 |
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 Joint Disorders: Juvenile Idiopathic Arthritis (JIA)) or old age.
Etiology
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 environmental factors (eg, viral infections) are thought to play a role.
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]) that contribute to these complexes, but destructive arthritis can occur in the absence of RF. 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 factors [TNF], 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 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. 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.
Symptoms and Signs
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. Involved joints become tender, with erythema, warmth, swelling, and limitation of motion. The joints 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 Fig. 2: Hand Disorders: Boutonnière and swan-neck deformities. ). Joint instability can also occur. Carpal tunnel syndrome can result from wrist synovitis compressing the median nerve. Popliteal (Baker's) cysts can develop, causing calf swelling and tenderness suggestive of deep venous thrombosis.
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, usually asymptomatic, are common in severe RA. Other extra-articular signs include vasculitis causing leg ulcers or mononeuritis multiplex, pleural or pericardial effusions, pulmonary nodules, pulmonary infiltrates or fibrosis, pericarditis, myocarditis, lymphadenopathy, Felty's syndrome, Sjögren's syndrome, scleromalacia, and episcleritis. Involvement of the cervical spine can cause atlantoaxial subluxation (see Neck and Back Pain: Atlantoaxial Subluxation) and spinal cord compression (see Spinal Cord Disorders: Spinal Cord Compression); it may worsen with extension of the neck (eg, during endotracheal intubation).
Diagnosis
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 Table 1: Joint Disorders: Diagnosing Rheumatoid Arthritis* . The presence of ≥ 4 criteria suggests the diagnosis. 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.
|
Table 1
|
| | |
| Diagnosing Rheumatoid Arthritis* |
|
Any 4 of the following criteria must be present to classify patients as having RA:
Arthritis of hand joints (wrist, metacarpophalangeal, or proximal interphalangeal joints)†
Morning stiffness for ≥ 1 h†
Serum rheumatoid factor (positive in < 5% of normal control subjects)
Imaging changes (hand x-ray changes typical of RA must include erosions or unequivocal bony decalcification)
|
|
*Based on criteria from the American Rheumatism Association (now the American College of Rheumatology).
|
|
†Must be present for ≥ 6 wk.
|
|
RFs, antibodies to human γ-globulin, are present in about 70% of patients with RA. However, RF, often in low titers, 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 (96%) for RA and, like RF, predict a worse prognosis.
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's syndrome). Acute-phase reactants (eg, thrombocytosis, elevated ESR, elevated C-reactive protein) 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, with reduced viscosity and usually 10,000 to 50,000 WBCs/μL; PMNs typically predominate, but > 50% may be lymphocytes and other mononuclear cells. Crystals are absent.
Differential diagnosis:
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.
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's 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 (see Joint Disorders: 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 (see Joint Disorders: 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 (see Joint Disorders: Ankylosing Spondylitis) may be differentiated by spinal and axial joint involvement, absence of subcutaneous nodules, and negative RF test.
Osteoarthritis (see Joint Disorders: Osteoarthritis (OA)) can be differentiated by the joints involved; the absence of rheumatoid nodules, systemic manifestations, or significant amounts of RF; and synovial fluid WBC counts < 2000/μL. Osteoarthritis of the hands most typically involves the DIP and proximal interphalangeal joints. RA does not affect the DIP joints.
Prognosis
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
Treatment involves a balance of rest and exercise, adequate nutrition, physical measures, drugs, and sometimes surgery. (See also the Canadian Rheumatology Association's Canadian Consensus Statement on Early Optimal Therapy in Early Rheumatoid Arthritis.)
Rest and nutrition:
Complete bed rest is rarely indicated, even for a short time; however, a program including judicious rest should be prescribed. An ordinary nutritious diet is generally sufficient. Rarely, patients have food-associated exacerbations; no specific foods have been noted 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) may partially relieve symptoms by transiently decreasing production of inflammatory prostaglandins.
Physical measures:
Joint splinting reduces local inflammation and may relieve severe symptoms. 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 to painful metatarsophalangeal joints decrease the pain of weight bearing. Molded shoes may be needed for severe deformities. 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.
Surgery:
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. 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 RA
The goal is to reduce inflammation as a means of preventing erosions and progressive deformity. 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. Sometimes low-dose systemic corticosteroids (prednisone < 10 mg daily) are 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.
NSAIDs:
Aspirin is no longer used for RA, as effective doses are often toxic. Only one NSAID should be given at a time (see Table 2: Joint Disorders: 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.
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 less likely to cause GI toxicity; however, they do not seem less likely to cause renal toxicity.
NSAIDs other than 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. The effect of NSAIDs on cardiovascular risk is still unclear. Creatinine levels can rise reversibly because of inhibited renal prostaglandins; less frequently, interstitial nephritis can occur. Patients with urticaria, rhinitis, or asthma from aspirin can have the same problems with these other NSAIDs.
|
Table 2
|
| | |
| NSAID Treatment of Rheumatoid Arthritis |
|
Drug
|
Usual Dosage (Oral)
|
Maximum Recommended Daily Dose
|
|
Nonselective
|
|
|
75 mg bid or 50 mg tid, 100 mg once/day sustained-release
|
150 mg
|
|
|
300–500 mg bid
|
1200 mg
|
|
|
300–600 mg qid
|
3200 mg
|
|
|
100 mg bid or tid
|
300 mg
|
|
|
400–800 mg qid
|
3200 mg
|
|
|
25 mg tid to qid, 75 mg bid sustained-release
|
200 mg
|
|
|
50–75 mg qid, 200 mg once/day sustained-release
|
300 mg
|
|
|
50 mg tid or qid
|
400 mg
|
|
|
1000–2000 mg/day in one dose or divided doses
|
2000 mg
|
|
|
250–500 mg bid
|
1500 mg
|
|
|
1200 mg once/day
|
1800 mg
|
|
|
20 mg once/day
|
20 mg
|
|
|
150–200 mg bid
|
400 mg
|
|
|
400 mg tid
|
1800 mg
|
|
COX-2 specific
|
|
|
200 mg once/day or bid
|
400 mg
|
|
|
7.5 mg once/day
|
15 mg
|
|
*COX-2 specificity of this drug is unclear.
COX = cyclooxygenase.
|
|
Traditional DMARDs:
(See Table 3: Joint Disorders: Other Drugs Used to Treat RA for specific dosage information and adverse effects of other drugs used to treat RA.)
|
Table 3
|
| | |
| Other Drugs Used to Treat RA |
|
Drug
|
Dosage
|
Adverse Effects
|
|
Traditional disease-modifying antirheumatic drugs (DMARDs)
|
|
Hydroxychloroquine
|
Initially, 400 mg po once/day (eg, with breakfast or dinner) for 4–12 wk, then sometimes reduced to 200 mg once/day
If improvement occurs, 200–400 mg once/day as long as effective
|
Usually, mild dermatitis
Myopathy
Generally, reversible corneal opacity
Occasionally, irreversible retinal degeneration
|
|
Leflunomide
|
20 mg once/day or, if adverse effects occur, reduced to 10 mg once/day
|
Skin reactions
Hepatic dysfunction
|
|
Methotrexate
|
Single oral dose once/wk, starting at 7.5 mg and gradually increased as needed to a maximum of 25 mg
Doses > 20 mg/wk best given sc to ensure bioavailability
|
Liver fibrosis (dose-related, often reversible)
Nausea
Possibly bone marrow suppression
Stomatitis
Rarely, pneumonitis (potentially fatal)
|
|
Sulfasalazine*
|
500 mg po in the evening, increased to 500 mg in the morning and 1000 mg in the evening, then increased to 1000–1500 mg bid
|
Bone marrow suppression
Gastric symptoms
Neutropenia
Hemolysis
Hepatitis
|
|
Corticosteroids, intra-articular injections
|
|
Methylprednisolone acetate
|
Depends on the joint
|
With long-term use:Inflammation and rarely infection at the injection site
|
|
Triamcinolone acetonide
|
Depends on the joint
|
|
Triamcinolone hexacetonide
|
10–40 mg, depending on the joint
|
|
Corticosteroids, systemic
|
|
Prednisone
|
Not to exceed 7.5 mg po once/day (except in patients with severe systemic manifestations)
|
With long-term use:Weight gain
Diabetes
Hypertension
Osteoporosis
|
|
Immunomodulatory, cytotoxic, or immunosuppressive drugs
|
|
Azathioprine
|
1 mg/kg (50–100 mg) po once/day or bid, increased† by 0.5 mg/kg/day after 6–8 wk, then q 4 wk to a maximum of 2.5 mg/kg/day
|
Liver toxicity
Bone marrow suppression
Possibly increased risk of cancer
With cyclosporine, impaired renal function
|
|
Cyclophosphamide
|
2–3 mg/kg po once/day or IV pulse therapy (may not be as effective): 0.75 g/m2 once/mo (increased to 1 g/m2 once/mo for 6 mo if WBC > 3000/µL), given over 30–60 min with oral or IV fluids and with mesna
|
|
Cyclosporine (an immunomodulatory drug)
|
50 mg po bid, not to exceed 1.75 mg/kg po bid
|
|
Biologic agents
|
|
Abatacept
|
750 mg given over 30 min IV at baseline, at 2 wk, at 4 wk, and q 4 wk thereafter
|
Pulmonary toxicity
Susceptibility to infection
Headache
URI
Sore throat
Nausea
|
|
Rituximab
|
1 g IV at baseline and at 2 wk
|
When the drug is being given:
Mild itching at the injection site
Rashes
Back pain
Hypertension or hypotension
Fever
After the drug is given:
Increased risk of infection and possibly cancer
Bone marrow suppression
|
|
IL-1 receptor antagonist
|
|
Anakinra
|
100 mg sc once/day
|
Injection site reactions
Immunosuppression
Bone marrow suppression
|
|
TNF-α antagonists
|
|
Adalimumab
|
40 mg sc once q 1–2 wk
|
Potential risk of infection (particularly TB) or cancer
Lymphoma
Liver toxicity
Bone marrow suppression
Abnormal liver function tests
Antinuclear antibodies with or without SLE
Demyelinating neurologic disorders
|
|
Etanercept
|
25 mg sc twice/wk or 50 mg sc once/wk
|
|
Infliximab
|
3-mg/kg IV infusion in saline at baseline, at 2 wk, and at 6 wk with subsequent injections q 8 wk (dosage may be increased to 10 mg/kg)
|
|
*Sulfasalazine is usually given as enteric-coated tablets.
†During dosage increases for azathioprine, CBC, AST, and ALT are monitored.
TNF = tumor necrosis factor.
|
|
These drugs seem to slow the progression of RA and are indicated in 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, but complete remissions are uncommon. Many result in evidence of decreased damage on imaging studies, presumably reflecting decreased disease activity. They have minimal immediate analgesic effects, so NSAIDs or low-dose corticosteroids must often be continued. Patients should be fully apprised of the risks of DMARDs and monitored carefully for evidence of toxicity.
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. Also, 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. 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. 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.
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 do 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, many 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 injections. Although infection occurs in only < 1:40,000, it must be considered if pain occurs > 24 h after injection.
Immunomodulatory, cytotoxic, and immunosuppressive drugs:
Treatment with azathioprine, cyclosporine (an immunomodulatory drug), or cyclophosphamide provides efficacy similar to DMARDs. However, these drugs are more toxic, particularly cyclophosphamide. 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 and cyclophosphamide.
Biologic agents:
Biologic response modifiers other than TNF-α antagonists can be used to target B cells or T cells.
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 in 6 mo. Mild adverse effects are common, and analgesia, corticosteroids, diphenhydramine, or a combination may need to be given concomitantly. Rituximab is given only to patients who have not improved after using a TNF inhibitor and methotrexate.
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.
Other agents:
Anakinra is a recombinant IL-1 receptor antagonist. IL-1 is heavily involved in the pathogenesis of RA. Infection and leukopenia can be a problem, particularly when given in combination with a TNF antagonist.
TNF-α antagonists (eg, adalimumab, etanercept, 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.
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. 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.
Last full review/revision February 2008 by Roy D. Altman, MD
Content last modified February 2008
| |
|
