Juvenile Rheumatoid Arthritis

Juvenile Rheumatoid Arthritis Introduction Juvenile rheumatoid arthritis (JRA) is a condition of chronic synovitis in children of which there are several distinct subgroups (Table 1). The classic adult-type rheumatoid arthritis does occur in children but is quite rare, the JRA subgroups seronegative* polyarthritis and systemic-onset disease also occur in adults but not frequently, the pauciarthritis of early childhood has not been recognized in adults, and the pauciarthritis of older children usually is classified as spondyloarthropathy in adults. The nomenclature for chronic childhood arthritis remains confusing (Table 2). Incidence and Epidemiology The true incidence of JRA is not known. Based on the estimate that approximately 5% of all cases of chronic so-called "rheumatoid" arthritis begin during childhood, there would be about 250,000 children who have JRA in the United States today. JRA certainly is not a rarity among the chronic diseases affecting children. There are no good studies of the comparative incidence of JRA in countries worldwide. Most forms of JRA are known to occur in countries where data are available; pauciarthritis of older children, related to spondyloarthropathy, is more common in populations such as the native Americans of western Canada, who have a high prevalence of HLA-B27, a human leukocyte antigen that is associated with human disease. No causes or risk factors have been identified for JRA. Antecedent causes that frequently are mentioned include infectious agents, immunologic abnormalities of the host, physical trauma to joints, psychological trauma to the child, and allergy or reactions to environmental agents. Some forms of JRA appear to have a familial occurrence, particularly older onset pauciarthritis, which often occurs in families whose members have ankylosing spondylitis or other spondyloarthropathies associated with HLA-B27. Familial occurrences of early childhood pauciarthritis and of seropositive arthritis also can be found, although not commonly, which is not surprising because both of these forms of arthritis have associations with genetically determined HLA types. There is no evidence that JRA is transmissible. The various subgroups of JRA appear to differ in gender, age at onset, types of complications, and prognosis, although the epidemiologic significance of these observations is unknown (Table 1). Pathophysiology The synovial tissue, or lining tissue of the joint, is the target for inflammation in JRA. Early results of synovial inflammation include hypertrophy of synovial tissue and secretion of increased amounts of joint fluid. Affected joints are swollen, limited in motion, stiff, painful, warm, and occasionally erythematous. Two or more of these objective signs are necessary to warrant the designation of arthritis (Table 3). Affected joints in JRA generally are marked by swelling, stiffness, and loss of motion; excruciating pain, bright erythema, or dramatic heat are suggestive of some other cause of synovitis, such as septic arthritis or acute rheumatic fever. The joint fluid in JRA contains increased numbers of cells, predominantly polymorphonuclear leukocytes; cell counts may range between 10,000 and 100,000/mm3, and synovial fluid glucose levels may be decreased.

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TABLE 1. Recognizable Subgroups Of JRA % OF SUBGROUP

PATIENTS

CHARACTERISTICS

Systemic-onset Disease

10% to 20%

Systemic manifestations Slight male preponderance Seronegativity: RF* and ANA* Severe arthritis in 25%

Polyarticular Disease

20% to 30%

Symmetric polyarthritis of

RF-negative polyarthritis

small and large joints Female preponderance Early or late childhood onset ANA in 25% Rheumatoid nodules common Severe arthritis in 10% to 15%

RF-positive polyarthritis

5% to 10%

Symmetric polyarthritis

of small and large joints Female preponderance Late childhood onset ANA in 50% to 75% Rheumatoid nodules common Severe arthritis in >50%

Pauciarticular Disease

30% to 40%

Arthritis of few joints

Early childhood-onset

Hips/sacroiliac joints spared Female preponderance Early childhood onset ANA in 60%, RF-negative Chronic iridocyclitis in 30% Mild arthritis

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Late childhood-onset

10% to 15%

Arthritis of few joints

Hips/sacroiliacs often affected Male preponderance Late childhood onset ANA-negative, RF-negative HLA-B27 in 75% Some will have spondyloarthropathy as adults

*RF = rheumatoid factor; ANA = antinuclear antibodies. The etiologic agent or agents for the synovitis in JRA are unknown. The synovitis is characterized by its chronicity. Immunologic mechanisms such as immune complex disease may perpetuate the synovitis, but full explanations for the chronicity of synovial inflammation remain to be found. If synovitis persists long enough in an individual joint, structures of the joint may be damaged. Because articular cartilage does not regenerate well, this destruction may be permanent. Fortunately, many children who have JRA seem to withstand prolonged periods of synovitis without incurring permanent joint destruction. The destructive mechanisms of rheumatoid synovium are not fully known. It is of interest to compare JRA synovitis with the synovitis of other types of arthritis. The synovitis of staphylococcal arthritis is extremely aggressive and will cause joint destruction within several days of onset, and the synovitis of classic adult rheumatoid arthritis often results in joint destruction within 1 year of disease onset. In contrast, the synovitis of the seronegative forms of JRA may not destroy joint structures even after years of activity. Such differences suggest distinctions either in the nature of the synovitis or of the host. TABLE 2. Names Currently Used To Describe Condition(s) of Chronic Synovitis in Children •

Juvenile rheumatoid arthritis

•

Juvenile chronic polyarthritis

•

Juvenile chronic arthritis

•

Still disease

•

Chronic childhood arthritis JRA may involve other organ systems in addition to the joints, and patterns of organ involvement differ in various

subgroups. Possible extraarticular manifestations include the iridocyclitis of early childhood pauciarticular disease; the rheumatoid nodules and rheumatoid vasculitis of seropositive disease; the fevers, rash, polyserositis, hepatosplenomegaly,

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lymphadenopathy, anemia, leukocytosis, and (rarely) myocarditis or interstitial lung disease or disseminated intravascular coagulation of systemic onset disease; and, at times, secondary amyloidosis affecting various organ systems. Growth retardation also is a well-known concomitant of a number of chronic diseases in children, including JRA. Clinical Manifestations The clinical manifestations of JRA are diverse. Although a number of clinically distinct subgroups of disease have been suggested, there is no complete agreement as to which subgroups are valid. The American Rheumatism Association currently recognizes three subgroups: systemic-onset disease, polyarticular-onset disease, and pauciarticular-onset disease. There is good evidence that the polyarticular and pauciarticular categorizations actually contain more than one subgroup (Table 1). Final delineation of these subgroups awaits the finding of definitive genetic or etiologic differences in disease. At present, recognition of the subgroups appears to be useful for the clinician both in the diagnosis and the management of patients. The common feature that children in all JRA subgroups share and that is necessary for diagnosis is chronic synovitis. TABLE 3. Objective Signs of Arthritis Joint Swelling --Synovial hypertrophy --Increased amounts of synovial fluid --Swelling of periarticular tissues Joint Pain --On motion --On palpation (tenderness) --At rest Loss of Joint Motion --Stiffness of joints Joint Warmth Joint Erythema Clinical Features SYSTEMIC-ONSET JRA Systemic-onset JRA, characterized by high intermittent fevers and other extraarticular manifestations (Table 4), affects about 10% to 20% of all patients who have JRA. There is a slight male preponderance. The disease may present at any age during childhood and occasionally presents during adulthood.

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The characteristic fevers of systemic-onset JRA are high and intermittent, with elevations to 39.5EC (103EF) or higher once or twice daily and subsequent returns to normal or even subnormal levels. Temperature elevations are seen most frequently in the evening, but they sometimes occur in both mornings and evenings. Patients may have "shaking" chills during the time of temperature rise. Febrile periods last for several consecutive weeks or months. Most patients also have a characteristic rash, which may occur anywhere on the body, is evanescent, and is found most often during periods of temperature elevation. Individual lesions are small (<1 cm in diameter), pale red macules, often with central area of clearing. The rash usually is asymptomatic, but occasionally may be pruritic. Other extraarticular manifestations are frequent. About two thirds of patients have either lymphadenopathy or hepatosplenomegaly; the degree of organ enlargement may be marked, and lymph node histology may resemble that of lymphoma. Results of liver function tests may be mildly abnormal, including slight transaminase elevations and mild hyperbilirubinemia; liver histology reveals nonspecific collections of periportal inflammatory cells. Pleuritis and pericarditis occur in about 50% of patients, although these complications generally are mild and may be entirely asymptomatic. When symptoms do occur, they include chest pain and dyspnea or discomfort of breathing. Rarely, severe pericarditis or even myocarditis occurs. Abdominal pain, related to either mesenteric adenitis or peritonitis, occurs in some patients. Elevated peripheral white blood cell counts, often shifted to the left, occur in most patients, and there may be severe anemia with hematocrit concentrations falling below 20%. Disseminated intravascular coagulation and severe hepatic dysfunction may occur. Iridocyclitis is conspicuous by its absence as an associated finding. The fever and other systemic manifestations of systemic JRA generally continue for several months, but not usually for longer than 6 consecutive months. Subsequent systemic episodes occur in about 50% of children in later years, but febrile periods rarely recur in adulthood. TABLE 4. Extra-articular Manifestations of Systemic Onset JRA •

High intermittent fever*

•

Rheumatoid rash

•

Hepatomegaly; mild hepatic dysfunction

•

Splenomegaly

•

Lymphadenopathy

•

Pleuritis (rarely interstitial pulmonary disease)

•

Pericarditis (rarely myocarditis)

•

Abdominal pain

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•

Leukocytosis

•

Severe anemia

•

Disseminated intravascular coagulation syndrome

*Necessary for diagnosis Prominent musculoskeletal involvement usually is manifest early in disease, although this may be overlooked in the face of the systemic illness. Nearly all children have severe myalgia, arthralgia, or transient arthritis during periods of temperature elevation; such transient musculoskeletal complaints may resolve dramatically during daily afebrile periods. At some time during the disease, nearly all affected children develop persistent arthritis of multiple joints that usually begins during the first few months of disease. Occasionally it may not occur until months or even years after the first febrile episode. Arthritis generally is polyarticular in distribution, affecting both large and small joints. About 25% of children who have systemic-onset disease develop chronic polyarthritis that exceeds the period of systemic manifestations and becomes the major problem in ultimate prognosis. The proper classification of patients who have systemic manifestations without objective arthritis is not settled. Although such patients may have systemic-onset JRA, they do not fulfill current official diagnostic criteria, which requires the presence of persistent arthritis for diagnosis. POLYARTICULAR JRA Polyarticular disease without the prominent systemic manifestations of systemic-onset JRA affects about 35% of children who have chronic arthritis. Two subgroups are included within this designation: rheumatoid factor (RF)-negative disease (20% to 30% of patients) and RF-positive disease (5% to 10% of patients). RF-negative (often called seronegative) polyarthritis may begin at any time during childhood, often during early childhood years. In contrast, RF-positive polyarthritis (seropositive arthritis) rarely begins before the eighth birthday. Both types affect girls more frequently than boys. It seems likely that the RF-positive polyarthritis of childhood is the equivalent of classic adult rheumatoid arthritis, which accounts for about 80% of adult rheumatoid arthritis. RF-negative polyarthritis is also well-recognized in adults, but it accounts for only about 20% of what is termed adult "rheumatoid arthritis." During the childhood years, seropositive arthritis differs not only in age of onset, but in extra-articular manifestations (notably, rheumatoid nodules and rheumatoid vasculitis) and in prognosis for joint destruction. Any synovial joints of the body may be affected in polyarticular JRA, although those of the lumbothoracic spine generally are spared. Symmetric polyarthritis of small joints of the hands, particularly of the proximal interphalangeal and metacarpophalangeal joints, and of the wrists is characteristic; small joints of the feet are similarly affected. Larger joints, such as the knees, ankles, and elbows, also are affected in most patients; hips, neck, shoulders, and temporomandibular joints are affected in about 50%. Patients may have mild systemic complaints, including low-grade fever, modest anemia, and slight hepatosplenomegaly; growth retardation or weight loss also may occur.

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Seronegative JRA This subgroup of disease is heralded by the insidious or sudden onset of polyarthritis, often in early childhood. The high fevers and rash of systemic-onset disease are absent. Affected children have swollen joints, stiffness after inactivity, loss of joint motion, and mild-to-moderate degrees of joint pain, tenderness, and warmth. Children who have seronegative disease often respond well to therapy and incur surprisingly little joint destruction despite months or years of synovitis. Patients have negative standard agglutination tests for RF at the onset of disease; such tests nearly always remain negative throughout the course of disease. Seropositive JRA This type of disease also is heralded by the sudden or insidious onset of arthritis, usually in many joints. Patients typically are older than 8 years at onset. Subcutaneous rheumatoid nodules often are found over pressure points, notably the elbows, the heels, the first metatarsophalangeal joints, and the knuckles and extensor surfaces of the fingers. Histologically such nodules are identical to those found in classic adult rheumatoid arthritis. A few patients have rheumatoid vasculitis, most frequently manifested as ulcerative lesions on the lower extremities, which is thought to result from the deposition of immune complexes of RF and immunoglobulin that cause inflammation of vascular walls. The arthritis of seropositive JRA often is rapidly progressive, with joint destruction occurring within 6 to 12 months of onset and a high chance of permanent joint disability. Occasionally, patients develop signs of Felty syndrome (characterized by splenomegaly with leukopenia) or Sj6gren syndrome (characterized by parotitis, dry eyes, and dry mouth); both of these constellations of symptoms and signs also are associated with classic adult rheumatoid arthritis. PAUCIARTICULAR ARTHRITIS Pauciarticular arthritis, or arthritis limited to only a few joints (Latin: pauci-few, articulus-joint), affects 40% to 50% of children who have JRA. This subgroup designation implies that arthritis remains limited to a few joints for the first 6 months of disease. Large joints characteristically are involved, and the distribution of affected joints is often asymmetric. Isolated small joints may be involved. It is difficult to define pauciarticular disease solely on the number of joints affected, although current American College of Rheumatology criteria specify four or fewer joints for this designation. However, a number of patients conform to the pattern and type of pauciarticular disease but have as many as eight or nine affected joints. There are at least two distinct subgroups of disease within pauciarticular JRA: pauciarthritis of early childhood (associated with antinuclear antibodies [ANAs] and chronic iridocyclitis) and the pauciarthritis of later childhood (associated with sacroiliitis, HLA B27, and risk of subsequent spondyloarthropathy). Probably these two subgroups do not account for all pauciarticular disease, but further delineations have not been made. Early Childhood-onset This subgroup, associated with chronic iridocyclitis and ANAs, appears to include 30% to 40% of all patients who have JRA. Girls are affected predominantly, and the age at onset is between the first and fifth birthdays in the majority of patients. No adult equivalent for this type of disease has been recognized. The joints affected most frequently are some combination of knees, ankles, and elbows. Although affected joints are swollen, warm, stiff, and lacking in motion, patients often function surprisingly well and with very little pain. The hips are

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affected rarely, and sacroiliitis is not an associated finding. If the arthritis remains pauciarticular for the first 3 to 6 months of disease, about 80% of patients do not develop polyarthritis in later years. Systemic complaints such as fever, malaise, and weight loss are minimal. As many as 30% of children who have early childhood-onset pauciarthritis develop chronic iridocyclitis at some time during the first 10 years of disease. The iris and ciliary body are inflamed insidiously and have the potential for scarring. Most affected patients have few early ocular symptoms or signs; a few complain of photophobia, eye pain, or red eyes. Early diagnosis of iridocyclitis is possible only if routine slit-lamp examinations are made; the slit lamp can detect the earliest signs of inflammation, that is, the presence of cells and protein in the anterior chamber. Slit-lamp examinations should be made every 3 months for the first 10 years of disease in children in this subgroup. Late sequelae of chronic iridocyclitis are visible to the ophthalmoscope or even to gross inspection of the eyes, including posterior synechiae (which result inan irregular or nonreactive pupil), band keratopathy (seen as a density in the sclera and cornea), and cataract formation; secondary glaucoma, visual loss, and even blindness can result from these scarring complications. Later Childhood-onset Pauciarticular disease associated with sacroiliitis and HLA B27 affects 10% to 15% of children who have so-called JRA. Males are affected predominantly, and the age of onset nearly always is after the eighth birthday. The family history frequently is positive for spondyloarthropathies or their concomitants, such as ankylosing spondylitis, Reiter disease, pauciarticular disease of either childhood or adulthood, spondylitis of either bowel disease or psoriasis, and acute iridocyclitis. This type of childhood disease probably should be classified with the spondyloarthropathies rather than under the designation JRA, but because these patients fulfill current diagnostic criteria for JRA at the beginning of the disease before they fulfill diagnostic criteria for spondyloarthropathies, they remain within the rubric of "JRA." Adult equivalents of this type of disease are well known and are classified generally as spondyloarthropathies. Affected joints are predominantly of the lower limbs (hips, knees, ankles, or foot joints); patients often have hip girdle involvement early in the disease. Onset of joint complaints may be sudden and incapacitating or insidious and associated with few symptoms. The arthritis often is episodic and not associated with joint destruction. Patients who have this type of pauciarthritis frequently have painful inflammation with swelling along tendons and at sites where tendons and ligaments attach to bone, especially in the area of the Achilles tendon. This condition has been called "enthesitis." Some children who present with enthesitises alone develop arthritis later; this combination has been referred to as the seronegative-enthesopathy-arthropathy syndrome. Patients may have evidence of radiographic sacroiliitis either at disease onset or during the period of the follow-up; sacroiliac involvement may be associated with symptoms. A few patients have bouts of acute iridocyclitis that closely resemble those of ankylosing spondylitis and Reiter syndrome. The prognosis for vision is quite good because attacks are symptomatic, usually treated early, and generally self-limited. In some patients, the disease progresses to the lumbar and thoracic spines, which then fulfills diagnostic criteria for ankylosing spondylitis, and features of other conditions, such as Reiter syndrome (conjunctivitis, urethritis, genital or oral ulcerative lesions, or chronic skin rashes as keratoderma blennorrhagicum affecting soles and palms) or inflammatory bowel disease (either ulcerative colitis or Crohn disease). The lumbar and thoracic spine arthritis of ankylosing spondylitis is heralded by pain in the back and can be documented by measured loss of flexion in the lumbar spine. Chest expansion also

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may decrease. A number of children who have this type of pauciarthritis never may fulfill diagnostic criteria for the various forms of spondyloarthropathy, thus remaining within the description of "JRA." Diagnosis Diagnosis of JRA rests on several bases (Table 5): onset of disease during childhood years, presence of chronic synovitis, and exclusion of a number of other diseases. Although the period of childhood usually is considered as being before the 16th birthday, some types of "JRA" do begin during adult years. The presence of objective synovitis is necessary for diagnosis (Table 3). Signs of objective synovitis include joint swelling, pain, loss of motion, warmth, or erythema; joint swelling is most specific. Joint pain alone with no other objective findings properly is called arthralgia rather than arthritis and is not sufficient for a diagnosis of JRA. Chronicity is an important diagnostic consideration. According to the official criteria, arthritis must be present for 6 consecutive weeks before a diagnosis of JRA can be made. It is important to avoid mislabeling transient conditions such as viral synovitis as a chronic disease such as JRA. Pain and dysfunction at musculoskeletal sites (eg, bones, muscles, ligaments, and nerves) should not be mistaken for arthritis; care must be taken to identify exact anatomic sites of musculoskeletal pain or dysfunction as accurately as possible to avoid confusing nonarthritic conditions with arthritis. Laboratory Studies There are no specific or diagnostic laboratory tests for JRA. Acute phase reactants such as the erythrocyte sedimentation rate and C-reactive protein generally are elevated and present during periods of inflammation, but none of these tests is diagnostic, and a number of children have normal sedimentation rates even during periods of active disease. A number of serologic tests are of interest, but none is diagnostic of JRA. RFs and ANAs commonly are referred to as "autoantibodies" because they can be shown to react with host tissues, but there is no evidence that such antibodies directly destroy tissues in JRA or other rheumatic diseases. They may be implicated in formation of immune complexes. RFs are antibodies that react with both host and foreign immunoglobulins of the IgG class. The exact antigens or stimuli responsible for production of RFs remain unknown. When measured by commonly used agglutination tests such as the latex agglutination test, RFs of the IgM immunoglobulin class are detected. Such IgM antibodies to IgG are the "classic" RFs that are associated with adult-onset rheumatoid arthritis. They are found only in the small subgroup of children who have RFpositive polyarthritis, the disease that is probably the childhood equivalent of classic adult rheumatoid arthritis. RFs do not cause rheumatoid arthritis, but they may help perpetuate tissue damage by formation of immune complexes. Explanations for the absence of classic RFs in the majority of children who have chronic synovitis remain to be found; infants and young children are capable of making IgM antibodies to IgG during other types of chronic inflammation such as that of subacute bacterial endocarditis or Toxocara canis infection where RFs also may be found. IgG or IgA antibodies to IgG, sometimes called "hidden" RFs, have been found in some children who are seronegative for RFs according to results of agglutination techniques, although the significance of these antibodies is uncertain, and they are not diagnostic. The ANAs are a family of antibodies that reacts with various nuclear constituents from human or other mammalian cells. ANAs are associated with systemic lupus erythematosus, but they also occur in a number of children who have JRA, most frequently those who have young-onset pauciarticular disease but also in some who have seronegative polyarthritis and seropositive disease. ANAs are not associated with systemic-onset disease or with the spondyloarthropic type of

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pauciarthritis. They are strongly associated with early childhood-onset pauciarticular JRA and with the occurrence of chronic iridocyclitis. Because levels of serum complement and its components are normal or elevated in JRA, these studies have little role in evaluation or follow-up of patients who have JRA. Deficiencies of complement components are associated with increased prevalences of rheumatic disorders, but such deficiencies are extremely rare. Serum immunoglobulin levels are normal or increased in children who have JRA; a few individuals who have hypogammaglobulinemia or IgA deficiency may be found to have chronic arthritis that resembles JRA. Serum albumin levels may be low in patients who have chronic disease. The histocompatibility antigen HLA B27 is strongly associated with ankylosing spondylitis and may be found frequently in the group of children who have late childhood pauciarthritis that is related to the spondyloarthropathies. HLA associations also are known for two other JRA subgroups, although recent studies demonstrate increasing complexity. Seropositive polyarthritis is associated with HLA DR4, as is classic adult rheumatoid arthritis. Pauciarthritis of early childhood(associated with ANAs and chronic iridocyclitis) has a complex set of associations, stated most simply as being with HLA DR8, HLA DR5, and HLA DR6; other loci such as DP and DQ also have demonstrated associations. HLA studies are of great interest in studying the nature and classification of JRA, but should not be considered diagnostic tests. The usefulness of RFs, ANAs, and histocompatibility types is limited; they are helpful primarily in classifying groups of patients. None of these tests is specific for or diagnostic of any form of childhood arthritis. RFs and ANAs may be transiently positive following intercurrent events such as infections, immunizations, or drug administration. Positive tests for ANAs may be helpful in suggesting a diagnosis in children who have pauciarthritis very early in disease and in identifying children at risk for eye disease. Joint fluid in JRA contains increased numbers of cells, particularly polymorphonuclear leukocytes, which may be as high as 100,000/cm3, and the level of glucose in joint fluid may be lowered There is no apparent value in seeking RFs in joint fluid. However, it is of utmost importance to seek evidence of bacterial infection via appropriate smears, cultures, and tests for bacterial antigen. Synovial fluid analysis is not diagnostic of JRA, but it is vital in excluding septic arthritis. Diagnosis of gout and pseudogout, both extremely rare conditions in childhood, rests on demonstration of urate and calcium pyrophosphate crystals, respectively, in synovial fluid. Standard radiographs are not diagnostic of early JRA, but may show diagnostic changes late in disease if joint destruction has occurred. Such late changes include narrowing of the "joint space" (loss of articular cartilage), erosions of subchondral or juxtaarticular bone, and various degrees of joint destruction. Early nonspecific changes include osteoporosis and occasionally changes of periostitis around affected joints; soft-tissue swelling may also be evident on radiographs. Radiographic changes may be diagnostic of sacroiliitis. The primary purpose of radiography in early disease is to exclude other conditions that might be associated with bony changes. Radiographs of the chest may be helpful in detecting pericarditis or pleuritis. Other imaging techniques, such as ultrasonography, computed tomography, and magnetic resonance imaging, may be helpful. Ultrasonography may help to delineate joint and soft-tissue structures, and magnetic resonance imaging can be valuable in demonstrating muscle lesions. Echocardiography can be diagnostic of pericarditis.

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TABLE 5. American College Of Rheumatology Cnterm agnos~ And Classification Of JRA Diagnostic Requirements For JRA •

Documented arthritis of one or more joints for 6 weeks or longer

•

Exclusion of other conditions associated with childhood arthritis --Other rheumatic diseases --Infectious diseases --Childhood malignancies --Nonrheumatic conditions of bones and joints --Miscellaneous conditions

Differential Diagnosis A number of conditions can be confused with JRA (Table 6) and must be considered and excluded before making the diagnosis of JRA. Usually, a careful history and physical examination, coupled with awareness of the diagnostic possibilities, will suffice. It is of particular importance not to overlook treatable diseases, such as infections of bones and joints or childhood malignancies. TABLE 6. Conditions That Can Resemble JRA Infectious Diseases • Septic arthritis • Lyme disease • Vital-related arthritis • "Reactive" arthritis • Osteomyelitis Childhood Malignancies • Leukemia • Neuroblastoma • Others Noninflammatory Conditions of Bones and Joints • Idiopathic limb pains ("growing pains") • Pain syndromes: fibromyalgia, reflex sympathetic dystrophy • Psychogenic musculoskeletal dysfunction • Musculoskeletal trauma • Avascular necrosis syndromes • Miscellaneous orthopedic conditions: Legg-Calv-Perthe disease, Slipped capital femoral epiphysis, Osgood-Schlatter disease, Patellofemoral syndrome, Discitis

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•Genetic and congenital diseases affecting the musculoskeletal system Rheumatic Diseases • Rheumatic fever • Ankylosing spondy!itis, spondyloarthropathies • Systemic lupus erythematosus • Dermatomyositis • Scleroderma • Vasculitis syndromes • Overlap syndromes ARTHRITIS OF INFECTIOUS DISEASE Several infectious processes can result in arthritis, including septic arthritis, "reactive" arthritis, and osteomyelitis. In septic arthritis, synovial tissue is infected directly by bacterial, viral, or other infectious agents. Diagnosis rests on a combination of suspicion, synovial fluid smears and cultures, blood cultures, and appropriate serologic studies. Patients who have septic arthritis may have more than one affected joint and do not always appear to be septic or systemically ill. Any child who has arthritis of recent onset should be suspected of having septic arthritis. Many nonbacterial agents, such as rubella, mumps, varicella, adenovirus, hepatitis B, and Mycoplasma, also can be associated with arthritis. Such arthritis generally occurs late in the course of clinical infection, although occasionally it precedes other manifestations. Children who have transient viral arthritis should not be mislabeled as having chronic disease. Acute transient hip synovitis (toxic synovitis, observation hip) may represent a viral-related process in children. Infection with Borrelia burgdorferi in the form of Lyme disease can result in arthritis, generally pauciarticular in nature, in both children and adults; Lyme arthritis almost always is responsive to appropriate antibiotic therapy. Parvovirus has been recognized recently as a cause of transient arthritis in children, with or without the accompanying clinical manifestations of Fifth disease. "Reactive" arthritis is a sterile arthritis that follows gastrointestinal infection with pathogens including Shigella, Salmonella, Yersinia, or Campylobacter sp in susceptible hosts; any child who has recent onset arthritis and gastroenteritis should be evaluated appropriately. Affected patients generally have histocompatibility antigen HLA B27. Childhood osteomyelitis sometimes can be confused with rheumatic disease; joints adjacent to infected metaphyseal areas of longbone may be swollen, but have sterile joint fluid. Accurate physical examination generally will clarify the picture; the pain and swelling are maximal over the metaphysis rather than the joint. Radiographic changes of osteomyelitis occur only after 7 or more days of disease; ultrasonography or bone scans may be valuable diagnostic aids in early disease. ARTHRITIS OF MALIGNANCY Any of the childhood malignancies can cause musculoskeletal complaints that closely mimic rheumatic disease, including the leukemias, neuroblastoma, lymphoma, Hodgkin disease, malignant histiocytosis, and rhabdomyosarcoma, as well as primary bone tumors such as osteogenic sarcoma and Ewing sarcoma. The "arthritis" of leukemia and other disseminated malignancies generally is due to infiltrations of malignant cells into structures around the joint, rather than to direct synovial

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involvement. Patients often are more ill than would be expected with JRA, and joint pain may be so severe that children refuse to use affected limbs. One or many joints may be affected. The "arthritis" may be transient or persistent. Diagnosis rests on suspicion of the possibility of malignancy, abnormal hematologic findings (leukopenia, abnormal leukocyte forms, severe anemia, thrombocytopenia), the presence of abnormal soft-tissue or bony masses, and definitive tests such as a bone marrow examination or biopsies. Radiographs and imaging studies of affected joints may show direct bone infiltration or nonspecific findings such as metaphyseal rarefactions or periostitis; unfortunately, however, imaging studies may appear normal and, therefore, are not helpful in a positive diagnostic sense. "ARTHRITIS" OF NONINFLAM-MATORY CONDITIONS A host of noninflammatory conditions can cause joint pains that are, at times, confused with JRA. These include idiopathic limb pains (growing pains) of childhood, various pain syndromes such as fibromyalgia and reflex sympathetic dystrophy, psychogenic musculoskeletal dysfunction, various types of musculoskeletal trauma, the avascular necrosis syndromes, slipping of the capital femoral epiphysis, and Osgood-Schlatter disease. Knee pain after quadriceps activity is the hallmark of the patellofemoral or chondromalacia patella syndrome, a common cause of knee pain in older children and teenagers; this condition may be associated with knee effusions and often is confused with arthritis. Discitis or inflammation of intervertebral disc spaces can cause back pain or pain referred to the hip girdle. A number of genetic and congenital syndromes affecting the musculoskeletal system can mimic arthritis, such as congenital dislocation of the hips, tarsal bone coalitions, and epiphyseal or metaphyseal dysplasia. Diagnosis of these various noninflammatory conditions that resemble arthritis rests on a careful history and physical examination, complete family histories, and often bone and joint imaging studies. ARTHRITIS OF OTHER RHEUMATIC DISEASES Any of the childhood rheumatic diseases may be associated with arthritis. Diagnosis of these conditions usually is possible on the basis of history and physical examination; all present relatively distinct constellations of symptoms and signs. Ankylosing spondylitis can present with pauciarticular or even polyarticular arthritis in childhood. The presence of objective spinal arthritis permits diagnosis, family history often is positive for spondyloarthropathy, and histocompatibility antigen HLA B27 usually is present. Reiter syndrome also may begin in childhood; arthritis with conjunctivitis and urethritis is suggestive of this diagnosis. Diarrhea and various skin rashesalso may be present, and family history often is positive for spondyloarthropathy. HLA B27 is strongly associated. Approximately 10% of children who have inflammatory bowel disease have associated arthritis that may affect peripheral joints or resemble ankylosing spondylitis. The peripheral type of arthritis generally is benign and affects only a few large joints. Tipoffs to inflammatory bowel disease include gastrointestinal complaints, weight loss or failure to thrive, erythema nodosum, mouth ulcers, and fever. Rheumatic fever is a poststreptococcal disease associated with migratory arthritis; the most characteristic finding is carditis. Other findings include rash, subcutaneous nodules, and chorea. Rheumatic fever rarely is a cause of chronic arthritis, so the differentiation from JRA should not be difficult. Systemic lupus erythematosus is a multisystem disease that often begins with arthritis. The arthritis rarely is as chronic as that of JRA, and the constellation of systemic manifestations is quite different. ANAs are present in nearly all cases of lupus, generally in high titers. Nephritis is a frequent finding in childhood lupus, as are decreased levels of serum hemolytic complement and elevated levels of antibodies to DNA, findings

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that are not associated with JRA. Dermatomyositis occasionally is associated with arthritis, but it is characterized by myositis and a distinctive rash. The various vasculitis syndromes, including Henoch-Sch6nlein vasculitis and Kawasaki disease, may cause arthritis, but the extraarticular manifestations of these syndromes are distinctive and different from those of JRA. Scleroderma is a chronic condition of hardening of skin that occasionally is associated with arthritis, but the skin changes of scleroderma are unlike those of JRA. Mixed connective tissue disease is an overlap syndrome that combines features of lupus, dermatomyositis, scleroderma, and JRA. The disease is characterized by the presence of high titers of ANAs reactive with ribonucleoprotein, generally apparent as high-titered speckled-pattern ANA. The arthritis of mixed connective tissue disease may closely resemble that of JRA, but the ANAs and extra-articular manifestations are different. In fasciitis, inflammation of fascial tissues results in pain and induration of extremities, arthropathy and contractures often affect the fingers and other joints, and eosinophilia of blood or tissue usually is present. Raynaud phenomenon occasionally is associated with joint complaints in children, but it is not associated with JRA, and its presence should raise the suspicion of scleroderma, mixed connective tissue disease, or lupus. A careful history and physical examination, appropriate imaging studies, and appropriate laboratory studies are effective in making the differential diagnosis of JRA. It is important to exclude potentially treatable diseases such as infections and malignancies, some of the noninflammatory conditions of bones and joints, and potentially fatal rheumatic diseases such as lupus dermatomyositis or rheumatic fever before settling on a diagnosis of JRA. Therapy A number of considerations are important in designing therapy for children who have JRA. These include identification of the particular disease manifestations requiring therapy in the individual patient; understanding of the natural history of JRA and its manifestations; recognition of the overall prognosis; and awareness of the special burden that chronic illness places on children, adolescents, and their families. ANTI-INFLAMMATORY AND ANTIRHEUMATIC AGENTS When planning therapy for the arthritic and musculoskeletal manifestations of JRA, the physician initially should determine the extent of joint involvement, the activity of the synovitis, the amount of joint destruction, the status of muscle strength, and the amount of joint deformity. The overall functional capacity of the child should be defined. For control of active synovitis, drugs of the anti-inflammatory and antirheumatic classes are used. None is curative, but currently available drug therapy can suppress synovitis satisfactorily in at least 80% of affected children. The approximately 20% of children who have relentless synovitis despite drug treatment usually have either systemic-onset disease, seropositive polyarthritis, or pauciarticular disease that has progressed to polyarthritis. Most patients who have seronegative polyarthritis or pauciarticular disease respond well to currently available therapy. Nonsteroidal anti-inflammatory drugs (NSAIDs) remain front-line and important agents in the treatment of JRA. NSAIDs available for use in children in the United States include salicylates, naproxen, tolmetin, ibuprofen, and indomethacin; a number of other agents are used in adult medicine but are not yet approved for use in children. It generally is accepted that two or more NSAIDs should be tried sequentially if necessary to ascertain whether an adequate clinical response will occur to any in this class of drugs. The fever and other extraarticular manifestations of systemic-onset JRA often respond to

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NSAIDs, and it has been suggested that the iridocyclitis of JRA may be ameliorated by these agents in combination with topical or systemic steroid therapy. As yet there are no data to explain why some patients appear to respond better to one of these agents than to another. NSAIDs frequently are used in combination, but there are few data to suggest whether synergism or antagonism may exist, and there is some indication of increased toxicity. The side effects of NSAIDs in children are appreciable. Salicylism and salicylate hepatotoxicity are well known, and salicylates also have been associated with Reye syndrome. All of the NSAIDs are potential gastric irritants and may be associated with gastritis or duodenal ulcer disease. Renal and hepatic toxicity also may occur. Dermal toxicity ("pseudoporphyria") has been described, particularly with naproxen therapy. Central nervous system effects may include headaches or behavior changes. Aspirin and some of the other NSAIDs interfere with platelet function and should be discontinued before anticipated surgery or procedures such as tooth extraction to avoid problems with prolonged bleeding. The search for effective advanced drug therapy, "disease-modifying" agents, or "slow-acting" drugs for therapy of JRA continues. Controlled studies have shown that the old standbys D-penicillamine, hydroxychloroquine, and oral gold are no more effective than placebo in the therapy of JRA. There have been no controlled studies of intramuscularly administered gold in JRA, but this approach appears to be falling from favor because of the requirement of weekly injections and close monitoring. Methotrexate has been shown to be an effective agent in many children who have severe JRA, and it is moving to the fore in the therapy of children whose disease is unresponsive to NSAIDs. Doses of 10 to 15 mg/m2 per week orally or intramuscularly are used. Some children who fail to respond to low-dose oral methotrexate appear to respond to higher doses. Low-dose oral methotrexate therapy has been associated with slowed progression of radiographic joint damage in children who have IRA. Although little is known of the long-term side effects of this agent in children, available evidence suggests that low doses have few serious adverse effects after treatment periods of up to 5 years. Optimal duration of methotrexate therapy remains open to question for both adults and children. Studies indicate that arthritis may recur when methotrexate is discontinued, suggesting that the drug acts as a suppressive rather than a remittive agent. A similar phenomenon has been described in children who have received methotrexate for treatment of dermatomyositis. No studies have described the results of discontinuing methotrexate therapy in a series of children who have JRA. "Disease-modifying" therapies that are being tried in therapy of JRA include sulfasalazine, intravenous immunoglobulin, corticosteroid therapy in various forms, and cyclosporin. Sulfasalazine is being used rather widely. Although "significant" improvement is described, there are no controlled studies, and hepatotoxicity has been described in several patients. Mixed results have been reported with intravenous immunoglobulin therapy. This form of therapy would seem attractive because of its success in Kawasaki disease, which bears a superficial resemblance to systemic JRA, but the results so far have been disappointing. Controlled studies currently are underway. Cyclosporin has been used in the therapy of JRA, but the numbers of patients treated are small, and there are no controlled trials. There is little enthusiasm for the prolonged use of oral corticosteroids in JRA, although they may be useful in the shortterm treatment of severe systemic disease and iridocyclitis. Deflazacort, a new glucocorticoid, has been shown to have fewer effects on linear growth and bone density than traditional corticosteroid therapy. The use of corticosteroid pulse therapy in JRA deserves more study and attention. Although this therapy is being used by many, particularly in intractable systemic-onset disease, there are no reported trials. Intra-articular steroid therapy can be very useful in the management of JRA, particularly when only a few joints are troublesome, and some experts advocate the simultaneous injection of multiple

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joints. However, unpleasant side effects of corticosteroid therapy remain problematic, particularly with prolonged use of parenteral steroids. It is apparent that the addition of methotrexate as a therapeutic agent has been of value in treating JRA. However, the duration of therapy required to maintain remissions remains undefined, as do the long-term side effects of many years of therapy in children and the potential usefulness and toxicity of higher-dose methotrexate. Other drugs recently added to the therapeutic armamentarium remain of questionable benefit. Better ways are needed to identify those patients at risk for severe disease, which would permit the appropriate use of earlier aggressive therapy. Our knowledge of drug combinations is woefully inadequate. Combination therapies with nonsteroidal and potential "disease-modifying" agents for children who have severe arthritis deserve further study. Combination therapy in childhood leukemia has been successful, but this may not be an appropriate model for JRA. A recent limited study from Moscow has described the use of pulse methylprednisolone plus cyclophosphamide and methotrexate in children who had systemic JRA, reporting some success. Many would hesitate to use such dramatic therapy in a generally non-life-threatening disease such as JRA. The severe anemia of systemic-onset JRA has been treated successfully with recombinant human erythropoietin, and the potentially fatal complication of secondary amyloidosis appears amenable to therapy with cytotoxic drugs. ADDITIONAL THERAPY Physical therapy and occupational therapy are extremely important components of treatment. Affected patients should be started on programs designed to preserve or regain joint range of motion and muscle strength. All patients should be taught exercises to be performed daily at home during the period of arthritis. Severely affected children also can benefit from inpatient or supervised outpatient physical therapy. Heat in the form of a hot morning bath is often valuable in alleviating troublesome morning stiffness. Activities such as swimming and tricycle riding are valuable in promoting strength and wellbeing. Children who have JRA should be encouraged to be active and to participate in as many normal activities of childhood as possible. Promoting and achieving independence in activities of daily living are paramount. Total bed rest nearly always is contraindicated. Children should attend regular schools and be trained and encouraged to function as normally as possible in a usual childhood environment. SURGERY Orthopedic surgery can play a role in therapy of JRA. Synovectomy, the removal of inflamed synovial tissue, is of very limited usefulness in early therapy, but orthopedic surgery has great promise in the rehabilitation of children who have severe JRA. Leg length inequality, which may result from asymmetric arthritis affecting the knees (andoccasionally the ankles), usually is transitory and can be managed by a temporary shoe lift; occasionally, surgery is required. Soft-tissue releases can alleviate contractures about joints, and total joint replacements, particularly of the hips and knees, may be of great benefit to children who experience joint destruction after they have reached reasonably full growth. THERAPY OF SYSTEMIC MANIFESTATIONS The systemic manifestations of systemic-onset JRA often respond to nonsteroidal therapy. Prolonged debilitating fevers and malaise, pericarditis or myocarditis with threat of cardiac decompensation, or severe anemia may be causes for instituting a

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short (several months duration) course of corticosteroid therapy. Systemic disease manifestations generally persist for fewer than 6 consecutive months, and steroid therapy rarely should exceed this time period. Corticosteroids usually are effective on a once-daily basis in initial doses of 1 to 2 mg of prednisone per kilogram of body weight. The dose can be tapered under a cover of nonsteroidal therapy as soon as fever and other manifestations have been suppressed. Administration of corticosteroids in doses large enough to cause cushingoid side effects should be avoided. Iridocyclitis is treated best by early detection and therapy. Patients at risk for iridocyclitis should undergo slit-lamp examinations four times annually. Initial therapy of iridocyclitis includes topical steroids and dilating agents combined with careful follow-up. Should topical therapy fail, either subtenons injections of corticosteroids or even systemic administration should be tried. Doses of corticosteroids should be high enough to control the ocular inflammation as monitored by slit-lamp examinations. Alternate-day dosage schedules may be effective. For late complications of band keratopathy and cataract, ocular surgery may restore vision. OVERALL MANAGEMENT OF THE PATIENT Appropriate management of the entire child is very important. The child and the family need to be well informed about JRA and reassured that although the disease is chronic, the outcome is good for the majority of patients. Children should be managed with optimism and encouraged to lead as full lives as possible and to avoid thinking of themselves as chronic invalids. Isolation from peers should be avoided. Children who are too ill or disabled to be self-sufficient and attend regular schools probably should be hospitalized for rehabilitation. The pediatrician or family doctor should be prepared to provide support for the many problems of childhood and adolescence that may be magnified by chronic illnesses. Teenagers may need guidance in making and achieving career plans. The support and counseling necessary for children who have chronic illness to develop independent and successful lives as adults remain vital. Prognosis Historically, JRA was believed to have a poor prognosis, with at least 50% of patients being seriously disabled and a number dying. The increased interest in this disease in the past 30 years has revealed that this gloomy prognosis is not true for most patients. There is some difference in outcome according to sub-group of disease, but overall, 75% to 80% of children can be expected to survive JRA without serious disability. JRA rarely is fatal, although in some parts of the world secondary amyloidosis is a cause of mortality. This complication appears to be exceedingly rare in the United States for reasons as yet not understood. Systemic-onset JRA, although a serious illness, is rarely fatal, particularly since the advent of modem drug therapy. Children at greatest risk for joint destruction appear to be those who have systemic-onset disease and those who have RF-positive polyarthritis. Iridocyclitis may be a cause of permanent disability if serious ocular damage is allowed to occur. An as yet undefined percentage of children who have older-onset pauciarticular disease will have the disability of spondyloarthropathy in adulthood, but the functional prognosis even for full-blown ankylosing spondylitis generally is good. Children who have JRA require careful follow-up through the period of active disease and should be made aware that there may be unexpected disease recurrences even after years of remission. Although there are no curative drugs, the combination of early diagnosis, available drag therapy, vigorous physical and occupational therapy, avoidance of invalidism, and careful follow-up seem to provide a bright outlook for the majority of affected children.

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