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EDITORIAL |
COBRA combination therapy in daily practice—getting back to the future
Department of Clinical Epidemiology and Biostatistics, VU University Medical Center, PK 6 Z 165, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands
Correspondence to: M. Boers. E-mail: keb.info{at}vumc.nl
The COBRA trial published in 1997 was among the first to prove the worth of ‘reversing the pyramid strategy’ in the treatment of rheumatoid arthritis (RA) [1]. This pyramid from the fifties offered most effective treatment as late as possible, under the false assumption that RA was in most cases a self-limiting disease, and that treatment was mostly toxic and did more harm than good. Wilske and Healey [2] attacked the pyramid approach in an editorial in 1990, suggesting treatment should be aimed at achieving disease control early.
The COBRA strategy was novel in two ways: first, it combined the drugs thought most effective at that time, sulphasalazine and the upcoming drug methotrexate; the latter drug was given at a dose (7.5 mg/wt) deemed low by current standards, but toxic at that time. Second, it reintroduced glucocorticoids in RA at a dose (prednisolone 60 mg/day) reserved up to this day for other auto-immune diseases such as myositis and lupus nephritis. In the COBRA schedule, this dose is rapidly lowered to 7.5 mg/day in a period of 7 weeks, creating an ‘extended oral pulse’ followed by low-dose therapy. The trial set out to answer two questions: (i) is it possible to induce remission or at least a strong reduction of disease activity? (ii) is it possible to maintain efficacy when the combination drugs are withdrawn? The answer to the first question was overwhelmingly positive: COBRA was much better in all aspects of disease activity reduction, including remission and reduction of radiographic damage progression, than the then standard of treatment, sulphasalazine. In addition, the incidence of serious adverse events and treatment discontinuations were also much lower in the COBRA group. The answer to the second question was, unfortunately, no. After tapering of prednisolone and methotrexate, most parameters of disease activity rejoined those of the sulphasalazine group so that differences in clinical measures were mostly lost at 1 yr. These findings led the editorialist at that time to conclude that COBRA was of uncertain benefit, despite the fact that differences in damage progression were maintained up to 18 months after start of therapy [3].
Since that time, much has happened. We have seen three anti-tumour necrosis factor (TNF) inhibitors, and more recently rituximab and abatacept proven highly effective in the treatment of RA, and we know of many more agents in the development stage. In early RA, combination of anti-TNF with high-dose methotrexate has shown impressive results in terms of remission induction and (near) arrest or even reversal of damage progression [4–6]. However, these results with the biologic agents have very nearly been matched by results from trials employing traditional agents in varying combinations and strategies, most in a ‘tight control’ setting where treatment decisions follow a protocol based on disease activity measurements [7–9]. In addition, a systematic review that summarized the findings of 15 trials including over 1400 patients left no doubt that glucocorticoids are disease modifying in the sense that they reduce damage progression [10]. Five-year follow-up of the original COBRA study cohort showed the COBRA treated group continued with a much lower yearly damage progression than the sulphasalazine group, despite similar treatment and disease activity levels: the first proof of true ‘disease modification’ of any treatment modality in RA [11]. In the BeSt study and subsequent 2-yr follow-up, early RA patients treated with a slightly modified COBRA strategy had the same outcome as patients treated with high-dose methotrexate and infliximab in terms of disease activity, damage progression and side-effect profile [12].
The above comprises an excellent ‘CV’ for tight control combination therapy in early RA, and especially for COBRA. Nevertheless, uptake in general practice has been poor. Reasons for this include concern over glucocorticoid toxicity, perceived difficulty with the dosing regimen, a dislike of glucocorticoids shared and reinforced by physician and patient, and the perception that the patient dislikes taking many pills [13]. Our group is currently conducting an implementation study to address these concerns and improve uptake [14]. In this context, it is highly encouraging to read the report in this issue of Rheumatology [15]. Clinicians in Leuven (one of the original COBRA trial centers) have incorporated COBRA into their practice, reserving it for cases with a poor prognosis. They report no difficulty in starting patients on this regimen. Even though the number of reported cases is quite small, the results are entirely compatible with the trial reports: good efficacy and limited toxicity. Although the results are not statistically significantly different for all measures at all time points, COBRA is numerically superior in almost all comparisons. Also, the perceived complexity of the initial treatment schedule is more than offset by the greatly reduced need to change the treatment schedule due to lack of efficacy or toxicity, confirming data of the BeSt trial. Finally, the cumulative dose of glucocorticoids is about 2 g over the 2 yrs: a clinically significant dose. However, over half of the patients in the comparison group needed glucocorticoids in their first year, and in the second year the patients still on glucocorticoids were double that of the COBRA group (40 vs 20%), resulting in a cumulative dose of 1 g over the 2 yrs.
In all, there can be no reasonable doubt that COBRA can give excellent results in the treatment of RA, at a fraction of the cost of biological therapy. It is time to get back to the future and start applying COBRA in our daily practice now. But we are not done. Future research should focus on optimizing the strategy, either in the direction of reducing potential toxicity while maintaining efficacy (e.g. reducing the glucocorticoid dose, increasing methotrexate, researching the utility of sulphasalazine) or in the direction of enhancing efficacy while controlling toxicity (e.g. adding drugs, fine-tuning the glucocorticoid schedule on the actual response of the patient, continuing low-dose glucocorticoids, etc.). This is an exciting era where new and old drugs can work together to realize the ultimate aim: universal remission induction in RA.
Disclosure statement: M.B. has received an unrestricted research grant from Schering-Plough, The Netherlands. M.B. has also been a member of data safety monitoring or advisory boards for Genetech, Novartis, BristolMyerSquibb, Sanofi-Aventis, Nitec, Savient and Combinatorx.
References
- Boers M, Verhoeven AC, Markusse HM, et al. Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis [published erratum appears in Lancet 1998;351:220]. Lancet (1997) 350:309–18.[CrossRef][Web of Science][Medline]
- Wilske KR, Healey LA. Remodeling the pyramid–a concept whose time has come. J Rheumatol (1989) 16:565–7.[Web of Science][Medline]
- Emery P. Rheumatoid arthritis: not yet curable with early intensive therapy. Lancet (1997) 350:304–5.[CrossRef][Web of Science][Medline]
- Breedveld FC, Weisman MH, Kavanaugh AF, et al. The PREMIER study: a multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis Rheum (2006) 54:26–37.[CrossRef][Web of Science][Medline]
- St Clair EW, van der Heijde DM, Smolen JS, et al. Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: a randomized, controlled trial. Arthritis Rheum (2004) 50:3432–43.[CrossRef][Web of Science][Medline]
- van der Heijde D, Klareskog L, Boers M, et al. Comparison of different definitions to classify remission and sustained remission: 1 year TEMPO results. Ann Rheum Dis (2005) 64:1582–7.
[Abstract/Free Full Text] - Möttönen T, Hannonen P, Leirisalo-Repo M, et al. Comparison of combination therapy with single-drug therapy in early rheumatoid arthritis: a randomised trial. Lancet (1999) 353:1568–73.[CrossRef][Web of Science][Medline]
- Grigor C, Capell H, Stirling A, et al. Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial. Lancet (2004) 364:263–9.[CrossRef][Web of Science][Medline]
- Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, et al. Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): a randomized, controlled trial. Arthritis Rheum (2005) 52:3381–90.[CrossRef][Web of Science][Medline]
- Kirwan JR, Bijlsma JW, Boers M, Shea BJ. Effects of glucocorticoids on radiological progression in rheumatoid arthritis. Cochrane Database Syst Rev (2007) CD006356.
- Landewe RB, Boers M, Verhoeven AC, et al. COBRA combination therapy in patients with early rheumatoid arthritis: long-term structural benefits of a brief intervention. Arthritis Rheum (2002) 46:347–56.[CrossRef][Web of Science][Medline]
- Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, et al. Comparison of treatment strategies in early rheumatoid arthritis: a randomized trial. Ann Intern Med (2007) 146:406–15.
[Abstract/Free Full Text] - van Tuyl LH, Plass AM, Lems WF, Voskuyl AE, Dijkmans BA, Boers M. Why are Dutch rheumatologists reluctant to use the COBRA treatment strategy in early rheumatoid arthritis? Ann Rheum Dis (2007) 66:974–6.
[Abstract/Free Full Text] - van Tuyl LH, Plass AM, Lems W, Voskuyl AE. Opinions of Dutch rheumatologists and patients on treatment of early rheumatoid arthritis with aggressive combination therapy (COBRA). Ann Rheum Dis (2007) 66(Suppl. 11):648.
- Verschueren P, Esselens G, Westhovens R. Daily Practice Effectiveness of a Step Down Treatment in comparison to a Tight Step Up for Early Rheumatoid Arthritis. Rheumatology (2007) 47:53–8.
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