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Rheumatoid Arthritis (RA)
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 yr and 50 yr, but can be during childhood (see Juvenile Idiopathic Arthritis) or old age.
Although 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-DR β1 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.
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 antibody [anti-CCP]) 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, TNF-α, granulocyte-macrophage colony-stimulating factor [GM-CSF], various ILs, interferon-γ) in the synovium. Release of inflammatory mediators probably contributes to the systemic and joint manifestations of RA.
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 IL-1 and TNF-α, 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 (PMNs) on average make up about 60% of WBCs 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.
Onset 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.
The disease progresses most rapidly during the first 6 yr, particularly the first year; 80% of patients develop some permanent joint abnormalities within 10 yr. The course is unpredictable in individual patients.
Joint symptoms are characteristically symmetric. Typically, stiffness lasts > 60 min 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:
However, virtually any joint, except uncommonly 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 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.
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, are common in severe RA.
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 frequently asymptomatic.
RA should be suspected in patients with polyarticular, symmetric arthritis, particularly if the wrists and 2nd and 3rd metacarpophalangeal joints are involved. Criteria for the diagnosis of RA are listed in Diagnosing Rheumatoid Arthritis*. Criteria include laboratory test results for RF, anti-CCP, and ESR or CRP. 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.
Diagnosing Rheumatoid Arthritis*
RFs, antibodies to human γ-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, SLE), granulomatous diseases, chronic infections (eg, viral hepatitis, subacute bacterial endocarditis, TB), and cancers. Low RF titers can also occur in 3% of the general population and 20% of the elderly. An RF titer measured by latex agglutination of > 1:80 or a positive anti-CCP test supports the diagnosis of RA.
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.
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. CBC with differential should be obtained. A normochromic (or slightly hypochromic)-normocytic anemia occurs in 80%; Hb is usually > 10 g/dL. If Hb is ≤ 10 g/dL, 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.
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 10,000 to 50,000 WBCs/μL; PMNs typically predominate, but >50% may be lymphocytes and other mononuclear cells. Crystals are absent.
Many disorders can simulate RA:
RF can be nonspecific and is often present in several autoimmune diseases; the presence of 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 < 2000 WBCs/μL (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 because of the lack of erosions and bone or cartilage damage.
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 has an additive arthritis.
Reactive arthritis can be differentiated by antecedent GI or GU 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 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.
Ankylosing spondylitis may be differentiated by spinal and axial joint involvement, absence of subcutaneous nodules, and a negative RF test.
Osteoarthritis can be differentiated by the joints involved; the absence of rheumatoid nodules, systemic manifestations, or significant amounts of RF; and by synovial fluid WBC counts <2000/μL. 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.
RA decreases life expectancy by 3 to 7 yr, with heart disease, infection, and GI bleeding accounting for most excess mortality; drug treatment, cancer, as well as the underlying disease may be responsible.
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 ESR, and high levels of RF or anti-CCP.
Treatment of RA involves a balance of rest and exercise, adequate nutrition, physical measures, drugs, and sometimes surgery. (See also the European League Against Rheumatism's 2013 update EULAR Recommendations for the Management of Rheumatoid Arthritis with Synthetic and Biological Disease-Modifying Antirheumatic Drugs .)
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 ω-3 fatty acids (in fish oils) for dietary ω-6 fatty acids (in meats) partially relieves symptoms in some patients by transiently decreasing production of inflammatory prostaglandins. Smoking cessation can increase life expectancy.
Joint splinting reduces local inflammation and may relieve severe symptoms of pain or compressive neuropathies. Cold may be applied to reduce pain from temporary worsening in one joint. 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 helpful. 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 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.
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, TNF-α antagonists, and IL-1 receptor antagonists, seem to slow the progression of RA. NSAIDs are of some help for the pain of RA but do not prevent erosions or disease progression 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.
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-α antagonist or an IL-1 receptor antagonist, a TNF-α antagonist or an IL-1 receptor antagonist plus a DMARD) are more effective than using DMARDs alone sequentially or in combination. In general, biologic agents (eg, TNF-α and IL-1 receptor antagonists) are not given in combination with each other due to increased frequency of infections. An example of initial therapy is
Aspirin is no longer used for RA, as effective doses are often toxic. Only one NSAID should be given at a time (see Table: 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 wk, 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 GI toxicity; however, they are not less likely to cause renal toxicity.
NSAIDs other than perhaps coxibs should be avoided in patients with previous peptic ulcer disease or dyspepsia. Other possible adverse effects of all NSAIDs include headache, confusion and other CNS symptoms, increased BP, worsening of hypertension, edema, and decreased platelet function. NSAIDs increase cardiovascular risk (see Nonopioid Analgesics). Creatinine levels can rise reversibly because of inhibited renal prostaglandins; less frequently, interstitial nephritis can occur. Patients with urticaria, rhinitis, or asthma caused by aspirin can have the same problems with these other NSAIDs.
NSAID Treatment of Rheumatoid Arthritis
(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.
Other Drugs Used to Treat Rheumatoid Arthritis
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 TNF-α antagonist or an IL-1 receptor 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 wk). 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 po once/day, reduces the likelihood of adverse effects. CBC, AST, ALT, and albumin and creatinine level should be determined about every 8 wk. When used early in the course of RA, efficacy may equal the biologic agents. Rarely, a liver biopsy is needed if liver function 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 mo during treatment. The drug should be stopped if no improvement occurs after 9 mo.
Sulfasalazine can alleviate symptoms and slow development of joint damage. It is usually given as enteric-coated tablets. Benefit should occur within 3 mo. Enteric coating or dose reduction may increase tolerability. Because neutropenia may occur early, CBCs should be obtained after 1 to 2 wk and then about every 12 wk during therapy. AST and ALT should be obtained at about 6-mo 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.
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 TB 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 h after injection.
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. It may be less toxic than azathioprine. Cyclophosphamide is no longer recommended due to its toxicity.
Biologic response modifiers other than TNF-α 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 mo. The course can be repeated after 6 mo. 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-α 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 IL-1 receptor antagonist. IL-1 is heavily involved in the pathogenesis of RA. Infection and leukopenia can be problems.
TNF-α antagonists (eg, adalimumab, etanercept, golimumab, certolizumab pegol, tocilizumab, and infliximab) 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.
Tocilizumab blocks the effect of IL-6 and has clinical efficacy in patients who have responded incompletely to other biologic agents.
Tofacitinib is a Janus kinase (JAK) inhibitor that is given orally with or without concomitant methotrexate to patients who do not respond to methotrexate alone or other biologic agents.
Although there are some differences among agents, the most serious problem is infection, particularly with reactivated TB. Patients should be screened for TB with PPD or an interferon-gamma release assay. Other serious infections can occur, including sepsis, invasive fungal infections, and infections due to other opportunistic organisms. It is not clear whether risk of lymphomas or other cancers is increased. Recent information suggests safety during pregnancy. TNF-α antagonists should probably be stopped before major surgery. Etanercept, infliximab, and adalimumab can and probably should be used with methotrexate. High-dose infliximab should not be used in patients with severe heart failure.
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-phase reactants (ESR or C-reactive protein).
RA decreases life expectancy by 3 to 7 yr (eg, due to GI 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, methotrexate, biologic agents such as TNF-α antagonists, an IL-1 antagonist, and other drugs that are immunomodulatory, cytotoxic, or immunosuppressive.
Drug NameSelect Trade
EtodolacNo US brand name
IbuprofenADVIL, MOTRIN IB
diphenhydramineNo US trade name
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