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Evaluating Patients With Arthritis of Recent Onset: Studies in Pathogenesis and Prognosis

Evaluating Patients With Arthritis of Recent Onset: Studies in Pathogenesis and Prognosis Abstract Inflammatory synovitis of recent onset poses a diagnostic and prognostic challenge to primary care physicians and rheumatologists. A lack of understanding of the underlying etiologic and pathogenic processes limits the ability to distinguish forms of arthritis that follow a benign, self-limiting course from forms that proceed to an aggressive, erosive disease requiring intensive immunosuppressive therapy. It is estimated that between 30% and 40% of patients presenting with early synovitis have disease that remains unclassified. Using data from a cohort of patients with early synovitis and reviewing current literature, we discuss investigational approaches toward a new classification of patients with early synovitis. Although a lack of understanding of this heterogeneous clinical syndrome has led clinicians to take a largely empirical approach to treatment thus far, the evolving awareness of disease predisposition at a genetic level and the expanding ability to specifically manipulate biological pathways may ultimately change the approach to this clinical problem. Synovitis of peripheral joints poses a challenging problem to clinicians. It can represent a benign, self-limited process requiring only symptomatic relief or the early stages of a progressive, destructive arthropathy. Although a presumptive diagnosis can be made in many cases, studies of cohorts of patients with early synovitis indicate that a significant proportion of these patients can only be classified as having an "undifferentiated arthropathy."1,2 Moreover, even when a diagnosis is made, establishing prognosis early in the disease course can be quite difficult. A lack of understanding of the etiologic or the pathogenic basis of most forms of synovitis continues to limit the ability to better classify the desire of these patients. To develop a better understanding of the pathogenesis and prognosis of early synovitis, a cohort of patients has been evaluated and followed up at the National Institutes of Health (NIH) for the past 5 years. Individuals diagnosed as having synovitis for less than 1 year were recruited from practicing clinicians. The patients were evaluated clinically, radiographically, serologically, and genetically. A synovial biopsy of an affected joint was performed at the initial visit to define the pathologic spectrum of early synovitis and to search for evidence of infectious triggers or amplifiers of the synovial inflammation. The patients then were followed up longitudinally to determine their outcome and response to therapy. To illustrate the clinical spectrum of early synovitis, 3 cases from the NIH cohort are presented. Case presentations Case 1 A 55-year-old white woman presenting with symmetric polyarthritis was evaluated at the NIH Clinical Center. Eleven months before evaluation, she developed an additive arthritis involving the wrists, small joints of the hands and feet, and the knees. She also experienced fatigue, prolonged morning stiffness, and soon was unable to perform her usual activities of daily living. Findings of hand radiographs showed soft tissue swelling around her wrist, periarticular osteopenia, and several small erosions in the proximal interphalangeal and metacarpophalangeal joints. Laboratory evaluation revealed a C-reactive protein (CRP) serum level of 6.93 mg/dL and a positive rheumatoid factor (RF) level in a serum titer of 160 IU/mL. HLA typing showed her to have 1 copy of the rheumatoid arthritis (RA)–associated DRB1∗0401 allele. Histopathological analysis of synovial biopsy tissue specimens showed a highly inflammatory lesion with numerous plasma cells, angiogenesis, and stromal proliferation (Figure 1). She was treated with an aggressive combination therapy, including prednisone, hydroxychloroquine, methotrexate, and sulfasalazine. During the subsequent year, she was almost in complete remission and was able to discontinue corticosteroids completely. Patient Analysis. A diagnosis of early RA can readily be made for this patient on the basis of symmetric polyarthritis, bilateral hand involvement, prolonged morning stiffness, a positive RF result, and early erosions. She met 6 of the 7 features included in the 1987 American Rheumatism Association criteria for RA.3 Although these criteria have been used widely in clinical and epidemiologic studies, their utility in the early diagnosis of RA is questionable and when applied cumulatively, the number of patients with early synovitis meeting the criteria increases over a 5-year period.4 In our own cohort, all patients presenting with RF-positive polyarthritis met these criteria. In addition, the criteria were met by 65% of patients presenting with RF-negative polyarthritis and by 50% of the patients presenting with RF-positive oligoarthritis. Thus, using this widely accepted definition of RA, the spectrum of early disease is actually quite broad. Irrespective of the diagnostic label, an important question is which patients with early synovitis will develop persistent destructive disease and thus are the best candidates for aggressive therapy. A number of parameters have been explored as potential early indicators of an unfavorable prognosis. Clinically, the early involvement of multiple joint areas, particularly large joints, such as the knees and shoulders, tends to portend a poor long-term outcome. Detection of a high serum titer of RF also is associated with more severe disease. Other novel autoantibodies recently have been characterized and found to be quite specific for RA, although their prognostic value is still uncertain. Preliminary data from our cohort suggest that patients with antibodies to an antigen called Sa appear to have more aggressive early disease, even if they are RF negative.5 Numerous epidemiologic studies have shown that RA is associated with specific alleles of the HLA-DRB1 gene, which encode for the QK/RRAA "shared epitope" (SE) sequence in the third hypervariable region of the molecule. This association may encompass other major histocompatibility genes linked in extended haplotypes. Identical twins who are homozygous for the SE alleles have a 50% concordance rate for RA, while twins that do not have the SE alleles have a concordance rate of only 10%.6 In addition to disease susceptibility, the presence of the SE allele(s) also may be a marker of disease severity, with the number and type conferring different risks. The HLA-DRB1∗0401 allele has been most closely associated with an unfavorable prognosis in white cohorts of patients with RA. Furthermore, homozygotic SE alleles is particularly predictive of unfavorable outcomes, such as in joint surgery.7 It has been proposed that the early detection of SE alleles soon after disease onset may be useful in establishing prognosis and in guiding early decisions regarding therapy. Unfortunately, this contention so far has not been well supported in clinical studies.8 Interestingly, it has been observed in 2 separate cohorts with early synovitis that the presence of the SE alleles is particularly predictive of early erosions in patients with RF-negative polyarthritis.9,10 It can thus be argued that testing for the presence of SE alleles, and possibly for RA-associated antibodies such as anti-Sa, may be of the most value in defining the prognosis of patients with early RF-negative polyarthritis. In contrast, these additional risk factors add only marginally to the known high risk associated with RF-positive disease. Further epidemiologic support will be needed to test this hypothesis. The presence of joint erosions early in the course of the disease is undoubtedly associated with poor functional outcome and disability11 and, once detected, RA erosions tend to progress. Findings of plain radiographs of the hands and feet tend to underestimate the prevalence of early RA erosions, and magnetic resonance imaging (MRI) has been shown to be a more sensitive modality for their detection.12 The pathogenesis of RA erosions continues to be an area of active research. The most widely held view suggests that a pannus of proliferative granulation tissue derived from chronically inflamed synovium directly invades and destroys the adjacent cartilage and bone, much like a locally invasive tumor. In view of this, it was hoped that the histopathological evaluation of synovial tissue biopsy specimens from patients with early synovitis could be of value in identifying patients destined to develop the most destructive, invasive lesions. The synovial biopsy specimen shown in Figure 1 demonstrates marked infiltration with lymphocytes, plasma cells, and macrophages, along with proliferation of synovial cells and exuberant neovascularization. This histopathological appearance, although highly characteristic of RA, is in fact not specific for this diagnosis, and differences between RA and other forms of synovitis appear to be, for the most part, quantitative rather than qualitative. Interestingly, we demonstrated that high levels of active metalloproteinases in the synovium are associated with the presence of early erosions, a finding indicating that differences in the chemical properties of the synovium may identify a more aggressive synovial lesion.13 Treatment of Early RA. Therapy for RA aims to relieve the patient's symptoms and to prevent progressive articular damage and its sequelae.14 Early initiation of disease-modifying antirheumatic drugs (DMARDs) offers the best opportunity to achieve these goals. The ultimate goal in the treatment of patients with RA should be to induce remission.15 Patients with RA traditionally have been treated using a cautious "step up" approach, starting with nonsteroidal anti-inflammatory drugs (NSAIDs) and then adding a single DMARD, such as methotrexate, sulfasalazine, hydroxychloroquine, or gold salts, depending on the clinical response. Unfortunately, a substantial number patients with aggressive RA sequentially did not respond to all available DMARDs and developed progressive erosive disease and disability. More recently, randomized controlled trials conducted in patients with early RA have shown that regimens combining methotrexate with other DMARDs achieved higher remission rates and less joint damage than single DMARD regimens, and did not increase toxicity.16,17 New, biologically based therapies, such as tumor necrosis factor α (TNF-α) inhibitors, used alone and in combination with methotrexate, are highly effective in reducing synovial inflammation and possibly retarding erosions.18 Despite these innovations, the consistent achievement of remission continues to be elusive in RA pharmacotherapy. Case 2 A 27-year-old white man presented with asymmetric oligoarthritis. Eight months before evaluation, he developed pain and swelling in the right ankle and forefoot, along with inflammatory lower back pain. He denied rashes, eye problems, or antecedent infections. His family history was significant for RA in a maternal grandmother and for ulcerative colitis in a sister. On physical examination, he had synovitis of the right ankle and several metatarsophalangeal joints, Achilles tendinitis, and tenderness over the right sacroiliac joint. Radiographic evaluation revealed bilateral grade I sacroilitis, inflammatory spurs at the Achilles tendons and plantar fascia, and small erosions in the metatarsophalangeal joints. Laboratory evaluation showed a CRP serum level of 1.44 mg/dL and a negative RF result. Specimen swabs of the oral, rectal, and penile areas were negative for Gonococcus and Chlamydia trachomatis. HLA typing showed HLA-B27 and 2 SE alleles, DRB1∗0101 and DRB1∗0404. Serologic evaluation demonstrated IgG and IgM antibodies to C trachomatis. A synovial biopsy specimen showed severe synovitis with angiogenesis and synovial cell hyperplasia, and polymerase chain reaction (PCR) also demonstrated C trachomatis ribosomal RNA, 16 Svedberg flotation unit. Over the next 4 years, his condition failed to respond to multiple drug regimens, including NSAIDs, oral corticosteroids, tetracyclines, methotrexate, and sulfasalazine, alone and in combination. He required a tenosynovectomy and tendon repair of the right Achilles tendon and both posterior tibialis tendons. At the time of this report, he continued to have clinically active synovitis and enthesitis. Patient Analysis. This patient presented with lower extremity oligoarthritis, enthesitis, sacroilitis, and a family history of ulcerative colitis. This is a typical presentation for reactive arthritis, a syndrome known to be associated with C trachomatis and HLA-B27; the patient had a positive result. The spondylarthropathies comprise a heterogeneous group of HLA-B27–associated disorders, including ankylosing spondylitis, reactive arthritis, undifferentiated spondylarthropathy, psoriatic arthritis, and arthritis associated with inflammatory bowel disease. The clinical features common to these disorders include asymmetric involvement of the peripheral joints, inflammation of the sacroiliac joints and spine, enthesitis, ocular inflammation, and mucocutaneous lesions. Enthesitis has been proposed as the primary pathologic lesion of the spondylarthropathies. Detailed MRI studies of patients with early synovitis have suggested that RA can potentially be differentiated from spondylarthropathies on this basis.19 Twenty percent of our cohort fulfilled the European Spondylarthropathy Study Group criteria,20 with most having what was diagnosed as reactive arthritis. This poorly defined clinical disorder is called Reiter syndrome when lower extremity oligoarthritis, urethritis, and conjunctivitis are present. However, incomplete forms, such as that seen in this patient, occur much more commonly. Irrespective of presentation, a high proportion of patients with reactive arthritis will be in remission at 1 year. Risk factors for an unfavorable outcome include hip involvement, highly elevated erythrocyte sedimentation rate, disease onset in patients younger than 16 years, poor response to NSAIDs, limitation of lumbar axis, dactylitis, and the presence of HLA-B27.21 Gastrointestinal tract infections with Salmonella, Shigella, Yersinia, or Campylobacter, and urogenital tract infections with C trachomatis are known triggers for the development of reactive arthritis. Recently, it also has been shown that some patients develop a reactive arthritis picture after a respiratory infection with Chlamydia pneumonia.22 In attempting to relate clinical presentations to antecedent infectious syndromes, we have found that symptoms suggestive of a recent infection were not unique to patients with reactive arthritis and, in fact, were quite common in our entire cohort of 201 patients with early synovitis (Table 1). Also, evaluation of antibody responses to a panel of known arthritogenic organisms did not better classify patients with early synovitis (Table 1). Although epidemiologic studies of these antibody responses in healthy populations are limited,23 a large study of female military recruits documented a surprisingly high rate of asymptomatic C trachomatis infection.24 On the other hand, it is clear that a definition of reactive arthritis that requires the specific identification of a gastrointestinal tract or urogenital tract pathogen underestimates the true prevalence of this syndrome. Bacterial cultures are typically negative in postenteric reactive arthritis. C trachomatis is identified in only 30% to 50% of patients with typical symptoms, such as urethritis. Using sensitive PCR techniques, microbial DNA and RNA from organisms, such as C trachomatis, have been detected in synovial tissue samples from a spectrum of patients with early synovitis25 and even in otherwise healthy individuals.26 The strong link between spondylarthropathies and infectious triggers in the context of HLA-B27 has spurred extensive research aiming to understand the pathogenic mechanisms underlying the interactions between the major histocompatibility complex and bacterial antigens.27 Studies in HLA-B27– transgenic mice and rats indicate that these animals develop features of human spondylarthropathies when not raised in a germ-free environment.28 A number of mechanisms have been postulated to explain the interaction between HLA-B27 and microbial pathogens in precipitating and sustaining disease, which are not necessarily mutually exclusive. The mechanisms include molecular mimicry between bacterial and endogenous antigens; synovial persistence of bacterial antigens, nucleic acids, and even whole organisms; persistence of organisms at distant sites of the body; and abnormal processing and presentation of microbial antigens.29 Regardless of the mechanism, these observations suggest a direct role for HLA-B27 in the pathogenesis of spondylarthropathies, likely involving bacterial antigen processing. Treatment of Early Spondylarthropathies. In general, patients who present with a clinical picture consistent with reactive arthritis tend to respond well to NSAID therapy and local corticosteroids. More controversial is the role of antibiotics in the early treatment of this syndrome. One study suggested that treating patients with Chlamydia-associated reactive arthritis with a 3-month course of limecycline reduced disease severity and significantly shorten disease duration.30 In patients with diarrhea-associated reactive arthritis, antibiotic therapy has generally not been shown to significantly change disease duration or outcome.31 Furthermore, any observed beneficial effects of tetracyclines may relate to their immune-modulatory or anti-inflammatory actions, rather than any antimicrobial effects. Thus, at present, the addition of prolonged courses of antibiotics to eradicate microbial organisms from the joint cannot generally be recommended for reactive arthritis. Case 3 A 26-year-old white woman presented with a 7-month history of migratory oligoarthritis. She experienced episodic joint swelling, typically lasting a few days, involving the knees, wrists, and small joints of the hands and feet. During any single episode, no more than 2 to 3 joints were swollen, tender, and stiff. NSAIDs provided symptomatic relief. She had no history of antecedent infections or skin rashes. Her family history was significant for severe, seropositive RA in a monozygotic twin sister. Radiographs of the hands and feet showed no erosions. The laboratory evaluation revealed an RF serum level of 510 IU/mL but a negative serum CRP result. On HLA typing, she had no RA-associated DRB1 alleles but was HLA-B27 positive. A synovial biopsy tissue specimen showed villous hypertrophic synovitis but was negative for any evidence of bacterial DNA. At the 1-year follow-up visit, she was clinically in remission and was not taking any medication. Patient Analysis. This patient has recurrent, self-limited synovitis associated with a strongly positive serum RF. She also has a significant family history of severe seropositive RA in a monozygotic twin, who, like her, presumably has no RA-associated DRB1 alleles but does have HLA-B27. The patient was classified as having undifferentiated arthritis and was in clinical remission after 1 year of observation. Recurrent episodes of synovitis, typically lasting a few days and then resolving completely, has been termed palindromic rheumatism. Although generally associated with a good prognosis, a proportion of patients subsequently develop RA, especially if RF is present. It is unclear whether her disease course ultimately will be similar to that of her twin sister or whether specific environmental factors will modify her clinical course. The diagnosis of between 30% and 40% of patients presenting with early synovitis remains unclassified. A subset of these patients presents with a lower extremity oligoarthritis and is thought to present a "forme fruste" of reactive arthritis; however, as discussed above, antibody titers and PCR evaluation have not been helpful in establishing common pathomechanisms.2 The prognosis of patients with undifferentiated arthritis is clearly better than that of patients with RA, and follow-up of our cohort has shown that 40% of the patients with undifferentiated arthritis were in remission and not taking drugs at 1-year follow-up. We do note that a substantial number of patients with undifferentiated arthritis in fact get treated empirically with corticosteroids and DMARDs, regimens generally reserved for patients with RA. This reflects the fact that there are insufficient data validating treatment approaches to this group of patients, and strategies developed for the treatment of patients with RA have been widely adopted to a spectrum of patients with synovitis of recent onset. Discussion As alluded to in the preceding case presentations and discussion, an incomplete understanding of the pathogenic mechanisms of synovitis has resulted in a largely empiric approach to the treatment of patients presenting with this heterogeneous clinical syndrome. There is a rapidly evolving understanding of the cellular and cytokine networks that mediate immune responses and inflammatory reactions. This has resulted in the development of biologically based therapies that precisely target specific cells, pathways, and molecules. The important role that T cells play in the pathogenesis of RA led to the development of therapies aiming to quantitatively reduce T-cell numbers by targeting the CD4 molecule. Despite the sound rationale behind the anti-CD4 strategy, the clinical results were disappointing. In contrast, therapies that inhibit the proinflammatory cytokine TNF-α effectively suppress systemic and articular inflammation and indeed may prevent the progression of articular damage. Two of these agents, etanercept and infliximab, are now approved for clinical use in patients with resistant RA. Their impact in early disease is being studied. The role of anti-TNF-α therapy in other forms of inflammatory arthritis, such as psoriatic arthritis and reactive arthritis, also is currently being explored. Despite the overall success of anti–TNF-α therapy, both controlled clinical trials and clinical experience in general indicate that approximately 30% of RA patients do not respond with a meaningful reduction in articular and/or systemic inflammation. This observation echoes the results seen with other disease-modifying antirheumatic drugs, for which the mechanism of action is less well defined. In most cases, the nonresponders "look" very much like the responders in terms of their clinical disease characteristics. Understanding the mechanisms underlying this lack of response may form the basis for a novel classification scheme for inflammatory arthropathies and potentially other inflammatory disorders, such as inflammatory bowel disease and vasculitis. Similarly, analysis of the effects of other targeted therapies currently at various stages of clinical development, including inhibitors of interleukin (IL) 1, IL-6, and IL-12, anti-inflammatory cytokines such as IL-10 and IL-4, protease inhibitors, and inhibitors of angiogenesis, should further delineate therapeutic subsets in inflammatory disorders. Ultimately, clinicians may have to develop expertise in manipulating specific biochemical pathways in a spectrum of inflammatory and autoimmune disorders. The role of microbial pathogens in the initiation and perpetuation of synovitis continues to be challenging. The hope of finding a single pathogen as an etiologic agent for a disease such as RA is now a remote possibility. As analysis techniques have become more sensitive and sophisticated, it has become increasingly evident that the synovium acts as a "sink" for a spectrum of microbial genes, proteins, and even whole organisms, particularly when it is inflamed. The relationship between these pathogens and articular inflammation has become, if anything, even less clear. It is likely that genetically determined immune responses to microbial agents are involved in promoting articular inflammation in certain individuals and not others. On the basis of the available data, testing for antibodies against arthritogenic organisms or testing of synovial fluid and tissue samples for microbial DNA, RNA, and antigens cannot be broadly recommended in the clinical setting.32 On the other hand, it is possible that the use of antibiotics to eradicate persistent pathogens may be an appropriate and effective strategy in specific populations of patients with early synovitis. To define such a population, there is the need for ongoing research to demonstrate unequivocal evidence of a persistent organism, and immune responses directed toward antigens derived from this pathogen. It is difficult to forget the lessons learned from Helicobacter pylori. In cases in which a microbial agent acts to trigger the synovitis, this process being sustained by some form of molecular mimicry, oral tolerization or vaccination strategies to arthritogenic antigens may be a more appropriate strategy. Conclusion Patients with synovitis of recent onset have widely divergent outcomes and response to therapeutic interventions. Our approach to these patients has largely been empiric and relatively lacking in insight regarding the heterogeneity of pathogenic mechanisms that underlie the clinical manifestations. There is currently an unprecedented opportunity to better understand and classify early synovitis and, in turn, refine and target the therapeutic approach. The evolving understanding of disease predisposition at a genetic level, along with the expanding ability to specifically manipulate biological pathways, will combine to dramatically change the approach to this clinical problem in the upcoming years. We hope that this will ultimately prevent the huge burden of lifelong morbidity that is associated with certain subsets of early synovitis. References 1. Hulsemann JL, Zeidler H. Undifferentiated arthritis in an early synovitis out-patient clinic. Clin Exp Rheumatol.1995;13:37-43.Google Scholar 2. Wollenhaupt J, Zeidler H. Undifferentiated arthritis and reactive arthritis. Curr Opin Rheumatol.1998;10:306-313.Google Scholar 3. Arnett FC, Edworthy SM, Bloch DA. et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum.1988;31:315-324.Google Scholar 4. Wiles N, Symmons DP, Harrison B. et al. Estimating the incidence of rheumatoid arthritis: trying to hit a moving target? Arthritis Rheum.1999;42:1339-1346.Google Scholar 5. Goldbach-Mansky R, Lee J, McCoy A. et al. Rheumatoid arthritis associated autoantibodies in patients with synovitis of recent onset. Arthritis Res.2000;2:236-243.Google Scholar 6. Jawaheer D, Thomson W, MacGregor AJ. et al. "Homozygosity" for the HLA-DR shared epitope contributes the highest risk for rheumatoid arthritis concordance in identical twins. Arthritis Rheum.1994;37:681-686.Google Scholar 7. Toussirot E, Auge B, Tiberghien P, Chabod J, Cedoz JP, Wendling D. HLA-DRB1 alleles and shared amino acid sequences in disease susceptibility and severity in patients from eastern France with rheumatoid arthritis. J Rheumatol.1999;26:1446-1451.Google Scholar 8. Mottonen T, Paimela L, Leirisalo-Repo M, Kautianen H, Ilonen J, Hannonen P. Only high disease activity and positive rheumatoid factor indicate poor prognosis in patients with early rheumatoid arthritis treated with "sawtooth" strategy. Ann Rheum Dis.1998;57:533-539.Google Scholar 9. El-Gabalawy HS, Goldbach-Mansky R, Smith D. et al. Association of HLA alleles and clinical features in patients with synovitis of recent onset. Arthritis Rheum.1999;42:1696-1705.Google Scholar 10. Harrison B, Thomson W, Symmons D. et al. The influence of HLA-DRB1 alleles and rheumatoid factor on disease outcome in an inception cohort of patients with early inflammatory arthritis. Arthritis Rheum.1999;42:2174-2183.Google Scholar 11. van der Heide A, Remme CA, Hofman DM, Jacobs JW, Bijlsma JW. Prediction of progression of radiologic damage in newly diagnosed rheumatoid arthritis. Arthritis Rheum.1995;38:1466-1474.Google Scholar 12. McQueen FM, Stewart N, Crabbe J. et al. Magnetic resonance imaging of the wrist in early rheumatoid arthritis reveals a high prevalence of erosions at four months after symptom onset. Ann Rheum Dis.1998;57:350-356.Google Scholar 13. Goldbach-Mansky R, Lee J, Hoxworth J. et al. Active synovial MMP-2 is associated with radiographic erosions in patients with early synovitis. Arthritis Res.2000;2:145-153.Google Scholar 14. Stenger AA, Van Leeuwen MA, Houtman PM. et al. Early effective suppression of inflammation in rheumatoid arthritis reduces radiographic progression. Br J Rheumatol.1998;37:1157-1163.Google Scholar 15. Emery P, Salmon M. Early rheumatoid arthritis: time to aim for remission? Ann Rheum Dis.1995;54:944-947.Google Scholar 16. Verhoeven AC, Bibo JC, Boers M, Boers M, Engel GI, van der Linden S.for the COBRA Trial Group. Cost-effectiveness and cost-utility of combination therapy in early rheumatoid arthritis: randomized comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone. Br J Rheumatol.1998;37:1102-1109.Google Scholar 17. Mottonen T, Hannonen P, Leirisalo-Repo M. et al. for the FIN-RACo trial group. Comparison of combination therapy with single-drug therapy in early rheumatoid arthritis: a randomised trial. Lancet.1999;353:1568-1573.Google Scholar 18. Fleischmann RM. Early diagnosis and treatment of rheumatoid arthritis for improved outcomes: focus on etanercept, a new biologic response modifier. Clin Ther.1999;21:1429-1442.Google Scholar 19. McGonagle D, Gibbon W, Emery P. Classification of inflammatory arthritis by enthesitis. Lancet.1998;352:1137-1140.Google Scholar 20. Dougados M, van der Linden S, Juhlin R. et al. The European Spondylarthropathy Study Group preliminary criteria for the classification of spondylarthropathy. Arthritis Rheum.1991;34:1218-1227.Google Scholar 21. Amor B, Santos RS, Nahal R, Listrat V, Dougados M. Predictive factors for the long-term outcome of spondyloarthropathies. J Rheumatol.1994;21:1883-1887.Google Scholar 22. Schumacher Jr HR. Reactive arthritis. Rheum Dis Clin North Am.1998;24:261-273.Google Scholar 23. Maki-Ikola O, Heesemann J, Toivanen A, Granfors K. High frequency of Yersinia antibodies in healthy populations in Finland and Germany. Rheumatol Int.1997;16:227-229Google Scholar 24. Gaydos CA, Howell MR, Pare B. et al. Chlamydia trachomatis infections in female military recruits. N Engl J Med.1998;339:739-744.Google Scholar 25. Wilkinson NZ, Kingsley GH, Jones HW, Sieper J, Brown J, Ward ME. The detection of DNA from a range of bacterial species in the joints of patients with a variety of arthritides using a nested, broad-range polymerase chain reaction. Rheumatology.1999;38:260-266.Google Scholar 26. Schumacher Jr HR, Arayssi T, Crane M. et al. Chlamydia trachomatis nucleic acids can be found in the synovium of some asymptomatic subjects. Arthritis Rheum.1999;42:1281-1284.Google Scholar 27. van der Linden S, van der Heijde DM. Ankylosing spondylitis and other B27 related spondylarthropathies. Baillieres Clin Rheumatol.1995;9:355-373.Google Scholar 28. Taurog JD. Arthritis in HLA-B27 transgenic animals. Am J Med Sci.1998;316:250-256.Google Scholar 29. Albert LJ, Inman RD. Molecular mimicry and autoimmunity. N Engl J Med.1999;341:2068-2074.Google Scholar 30. Lauhio A, Leirisalo-Repo M, Lahdevirta J, Saikku P, Repo H. Double-blind, placebo-controlled study of three-month treatment with lymecycline in reactive arthritis, with special reference to Chlamydia arthritis. Arthritis Rheum.1991;34:6-14.Google Scholar 31. Sieper J, Fendler C, Laitko S. et al. No benefit of long-term ciprofloxacin treatment in patients with reactive arthritis and undifferentiated oligoarthritis: a three-month, multicenter, double-blind, randomized, placebo-controlled study. Arthritis Rheum.1999;42:1386-1396.Google Scholar 32. Wollenhaupt J, Schnarr S, Kuipers JG. Bacterial antigens in reactive arthritis and spondarthritis: rational use of laboratory testing in diagnosis and follow-up. Baillieres Clin Rheumatol.1998;12:627-647.Google Scholar http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA American Medical Association

Evaluating Patients With Arthritis of Recent Onset: Studies in Pathogenesis and Prognosis

JAMA , Volume 284 (18) – Nov 8, 2000

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Abstract

Abstract Inflammatory synovitis of recent onset poses a diagnostic and prognostic challenge to primary care physicians and rheumatologists. A lack of understanding of the underlying etiologic and pathogenic processes limits the ability to distinguish forms of arthritis that follow a benign, self-limiting course from forms that proceed to an aggressive, erosive disease requiring intensive immunosuppressive therapy. It is estimated that between 30% and 40% of patients presenting with early synovitis have disease that remains unclassified. Using data from a cohort of patients with early synovitis and reviewing current literature, we discuss investigational approaches toward a new classification of patients with early synovitis. Although a lack of understanding of this heterogeneous clinical syndrome has led clinicians to take a largely empirical approach to treatment thus far, the evolving awareness of disease predisposition at a genetic level and the expanding ability to specifically manipulate biological pathways may ultimately change the approach to this clinical problem. Synovitis of peripheral joints poses a challenging problem to clinicians. It can represent a benign, self-limited process requiring only symptomatic relief or the early stages of a progressive, destructive arthropathy. Although a presumptive diagnosis can be made in many cases, studies of cohorts of patients with early synovitis indicate that a significant proportion of these patients can only be classified as having an "undifferentiated arthropathy."1,2 Moreover, even when a diagnosis is made, establishing prognosis early in the disease course can be quite difficult. A lack of understanding of the etiologic or the pathogenic basis of most forms of synovitis continues to limit the ability to better classify the desire of these patients. To develop a better understanding of the pathogenesis and prognosis of early synovitis, a cohort of patients has been evaluated and followed up at the National Institutes of Health (NIH) for the past 5 years. Individuals diagnosed as having synovitis for less than 1 year were recruited from practicing clinicians. The patients were evaluated clinically, radiographically, serologically, and genetically. A synovial biopsy of an affected joint was performed at the initial visit to define the pathologic spectrum of early synovitis and to search for evidence of infectious triggers or amplifiers of the synovial inflammation. The patients then were followed up longitudinally to determine their outcome and response to therapy. To illustrate the clinical spectrum of early synovitis, 3 cases from the NIH cohort are presented. Case presentations Case 1 A 55-year-old white woman presenting with symmetric polyarthritis was evaluated at the NIH Clinical Center. Eleven months before evaluation, she developed an additive arthritis involving the wrists, small joints of the hands and feet, and the knees. She also experienced fatigue, prolonged morning stiffness, and soon was unable to perform her usual activities of daily living. Findings of hand radiographs showed soft tissue swelling around her wrist, periarticular osteopenia, and several small erosions in the proximal interphalangeal and metacarpophalangeal joints. Laboratory evaluation revealed a C-reactive protein (CRP) serum level of 6.93 mg/dL and a positive rheumatoid factor (RF) level in a serum titer of 160 IU/mL. HLA typing showed her to have 1 copy of the rheumatoid arthritis (RA)–associated DRB1∗0401 allele. Histopathological analysis of synovial biopsy tissue specimens showed a highly inflammatory lesion with numerous plasma cells, angiogenesis, and stromal proliferation (Figure 1). She was treated with an aggressive combination therapy, including prednisone, hydroxychloroquine, methotrexate, and sulfasalazine. During the subsequent year, she was almost in complete remission and was able to discontinue corticosteroids completely. Patient Analysis. A diagnosis of early RA can readily be made for this patient on the basis of symmetric polyarthritis, bilateral hand involvement, prolonged morning stiffness, a positive RF result, and early erosions. She met 6 of the 7 features included in the 1987 American Rheumatism Association criteria for RA.3 Although these criteria have been used widely in clinical and epidemiologic studies, their utility in the early diagnosis of RA is questionable and when applied cumulatively, the number of patients with early synovitis meeting the criteria increases over a 5-year period.4 In our own cohort, all patients presenting with RF-positive polyarthritis met these criteria. In addition, the criteria were met by 65% of patients presenting with RF-negative polyarthritis and by 50% of the patients presenting with RF-positive oligoarthritis. Thus, using this widely accepted definition of RA, the spectrum of early disease is actually quite broad. Irrespective of the diagnostic label, an important question is which patients with early synovitis will develop persistent destructive disease and thus are the best candidates for aggressive therapy. A number of parameters have been explored as potential early indicators of an unfavorable prognosis. Clinically, the early involvement of multiple joint areas, particularly large joints, such as the knees and shoulders, tends to portend a poor long-term outcome. Detection of a high serum titer of RF also is associated with more severe disease. Other novel autoantibodies recently have been characterized and found to be quite specific for RA, although their prognostic value is still uncertain. Preliminary data from our cohort suggest that patients with antibodies to an antigen called Sa appear to have more aggressive early disease, even if they are RF negative.5 Numerous epidemiologic studies have shown that RA is associated with specific alleles of the HLA-DRB1 gene, which encode for the QK/RRAA "shared epitope" (SE) sequence in the third hypervariable region of the molecule. This association may encompass other major histocompatibility genes linked in extended haplotypes. Identical twins who are homozygous for the SE alleles have a 50% concordance rate for RA, while twins that do not have the SE alleles have a concordance rate of only 10%.6 In addition to disease susceptibility, the presence of the SE allele(s) also may be a marker of disease severity, with the number and type conferring different risks. The HLA-DRB1∗0401 allele has been most closely associated with an unfavorable prognosis in white cohorts of patients with RA. Furthermore, homozygotic SE alleles is particularly predictive of unfavorable outcomes, such as in joint surgery.7 It has been proposed that the early detection of SE alleles soon after disease onset may be useful in establishing prognosis and in guiding early decisions regarding therapy. Unfortunately, this contention so far has not been well supported in clinical studies.8 Interestingly, it has been observed in 2 separate cohorts with early synovitis that the presence of the SE alleles is particularly predictive of early erosions in patients with RF-negative polyarthritis.9,10 It can thus be argued that testing for the presence of SE alleles, and possibly for RA-associated antibodies such as anti-Sa, may be of the most value in defining the prognosis of patients with early RF-negative polyarthritis. In contrast, these additional risk factors add only marginally to the known high risk associated with RF-positive disease. Further epidemiologic support will be needed to test this hypothesis. The presence of joint erosions early in the course of the disease is undoubtedly associated with poor functional outcome and disability11 and, once detected, RA erosions tend to progress. Findings of plain radiographs of the hands and feet tend to underestimate the prevalence of early RA erosions, and magnetic resonance imaging (MRI) has been shown to be a more sensitive modality for their detection.12 The pathogenesis of RA erosions continues to be an area of active research. The most widely held view suggests that a pannus of proliferative granulation tissue derived from chronically inflamed synovium directly invades and destroys the adjacent cartilage and bone, much like a locally invasive tumor. In view of this, it was hoped that the histopathological evaluation of synovial tissue biopsy specimens from patients with early synovitis could be of value in identifying patients destined to develop the most destructive, invasive lesions. The synovial biopsy specimen shown in Figure 1 demonstrates marked infiltration with lymphocytes, plasma cells, and macrophages, along with proliferation of synovial cells and exuberant neovascularization. This histopathological appearance, although highly characteristic of RA, is in fact not specific for this diagnosis, and differences between RA and other forms of synovitis appear to be, for the most part, quantitative rather than qualitative. Interestingly, we demonstrated that high levels of active metalloproteinases in the synovium are associated with the presence of early erosions, a finding indicating that differences in the chemical properties of the synovium may identify a more aggressive synovial lesion.13 Treatment of Early RA. Therapy for RA aims to relieve the patient's symptoms and to prevent progressive articular damage and its sequelae.14 Early initiation of disease-modifying antirheumatic drugs (DMARDs) offers the best opportunity to achieve these goals. The ultimate goal in the treatment of patients with RA should be to induce remission.15 Patients with RA traditionally have been treated using a cautious "step up" approach, starting with nonsteroidal anti-inflammatory drugs (NSAIDs) and then adding a single DMARD, such as methotrexate, sulfasalazine, hydroxychloroquine, or gold salts, depending on the clinical response. Unfortunately, a substantial number patients with aggressive RA sequentially did not respond to all available DMARDs and developed progressive erosive disease and disability. More recently, randomized controlled trials conducted in patients with early RA have shown that regimens combining methotrexate with other DMARDs achieved higher remission rates and less joint damage than single DMARD regimens, and did not increase toxicity.16,17 New, biologically based therapies, such as tumor necrosis factor α (TNF-α) inhibitors, used alone and in combination with methotrexate, are highly effective in reducing synovial inflammation and possibly retarding erosions.18 Despite these innovations, the consistent achievement of remission continues to be elusive in RA pharmacotherapy. Case 2 A 27-year-old white man presented with asymmetric oligoarthritis. Eight months before evaluation, he developed pain and swelling in the right ankle and forefoot, along with inflammatory lower back pain. He denied rashes, eye problems, or antecedent infections. His family history was significant for RA in a maternal grandmother and for ulcerative colitis in a sister. On physical examination, he had synovitis of the right ankle and several metatarsophalangeal joints, Achilles tendinitis, and tenderness over the right sacroiliac joint. Radiographic evaluation revealed bilateral grade I sacroilitis, inflammatory spurs at the Achilles tendons and plantar fascia, and small erosions in the metatarsophalangeal joints. Laboratory evaluation showed a CRP serum level of 1.44 mg/dL and a negative RF result. Specimen swabs of the oral, rectal, and penile areas were negative for Gonococcus and Chlamydia trachomatis. HLA typing showed HLA-B27 and 2 SE alleles, DRB1∗0101 and DRB1∗0404. Serologic evaluation demonstrated IgG and IgM antibodies to C trachomatis. A synovial biopsy specimen showed severe synovitis with angiogenesis and synovial cell hyperplasia, and polymerase chain reaction (PCR) also demonstrated C trachomatis ribosomal RNA, 16 Svedberg flotation unit. Over the next 4 years, his condition failed to respond to multiple drug regimens, including NSAIDs, oral corticosteroids, tetracyclines, methotrexate, and sulfasalazine, alone and in combination. He required a tenosynovectomy and tendon repair of the right Achilles tendon and both posterior tibialis tendons. At the time of this report, he continued to have clinically active synovitis and enthesitis. Patient Analysis. This patient presented with lower extremity oligoarthritis, enthesitis, sacroilitis, and a family history of ulcerative colitis. This is a typical presentation for reactive arthritis, a syndrome known to be associated with C trachomatis and HLA-B27; the patient had a positive result. The spondylarthropathies comprise a heterogeneous group of HLA-B27–associated disorders, including ankylosing spondylitis, reactive arthritis, undifferentiated spondylarthropathy, psoriatic arthritis, and arthritis associated with inflammatory bowel disease. The clinical features common to these disorders include asymmetric involvement of the peripheral joints, inflammation of the sacroiliac joints and spine, enthesitis, ocular inflammation, and mucocutaneous lesions. Enthesitis has been proposed as the primary pathologic lesion of the spondylarthropathies. Detailed MRI studies of patients with early synovitis have suggested that RA can potentially be differentiated from spondylarthropathies on this basis.19 Twenty percent of our cohort fulfilled the European Spondylarthropathy Study Group criteria,20 with most having what was diagnosed as reactive arthritis. This poorly defined clinical disorder is called Reiter syndrome when lower extremity oligoarthritis, urethritis, and conjunctivitis are present. However, incomplete forms, such as that seen in this patient, occur much more commonly. Irrespective of presentation, a high proportion of patients with reactive arthritis will be in remission at 1 year. Risk factors for an unfavorable outcome include hip involvement, highly elevated erythrocyte sedimentation rate, disease onset in patients younger than 16 years, poor response to NSAIDs, limitation of lumbar axis, dactylitis, and the presence of HLA-B27.21 Gastrointestinal tract infections with Salmonella, Shigella, Yersinia, or Campylobacter, and urogenital tract infections with C trachomatis are known triggers for the development of reactive arthritis. Recently, it also has been shown that some patients develop a reactive arthritis picture after a respiratory infection with Chlamydia pneumonia.22 In attempting to relate clinical presentations to antecedent infectious syndromes, we have found that symptoms suggestive of a recent infection were not unique to patients with reactive arthritis and, in fact, were quite common in our entire cohort of 201 patients with early synovitis (Table 1). Also, evaluation of antibody responses to a panel of known arthritogenic organisms did not better classify patients with early synovitis (Table 1). Although epidemiologic studies of these antibody responses in healthy populations are limited,23 a large study of female military recruits documented a surprisingly high rate of asymptomatic C trachomatis infection.24 On the other hand, it is clear that a definition of reactive arthritis that requires the specific identification of a gastrointestinal tract or urogenital tract pathogen underestimates the true prevalence of this syndrome. Bacterial cultures are typically negative in postenteric reactive arthritis. C trachomatis is identified in only 30% to 50% of patients with typical symptoms, such as urethritis. Using sensitive PCR techniques, microbial DNA and RNA from organisms, such as C trachomatis, have been detected in synovial tissue samples from a spectrum of patients with early synovitis25 and even in otherwise healthy individuals.26 The strong link between spondylarthropathies and infectious triggers in the context of HLA-B27 has spurred extensive research aiming to understand the pathogenic mechanisms underlying the interactions between the major histocompatibility complex and bacterial antigens.27 Studies in HLA-B27– transgenic mice and rats indicate that these animals develop features of human spondylarthropathies when not raised in a germ-free environment.28 A number of mechanisms have been postulated to explain the interaction between HLA-B27 and microbial pathogens in precipitating and sustaining disease, which are not necessarily mutually exclusive. The mechanisms include molecular mimicry between bacterial and endogenous antigens; synovial persistence of bacterial antigens, nucleic acids, and even whole organisms; persistence of organisms at distant sites of the body; and abnormal processing and presentation of microbial antigens.29 Regardless of the mechanism, these observations suggest a direct role for HLA-B27 in the pathogenesis of spondylarthropathies, likely involving bacterial antigen processing. Treatment of Early Spondylarthropathies. In general, patients who present with a clinical picture consistent with reactive arthritis tend to respond well to NSAID therapy and local corticosteroids. More controversial is the role of antibiotics in the early treatment of this syndrome. One study suggested that treating patients with Chlamydia-associated reactive arthritis with a 3-month course of limecycline reduced disease severity and significantly shorten disease duration.30 In patients with diarrhea-associated reactive arthritis, antibiotic therapy has generally not been shown to significantly change disease duration or outcome.31 Furthermore, any observed beneficial effects of tetracyclines may relate to their immune-modulatory or anti-inflammatory actions, rather than any antimicrobial effects. Thus, at present, the addition of prolonged courses of antibiotics to eradicate microbial organisms from the joint cannot generally be recommended for reactive arthritis. Case 3 A 26-year-old white woman presented with a 7-month history of migratory oligoarthritis. She experienced episodic joint swelling, typically lasting a few days, involving the knees, wrists, and small joints of the hands and feet. During any single episode, no more than 2 to 3 joints were swollen, tender, and stiff. NSAIDs provided symptomatic relief. She had no history of antecedent infections or skin rashes. Her family history was significant for severe, seropositive RA in a monozygotic twin sister. Radiographs of the hands and feet showed no erosions. The laboratory evaluation revealed an RF serum level of 510 IU/mL but a negative serum CRP result. On HLA typing, she had no RA-associated DRB1 alleles but was HLA-B27 positive. A synovial biopsy tissue specimen showed villous hypertrophic synovitis but was negative for any evidence of bacterial DNA. At the 1-year follow-up visit, she was clinically in remission and was not taking any medication. Patient Analysis. This patient has recurrent, self-limited synovitis associated with a strongly positive serum RF. She also has a significant family history of severe seropositive RA in a monozygotic twin, who, like her, presumably has no RA-associated DRB1 alleles but does have HLA-B27. The patient was classified as having undifferentiated arthritis and was in clinical remission after 1 year of observation. Recurrent episodes of synovitis, typically lasting a few days and then resolving completely, has been termed palindromic rheumatism. Although generally associated with a good prognosis, a proportion of patients subsequently develop RA, especially if RF is present. It is unclear whether her disease course ultimately will be similar to that of her twin sister or whether specific environmental factors will modify her clinical course. The diagnosis of between 30% and 40% of patients presenting with early synovitis remains unclassified. A subset of these patients presents with a lower extremity oligoarthritis and is thought to present a "forme fruste" of reactive arthritis; however, as discussed above, antibody titers and PCR evaluation have not been helpful in establishing common pathomechanisms.2 The prognosis of patients with undifferentiated arthritis is clearly better than that of patients with RA, and follow-up of our cohort has shown that 40% of the patients with undifferentiated arthritis were in remission and not taking drugs at 1-year follow-up. We do note that a substantial number of patients with undifferentiated arthritis in fact get treated empirically with corticosteroids and DMARDs, regimens generally reserved for patients with RA. This reflects the fact that there are insufficient data validating treatment approaches to this group of patients, and strategies developed for the treatment of patients with RA have been widely adopted to a spectrum of patients with synovitis of recent onset. Discussion As alluded to in the preceding case presentations and discussion, an incomplete understanding of the pathogenic mechanisms of synovitis has resulted in a largely empiric approach to the treatment of patients presenting with this heterogeneous clinical syndrome. There is a rapidly evolving understanding of the cellular and cytokine networks that mediate immune responses and inflammatory reactions. This has resulted in the development of biologically based therapies that precisely target specific cells, pathways, and molecules. The important role that T cells play in the pathogenesis of RA led to the development of therapies aiming to quantitatively reduce T-cell numbers by targeting the CD4 molecule. Despite the sound rationale behind the anti-CD4 strategy, the clinical results were disappointing. In contrast, therapies that inhibit the proinflammatory cytokine TNF-α effectively suppress systemic and articular inflammation and indeed may prevent the progression of articular damage. Two of these agents, etanercept and infliximab, are now approved for clinical use in patients with resistant RA. Their impact in early disease is being studied. The role of anti-TNF-α therapy in other forms of inflammatory arthritis, such as psoriatic arthritis and reactive arthritis, also is currently being explored. Despite the overall success of anti–TNF-α therapy, both controlled clinical trials and clinical experience in general indicate that approximately 30% of RA patients do not respond with a meaningful reduction in articular and/or systemic inflammation. This observation echoes the results seen with other disease-modifying antirheumatic drugs, for which the mechanism of action is less well defined. In most cases, the nonresponders "look" very much like the responders in terms of their clinical disease characteristics. Understanding the mechanisms underlying this lack of response may form the basis for a novel classification scheme for inflammatory arthropathies and potentially other inflammatory disorders, such as inflammatory bowel disease and vasculitis. Similarly, analysis of the effects of other targeted therapies currently at various stages of clinical development, including inhibitors of interleukin (IL) 1, IL-6, and IL-12, anti-inflammatory cytokines such as IL-10 and IL-4, protease inhibitors, and inhibitors of angiogenesis, should further delineate therapeutic subsets in inflammatory disorders. Ultimately, clinicians may have to develop expertise in manipulating specific biochemical pathways in a spectrum of inflammatory and autoimmune disorders. The role of microbial pathogens in the initiation and perpetuation of synovitis continues to be challenging. The hope of finding a single pathogen as an etiologic agent for a disease such as RA is now a remote possibility. As analysis techniques have become more sensitive and sophisticated, it has become increasingly evident that the synovium acts as a "sink" for a spectrum of microbial genes, proteins, and even whole organisms, particularly when it is inflamed. The relationship between these pathogens and articular inflammation has become, if anything, even less clear. It is likely that genetically determined immune responses to microbial agents are involved in promoting articular inflammation in certain individuals and not others. On the basis of the available data, testing for antibodies against arthritogenic organisms or testing of synovial fluid and tissue samples for microbial DNA, RNA, and antigens cannot be broadly recommended in the clinical setting.32 On the other hand, it is possible that the use of antibiotics to eradicate persistent pathogens may be an appropriate and effective strategy in specific populations of patients with early synovitis. To define such a population, there is the need for ongoing research to demonstrate unequivocal evidence of a persistent organism, and immune responses directed toward antigens derived from this pathogen. It is difficult to forget the lessons learned from Helicobacter pylori. In cases in which a microbial agent acts to trigger the synovitis, this process being sustained by some form of molecular mimicry, oral tolerization or vaccination strategies to arthritogenic antigens may be a more appropriate strategy. Conclusion Patients with synovitis of recent onset have widely divergent outcomes and response to therapeutic interventions. Our approach to these patients has largely been empiric and relatively lacking in insight regarding the heterogeneity of pathogenic mechanisms that underlie the clinical manifestations. There is currently an unprecedented opportunity to better understand and classify early synovitis and, in turn, refine and target the therapeutic approach. The evolving understanding of disease predisposition at a genetic level, along with the expanding ability to specifically manipulate biological pathways, will combine to dramatically change the approach to this clinical problem in the upcoming years. We hope that this will ultimately prevent the huge burden of lifelong morbidity that is associated with certain subsets of early synovitis. References 1. Hulsemann JL, Zeidler H. Undifferentiated arthritis in an early synovitis out-patient clinic. 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Journal

JAMAAmerican Medical Association

Published: Nov 8, 2000

Keywords: arthritis,synovitis,therapeutic immunosuppression,heterogeneity

References