Over the last decade, a number of changes have occurred that have improved outcomes for patients with rheumatoid arthritis (RA). These changes include the realization that early therapy with disease-modifying antirheumatic drugs (DMARDs) is critical for optimizing long-term results (1–3), that combinations of DMARDs are well tolerated and provide greater relief than that provided by DMARD monotherapy (4–7), and that biologic agents targeting tumor necrosis factor α (TNFα) promptly and substantially decrease disease activity in many patients with RA (8–10). Additionally, it has been shown once again that steroids are disease-modifying agents (11). Arguably, the most important of these changes is the increased awareness that early therapy is critical.

Two studies have independently demonstrated that even a brief delay (as little as 8–9 months) in starting DMARD therapy has a significant impact on disease parameters years later (1, 2). This finding is particularly remarkable because those studies were performed with drugs (oral gold and hydroxychloroquine) that are considered to be among the least effective of the DMARDs. A third study, in which DMARD therapy was delayed for a period of up to 1 year, had similar results (3). Additionally, mortality among RA patients who present early is lower than that among those who present late in the course of disease (12). Recognition that erosive changes occur early in the disease, often in the first 1 year (13, 14), has also highlighted the importance of early intervention.

Therefore, although it is increasingly clear that RA patients should receive early DMARD therapy, many critical questions remain: how early is early enough, and should we measure this chronologically (i.e., according to the duration of disease) or by trying to define different pathophysiologic stages? Should combinations of DMARDs be used for all patients? Should we be using step-down or induction therapy? Should all patients receive steroids? What is the role of TNF inhibition or use of minocycline in early disease? Is there a true window of opportunity during which treatments have a greater impact on long-term outcomes? And, perhaps most important, can factors be identified that allow us to predict in a differential manner which subsets of patients will respond best to different therapies?

The report by Landewé et al in this issue of Arthritis & Rheumatism (15) and the parent trial on which it is based (5) provide insight into some of these issues. More than a decade ago, Wilske and Healey introduced the “step-down bridge” concept (16). They argued that combinations of drugs should be used to quickly shut off inflammation, and then as many as possible should be tapered off while maintaining control of the disease. Until the initial results of the Combinatietherapie Bij Reumatoide Artritis (COBRA) trial were published in 1997 (5), there had been no confirmation of this attractive hypothesis. Therefore, the continuing results from this trial are of great interest. In the original COBRA trial, 155 patients with early RA (median duration 4 months) were randomized to receive either combination therapy with sulfasalazine (2 gm/day), methotrexate (7.5 mg/week), and prednisolone or sulfasalazine alone. Prednisolone was given in a dosage of 60 mg/day for the first week and then rapidly tapered to 7.5 mg/day. Prednisolone was stopped after week 28, and methotrexate was stopped after week 40. After that point, all patients received similar treatment.

Although some investigators have dismissed the results of the COBRA trial, either because certain benefits in the combination-therapy group were transient or because of the relatively high initial dosage of steroids that was used, the COBRA trial was clearly pivotal. Expanding on an editorial by Emery (17) that accompanied publication of the original study, I believe the important findings of the COBRA trial are the following: 1) inflammation can be suppressed quickly in early RA, benefiting patients for at least the duration of the suppression; 2) combination therapy is not necessarily more toxic than monotherapy (more withdrawals occurred in the sulfasalazine-alone group); and 3) when induction therapy is stopped, patients who have received it begin to clinically resemble those who have not.

The critical question about this trial that many rightfully asked was whether there was any real long-term advantage to this treatment approach. The results now presented by Landewé et al strongly suggest that the answer to this question is a resounding yes. They report that patients in the original combination-therapy group had less radiologic progression at 4 years compared with the original monotherapy group, and, more important, their disease continues to progress at a slower rate.

Clinicians have long debated whether there exists a period of time during early RA when some patients may respond to intervention in a fundamentally different way than they would if therapy were delayed. Composite results from the COBRA trial suggest that there may indeed be a “window of opportunity” when rapid suppression of disease decreases or resets the rate of progression for years to come. Results of the Early Rheumatoid Arthritis (ERA) trial, in which etanercept was compared with methotrexate (10), may provide further support for the importance of rapid suppression. Although the clinical outcomes in patients in that trial (American College of Rheumatology 20%, 50%, or 70% criteria) (18) were not different at 1 year, etanercept clearly suppressed inflammation more rapidly, as measured by C-reactive protein levels. The importance of such rapid suppression is supported by a recent followup report suggesting that the rate of radiologic progression in the etanercept group continues to be slower than that in the methotrexate group at 2 years (19).

The long-term results from the COBRA trial and the early results from the ERA trial suggest that the rate of radiologic progression in RA can be reset by rapidly and aggressively suppressing the inflammatory response. With all this in mind, should clinicians now strive not only to start DMARDs as early as possible, but also to use combination DMARD therapy or induction therapy (with steroids or TNF inhibitors) in all patients with early RA?

The vast majority of trials that have compared combination DMARD therapy with DMARD monotherapy in early RA have shown superior outcomes for the groups treated with combinations. In addition to the COBRA trial, these include the Finnish Rheumatoid Arthritis Combination Therapy Trial (6), in which the combination of methotrexate-sulfasalazine-hydroxychloroquine and prednisolone was superior to sulfasalazine with or without prednisolone, and the trial by Calguneri et al (7), in which triple therapy with methotrexate-sulfasalazine-hydroxychloroquine was superior to 2-drug combinations, and 2-drug combinations were superior to monotherapy. Furthermore, the results of the study by Kirwan and colleagues (11, 20), in which the addition of prednisolone to conventional therapy slowed radiologic progression compared with conventional therapy alone, also support use of combination DMARD therapy. Therefore, although all available data support use of combination DMARD therapy in early RA, most clinicians favor the approach of rapidly stepping up DMARD therapy in those patients who have suboptimal responses to DMARD monotherapy. Unfortunately, the critically important trial comparing these 2 approaches has not been undertaken.

If, as results of the COBRA (5, 15) and ERA trials (10, 19) suggest, there is a window of opportunity in early disease during which the rate of radiologic progression can be reset, the time to consider induction therapy in early RA may have arrived. It has been known for more than 50 years that inflammation in RA can be predictably and rapidly suppressed with steroids; recently, TNF inhibitors have also been shown to do this. Therefore, a trial comparing induction therapy with steroids and induction therapy with TNF inhibitors would be of great interest. Induction therapy with these agents would have the added benefit of not continuing steroids or TNF inhibition for a prolonged period, thus avoiding the concern of long-term toxicity.

The COBRA trial has taught us much. As is the case with many successful clinical trials, it also has raised many intriguing questions. Trials comparing different approaches with induction therapy and studies comparing initial combination DMARD therapy with a rapid step-up approach are anxiously awaited. Ultimately, in order to provide the correct treatment to the majority of patients during “the window of opportunity,” factors that allow us to predict in a differential manner which patients will respond to and tolerate individual therapies must be elucidated.


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  • 1
    Egsmose C, Lund B, Borg G, Pettersson H, Berg E, Brodin U, et al. Patients with rheumatoid arthritis benefit from early 2nd line therapy: 5-year followup of a prospective double blind placebo controlled study. J Rheumatol 1995; 22: 220813.
  • 2
    Tsakonas E, Fitzgerald AA, Fitzcharles MA, Cividino A, Thorne JC, M'Seffar A, et al. Consequences of delayed therapy with second-line agents in rheumatoid arthritis: a 3 year followup on the hydroxychloroquine in early rheumatoid arthritis (HERA) study. J Rheumatol 2000; 27: 6239.
  • 3
    Van der Heide A, Jacobs JW, Bijlsma JW, Heurkens AH, van Booma-Frankfort C, van der Veen MJ, et al. The effectiveness of early treatment with “second-line” antirheumatic drugs: a randomized, controlled trial. Ann Intern Med 1996; 124: 699707.
  • 4
    O'Dell JR, Haire CE, Erikson N, Drymalski W, Palmer W, Eckhoff PJ, et al. Treatment of rheumatoid arthritis with methotrexate alone, sulfasalazine and hydroxychloroquine, or a combination of all three medications. N Engl J Med 1996; 334: 128791.
  • 5
    Boers M, Verhoeven AC, Markusse HM, van de Laar MA, Westhovens R, van Denderen JC, et al. Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis. Lancet 1997; 350: 30918.
  • 6
    Mottonen R, Hannonen P, Leirisalo-Repo M, Nissila M, Kautiainen H, Korpela M, et al. Comparison of combination therapy with single-drug therapy in early rheumatoid arthritis: a randomised trial. Lancet 1999; 353: 156873.
  • 7
    Calguneri M, Pay S, Caliskaner Z, Apras S, Kiraz S, Ertenli I, et al. Combination therapy versus monotherapy for the treatment of patients with rheumatoid arthritis. Clin Exp Rheumatol 1999; 17: 699704.
  • 8
    Elliott MJ, Maini RN, Feldmann M, Kalden JR, Antoni C, Smolen JS, et al. Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor α (cA2) versus placebo in rheumatoid arthritis. Lancet 1994; 344: 110510.
  • 9
    Moreland LW, Baumgartner SW, Schiff MH, Tindall EA, Fleischmann RM, Weaver AL, et al. Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein. N Engl J Med 1997; 337: 1417.
  • 10
    Bathon JM, Martin RW, Fleischmann RM, Tesser JR, Schiff MH, Keystone EC, et al. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med 2000; 343: 158693.
  • 11
    Kirwan JR and the Arthritis and Rheumatism Council Low-Dose Glucocorticoid Study Group. The effect of glucocorticoids on joint destruction in rheumatoid arthritis. N Engl J Med 1995; 333: 1426.
  • 12
    Symmons DPM, Jones MA, Scott DL, Prior P. Long-term mortality outcome in patients with rheumatoid arthritis: early presenters continue to do well. J Rheumatol 1998; 25: 10727.
  • 13
    Van der Heijde DM. Joint erosions and patients with early rheumatoid arthritis. Br J Rheumatol 1995; 34: 748.
  • 14
    McGonagle D, Green MJ, Proudman S, Richardson C, Veale D, O'Connor P, et al. The majority of patients with rheumatoid arthritis have erosive disease at presentation when magnetic resonance imaging of the dominant hand is employed. Br J Rheumatol 1997; 36 ( Suppl): 230.
  • 15
    Landewé RBM, Boers M, Verhoeven AC, Westhovens R, van de Laar MA, Markusse HM, et al. COBRA combination therapy in patients with early rheumatoid arthritis: long-term structural benefits of a brief intervention. Arthritis Rheum 2002; 46: 34756.
  • 16
    Wilske KR, Healey LA. Remodeling the pyramid: a concept whose time has come. J Rheumatol 1989; 16: 5657.
  • 17
    Emery P. Rheumatoid arthritis: not yet curable with early intensive therapy [editorial]. Lancet 1997; 350: 3045.
  • 18
    Felson DT, Anderson JJ, Boers M, Bombardier C, Furst D, Goldsmith C, et al. Preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum 1995; 38: 72735.
  • 19
    Genovese M, Martin R, Fleischmann R, Keystone E, Bathon J, Spencer-Green G, et al. Enbrel® (etanercept) vs methotrexate (MTX) in early rheumatoid arthritis (ERA trial): two-year follow-up [abstract]. Arthritis Rheum 2000; 43 Suppl 9: S269.
  • 20
    Hickling P, Jacoby RK, Kirwan RJ, and the Arthritis and Rheumatism Council Low Dose Glucocorticoid Study Group. Joint destruction after glucocorticoids are withdrawn in early rheumatoid arthritis. Br J Rheumatol 1998; 37: 9306.