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Rheumatoid Arthritis (RA)

By

Apostolos Kontzias

, MD, Stony Brook University School of Medicine

Last full review/revision May 2020| Content last modified May 2020
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Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that primarily involves the joints. RA 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 help control symptoms and slow disease progression.

RA 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) or old age.

Etiology

Although rheumatoid arthritis (RA) 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.

Pathophysiology

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 (RA), including cartilage and bone destruction (1).

In seropositive RA, accumulating evidence suggests that anti-CCP antibodies appear long before any signs of inflammation (2). Additionally, anti-carbamylated protein (anti-CarP) antibodies (3) predict more radiologic progression in anti-CCP–negative RA patients. Progression to RA in the preclinical phase depends on autoantibody epitope spreading in which there are immune responses to the release of self-antigens with subsequent inflammation (4).

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 RA. They are granulomas consisting of a central necrotic area surrounded by palisaded histiocytic macrophages, all enveloped by lymphocytes, plasma cells, and fibroblasts. Nodules and vasculitis 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

Onset of rheumatoid arthritis (RA) is usually insidious, often beginning with systemic and joint symptoms. Systemic symptoms include early morning stiffness of affected joints, 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 joints

  • Shoulders

  • Elbows

  • Hips

  • Knees

  • Ankles

However, virtually any joint, except the distal interphalangeal (DIP) joints, may be involved. The axial skeleton is rarely involved except for the upper cervical spine. Synovial thickening is detectable. Joints are often held in flexion to minimize pain, which results from joint capsular distention.

Fixed deformities, particularly flexion contractures, may develop rapidly; ulnar deviation of the fingers with an ulnar slippage of the extensor tendons off the metacarpophalangeal joints is typical, as are swan-neck deformities and boutonnière deformities (see Figure: Boutonnière and swan-neck deformities). Joint instability due to stretching of the joint capsule can also occur. Carpal tunnel syndrome can result from wrist synovitis compressing the median nerve. Popliteal (Baker) cysts can develop, causing calf swelling and tenderness suggestive of deep venous thrombosis.

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, occiput). Visceral nodules (eg, pulmonary nodules), usually asymptomatic, occur in severe RA. Pulmonary nodules of RA cannot be distinguished from pulmonary nodules of other etiology without biopsy.

Other extra-articular signs include vasculitis causing leg ulcers or mononeuritis multiplex, pleural or pericardial effusions, pulmonary infiltrates or fibrosis, pericarditis, myocarditis, lymphadenopathy, Felty syndrome, Sjögren syndrome, scleromalacia, and episcleritis. Involvement of the cervical spine can cause atlantoaxial subluxation and spinal cord compression; subluxation may worsen with extension of the neck (eg, during endotracheal intubation). Importantly, cervical spine instability is most often asymptomatic.

Examples of Rheumatoid Nodules

Diagnosis

  • 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 RA 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 Classification Criteria for Rheumatoid Arthritis). Other causes of symmetric polyarthritis, particularly hepatitis C, must be excluded. Patients should have a serum RF test, hand and wrist x-rays, and baseline x-rays of affected joints to document future erosive changes. In patients who have prominent lumbar symptoms, alternative diagnoses should be investigated.

Table
icon

Classification Criteria for Rheumatoid Arthritis a

Finding

Score

Criteria for evaluation:

  • At least 1 joint with definite clinical synovitis (swelling)

  • Synovitis not better explained by another disorder

Classification criteria for RA is a score-based algorithm. Scores for categories A‒D are added; a score ≥ 6 (highest possible total 10) is needed to classify a patient as having definite RA.a

A. Joint involvementb

1 large jointc

0

2‒10 large joints

1

1‒3 small jointsd (with or without involvement of large joints)

2

4‒10 small joints (with or without involvement of large joints)

3

>10 jointse (at least 1 small joint)

5

B. Serology (at least 1 test result is needed for classification)

Negative RF and negative anti-CCP

0

Low-positivef RF or low-positive anti-CCP

2

High-positiveg RF or high-positive anti-CCP

3

C. Acute-phase reactants (at least 1 test result is needed for classification)

Normal CRP and normal erythrocyte sedimentation rate

0

Abnormal CRP or abnormal erythrocyte sedimentation rate

1

D. Duration of symptoms (based on patient's report)

< 6 weeks

0

≥ 6 weeks

1

a Patients with a score of < 6 can be reassessed; they may meet the criteria for RA cumulatively over time.

b Distal interphalangeal joints, first carpometacarpal joints, and first metatarsophalangeal joints are excluded from assessment.

c Large joints are the shoulders, elbows, hips, knees, and ankles.

d Small joints are the metacarpophalangeal joints, proximal interphalangeal joints, 2nd‒5th metatarsophalangeal joints, thumb interphalangeal joints, and wrists.

e These joints may include other joints not specifically listed elsewhere (eg, temporomandibular, acromioclavicular, sternoclavicular).

f Low positive indicates levels between 1 and 3 times the upper limit of normal.

g High positive indicates levels at least 3 times the upper limit of normal.

Anti-CCP = anticitrullinated protein antibody; CRP = C-reactive protein; RF = rheumatoid factor.

Adapted from Aletaha D, Neogi T, Silman AJ, et al: 2010 Rheumatoid arthritis classification criteria: An American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 62 (9):2569–2581, 2010.

RFs, antibodies to human gamma-globulin, are present in about 70% of patients with RA. However, RF, often in low titers (levels can vary between laboratories), occurs in patients with other diseases, including other connective tissue diseases (eg, systemic lupus erythematosus), granulomatous diseases, chronic infections (eg, viral hepatitis, bacterial endocarditis, tuberculosis), and cancers. Low RF titers can also occur in 3% of the general population and 20% of the elderly. 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 RA 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 RA 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 RA 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 RA from other inflammatory arthritides (eg, septic and crystal-induced arthritis). In RA, 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 (RA):

RF can be nonspecific and is often present in several autoimmune diseases; the presence of anticyclic citrullinated peptide (anti-CCP) antibodies is more specific for RA. For example, hepatitis C can be associated with an arthritis similar to RA clinically and that is RF-positive; however, anti-CCP is negative.

Some patients with crystal-induced arthritis may meet criteria for RA; however, synovial fluid examination should clarify the diagnosis. The presence of crystals makes RA unlikely. Joint involvement and subcutaneous nodules can result from gout, cholesterol, and amyloidosis as well as RA; aspiration or biopsy of the nodules may occasionally be needed.

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 RA, deformities in SLE are usually reducible and lack erosions and bone or cartilage damage on imaging studies.

Arthritis similar to RA can also occur in other rheumatic disorders (eg, polyarteritis, systemic sclerosis, dermatomyositis, or polymyositis), or there can be features of more than one disease, which suggests an overlap syndrome or mixed connective tissue disease.

Sarcoidosis, Whipple disease, 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, RA tends to involve additional joints over time.

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 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. DIP joint involvement and severely mutilating arthritis (arthritis mutilans) is strongly suggestive, as is the presence of a diffusely swollen (sausage) digit. Distinguishing between psoriatic arthritis and RA is important because response to specific drugs differs.

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 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. RA does not affect the DIP joints.

Prognosis

Rheumatoid arthritis (RA) 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 RA. (See also the European League Against Rheumatism's (EULAR) recommendations for cardiovascular disease risk management in patients with RA and other forms of inflammatory joint disorders.)

At least 10% of patients are eventually severely disabled despite full treatment. Whites 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 RF or anticyclic citrullinated peptide (anti-CCP).

Treatment

  • Supportive measures (eg, smoking cessation, nutrition, rest, physical measures, analgesics)

  • Drugs that modify disease progression

  • Nonsteroidal anti-inflammatory drugs as needed for analgesia

Treatment of rheumatoid arthritis (RA) involves a balance of rest and exercise, adequate nutrition, physical measures, drugs, and sometimes surgery. (See also the American College of Rheumatology's 2015 guidelines for the treatment of rheumatoid arthritis and the European League Against Rheumatism's 2019 update EULAR Recommendations for the Management of Rheumatoid Arthritis with Synthetic and Biological Disease-Modifying Antirheumatic Drugs.)

Lifestyle measures

Complete bed rest is rarely indicated, even for a short time; however, a program including judicious rest should be encouraged.

An ordinary nutritious diet is appropriate. Rarely, patients have food-associated exacerbations; no specific foods have reproducibly been shown to exacerbate RA. Food and diet quackery is common and should be discouraged. 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.

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 RA 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 should not be fatiguing. 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.

Massage by trained therapists, traction, and deep heat treatment with diathermy or ultrasonography may be useful adjunctive therapies to anti-inflammatory drugs.

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 cannot tolerate 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.

Drugs for Rheumatoid Arthritis (RA)

The goal is to reduce inflammation as a means of preventing erosions, progressive deformity, and loss of joint function. Disease-modifying antirheumatic drugs (DMARDs) are used early, often in combination. Other drug classes, including 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 RA. nonsteroidal anti-inflammatory drugs are of some help for the pain of RA but do not prevent erosions or disease progression, may increase cardiovascular risk, and thus should be used only as adjunctive therapy. Low-dose systemic corticosteroids (prednisone < 10 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.

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. An example of initial therapy is

  • 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 methotrexate is increased after 3- to 5-week intervals to a maximum of 25 mg orally or by injection once/week (oral bioavailability decreases above 15 mg in a single dose).

  • If response is not adequate, a biologic agent should be added; alternatively, triple therapy with methotrexate, hydroxychloroquine, and sulfasalazine is an option.

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

Nonsteroidal anti-inflammatory drugs (NSAIDs)

Aspirin is no longer used for RA because effective doses are often toxic. Only one NSAID should be given at a time (see Table: 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 RA 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 comparable 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 other than perhaps coxibs should be avoided in patients with previous peptic ulcer disease or dyspepsia; gastric acid suppressive therapy should be provided in these patients. Other possible adverse effects of all NSAIDs include headache, confusion and other central nervous system symptoms, increased BP, worsening of hypertension, edema, and decreased platelet function; however, celecoxib has no significant antiplatelet effect. NSAIDs increase cardiovascular risk (see Nonopioid Analgesics). Creatinine levels can rise reversibly because of inhibited renal prostaglandins and reduced renal blood flow; less frequently, 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
icon

Nonsteroidal Anti-inflammatory Drug (NSAID) Treatment of Rheumatoid Arthritis

Drug

Usual Dosage (Oral)

Maximum Recommended Daily Dose

Nonselective NSAIDs

Diclofenac

75 mg 2 times a day or 50 mg 3 times a day

100 mg once/day sustained-release

150 mg

Etodolac

300–500 mg 2 times a day

1200 mg

Fenoprofen

300–600 mg 4 times a day

3200 mg

Flurbiprofen

100 mg 2 or 3 times a day 

300 mg

Ibuprofen

400–800 mg 4 times a day

3200 mg

Indomethacin

25 mg 3 to 4 times a day

75 mg 2 times a day sustained-release

200 mg

Ketoprofen

50–75 mg 4 times a day

200 mg once/day sustained-release

300 mg

Meclofenamate

50 mg 3 or 4 times a day

400 mg

Meloxicam*

7.5 mg once/day

15 mg

Nabumetone

1000–2000 mg/day in 1 dosage or in divided dosages (500–1000 mg 2 times a day)

2000 mg

Naproxen

250–500 mg 2 times a day

1500 mg

Oxaprozin

1200 mg once/day

1800 mg

Piroxicam

20 mg once/day

20 mg

Sulindac

150–200 mg 2 times a day

400 mg

Tolmetin

400 mg 3 times a day

1800 mg

Cyclooxygenase-2 (COX-2) selective NSAIDs

Celecoxib

200 mg once/day or 2 times a day

400 mg

*COX-2 specificity of this drug is unclear.

Traditional disease-modifying antirheumatic drugs (DMARDs)

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

DMARDs seem to slow the progression of RA and are indicated for nearly all patients with RA. 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
icon

Other Drugs Used to Treat Rheumatoid Arthritis

Drug

Dosage

Adverse Effects

Traditional disease-modifying antirheumatic drugs (DMARDs)

Hydroxychloroquine

5 mg/kg orally once/day (eg, with breakfast or dinner) or in 2 divided dosages (eg, 2.5 mg every 12 hours)

Usually mild dermatitis

Myopathy

Corneal opacity (generally reversible)

Occasionally irreversible retinal degeneration

Leflunomide

20 mg orally once/day or, if adverse effects occur, reduced to 10 mg once/day

Skin reactions

Hepatic dysfunction

Alopecia

Diarrhea

Peripheral neuropathy

Methotrexate

Single oral dose once/week, starting at 10 to 15 mg and gradually increased as needed to a maximum of 25 mg

Doses > 20 mg/week best given subcutaneously to ensure bioavailability

Liver fibrosis (dose-related, often reversible)

Nausea

Malaise

Bone marrow suppression

Stomatitis

Rarely pneumonitis

Sulfasalazine*

500 mg orally in the evening, increased to 500 mg in the morning and 1000 mg in the evening, then increased to 1000–1500 mg 2 times a day

Bone marrow suppression

Gastric symptoms

Neutropenia

Hemolysis

Hepatitis

Corticosteroids, intra-articular injections

Methylprednisolone acetate

Depends on the joint

With long-term use: Rarely infection at the injection site

Triamcinolone acetonide

Depends on the joint

Triamcinolone hexacetonide

10–40 mg, depending on the joint

Corticosteroids, systemic

Prednisone

Prednisolone

Attempts should be made to avoid exceeding 7.5 mg orally once/day (except in patients with severe systemic manifestations)

With long-term use:

  • Weight gain

  • Diabetes

  • Hypertension

  • Osteoporosis

  • Cataracts

Immunomodulatory, cytotoxic, or immunosuppressive drugs

Azathioprine

1 mg/kg (50–100 mg) orally 1 or 2 times a day, increased† by 0.5 mg/kg/day after 6–8 weeks, then every 4 weeks to a maximum of 2.5 mg/kg/day

Liver toxicity

Bone marrow suppression

Increased risk of cancers (eg, lymphoma, nonmelanoma skin cancers)

With cyclosporine, impaired renal function, hypertension, and risk of diabetes

Cyclosporine (an immunomodulatory drug)

50 mg orally 2 times a day, not to exceed 1.75 mg/kg orally 2 times a day

Biologic agents

Abatacept

Initially an IV loading dose of 500 mg IV for patients weighing < 60 kg, 750 mg IV for patients weighing 60–100 kg, and 1 g IV for patients weighing > 100 kg, then same dose on weeks 2 and 4 later, and then every 4 weeks

or

125 mg subcutaneously once/week with or without one IV loading dose 1 week previously

Pulmonary toxicity

Susceptibility to infection

Headache

Upper respiratory infection

Sore throat

Nausea

Rituximab

1 g IV at baseline and at 2 weeks (methylprednisolone 60–125 mg IV is given with each dose of rituximab to prevent hypersensitivity reactions)

When the drug is being given:

  • Mild itching at the injection site

  • Rashes

  • Back pain

  • Hypertension or hypotension

  • Fever

After the drug is given:

  • Slightly increased risk of infection and possibly cancer

  • Hypogammaglobulinemia

  • Neutropenia

  • Reactivation of hepatitis B

Interleukin-6 (IL-6) inhibitors‡

Sarilumab

200 mg subcutaneously once every 2 weeks

Dosage can be reduced to 150 mg once every 2 weeks

Neutropenia

Thrombocytopenia

Transaminase elevation

Tocilizumab

8 mg/kg IV every 4 weeks, to a maximum 800 mg/dose

or

162 mg subcutaneously every other week followed by an increase to every week based on clinical response in patients weighing < 100 kg

162 mg subcutaneously every week in patients weighing > 100 kg

Potential risk of infection (particularly opportunistic organisms)

Neutropenia

Thrombocytopenia

Gastrointestinal perforation

Anaphylaxis

Transaminase elevation

Interleukin-1 (IL-1) receptor inhibitor‡

Anakinra

100 mg subcutaneously once/day

Injection site reactions

Immunosuppression

Neutropenia

Tumor necrosis factor (TNF)-alpha antagonists‡

Adalimumab

Adalimumab-atto

Adalimumab-adbm 

Adalimumab-adaz 

Adalimumab-bwwd

Adalimumab-afzb

40 mg subcutaneously once every 2 weeks

Potential risk of reactivation of infection (particularly tuberculosis and fungal infections)

Reactivation of hepatitis B

Nonmelanoma skin cancers

Antinuclear antibodies with or without clinical systemic lupus erythematosus (SLE)

Demyelinating neurologic disorders

Heart failure

Certolizumab pegol

400 mg subcutaneously (as 2 subcutaneous injections of 200 mg) once and then repeat at week 2 and week 4, followed by 200 mg subcutaneously every 2 weeks (or 400 mg subcutaneously every 4 weeks)

Etanercept

Biosimilars:

Etanercept-szzs

Etanercept-ykro

50 mg subcutaneously once/week

Golimumab

50 mg subcutaneously once every 4 weeks

Infliximab

Biosimilars:

Infliximab-dyyb

Infliximab-abda

Infliximab-qbtx

Infliximab-axxq

3-mg/kg IV infusion in saline at baseline, at 2 weeks, and at 6 weeks with subsequent injections every 8 weeks (dosage may be increased to 10 mg/kg)

Janus kinase (JAK) inhibitors‡

Baricitinib

2 mg orally once/day

Risk of infection, particularly varicella-zoster virus reactivation

Nonmelanoma skin cancers

Hypercholesterolemia

Venous thromboembolism

Tofacitinib

5 mg orally 2 times a day

Risk of infection, particularly varicella-zoster virus reactivation

Nonmelanoma skin cancers

Hypercholesterolemia

Venous thromboembolism

Upadacitinib

15 mg orally once/day

Risk of infection, particularly varicella-zoster virus reactivation

Nonmelanoma skin cancers

Hypercholesterolemia

Venous thromboembolism

* Sulfasalazine is usually given as enteric-coated tablets.

† During dosage increases for azathioprine, complete blood count, aspartate aminotransferase, and alanine aminotransferase are monitored.

‡ These drugs are biologic agents.

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 RA. 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 weeks. When used early in the course of RA, 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.

Hydroxychloroquine can also control symptoms of mild RA. 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 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.

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.

Parenteral gold compounds are not commonly used anymore.

Corticosteroids

Systemic corticosteroids decrease inflammation and other symptoms more rapidly and to a greater degree than other drugs. They also seem to slow bone erosion. However, 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 to maintain function only until another DMARD has taken effect.

Corticosteroids may be used for severe joint or systemic manifestations of RA (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) provides efficacy similar to DMARDs. However, these drugs are more toxic. Thus, they are used only for patients in whom treatment with DMARDs has failed or to decrease the need for corticosteroids. They are used infrequently unless there are extra-articular complications. For maintenance therapy with azathioprine, the lowest effective dose should be used. Low-dose cyclosporine may be effective alone or when combined with methotrexate but is rarely used anymore. It may be less toxic than azathioprine. Cyclophosphamide is no longer recommended due to its toxicity.

Biologic agents

Biologic response modifiers other than tumor necrosis factor (TNF)-alpha antagonists can be used to target B cells or T cells. These agents are typically not combined with each other.

Rituximab is an anti-CD 20 antibody that depletes B cells. It can be used in refractory patients. 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 is usually restricted to patients who have not improved after using a TNF-alpha inhibitor and methotrexate. Rituximab therapy has been associated with progressive multifocal leukoencephalopathy, mucocutaneous reactions, delayed leukopenia, and hepatitis B reactivation.

Abatacept, a soluble fusion cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) Ig, is indicated for patients with RA with an inadequate response to other DMARDs.

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

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. TNF-alpha antagonists should probably be stopped before major surgery to decrease the risk of perioperative infection. 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. Risk of lymphomas is not increased in RA patients who are treated with TNF inhibitors (1).

Sarilumab is an interleukin-6 (IL-6) inhibitor. It is available for adults with moderately to severely active RA 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.

Baricitinib is an oral Janus kinase (JAK) inhibitor. It is indicated for adults with moderately to severely active RA 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.

Although there are some differences among agents, the most serious problem is infection, particularly with reactivated tuberculosis. Patients should be screened for tuberculosis 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.

Treatment reference

  • 1. Minozzi S, Bonovas S, Lytras T, et al: Risk of infections using anti-TNF agents in rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis: A systematic review and meta-analysis. Expert Opin Drug Saf 15(sup1):11–34, 2016. doi: 10.1080/14740338.2016.1240783.

Key Points

  • Rheumatoid arthritis (RA) 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 mononeuritis multiplex, pleural or pericardial effusions, pulmonary nodules, pulmonary infiltrates or fibrosis, pericarditis, myocarditis, lymphadenopathy, Felty syndrome, Sjögren syndrome, scleromalacia, and episcleritis.

  • Take x-rays but diagnose primarily by specific clinical criteria and 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).

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

  • Treat almost all patients early and 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.

More Information

Drugs Mentioned In This Article

Drug Name Select Trade
MEDROL
CIMZIA
PLAQUENIL
CYTOXAN (LYOPHILIZED)
No US trade name
No US brand name
KENALOG
AZULFIDINE
OTREXUP
INDOCIN
IMURAN
ORAPRED, PRELONE
NEORAL, SANDIMMUNE
ANSAID, OCUFEN
SANTYL
ARAVA
ACTEMRA
XELJANZ
Baricitinib
ENBREL
REMICADE
HUMIRA
RAYOS
NEXCEDE
CATAFLAM, VOLTAREN
NALFON
ADVIL, MOTRIN IB
MOBIC
CELEBREX
ORENCIA
FELDENE
Sarilumab
DAYPRO
RITUXAN
SIMPONI
CLINORIL
ALEVE, NAPROSYN
KINERET
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