A chron ic syndrome characterized by nonspecific, usually symmetric inflammation of the peripheral joints, potentially resulting in progressive destruction of articular and periarticular structures; generalized manifestations may also be present.
Etiology and Incidence
Etiology is unknown. The immunologic changes may be initiated by multiple factors. About 1% of all populations are affected, women 2 to 3 times more commonly than men. Onset may be at any age, but it most often occurs between the ages of 25 and 50 yr.
In chronically affected joints, the normally delicate synovial membrane develops many villous folds and thickens because of increased numbers and size of synovial lining cells and colonization by lymphocytes and plasma cells. The lining cells produce a variety of materials, including collagenase, interleukin-1, and prostaglandins. The colonizing cells, initially perivenular but later forming lymphoid follicles with germinal centers, synthesize interleukin-2, other kinins, rheumatoid factor (RF) and other immunoglobulins. Fibrin deposition, fibrosis, and necrosis also are present. These findings are typical but not diagnostic. Hyperplastic synovial tissue (pannus) may erode cartilage, subchondral bone, articular capsule, and ligaments. Polymorphonuclear leukocytes are not prominent in the synovium but often predominate in the synovial fluid.
The rheumatoid nodule, seen in 30 to 40% of patients and usually found subcutaneously at sites subject to trauma, is the most characteristic pathologic lesion. It is a nonspecific necrobiotic granuloma consisting of a central necrotic area surrounded by "palisaded" mononuclear cells with their long axes radiating from the center, all enveloped by lymphocytes and plasma cells. Nodules and vasculitis have been found at necropsy in many visceral organs in severe cases of RA but are clinically significant in only a few cases.
Symptoms and Signs
Onset may be abrupt, with simultaneous inflammation in multiple joints, or (more frequently) insidious, with progressive joint involvement. Tenderness in nearly all "active" (inflamed) joints is the most sensitive physical sign. Synovial thickening, the most specific physical finding, eventually occurs in most active joints. Symmetric involvement of small hand joints (especially proximal interphalangeal and metacarpophalangeal), feet (metatarsophalangeal joints), wrists, elbows, and ankles is typical, but initial manifestations may occur in any joint. Stiffness lasting >30 min on arising in the morning or after prolonged inactivity is common; early afternoon fatigue and malaise also occur. Deformities, particularly flexion contractures, may develop rapidly. Ulnar deviation of the fingers with slippage of the extensor tendons off the metacarpophalangeal joints is typical. The carpal tunnel syndrome can result from wrist synovitis. Ruptured popliteal cysts can mimic deep venous thrombosis.
Subcutaneous rheumatoid nodules, though not usually an early manifestation, can be a major aid in diagnosis. Visceral nodules, vasculitis causing leg ulcers or mononeuritis multiplex, pleural or pericardial effusions, lymphadenopathy, Sjogren's syndrome, and episcleritis are other extra-articular manifestations. Fever may be present and is usually low-grade, except in the adult-onset Still's disease, a seronegative RA-like polyarthritis with prominent systemic features.
Laboratory and X-ray Findings
A normochromic (or slightly hypochromic)-normocytic anemia, typical of other chronic diseases, is found in 80% of cases; the Hb is usually >10 gm/dL but may rarely be as low as 8 gm/dL. Superimposed iron deficiency or other causes of anemia should be sought if the Hb is lesser 10 gm/dL. Neutropenia is found in 2% of cases, often with splenomegaly (Felty's syndrome). Mild polyclonal hypergammaglobulinemia and thrombocytosis may be present.
The ESR is elevated in 90% of cases. Antibodies to altered gamma-globulin, the so-called rheumatoid factors (RFs), as detected by agglutination tests (eg, the latex fixation test) that show IgM RF, are found in about 70% of cases. Though RFs are not specific for RA and are found in many diseases (including granulomatous diseases, chronic liver disease, and SBE), a high RF titer provides helpful confirmation when the typical clinical syndrome is present. The latex and bentonite tube dilution tests, utilizing human IgG adsorbed to particulate carriers such as latex or bentonite, are less specific but more sensitive than the sensitized sheep cell test using rabbit IgG. In most laboratories, a latex fixation tube dilution titer of 1:160 is considered the lowest positive value favoring a diagnosis of RA. A very high RF titer suggests a worse prognosis and is often associated with progressive disease, nodules, vasculitis, and pulmonary involvement. The titer can be influenced by treatment or spontaneous improvement and often falls as inflammatory joint activity decreases.
The synovial fluid, abnormal during active joint inflammation, is cloudy and sterile, has reduced viscosity, and usually contains 3000 to 50,000 WBCs/ÁL. Polymorphonuclear cells typically predominate, but > 1/2 of the cells may be lymphocytes and other mono-nuclear cells. Leukocyte cytoplasmic inclusions may be seen on a wet smear but are also present in other inflammatory effusions. Synovial fluid complement is often lesser 30% of the serum level. Crystals are absent in pure RA, excluding gout and pseudogout.
Radiologically, only soft tissue swelling is seen in the first months of the disease. Subsequently, periarticular osteoporosis, joint space (articular cartilage) narrowing, and marginal erosions may be present. The rate of deterioration, both radiologically and clinically, is highly variable.
The American College of Rheumatology (formerly, the American Rheumatism Association) has proposed new simplified criteria for the diagnosis of RA (see TABLE 106-1) that eliminate the previous terminology of "possible," "probable," "definite," and "classic." While primarily intended as a communication aid for those in clinical research, these criteria can serve as a guide to clinical diagnosis. Almost any other disease that causes arthritis must still be considered as a potential exclusion. Some patients with crystal-induced arthritis can meet the new proposed criteria, so that synovial fluid examination may often be helpful to exclude these. Most exclusions should be considered relative, since 2 diseases causing arthritis occasionally coexist.
When diagnosis is in doubt, subcutaneous nodules should be biopsied to differentiate gouty tophi, amyloid, and other nodules.
RA shares many features of other collagen vascular diseases, particularly SLE, but the latter usually can be distinguished by the characteristic skin lesions on light-exposed areas, temporal-frontal hair loss, oral and nasal mucosal lesions, joint fluid with a WBC count often lesser 2000/ÁL (predominantly mononuclear cells), positive antibodies to double-stranded DNA, renal disease, and low serum complement levels. LE cells, positive antinuclear factors, and visceral organ involvement are found in about 5% of otherwise typical RA patients, giving rise to the term "overlap syndrome." Some of these cases may represent severe RA; others have associated SLE or other collagen disease. Polyarteritis, progressive systemic sclerosis, and dermato(poly)myositis may have features that resemble RA.
Sarcoidosis, amyloidosis, Whipple's disease, and other systemic diseases may involve joints; biopsy of appropriate tissues often differentiates these conditions. Acute rheumatic fever is differentiated by a migratory pattern of joint involvement and evidence of antecedent streptococcal infection (culture or changing antistreptolysin-O [ASO] titer). Changing cardiac murmurs, chorea, and erythema marginatum are much less common in adults than in children. Infectious arthritis usually is monoarticular or asymmetric. Diagnosis depends on identification of the causative agent. Infection can be superimposed on a joint affected by RA. Gonococcal arthritis usually presents as a migratory arthritis also involving tendons around the wrist and ankle and finally settling in 1 or 2 joints. Lyme disease can occur without the classic history of tick bite and rash; it can be screened for serologically. Knees are most commonly involved. Reiter's syndrome is characterized by asymmetric involvement of the heel, sacroiliac joints, and large joints of the leg and by urethritis, conjunctivitis, iritis, painless buccal ulcers, and balanitis circinata, or keratodermia blennorrhagica on the soles and elsewhere. Serum and joint fluid complement levels are often elevated. Psoriatic arthritis tends to be asymmetric and is not usually associated with rheumatoid factor, but differentiation may be difficult in the absence of characteristic nail or skin lesions. Distal interphalangeal joint involvement and arthritis mutilans can be suggestive. Ankylosing spondylitis may be differentiated by its predilection for males, spinal and axial distribution of joint involvement, absence of subcutaneous nodules, and negative rheumatoid factor test. Gout may be mono- or polyarticular, with complete recovery between acute attacks early in the disease. Chronic gout may mimic RA. Typical needle- or rod-like birefringent monosodium urate crystals with negative elongation are present in the synovial effusion and can be seen by compensated polarized light. Hyperuricemia does not establish gout as the diagnosis. Response to colchicine is suggestive of gout, but other diseases may also subside with colchicine, or spontaneously. Calcium pyrophosphate crystal deposition disease may produce mono- or polyarticular acute or chronic arthritis, but the presence of weakly birefringent rodlike or rhomboid calcium pyrophosphate dihydrate crystals with positive elongation in joint fluid and x-ray evidence of articular cartilage calcification (chondrocalcinosis) differentiate this condition. Osteoarthritis (OA) often involves the proximal and distal interphalangeal joints, first carpometacarpal and first metatarsophalangeal joints, knees, and spine. Symmetry of involvement, prominent joint swelling (mostly due to bony enlargement) with some signs of inflammation, joint instability, and subchondral cysts on x-ray may prove confusing; the absence of rheumatoid factor, rheumatoid nodules, and systemic involvement along with the characteristic OA pattern of joint involvement with synovial fluid leukocyte counts lesser 1000 to 2000/ÁL permit differentiation from RA.
As many as 75% of patients improve somewhat with conservative treatment during the first year of disease; but > 10% are eventually disabled despite full treatment, and the disease has a major impact on the lives of many others.
Rest and nutrition: Complete bed rest is occasionally indicated for a short period during the most active painful stage of severe disease. In less severe cases, regular rest periods should be prescribed and carefully explained. Splints provide local joint rest. An ordinary nutritious diet is generally sufficient. Rare patients have food-associated exacerbations. Fish or plant oil supplementation is currently under investigation and may provide some amelioration of symptoms. Food and diet quackery is common and should be discouraged.
Salicylates are relatively safe, inexpensive, analgesic, and anti-inflammatory and are the traditional cornerstone of drug therapy in RA. Aspirin (acetylsalicylic acid) is begun with 0.6 to 1.0 gm (two to three 300-mg tablets) qid with meals and a bedtime snack. Dosage is then adjusted upward until achieving a maximally effective or mildly toxic dose (eg, tinnitus, diminished hearing). The final dose may vary from 3 to 6.5 gm (about ten to twenty-two 300-mg tablets). The average dose is 4.5 gm (15 tablets) per day. Antacids or sucralfate between meals can be taken for mild GI symptoms without discontinuing the aspirin. Enteric-coated and buffered tablets offer some advantage in patients with concomitant dyspepsia from gastritis or hiatus hernia. Misoprostol used along with aspirin may decrease the chance of erosion and bleeding gastric ulcer in high-risk patients, but it may cause diarrhea and does not prevent duodenal ulcer nor help nausea or epigastric pain. Sustained-release tablets provide longer relief for some patients and may be given at bedtime. Patients awakened at night by severe pain may take a dose at 2 or 3 am . Nonacetylated salicylates such as salsalate and choline magnesium salicylate seem to have better GI tolerance than aspirin and do not impair platelet adhesiveness, but they may not be as effective as anti-inflammatory agents.
Other NSAIDs are available for patients who do not tolerate sufficient aspirin to obtain a good effect or for whom less frequent dosing offers a major advantage, such as improved compliance. Usually only one agent should be given at a time.
Indomethacin 25 mg is given orally tid or qid with food or immediately after meals. Maximum dosage should be 150 to 200 mg/day. A 75-mg sustained-release capsule is also available for bid dosage. Ibuprofen 400 to 800 mg qid can be given; the larger dosage usually is needed. Naproxen may require only a 250-mg tablet bid; a total of 1250 mg/day may be used. Fenoprofen is given 300 to 600 mg qid; daily dose should not exceed 3200 mg. Tolmetin usually is initiated with 400 mg tid; the maximum recommended daily dose is 2000 mg. Sulindac is given 150 to 200 mg bid. Meclofenamate is given 200 to 400 mg/day. Ketoprofen is given 150 to 300 mg/day. Piroxicam has a single recommended dosage of 20 mg once/day. Flurbiprofen, the most recently marketed agent, is given 100 mg bid or tid. Diclofenac can be given 75 mg bid or 50 mg qid. Doses of all agents can be increased every 2 wk until response is maximal or maximum dosage is reached. Agents should be tried for at least 2 to 3 wk before assuming inefficacy.
Adverse effects of NSAIDs: Though often less irritating to the GI tract than aspirin, these other NSAIDs can also produce gastric symptoms and GI bleeding. They should be avoided during active ulcer disease. Use with meals and antacids can decrease upper GI symptoms. Misoprostol can be used with salicylates, as described above. Other possible side effects include headache, confusion and other CNS symptoms, worsening of hypertension, edema, and decreased platelet adhesiveness. As with aspirin, liver enzymes can be mildly elevated. Creatinine levels can rise because of inhibition of renal prostaglandins; less frequently, interstitial nephritis can occur. Patients with urticaria, rhinitis, or asthma from aspirin can have the same problems with the other NSAIDs. Agranulocytosis has been reported.
Slowly acting drugs: Optimal timing of their addition to therapy is under evaluation. Early use may be indicated in rapidly progressive disease. Generally, if aspirin or other NSAIDs are not sufficiently beneficial after 3 to 4 mo of treatment, addition of one of the slow-acting or potentially disease-modifying agents such as gold, penicillamine, hydroxychloroquine, or sulfasalazine should be considered.
Gold compounds usually are given in addition to salicylates or other NSAIDs if aspirin or 1 or 2 other NSAIDs do not provide sufficient relief or suppression of active joint inflammation. In some patients, gold may produce clinical remission and decrease the formation of new bony erosions. Parenteral preparations include gold sodium thiomalate or gold thioglucose (aurothioglucose). Gold is given IM at weekly intervals: 10 mg the first week, 25 mg the second, and 50 mg/wk thereafter until a total of 1 gm has been given or significant improvement is apparent. When maximum improvement is achieved, dosage is gradually decreased to 50 mg every 2 to 4 wk. Relapse usually occurs in 3 to 6 mo if no further gold is given following remission. Improvement often can be sustained for several years with prolonged maintenance administration.
Gold compounds are contraindicated in patients with significant hepatic or renal disease, or blood dyscrasia. Before receiving gold, the patient should have a urinalysis, hemoglobin, total and differential WBC count, and platelet count. These tests should be repeated before each injection during the first month and every 1 to 2 wk thereafter. Presence of the HLA antigen DR3 may predict an increased risk of renal and possibly other side effects from both gold and penicillamine. Toxic reactions to gold include pruritus, dermatitis, stomatitis, albuminuria with or without a nephrotic syndrome, agranulocytosis, thrombocytopenic purpura, and aplastic anemia. Other less common side effects include diarrhea, hepatitis, pneumonitis, and neuropathy. Gold should be discontinued when any of the above manifestations appear. Eosinophilia >5% and pruritus may precede appearance of a rash and are possible danger signals. Dermatitis usually is pruritic and ranges in severity from a single eczematous patch to generalized and, very rarely, fatal exfoliation.
Minor toxic manifestations (eg, mild pruritus or minor rash) may be eliminated by temporarily withholding gold therapy, then resuming it cautiously after the rash has been gone about 2 wk. However, if toxic symptoms progress, gold should be withheld and the patient given a corticosteroid. A topical corticosteroid or oral prednisone 15 to 20 mg/day in divided doses is given for mild gold dermatitis; larger doses may be needed for hematologic complications. A gold chelating agent, dimercaprol 2.5 mg/kg, may be given IM up to 4 to 6 times/day for the first 2 days and then bid for 5 to 7 days after a severe gold reaction. A transient nitritoid reaction with flushing, tachycardia, and faintness can occur several minutes after injections of gold sodium thiomalate. This may occur more often if the gold is not stored out of direct light. If these reactions occur, aurothioglucose can be used, as this does not seem to cause them.
An oral gold compound, auranofin, 3 mg bid or 6 mg once daily, may be tried for at least 6 mo and, if necessary and tolerated, increased to 3 mg tid for 3 more months. If the response is not favorable, auranofin should be discontinued. Unlike with injectable gold, diarrhea and other GI symptoms are prominent side effects. Renal and mucocutaneous side effects appear to be fewer than with IV gold, but long-term effects of auranofin are not known. Urinalysis, hemoglobin, and leukocyte, differential, and platelet counts should be done at least monthly.
Penicillamine given orally may have a beneficial effect similar to that of gold and may be used in some cases if gold fails or produces toxicity in patients with active RA. Suggested dosages start at 250 mg/day for 30 to 90 days; the dose is then increased to 500 mg/day for another 30 to 90 days and, if definite improvement does not occur, may be increased to 750 mg/day for 60 days. When the patient starts to respond, further increases should not be made. The dose should be kept to the minimally effective level. Before therapy, and every 2 to 4 wk during treatment, platelets must be checked and urinalysis and CBC performed. Side effects requiring discontinuation are more common than with gold. Penicillamine can cause marrow suppression, proteinuria, nephrosis, other serious toxic effects (including myasthenia gravis, pemphigus, Goodpasture's syndrome, poly-myositis, or a lupuslike syndrome), or a rash and a foul taste, all of which require discontinuation. Fatalities due to penicillamine have been reported. The drug should be given by, or with guidance from, one experienced with its use, and its effects must be monitored carefully.
Hydroxychloroquine can also control symptoms of moderately active RA. Toxic effects usually are mild and include dermatitis, myopathy, and generally reversible corneal opacity. However, irreversible retinal degeneration has been reported. Ophthalmologic evaluation with testing of visual fields using a red test object is required before, and every 6 mo during, treatment. An initial dosage of 200 mg is given orally bid with breakfast and the evening meal; therapy is continued at that dosage for about 6 mo. The drug should be discontinued if the patient fails to manifest any improvement after 6 mo. If definite improvement is achieved, the dosage can often be decreased to 200 mg/day and continued as long as effective. Frequent eye examinations must be continued.
Sulfasalazine, long used for ulcerative colitis, is now increasingly used for RA (for which it was originally synthesized). It is usually given as enteric-coated tablets, starting with 500 mg/day and increasing by 500 mg at weekly intervals to 2 gm/day. Benefit should be seen within 3 mo. Toxic effects may include gastric symptoms, neutropenia, hemolysis, hepatitis, and rash.
Corticosteroids are the most dramatically effective short-term anti-inflammatory drugs. RA, however, is usually active for years, and clinical benefit from corticosteroids often diminishes with time. Corticosteroids do not appear to prevent the progression of joint destruction. Furthermore, when the disease is active, severe rebound phenomena follow their withdrawal. Because of their side effects, corticosteroids should be given only after careful and usually prolonged evaluation of less potentially hazardous drugs. Corticosteroids do promptly suppress clinical manifestations for many patients and may be used to maintain joint function and allow continued performance of customary duties, but the patient should be cautioned about complications occurring with long-term use. Dosage should not exceed 7.5 mg/day of prednisone, except for patients with severe systemic manifestations of RA such as vasculitis, pleurisy, or pericarditis. Large "loading doses" followed by rapid dosage reduction are not generally recommended (although they have been used), nor is alternate-day therapy, since RA usually is too symptomatically active on the days corticosteroids are not given. Relative contraindications to the use of corticosteroids include peptic ulcer, hypertension, untreated infections, diabetes mellitus, and glaucoma. TB should be ruled out before corticosteroid therapy is begun.
Intra-articular injections of corticosteroid esters may temporarily help to control local synovitis in 1 or 2 particularly painful joints. Triamcinolone hexacetonide may suppress inflammation for the longest period; prednisolone tertiary-butylacetate also is effective. The 21-phosphate preparations of prednisolone or dexamethasone are not recommended because of rapid clearance from the joint and very short duration of action. Overuse of the recently injected, less painful joint may accelerate joint destruction. Since corticosteroid esters are crystalline, local inflammation transiently increases within a few hours in about 2% of injections.
Cytotoxic or immunosuppressive drugs such as methotrexate and azathioprine are increasingly used in management of severe, active RA. They can suppress inflammation and may allow reduction of corticosteroid doses. Major side effects can occur with these drugs, however, including liver disease, pneumonitis, bone marrow suppression, and, possibly, increased risk of malignancy following long-term use of azathioprine. Patients should be fully informed of these potential side effects and are generally advised to be under the supervision of a specialist. In recent years, methotrexate has been widely used to treat RA, may be used reasonably early in the course of severe active disease (as benefit is often seen in 3 to 4 wk), and can be given 2.5 to 15 mg in a single dose once weekly. It is usually started at 7.5 mg/wk and gradually increased as needed. It should be avoided in alcoholics and diabetics. Liver function must be monitored, and a liver biopsy may be needed if the patient continues to use this agent. Clinically significant liver fibrosis is fortunately uncommon. Complete blood counts should be done regularly. A rare fatal complication is pneumonitis. Severe relapses of arthritis can occur after withdrawal. Azathioprine should be initiated at about 1 mg/kg/day (50 to 100 mg) as a single oral dose or bid; dosage can be increased by 0.5 mg/kg/day after 6 to 8 wk at 4-wk intervals to a maximum of 2.5 mg/kg/day. Maintenance should be at the lowest effective dose. Although not approved for RA in the USA, cyclophosphamide also is proven effective but is used less often because of greater risks of toxicity. Other experimental therapies such as cyclosporine, anti-T-cell antibodies, lymphopheresis, and total lymphoid radiation are still being studied.
Exercise, physiotherapy, and surgery: Flexion contractures can be prevented and muscle strength restored most successfully after the inflammation is suppressed. Joint splinting reduces local inflammation and may relieve symptoms. Before the acute inflammatory process is controlled, passive exercise to prevent contracture is given carefully and within the limits of pain. Active exercise to restore muscle mass and preserve the normal range of joint motion is desirable as inflammation subsides, but should not be fatiguing. Self-help devices have enabled many patients with severe debilitating RA to perform activities essential to daily living. Orthopedic shoes or athletic shoes with good heel and arch support can be modified using inserts to fit individual needs, and are frequently helpful; metatarsal bars placed posteriorly to painful metatarsophalangeal joints decrease the pain of weight-bearing.
Established flexion contractures may require intensive exercise, serial splinting, or orthopedic measures. Though synovectomy provides only temporary relief of inflammation, it may be used in key joints to help preserve joint function if anti-inflammatory drugs have been unsuccessful. Arthroplasty with prosthetic replacement of joint parts is indicated if the degree of joint damage severely limits function. Total hip and knee replacements are the most consistently successful of available prosthetic procedures. Prosthetic hips and knees cannot be expected to tolerate resumption of activities such as vigorous athletics. Excision of subluxated painful metatarsophalangeal joints may greatly aid walking. Thumb fusions may provide stability for pinch. Neck fusion may be needed for cord compression. Surgical procedures must always be considered in terms of the total disease. Deformed hands and arms limit crutch use during rehabilitation; seriously affected knees and feet prevent full benefit from hip surgery. Reasonable objectives for the patient must be determined and function must be considered before appearance. Surgery may be undertaken while the disease is active.
Fluid & Electrolyte