Title: Early rheumatoid arthritis: a medical emergency?
Abstract: In this issue of The American Journal of Medicine, Lard et al. (1Lard L.R. Visser H. Speyer I. et al.Early versus delayed treatment in patients with recent-onset rheumatoid arthritis: comparison of two cohorts who received different treatment strategies.Am J Med. 2001; 111: 446-451Abstract Full Text Full Text PDF PubMed Scopus (470) Google Scholar) report that early treatment (within 2 weeks of diagnosis) of patients with rheumatoid arthritis provides better outcomes at 2 years of disease than does delayed treatment, and they conclude that both patients and physicians should consider early-onset rheumatoid arthritis as a medical emergency. Their study corroborates previous reports on the benefit of early management of the disease (2Boers M. Verhoeven A.C. Markusse H.M. et al.Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis.Lancet. 1997; 350: 309-318Abstract Full Text Full Text PDF PubMed Scopus (990) Google Scholar, 3Egsmose C. Lund B. Borg G. et al.Patients with rheumatoid arthritis benefit from early 2nd line therapy 5-year follow-up of a prospective double blind placebo controlled study.J Rheumatol. 1995; 22: 2208-2213PubMed Google Scholar, 4van der Heide A. Jacobs J.W.G. Bijlsma J.W.J. et al.The effectiveness of early treatment with "second-line" antirheumatic drugs.Ann Intern Med. 1996; 124: 699-707Crossref PubMed Scopus (458) Google Scholar). If one accepts the argument that the acute and chronic consequences of rheumatoid arthritis (joint swelling, joint damage, and loss of function) are due to persistent, inadequately controlled inflammation, then control of the abnormal inflammatory process is the fundamental step in managing all patients with the disease. Clearly, a goal of early management is to eliminate symptoms while returning the patient to normal physical and vocational function with structurally normal joints. However, we can hope to achieve this objective only by treating at the onset of the disease, before irreversible cartilage damage has occurred. Long-term observational studies have confirmed the association between inadequately controlled chronic inflammation leading to joint destruction and progressive functional decline. The current treatment goals are to decrease the costs associated with joint arthroplasty, hospitalization, and disability, and to prevent the diminished quality of life and premature mortality. Before the early 1990s, a major reason for delaying the initiation of "second-line therapies," or disease-modifying antirheumatic drugs (DMARDs), was the misconception that rheumatoid arthritis was a benign disease and that many DMARDs were prohibitively toxic. We now know that rheumatoid arthritis is not innocuous and that many DMARDs are well tolerated and not invariably associated with serious adverse events. In addition to its considerable associated morbidity and economic cost, rheumatoid arthritis leads to premature mortality (5Reilly P.A. Cosh J.A. Maddison P.J. et al.Mortality and survival in rheumatoid arthritis a 25 year prospective study of 100 patients.Ann Rheum Dis. 1990; 49: 363-369Crossref PubMed Scopus (216) Google Scholar), reducing average life expectancy by approximately 10 years. Furthermore, the indirect costs (primarily work-related disability) are at least twice as high as those of direct patient costs, leading to total disease-related losses of approximately $26 to $36 billion annually in the United States (6Birnbaum H.G. Barton M. Greenberg P.E. et al.Direct and indirect costs of rheumatoid arthritis to an employer.J Occup Environ Med. 2000; 42: 588-596Crossref PubMed Scopus (62) Google Scholar). Because rheumatoid arthritis is a chronic disease that often begins at a young age and persists for the lifetime of the patient, its management varies among patients depending on the aggressiveness of the disease; the specific joints involved; and the patient's age and lifestyle, physical function level, work disability, and social and emotional support. Although compelling data are emerging that suggest that early treatment with DMARDs provides better short-term and perhaps better long-term outcomes (2Boers M. Verhoeven A.C. Markusse H.M. et al.Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis.Lancet. 1997; 350: 309-318Abstract Full Text Full Text PDF PubMed Scopus (990) Google Scholar, 3Egsmose C. Lund B. Borg G. et al.Patients with rheumatoid arthritis benefit from early 2nd line therapy 5-year follow-up of a prospective double blind placebo controlled study.J Rheumatol. 1995; 22: 2208-2213PubMed Google Scholar, 4van der Heide A. Jacobs J.W.G. Bijlsma J.W.J. et al.The effectiveness of early treatment with "second-line" antirheumatic drugs.Ann Intern Med. 1996; 124: 699-707Crossref PubMed Scopus (458) Google Scholar, 7Bathon J.M. Martin R.W. Fleischmann R.M. et al.A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis.N Engl J Med. 2000; 343: 1586-1593Crossref PubMed Scopus (1672) Google Scholar, 8Tsakonas E. Fitzgerald A.A. Fitzcharles M. et al.Consequences of delayed therapy with second-line agents in rheumatoid arthritis a 3-year follow-up on the Hydroxychloroquine in Early Rheumatoid Arthritis (HErheumatoid arthritis) Study.J Rheumatol. 2000; 27: 623-629PubMed Google Scholar, 9Stenger A.A.M.E. Van Leeuwen M.A. Hartman P.M. et al.Early effective suppression of inflammation in rheumatoid arthritis reduces radiographic progression.Br J Rheumatol. 1998; 37: 1157-1163Crossref PubMed Google Scholar), several questions remain. Which patients should be treated early and aggressively? What is the best therapy in the early course of the disease? How can we encourage the referral of patients with early-onset rheumatoid arthritis to rheumatologists who are experienced with recently approved state-of-the-art treatments? Signs that a marked change in treatment strategy might be warranted began with reports in the late 1980s and early 1990s on the increased mortality associated with rheumatoid arthritis. In the early 1990s, several clinical investigators in Europe developed early-arthritis clinics to establish the diagnosis of rheumatoid arthritis promptly, to optimize patient function as quickly as possible, to suppress acute inflammation, and to institute early therapy with DMARDs. These clinics have also served to establish important inception cohorts. Analysis of these cohorts after at least 10 to 15 years of follow-up may allow us to determine whether earlier, more aggressive care has made an impact on the morbidity and mortality associated with this disease. The article by Lard et al. (1Lard L.R. Visser H. Speyer I. et al.Early versus delayed treatment in patients with recent-onset rheumatoid arthritis: comparison of two cohorts who received different treatment strategies.Am J Med. 2001; 111: 446-451Abstract Full Text Full Text PDF PubMed Scopus (470) Google Scholar) involves patients from one of these early-arthritis clinics. There are several options for treating a patient with early-onset rheumatoid arthritis who does not respond to nonsteroidal anti-inflammatory drugs (NSAIDs). These include traditional DMARDs such as hydroxychloroquine (or chloroquine), sulfasalazine (or salazopyrine), gold salts, and methotrexate, and newer agents such as leflunomide and the tumor necrosis factor inhibitors etanercept and infliximab. Recent data suggest that treatment with a combination of DMARDs is more effective than monotherapy (2Boers M. Verhoeven A.C. Markusse H.M. et al.Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis.Lancet. 1997; 350: 309-318Abstract Full Text Full Text PDF PubMed Scopus (990) Google Scholar, 10O'Dell J.R. Haire C.E. Erickson N. 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: 1287-1291Crossref PubMed Scopus (611) Google Scholar). Leflunomide, etanercept, infliximab, cyclosporine, and sulfasalazine, used in combination with methotrexate, are more effective than methotrexate alone for patients initially treated with methotrexate but who had an incomplete response (11Hughes L.B. Moreland L.W. New therapeutic approaches to the management of rheumatoid arthritis.Biodrugs. 2001; 15: 379-393Crossref PubMed Scopus (21) Google Scholar). Because of the lack of randomized controlled trials comparing these combination therapies, however, we have insufficient data to decide which agent might be most effective combined with methotrexate. Factors influencing choice of treatment are the patient's disease activity, functional status (ability to perform activities of daily living), underlying medical conditions, lifestyle (e.g., child-bearing potential, social use of alcohol), and work status. The time to effectiveness onset of each drug, their potential toxicities, the necessity of monitoring for adverse events, and the route of administration (subcutaneous, oral, or intravenous) also affect these decisions. Toxicity is a concern when combining immune-modulating agents for patients with rheumatoid arthritis. The risks of aggressive early therapy must be weighed against the potential improvements in signs and symptoms and potential decrements in radiographic joint damage, societal costs, and mortality. With the sequencing of the human genome, increasing knowledge of genetic polymorphisms, and burgeoning field of pharmacogenetics, however, the era of personalized medicine—of prescribing drugs based on genetic predictors of clinical response—may soon be realized (12Bridges Jr, S.L. The genetics of rheumatoid arthritis influences on susceptibility severity, and treatment response.Curr Rheumatol Rep. 1999; 1: 164-171Crossref PubMed Scopus (19) Google Scholar, 13Roses A.D. Pharmacogenetics and the practice of medicine.Nature. 2000; 405: 857-865Crossref PubMed Scopus (694) Google Scholar). At present, reimbursement issues often influence the use of specific therapies. Some medications such as etanercept, which is self administered subcutaneously, are not covered by Medicare; furthermore, some insurance carriers will not approve the use of more expensive drugs such as tumor necrosis factor inhibitors unless prior treatment with DMARDs was unsuccessful. Identifying genetic markers of clinical response and toxicity may help reduce expenses related to treatment by optimizing the initial choice of agents, reducing costs of laboratory monitoring, and minimizing adverse effects. For many chronic illnesses, premature death serves as a benchmark for disease severity and provides a rationale for aggressive therapy. Although first reported in 1953, the concept of premature mortality due to rheumatoid arthritis has only recently been widely recognized. Several comorbid conditions—for example, cardiovascular disease, infections, malignancies, and gastrointestinal disorders, with cardiovascular disease associated with approximately 50% of all deaths—may explain this increased mortality, which is more prevalent among men than women (5Reilly P.A. Cosh J.A. Maddison P.J. et al.Mortality and survival in rheumatoid arthritis a 25 year prospective study of 100 patients.Ann Rheum Dis. 1990; 49: 363-369Crossref PubMed Scopus (216) Google Scholar). Inflammation most likely plays a key role in cardiovascular disease, whereas C-reactive protein is an independent risk factor for cardiovascular disease in both women and men who are healthy (14Ridker P.M. Hennekens C.H. Buring J.E. Rifai N. C-Reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women.N Engl J Med. 2000; 342: 836-843Crossref PubMed Scopus (4968) Google Scholar). Disease activity, as measured by the number of swollen joints, has been shown to be an independent risk factor for cardiovascular-related death among Pima Indians with rheumatoid arthritis (15Jacobsson L.T.H. Turesson C. Hanson R.L. et al.Joint swelling as a predictor of death from cardiovascular disease in a population study of Pima Indians.Arthritis Rheum. 2001; 44: 1170-1176Crossref PubMed Scopus (61) Google Scholar). Similarly, a retrospective study showed that inflammation reflected in high erythrocyte sedimentation rates was predictive of the first cardiovascular event in patients with rheumatoid arthritis (16Wallberg-Jonsson S. Johansson H. Ohman M. Rantapaa-Dahlqvist S. Extent of inflammation predicts cardiovascular disease and overall mortality in seropositive rheumatoid arthritis. A retrospective cohort study from disease onset.J Rheumatol. 1999; 26: 256-257Google Scholar). Medications commonly prescribed for patients with rheumatoid arthritis may also contribute to cardiovascular disease. Glucocorticoids and NSAIDs can exacerbate hypertension. Glucocorticoids may alter lipid profiles, and both methotrexate and sulfasalazine can increase serum homocysteine levels. The past 3 years have seen a plethora of data on DMARDs, in particular biologic therapies that inhibit the proinflammatory activities of tumor necrosis factor and interleukin-1 (IL-1), thereby slowing or preventing structural damage in rheumatoid arthritis (7Bathon J.M. Martin R.W. Fleischmann R.M. et al.A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis.N Engl J Med. 2000; 343: 1586-1593Crossref PubMed Scopus (1672) Google Scholar, 11Hughes L.B. Moreland L.W. New therapeutic approaches to the management of rheumatoid arthritis.Biodrugs. 2001; 15: 379-393Crossref PubMed Scopus (21) Google Scholar, 17Lipsky P.E. van der Heijde D.M.F.M. St. Clair E.W. et al.Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study GroupInfliximab and methotrexate in the treatment of rheumatoid arthritis.N Engl J Med. 2000; 343: 1594-1602Crossref PubMed Scopus (2936) Google Scholar, 18Jiang Y. Genant H.K. Watt I. et al.A multicenter, double-blind, dose-ranging, randomized, placebo-controlled study of recombinant human interleukin-1 receptor antagonist in patients with rheumatoid arthritis radiologic progression and correlation of Genant and Larsen scores.Arthritis Rheum. 2000; 43: 1001-1009Crossref PubMed Scopus (400) Google Scholar). It remains to be seen whether these potent therapies will mitigate cardiovascular disease in rheumatoid arthritis. Despite the potential adverse effects of medications, the concept of waiting months or years before starting DMARD therapy is anathema. Unfortunately, no demographic, clinical, or genetic factors can predict disease severity or long-term outcome for a patient, although the presence of serum rheumatoid factor, radiographic signs of early erosive disease, and a high level of disease activity correlate with poor outcomes in population-based studies. Today's rheumatologists are instituting DMARD therapy immediately after the diagnosis of rheumatoid arthritis. Published data have documented that patients with rheumatoid arthritis and aggressive synovitis develop radiographically evident joint damage within the first 2 years of disease, with 50% of total radiographic damage occurring within the first 6 years. In studies performed before biologic agents were available, 50% of patients became disabled within 5 years of diagnosis. To prevent substantial morbidity and mortality, early control of inflammation is critical. Recent published data on the benefits of early, aggressive treatment support early referral. Perhaps the biggest breakthrough since corticosteroids in treating the disease is tumor necrosis factor inhibitors, which are highly effective in preventing erosions and joint damage (7Bathon J.M. Martin R.W. Fleischmann R.M. et al.A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis.N Engl J Med. 2000; 343: 1586-1593Crossref PubMed Scopus (1672) Google Scholar, 17Lipsky P.E. van der Heijde D.M.F.M. St. Clair E.W. et al.Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study GroupInfliximab and methotrexate in the treatment of rheumatoid arthritis.N Engl J Med. 2000; 343: 1594-1602Crossref PubMed Scopus (2936) Google Scholar). Leflunomide, a pyrimidine antagonist, has an efficacy profile similar to that of methotrexate, and slows radiographic progression (19Smolen J.S. Kalden J.R. Scott D.L. et al.European Leflunomide Study GroupEfficacy and safety of leflunomide compared with placebo and sulphasalazine in active rheumatoid arthritis a double-blind, randomised, multicentre trial.Lancet. 1997; 353: 259-266Google Scholar). Blockade of IL-1 by a recombinant IL-1 receptor antagonist (anakinra) also retards the development of bone erosions (18Jiang Y. Genant H.K. Watt I. et al.A multicenter, double-blind, dose-ranging, randomized, placebo-controlled study of recombinant human interleukin-1 receptor antagonist in patients with rheumatoid arthritis radiologic progression and correlation of Genant and Larsen scores.Arthritis Rheum. 2000; 43: 1001-1009Crossref PubMed Scopus (400) Google Scholar). Other biologic agents aimed at components of immune system and inflammatory pathways are under study in clinical trials. An emerging area of research is analyzing the appropriateness of care for patients with chronic diseases (20MacLean C.H. Louie R. Leake B. et al.Quality of care for patients with rheumatoid arthritis.JAMA. 2000; 284: 984-992Crossref PubMed Scopus (189) Google Scholar). In a study of 1355 patients with rheumatoid arthritis (4878 person-years of observation), health care quality was suboptimal for rheumatoid arthritis, as well as for comorbid disease and health maintenance. Patients who had contact with a relevant specialist received substantially higher quality care than did patients without such contact. Notably, half of the study population was never evaluated by a relevant specialist. These findings have substantial implications for health care policies regarding optimal roles of generalists and specialists in the management of complex chronic diseases. Health care models that rely on primary care physicians as overseers of care and restrict access to specialists are suboptimal for patients with rheumatoid arthritis. A major obstacle to the effective treatment of patients with early-onset rheumatoid arthritis is the substantial delay in diagnosis and referral to a rheumatologist. One of today's challenges is to optimize collaboration between primary care physicians and rheumatologists. In addition, educational efforts are needed to increase physician awareness of comorbid diseases in patients with this chronic illness. A primary challenge is to ensure equal access to and use of health care services by patients with chronic diseases. It is unclear whether sociodemographic variables such as lower socioeconomic status influence disability as a direct consequence of delayed referral to rheumatologists. A study of Medicare outpatient claims reported that only one third of older patients with rheumatoid arthritis, compared with only 42% of older patients with systemic lupus erythematosus, saw a rheumatologist during a 1-year period (21Katz J.N. Barrett J. Liang M.H. et al.Utilization of rheumatology physician services by the elderly.Am J Med. 1998; 105: 312-318Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar). More importantly, African-American patients made fewer visits to rheumatologists than did whites, particularly among women. Besides educational programs for medical gatekeepers and facilitation of subspecialty consultation, population-based interventions are needed to encourage patients to seek subspecialty care early in the course of the disease to obtain prompt DMARD therapy. In summary, the diagnosis of rheumatoid arthritis should be considered a medical urgency that requires prompt diagnosis and referral to a rheumatologist who can institute appropriate treatment. Recognizing that it is a progressive disease, as measured by radiographic damage, work disability, and premature death, supports a rationale for aggressively using DMARDs and the new, targeted biologic response modifiers such as tumor necrosis factor and IL-1 inhibitors to better manage this costly, crippling disease. The assistance of Bettie Stone in preparing the manuscript and the helpful comments from Gene Ball, MD, and Ted Mikuls, MD, are much appreciated.