Arthritis & Rheumatism

Guidelines for the Management of Rheumatoid Arthritis

American College of Rheumatology Ad Hoc Committee on Clinical Guidelines

Rheumatoid arthritis (RA) is an autoimmune disorder of unknown etiology characterized by symmetric, erosive synovitis and sometimes multisystem involvement (1). Most patients exhibit a chronic fluctuating course of disease that, if left untreated, results in progressive joint destruction, deformity, disability, and premature death (2). RA results in more than 9 million physician visits and more than 250,000 hospitalizations per year (3). It frequently affects patients in their most productive years, and thus, disability results in major economic loss. It has been estimated that working individuals with arthritis have a yearly earnings deficit of $17.6 billion (1986 dollars) compared with earnings of individuals without arthritis, and $6.5 billion of this shortfall is attributable to RA (3).

RA affects 1% of the adult population (2). This low prevalence means that the average physician often develops little experience with its diagnosis or management. The following guidelines for the management of RA assume a correct diagnosis, which may be difficult in the earlier stages (4). If there is any uncertainty about the diagnosis, consultation with a rheumatologist should be considered.

A detailed algorithm for management would be an unjustified simplification of the many decisions that must be made over the course of a patient's illness. Instead, these guidelines outline the treatment options, the critical decisions, and the essential skills and knowledge necessary for optimal care. This set of guidelines was developed by a group of rheumatologists, primary care physicians who practice rheumatology, and other arthritis health professionals based on consensus, and on literature review where published data were available. Separate guidelines address the monitoring of medications used in RA (5). Although much is known, the lack of data necessitates that these guidelines must also be based in part on community standards of care.

Goals of treating rheumatoid arthritis

There is no known cure for RA or means of preventing it. Optimal management requires early diagnosis and timely introduction of agents that reduce the probability of irreversible joint damage. Figure 1 outlines an approach to the evaluation and treatment of the patient after the diagnosis has been established. Periodic assessment of disease activity, drug toxicity, and the effectiveness of the treatment program is essential, with revisions of the treatment program as necessary.

Figure 1. Management of rheumatoid arthritis. See the text for a discussion of monitoring of disease activity and adequacy of the treatment program, and for descriptions of persistent active disease and disease remission. NSAID = nonsteroidal antiinflammatory drug; DMARD = disease-modifying antirheumatic drug.

Studies show that patients with active, polyarticular, rheumatoid factor (RF)-positive RA have a >70% probability of developing joint damage or erosions within 2 years of the onset of disease (6-10). Other studies suggest that early aggressive treatment may alter the disease course (11,12), and most rheumatologists who care for patients with RA favor aggressive treatment early in the course of the disease.

While the ultimate goal of treating RA is to induce a complete remission, this occurs only in rare cases. Complete remission is defined as the absence of 1) symptoms of active inflammatory joint pain (in contrast to mechanical joint pain), 2) morning stiffness, 3) fatigue, 4) synovitis on joint examination, 5) progression of radiographic damage on sequential radiographs, and 6) elevated erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) level (13). If complete remission is not achieved, the management goals are to control disease activity, alleviate pain, maintain function for essential activities of daily living and work, maximize quality of life, and slow the rate of joint damage.

Table 1. Baseline evaluation of patients with rheumatoid arthritis

Initial evaluation and treatment of rheumatoid arthritis

The initial evaluation of the patient with RA should document symptoms of active disease (joint pain, morning stiffness, fatigue), functional status, objective evidence of disease activity (synovitis, ESR or CRP level), mechanical joint problems, the presence of extraarticular disease and comorbid conditions, and the presence of radiographic damage in selected involved joints (Table 1). Later comparison with this baseline information facilitates assessment of disease progression and response to treatment.

Careful history-taking, a complete review of systems, and a thorough physical examination (both general and musculoskeletal) are necessary. The severity and duration of morning stiffness and constitutional symptoms such as fatigue should be recorded. Patient's and physician's global assessment, tender and swollen joint counts, a quantitative assessment of pain by a visual analog scale or other mechanism, and functional evaluation are useful parameters to follow during the course of the disease (14,15).

Baseline laboratory evaluations should include complete blood cell count (CBC), platelet count, chemistry profile, RF measurement, and measurement of ESR or CRP. Evaluation of renal and hepatic function is necessary since many antirheumatic agents have renal or hepatic toxicity and may be contraindicated if these organs are impaired. Initial radiographs of the hands and/or feet should be obtained since structural damage cannot be deduced by physical examination alone. Arresting and preventing structural damage is a primary goal of therapy, and repeat radiographic studies of sentinel or major involved joints may be needed periodically.

Managed or coordinated multidisciplinary care is efficacious in maintaining the function and productivity of patients with RA (16-24). Depending on the patient's problems, expertise from nursing, physical and occupational therapy (25-29), social work, health education, clinical psychology, vocational rehabilitation (30), podiatry, and/or orthopedic surgery perspectives may be needed. For example, patients with active RA who have compromised joint range of motion or function secondary to the disease benefit from instruction by rehabilitation specialists on how to protect their joints, maintain range of motion of their joints, conserve energy, and strengthen their muscles.

A longitudinal treatment plan needs to be developed with the patient. The discussion should address disease prognosis and treatment options, taking into account the costs, adverse effects, expected time for response, and monitoring requirements of pharmacologic agents, in addition to the patient's preferences. Expectations for treatment and potential barriers to carrying out the recommendations should be discussed. Patient education is critical to engaging the patient in an effective partnership for managing the disease. Useful patient education materials are available from the Arthritis Foundation.

The aggressiveness and timing of the treatment program require an assessment of prognosis. Poor prognosis is suggested by earlier age at onset, high titer of RF, elevated ESR, and swelling of >20 joints (31). Extraarticular manifestations of RA, including rheumatoid nodules, Sjogren's syndrome, episcleritis and scleritis, interstitial lung disease, pericardial disease, systemic vasculitis, and Felty's syndrome, indicate a worse prognosis. These manifestations may vary in severity and significance. Consultation with a rheumatologist is advised for their treatment.

The history, joint examination, and functional assessment are the primary tools used to assess prognosis during the first 2 years of disease.

Drug treatment of rheumatoid arthritis

Nonsteroidal antiinflammatory drugs (NSAIDs). The initial drug treatment of RA usually involves the use of NSAIDs to reduce joint pain and swelling and improve function (Table 2). NSAIDs have analgesic and antiinflammatory properties but do not alter the course of the disease or prevent joint destruction.

Table 2. Use of nonsteroidal antiinflammatory drugs for rheumatoid arthritis

There are no significant differences in efficacy among the NSAIDs, although there are some differences in the incidence of side effects. Salicylates are inexpensive, and blood levels may be measured to confirm that there has been an adequate antiinflammatory dose and to assess compliance. The choice of NSAID is based principally on cost, duration of action, and patient preference (32). Analgesic effects of salicylates and NSAIDs are prompt in onset, but reduction of signs of inflammation may take up to 1-2 weeks.

To reduce gastrointestinal (GI) toxicity, patients should take NSAIDs with food, rather than on an empty stomach. Patients with NSAID-induced GI intolerance or toxicity may require the concomitant use of GI-protective agents (e.g., the prostaglandin analog misoprostol) (33,34). Use of GI-protective agents when NSAID treatment is started should be considered for elderly patients and patients with prior peptic ulcer disease, GI bleeding, or cardiovascular disease (33). Patients should be informed about the potential symptoms of gastric irritation or bleeding, with instructions to stop the medication and contact the physician in the event of serious problems. Older patients, patients with comorbid diseases (e.g., hypertension, diabetes, congestive heart failure, renal impairment, cirrhosis, or other states of renal hypoperfusion), and patients taking concurrent medications that reduce renal blood flow (such as diuretics) must be monitored carefully for renal insufficiency when given NSAIDs. NSAIDs are associated with lower rates of GI bleeding and cause fewer GI side effects than antiinflammatory doses of non-enteric-coated aspirin (35).

The frequency of some side effects may vary among different NSAIDs. Combinations of 2 or more NSAIDs should be avoided since they are no more effective and may have additive adverse effects (32).

Disease-modifying antirheumatic drugs (DMARDs). All patients whose RA remains active despite adequate treatment with NSAIDs are candidates for DMARD therapy (Table 3). Active RA may lead to irreversible joint damage even in the early months of the disease (9); while NSAIDs and glucocorticoids may alleviate symptoms, joint damage may occur and progress. DMARDs have the potential to reduce or prevent joint damage, preserve joint integrity and function, and, ultimately, to reduce the total costs of health care and maintain economic productivity of the patient with RA. These drugs include hydroxychloroquine (HCQ), sulfasalazine (SSZ), methotrexate (MTX), gold salts, D-penicillamine (DP), and azathioprine (AZA).

Table 3. Use of disease-modifying antirheumatic drugs for rheumatoid arthritis

Timing is critical. The initiation of DMARD therapy should not be delayed beyond 3 months for any patient with an established diagnosis who, in spite of adequate treatment with NSAIDs, has ongoing joint pain, significant morning stiffness or fatigue, active synovitis, or persistent elevation of the ESR or CRP level. Rheumatology consultation should be considered for confirmation of the diagnosis of RA and for the decision regarding the initiation and selection of a DMARD. The goal of treatment is to intervene in the disease before joints are damaged. Any untreated patient with persistent synovitis and joint damage already documented by joint examination or radiography should have DMARD treatment started promptly to prevent or slow further damage.

DMARDs have common characteristics. All are relatively slow acting, with a delay of 1-6 months before a clinical response is evident. Efficacy cannot be predicted for the individual patient, but up to two-thirds of patients may have a response to these agents. Each DMARD has specific toxicity that requires careful monitoring. Detailed descriptions of drug toxicity and recommendations for monitoring are specified in the American College of Rheumatology (ACR) Guidelines for Monitoring Drug Therapy in Rheumatoid Arthritis (5). The decision to start a DMARD must be preceded by a discussion with the patient about the expectations of risks versus benefits of the treatment.

Many factors influence the choice of a DMARD for an individual patient (Table 4). From the patient's perspective, the convenience of administration of the drug, the requirements of the monitoring program, the costs of the medication and its monitoring, the time until expected benefit, and the frequency and potential seriousness of adverse reactions are important considerations. The physician should also assess patient factors such as compliance and comorbid diseases, the severity and prognosis of the patient's disease, and the physician's own confidence in administering and monitoring the drug.

Table 4. Disease-modifying antirheumatic drugs used in treatment of rheumatoid arthritis*

* GI = gastrointestinal; IM = intramuscular; elevated LFTs = elevated results on liver function tests.

[dagger] For more detailed information on monitoring the symptoms and signs of toxicity, see the American College of Rheumatology Guidelines for Monitoring Drug Therapy in Rheumatoid Arthritis (5).

It is not known which is the best initial DMARD for patients with RA. Because of safety, convenience, and cost, HCQ or SSZ is often the initial selection for patients with milder disease. Generally well tolerated, HCQ requires no laboratory monitoring, although patients need periodic ophthalmologic examinations for early detection of reversible retinal toxicity (i.e., maculopathy manifested by decreased night vision or loss of peripheral vision) (36-38). SSZ requires monitoring (i.e., periodic CBC) for rare hematologic complications. Within 1-6 months, the response to these agents should be apparent and the need for a change in therapy may be determined.

Many rheumatologists select MTX as the initial DMARD, especially for patients with severe disease as evidenced by the presence of RF positivity, erosions, or extraarticular manifestations. MTX is the DMARD with the most predictable benefit. More than 50% of patients taking MTX continue the drug beyond 3 years, longer than any other DMARD (38-43). Disadvantages of MTX include its expense and the need for laboratory monitoring. Stomatitis, nausea, diarrhea, and perhaps alopecia from MTX use may decrease with concomitant folic acid (44,45) or folinic acid (46) treatment, without loss of efficacy. Liver disease, renal impairment, significant lung disease, or alcohol abuse are relative contraindications for MTX therapy. The risk of liver toxicity is small, but liver function must be monitored (47). The ACR guidelines for monitoring liver toxicity in patients receiving MTX state that liver biopsy should be performed in patients who develop liver function blood test abnormalities that persist during treatment with, or after discontinuation of, the drug (47). Rare but potentially serious and even life-threatening pulmonary toxicity may occur any time with MTX at any dosage. Rarely, lymphoproliferative disorders may occur in patients taking MTX (48), but the relationship to the medication is unclear. This relationship is addressed in more detail in the guidelines for monitoring drug treatment in RA (5).

Intramuscular gold treatment is effective (49- 51), but weekly intramuscular injections are required for 22 weeks before less frequent maintenance dosing is initiated. Monitoring for proteinuria, thrombocytopenia, and neutropenia should be performed prior to each weekly injection. In patients receiving long-term gold therapy (>6 months), toxicity monitoring may be performed with every other injection. Although oral gold is more convenient than injectable gold, there is a long delay (up to 6 months) before benefit is evident, and it is less efficacious (50,52).

DP is effective (50,51,53,54), but its use is limited by an inconvenient dosing schedule (i.e., slow increases in dosage) and infrequent but potentially serious complications of autoimmune diseases such as Goodpasture's syndrome or myasthenia gravis. AZA, a purine analog myelosuppressant, has demonstrated benefit for controlling RA (50,51). Low-dose cyclophosphamide is effective, but carcinogenic. Although studies have documented the efficacy of cyclosporin A in the treatment of RA, it has not yet received Food and Drug Administration (FDA) approval for use in RA (55,56), and its use is limited by cost and potential renal toxicity.

For women of childbearing age, effective contraception is required when most DMARDs are prescribed (5). The drug regimen will need modification if the patient is or wishes to become pregnant, or if breastfeeding is contemplated (5).

Whether DMARDs should be given in a sequential or additive manner for patients with persistently active disease remains controversial (31,51,57). Rheumatology referral is strongly recommended for patients with refractory disease in whom combination DMARDs are considered. Some rheumatologists initiate treatment with a combination of several DMARDs and gradually withdraw the drugs as disease control is achieved (58). Most rheumatologists use combinations of DMARDs to treat patients who have had a partial response to a DMARD or whose disease has been refractory to different individual DMARDs. The most commonly used combinations are MTX/ HCQ, MTX/SSZ, and gold/HCQ (59-63). Studies are needed to determine the most effective combination of DMARDs for use in RA.

The majority of patients with active RA receive an NSAID and at least 1 DMARD, with or without low-dose oral glucocorticoids. If disease remission is observed, regular NSAID or systemic glucocorticoid treatment may no longer be needed. DMARDs control RA but usually do not cure the disease. For that reason, if remission or optimal control of RA is achieved with a DMARD, it should be continued at a maintenance dosage. Discontinuing a DMARD may reactivate disease or cause a ``rebound flare,'' with no assurance that disease control will be reestablished upon resumption of the medication.

Glucocorticoids. Low-dose oral glucocorticoids (<=10 mg prednisone daily or equivalent) and local injections of glucocorticoids are highly effective for relieving symptoms in patients with active RA (Table 5). Low-dose glucocorticoids appear to slow the rate of joint damage (64). The adverse effects of systemic glucocorticoids, especially when taken in higher doses for extended periods of time, limit their use, however. When administered by an experienced physician, glucocorticoid injection of joints and periarticular structures is safe and effective. Injecting 1 or a few of the most involved joints in a patient early in the course of RA may provide local and even systemic benefit. The effects are sometimes dramatic, but may be temporary. Prompt improvement from intraarticular glucocorticoids helps to instill confidence that treatment can be effective. A patient who has flare in 1 or a few joints can be treated successfully by injection of the flaring joint or joints, without requiring a major change in the prescribed regimen. Local glucocorticoid injections may also allow the patient to participate more fully in rehabilitation programs to restore lost joint function.

Table 5. Use of glucocorticoid therapy for rheumatoid arthritis

Not all joint flares in RA are from the disease. Joint infection must be considered and ruled out before local glucocorticoid injection. In general, the same joint should not be injected more than once within 3 months. The need for repeated joint injections in the same joint or for multiple joint injections indicates the need to reassess the adequacy of the overall treatment program.

The adverse effects of systemic glucocorticoids increase with higher doses and longer duration of treatment. For uncomplicated RA, prednisone should not be given at a dosage higher than 10 mg daily. Every effort should be made to limit its use to a short course or, if maintenance treatment is necessary, to use the lowest possible dosage.

Low-dose oral glucocorticoids may benefit the patient during the period before a DMARD has gained its full effect and at times when the disease is severe enough to affect the patient's function, sleep, or ability to work. Glucocorticoids are also used for patients with refractory RA in whom trials of NSAIDs and DMARDs have failed. For patients receiving systemic glucocorticoids who exhibit stable or improving disease, tapering of the dosage and eventual discontinuation of the medication should be attempted.

Surgery

Even if joint inflammation is successfully controlled or eliminated with medication, patients with chronic RA may be symptomatic from joint damage. If, in spite of optimal medical treatment, the patient has unacceptable pain and/or limitation of function because of structural joint damage, surgery should be considered. The most successful surgical procedures for RA are carpal tunnel release, resection of the metatarsal heads, and total hip and total knee arthroplasty. Outcomes of surgery and complication rates are related to the volume of surgery (i.e., number of surgeries performed annually at an institution), timing of surgery, experience of the surgeon, patient's preoperative medical status, and postoperative management and rehabilitation. Occupational and physical therapy expertise is an important component of restoring and optimizing function, especially after total knee arthroplasty, shoulder surgery, and hand surgery.

Monitoring rheumatoid arthritis activity and the safety and adequacy of the treatment program

Monitoring of the patient's illness and his or her response to treatment varies with disease severity, activity, and the drug regimen used, but all patients need to be followed up indefinitely. Patients whose disease is in remission may be seen semiannually, with the frequency of laboratory or other monitoring dictated by the drug program. Patients with early disease, flares, or persistently active disease require more frequent physician visits until disease control is established.

At each visit the physician must assess whether the disease is active (Table 6). Symptoms of inflammatory (as contrasted with mechanical) joint disease, prolonged morning stiffness, fatigue, and active synovitis seen on joint examination indicate active disease and the need to consider changing the treatment program. The joint examination may not adequately reflect disease activity and structural damage. Therefore, periodic measurements of ESR or CRP and functional status and radiographic examinations of involved joints should be performed. Functional status assessment may be performed with questionnaires such as the Arthritis Impact Measurement Scales (65) or the Health Assessment Questionnaire (66).

Table 6. Monitoring rheumatoid arthritis activity

If the patient's disease is active or progressing, other options, including consultation with a rheumatologist, should be considered. If disease activity is confined to 1 or a few joints, local glucocorticoid injection may help. Change in the drug regimen may be considered, especially increasing DMARD dosage, changing the DMARD, or adding a DMARD. Patients with severe symptoms may need to start taking or to increase the dosage of systemic glucocorticoids. Active joint disease may be aggravated by physical activity; consultation with a physical therapist, occupational therapist, and/or vocational counselor should be considered. Periods of rest, time off from work, changes in occupation, or stopping work may be necessary. For symptoms that are mechanical, surgical options need to be explored.

Refractory rheumatoid arthritis

RA may run a resistant course, with progressive disability and joint damage. Rheumatology re ferral is strongly recommended for patients with refractory disease. Medications which are not yet FDA-approved for treating RA (such as cyclosporine) may be useful. Some patients may be candidates for treatment with investigational pharmacologic or biologic agents. Patients with refractory RA frequently require treatment with systemic glucocorticoids and/or analgesics. With a chronic disease like RA, every effort should be made to avoid creating dependency upon narcotic analgesics, although some use may be justified. The longitudinal management of the patient with RA depends on mutual trust and confidence between the patient and his/her health care providers, who are expected to be supportive, empathetic, and knowledgeable.

The responsibilities of primary and specialty care physicians

Depending on the health care setting, the majority of the care of the patient with RA may be provided by a single physician (primary care physician, rheumatologist, or rheumatologist who also provides primary care), or the responsibility may be shared. The role of the primary care physician is to recognize and diagnose RA at its onset and to ensure that the patient receives timely treatment before permanent joint damage has occurred. The rheumatologist should provide support and consultation to the patient and his or her primary care physician in the diagnosis and treatment of RA. Since the level of training and experience in diagnosing and caring for RA varies among primary care physicians, the responsibility for accurate diagnosis and monitoring of RA activity and/or drug toxicity may appropriately be assigned to a rheumatologist. If the care of a patient with RA is to be shared, an explicit plan for monitoring RA disease activity (Table 6) and/or drug toxicity needs to be formulated. The patient's preference may be the most important factor in deciding which physician(s) assume responsibility for care.

General health maintenance

A general health maintenance strategy should be developed and responsibility coordinated among the patient's health care providers. Routine prevention measures should be recommended and risk factors modified. The lifespan of a patient with RA may be shortened by infection, pulmonary disease, renal disease, or GI bleeding (30). Patients at risk for GI bleeding may benefit from avoidance of gastric irritants and the use of gastroprotective drug therapy. For patients at risk for osteoporosis (by history, inactivity, and/or glucocorticoid treatment), evaluation with bone densitometry at baseline and treatment with calcium supplementation, vitamin D (400 units daily), bisphosphonates, or calcitonin should be considered. Estrogen replacement therapy should be discussed with postmenopausal women.

Summary

RA is a chronic progressive polyarthritis (with varying systemic features) associated with substantial disability and economic losses. Successful treatment to limit joint damage and functional loss requires early diagnosis and timely initiation of disease-modifying agents. The goal of treatment is to arrest the disease and to achieve remission. Although remission rarely occurs, patients may still benefit from pharmacologic, nonpharmacologic, and if necessary, surgical inter ventions. Optimal longitudinal treatment requires comprehensive coordinated care and the expertise of a number of providers. Essential components of management include 1) establishment of the diagnosis of RA (versus other forms of polyarthritis), 2) systematic and regular evaluation of disease activity, 3) patient education/rehabilitation interventions, and initial treatment with NSAIDs, 4) use of DMARDs, 5) possible use of local or low-dose oral glucocorticoids, 6) minimization of the impact on the individual's function, 7) assessment of the adequacy of the treatment program, and 8) general health maintenance.

ACKNOWLEDGMENTS

The authors thank Drs. Mary Charlson, Doyt Conn, John Eisenberg, John Esdaile, Christine Evelyn, Herbert Kaplan, Donald Middleton, Daniel Rahn, Shaun Ruddy, Burton Sack, Michael Schiff, Terence Starz, Bruce Trimble, Michael Weinblatt, Jeffrey Wilson, and the American College of Rheumatology Committee on Rheumatologic Care for their thoughtful critique. We also thank Donna Cosola, Steven Echard, Jacqueline Mazzie, and Mary Scamman for technical assistance with the preparation of the manuscript.

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Members of the Ad Hoc Committee on Clinical Guidelines are as follows. C. Kent Kwoh, MD (co-chair): Case Western Reserve University, Cleveland, Ohio; Robert W. Simms, MD (co-chair): Boston University School of Medicine, Boston, Massachusetts; Larry G. Anderson, MD: Rheumatology Associates, Portland, Maine; Diane M. Erlandson, RN, MS, MPH: Harvard School of Public Health, Boston, Massachusetts; Jerry M. Greene, MD: Veterans Affairs Medical Center, West Roxbury, Massachusetts; Carolee Moncur, PhD, PT: University of Utah, Salt Lake City; James R. O'Dell, MD: University of Nebraska Medical Center, Omaha; Alison J. Partridge, LICSW: Robert B. Brigham Multipurpose Arthritis and Musculoskeletal Diseases Center, Boston, Massachusetts; W. Neal Roberts, MD: Medical College of Virginia, Richmond; Mark L. Robbins, MD, MPH: Harvard Pilgrim Health Care, Boston, Massachusetts; Robert A. Yood, MD: Fallon Clinic, Worcester, Massachusetts; Matthew H. Liang, MD, MPH: Brigham and Women's Hospital, Boston, Massachusetts.

Address reprint requests to American College of Rheumatology, 1800 Century Place, Suite 250, Atlanta, GA 30345 .

Submitted for publication August 9, 1995; accepted in revised form March 4, 1996.