High-risk patients were randomized into one of three treatment arms: Combination therapy for early Rheumatoid Arthritis (COBRA) Classic, consisting of MTX, sulfasalazine and a weekly step-down scheme of oral prednisone;   COBRA Slim, consisting of MTX and a weekly step-down scheme of oral prednisone, and COBRA Avant Garde, consisting of MTX leflunomide and a weekly step-down scheme of oral prednisone.  

Low-risk patients were randomly placed in either the COBRA Slim protocol or MTX tight step-up, consisting of MTX alone. A target of disease activity score calculated with C-reactive protein (DAS28-CRP) of 3.2 was set. Beginning at Week 8, patients not reaching this target received treatment adjustments that were pre-determined for each treatment arm.

For high-risk patients, combined DMARD regimens did not result in increased efficacies at Week 52 over COBRA Slim, the simplest of the treatment regimens. Each of the 3 high-risk treatment strategies was demonstrated to be similarly effective. Of the high-risk patients, remission was achieved in 64.3% (63/98) in the COBRA Classic arm, in 60.2% (59/98) of high risk patients in the COBRA Slim arm, and in 62.4% (58/93) high risk patients in the COBRA Avant Garde arm. 

Patients randomized to COBRA Slim experienced fewer adverse events. The authors noted that the prognostic markers used to divide patients into high- and low-risk categories failed to predict treatment response.  Though they received the identical regimen, high-risk patients randomized to COBRA Slim scored better in European League Against Rheumatism (EULAR) response and health assessment questionnaire scores than low-risk COBRA Slim patients. Efficacy and safety results were similar for patients in both arms of the low-risk groups after 52 weeks.

Summary and Clinical Applicability

The authors endorsed the use of COBRA Slim, the simplest glucocorticoid/DMARD regimen tested. They wrote, “In conclusion, we propose an effective, safe, feasible and standardized initial treat-to-target strategy, COBRA Slim, yielding excellent results in all patients with ERA regardless of classical prognostic markers, with high remission rates and low numbers of patients remaining on chronic GC or biological therapy.”

Limitations and Disclosures

  • Assessments of medication adherence not performed
  • A priori superiority design, “therefore, we were only capable to demonstrate non-superiority of COBRA Classic and COBRA Avant Garde versus COBRA Slim and not non-inferiority or equivalence”, according to researchers

Leflunomide was made available for free by SANOFI Belgium without any influence on trial design. Funding was provided by the Flemish Governmental Agency for Innovation by Science and Technology (IWT), the Fund for Scientific Research in Rheumatology (FWRO). Dr. Verschueren holds the unrestricted Pfizer chair ‘Early RA management’ at the KU Leuven.

Reference

  1. Verschueren P, De Cock D, Corluy L, et al. Effectiveness of methotrexate with step-down glucocorticoid remission induction (COBRA Slim) versus other intensive treatment strategies for early rheumatoid arthritis in a treat-to-target approach: 1-year results of CareRA, a randomised pragmatic open-label superiority trial. Ann Rheum Dis. doi:10.1136/annrheumdis-2016-209212.

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