SYMPOSIUM ON ARTHRITIS

Damage control in rheumatoid arthritis

Hard-hitting, early treatment is crucial to curbing joint destruction

Sakeba N. Issa, MD; Eric M. Ruderman, MD

VOL 116 / NO 5 / NOVEMBER 2004 / POSTGRADUATE MEDICINE

CME learning objectives

• To become familiar with the clinical and laboratory findings pertinent to diagnosis of rheumatoid arthritis
• To review the goals of therapy for rheumatoid arthritis and the clinical parameters that drive treatment decisions
• To recognize the range of therapies available for rheumatoid arthritis

Dr Ruderman has received research support from Amgen Inc, Abbott Laboratories, and Centocor, Inc, and has served as a consultant or received honoraria from Amgen, Abbott, and Wyeth. The authors disclose no unlabeled uses of any product mentioned in this article.

Preview: Right from the onset, rheumatoid arthritis is an aggressive disease that can quickly alter joint structure and integrity. Such rapid pathogenesis requires that the diagnosis be established early and aggressive therapy initiated swiftly. In this article, Drs Issa and Ruderman describe what is known about the cause, progression, and outcomes of rheumatoid arthritis. They review the steps toward its diagnosis and urge that treatment be started promptly--to both contain disease and reduce joint destruction as soon as possible.
Issa SN, Ruderman EM. Damage control in rheumatoid arthritis: hard-hitting, early treatment is crucial to curbing joint destruction. Postgrad Med 2004;116(5):14-24

Rheumatoid arthritis, a chronic autoimmune disease characterized by symmetrical and erosive joint disease, has a prevalence of about 1% worldwide (1). It is best defined by the clinical descriptors found in the 1987 criteria of the American Rheumatism Association (2) (table 1). Although these classification criteria may be helpful, they are not always definitive, and they are not intended for use in diagnosis of the disease in an individual patient. Moreover, the diagnosis of rheumatoid arthritis may become obvious only with time, because other causes of synovitis, such as systemic lupus erythematosus or seronegative spondyloarthropathies, may be initially indistinguishable from this disease.

Table 1. 1987 American Rheumatism Association classification criteria for rheumatoid arthritis*

Morning stiffness that lasts >1 hr** Swelling in three or more joints** Swelling in hand joints** Symmetrical joint swelling** Erosions or decalcification seen on hand radiographs Rheumatoid nodules Presence of serum rheumatoid factor *Definite rheumatoid arthritis is defined by presence of four of the seven criteria. **Must be present for >6 wk. Information from Arnett et al (2).

Disease progression

Although the etiology and pathogenesis of rheumatoid arthritis remain incompletely elucidated, recent data suggest that this disease is driven, in part, by interaction between T cells and macrophages within the joint, as well as by the proinflammatory cytokines that these cells produce (3). Inflammatory cells stimulate the synovial lining to become both hyperplastic and hypertrophic. As it grows, the synovium forms aggressive inflammatory tissue, or pannus, which begins to erode into the bone and cartilage within the joint capsule. Enzymes that promote degradation, such as collagenase, serve to break down the framework structure of cartilage, bone, and other connective tissues.

The peak age at onset of rheumatoid arthritis is in the fourth and fifth decades, although it may begin at any time, including childhood. The disease affects at least twice as many women as men (4); its greater incidence among females suggests an influence of hormonal and reproductive factors.

The clinical course of rheumatoid arthritis follows an onset that may be acute, gradual, or subacute. A gradual onset is most common and occurs in at least 50% of new cases (5-7). The natural history of the disease may vary greatly and ranges from self-limited disease to progressive arthritis with severe outcomes.

Rheumatoid arthritis begins predominately as an articular disease but may also present with periarticular manifestations, such as bursitis, tenosynovitis, and carpal tunnel syndrome. Rarely, extra-articular manifestations, such as serositis or interstitial lung disease, may be its first sign. Rheumatoid arthritis is a peripheral polyarthritis. Joint symptoms may wax and wane; however, joint involvement tends to be additive rather than migratory.

Clinical features

The most characteristic clinical feature of early rheumatoid arthritis is arthritis involving the metacarpophalangeal joints and proximal interphalangeal joints of both hands (5,6). Foot involvement, especially of the metatarsophalangeal joints, is also common in early rheumatoid arthritis and has a pattern similar to that occurring in the hand.

A joint is considered "active" if it is tender to palpation, swollen, or painful on passive range of motion. Stiffness occurring in the mornings or after prolonged periods of inactivity is a common manifestation of almost all inflammatory arthropathies. However, morning stiffness that lasts more than an hour is an indicator of significant joint inflammation and rarely occurs in diseases other than rheumatoid arthritis (8).

Rheumatoid nodules develop in about 50% of patients with the disease, are highly specific for rheumatoid arthritis, and in general are associated with active disease (9). These nodules are typically subcutaneous and may differ in size from a few millimeters to several centimeters. They are found most commonly over the extensor surface of the proximal forearm but may also occur at any location under pressure, such as the Achilles tendon and tendons of the hand and the back of the head.

Laboratory evaluation

Laboratory abnormalities that occur in rheumatoid arthritis include the presence of rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibody. The RF test measures IgM autoantibodies that are directed against the Fc portion of IgG. Patients who test positive for RF are described as being seropositive. Although about 85% of patients become seropositive at some point, this test alone is neither sufficient nor necessary to make the diagnosis (9).

A patient who has a negative RF test early in the course of disease may ultimately have a positive one, and thus retesting at 6 months may be appropriate. However, once a positive result is identified, serial measurements of RF titer are not helpful in monitoring the course of disease. A positive RF test may also be seen in association with other diseases, such as chronic infections and malignancies (9).

Anti-CCP antibodies may be found in some patients with rheumatoid arthritis and, rarely, in other diseases (9,10). The sensitivity of the anti-CCP antibody test is comparable to that of the IgM RF test, but the specificity is 90% to 96%, making it the most specific evaluation for rheumatoid arthritis (10,11).

Measurement of anti-CCP antibody is not the definitive test for rheumatoid arthritis. However, it does appear to be a useful tool in diagnosis or exclusion of this disease in patients with polyarthritis, and it is becoming more commonly used in clinical practice. Presence of anti-CCP antibody and RF is associated with greater disease severity, suggesting their usefulness as markers of prognosis (12).

Other laboratory abnormalities in rheumatoid arthritis include elevations in test results that are indicative of acute phase reactants, such as increases in the erythrocyte sedimentation rate and C-reactive protein level. These indicators are less specific than RF or anti-CCP antibody, but they may be helpful in distinguishing rheumatoid arthritis from noninflammatory diseases such as osteoarthritis when physical signs are not prominent. Erythrocyte sedimentation rate and C-reactive protein level are also used to monitor therapy; unlike the RF value, these measurements do fluctuate with disease activity.

Anemia of chronic disease is commonly found in rheumatoid arthritis; leukocytosis, thrombocytosis, and hypoalbuminemia are often seen in active disease. Antinuclear antibodies may be detected in about 40% of patients with rheumatoid arthritis (13). Analysis of fluid aspirated from involved joints, although not necessary for diagnosis, demonstrates the leukocytosis typical of inflammatory arthritis.

Radiographic studies

Early in the disease, it is appropriate to obtain plain radiographs of the hands and wrists, and a view of both feet, to evaluate for joint-space narrowing, bone erosions, and periarticular osteopenia, which is the first radiographic sign of rheumatoid arthritis. These radiographs identify damage that has already occurred and serve as a baseline for monitoring disease progression. Within the first year of rheumatoid arthritis, erosions can be identified on plain radiographs in 15% to 30% of patients (14,15). Ultimately, up to 90% of patients have radiographically evident bone erosions and joint-space narrowing, usually within 2 or 3 years after diagnosis (14,15).

Although magnetic resonance imaging is a more sensitive technique than plain radiography for identification of erosions in cartilage and bone, its role in management of rheumatoid arthritis is unclear (16). There has been recent interest in using ultrasound imaging for detection of inflammation in joints that are otherwise normal on physical examination (17).

DMARD therapy

The first steps in rheumatoid arthritis management are to establish the diagnosis and to perform a baseline evaluation (table 2). The diagnosis should prompt early initiation of aggressive treatment, since rheumatoid arthritis is itself aggressive from the start. The American College of Rheumatology published its updated management guidelines in 2002 (figure 1), recommending that disease-modifying antirheumatic drugs (DMARDs) should be started within 3 months of diagnosis of rheumatoid arthritis (18).

Table 2. Assessment of disease activity in rheumatoid arthritis*

Degree of joint pain Duration of morning stiffness Presence of synovitis Presence of fatigue Limitation of function Evidence or progression of loss of motion, instability, malalignment, and/or deformity Progression of radiographically evident joint damage Elevation in erythrocyte sedimentation rate or C-reactive protein level *For evaluation of subjective and objective evidence of active disease and periodic assessment of disease progression.

Effective DMARD use alters the course of disease by slowing the progression of joint destruction; these medications are therefore most beneficial when started before extensive damage has occurred (18). Examples of commonly used DMARDs are methotrexate (Rheumatrex Dose Pack, Trexall), leflunomide (Arava), hydroxychloroquine sulfate (Plaquenil), sulfasalazine (Azulfidine), and azathioprine (Imuran). (At present, oral or parenteral gold, D-penicillamine [Cuprimine, Depen], and minocycline hydrochloride [Dynacin, Minocin] are used infrequently.) Most physicians also prescribe nonsteroidal anti-inflammatory drugs as adjunctive therapy. Low-dose corticosteroids provide rapid relief of pain and stiffness and may be used as bridge therapy at the initiation of a slower-acting DMARD.

The selection of a DMARD depends on many factors. The physician and the individual patient should take into account the drug's relative efficacy, convenience of administration, medication-monitoring regimen, potential side effects, and cost, along with the expense of monitoring and the risk of toxicity.

The patient's ability to adhere to the therapeutic regimen and to comply with appropriate monitoring requirements, as well as the presence of comorbid disease, should be considered when choosing a DMARD. Women of childbearing age must use an effective contraceptive method when taking a DMARD, particularly leflunomide or methotrexate, which are known teratogens.

Typically, methotrexate is the initial DMARD of choice for treatment of active rheumatoid arthritis. The starting dose is usually 7.5 or 10 mg administered orally or subcutaneously once a week. The dose may be escalated each month by 5 to 7.5 mg per week until the usual effective maintenance dose of 15 to 25 mg per week is reached. Because the therapeutic effect of methotrexate taken in this manner may be delayed for up to 4 months, corticosteroids--such as prednisone and prednisolone--are used to reduce acute symptoms of a flare or as a bridge to long-term DMARD therapy.

However, because long-term use of corticosteroids is associated with such toxic effects as osteoporosis, cataracts, hypertension, diabetes, and immunosuppression, their use should be reduced to a minimal maintenance dose or discontinued when possible, usually after 4 to 6 months. Despite appropriate DMARD therapy, some patients continue to require a low dose of a corticosteroid. In these patients, bone density monitoring and supplementation with calcium and vitamin D may be necessary.

Patients should be periodically reevaluated for evidence of disease activity or progression (see table 2) and evidence of toxic effects due to the therapeutic regimen. Response to therapy in rheumatoid arthritis is typically measured by clinical or radiographic changes, or both. Clinical response parameters attempt to account for disease activity and include the number of actively involved joints, the patient's functional ability to perform self-care and other activities (table 3), and the level of perceived pain.

Table 3. Clinical assessment of functional capacity and activities of daily living in patients with rheumatoid arthritis

Functional capacity Normal function despite or without symptoms Some disability, but able to perform normal activities without special devices or assistance Activities restricted; special devices or personal assistance required Totally dependent Activities of daily living Mobility: Able to walk, climb, use transport, and make bed-to-chair transfers Personal care: Able to eat, dress, wash, groom, and use toilet Special hand functions: Able to use door handles, open sealed jars, carry items, and use keys, coins, pen, and scissors Work and play activities: Able to work outside the home, do light and heavy work in the home, and participate in hobbies and sports

Poor clinical response--defined as ongoing disease activity after 3 months of maximally tolerated therapy--or radiographically evident progression of bone erosions or joint-space narrowing, or both, indicates that therapy is suboptimal. An incomplete therapeutic effect should prompt an escalation in dose of the current medication, if possible, or introduction of a second DMARD or a biologic response modifier (see figure 1).

Biologic response modifiers

When disease is more severe, when standard DMARD therapy is contraindicated, or when single-agent or combination DMARD treatment is inadequate, introduction of biologic response modifiers that inhibit tumor necrosis factor alpha (TNF-alpha) or interleukin-1 (IL-1) should be considered. The currently available biologic response modifiers etanercept (Enbrel), infliximab (Remicade), and adalimumab (Humira) target TNF-alpha, one of the key proinflammatory cytokines involved in the inflammatory process of rheumatoid arthritis. Inhibition of TNF-alpha reduces clinical signs and symptoms of the disease and radiographically evident joint damage (19-24). Anakinra (Kineret), an inhibitor of IL-1, another important proinflammatory cytokine in rheumatoid arthritis, has also been shown to be effective in this disease (25).

Anti-TNF-alpha agents, in particular, have markedly improved the ability to control disease activity in patients whose rheumatoid arthritis has been refractory to other therapies. The dramatic clinical responses seen with these agents have spurred their use earlier in the course of disease. However, it remains to be seen whether long-term clinical and structural outcomes are sufficiently better with these agents than with methotrexate to justify their significantly higher costs. Recent data have suggested that the highest rate of response may be obtained by early combination of methotrexate and an anti-TNF-alpha agent (26). Again, long-term follow-up of this approach will be necessary to determine whether it should become the standard of care.

Additional therapies

Finally, given the chronic waxing and waning course of rheumatoid arthritis, it is critical to involve the patient in development of a longitudinal treatment plan. The presence of active inflammatory joint disease and structural damage may impair physical function. Patients may therefore benefit from physical or occupational therapy. Exercises to increase muscle strength and range of motion help preserve joint motion. Even when performed as infrequently as once or twice a week, these exercises may improve function and do not worsen disease activity (27). Psychosocial factors also need to be addressed, because perceived self-efficacy and beliefs about illness have been shown to affect patient outcome and adherence to treatment (28).

Conclusion

The crux of effective rheumatoid arthritis management is early diagnosis and early initiation of DMARD therapy. Because no definitive diagnostic test for rheumatoid arthritis is available, proper diagnosis is based on a combination of clinical, laboratory, and radiographic findings. Early diagnosis is crucial so that an appropriately aggressive treatment regimen may be instituted early and irreversible damage may be limited. The ultimate objectives of treatment are to halt disease progression and maintain the patient's function.

References

1. Hochberg MC. Adult and juvenile rheumatoid arthritis: current epidemiologic concepts. Epidemiol Rev 1981;3:27-44
2. 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(3):315-24
3. Arend WP, Dayer JM. Cytokines and cytokine inhibitors or antagonists in rheumatoid arthritis. Arthritis Rheum 1990;33(3):305-15
4. Goronzy J, Weyand C. Rheumatoid arthritis: epidemiology, pathology, and pathogenesis. In: Klippel JH, Crofford LJ, Stone J, et al, eds. Primer on the rheumatic diseases. 12th ed. Atlanta: Arthritis Foundation, 2001:209-17
5. Fleming A, Crown JM, Corbett M. Early rheumatoid disease. I. Onset. Ann Rheum Dis 1976;35(4):357-60
6. Fleming A, Benn RT, Corbett M, et al. Early rheumatoid disease. II. Patterns of joint involvement. Ann Rheum Dis 1976;35(4):361-4
7. Jacoby RK, Jayson MI, Cosh JA. Onset, early stages, and prognosis of rheumatoid arthritis: a clinical study of 100 patients with 11-year follow-up. Br Med J 1973;2(5858):96-100
8. Edworthy SM. Morning stiffness: Sharpening an old saw? J Rheumatol 1999;26(5):1015-7
9. Anderson R. Rheumatoid arthritis: clinical and laboratory features. In: Klippel et al, eds (4), pp 218-24
10. Lee DM, Schur PH. Clinical utility of the anti-CCP assay in patients with rheumatic diseases. Ann Rheum Dis 2003;62(9):870-4
11. Schellekens GA, de Jong BA, van den Hoogen FH, et al. Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies. J Clin Invest 1998;101(1):273-81
12. Bas S, Genevay S, Meyer O, et al. Anti-cyclic citrullinated peptide antibodies, IgM and IgA rheumatoid factors in the diagnosis and prognosis of rheumatoid arthritis. Rheumatology (Oxford) 2003;42(5):677-80
13. Solomon DH, Kavanaugh AJ, Schur PH; American College of Rheumatology Ad Hoc Committee on Immunologic Testing Guidelines. Evidence-based guidelines for the use of immunologic tests: antinuclear antibody testing. Arthritis Rheum 2002;47(4):434-44
14. van der Heijde DM, van Leeuwen MA, van Riel PL, et al. Biannual radiographic assessments of hands and feet in a three-year prospective followup of patients with early rheumatoid arthritis. Arthritis Rheum 1992;35(1):26-34
15. Fuchs HA, Kaye JJ, Callahan LF, et al. Evidence of significant radiographic damage in rheumatoid arthritis within the first 2 years of disease. J Rheumatol 1989;16(5):585-91
16. Klarlund M, Ostergaard M, Jensen KE, et al. Magnetic resonance imaging, radiography, and scintigraphy of the finger joints: one year follow up of patients with early arthritis. The TIRA Group. Ann Rheum Dis 2000;59(7):521-8
17. Terslev L, Torp-Pedersen S, Savnik A, et al. Doppler ultrasound and magnetic resonance imaging of synovial inflammation of the hand in rheumatoid arthritis: a comparative study. Arthritis Rheum 2003;48(9):2434-41
18. American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Guidelines for the management of rheumatoid arthritis: 2002 update. Arthritis Rheum 2002;46(2):328-46
19. Furst DE, Keystone EC, Breedveld FC, et al. Updated consensus statement on tumour necrosis factor blocking agents for the treatment of rheumatoid arthritis and other rheumatic diseases (April 2001). Ann Rheum Dis 2001;60(Suppl 3):iii2-5
20. Lipsky PE, van der Heijde DM, St Clair EW, et al; Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. Infliximab and methotrexate in the treatment of rheumatoid arthritis. N Engl J Med 2000;343(22):1594-602
21. Moreland LW, Schiff MH, Baumgartner SW, et al. Etanercept therapy in rheumatoid arthritis: a randomized, controlled trial. Ann Intern Med 1999;130(6):478-86
22. Bathon JM, Martin RW, Fleischmann RM, et al. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med 2000;343(22):1586-93 [Errata, N Engl J Med 2001;344(3):240 and N Engl J Med 2001;344(1):76]
23. Genovese MC, Bathon JM, Martin RW, et al. Etanercept versus methotrexate in patients with early rheumatoid arthritis: two-year radiographic and clinical outcomes. Arthritis Rheum 2002;46(6):1443-50
24. Rau R. Adalimumab (a fully human anti-tumour necrosis factor alpha monoclonal antibody) in the treatment of active rheumatoid arthritis: the initial results of five trials. Ann Rheum Dis 2002;61(Suppl 2):ii70-3
25. Cohen S, Hurd E, Cush J, et al. Treatment of rheumatoid arthritis with anakinra, a recombinant human interleukin-1 receptor antagonist, in combination with methotrexate: results of a twenty-four-week, multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2002;46(3):614-24
26. Klareskog L, van der Heijde D, de Jager JP, et al; TEMPO (Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes) study investigators. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial. Lancet 2004;363(9410):675-81
27. Hakkinen A, Sokka T, Kotaniemi A, et al. A randomized two-year study of the effects of dynamic strength training on muscle strength, disease activity, functional capacity, and bone mineral density in early rheumatoid arthritis. Arthritis Rheum 2001;44(3):515-22
28. Schiaffino KM, Revenson TA, Gibofsky A. Assessing the impact of self-efficacy beliefs on adaptation to rheumatoid arthritis. Arthritis Care Res 1991;4(4):150-7

Dr Issa is a clinical fellow and Dr Ruderman is assistant professor of medicine, division of rheumatology, Northwestern University Feinberg School of Medicine, Chicago. Correspondence: Eric M. Ruderman, MD, 675 N St Clair St, 14-100, Chicago, IL 60611. E-mail: e-ruderman@northwestern.edu.

Symposium Index

• DAMAGE CONTROL IN RHEUMATOID ARTHRITIS: Hard-hitting, early treatment is crucial to curbing joint destruction. By Sakeba N. Issa, MD, Eric M. Ruderman, MD
• TREATMENT UPDATE ON SPONDYLOARTHROPATHY: From NSAIDs and DMARDs to anti-TNF-alpha agents. By Allen P. Anandarajah, MD, Christopher T. Ritchlin, MD
• Clinical Commentary. RAISING EXPECTATIONS FOR ARTHRITIS TREATMENT: Biologic response modifiers are making remission possible. By Marc D. Cohen, MD

Please send technical questions related to the Web site to Ann Harste