COBRA combination therapy in patients with early rheumatoid arthritis: Long‐term structural benefits of a brief intervention

Abstract

Objective. The Combinatietherapie Bij Reumatoide Artritis (COBRA) trial demonstrated that stepdown combination therapy with prednisolone, methotrexate, and sulfasalazine (SSZ) was superior to SSZ monotherapy for suppressing disease activity and radiologic progression of rheumatoid arthritis (RA). The current study was conducted to investigate whether the benefits of COBRA therapy were sustained over time, and to determine which baseline factors could predict outcome.Methods. All patients had participated in the 56-week COBRA trial. During followup, they were seen by their own rheumatologists and were also assessed regularly by study nurses; no treatment protocol was specified. Disease activity, radiologic damage, and functional ability were the primary outcome domains. Two independent assessors scored radiographs in sequence according to the Sharp/van der Heijde method. Outcomes were analyzed by generalized estimating equations on the basis of intent-to-treat, starting with data obtained at the last visit of the COBRA trial (56 weeks after baseline).Results. At the beginning of followup, patients in the COBRA group had a significantly lower mean time-averaged 28-joint disease activity score (DAS28) and a significantly lower median radiologic damage (Sharp) score compared with those in the SSZ monotherapy group. The functional ability score (Health Assessment Questionnaire [HAQ]) was similar in both groups. During the 4-5 year followup period, the timeaveraged DAS28 decreased 0.17 points per year in the SSZ group and 0.07 in the COBRA group. The Sharp progression rate was 8.6 points per year in the SSZ group and 5.6 in the COBRA group. After adjustment for differences in treatment and disease activity during followup, the between-group difference in the rate of radiologic progression was 3.7 points per year. The HAQ score did not change significantly over time. Independent baseline predictors of radiologic progression over time (apart from treatment allocation) were rheumatoid factor positivity, Sharp score, and DAS28.Conclusion. An initial 6-month cycle of intensive combination treatment that includes high-dose corticosteroids results in sustained suppression of the rate of radiologic progression in patients with early RA, independent of subsequent antirheumatic therapy.Rheumatoid arthritis (RA) is a chronic, potentially disabling disease characterized by inflammation of the joints, periarticular bone resorption and cartilage

Sulfasalazine is a potent inhibitor of the reduced folate carrier: Implications for combination therapies with methotrexate in rheumatoid arthritis

“…Another strategy of the rheumatologist for enhancing the efficacy of the combination of MTX plus SSZ is the addition of a third drug (e.g., hydroxychloroquine [13] or prednisone [14]) to the MTX-SSZ combination. Although the objective of this study was not to elucidate a mechanistic basis for the efficacy of the triple DMARD therapy, recent studies by our group (47) did indicate that CEM/SSZ cells displayed enhanced sensitivity to both chloroquine and dexamethasone.…”

“…In fact, addition of a third component such as hydroxychloroquine (12,13) or prednisone (14) is usually required to significantly improve clinical efficacy. Furthermore, one notable adverse effect observed was a persistent increase in plasma homocysteine levels in patients with RA who were receiving the combination of MTX and SSZ, compared with those receiving single-drug therapy (15,16).…”

The Immunopharmaceutical Effects and Mechanisms of Herb Medicine

“…While no single agent was proven to be enough to control disease progression, current acceptable therapy for rheumatoid arthritis is aimed to attenuate disease activity with a combination of disease-modifying anti-rheumatic drugs such as methotrexate, sulfasalazine, leflunomide, hydroxychloroquine, cyclosporin, azathioprine, etc. (34)(35)(36). The purpose of a combination therapy is to obtain synergistically therapeutic effects of drugs with different immunomodulatory mechanisms and, in the meantime, to reduce side effects from each drug by decreasing their dosages.…”

My Treatment Approach to Rheumatoid Arthritis

“…Two European studies, COBRA (Combination Therapy in Rheumatoid Arthritis) and BeSt (Behandel-Stratieën) trial, found that a high-dose oral prednisone regimen (60 mg, tapering to 7.5 mg by week 6, then stopping after week 12) in combination with other conventional DMARDs substantially inhibited the progression of radiographic joint damage, and this effect was sustained over many years. 35,69 In particular, the BeSt study findings suggest that the addition of highdose prednisone therapy may mitigate the advantage of initial biologic therapy, in this case with infliximab, further supporting our approach of not using a biologic agent initially. To date, no studies have evaluated a more intermediate starting dose (ie, 20 mg/d).…”