Rheumatoid arthritis (RA) is a chronic systemic inflammtory process characterized by a pattern of morbidity in diathrodial joints. Tendons, ligaments, fascia, muscle, and bone can be jeopardized by the inflammatory process. Mediators of inflammation can extend the involvement into many different organ structures. For uniformity in investigative protocols and epidemiologic studies, the American Rheumatism Association (ARA) has established a set of diagnostic criteria (Table 433-1). These criteria are not based on theoretic knowledge of the etiology and pathogenesis of RA; current knowledge is insufficient for such a purpose. Accordingly, criteria developed to ensure the absence of bias from statistical summaries should not be taken as definitive in case-by-case clinical practice. Also established in the same source are 20 criteria that exclude a diagnosis of RA. These criteria indicate other rheumatic diseases that mimic some of the early signs of RA. Advances in rheurnatology since these criteria were revised (1958) would make it possible to extend the list considerably today. RA occurs worldwide in all races and ethnic groups. By the usual diagnostic criteria the disease (or family of diseases?) is two or three times more prevalent among females than among males, but application of narrower criteria such as seropositivity (presence of rheumatoid factors [RF]; see below under Etiology) or roentgenographic indications of tissue erosion show less association with gender. The peak incidence, onset is between the fourth and sixth decades, but the prevalence continues to increase into the seventh decade. Determinations of overall prevalence in various studies of various populations have ranged from 0.3 to 1.5 per cent. We may take 1 per cent as a rough figure for the prevalence of RA in the general adult population.

TABLE 433-1. ARA DIAGNOSTIC CRITERIA FOR RA

Among these criteria only the finding of morning stiffness can be based on patient's report. The first five criteria must be found continuously for at least six weeks. Classic RA requires 7 of the 11. Definite RA requires 5 of the 11.

• Morning stiffness
• Pain on motion or tenderness in at least one joint
• Swelling in at least one joint
• Swelling in a second joint (any interval free of joint symptoms between the two joint involvements may not be more than three months)
• Simultaneous involvement of the same joint on both sides of the body
• Subcutaneous nodules on bony prominences or extensor surfaces or in juxta-articular regions Roentgenographic findings typical of RA
• Positive agglutination test result for rheumatoid factor
• A poor mucin precipitate (with shreds and cloudy solution) obtained on adding synovial fluid to dilute acetic acid
• Characteristic histologic changes in the synovium
• Characteristic histologic changes in subcutaneous nodules

High titers of RF are associated with more severe and active joint disease and with the presence of rheumatoid nodules. RF may react only with autologous IgGs or with isologous ones and sometimes even with the IgG of other species (heterologous) as well. IgM RF can react with five IgG molecules to produce very large complexes with sedimentation constants of 22S. Intermediate-size complexes (between 7S and 19S) containing only IgG molecules, some of which have rheumatoid activity against self and usually consist of three molecules, can be discerned. There is some evidence that these complexes occur to a greater extent in those individuals with widespread systemic disease and vasculitis.

Seropositive RA, at least, clearly can be classified as an autoimmune disorder, since RF are antibodies against autologous IgG. The cause of their production remains unknown. The antigenic epitope on the Fc portion of the IgG molecule appears to be absent or inaccessible in normal IgG. Alteration in the IgG could be caused by its binding to some specific antigen. Some evidence for this is provided by findings of RF in bacterial endocarditis and in other diseases involving chronic antigenic stimulation. Association has been found between RA and the Epstein-Barr virus, a polyclonal stimulator of B cells. It has been suggested that RF may be produced in certain individuals as a result of a special host response to this virus. Despite the extremely strong association of RF with RA, they clearly do not cause the disease, since they occur with other diseases and sometimes in healthy individuals, and furthermore because transfusion of RF into normal volunteers does not initiate inflammation. Nonetheless, the association indicates some fundamental process taking place within the synovial tissues. Multicentric immunoreactivity in various synovial tissues, with a dependence on the total available clonal repertoires, may be involved. The B lymphocytes of susceptible individuals may react in special ways against a variety of antigens and subsequently stimulate the production of RF.

There are numerous examples of polyarthritis in association with microorganisms, including the streptococci, clostridia, diphtheroids, and mycoplasmas. Associations of several viral diseases with inflammatory rheumatic syndromes suggest that RA itself could be caused by a virus. The striking synovitis sometimes seen following rubella infections and the arthritis that may precede the onset of jaundice in infectious hepatitis are interesting examples of such associations. The Ross River virus can producv an epidemic syndrome that clinically resembles systemic-onset juvenile chronic arthritis. Profound joint manifestations can be produced by the arboviruses, particularly of the togavirus family. Recently considerable interest has centered on the possibility that a parvovirus may be associated with an RA-like disease. Lyme arthritis, which is caused by a spirochete, can become a chronic rheumatoid disease, although clearly separable from RA. Many animal models of RA are caused by microorganisms or their products. Others involve immunologic reactivity against adjuvant or against bacterial cell wall peptidoglycans. All of these models involve erosive, destructive, fibrosing joint pathology.

The MRL-1 mouse provides an interesting animal model in which a syndrome closely resembling RA is evidently genetic in origin, without apparent dependence on any infectious agent. Further, a great deal of intensive research has failed to produce any direct evidence for an infectious origin of RA. PATHOLOGY. The first apparent events in the rheumatoid synovium include microvascular injury and moderate proliferation of synovial lining cells. These are generally taken to be cause and effect, but opinions differ as to which is which. They are accompanied by edema or inflammation. Polymorphonuclear leukocytes (PMNs) appear in the synovial lining, and in its small blood vessels inflammatory cells and tiny thrombi can often be found. Phagocytosis involving large mononuclear cells accompanies the proliferation. Collagenase, elastase, cathepsins, and prostaglandins are released. Fibrin is formed at the synovial lining and incorporated into the synovium, which thus begins to encroach into the joint cavity. Some of the fibrin can break loose and form "rice grains" in the joint cavity. The interior surface of the synovium becomes villous, thus increasing its surface area more than proportionally to its increasing volume. The synovium proliferating in this manner is referred to as the parmus.  

Hyperplasia and hypertrophy occur among the lining cells, of which the number of layers is doubled or trebled. Soon the proliferating synovium is vascularized by arterioles, capillaries, and venules, sustaining the pathologic process. Segmental vascular changes occur, often accompanied by venous distention and infiltration of the arterial walls by PMNs and by areas of thrombosis and perivascular hemorrhage. The normally acellular subsynovial stroma becomes packed with inflammatory cells, largely mononuclear, which may collect into aggregates or follicles. In rare cases one can find true germinal centers. Follicles are usually dominated by lymphocytes surrounded by a layer of plasma cells. Immunofluorescence shows large numbers of Ig-secreting B cells, but the majority of lymphocytes in the RA synovium are T cells. Eventually some synovial cells differentiate to fibroblasts. The formation of the parmus, with inflammatory destruction of soft tissues, causes laxity of ligaments and tendons and thus, with aggravation by mechanical pressure and regular use, typical deformities occur. Ultimately there is erosion of juxta-articular bone around the margins of the pannus and invasion by the parmus of subchondral tissue. Although cysts and loss of cartilage can generally be observed roentgenographically, the erosion of bone so characteristic of advanced RA is less commonly seen.

PATHOGENESIS. Two general ideas have dominated the discussion of pathogenesis. One is that extravascular immune complex formation incites the inflammatory response; the other attributes the inflammation to cellular hypersensitivity. According to the latter, an accumulation of activated T cells in the synovium produces soluble factors, specifically lymphokines, which stimulate the proliferation of the synoviurn and the general inflammation. The occurrence of an arthritic syndrome similar to RA in some agammaglobulinernic children suggests an important role for the cellular immune reaction in rheumatoid synovitis.

According to the concept of inflammation based on the formation of immune complexes, the immune response is triggered sufficiently, and perhaps specifically, against some foreign antigen. This must involve a host response determined by the genotype of the individual. Thus an association with histocompatibility markers may be expected, as has been noted between seropositive RA and the HLA-D4 and HLADR4 markers. Studies using DNA restriction fragment length polymorphisms appear to have revealed more specific molecular genetic markers associated with RA. The host response seems to involve a local reaction within a subset of the synovial joints. RA appears to be a multicentric immune response, with variables that differ from one joint to another determining the reaction of the synovial tissue at each joint. Therefore different B cell clonal reactivity might be found in different joints of one individual.

Antigen-antibody complexes formed within the joint cavity in this process can become trapped in hyaline cartilage and fibrocartilage, where they can cause changes in matrix macromolecules. Within the synovial fluid, the immune response activates the complement system, kinins, phagocytic cells, and lysosomal enzyme release. Mediators produced in this process stimulate synovial cells to proliferate and to produce proteinases and prostaglandins. These products cause dissolution of the connective tissue macromolecules within the associated connective tissue and the articular cartilage. Mediators also activate fibroblasts to produce a denser, richer connective tissue matrix and further synovial proliferation. Complexes in the synovial fluid can fix and activate complement and perpetuate the inflammatory process. In order for destruction of joint tissue to progress, the usual control mechanisms that inhibit both clegradative enzymes and their activators must be overwhelmed by saturation of the synovial fluid and the tissue inhibitors of -specific enzyme systems. This course leads to a chronic proliferation of cells, stimulation of enzyme systems, and destruction of normal tissue matrices.

Collagenase production seems to be markedly stimulated in synovial sites in the presence of interleukin 1, derived from mononuclear macrophages. This enzyme is generally inactive when released from synovial cells but may be activated by appropriate proteolytic enzymes. Plasmin may be the key activator. Synovial cells produce a plasminogen activator that converts plasminogen in the circulation to plasmin, which then activates latent collagenase bound to collagen fibrils. This promotes rapid destruction of collagenous tissue.

CLINICAL FEATURES. A diagnosis of RA is compatible with a wide range of clinical courses, ranging from a few months of discomfort to decades of severe disability. Perhaps two thirds of cases begin with symptoms arising gradually over a period of weeks or months. Malaise and fatigue characterize this period, often in conjunction with diffuse musculoskeletal pain. As the disease advances specific joints exhibit pain, tenderness, swelling, and redness. The pattern of joint involvement is typically symmetric, involving the hands, wrists, elbows, and shoulders, but usually sparing the distal interphalangeal (DIP) joints. Symmetry and the sparing of the DIP joints are helpful in differentiating RA from other arthritides.

A frequent complaint is that of stiffness following inactivity. It can occur in the morning upon arising or following prolonged sitting. It is described by some as a "gelling" process and seems to be a~ssociated with edema within the inflamed tissues. So characteristic is this symptom that the duration of morning stiffness has been taken as a guide to the severity of the inflammatory process. In most clinical studies of RA, it is a useful bit of quantitative data with which to follow the activity of the disease. As the process evolves, the patient may have increasing difficulty with pain and stiffness. This limits the ability to move about, climb stairs, open doors, open jars, or to do detailed small movements, such as sewing. The patient may develop an associated psychologic depression and weight loss, and sometimes a low-grade fever may occur in association with the systemic manifestations of the disease.

An acute onset of disease is seen in about 20 per cent of patients. "Acute" refers to the rapid build-up of symptoms over a period of a few days. Occasionally an individual retires in the evening with no symptoms and wakes up the next morning with acute generalized RA. Such rapid onset of pain involving joints and surrounding soft tissues, as well as muscles, can mimic, and must be differentiated from, acute myositis, viral syndromes, or if focal, even septic arthritis.

RA typically is intermittent in early stages but becomes more sustained as it progresses. However, as remarked above, the course varies greatly. Some patients show an unrelenting progression to severe disability and even, rarely, mortality, but repeated periods of some degree of remission are the general rule. An ARA committee has proposed criteria for clinical remission of rheumatoid arthritis. At least five of the following requirements must be fulfilled for at least two consecutive months: (1) duration of morning stiffness not exceeding 15 minutes; (2) no fatigue; (3) no joint pain (by history); (4) no joint tenderness or pain on motion; (5) no soft tissue swelling in joints or tendon sheaths; and (6) erythrocyte sedimentation rate by Westergren method less than 30 mm per hour for females or 20 mm per hour for males.

Uniform standards for the evaluation of functional capacity may be particularly useful in dealing with patients with RA. Although there have been a number of suggested systems, we may accept the following for a rough division:

Class I-No restriction of ability to perform normal activities.

Class II-Moderate restriction but adequate for normal activities.

Class III-Marked restriction, inability to perform most duties of the patient's usual occupation or self-care.

Class IV-Incapacitation or confinement to a bed or wheelchair.

DIFFERENTIAL DIAGNOSIS. The differential considerations in the diagnosis of RA are numerous. Although there is seldom confusion in classic RA, diagnosis can be more difficult in patients with early acute polyarthritis or those with involvement of only a few joints. One must consider osteoarthritis, gout, chondrocalcinosis, systemic lupus erythematosus, and progressive systemic sclerosis as the more common diseases that might be confused with RA. In addition, a variety of systemic diseases, including sarcoidosis, inflammatory bowel disease, Whipple's disease, amyloidosis, chronic infection, and malignancies, can all be manifested by arthritic syndromes mimicking RA. Therefore, a complete medical evaluation is indicated in all patients with joint manifestations. One must assess the patient for general systemic diseases and also for curable causes, such as bacterial infections. The careful analysis of synovial fluid is critical in the differentiation of rheumatoid arthritis from chronic gout and chondrocalcinosis. Critical evaluation of inflammatory joint effusions is useful not only for diagnosis but also as a guide for therapeutic responses.

ARTICULAR MANIFESTATIONS. RA can affect any diarthrodial joint. Those most commonly involved are the small joints of the hands, wrists, knees, and feet. As the disease spreads it may involve elbows, shoulders, sternoclavcular joints, hips, and ankles. The temporomandibular and crico arytenoid joints are less frequently involved. Spinal involve ment in RA is generally limited to the upper cervical articu lations, at least from the standpoint of clinically significant lesions.

Hands. One of the most common early signs of disease is swelling of the proximal interphalangeal (PIP) joints, giving the fingers a fusiform or spindle-shaped appearance. This is generally associated with bilateral and symmetric swelling of the metacarpophalangeal (MCP) joints (Fig. 433-1). Although the distal interphalangeal (DIP) joints can be involved, they generally are not, and this is useful in discriminating RA from osteoarthritis. Soft tissue laxity gives rise to u1nar deviation of the fingers (Fig. 433-2A), which is frequently accompanied by palmar subluxation of the proximal phalanges. Swan neck deformities develop through hyperextension of the PIP joints in conjunction with flexion of the DIP joints (Fig. 433-2B). Flexion deformity of the PIP joints and extension of the DIP joints give rise to the boutonni6re deformity. These changes are associate With loss of strength in the hands and frequently loss of the ability to maintain a good pinch. Synovial erosions of tendons may lead to their rupture and thus to sudden loss of the ability to extend the fingers.

Wrists. The wrists are almost invariably involved in RA and frequently demonstrate easily palpable, boggy synovium. Such synovial proliferation on the volar aspect may compress the median nerve and produce the carpal tunnel syndrome. This consists of paresthesia and dysesthesia of the thumb and the second and third digits and the radial aspect of the fourth digit. It may also be accompanied by atrophy of the thenar eminence. Frequently, one of the first losses of motion in RA is the inability to clorsiflex the wrist fully. Normally the wrist should be able to move through nearly 180 degrees from palmar to dorsiflexion.

Knees. Synovial hypertrophy and effusion in these weightbearing joints place them among the more frequently affected joints in RA. Effusions may be detected by balloting the patella or by observing a "bulge sign" along the patella when fluid is pushed into the suprapatellar pouch and then expressed back into the joint. One may expect to see quadriceps atrophy in association with chronic knee arthritis. Baker's cysts may form owing to enlargement of the sernimembranous bursa into the popliteal space. Such synovial cysts may occasionally dissect and rupture and can give rise to symptoms mimicking acute thrombophlebitis. Sonograms and arthrograms may be useful for confirmation of the diagnosis. Destruction of soft tissue about the knee can also give rise to marked joint instability.

Feet and Ankles. Arthritis is common in the feet and may involve changes analogous to those described in the hands. Cock-up of the toes may produce subluxation of the metatarsal heads and finally a clawlike appearance.

Neck. Neck pain and stiffness are frequent in RA. As in other joints, the rheumatoid process can lead to the erosion of bone in the cervical vertebrae. Sustained erosion may produce atlantoaxial subluxation and thus cervical dislocation, spinal cord compression, and finally neurologic manifestations in rare cases. There is also a possibility of torsion and compression of the vertebral arteries, with vertebrobasilar insufficiency and syncope on downward gaze as symptoms. Occipital and occasionally more extensive headache is a frequent complaint. Localized tenderness, muscle spasm, and limitation of rotary motion may be found with neck involvement; limitations of flexion and extension of the cervical spine are less common. Uncontrollable head tilt may occur as a symptom of lateral mass collapse of the C1 and C2 vertebrae.

Elbows. Erosion around the margins of a pannus can easily eradicate the paraolecranon grooves. Often, even in early RA, the elbow does not relax into a fully extended position. Loss of joint space and deterioration of congruity occur as in other joints. Particularly in the elbow, this may facilitate dislocation of the joint.

Shoulders. Involvement of the glenohumeral, acromioclavicular, and thoracoscapular joints is a common feature of the advanced, but not the early, course of RA. Limitation of motion and tenderness just below and lateral to the coracoid process are typical symptoms, Noticeable swelling is rare. Joint destruction typically involves rupture of the joint capsule and subluxation of the humerus.

Hips. The deep location of the joint may hide swelling and tenderness. Physician and patient should therefore be alert to limitation of joint motion, which may be manifested by a change of gait. Pain in the groin, or sometimes even the buttocks or lower back, may be symptomatic of hip involvement. Because the hip joint capsule has poor distensibility, great pain can result if a massive effusion occurs. Arthrocentesis should be done to rule out infection in such a case.

EXTRA-ARTICULAR MANIFESTATIONS. The occurrence of constitutional symptoms, occasionally a low-grade fever and minimal lymphadenopathy, are to be expected in RA. As the disease progresses, muscle atrophy, weakness, and sometimes the development of tremor can be seen. The latter is presumably caused by muscle fatigue and is usually associated with more severe disease and a poor prognosis. Skin. Subcutaneous nodules may develop at some time in approximately 20 to 25 per cent of patients. They are nearly always associated with seropositive disease and are found most frequently in the rapidly progressive and destructive form of the disease. Periarticular structures and areas subject to pressure, such as the elbows, the occiput, or the sacrum, tend to be the primary sites for subcutaneous nodules. They may occasionally break down or become infected but generally are asymptomatic.

A vasculitic process in the skin often produces small brown spots or splinter-shaped lesions, frequently in the nail folds or in the digital pulp. Larger areas of ischernic involvement may occur in the lower extremities with infarction of a toe or the development of skin sloughs over the malleoli. Histologic examination of the involved area may show leukocytoclastic vasculitis, or only a mild venulitis with a relatively bland proliferation of affected digital vessels. It may also be a severe and widespread necrotizing vasculitis of the small and medium-sized arteries, indistinguishable from polyarteritis nodosa. Rheumatoid vasculitis is frequently associated with high fever and other manifestations of systemic disease, including a depression of serum complement. Another common skin manifestation is a tendency to easy bruisability and production of ecchymotic lesions. This seems to be caused by the general fragility of the skin in RA and is possibly associated with the systemic manifestations of -the inflammatory process.

Cardiac Manifestations. Although symptomatic cardiac disease is not common in RA, a relatively frequent symptomatic lesion is acute pericarditis. It is unrelated to the duration of the arthritis and seems to appear most often in seropositive disease. The pericardial fluid characteristics include a low glucose concentration, increased lactic dehydrogenase (LDH) level, elevated immunoglobulin levels, and low complement activity. Echocardiography is a sensitive diagnostic tool for pericarditis in RA. Pericardial disease rn~y vary from a mild, fleeting process to a sizable effusion to cardiac tamponade and death. Some evidence of pericardial involvement with old fibrinous adhesions is found in about 40 per cent of RA patients at autopsy. The rare pericardial tamponade is life-threatening. Typical symptoms are chest pain, dyspnea, and peripheral edema. A few cases have a pericardial. friction rub. The pericardial fluid will generally have glucose levels below 15 mg per cleciliter, protein levels above 4 grams per cleciliter, and LDH levels greater than in serum. The more common constrictive pericarditis is characterized by dyspnea, clinical right heart failure, peripheral edema, and increased jugular venous pressure. Fever, chest pain, pericardial friction rubs, Kussmaul's sign, and pulsus paradoxus can also occur. The definitive sign is the prominent y descent of the jugular venous pulse, demonstrated by right-side cardiac catheterization. Lesions similar to rheumatoid nodules may be found involving the myocardium and the valves. Sometimes a focal interstitial myocarditis and arteritis of coronary vessels may be recognized. Occasionally valvular insufficiency, conduction abnormalities, and myocardial infarction secondary to these inflammatory lesions may be seen as clinical manifestations of rheumatoid heart disease.

Pulmonary Manifestations. Rheumatoid pleural disease, although frequently found at autopsy, is most commonly asymptornatic. Occasionally a pleural effusion may be of sufficient size to cause respiratory limitation. Neoplasm and infection should be ruled out based on a pleural tap. Typically the pleural fluid is exudative, and white cell counts vary greatly but generally are less than 5000 per microliter. Glucose levels tend to be low, and the LDH enzyme level is high. Total hemolytic complement, C3, and C4 levels are low. Immune complexes and RF are frequently found in the pleural fluid. Intrapulmonary nodules may also be seen. Although they are usually asymptomatic, they may become infected and may cavitate or rupture into the pleural space with the production of a pneurnothorax. Similar but distinct nodular infiltrates may also be seen in rheumatoid lungs in association with pneurnoconiosis (Caplan's syndrome). Finally one may see a diffuse interstitial fibrosis with pneumonitis. This may progress to a honeycomb appearance on the roentgenogram, bronchiectasis, chronic cough, and progressive dyspnea. Pulmonary function tests will show a diminished compliance and a restrictive ventilatory pattern. Large airways are not involved. An irreversible combination of respiratory insufficiency and resultant right-side cardiac failure is possible. Chronic inflammatory cell infiltration with neutrophils and eosinophils can forewarn of this possibility, Rarely small airway obstruction may develop into a necrotizing bronchiolitis. This has been associated with therapies with gold and D-penicillamine.

Neurologic Manifestations. Rheumatoid vasculitis is frequently associated with a mononeuritis multiplex syndrome in which there is patchy sensory loss in one or more of the extremities, frequently in association with foot drop or wrist drop. Biopsy of the sural nerve (when there is an abnormal conduction time) can confirm the diagnosis of vasculitis. As mentioned previously, neurologic complaints can also be i produced in association with proliferating synovium causing compression of nerves. This can result in conditions such as a median neuropathy (carpal tunnel syndrome) or a tarsal tunnel syndrome with foot drop caused by an anterior fibial nerve palsy. Although the central nervous system is usually spared, rheumatoid vasculitis and rheumatoid nodule-Re granulomas have been known to occur in the meninges.

Ophthalmologic Manifestations. Episcleritis is a self-limit- ing condition and may develop in association with mild painand discomfort. Sjogren's syndrome can occur and cause corneal and conjunctival lesions associated with dryness of the eyes. Scleritis can be accompanied by severe pain and occasional visual impairment. Lesions may be found in the superior sclera as raised yellow nodules surrounded by a hyperemia of the deep scleral vessels. If this progresses over a period of time, allowing the dark blue color of the choroid beneath to show through, it is termed scleromalacia perforans. The histologic picture is similar to that of the rheumatoid 51 nodule.

Felty's Syndrome. This syndrome is found in chronic RA associated with splenomegaly, lymphadenopathy, anemia, thrombocytopenia, and a selective leukopenia involving only the neutrophils. Most cases occur among seropositive patients with very active arthritis and systemic manifestations such as fever, fatigue, anorexia, and weight loss. Hyperpigmentation and leg ulcers can occur in association with Felty's syndrome. HLA-DR4 has been reported to characterize 95 per cent of vatients. Although hvversplenism is Drovosed as one cause phosphamide, chlorambucil, and methotrexate have been used to treat especially severe unremitting RA. Currently the most effective form of immunosuppressive therapy for RA appears to be methotrexate.* Even once-a-week oral dosage of 7.5 mg seems efficacious.

For especially difficult-to-manage patients, experimental approaches include plasmapheresis, leukapheresis, and total lymph node irradiation. All of these procedures are experimental, and long-term effects are unknown.

Because of its side effects, long-term corticosteroid therapy is generally shunned by most rheumatologists. Patients with active rheumatoid disease do not tolerate alternate-day steroids well, and therefore one quickly gets into a pattern of daily therapy. Although they can be useful in patients with neuropathy, vasculitis, pleuritis, pericarditis, scleritis, and related conditions, for the usual patient with only joint disease it is wise to avoid them. Local steroid injections can sometimes be helpful for the relief of persistent effusions or to get patients more mobile in preparation for appropriate physical therapy.

Finally, reconstructive orthopedic surgery is of very great importance. Perhaps the greatest contribution of the last decade to the management of RA has been the development of superb techniques for joint replacement. The use of prosthetic devices for hip and knee joints has given excellent results, and the results for ankle, elbow, and shoulder replacement are improving rapidly.

JUVENILE CHRONIC ARTHRITIS

Rheumatic diseases are not rare in children, but they differ notably from RA. For this reason the term juvenile chronic arthritis (JCA) is used, rather than juvenile rheumatoid arthritis. The various subclasses have not yet been fully defined, but currently JCA is subdivided into systemic onset disease, polyarticular onset disease, and pauciarticular onset disease.

Systemic onset arthritis, or Still's disease, accounts for about 20 per cent of patients. It can begin at any age. RF and antinuclear antibody are generally not found. Clinical characteristics include a high intermittent fever, maculopapular rash, polyserositis, lymphadenopathy, hepatosplenornegaly, leukocytosis, and anemia. Although the disease is rarely lifethreatening, it can be confused with leukemia or infection. A chronic polyarthritis usually develops in these patients within the first few months of the disease but sometimes not until years later.

Polyarticular onset disease without extra-articular manifestations occurs in approximately 40 per cent of patients. There is a female preponderance. The majority are seronegative. Seropositive patients are generally over eight years old at onset. Antinuclear antibodies are often found. These patients may have malaise, low-grade fever, adenopathy, anemia, and growth retardation. Cervical spine involvement is common, most typically at the C2-C3 apophyseal joints.

Pauciarticular onset disease accounts for the remaining 40 per cent of JCA patients. There are at least two subgroups within this group. One is characterized by early onset. It shows a female preponderance. The serum in this group is often positive for antinuclear antibodies but negative for RF. Some tend to develop inflammation of the anterior uveal tract (iridocyclitis). Occasionally this is the major manifestation; it can progress to blindness. Therefore evaluation of these children for progressive ophthalmologic manifestations is important. A second subgroup with pauciarticular onset has a strong male preponderance. Many of these patients are HLAB27 positive and appear as young children with spondyloarthropathy.

Treatment is difficult, but fortunately most patients with JCA have a relatively benign course. Aspirin is a basic standby, and physical and psychosocial support are indicated.

ADULT-ONSET STILL'S DISEASE

As already mentioned, Still's disease is one form of juvenileonset chronic arthritis; adult-onset cases have also been found, with clinical features almost identical to those of juvenileonset cases. Patients exhibit high fever, polyarthritis, tenosynovitis, and a salmon-colored maculopapular measles-like rash, particularly over the trunk and along pressure lines. Nodules sometimes occur. The fever and rash are most characteristic of the onset and point to the diagnosis of adultonset Still's disease. Pericarditis and pleural effusions have been reported but are generally mild. Other systemic manifestations do occur. Acute symptoms generally respond to an adequate dose of salicylates, but occasionally NSAIDs or even prednisone may be necessary for short periods of time.