Diagnosis and Management of Rheumatoid Arthritis

J. ADAM RINDFLEISCH, M.D., and DANIEL MULLER, M.D., PH.D. University of Wisconsin–Madison, Madison, Wisconsin

Rheumatoid arthritis is a chronic inflammatory disease characterized by uncontrolled proliferation of synovial tissue and a wide array of multisystem comorbidities. Prevalence is estimated to be 0.8 percent worldwide, with women twice as likely to develop the disease as men. Untreated, 20 to 30 percent of persons with rheumatoid arthritis become permanently work-disabled within two to three years of diagnosis. Genetic and environmental factors play a role in pathogenesis. Although laboratory testing and imaging studies can help confirm the diagnosis and track disease progress, rheumatoid arthritis primarily is a clinical diagnosis and no single laboratory test is diagnostic. Complications of rheumatoid arthritis may begin to develop within months of presentation; therefore, early referral to or consultation with a rheumatologist for initiation of treatment with disease-modifying antirheumatic drugs is recommended. Several promising new disease-modifying drugs recently have become available, including leflunomide, tumor necrosis factor inhibitors, and anakinra. Nonsteroidal anti-inflammatory drugs, corticosteroids, and nonpharmacologic modalities also are useful. Patients who do not respond well to a single disease-modifying drug may be candidates for combination therapy. Rheumatoid arthritis is a lifelong disease, although patients can go into remission. Physicians must be aware of common comorbidities. Progression of rheumatoid arthritis is monitored according to American College of Rheumatology criteria based on changes in specific symptoms and laboratory findings. Predictors of poor outcomes in early stages of rheumatoid arthritis include low functional score early in the disease, lower socioeconomic status, early involvement of many joints, high erythrocyte sedimentation rate or C-reactive protein level at disease onset, positive rheumatoid factor, and early radiologic changes. (Am Fam Physician 2005;72:1037-47, 1049-50. Copyright © 2005 American Academy of Family Physicians.)
Patient information: A handout on rheumatoid arthritis, written by the authors of this article, is provided on page 1049.


heumatoid arthritis is characterized by persistent joint synovial tissue inflammation. Over time, bone erosion, destruction of cartilage, and complete loss of joint integrity can occur. Eventually, multiple organ systems may be affected. Rheumatoid arthritis is the most common inflammatory arthritis, affecting 0.8 percent of the adult population worldwide. Onset usually occurs between 30 and 50 years of age. Incidence in the United States is estimated as 25 per 100,000 persons for men and 54 per 100,000 persons for women.1 Rheumatoid arthritis is responsible for an estimated 250,000 hospitalizations and 9 million physician visits each year.2 Its economic impact is magnified by the high level of funcwww.aafp.org/afp

tional impairment it causes: untreated, 20 to 30 percent of persons with rheumatoid arthritis become permanently work-disabled within three years of diagnosis.3 Etiology and Pathophysiology The etiology of rheumatoid arthritis is not fully understood. Evidence points to a complex interplay between environmental and genetic factors. In monozygotic twins, there is a more than 30 percent concordance rate for rheumatoid arthritis development, and 80 percent of whites with rheumatoid arthritis express the HLA-DR1 or -DR4 subtypes. These and other regions of the Major Histocompatibility Complex may confer susceptibility to more severe disease by causing a specific arthrogenic peptide to be presented to CD4+ T cells.4
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Combination therapy may be more effective than treatment with one drug alone. The distal interphalangeal joints and sacroiliac joints tend not to be affected. podiatrists. Number 6 ◆ www. Neovascularization then occurs. 1038 American Family Physician Rheumatoid arthritis primarily is a clinical diagnosis. occupational therapists. preferably within 12 weeks. Over time. Patients commonly present with pain and stiffness in multiple joints. The wrists are nearly always involved. 14 29 13 13 13 2 2. A = consistent.aafp. proteinases. DMARD = disease-modifying antirheumatic drug. 16-18 2.aafp.xml. Blood vessels in the affected joint become occluded with small clots or inflammatory cells. For information about the SORT evidence rating system. Intra-articular corticosteroid injections can be helpful but should not be administered more than three times in one year. Three in four women with rheumatoid arthritis experience significant improvement in symptoms when pregnant. Low-dose oral corticosteroids are effective for symptom relief but have a high risk of toxicity. expert opinion.6 Consumption of more than three cups of coffee daily—particularly decaffeinated coffee—also may contribute. diseaseoriented evidence. B = inconsistent or limited-quality patient-oriented evidence. and measurement instruments such as the European League Against Rheumatism response criteria are useful for tracking disease progression. C = consensus. and C-reactive protein may indicate treatment response. In 8 to 15 percent of patients. such as an infectious illness. pharmacists. patients should have access to a wide range of health care professionals. good-quality patient-oriented evidence. preferably one-to-one. usual practice. Multiple cytokines. 15 13.7 and oral contraceptive use6 are associated with decreased risk. Lymphocytes infiltrate perivascular regions. possibly autoimmune or infectious. erythrocyte sedimentation rate. a positive family history. as are the proximal interphalangeal and metacarpophalangeal joints. In approximately 15 percent of patients.7 High vitamin D intake. therefore.org/afpsort.1. at least in the short term. dietitians. and endothelial cells proliferate. or case series.org/afp September 15. although one third of patients initially experience symptoms at just one location or a few scattered sites. symptoms emerge over weeks to months. Exercise is beneficial for aerobic capacity and muscle strength with no detrimental effects on disease activity or pain levels. In most patients. 2005 . tender to the touch. NSAID = nonsteroidal anti-inflammatory drug.5. symptoms begin within a few days of a specific inciting event.4 risk factors usually with a recurrence after delivery. weakness. but they usually are not Volume 72. or fatigue. physical therapists. NSAIDs should be prescribed in the lowest dose that provides symptom relief and should be cut back after a good response to DMARDs is achieved.5 Joints most commonly affected are those with the highest ratio of synovium to articular cartilage.sort: kEy rEcommEnDations for PracticE Clinical recommendation Patients with rheumatoid arthritis should be treated as early as possible with DMARDs to control symptoms and delay disease progression.1. onset occurs more rapidly over days to weeks. including their primary care physicians. 14. and warm. changes in hemoglobin. 35 C 30 C 28 Joint damage in rheumatoid arthritis begins with the proliferation of synovial macrophages and fibroblasts after a triggering incident. see page 983 or http://www. therefore. Gastroprotection should be used if patients are older than 65 years or have a history of peptic ulcer disease. rheumatologists. the lowest dosage possible should be used for the shortest period possible. Patient education. silicate exposure. and social workers. Diagnosis tyPical PrEsEntation Female sex. and smoking are associated with an increased risk for developing rheumatoid arthritis.8 tea consumption.5 Rheumatoid joints typically are boggy. Efficacy of treatment should be monitored. forming invasive pannus tissue.5 A systematic review 9 of 24 studies did not support a link between breast implants and connective tissue disorders. Evidence rating A C C A B C A A C References 2. A multidisciplinary team approach is beneficial. causing further joint destruction and the development of systemic complications. older age. starting with one joint and often accompanied by prodromal symptoms of anorexia. and growth factors are released. interleukins. inflamed synovial tissue begins to grow irregularly. Patients with persistent inflammatory joint disease (longer than six to eight weeks) already receiving analgesics or NSAIDs should be considered for rheumatology referral. nursing specialists. Pannus invades and destroys cartilage and bone. should be provided when rheumatoid arthritis is diagnosed.

aafp. erythematous.rheumatoid arthritis TABLE 1 revised american rheumatism association criteria for classification of rheumatoid arthritis Percentage with rheumatoid arthritis if sign or symptom is*: Sign or symptom Morning stiffness Arthritis of three or more joint areas Hand joint involvement Symmetric arthritis Rheumatoid nodules Serum rheumatoid factor positive Definition Stiffness in or around the affected joints for at least one hour after initiating movement Three or more of the following joints noted to be fluid-filled or have soft tissue swelling: wrist. elbow. and a joint aspiration should be considered if gout is suspected. However. elbow.5.4 0. PIP. axillary. During the initial visit. patients should be asked about degree of pain. ankle. ankle.13 summarizes the test findings associated with rheumatoid arthritis. or bony prominences Positive result using any laboratory test that has a positive predictive value of 95 percent or more (i.org/afp . †—PIP. especially in an acute presentation. Infection-related reactive September 15. Some patients complain of “puffy” hands secondary to increased blood flow to inflamed areas. Prominent epitrochlear. rheumatoid factor. or PIP joints among the symptomatic joints observed Right and left joints involved for one or more of following: wrist.9 1. as may an array of endocrine and other disorders (Table 2). is positive in no more than 5 percent of patients without rheumatoid arthritis) Hand and wrist films show typical changes of erosions or loss of density adjacent to affected joints LR+ 1.. LR+ = positive likelihood ratio. and other systemic complaints may arise. knee. fatigue.6 0. and erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP).10 Diagnostic critEria arthropathies. rheumatoid arthritis is diagnosed formally using seven American Rheumatism Association (ARA) criteria (Table 1). MCP.2 Table 32. and cervical lymph nodes may be noted. The American College of Rheumatology Subcommittee on Rheumatoid Arthritis (ACRSRA) recommends that baseline laboratory evaluations include a complete blood cell count with differential. Patients often hold joints in flexion to minimize painful distension of joint capsules. 2005 ◆ Volume 72. MTP Wrist. MCP. Muscles near inflamed joints often atrophy. PIP= proximal interphalangeal.0 8. early treatment decreases American Family Physician 1039 Rheumatoid arthritis must be differentiated from a number of other disorders. and functional limitations. LR− = negative likelihood ratio. Baseline evaluation of renal and hepatic function also is recommended because these findings will guide medication choices. A careful joint examination looking for the characteristics described above is vital. MCP= metacarpophalangeal. extensor surfaces. malaise.4 LR0.8 79 21 *—Assumes overall probability of rheumatoid arthritis of 30 percent. PIP.e.4 33 29 50 74 12 17 25 13 Radiographic changes 11 0. Number 6 www. MTP= metatarsophalangeal.5 1. MCP. several tests can provide objective data that increase diagnostic certainty and allow disease progression to be followed.5 0. and MTP joints need not be absolutely symmetrical.5 Present 39 32 Absent 14 13 1. DiffErEntial Diagnosis No single diagnostic test definitively confirms the diagnosis of rheumatoid arthritis. knee. Morning stiffness lasting at least 45 minutes after initiating movement is common. duration of stiffness and fatigue. Diagnostic tEsts In clinical trials. seronegative spondyloarthropathies. a definitive diagnosis using these criteria may be difficult to obtain early in the disease process.4 0. Information from references 11 and 12. and other connective tissue diseases such as systemic lupus erythematosus may have symptoms in common with rheumatoid arthritis. MCP.10 Gout rarely coexists with rheumatoid arthritis. Low-grade fever.12 In typical outpatient practice.2 3. treatment Joint destruction in rheumatoid arthritis begins within a few weeks of symptom onset.11.5.98 0.5. Weakness is commonly out of proportion to pain on examination. MTP† Subcutaneous nodules in regions surrounding joints.

but details are outside the scope of this article. and/or rash. However. with good evidence of beneficial effect. inflammatory bowel disease. where he also is an integrative medicine consultant. Iron studies and skin coloration changes may guide diagnosis. Rule out murmurs. Tend to be more asymmetric than rheumatoid arthritis. it is imperative to diagnose the disease and initiate treatment as soon as possible. Rheumatoid arthritis. Number 6 ◆ 1040 American Family Physician www. (4) a number of new DMARDs are available.15 This change of approach is a result of several research findings: (1) joint damage begins early in the disease14 . Volume 72. high fever. 2005 ..2 Therapeutic goals include preservation of function and quality of life. DANIEL MULLER. and initiation of a DMARD.. sexually acquired. reactive arthritis Still’s disease Thyroid disease Viral arthritis Comments Such as scleroderma and lupus Evaluate for trigger points. M. or minocycline (Minocin). The ACRSRA recommends that patients with suspected rheumatoid arthritis be referred within three months of presentation for confirmation of diagnosis and initiation of treatment with diseasemodifying antirheumatic drugs (DMARDs). ADAM RINDFLEISCH. leflunomide (Arava). Wis.2. Mills St...aafp. (3) the benefits of DMARDs may be enhanced when the drugs are used in combination16-18 . joint protection. Dr. PharmacothEraPy the authors J. but calcium pyrophosphate deposition disease can accompany rheumatoid arthritis. Madison... leukocytosis with left shift.5 Figure 12. Consider thyroid-stimulating hormone level depending on symptoms. Adam Rindfleisch. Joints often erythematous. and only with progression of symptoms were dosages changed or additional medications added. or related to gastrointestinal disorders.TABLE 2 Differential Diagnosis of rheumatoid arthritis Diagnosis Connective tissue diseases Fibromyalgia Hemochromatosis Infectious endocarditis Polyarticular gout Polymyalgia rheumatica Sarcoidosis Seronegative spondyloarthropathies. Patients with more severe disease or radiographic changes should begin treatment with methotrexate. Reiter’s comorbidities. a “reverse pyramid” approach now is favored. as are hypercalcemia and chest film findings. M. is associate professor in the Departments of Medicine (Rheumatology) and Medical Microbiology/Immunology at the University of Wisconsin– Madison. Consider parvovirus. sulfasalazine (Azulfidine).14 Therefore.4)..PHIL. M.D. 777 S. Baltimore. If symptoms are not adequately controlled. Evaluate for history of psoriasis. He obtained his medical microbiology degree at the University of Wisconsin–Madison and his medical degree at the State University of New York at Stony Brook.D. liver dysfunction. Pharmacotherapy for rheumatoid arthritis generally involves a nonsteroidal anti-inflammatory drug (NSAID) for control of pain. Reactive arthritis can be postinfective. Muller completed a residency in internal medicine and a fellowship in rheumatology at the University of North Carolina at Chapel Hill. He received his medical degree from Johns Hopkins University School of Medicine.D. M. M. podagra commonly found. minimization of pain and inflammation.4 outlines an approach to the treatment of a patient with rheumatoid arthritis. Address correspondence to J. pharmacologic treatment of rheumatoid arthritis was managed using a pyramid approach: symptom-alleviating treatment was started at diagnosis. England.D.. PH. is clinical instructor and academic fellow in the Department of Family Medicine at the University of Wisconsin–Madison in Madison. More commonly involve the joints of the spine.Phil. unlike polymyalgia rheumatica. rarely presents with pain in the proximal joints of the extremities only. Reprints are not available from the authors. sore throat.19 Patients with mild disease and normal radiographic findings can begin treatment with hydroxychloroquine (Plaquenil). although methotrexate also is an option. splenomegaly. gout and rheumatoid arthritis rarely coexist. and history of intravenous drug use. and control of systemic complica- tions. and completed a family practice residency with the University of Wisconsin–Madison. Dr. in which DMARDs are initiated quickly to slow disease progression as early as possible (Figure 12. Granulomas likely. (2) DMARDs have significant benefits when used early. Tends to present with fever. WI 53715. Other analgesics also may be used. hepatitis B.org/afp September 15. In past decades. Rindfleisch obtained his master’s degree in comparative social research at the University of Oxford. with selective use of low-dose oral or intra-articular glucocorticoids. the rate of disease progression. Information from references 5 and 10.

Limited value as a screening study for rheumatoid arthritis Normal or elevated Elevated alpha-1 and alpha-2 globulins possible. Negative in 30 percent of patients early in illness. azathioprine (Imuran).20 Steroid dosages should be kept at a minimum because of the high risk of side effects. the effects are temporary. September 15. various viral. disease severity. When a single inflamed joint contributes to significant disability.2 Symptoms may recur with steroid discontinuation. 5. Compliance. and 13. straw-colored fluid with fibrin flecks often seen. not an accurate measure of disease progression. although not as likely to change as a direct effect of disease. also may be normocytic or microcytic. to avoid rebound effects. Often increased to >30 mm per hour. or cyclooxygenase-2 inhibitors are used for initial treatment of rheumatoid arthritis to reduce joint pain and swelling. lupus. cultures are negative. Steroids at dosages equivalent to less than 10 mg of prednisone daily are highly effective for relieving symptoms of rheumatoid arthritis2 and can slow joint damage. Normal or slightly elevated alkaline phosphatase Usually increased May be normal or show osteopenia or erosions near joint spaces in early disease.000 to 25. The American College of Rheumatology (ACR) guidelines2 recommend that patients being treated with glucocorticoids take 1. Microscopic hematuria or proteinuria may be present in many connective tissue diseases.2. Number 6 www. However. 5. Consider if an affected joint can be tapped and diagnosis is uncertain. more specific than rheumatoid factor (90 versus 80 percent). over a month or more. parasitic. 2005 ◆ and abnormalities in blood glucose levels. neoplastic disease.rheumatoid arthritis TABLE 3 laboratory and imaging findings associated with rheumatoid arthritis Laboratory test C-reactive protein* Erythrocyte sedimentation rate* Hemoglobin/hematocrit* Liver function* Platelets* Radiographic findings of involved joints* Rheumatoid factor* Associated findings Typically increased to > 0.2 DMARDs. hemoglobin averages around 10 g per dL (100 g per L). not readily available in many laboratories. NSAIDs. Infectious arthritis should be ruled out before injections are performed.aafp. Individual drug categories are discussed below. especially when high dosages were used. which include osteoporosis.21 Systemic steroids often are used as “bridging therapy” during the period when DMARDs have been initiated but have not yet taken effect.7 picograms per mL. Slightly decreased.500 mg of calcium and 400 to 800 IU of vitamin D daily. can be positive in numerous other processes (e. may be used to monitor disease course. can repeat six to 12 months after disease onset. salicylates. DMARDs should be considered for all patients with rheumatoid arthritis. injection of glucocorticoids is a safe and effective intervention. wrist and ankle films are useful as baselines for comparison with future studies. scleroderma. Sjögren’s syndrome. sarcoidosis. but some of the newer DMARDs have a relatively rapid onset of action. cataracts. and most rheumatologists withdraw steroids slowly. and they should be observed closely for symptoms of gastrointestinal side effects. or combination therapy (methotrexate plus one of the newer agents) may be considered. in rheumatoid arthritis.000 white blood cells per mm3 (5 to 25 3 109 per L) with 85 percent polymorphonuclear leukocytes a common finding. The American Family Physician 1041 Volume 72. given recent findings regarding potential adverse effects. there are no crystals. and fluid glucose level typically is low. however. fluid may clot at room temperature. and the presence of various comorbidities guide medication choice. normochromic anemia.org/afp . cushingoid symptoms.13 Cyclooxygenase-2 inhibitors must be used with caution. increases sensitivity when used in combination with rheumatoid factor. NOTE: Renal function.. Information from references 2. may be used to monitor disease course. May be increased Tends to correlate well with disease progression. if initially negative. they should not be used alone. because they do not alter the disease course. physician experience. NSAIDs. or bacterial infections). White blood count* Anticyclic citrullinated peptide antibody Antinuclear antibody Complement levels Immunoglobulins Joint fluid evaluation Urinalysis *—Recommended for initial evaluation for rheumatoid arthritis.g. should be followed to assess renal effects of drug therapy. Glucocorticoids.2 Patients with rheumatoid arthritis are almost two times more likely to have serious complications from NSAID use than patients with osteoarthritis.

Adequate control of joint pain and swelling? Yes No Monitor disease activity every three to six months. or add a biologic agent to methotrexate. figure 1. Increasing evidence indicates that combinations of DMARDs can be more effective than single-drug regimens. leflunomide. Annual radiographs Switch from methotrexate to leflunomide (Arava) or azathioprine (Imuran). infliximab (Remicade). but in more severe cases.† *—The following laboratory tests should be performed before methotrexate therapy begins. at 25 mg.treatment approach for a Patient with rheumatoid arthritis Diagnosed rheumatoid arthritis In anticipation of possible future biologic therapy: Check tuberculosis and candida control skin tests before placing on steroids or other DMARDs. When starting methotrexate. or minocycline (Minocin) Adequate control of joint pain and swelling? No Yes Trial of methotrexate. switch to SC or IM.) Information from references 2 and 4. platelets.2 Sulfasalazine or hydroxychloroquine often are started first. every two months: complete blood count with differential. aspartate transaminase levels. albumin levels. Women of childbearing age should use adequate contraception when taking certain DMARDs because they could be harmful Volume 72. most commonly used medications are methotrexate. IM = intramuscular.* 10 to 15 mg once per week ± hydroxychloroquine ± sulfasalazine Adequate control of joint pain and swelling? Yes No Increase dosage of methotrexate to 20 mg orally once per week. sulfasalazine. hydroxychloroquine. Baseline chest radiograph Erosions visible on radiograph? No Mild disease Yes Moderate or severe disease Trial of hydroxychloroquine (Plaquenil). sulfasalazine (Azulfidine). decrease the dosage of methotrexate to 10 to 15 mg once per week.org/afp September 15. or add leflunomide or azathioprine to methotrexate†. every two weeks for six weeks. 2005 .aafp. (DMARD = disease-modifying antirheumatic drug. then. add 1 mg oral folic acid per day to decrease side effects. SC = subcutaneous. †—When adding another DMARD to methotrexate. and creatinine levels. Number 6 ◆ www. methotrexate or combination 1042 American Family Physician therapy may be first-line treatment. and caution the patient to avoid alcohol. Algorithm for treatment of a patient with rheumatoid arthritis. if normal. and etanercept (Enbrel).

or ACR 70. number of swollen joints. positive rheumatoid factor. above) to any treatment.org/afp American Family Physician 1043 . September 15. increased risk of infection. and acute phase response (as measured by CRP or ESR). lower education level. or early radiologic changes. usually those with the most severe forms of the disease. lower socioeconomic status. Several new drugs with novel mechanisms of action have emerged in recent years.17 Adalimumab (Humira) also is a recombinant human IgG1 antibody and has an additive effect when taken with methotrexate. and early involvement of many joints.31 acupuncture.6.13.25 aDjunctivE thEraPiEs Duration of trEatmEnt Rheumatoid arthritis is a lifelong illness. tumor necrosis factor (TNF) antagonists. Etanercept is a soluble TNF-receptor fusion protein. Table 55 lists the most common of these.html). Patients who had a poor response to methotrexate had a greater response with infliximab than placebo (52 versus 17 percent. significant disease persists despite treatment. In clinical trials. and it was found to prevent new joint erosions in 80 percent of patients over a two-year period.13.23 but it elicits improvement in symptoms much more rapidly. loss of motion is significant. and anakinra (Kineret).aafp. Combinations of methotrexate and the new biologic agents can lead to remission in 30 to 40 percent of patients with rheumatoid arthritis. pain level. or functional impairment is severe. often within two weeks. especially tuberculosis reactivation.rheumatoid arthritis to a fetus. Rituximab (Rituxan).13 Radiologic assessment scales also are useful. Changes in hemoglobin.22 TNF antagonists lower the levels of TNF-a.aafp.35 The standardized all-cause mortality ratio for patients with rheumatoid arthritis compared with the general population is 1.23 Infliximab.16.19 Leflunomide is a competitive inhibitor of an intracellular enzyme needed for de novo pyrimidine synthesis by activated lymphocytes. Author disclosure: Nothing to disclose A number of additional.19 lists DMARD dosing regimens. including leflunomide.19 Anakinra is a recombinant interleukin-1 receptor antagonist. Therapeutic fasting. most often ACR 20. ESR. and adverse effects. Newer DMARDs. which is present in increased concentrations in the synovial fluid in patients with rheumatoid arthritis.15 Thirty percent of patients with rheumatoid arthritis.13 However. patients with milder disease tend to benefit from early treatment. Several randomized controlled trials19. physical disability score. 2005 ◆ Volume 72.26 as have spa therapies27 and exercise. global disease activity (as assessed by the patient or by an observer). health assessment questionnaires may be a more useful means of evaluating disease progression. is a chimeric IgG1 anti–TNF-α antibody.18 TNF antagonists are associated with an increased risk of infection.19 Table 42. dietary supplementation of essential fatty acids. A study of patients with rheumatoid arthritis onset in the 1980s showed no increase in mortality with rheumatoid arthritis in the first eight to 13 years following diagnosis. Adverse effects include skin irritation at the site of injection. The numbers represent the percentage of improvement in the following criteria: number of tender joints.19 Other new DMARDs are in development.26 and splinting. but for most patients. Prognosis is worse in patients who have a high ESR or CRP level at disease onset. Evidence is inconclusive regarding herbal medications.32 Surgery should be considered when pain is unacceptable.13 comPlications Physicians should monitor patients with rheumatoid arthritis for potential complications. number needed to treat = 3). Its long-term effects are comparable with methotrexate in some studies. Examples include the European League Against Rheumatism response criteria for rheumatoid arthritis and various daily activity score surveys.2.24 have found it to be more effective than placebo when administered alone or in combination with methotrexate. will not demonstrate an ACR 20 response (see Duration of Treatment section. nonpharmacologic treatments for rheumatoid arthritis have been tried. ACR 50. and journaling have shown benefit.19 Complete remission rarely occurs. but platelet count and rheumatoid factor levels tend not to correlate well. times to onset of benefit. and leukopenia. Number 6 www. which are numerous. and CRP may serve as helpful indicators of response to treatment. costs. Anti–interleukin-6 receptor antibodies also are being evaluated. Prognosis Predictors of poor outcomes in the early stages of rheumatoid arthritis include a relatively low functional score early in the disease progression.36 but this may decrease with long-term use of new DMARDs. has shown promise in preliminary studies. strong family history of the disease.2.2 More information about nonmedical therapies is available in the online version of this article (http://www. another TNF antagonist. improvement has been tracked using the ACR improvement criteria.33 For the individual patient.19 Leflunomide slows progression of joint damage as measured radiographically.34 Treatment should be guided by individual clinical response to various interventions. an antibody to a surface receptor on B cells.org/afp/20050915/1037.28 Patient education29 and a multidisciplinary approach to patient care30 provide at least short-term benefits.

dizziness. TNF = tumor necrosis factor. and 6. alopecia. joint pain.251 Auranofin (Ridaura) 215 Azathioprine (Imuran) Cyclosporine (Gengraf. hypertrichosis Rare: hypertension. IM = intramuscular.433 Minocycline (Minocin) Staphylococcal protein A immunoadsorption (Prosorba column) Sulfasalazine (Azulfidine) 100 mg orally twice per day Extracorporeal.316 Time to benefit A few days to four months‡ Within 12 weeks. LFT = liver function test. weekly for 12 weeks 2 to 3 g orally per day in divided doses One to three months Three months 48 (14 to 31) One to three months DMARD = disease-modifying antirheumatic drug. diarrhea. reversible oligospermia. diarrhea. highly teratogenic. increased infection risk. skin pigmentation Hypotension and anemia during procedure. proteinuria. abnormal LFTs Rare: low WBC and platelets. vasomotor symptoms after injection Rare: leukopenia. or SC per week 1. contact lens staining. gingival hypertrophy. then 10 to 20 mg orally per day 12 to 25 mg orally. TB = tuberculosis. rash. rash. rash. Neoral. AST = aspartate transaminase. fatigue Nausea. SC = subcutaneous.383 (for eight weeks) 372 A few days to four months‡ Four to 12 weeks (tending toward four) One to two months Leflunomide (Arava) Methotrexate Oral: 79 (57 to 65) IM or SC: (18 to 20) 231 (115 to 147) 20. 13. nausea Rare: hypersensitivity Diarrhea Rare: leukopenia Nausea Rare: leukopenia. late autoimmune disease Contraindicated in infection. fatigue. paresthesias. diarrhea. even after discontinuation Rare: leukopenia. 2. ALT = alanine transaminase. renal disease.5 to 5 mg per kg orally per day 250 to 750 mg orally per day 25 mg SC twice per week or 50 mg SC per week 200 to 400 mg orally per day Cost (generic)* $1. thrombocytopenia. and 19. Epstein-Barr virus– related lymphoma. retinal toxicity Anakinra (Kineret) 1. hepatitis. tremor. thrombocytopenia Nausea. including TB reactivation Rare: demyelinating disorders Infections and decreased neutrophil counts. lasting effects by 24 weeks Four to six months Two to three months Two to four months Three to six months A few days to 12 weeks Two to six months Adverse effects Infusion reactions. catheter site infection. pneumonitis. IM. IV = intravenous. sepsis Nausea. colitis Infusion reactions. mouth ulcers. increased infection risk. rash. abnormal LFTs Rare: leukopenia 3 mg per kg IV at weeks zero. mild injection site reactions Rare: demyelination Nausea. reversible platelet decrease Rare: proteinuria. loss of taste.316 Hydroxychloroquine (Plaquenil) IM gold Gold sodium thiomalate (Myochrysine) Aurothioglucose (Solganal) Infliximab (Remicade) 57 (33 to 37) 25 to 50 mg IM every two to four weeks 34 Six to eight weeks Mouth ulcers. rash. including TB reactivation Rare: demyelinating disorders Nausea. WBC = white blood count. . CBC = complete blood count. alopecia. myopathy. headache. nodulosis Dizziness. headaches. sepsis. headaches Rare: abdominal pain. then every eight weeks§ 100 mg orally per day for three days. headaches. alopecia. liver disease. Information from references 2. mouth ulcers. generic) D-Penicillamine (Cuprimine) Etanercept (Enbrel) 76 (39 to 40) 288 to 231 (288 to 326) 35 to 95 1. sepsis.TABLE 4 DmarDs for treatment of rheumatoid arthritis DMARD Adalimumab (Humira) Dosage 40 mg SC every two weeks 100 to 150 mg SC per day 3 mg orally twice per day or 6 mg orally per day 50 to 150 mg orally per day 2. lymphoma Nausea.

and adjust dose as needed. Used only in refractory patients when many other treatments have failed. Can be used when diagnosis uncertain. Has modest effects compared with other DMARDs. slows joint damage. then every one to three months Creatinine every two weeks until dose is stable. and other infections. adverse effects limit use. then every three months *—Average wholesale cost for one month’s supply (unless otherwise indicated). histoplasmosis. Montvale. based on Red Book. . CBC. CBC. Rapid onset (eight to 13 weeks). and adjust dose as needed. 2004.19 but may vary among physicians for some medications. and other infections. then every three months CBC and urine protein (by dipstick) every one to three months Comments Monoclonal antibody to TNF-a. CBC and urinary protein by dipstick every two weeks until dose is stable. Inhibits pyrimidine synthesis and may suppress T-cell activation. ‡—When combined with methotrexate. liver biopsy if no resolution on discontinuation. used when treatment with another DMARD has failed. can be eliminated from system with cholestyramine in patients wishing to conceive. Combination of TNF receptor and portion of IgG1. †—Monitoring guidelines are based on consensus guidelines and expert recommendations2. CBC and ALT at baseline and monthly until dose is stable. may continue every two to three months thereafter. then monthly. repeat AST or ALT in two to four weeks if initially elevated. modest effects compared with other medications. then with each injection Has significant withdrawal rate in trials because of toxicity. creatinine. creatinine. CBC and ALT at baseline and monthly until dose is stable. Effective in combination with prednisone for management of newonset rheumatoid arthritis. and LFTs monthly for six months. N. can be used when cause of polyarthritis uncertain. Monitor for TB. Used less commonly than other DMARDs. None needed Follow CBC Monoclonal antibody to TNF-a. histoplasmosis. Significant clinical benefit up to one year. repeat AST or ALT in two to four weeks if initially elevated. then every one to three months CBC and ALT at baseline and monthly until dose is stable. CBC every two to four weeks for three months. can be used when diagnosis uncertain. §—May be increased if incomplete response. improves multiple clinical outcomes and delays radiographic changes.rheumatoid arthritis Monitoring† Monitor for TB. Hepatitis B and C serology in high-risk patients. Rapid onset (six to 10 weeks). and LFTs monthly for six months. inhibits TNF-a. CBC every one to two weeks until dose is stable. and potassium level tests CBC and urinary protein by dipstick every two weeks until dose is stable. LFTs. coated forms available. enteric. often combined with newer DMARDs. Interleukin-1 receptor antagonist.: Medical Economics Data. CBC at baseline. reduces disease activity with acceptable safety. then every one to two months. moderate effect but relatively low toxicity. tends to produce more sustained results over time than other DMARDs and lowers all-cause mortality. Eye examinations every 12 months in patients older than 40 years and those with previous eye disease Has greater toxicity and is used less commonly than other DMARDs. monthly for three months. may continue every two to three months thereafter. shown to reduce disease activity with acceptable safety. then every one to two months. consider CBC. may continue every two to three months thereafter.J.

2005:996-1042. et al. Criswell LA. Saag KG. pleuritis—present in 20 percent at onset of disease. 7. 2005:1043-78. 50:72-7. not usually associated with pleuritic pain. vocal cords. 6. Clin Exp Rheum 2003. Merlino L. 10. A 55-year-old woman with rheumatoid arthritis. Cerhan JR. Philadelphia: W. Mikuls TR. lymphomas and leukemias two to three times more common in patients with rheumatoid arthritis. peripheral neuropathy. Ulnar deviation at metacarpophalangeal joints. Philadelphia: WB Saunders. Forms include distal arteritis. connecting bursa to the skin. 2005 .46:328-46. Welch V.aafp. increased risk of developing if male sex. More likely to be an effect of rheumatoid arthritis treatment.283:524-31. increased risk of tendon rupture Frozen shoulder may develop.17:307-15. with flexed DIP and hyperextended PIP. cutaneous lesions. Wells G. with gradual onset of upper extremity weakness and paresthesias. 7th ed. Clinical features of rheumatoid arthritis. Sledge CB. Page J. including on the sclera. Burma M. Tugwell P. 1046 American Family Physician www. Kuder SA. myocarditis—diffuse inflammation can occur. arteritis of viscera. increased risk for various solid tumors. Goldring SR. Cutaneous sinuses form near affected joints. BMJ 1995. high rheumatoid factor titers. Harris ED. and caffeine consumption and risk of rheumatoid arthritis: results from the Iowa Women’s Health Study. myelopathy can occur. Kelley’s Textbook of rheumatology. Firestein GS. eds. popliteal cysts can arise. 3. Vitamin D intake is inversely associated with rheumatoid arthritis: results from the Iowa Women’s Health Study. tea. interstitial fibrosis—rales may be noted on lung examination. Amos RS. Guidelines for the management of rheumatoid arthritis: 2002 update. usually found on extensor surfaces of the limbs or other pressure points. pericarditis. Akil M. three fourths of patients have anemia of chronic disease. Merlino LA. Rheumatoid arthritis—I: clinical features and diagnosis. Criswell LA. may form nearly anywhere. perhaps because of nonsteroidal anti-inflammatory drugs. associated with increased risk of myocardial infarction. one fourth of patients respond to iron therapy. Episcleritis rarely occurs. Saunders. 4.44:2477-84. American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. 5. Often have necrotic tissue in their centers. Number 6 ◆ September 15. Rev Environ Health 2002. Etiology and pathogenesis of rheumatoid arthritis. Caution must be used during endotracheal intubation. Lung nodules can coexist with cancers and form cavitary lesions. Peterson J. rEfErEncEs 1. C4-C5 and C5-C6 subluxations are possible. atrioventricular block—rare. Kelley WN. Cerhan JR. Arthritis Rheum 2004. 2. Kelley’s Textbook of rheumatology. Arthritis Rheum 2002. eds. In: Ruddy S.B. et al. Peshimam AZ. swan neck deformity—the reverse of boutonniere.310:587-90. with hoarseness and laryngeal pain. Kelley WN. found in 20 to 35 percent of patients with rheumatoid arthritis. genitourinary cancer risk is reduced in rheumatoid arthritis. May be secondary to treatments. Arthritis Rheum 2002. Coffee. Sledge CB. Curtis J. Arthritis Rheum 2001.TABLE 5 complications of untreated rheumatoid arthritis Complication Anemia Cancer Comments Correlates with erythrocyte sedimentation rate and disease activity. may see loss of lordosis of the neck and decreased range of motion. ABC of rheumatology. cricoarytenoid joint inflammation can arise. may or may not be symptomatic. Tenosynovitis of transverse ligament can lead to instability of atlas on axis. Davison C. may see joint space narrowing on lateral cervical spine films. Work disability in early rheumatoid arthritis. Pericarditis—one third of patients may have asymptomatic pericardial effusion at diagnosis. treatment with steroids.org/afp Volume 72. carpal and tarsal tunnel syndromes common. boutonniere deformity—flexed PIP and hyperextended DIP. thumb hyperextension. Mikuls TR. Sokka T. Mudano AS. Information from reference 5.21(5 suppl 31):S71-4. or vertebral bodies. 7th ed. Agraharam S.46:83-91. number of disease-modifying antirheumatic drugs prescribed. sacrum. Harris ED. JAMA 2000. and coronary arteritis. DIP = distal interphalangeal. Cardiac complications Cervical spine disease Eye problems Fistula formation Increased infections Hand joint deformities Other joint deformities Respiratory complications Rheumatoid nodules Vasculitis PIP = proximal interphalangeal. 8. Do silicone breast implants cause rheumatologic disorders? A systematic review for a court-appointed national science panel. 9. avoid flexion films until odontoid fracture ruled out if injury is suspected. In: Ruddy S. Harris ED. Environmental risk factors for rheumatoid arthritis.

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