Advances in the treatment of early rheumatoid arthritis
Edward M.J. Vital
Rheumatoid arthritis is the most common reversible disability in the world, and its economic burden has been estimated to be between $3,600 and $60,300 annually per patient. (1) In this issue of AFP, Drs. Rindfleisch and Muller (2) summarize the approach to the patient with newly diagnosed rheumatoid arthritis. Developments in therapies for rheumatoid arthritis provide the opportunity not only to ameliorate inflammation and improve short-term quality of life for patients, but also to change the course of the disease to prevent joint destruction and long-term disability. The key to this approach has been the recognition of the “window of opportunity,” the critical stage of early disease when patients are most responsive to treatment and have the most potential for lifelong benefit. (3) We are entering an era in which remission rather than control of symptoms can be the aim of therapy; however, with increasingly complex treatments, early diagnosis and intervention are more important than ever.
The traditional approach to treating patients with rheumatoid arthritis was to begin with nonsteroidal anti-inflammatory drugs alone and reserve disease-modifying treatments for the most severely affected patients or those with destructive disease. Therefore, disease-modifying antirheumatic drugs (DMARDs) generally were prescribed later in the natural history of the disease. This was partly because it was underappreciated how early structural destruction and loss of function begin to occur, and because the earlier DMARDs often were ineffective or poorly tolerated.
Novel imaging techniques such as magnetic resonance imaging (MRI) and ultrasonography have provided a window into the early inflammatory process and the onset of erosive disease. Synovitis may be subclinical and more widespread than can be detected by examination alone. (4) There is evidence of bone damage, undetectable by conventional radiography, within weeks of the onset of symptoms. There also is evidence that early erosion detected by MRI and ultrasonography will predict later, more clinically relevant destructive disease that can be seen on plain radiographs. (4,5)
Given the evidence for destructive changes in early disease, it is not surprising that delaying treatment has adverse consequences. The Finnish Rheumatoid Arthritis Combination Therapy trial found that a delay in instituting DMARD therapy of as little as a few months after the onset of symptoms would make remission less likely and was the most important variable determining likelihood of remission. (6) However, early diagnosis remains difficult. The cardinal distinguishing feature of rheumatoid arthritis is its chronicity, and therefore making a diagnosis early is challenging. Early rheumatoid arthritis may present as an undifferentiated arthritis, and self-limiting arthritides such as postviral arthritis may fulfill criteria for rheumatoid arthritis. In general, the American College of Rheumatology criteria are not useful in early arthritis. The most important factor predicting persistent synovitis is duration of symptoms greater than 12 weeks, but presence of rheumatoid factor and the shared epitope (a single antigenic site on a protein to which an antibody binds) are predictive to a lesser extent.
In addition to determining sufficiently early that a patient’s symptoms are caused by rheumatoid arthritis, important questions about treatment of early inflammatory arthritis remain: (1) how to identify patients who need more aggressive treatment, and (2) how to treat to ensure the best long-term prognosis.
How can we identify patients who need more aggressive treatment? If early aggressive treatment with combination DMARDs and expensive biologic agents is advocated, then it is important to stratify patients according to prognosis for these treatments. The presence of erosions at presentation has been shown to be predictive of more erosive disease subsequently. (7) Ultrasonography has been shown to be six times more sensitive than conventional radiographs for erosions in early rheumatoid arthritis. (8) Ultrasonography, with the other markers of persistence mentioned above, is therefore a useful tool for earlier identification of patients in need of long-term treatment, as an alternative to waiting for a destructive arthropathy to become clinically evident. It also can identify those patients who will experience more severely destructive disease. Patients with poor prognosis for destructive disease are likely to have increased benefit from early aggressive treatment, although to date, trials of such treatments have not stratified patients in this way.
How can we treat to ensure the best long-term prognosis? With the treatment aim of remission in mind, and to optimize treatment at the stage of greatest potential, the challenge is to find the most effective treatment in early disease with the greatest long-term benefit. Two strategies have shown efficacy: combinations of DMARDs at outset in a “step-down” approach, and biologic agents.
In step-down combination therapy, several agents are introduced simultaneously at first, gradually reducing to one maintenance agent. For example, combination therapy might include sulfasalazine (Azulfidine; 2 g per day), methotrexate (7.5 mg per week), and prednisone (60 mg per day, reducing weekly to 7.5 mg per day), with the prednisone and methotrexate tapered and stopped after 28 and 40 weeks, respectively. (9) This type of treatment recently has shown improved efficacy over single-DMARD therapy in several large trials. (9,10) Importantly, the benefits of combination therapy at outset persisted for several years after the study, regardless of therapy thereafter. (11) One reason for reluctance to initiate high-dose DMARDs in patients with early arthritis was concern about toxicity. This is not justified, because there has been no increased frequency of adverse events in combination therapy compared with standard dose, single-drug treatment.
The new biologic agents (inf liximab [Remicade], etanercept [Enbrel], and adalimumab [Humira]) are highly potent in treating synovitis and preventing radiologic progression in established rheumatoid arthritis that is resistant to standard DMARD therapy. In view of the clear evidence for long-term prevention of structural damage and disability provided by aggressive early intervention, biologic therapy in early arthritis is a logical progression. The combination of infliximab and methotrexate is superior to methotrexate alone in patients with early arthritis in terms of controlling disease activity, preventing erosions, and preserving function. (12)
A variety of novel treatments for rheumatoid arthritis are under investigation. These study results will add to our knowledge of the pathogenesis of rheumatoid arthritis and further add to our ability to manipulate, and perhaps even cure, this disease.
(1.) Rat AC, Boissier MC. Rheumatoid arthritis: direct and indirect costs. Joint Bone Spine 2004;71:518-24.
(2.) Rindfleisch JA, Muller D. Diagnosis and management of rheumatoid arthritis. Am Fam Physician 2005;72:1037-47.
(3.) Quinn MA, Emery P. Window of opportunity in early rheumatoid arthritis: possibility of altering the disease process with early intervention. Clin Exp Rheumatol 2003;21(5 suppl 31):S154-7.
(4.) McGonagle D, Conaghan PG, O’Connor P, Gibbon W, Green M, Wakefield R, et al. The relationship between synovitis and bone changes in early untreated rheumatoid arthritis: a controlled magnetic resonance imaging study. Arthritis Rheum 1999;42:1706-11.
(5.) McQueen FM, Benton N, Crabbe J, Robinson E, Yeoman S, McLean L, et al. What is the fate of erosions in early rheumatoid arthritis? Tracking individual lesions using x-rays and magnetic resonance imaging over the first two years of disease. Ann Rheum Dis 2001;60:859-68.
(6.) Mottonen T, Hannonen P, Korpela M, Nissila M, Kautiainen H, Ilosen J, et al. Delay to institution of therapy and induction of remission using single-drug or combination-disease-modifying antirheumatic drug therapy in early rheumatoid arthritis. Arthritis Rheum 2002;46:894-8.
(7.) Guillemin F, Gerard N, van Leeuwen M, Smedstad LM, Kvein TK, van den Heuvel W, et al. Prognostic factors for joint destruction in rheumatoid arthritis: a prospective longitudinal study of 318 patients. J Rheumatol 2003;30:2585-9.
(8.) Wakefield, RJ, Gibbon WW, Conaghan PG, O’Connor P, McGonagle D, Pease C, et al. The value of sonography in the detection of bone erosion in patients with rheumatoid arthritis: a comparative study with conventional radiography. Arthritis Rheum 2000;43:2762-70.
(9.) Boers M, Verhoeven AC, Markusse HM, van de Laar MA, Westhovens R, van Denderen JC, et al. Randomised comparison of combined stepdown prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis. Lancet 1997;350:309-18.
(10.) Mottonen T, 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. FIN-RACo trial group. Lancet 1999;353:1568-73.
(11.) Landewe RB, 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;46:347-56.
(12.) St Clair EW, van der Heijde DM, Smolen JS, Maini RN, Bathon JM, Emery P, et al. Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: a randomized, controlled trial. Arthritis Rheum 2004;50:3432-43.
EDWARD M. J. VITAL, M.B.CH.B.
The General Infirmary at Leeds
Leeds, United Kingdom
PAUL EMERY, M.A., M.D.
University of Leeds Faculty of Medicine and Health
Leeds, United Kingdom
EDWARD M. J. VITAL, M.B.CH.B., M.R.C.P., is specialist registrar in the Department of Rheumatology at the General Infirmary at Leeds, United Kingdom.
PAUL EMERY, M.A., M.D., F.R.C.P., is professor of rheumatology in the Academic Unit of Musculoskeletal Disease at the University of Leeds Faculty of Medicine and Health, United Kingdom.
Address correspondence to Professor Paul Emery, Academic Unit of Musculoskeletal Disease, University of Leeds, 36 Clarendon Road, Leeds LS2 9JT, United Kingdom (e-mail: p.emery@leeds. ac.uk). Reprints are not available from the authors.
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