Initial High-Dose Prednisolone Combination Therapy Using COBRA and COBRA-Light in Early Rheumatoid Arthritis

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Abstract

Treatment with initial high-dose prednisolone and a combination of methotrexate (MTX) and sulfasalazine (SSZ) according to the COBRA regimen (Dutch acronym for combinatietherapie bij reumatoide artritis, ‘combination therapy for rheumatoid arthritis'), has repeatedly been demonstrated to be very effective in early rheumatoid arthritis (RA). COBRA combination therapy is superior to initial monotherapy of SSZ and MTX, is also associated with a good long-term outcome, is as safe as other treatment regimes, and performs as well as the combination of high-dose MTX and the tumor necrosis factor antagonist infliximab. A pilot study with an intensified version of the COBRA combination therapy showed that strict monitoring and aggressive treatment intensification based on the Disease Activity Score can result in a remission rate of 90% in patients with active early RA. Also, the first results indicate that an attenuated variation on COBRA combination therapy, called ‘COBRA-light', is effective in decreasing disease activity and is generally well tolerated. Based on these results, we conclude that initial high-dose prednisolone in combination with MTX and SSZ could or should be the first choice in early active RA since it is effective and safe, and the cost price of the drugs is low.

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Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis.

Harrie Verhoeven, Pieter Jacobs, H Schouten … (1997)

The value of intensive combination therapy in early rheumatoid arthritis is unproven. In a multicentre, double-blind, randomised trial (COBRA), we compared the combination of sulphasalazine (2 g/day), methotrexate (7.5 mg/week), and prednisolone (initially 60 mg/day, tapered in 6 weekly steps to 7.5 mg/day) with sulphasalazine alone. 155 patients with early rheumatoid arthritis (median duration 4 months) were randomly assigned combined treatment (76) or sulphasalazine alone (79). Prednisolone and methotrexate were tapered and stopped after 28 and 40 weeks, respectively. The main outcomes were the pooled index (a weighted change score of five disease activity measures) and the Sharp/Van der Heijde radiographic damage score in hands and feet. Independent health-care professionals assessed the main outcomes without knowledge of treatment allocation. At week 28, the mean pooled index was 1.4 (95% CI 1.2-1.6) in the combined treatment group and 0.8 (0.6-1.0) in the sulphasalazine group (p < 0.0001). At this time, 55 (72%) and 39 (49%) patients, respectively, were improved according to American College of Rheumatology criteria. The clinical difference between the groups decreased and was no longer significant after prednisolone was stopped, and there were no further changes after methotrexate was stopped. At 28 weeks, the radiographic damage score had increased by a median of 1 (range 0-28) in the combined-therapy group and 4 (0-44) in the sulphasalazine group (p < 0.0001). The increases at week 56 (2 [0-43] vs 6 [0-54], p = 0.004), and at week 80 (4 [0-80] vs 12 [0-72], p = 0.01) were also significant. Further analysis suggests that combined therapy immediately suppressed damage progression, whereas sulphasalazine did so less effectively and with a lag of 6 to 12 months. There were fewer withdrawals in the combined therapy than the sulphasalazine group (6 [8%] vs 23 [29%]), and they occurred later. This combined-therapy regimen offers additional disease control over and above that of sulphasalazine alone that persists for up to a year after corticosteroids are stopped. Although confirmatory studies and long-term follow-up are needed, this approach may prove useful in the treatment of early rheumatoid arthritis.

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Low-dose prednisone inclusion in a methotrexate-based, tight control strategy for early rheumatoid arthritis: a randomized trial.

Peter A. T. M. Geurts, Floris P. J. G. Lafeber, Koen Verstappen … (2012)

Treatment strategies for tight control of early rheumatoid arthritis (RA) are highly effective but can be improved. To investigate whether adding prednisone, 10 mg/d, at the start of a methotrexate (MTX)-based treatment strategy for tight control in early RA increases its effectiveness. A 2-year, prospective, randomized, placebo-controlled, double-blind, multicenter trial (CAMERA-II [Computer Assisted Management in Early Rheumatoid Arthritis trial-II]). (International Standard Randomised Controlled Trial Number: ISRCTN 70365169) 7 hospitals in the Netherlands. 236 patients with early RA (duration <1 year). Patients were randomly assigned to an MTX-based, tight control strategy starting with either MTX and prednisone or MTX and placebo. Methotrexate treatment was tailored to the individual patient at monthly visits on the basis of predefined response criteria aiming for remission. The primary outcome was radiographic erosive joint damage after 2 years. Secondary outcomes included response criteria, remission, and the need to add cyclosporine or a biologic agent to the treatment. Erosive joint damage after 2 years was limited and less in the group receiving MTX and prednisone (n = 117) than in the group receiving MTX and placebo (n = 119). The MTX and prednisone strategy was also more effective in reducing disease activity and physical disability, achieving sustained remission, and avoiding the addition of cyclosporine or biologic treatment. Adverse events were similar in both groups, but some occurred less in the MTX and prednisone group. A tight control strategy for RA implies monthly visits to an outpatient clinic, which is not always feasible. Inclusion of low-dose prednisone in an MTX-based treatment strategy for tight control in early RA improves patient outcomes. Catharijne Foundation.

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COBRA combination therapy in patients with early rheumatoid arthritis: long-term structural benefits of a brief intervention.

Marie Westedt, Iris Markusse, Robert Landewé … (2002)

The Combinatietherapie Bij Reumatoide Artritis (COBRA) trial demonstrated that step-down 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. 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). 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 time-averaged 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. 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.

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Journal ID (publisher-id): NIM

Journal ID (nlm-ta): Neuroimmunomodulation

Journal ID (doi): 10.1159/issn.1021-7401

Title: Neuroimmunomodulation

Publisher: S. Karger AG

ISBN: 978-3-318-02711-2

ISBN: 978-3-318-02712-9

ISSN (Print): 1021-7401

ISSN (Electronic): 1423-0216

Publication date Subscription-year: 2015

Publication date (Print): September 2014

Publication date (Electronic): 12 September 2014

Volume: 22

Issue: 1-2

Pages: 51-56

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Departments of ^aRheumatology and ^bEpidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands

Author notes

*Linda A. Rasch, Department of Rheumatology, VU University Medical Center, Room ZH 3A-54, De Boelelaan 1117, NL-1081 HV Amsterdam (The Netherlands), E-Mail l.rasch@vumc.nl

Article

Publisher ID: 362728 Other ID: Neuroimmunomodulation 2015;22:51-56

DOI: 10.1159/000362728

PubMed ID: 25227967

SO-VID: 99dd395e-b879-4a03-b4bf-8239367dd32a

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Initial High-Dose Prednisolone Combination Therapy Using COBRA and COBRA-Light in Early Rheumatoid Arthritis

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Most cited references 14

Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis.

Low-dose prednisone inclusion in a methotrexate-based, tight control strategy for early rheumatoid arthritis: a randomized trial.

COBRA combination therapy in patients with early rheumatoid arthritis: long-term structural benefits of a brief intervention.

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