Merck Manual

Please confirm that you are a health care professional

honeypot link

Rheumatoid Arthritis (RA)

By

Kinanah Yaseen

, MD, Cleveland Clinic

Last review/revision Nov 2022
View Patient Education
Topic Resources

Rheumatoid arthritis is a chronic systemic autoimmune disease that primarily involves the joints. Rheumatoid arthritis causes damage mediated by cytokines, chemokines, and metalloproteases. Characteristically, peripheral joints (eg, wrists, metacarpophalangeal joints) are symmetrically inflamed, leading to progressive destruction of articular structures, usually accompanied by systemic symptoms. Diagnosis is based on specific clinical, laboratory, and imaging features. Treatment involves drugs, physical measures, and sometimes surgery. Disease-modifying antirheumatic drugs can reduce symptoms and slow disease progression.

Rheumatoid arthritis affects about 1% of the population. Women are affected 2 to 3 times more often than men. Onset may be at any age, most often between 35 years and 50 years, but can be during childhood (see Juvenile Idiopathic Arthritis Juvenile Idiopathic Arthritis (JIA) Juvenile idiopathic arthritis is a group of rheumatic diseases that begins by age 16. Arthritis, fever, rash, adenopathy, splenomegaly, and iridocyclitis are typical of some forms. Diagnosis... read more Juvenile Idiopathic Arthritis (JIA) ) or old age.

Etiology of Rheumatoid Arthritis

Although rheumatoid arthritis involves autoimmune reactions, the precise cause is unknown; many factors may contribute. A genetic predisposition has been identified and, in White populations, localized to a shared epitope in the HLA-DRB1 locus of class II histocompatibility antigens. Unknown or unconfirmed environmental factors (eg, viral infections, cigarette smoking) are thought to play a role in triggering and maintaining joint inflammation.

Risk factors for rheumatoid arthritis include the following:

Etiology references

  • 1. Block KE, Zheng Z, Dent AL, et al: Gut microbiota regulates K/BxN autoimmune arthritis through follicular helper T but not Th17 cells. J Immunol 196(4):1550-7, 2016. doi: 10.4049/jimmunol.1501904

  • 2. Wegner N, Wait R, Sroka A, et al: Peptidylarginine deiminase from Porphyromonas gingivalis citrullinates human fibrinogen and α-enolase: implications for autoimmunity in rheumatoid arthritis. Arthritis Rheum 62(9):2662-72, 2010. doi: 10.1002/art.27552

Pathophysiology of Rheumatoid Arthritis

Prominent immunologic abnormalities include immune complexes produced by synovial lining cells and in inflamed blood vessels. Plasma cells produce antibodies (eg, rheumatoid factor [RF], anticyclic citrullinated peptide [anti-CCP] antibody) that contribute to these complexes, but destructive arthritis can occur in their absence. Macrophages also migrate to diseased synovium in early disease; increased macrophage-derived lining cells are prominent along with vessel inflammation. Lymphocytes that infiltrate the synovial tissue are primarily CD4+ T cells. Macrophages and lymphocytes produce pro-inflammatory cytokines and chemokines (eg, tumor necrosis factor [TNF]-alpha, granulocyte-macrophage colony-stimulating factor [GM-CSF], various interleukins, interferon-gamma) in the synovium. Released inflammatory mediators and various enzymes contribute to the systemic and joint manifestations of rheumatoid arthritis, including cartilage and bone destruction (1 Pathophysiology references Rheumatoid arthritis is a chronic systemic autoimmune disease that primarily involves the joints. Rheumatoid arthritis causes damage mediated by cytokines, chemokines, and metalloproteases.... read more Pathophysiology references ).

In seropositive rheumatoid arthritis, accumulating evidence suggests that anti-CCP antibodies appear long before any signs of inflammation (2 Pathophysiology references Rheumatoid arthritis is a chronic systemic autoimmune disease that primarily involves the joints. Rheumatoid arthritis causes damage mediated by cytokines, chemokines, and metalloproteases.... read more Pathophysiology references ). Additionally, anti-carbamylated protein (anti-CarP) antibodies (3 Pathophysiology references Rheumatoid arthritis is a chronic systemic autoimmune disease that primarily involves the joints. Rheumatoid arthritis causes damage mediated by cytokines, chemokines, and metalloproteases.... read more Pathophysiology references ) predict more radiologic progression in anti-CCP–negative rheumatoid arthritis patients. Progression to rheumatoid arthritis in the preclinical phase depends on autoantibody epitope spreading in which there are immune responses to released self-antigens with subsequent increased inflammation (4 Pathophysiology references Rheumatoid arthritis is a chronic systemic autoimmune disease that primarily involves the joints. Rheumatoid arthritis causes damage mediated by cytokines, chemokines, and metalloproteases.... read more Pathophysiology references ).

In chronically affected joints, the normally thin synovium proliferates, thickens, and develops many villous folds. The synovial lining cells produce various materials, including collagenase and stromelysin, which contribute to cartilage destruction, and interleukin-1 (IL-1) and TNF-alpha, which stimulate cartilage destruction, osteoclast-mediated bone absorption, synovial inflammation, and prostaglandins (which potentiate inflammation). Fibrin deposition, fibrosis, and necrosis are also present. Hyperplastic synovial tissue (pannus) releases these inflammatory mediators, which erode cartilage, subchondral bone, articular capsule, and ligaments. Polymorphonuclear leukocytes on average make up about 60% of white blood cells in the synovial fluid.

Rheumatoid nodules develop in about 30% of patients with rheumatoid arthritis. They are granulomas consisting of a central necrotic area surrounded by palisaded histiocytic macrophages, all enveloped by lymphocytes, plasma cells, and fibroblasts. Nodules can also develop in visceral organs.

Pathophysiology references

  • 1. McInnes IB, Schett G: The pathogenesis of rheumatoid arthritis. N Engl J Med 365(23):2205–2219, 2011. doi:10.1056/NEJMra1004965

  • 2. Rantapaa-Dahlqvist S, de Jong BA, Berglin E, et al: Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum 48:2741–2749, 2003. doi: 10.1002/art.11223

  • 3. Brink M, Verheul MK, Rönnelid J, et al: Anti-carbamylated protein antibodies in the pre-symptomatic phase of rheumatoid arthritis, their relationship with multiple anti-citrulline peptide antibodies and association with radiological damage. Arthritis Res Ther 17:25, 2015. doi: 10.1186/s13075-015-0536-2

  • 4. Sokolove J, Bromberg R, Deane KD, et al: Autoantibody epitope spreading in the pre-clinical phase predicts progression to rheumatoid arthritis. PLoS ONE 7(5):e35296, 2012. doi: 10.1371/journal.pone.0035296

Symptoms and Signs of Rheumatoid Arthritis

Onset of rheumatoid arthritis is usually insidious, often beginning with systemic and joint symptoms. Systemic symptoms include generalized afternoon fatigue and malaise, anorexia, generalized weakness, and occasionally low-grade fever. Joint symptoms include pain, swelling, and stiffness. Occasionally, the disease begins abruptly, mimicking an acute viral syndrome.

The disease progresses most rapidly during the first 6 years, particularly the first year; 80% of patients develop some permanent joint abnormalities within 10 years. The course is unpredictable in individual patients.

Joint symptoms are characteristically symmetric. Typically, stiffness lasts > 60 minutes after rising in the morning but may occur after any prolonged inactivity (called gelling). Involved joints become tender, with erythema, warmth, swelling, and limitation of motion. The joints primarily involved include the following:

  • Wrists and the index (2nd) and middle (3rd) metacarpophalangeal joints (most commonly involved)

  • Proximal interphalangeal joints

  • Metatarsophalangeal joint

  • Shoulders

  • Elbows

  • Hips

  • Knees

  • Ankles

However, virtually any joint, except the distal interphalangeal (DIP) joints, may be involved. Initial manifestations include

  • Monoarthritis of knee, wrist, shoulder, or ankle

  • Polymyalgia rheumatica–like presentation predominantly with shoulder and hip girdle involvement, especially in older patients

  • Palindromic rheumatism, characterized by recurrent attacks of joint and tendon sheath pain with swelling

  • Joint swelling without chronic joint damage

  • Robustus rheumatoid arthritis with proliferative synovitis but minimal pain

Lower spine involvement is not characteristic of rheumatoid arthritis, but cervical spine inflammation can result in instability, which can become an emergency. Synovial thickening and swelling are often detectable. Joints are often held in flexion to minimize pain, which results from joint capsular distention.

Cervical spine involvement is common in longstanding active disease and usually presents as pain and stiffness, sometimes with radicular pain or features of myelopathy with hyperreflexia and occipital headache.

Cricoarytenoid joint arthritis can manifest as voice hoarseness and respiratory stridor.

Examples of Fixed Deformities

Boutonnière and swan-neck deformities

Boutonnière and swan-neck deformities

Extra-articular manifestations

Subcutaneous rheumatoid nodules are not usually an early sign but eventually develop in up to 30% of patients, usually at sites of pressure and chronic irritation (eg, the extensor surface of the forearm, metacarpophalangeal joints, soles of feet). Paradoxically, rheumatoid nodules can increase in patients taking methotrexate, despite lessening of joint inflammation. Visceral nodules (eg, pulmonary) are usually asymptomatic and may occur in severe rheumatoid arthritis. Pulmonary nodules of rheumatoid arthritis cannot be distinguished from pulmonary nodules of other etiology without biopsy.

Other extra-articular signs include vasculitis Cutaneous Vasculitis Cutaneous vasculitis refers to vasculitis affecting small- or medium-sized vessels in the skin and subcutaneous tissue but not the internal organs. Cutaneous vasculitis may be limited to the... read more Cutaneous Vasculitis causing leg ulcers, digital ischemia, or multiple mononeuropathy (mononeuritis multiplex), pleural or pericardial effusions, obliterative bronchiolitis, interstitial lung disease Overview of Interstitial Lung Disease Interstitial lung diseases are a heterogeneous group of disorders characterized by alveolar septal thickening, fibroblast proliferation, collagen deposition, and, if the process remains unchecked... read more , pericarditis Pericarditis Pericarditis is inflammation of the pericardium, often with fluid accumulation in the pericardial space. Pericarditis may be caused by many disorders (eg, infection, myocardial infarction, trauma... read more Pericarditis , myocarditis Myocarditis Myocarditis is inflammation of the myocardium with necrosis of cardiac myocytes. Myocarditis may be caused by many disorders (eg, infection, cardiotoxins, drugs, and systemic disorders such... read more Myocarditis , lymphadenopathy Lymphadenopathy Lymphadenopathy is palpable enlargement of ≥ 1 lymph nodes. Diagnosis is clinical. Treatment is of the causative disorder. (See also Overview of the Lymphatic System.) Lymph nodes are present... read more Lymphadenopathy , Felty syndrome, Sjögren syndrome Sjögren Syndrome Sjögren syndrome is a relatively common chronic, autoimmune, systemic, inflammatory disorder of unknown cause. It is characterized by dryness of the mouth, eyes, and other mucous membranes ... read more Sjögren Syndrome , scleromalacia, and episcleritis Episcleritis Episcleritis is self-limiting, recurring, usually idiopathic inflammation of the episcleral tissue that does not threaten vision. Symptoms are a localized area of hyperemia of the globe, irritation... read more Episcleritis .

Examples of Rheumatoid Nodule

Diagnosis of Rheumatoid Arthritis

  • Clinical criteria

  • Serum rheumatoid factor (RF), anticyclic citrullinated peptide (anti-CCP), and erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP)

  • X-rays

Rheumatoid arthritis should be suspected in patients with polyarticular, symmetric arthritis, particularly if the wrists and 2nd and 3rd metacarpophalangeal joints are involved. Classification criteria serve as a guide for establishing the diagnosis of rheumatoid arthritis and are helpful in defining standardized treatment populations for study purposes. Criteria include laboratory test results for RF, anti-CCP, and ESR or CRP (see table ). However, diagnosis requires documented joint inflammation and should not be based on laboratory testing alone.

Other causes of symmetric polyarthritis, particularly hepatitis C, must be excluded. Obtaining baseline x-rays of affected joints should be considered to help document progression of disease (erosive changes, joint space narrowing) over time. In patients who have prominent lumbar symptoms, alternative diagnoses should be investigated.

Table

RFs, antibodies to human gamma-globulin, are present in about 70% of patients with rheumatoid arthritis. However, RF, often in low titers (levels can vary between laboratories), occurs in patients with other diseases, including

Low RF titers can also occur in 3% of the general population and 20% of older patients. Very high RF titers can occur in patients with hepatitis C infection and sometimes in patients with other chronic infections. An RF titer measured by latex agglutination of > 1:80 or a positive anti-CCP test supports the diagnosis of rheumatoid arthritis in the appropriate clinical context, but other causes must be excluded.

Anti-CCP antibodies have high specificity (90%) and sensitivity (about 77 to 86%) for rheumatoid arthritis and, like RF, predict a worse prognosis. RF and anti-CCP values do not fluctuate with disease activity. Anti-CCP antibodies are notably absent in patients with hepatitis C who may have a positive RF titer and joint swelling related to the viral infection.

X-rays show only soft-tissue swelling during the first months of disease. Subsequently, periarticular osteoporosis, joint space (articular cartilage) narrowing, and marginal erosions may become visible. Erosions often develop within the first year but may occur any time. MRI seems to be more sensitive and detects earlier articular inflammation and erosions. In addition, abnormal subchondral bone signals (eg, bone marrow lesions, bone marrow edema) around the knee suggest progressive disease.

If rheumatoid arthritis is diagnosed, additional tests help detect complications and unexpected abnormalities. Complete blood count with differential should be obtained. A normochromic (or slightly hypochromic)-normocytic anemia occurs in 80%; hemoglobin is usually > 10 g/dL (100 g/L). If hemoglobin is 10 g/dL (100 g/L), superimposed iron deficiency or other causes of anemia should be considered. Neutropenia occurs in 1 to 2% of cases, often with splenomegaly (Felty syndrome). Acute-phase reactants (eg, thrombocytosis, elevated ESR, elevated CRP) reflect disease activity. A mild polyclonal hypergammaglobulinemia often occurs. ESR is elevated in 90% of patients with active disease.

Validated measures of disease activity include the Rheumatoid Arthritis Disease Activity Score DAS-28 and Rheumatoid Arthritis Clinical Disease Activity Index.

Synovial fluid examination is necessary with any new-onset effusion to rule out other disorders and differentiate rheumatoid arthritis from other inflammatory arthritides (eg, septic and crystal-induced arthritis). In rheumatoid arthritis, during active joint inflammation, synovial fluid is turbid, yellow, and sterile, and usually has white blood cell counts 10,000 to 50,000/mcL (10.0 x109/L to 50.0 x109/L); polymorphonuclear leukocytes typically predominate, but > 50% may be lymphocytes and other mononuclear cells. Crystals are absent.

Differential diagnosis

Many disorders can simulate rheumatoid arthritis:

Some patients with crystal-induced arthritis, especially calcium pyrophosphate arthritis Calcium Pyrophosphate Arthritis Calcium pyrophosphate arthritis (CPP arthritis) involves intra-articular and/or extra-articular deposition of calcium pyrophosphate dihydrate (CPPD) crystals. Manifestations are protean and... read more Calcium Pyrophosphate Arthritis , may meet criteria for rheumatoid arthritis; however, synovial fluid examination should clarify the diagnosis. The presence of crystals makes rheumatoid arthritis unlikely, although calcium pyrophosphate crystal disease and rheumatoid arthritis may coexist in the same patient. Joint involvement and subcutaneous nodules can result from SLE, gout, cholesterol, and amyloidosis Amyloidosis Amyloidosis is any of a group of disparate conditions characterized by extracellular deposition of insoluble fibrils composed of misaggregated proteins. These proteins may accumulate locally... read more Amyloidosis as well as rheumatoid arthritis; aspiration or biopsy of the nodules may occasionally be needed.

SLE Systemic Lupus Erythematosus (SLE) Systemic lupus erythematosus is a chronic, multisystem, inflammatory disorder of autoimmune etiology, occurring predominantly in young women. Common manifestations may include arthralgias and... read more Systemic Lupus Erythematosus (SLE) usually can be distinguished if there are skin lesions on light-exposed areas, hair loss, oral and nasal mucosal lesions, absence of joint erosions in even long-standing arthritis, joint fluid that often has white blood cell counts < 2000/mcL (2.0 x109/L) (predominantly mononuclear cells), antibodies to double-stranded DNA, renal disease, and low serum complement levels. In contrast to rheumatoid arthritis, swan neck and ulnar deviation deformities in SLE are usually reducible.

Sarcoidosis Sarcoidosis Sarcoidosis is an inflammatory disorder resulting in noncaseating granulomas in one or more organs and tissues; etiology is unknown. The lungs and lymphatic system are most often affected, but... read more Sarcoidosis , Whipple disease Whipple Disease Whipple disease is a rare systemic illness caused by the bacterium Tropheryma whipplei. Main symptoms are arthritis, weight loss, abdominal pain, and diarrhea. Diagnosis is by small-bowel... read more , multicentric reticulohistiocytosis, and other systemic diseases may involve joints; other clinical features and tissue biopsy sometimes help differentiate these conditions. Acute rheumatic fever has a migratory pattern of joint involvement and evidence of antecedent streptococcal infection (culture or changing antistreptolysin O titer); in contrast, rheumatoid arthritis tends to involve additional joints over time.

Reactive arthritis Reactive Arthritis Reactive arthritis is an acute spondyloarthropathy that often seems precipitated by an infection, usually genitourinary or gastrointestinal. Common manifestations include asymmetric arthritis... read more Reactive Arthritis can be differentiated by antecedent gastrointestinal or genitourinary symptoms; asymmetric involvement and pain at the Achilles insertion of the heel, sacroiliac joints, and large joints of the leg; conjunctivitis; iritis; painless buccal ulcers; balanitis circinata; or keratoderma blennorrhagicum on the soles and elsewhere.

Psoriatic arthritis Psoriatic Arthritis Psoriatic arthritis is a seronegative spondyloarthropathy and chronic inflammatory arthritis that occurs in people with psoriasis of the skin or nails. The arthritis is often asymmetric, and... read more Psoriatic Arthritis tends to be asymmetric and is not usually associated with RF, but clinical differentiation may be difficult in the absence of nail or skin lesions. Distal interphalangeal joint involvement and severely mutilating arthritis (arthritis mutilans) is strongly suggestive, as is the presence of a diffusely swollen (sausage) digit. Psoriatic arthritis may involve the sacroiliac joints and lower spine. Distinguishing between psoriatic arthritis and rheumatoid arthritis is important because response to some specific drugs differs.

Ankylosing spondylitis Ankylosing Spondylitis Ankylosing spondylitis is the prototypical spondyloarthropathy and a systemic disorder characterized by inflammation of the axial skeleton, large peripheral joints, and digits; nocturnal back... read more Ankylosing Spondylitis may be differentiated by spinal and axial joint involvement, absence of subcutaneous nodules, and a negative RF test. The HLA-B27 allele is present in 90% of White patients with ankylosing spondylitis.

Osteoarthritis Osteoarthritis (OA) Osteoarthritis is a chronic arthropathy characterized by disruption and potential loss of joint cartilage along with other joint changes, including bone hypertrophy (osteophyte formation). Symptoms... read more Osteoarthritis (OA) can be differentiated by the joints involved; the absence of rheumatoid nodules, systemic manifestations, or significant amounts of RF; and by synovial fluid white blood cell counts < 2000/mcL (2.0 x109/L). Osteoarthritis of the hands most typically involves the DIP joints, bases of the thumbs, and proximal interphalangeal joints and may involve the metacarpophalangeal joints, but typically spares the wrist. Rheumatoid arthritis does not affect the DIP joints. Rheumatoid arthritis is characterized by clinically apparent, symmetric, small joint inflammation with frequent wrist involvement.

Prognosis for Rheumatoid Arthritis

Rheumatoid arthritis decreases life expectancy by 3 to 7 years, with heart disease, infection, and gastrointestinal bleeding accounting for most excess mortality; drug treatment, cancer, as well as the underlying disease may be responsible. Disease activity should be controlled to lower cardiovascular disease risk in all patients with rheumatoid arthritis. (See also the European League Against Rheumatism's (EULAR) recommendations for cardiovascular disease risk management in patients with rheumatoid arthritis and other forms of inflammatory joint disorders.)

At least 10% of patients are eventually severely disabled despite full treatment. White people and women have a poorer prognosis, as do patients with subcutaneous nodules, advanced age at disease onset, inflammation in 20 joints, early erosions, cigarette smoking, high erythrocyte sedimentation rate, and high levels of rheumatoid factor or anticyclic citrullinated peptide (anti-CCP).

Treatment of Rheumatoid Arthritis

  • Nonpharmacological measures: Smoking cessation, healthy, balanced nutrition, physical joint protective measures, quality sleep

  • Pharmacological measures: Medications that modify disease progression and nonsteroidal anti-inflammatory drugs (NSAIDs) as needed for analgesia

Treatment of rheumatoid arthritis involves a balance of rest and exercise, adequate nutrition, physical measures, drugs, and sometimes surgery. Early diagnosis and treatment in rheumatoid arthritis predict improved outcomes. A treat-to-target approach to achieve full disease remission or minimal disease activity has been recommended by the American College of Rheumatology (ACR) (1 Treatment references Rheumatoid arthritis is a chronic systemic autoimmune disease that primarily involves the joints. Rheumatoid arthritis causes damage mediated by cytokines, chemokines, and metalloproteases.... read more Treatment references ) and European League Against Rheumatism (EULAR) (2 Treatment references Rheumatoid arthritis is a chronic systemic autoimmune disease that primarily involves the joints. Rheumatoid arthritis causes damage mediated by cytokines, chemokines, and metalloproteases.... read more Treatment references ) recommendations for the management of rheumatoid arthritis.

Lifestyle measures

Complete bed rest is rarely indicated, even for a short time; however, a program including judicious rest should be encouraged. Quality sleep should be encouraged, because poor sleep increases pain.

An ordinary nutritious diet is appropriate. Rarely, patients have food-associated exacerbations; no specific foods have reproducibly been shown to exacerbate or lessen the symptoms of rheumatoid arthritis. Substituting omega-3 fatty acids (in fish oils) for dietary omega-6 fatty acids (in meats) partially relieves symptoms in some patients by transiently decreasing production of inflammatory prostaglandins and possibly by modifying the gut microbiome. Smoking cessation can increase life expectancy.

Food and diet misinformation targeting rheumatoid arthritis patients is common, and patients should be directed to reliable sources of information.

Physical measures

Joint splinting reduces local inflammation and may relieve severe symptoms of pain or compressive neuropathies. Cold may be applied to reduce joint pain and swelling. Orthopedic or athletic shoes with good heel and arch support are frequently helpful; metatarsal supports placed posteriorly (proximal) to painful metatarsophalangeal joints decrease the pain of weight bearing. Molded shoes may be needed for severe deformities. Occupational therapy and self-help devices enable many patients with debilitating rheumatoid arthritis to perform activities of daily living.

Exercise should proceed as tolerated. During acute inflammation, passive range-of-motion exercise helps prevent flexion contractures. Heat therapy can be applied to help alleviate stiffness. Range-of-motion exercises done in warm water are helpful because heat improves muscle function by reducing stiffness and muscle spasm. However, contractures can be prevented and muscle strength can be restored more successfully after inflammation begins to subside; active exercise (including walking and specific exercises for involved joints) to restore muscle mass and preserve range of joint motion are recommended. Flexion contractures may require intensive exercise, casting, or immobilization (eg, splinting) in progressively more stretched-open positions. Paraffin baths can warm digits and facilitate finger exercise.

Surgery

Surgery may be considered if drug therapy is unsuccessful. Surgery must always be considered in terms of the total disease and patient expectations. For example, deformed hands and arms limit crutch use during rehabilitation; seriously affected knees and feet limit benefit from hip surgery. Reasonable objectives for each patient must be determined, and function must be considered; straightening ulnar-deviated fingers may not improve hand function. Surgery may be done while the disease is active.

Arthroplasty with prosthetic joint replacement is indicated if damage severely limits function; total hip and knee replacements are most consistently successful. Prosthetic hips and knees may limit vigorous activity (eg, competitive athletics). Excision of subluxed painful metatarsophalangeal joints may greatly aid walking. Thumb fusions may provide stability for pinch. Neck fusion may be needed for C1-2 subluxation with severe pain or potential for spinal cord compression. Arthroscopic or open synovectomy can relieve joint inflammation but only temporarily unless disease activity can be controlled. Withholding some immunosuppressive medications at the time of arthroplasty should be considered to limit the risk of infection. Even low-dose prednisone (< 7.5 mg a day) may increase infectious risk.

Treatment references

  • 1. Fraenkel L, Bathon JM, England BR, et al: 2021 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol 73(7):1108-1123, 2021. doi:10.1002/art.41752

  • 2. Smolen JS, Landewé RBM, Bijlsma JWJ, et al: EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann Rheum Dis 79(6):685-699, 2020. doi:10.1136/annrheumdis-2019-216655

Drugs for Rheumatoid Arthritis

The goal is to reduce inflammation to prevent erosions, progressive deformity, and loss of joint function. A treat-to-target approach to achieve full disease remission or minimal disease activity has been suggested (1 Drugs for rheumatoid arthritis references Rheumatoid arthritis is a chronic systemic autoimmune disease that primarily involves the joints. Rheumatoid arthritis causes damage mediated by cytokines, chemokines, and metalloproteases.... read more Drugs for rheumatoid arthritis references , 2 Drugs for rheumatoid arthritis references Rheumatoid arthritis is a chronic systemic autoimmune disease that primarily involves the joints. Rheumatoid arthritis causes damage mediated by cytokines, chemokines, and metalloproteases.... read more Drugs for rheumatoid arthritis references ). Disease-modifying antirheumatic drugs (DMARDs) are used early, often in combination. Biologic agents such as tumor necrosis factor (TNF)-alpha antagonists, an interleukin (IL)-1 receptor inhibitor, IL-6 blockers, B-cell depleters, T-cell costimulatory molecule modulators, and Janus kinase (JAK) inhibitors, seem to slow the progression of rheumatoid arthritis. Nonsteroidal anti-inflammatory drugs are of some help for the pain of rheumatoid arthritis, but they do not prevent erosions or disease progression, may slightly increase cardiovascular risk, and thus should be used as adjunctive therapy. Low-dose systemic corticosteroids (prednisone < 7.5 mg once/day) may be added to control severe polyarticular symptoms, usually with the objective of replacement with a DMARD. Intra-articular depot corticosteroids can control severe monarticular or even oligoarticular symptoms but with chronic use may have adverse metabolic effects, even in low doses. Studies indicate infectious and metabolic adverse effects from even low-dose chronic corticosteroid use, thus limitation of use is a treatment priority.

The optimal combinations of drugs are not yet clear. However, some data suggest that certain combinations of drugs from different classes (eg, methotrexate plus other DMARDs, a rapidly tapered corticosteroid plus a DMARD, methotrexate plus a TNF-alpha antagonist, or a TNF-alpha antagonist plus a DMARD) are more effective than using DMARDs alone sequentially or in combination with other DMARDs. In general, biologic agents are not given in combination with each other due to increased frequency of infections. The following is an example of initial therapy:

  • Methotrexate 10 to 15 mg orally once/week (with folic acid 1 mg orally once/day) is given.

  • If tolerated and not adequate, the dosage of weekly methotrexate is increased at 3- to 5-week intervals to a maximum of 25 mg orally or by injection (oral bioavailability decreases above 15 mg in a single dose).

  • If response is not adequate, a biologic agent is usually added. Alternatively, triple therapy with methotrexate, hydroxychloroquine, and sulfasalazine is a cost-effective option, but long-term tolerability is challenging.

Leflunomide may be used instead of methotrexate or added to methotrexate with close monitoring of serum transaminase levels and complete blood count.

Methotrexate and leflunomide (and some other medications) must be avoided if pregnancy is anticipated.

Nonsteroidal anti-inflammatory drugs (NSAIDs)

Aspirin is no longer used for rheumatoid arthritis because effective doses are often toxic. Only one NSAID should be given at a time (see table NSAID Treatment of Rheumatoid Arthritis Nonsteroidal Anti-inflammatory Drug (NSAID) Treatment of Rheumatoid Arthritis Nonsteroidal Anti-inflammatory Drug (NSAID) Treatment of Rheumatoid Arthritis ), although patients may also take aspirin at 325 mg/day for its antiplatelet cardioprotective effect. Because the maximal response for NSAIDs can take up to 2 weeks, doses should be increased no more frequently than this. Doses of drugs with flexible dosing can be increased until response is maximal or maximum dosage is reached. All NSAIDs treat the symptoms of rheumatoid arthritis and decrease inflammation but do not alter the course of the disease; thus, they are only used adjunctively.

NSAIDs inhibit cyclooxygenase (COX) enzymes and thus decrease production of prostaglandins. Some prostaglandins under COX-1 control have important effects in many parts of the body (ie, they protect gastric mucosa and inhibit platelet adhesiveness). Other prostaglandins are induced by inflammation and are produced by COX-2. Selective COX-2 inhibitors, also called coxibs (eg, celecoxib), seem to have efficacy similar to nonselective NSAIDs and are slightly less likely to cause gastrointestinal toxicity; however, they are not less likely to cause renal toxicity. Celecoxib 200 mg orally once/day has a comparable cardiovascular safety profile to nonselective NSAIDs. It remains unclear whether full-dose celecoxib (200 mg orally 2 times a day ) has cardiovascular risks comparable to the nonselective NSAIDs.

NSAIDs should generally be avoided in patients with previous peptic ulcer disease or dyspepsia; gastric acid suppressive therapy should be provided in these patients if an NSAID is used (eg, short term). Other possible adverse effects of all NSAIDs include headache, confusion and other central nervous system symptoms, increased blood pressure, worsening of hypertension, edema, and decreased platelet function; however, celecoxib has no significant antiplatelet effect. NSAIDs may increase cardiovascular risk (see Treatment of Pain/Nonopioid Analgesics Nonopioid Analgesics ). Creatinine levels can rise reversibly because of inhibited renal prostaglandins and reduced renal blood flow; rarely, interstitial nephritis can occur. Patients with urticaria, rhinitis, or asthma caused by aspirin can have the same problems with these other NSAIDs, but celecoxib may not cause these problems.

NSAIDs should be used at the lowest possible dose needed to mitigate their adverse effects.

Table

Traditional disease-modifying antirheumatic drugs (DMARDs)

(See table Other Drugs Used to Treat Rheumatoid Arthritis Other Drugs Used to Treat Rheumatoid Arthritis Other Drugs Used to Treat Rheumatoid Arthritis for specific dosage information and adverse effects of other drugs used to treat rheumatoid arthritis.)

DMARDs seem to slow the progression of rheumatoid arthritis and are indicated for nearly all patients with rheumatoid arthritis. They differ from each other chemically and pharmacologically. Many take weeks or months to have an effect. About two thirds of patients improve overall, and complete remissions are becoming more common. Many DMARDs result in evidence of decreased damage on imaging studies, presumably reflecting decreased disease activity. Patients should be fully apprised of the risks of DMARDs and monitored closely for evidence of toxicity.

Table

When choosing DMARDs, the following principles should be considered:

  • Combinations of DMARDs may be more effective than single drugs. For example, hydroxychloroquine, sulfasalazine, and methotrexate together are more effective than methotrexate alone or the other two together.

  • Combining a DMARD with another drug, such as methotrexate plus a tumor necrosis factor (TNF)-alpha antagonist or a rapidly tapered corticosteroid, may be more effective than using DMARDs alone.

Methotrexate is a folate antagonist with immunosuppressive effects at high dose. It is anti-inflammatory at doses used in rheumatoid arthritis. It is very effective and has a relatively rapid onset (clinical benefit often within 3 to 4 weeks). Methotrexate should be used with caution, if at all, in patients with hepatic dysfunction or renal failure. Alcohol should be avoided. Supplemental folate, 1 mg orally once/day, reduces the likelihood of adverse effects. Complete blood count (CBC), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and albumin and creatinine level should be determined about every 8 to 12 weeks. When used early in the course of rheumatoid arthritis, efficacy may equal the biologic agents. Rarely, a liver biopsy is needed if liver test findings are persistently twice the upper limit of normal or more and the patient needs to continue to use methotrexate. Severe relapses of arthritis can occur after withdrawal of methotrexate. Paradoxically, rheumatoid nodules may enlarge with methotrexate therapy. In rheumatoid arthritis patients with stable parenchymal lung disease, methotrexate can be continued with close monitoring of their respiratory status, if the methotrexate is controlling joint inflammation.

Hydroxychloroquine can also control symptoms of mild rheumatoid arthritis. Funduscopic examination should be done and visual fields should be assessed before and every 12 months during treatment. The drug should be stopped if no joint improvement occurs after 9 months.

Sulfasalazine can alleviate symptoms and slow development of joint damage. It is usually given as enteric-coated tablets. Benefit should occur within 3 months. Enteric coating or dose reduction may increase tolerability. Because neutropenia may occur early, CBCs should be obtained after 1 to 2 weeks and then about every 12 weeks during therapy. AST and ALT should be obtained at about 6-month intervals and whenever the dose is increased. In male patients, sulfasalazine may cause reversible oligospermia.

Leflunomide interferes with an enzyme involved with pyrimidine metabolism. It is about as effective as methotrexate but is less likely to suppress bone marrow, cause abnormal liver function, or cause pneumonitis. Alopecia and diarrhea are fairly common at the onset of therapy but may resolve with continuation of therapy.

Corticosteroids

Systemic corticosteroids decrease inflammation and other symptoms more rapidly and to a greater degree than other drugs. They may not prevent joint destruction, and their clinical benefit often diminishes with time. Furthermore, rebound often follows the withdrawal of corticosteroids in active disease. Because of their long-term adverse effects, some doctors recommend that corticosteroids are given only for short periods of time to maintain function until a DMARD has taken effect.

Corticosteroids may be used for severe joint or systemic manifestations of rheumatoid arthritis (eg, vasculitis, pleurisy, pericarditis). Relative contraindications include peptic ulcer disease, hypertension, untreated infections, diabetes mellitus, and glaucoma. The risk of latent tuberculosis should be considered before corticosteroid therapy is begun.

Intra-articular injections of depot corticosteroids may temporarily help control pain and swelling in particularly painful joints. Triamcinolone hexacetonide may suppress inflammation for the longest time. Triamcinolone acetonide and methylprednisolone acetate are also effective. No single joint should be injected with a corticosteroid more than 3 to 4 times a year, as too-frequent injections may accelerate joint destruction (although there are no specific data from humans to support this effect). Because injectable corticosteroid esters are crystalline, local inflammation transiently increases within a few hours in < 2% of patients receiving injections. Although infection occurs in only < 1:40,000 patients, it must be considered if pain occurs > 24 hours after injection.

Immunomodulatory, cytotoxic, and immunosuppressive drugs

Treatment with azathioprine or cyclosporine (an immunomodulatory drug) may provide efficacy similar to DMARDs. However, these drugs are more toxic and less well studied. Thus, they are used only for patients in whom treatment with more traditional DMARDs has failed. They are used infrequently unless there are extra-articular complications.

Biologic agents

Tumor necrosis factor (TNF)-alpha antagonists (eg, adalimumab, etanercept, golimumab, certolizumab pegol, infliximab, and their biosimilars) reduce the progression of erosions and reduce the number of new erosions. Although not all patients respond, many have a prompt, dramatic feeling of well being, sometimes with the first injection. Inflammation is often dramatically reduced. These drugs are often added to methotrexate therapy to increase the effect and possibly prevent the development of drug-neutralizing antibodies.

Recent information suggests safety during pregnancy with TNF inhibitors and anakinra (3 Drugs for rheumatoid arthritis references Rheumatoid arthritis is a chronic systemic autoimmune disease that primarily involves the joints. Rheumatoid arthritis causes damage mediated by cytokines, chemokines, and metalloproteases.... read more Drugs for rheumatoid arthritis references ). TNF-alpha antagonists should probably be stopped before major surgery to decrease the risk of perioperative infection (4 Drugs for rheumatoid arthritis references Rheumatoid arthritis is a chronic systemic autoimmune disease that primarily involves the joints. Rheumatoid arthritis causes damage mediated by cytokines, chemokines, and metalloproteases.... read more Drugs for rheumatoid arthritis references ). Etanercept, infliximab, and adalimumab can be used with or without methotrexate. TNF inhibitors may predispose to heart failure and thus are relatively contraindicated in stage 3 and stage 4 heart failure. There is a minimal risk of lymphoma in rheumatoid arthritis patients who are being treated with TNF inhibitors. 2015 ACR guidelines conditionally recommended using DMARDs, rituximab, or abatacept instead of TNF inhibitors in patients with history of lymphoma (5 Drugs for rheumatoid arthritis references Rheumatoid arthritis is a chronic systemic autoimmune disease that primarily involves the joints. Rheumatoid arthritis causes damage mediated by cytokines, chemokines, and metalloproteases.... read more Drugs for rheumatoid arthritis references ). Evidence regarding solid tumors in TNF inhibitors is mixed. Other possible adverse events of TNF inhibitors include injection site reaction, acute and delayed infusion reaction, demyelinating disease, granulomatous diseases such as sarcoidosis, cytopenias (especially neutropenia), cutaneous vasculitis, and rarely antineutrophilic cytoplasmic associated vasculitis.

Sarilumab is an interleukin-6 (IL-6) inhibitor. It is available for adults with moderately to severely active rheumatoid arthritis who have had an inadequate response to or are intolerant of one or more DMARDs.

Tocilizumab is an IL-6 inhibitor and has clinical efficacy in patients who have responded incompletely to other biologic agents.

Abatacept, a soluble fusion cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) Ig, is indicated for patients with rheumatoid arthritis with an inadequate response to other DMARDs, and conditionally recommended over other biologic DMARDs in patients with rheumatoid arthritis and non-tuberculous mycobacterial lung disease.

Anakinra is a recombinant interleukin-1 (IL-1) receptor. IL-1 is heavily involved in the pathogenesis of rheumatoid arthritis. Infection and leukopenia can be problems. It is used less often because it must be given every day.

Rituximab is an anti-CD 20 antibody that depletes B cells. It can be used in patients refractory to other treatments. Response is often delayed but may last 6 months. The course can be repeated after 6 months. Mild adverse effects are common, and analgesia, corticosteroids, diphenhydramine, or a combination may need to be given concomitantly. Rituximab therapy has been associated with progressive multifocal leukoencephalopathy (as have other immunosuppressive drugs), mucocutaneous reactions, delayed leukopenia, and hepatitis B reactivation with hepatic necrosis. Patients on rituximab may have a blunted immune response to the COVID-19 vaccine COVID-19 Vaccine COVID-19 vaccines provide protection against COVID-19, the disease caused by infection with the SARS-CoV-2 virus. Vaccination is the most effective strategy to prevent severe illness and death... read more and have poorer outcomes if infected with SARS-CoV-2. Therefore, rituximab is now generally reserved for patients who did not respond to other biologic DMARDs (including a combined TNF-alpha inhibitor and methotrexate) and to those with lymphoproliferative disorders.

Rituximab therapy might be gradually discontinued if the patient has had low disease activity or been in remission for at least 6 months.

Although there are some differences among agents, the most serious concern with the biologics and targeted DMARDs is infection, particularly with reactivated tuberculosis. Patients should be screened for tuberculosis Screening for TB Tuberculosis is a chronic, progressive mycobacterial infection, often with an asymptomatic latent period following initial infection. Tuberculosis most commonly affects the lungs. Symptoms include... read more Screening for TB with purified protein derivative (PPD) or an interferon-gamma release assay. Other serious infections can occur, including sepsis, invasive fungal infections, and infections due to other opportunistic organisms. Patients should be up to date on vaccinations Overview of Immunization Immunity can be achieved Actively by using antigens (eg, vaccines, toxoids) Passively by using antibodies (eg, immune globulins, antitoxins) A toxoid is a bacterial toxin that has been modified... read more prior to treatment with a biologic agent.

Janus kinase (JAK) inhibitors

Janus kinase (JAK) inhibitors are small molecule agents that interfere with the communication between cells that coordinate inflammation by inhibiting the enzyme JAK. JAK inhibitors include tofacitinib, baricitinib, and upadacitinib. (See also table .) JAK inhibitors carry an increased incidence of herpes zoster, thus vaccination against zoster Herpes Zoster Vaccine Chickenpox (varicella) and shingles ( herpes zoster) are caused by the varicella-zoster virus; chickenpox is the acute invasive phase of the virus, and shingles represents reactivation of the... read more is strongly suggested prior to use of these medications.

Baricitinib is an oral Janus kinase (JAK) inhibitor. It is indicated for adults with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more TNF antagonists.

Tofacitinib is a JAK inhibitor that is given orally with or without concomitant methotrexate to patients who do not respond to methotrexate alone or other biologic agents.

Upadacitinib is a JAK inhibitor that is given orally to adults with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate. Other JAK inhibitors that may soon become available in the US include filgotinib and peficitinib.

A prospective, randomized, open-label study compared the JAK inhibitor tofacitinib (5 and 10 mg doses) with TNF-alpha antagonists. After a median follow-up of 4 years, the results showed a higher risk of major adverse cardiovascular events (MACEs) and cancer with tofacitinib than with TNF-alpha antagonists, especially in patients over age 50 years and with at least 1 risk factor for cardiovascular disease (6 Drugs for rheumatoid arthritis references Rheumatoid arthritis is a chronic systemic autoimmune disease that primarily involves the joints. Rheumatoid arthritis causes damage mediated by cytokines, chemokines, and metalloproteases.... read more Drugs for rheumatoid arthritis references ).

Drugs for rheumatoid arthritis references

  • 1. Fraenkel L, Bathon JM, England BR, et al: 2021 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol 73(7):1108-1123, 2021. doi:10.1002/art.41752

  • 2. Smolen JS, Landewé RBM, Bijlsma JWJ, et al: EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann Rheum Dis 79(6):685-699, 2020. doi:10.1136/annrheumdis-2019-216655

  • 3. Sammaritano LR, Bermas BL, Chakravarty EE, et al: 2020 American College of Rheumatology guideline for the management of reproductive health in rheumatic and musculoskeletal diseases. Arthritis Care Res (Hoboken) 72(4):461-488, 2020. doi:10.1002/acr.24130

  • 4. Goodman SM, Springer BD, Chen AF, et al: 2022 American College of Rheumatology/American Association of Hip and Knee Surgeons guideline for the perioperative management of antirheumatic medication in patients with rheumatic diseases undergoing elective total hip or total knee arthroplasty. Arthritis Care Res (Hoboken) 74(9):1399-1408, 2022. doi:10.1002/acr.24893

  • 5. Singh JA, Saag KG, Bridges SL Jr, et al: 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol 68(1):1-26, 2016. doi:10.1002/art.39480

  • 6. Ytterberg SR, Bhatt DL, Mikuls TR, et al: Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritis. N Engl J Med 386(4):316-326, 2022. doi:10.1056/NEJMoa2109927

Key Points

  • Rheumatoid arthritis is a systemic inflammatory disorder.

  • The most characteristic manifestation is a symmetric polyarthritis involving peripheral joints such as wrists and metacarpophalangeal and metatarsophalangeal joints, often with constitutional symptoms.

  • Extra-articular findings can include rheumatoid nodules, vasculitis causing leg ulcers or multiple mononeuropathy, pleural or pericardial effusions, pulmonary nodules, pulmonary infiltrates or fibrosis, pericarditis, myocarditis, lymphadenopathy, Felty syndrome, Sjögren syndrome, scleromalacia, and episcleritis.

  • X-rays are helpful, but early diagnosis is primarily by recognizing specific clinical findings and demonstrating abnormal laboratory test results, including autoantibodies (serum rheumatoid factor and anti-cyclic citrullinated peptide antibody) and acute-cell phase reactants (erythrocyte sedimentation rate or C-reactive protein). Diagnosis requires documented joint inflammation and should not be based on laboratory testing alone.

  • Rheumatoid arthritis decreases life expectancy by 3 to 7 years (eg, due to gastrointestinal bleeding, infection, or coronary heart disease) and causes severe disability in 10% of patients.

  • Treat almost all patients aggressively early, primarily with drugs that modify disease activity.

  • Drugs that modify disease activity include traditional DMARDs (particularly methotrexate), biologic agents such as tumor necrosis factor (TNF)-alpha antagonists or other non-TNF biologic agents, and other drugs that are immunomodulatory, cytotoxic, or immunosuppressive.

View Patient Education
NOTE: This is the Professional Version. CONSUMERS: View Consumer Version
quiz link

Test your knowledge

Take a Quiz! 
iOS ANDROID
iOS ANDROID
iOS ANDROID
TOP