AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
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INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
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• Follow-up
• Miscellaneous
• Multimedia
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Background

Juvenile rheumatoid arthritis (JRA) is not a single disease. Rather, it is a group of diseases of unknown etiology, which are manifested by chronic joint inflammation.

Advances in treatment during the last 30 years have changed the prognosis for the more severe forms of this disease. Initial treatment limited to the use of salicylates and then other nonsteroidal anti-inflammatory drugs (NSAIDs) resulted in many patients becoming wheelchair bound. Other patients underwent synovectomies to remove excess tissue resulting from uncontrolled arthritis. The addition of second-line drugs, starting with gold salt injections and then replaced by the much more effective methotrexate (MTX), improved the outlook for these patients. These medications are administered in the context of a team approach in pediatric rheumatology centers, where physical and occupational therapy have permitted greatly improved physical function.

The approval of etanercept, a biologic antagonist to tumor necrosis factor (TNF), has ushered in a new era of treatment more closely tailored to the pathophysiology of the disease. Other biologic agents, such as anakinra, an interluekin-1 (IL-1) receptor antagonist, may play a role in selected patients who are unresponsive to second-line drugs. In the future, inhibition of IL-6 may prove to be effective in systemic patients with JRA who have elevated levels.

Pathophysiology

The etiology of JRA is unknown. Chronic inflammation of synovium is characterized by B lymphocyte infiltration and expansion. Macrophages and T-cell invasion are associated with the release of cytokines, which evoke synoviocyte proliferation. A 2001 study by Scola et al found synovium to contain messenger RNA for vascular endothelial growth factor, angiopoietin 1, and their respective receptors, suggesting that induction of angiogenesis by products of lymphocytic infiltration may be involved in persistence of disease. The resulting thickened pannus causes joint destruction. In many patients, predominance of cytokines associated with tissue destruction, including interleukin-6 and TNF, suggests the possibility of improved responsiveness to specific biologic agents targeting these factors.

Frequency

United States

Prevalence of JRA has been estimated to be 10-20 cases per 100,000 children. Prevalence data vary (11-83 cases per 100,000), depending upon the location of the study. Pauciarticular and polyarticular disease occur more frequently in girls, while both sexes are affected with equal frequency in systemic-onset disease.

International

JRA appears to occur more frequently in certain populations (eg, Native Americans) from such disparate areas as British Columbia and Norway. A study in Sweden found prevalence similar to that in Minnesota, approximately 85 cases per 100,000 population.

Mortality/Morbidity

• No recent studies have quantitated mortality in JRA. However, the mortality rate is less than 1% and is often associated with the evolution of disease to manifestations of other rheumatic diseases, such as systemic lupus erythematosus (SLE) or scleroderma. Such progression has been reported to be associated with high titer antinuclear antibodies (ANA) at presentation in some children.
• Patients with JRA may experience complications specific to their disease subset (see Clinical). The most typical type of morbidity in patients with JRA relates to adverse effects of medications, particularly NSAIDs. Abdominal pain related to gastritis or ulcer disease, hepatotoxicity, and occasionally, renal toxicity are sufficiently frequent to warrant routine laboratory screening.
• Significant psychologic morbidity (eg, situational depression, anxiety, problems functioning in school) can occur in all subtypes. Morbidity experienced in problems with quality of life is being actively investigated. Such problems may occur in children with all subtypes and may be the result of additional factors, such as socioeconomic status and family problems.

Race

Few studies documenting racial differences exist. However, in 1997, Schwartz and colleagues found that, compared to whites, blacks with JRA were older and less likely to test positive for ANA or to have uveitis; however, blacks were more likely to test positive for immunoglobulin M rheumatoid factor.

Sex

Pauciarticular and polyarticular JRA tend to affect girls more often than boys. Systemic-onset disease occurs with equal frequency in boys and girls.

Age

Pauciarticular JRA tends to affect children in early childhood. Systemic-onset disease can also occur in early childhood; however, it is sometimes observed in late childhood or early adolescence. Polyarticular JRA can occur throughout childhood and adolescence. Rheumatoid factor–positive disease, similar to rheumatoid arthritis in adults, is more often found in adolescents.

CLINICAL

Section 3 of 11  

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History

Juvenile rheumatoid arthritis (JRA) is classified as systemic, pauciarticular, or polyarticular disease according to onset within the first 6 months.

• General history of JRA includes the following:
• • Disease onset is either insidious or abrupt, with morning stiffness and arthralgia during the day.
  • Individuals with JRA may have a school history of absences, and their abilities to participate in physical education classes may reflect severity of the disease. Typically, patients with JRA and their parents and/or caregivers are concerned about missing school; in contrast, when psychogenic factors predominate (eg, pain syndromes), patients and their parents and/or caregivers are more worried about returning to school than about missing school.
  • Limping may be observed in individuals with more severe JRA; however, the presence of limping also raises the possibility of trauma or another orthopedic problem.
  • Injury suggests the possibility of trauma to a joint (eg, meniscal tear).
  • A preceding illness raises the possibility of infectious trigger of JRA or postinfectious arthritis.
  • Illness in pets with a history of enteritis raises the possibility of reactive arthritis.
  • History of travel with exposure to ticks raises the possibility of arthritis caused by Lyme disease.
  • Gastrointestinal symptoms raise the possibility of inflammatory bowel disease.
  • Very severe joint pain raises the possibility of acute rheumatic fever (also suggested by migratory but not additive arthritis, with fevers), acute lymphocytic leukemia (with metaphyseal pain on examination, decrease in 2 or more cell lines), septic arthritis, or osteomyelitis.
  • Weight loss without diarrhea may be observed in individuals with active JRA and is sometimes associated with anorexia. This symptom is also observed in individuals with acute lymphocytic leukemia with other obvious findings (eg, decrease in at least 2 cell lines, severe bone pain).
  • Weight loss with diarrhea may be observed in persons with inflammatory bowel disease.
  • Photophobia may be observed in persons with usually asymptomatic uveitis.
  • Orthopnea suggests pericarditis in children with systemic JRA; the differential diagnosis includes SLE and viral pericarditis.
• Systemic-onset JRA is characterized by spiking fevers, typically occurring several times each day, with temperature returning to the reference range or below the reference range.
• • Systemic-onset JRA may be accompanied by an evanescent rash, which is typically linear, affecting the trunk and extremities.
  • Arthralgia is often present. Frank joint swelling is atypical; arthritis may not occur for months following onset, making diagnosis difficult.
  • Some children may have a generalized myalgia.
  • Localization to proximal muscles raises the possibility of a myositis.
• Pauciarticular disease is characterized by arthritis affecting 4 or fewer joints.
• • Typically, larger joints (eg, knees, ankles, wrists) are affected.
  • Monoarticular arthritis in a hip is highly unusual.
  • Consider Legg-Calvé-Perthes disease; toxic synovitis of the hip; septic arthritis; osteomyelitis; or, in an older child, slipped capital femoral epiphysis or chondrolysis of the hip.
  • When the knee is affected, limping may be noted, particularly in the mornings.
  • Chronic involvement can result in atrophy of extensor muscles in the thigh, tight hamstring ligaments, and knee flexion contractures.
• Polyarticular disease affects at least 5 joints.
• • Both large and small joints can be involved, often in symmetric bilateral distribution.
  • Severe limitations in motion are usually accompanied by weakness and decreased physical function.

Physical

A detailed physical examination is a critical tool in diagnosing JRA. Physical findings are important to provide criteria for diagnosis and to detect abnormalities suggestive of other possible diagnoses. The diagnosis of JRA is based on the physical finding of arthritis (or synovitis) in at least one joint that persists for at least 6 weeks, with other causes being excluded and with onset when the individual is younger than 16 years. Arthritis on examination is defined as either joint swelling (although trauma can also cause swelling and may need to be excluded) or the combination of limited motion with pain (on motion or to palpation). The hips and small joints in the spine, when affected by synovitis, do not demonstrate swelling but demonstrate the combination of loss of motion and pain.

• A definite diagnosis of systemic-onset JRA must await the eventual development of arthritis, which may not occur for months.
• • Evanescent salmon-pink rash, often linear, is found on the trunk and the extremities; this rash is worse with fever.
  • Hepatosplenomegaly is often present.
  • Lymphadenopathy is sometimes present.
  • Muscle tenderness to palpation may be observed.
  • Rarely, serositis, which raises the possibility of SLE, is found.
• In individuals with pauciarticular JRA, 4 or fewer joints are affected; often, only a single joint is affected (see Media file 1).
• • Typically, large weight-bearing joints, knees, and ankles are affected.
  • Involvement of a few small joints in the hands is atypical and suggests eventual development of polyarticular JRA or, occasionally, psoriasis years later, with retrospective diagnosis of psoriatic arthritis.
  • Muscle atrophy, often of extensor muscles (eg, vastus lateralis, quadriceps when knee affected) is found.
  • Flexion contractures in the knees and, less commonly, the wrists are found.
• In persons with polyarticular JRA, 5 or more joints are affected (see Media file 2).
• • Weight-bearing joints are affected, and symmetric involvement of small joints in the hands is found (see Media file 4).
  • Pain with decreased range of motion in the cervical spine is sometimes found.
• Other findings in persons with JRA are as follows:
• • Ocular: Photophobia, in uveitis (usually asymptomatic on onset), and synechiae (ie, irregular iris perimeter resulting from postinflammatory adhesions of iris to lens) may be found (see Media file 7).
  • Cardiovascular: Orthopnea and rub suggest pericarditis (rub may be absent with large pericardial effusion). S₃, basilar rales, and hepatomegaly suggestive of heart failure may rarely be observed, when myocarditis occurs in individuals with systemic JRA.

Causes

The specific causes of JRA remain undefined.

DIFFERENTIALS

Section 4 of 11  

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Other Problems to be Considered

Many conditions may manifest with arthritis of brief duration. Postinfectious arthritis typically affects large joints. This syndrome is clinically indistinguishable from the early phase of juvenile rheumatoid arthritis (JRA), particularly because JRA can be triggered by viral infections. Patients with acute lymphocytic leukemia can present with joint pain and even the physical findings of arthritis. Expansion of lymphoblasts in bone metaphyses can result in pain, which is typically severe. Thrombocytopenia is rare in persons with JRA; its presence, although it raises the possibility of SLE, also suggests the possibility of leukemia. The differential count in JRA often demonstrates a relative lymphopenia, presumably because of egress of activated lymphocytes from circulation into synovium. Lymphocytosis is uncharacteristic of JRA and raises the possibility of leukemia, particularly when a neutropenia is present.

Spondyloarthropathy is a chronic disease characterized by periods of inflammation of tendons and ligaments, particularly at the area of insertion into bone (entheses). Often, children and adolescents with spondyloarthropathy present with arthritis, making the distinction from JRA difficult. Furthermore, some children occasionally develop a disease that appears to be a combination of the 2 diseases. Nevertheless, although enthesitis can be observed in persons with pauciarticular and polyarticular JRA, the eventual evolution of arthritis to a predominant enthesitis is more characteristic of spondyloarthropathy. The presence of the human leukocyte antigen (HLA) B27 is helpful in suggesting the diagnosis. However, radiographic changes observed in adults (eg, sclerosis of the sacroiliac joints, bamboo spine) are rare in childhood and adolescence.

WORKUP

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Lab Studies

• Laboratory studies support the diagnosis of juvenile rheumatoid arthritis (JRA) and, in many patients, are a helpful means of monitoring success of medical treatment. Initial evaluation should include the following:
• • Erythrocyte sedimentation rate (ESR)
    • ESR is always elevated in children with systemic JRA, is usually elevated in those with polyarticular disease, but is often within the reference range in those with pauciarticular disease.
    • When elevated, ESR may be used to monitor success of medical treatment.
  • CBC with differential and platelet count
    • Lymphopenia is not uncommon because of emigration of activated lymphocytes out of the circulation into synovium.
    • Neutropenia is uncommon and, particularly with lymphocytosis or thrombocytopenia, raises the possibility of acute lymphocytic leukemia.
    • Thrombocytopenia may also be observed in persons with SLE presenting with arthritis.
    • Anemia may result from chronic active JRA; often microcytic, anemia is usually refractive to treatment with iron.
  • Alanine aminotransferase (ALT) test: Obtain ALT levels to exclude the possibility of hepatitis (viral or autoimmune) prior to initiating treatment with NSAIDs, which can cause hepatotoxicity.
  • Urinalysis with microscopic examination: Perform a urinalysis to exclude the possibility of infection (as a trigger of JRA or transient postinfectious arthritis) and nephritis (observed in individuals with SLE).
  • Antinuclear antibody
    • ANA is observed in as many as 25% of children with JRA, particularly in patients with pauciarticular disease.
    • Titers of 1:80 or higher are positive; a 1:40 titer or lower is negative.
    • When found in young girls, a positive ANA is a marker of increased risk of uveitis.
    • Very high titers may sometimes be associated with evolution to other rheumatic disease (eg, SLE).
    • Titers otherwise do not correlate with disease activity.
  • Rheumatoid factor: Rare in persons with systemic JRA, rheumatoid factor is considered a marker for persistence of polyarticular JRA into adulthood.
• Other laboratory tests for systemic JRA include the following:
• • Total protein and albumin: Levels are often decreased during active disease.
  • Fibrinogen and D-dimer: Levels are often elevated in individuals with active disease.

Imaging Studies

• Radiography of affected joints (see Media file 3 and Media file 6): When only a single joint is affected, radiography is important to exclude other diseases, such as osteomyelitis or septic arthritis.
• Bone scanning: When physical findings do not document definite arthritis, consider bone scanning as a means of identifying a potential focus of osteomyelitis or other abnormality.
• MRI
• • Perform MRI of the affected joint, with gadolinium injection to enhance inflamed synovium.
  • MRI is helpful when considering trauma in the differential diagnosis.
• CT scanning of long bones: Perform when considering osteoid osteoma in a child with lower extremity pain (often at night) and unremarkable findings on physical examination.
• Echocardiography
• • This is performed in a child with possible systemic JRA and with fevers.
  • Perform echocardiography in an individual who has orthopnea by history or a rub to exclude pericarditis.
  • • In a person who has nonspecific rash, adenopathy, and possible mucocutaneous changes, perform echocardiography to exclude coronary arterial dilation resulting from (possibly atypical) Kawasaki disease.
    • In an individual who has findings suggestive of SLE (eg, nephritis, pleuritic chest pain, thrombocytopenia), perform echocardiography to exclude valvular disease, although mild dilation may be seen in some patients with systemic JRA.

Other Tests

• Dual-energy radiograph absorptiometry (DXA) scanning: Perform DXA scanning to document osteopenia in children with polyarticular JRA.

Procedures

• Arthrocentesis: Perform arthrocentesis to exclude septic arthritis in a child with monoarticular swelling.
• Synovial biopsy: This procedure may be helpful to exclude other diagnoses, particularly when the knee is affected (eg, villonodular synovitis, granulomatous arthritis).
• Pericardiocentesis: Perform this in an ICU setting to treat severe pericarditis.

Histologic Findings

Synovial biopsy may demonstrate synovial infiltration with plasma cells, mature B lymphocytes, and T lymphocytes, with areas of synovial thickening and fibrosis.

TREATMENT

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Medical Care

Medical care of children with juvenile rheumatoid arthritis (JRA) must be provided in the context of a team-based approach, considering all aspects of their illness (eg, physical functioning in school, psychological adjustment to disease). Using medications in the absence of an appropriate physical therapy program and attention to problematic social issues of the family is not successful. Success of medications is monitored best with repeated physical examinations and history. Both the number of joints involved and the duration of morning stiffness should demonstrate continued decrease, with elimination reflecting success.

Surgical Care

Surgery is not usually needed; however, some children with persisting pauciarticular JRA, despite medical treatment, may benefit from intra-articular steroid injection. Such injections may also be effective in treating temporomandibular arthritis in children with polyarticular JRA. Usually, delay joint replacement (often of the hips, in patients with polyarticular JRA) until bone growth has completed, which is reflected by epiphyseal closure. The consistent effective use of medical treatment has consigned synovectomy to a rarely used intervention.

Consultations

• The subspecialty team includes the following:
• • Pediatric rheumatologist (when available)
  • Nurses (who help with education)
  • Physical and occupational therapists: Nonmedical approaches (eg, physical and occupational therapy) are an important part of treatment. At presentation, arthritis may be so active as to preclude the use of an aggressive program of muscle strengthening. Nevertheless, the use of pain modalities during this period may permit the gradual introduction of an active program of exercises and stretching.
  • Social workers: Social work evaluation helps to determine how well each family is coping with their child's disease in terms of emotional and financial resources. Social workers can offer invaluable guidance for helping children to maintain healthy relationships both within their families and at school. Transition programs for adolescents with arthritis can help prepare them for higher education and future vocations.
• Pediatric ophthalmologists help provide slit-lamp examinations to exclude uveitis.
• Pediatric orthopedic surgeons can offer consultation when orthopedic diagnoses are being considered.
• The development of profound anemia or a drop in 2 or more cell lines may require the help of a pediatric hematologist.
• A pediatric gastroenterologist may help with hepatic abnormalities or symptoms suggesting inflammatory bowel disease.

Diet

No specific diet helps in the treatment of JRA. However, because active JRA has been associated with decreased osteoblastic activity and a risk of osteopenia, encourage the inclusion of at least 3 servings of calcium-rich foods each day. Consider behavioral intervention when poor calcium intake persists.

Activity

Encourage patients with JRA to be as active as possible. Except in individuals with severe systemic disease, bed rest is not a part of the treatment. In fact, the more active the patient the better the long-term prognosis is. Children may experience increased pain during routine physical activities. As a result, these children must be allowed to self-limit their activities, particularly during physical education classes. A consistent physical therapy program, with attention to stretching exercises, pain modalities, joint protection, and home exercises, can help ensure that patients with JRA are as active as possible.

MEDICATION

Section 7 of 11  

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• Follow-up
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Classes of medications are suggested below, and specific drugs are covered in detail by category. See the therapeutic algorithm in Media file 8.

NSAIDs are used to treat all subtypes of juvenile rheumatoid arthritis (JRA). These medications are effective because of inhibition of prostaglandin synthesis. Naproxen is listed below as an example of an NSAID used in treatment; other NSAIDs commonly used include ibuprofen, tolmetin, diclofenac, and indomethacin. In addition, sulfasalazine is sometimes used as a second anti-inflammatory drug in some children with persisting pauciarticular and polyarticular disease. Its use may be considered as an intermediate step prior to adding a second-line drug such as MTX.

Aspirin is no longer the drug of first choice because of the increased frequency of gastric toxicity and hepatotoxicity when compared to other NSAID medications. Recently, the discovery that cyclooxygenase (COX) in gastric and intestinal endothelium (ie, COX-1) is different in structure from that in leukocytes (ie, COX-2) has led to the development of anti-inflammatory drugs specific for COX-2. COX-2 inhibitors have been found to be effective in treatment of adults with rheumatoid arthritis. Studies of COX-2 inhibitors in persons with JRA are being planned. Besides the benefit of greatly reducing gastric toxicity (although hepatotoxicity remains a possible adverse event), COX-2 inhibitors do not inhibit platelet aggregation. Thus, these agents may find a role in the treatment of inflammatory conditions in which a bleeding diathesis is a potential problem, such as in the postoperative setting.

NSAIDs alone are usually adequate for treatment of pauciarticular disease. However, an aggressive arthritis sometimes develops in this subtype, requiring the need to add a second-line drug. Various second-line drugs have been used in addition to first-line NSAIDs. Gold salt injections were used until approximately 15 years ago, when studies by the Pediatric Rheumatology Collaborative Study Group demonstrated the efficacy of PO MTX. Subsequent studies have demonstrated that some children with polyarticular arthritis unresponsive to PO MTX benefit from SC or IM administration. The use of high-dose IV steroids in selected patients has been beneficial in some patients, particularly during an early period before MTX may have a full therapeutic effect.

Recently, etanercept, a biologic agent administered SC twice weekly and containing a receptor to TNF ligated to an Fc portion of immunoglobulin, has been found to be effective in controlling polyarticular arthritis not controlled by conventional medical treatment. Prescribe this medication for those children treated by pediatric rheumatology centers who are unresponsive to treatment including conventional second-line drugs.

Finally, the treatment of systemic JRA may require, in addition to treatment with NSAIDs, the careful use of either PO or high-dose pulse IV corticosteroids. Such treatment is best reserved for patients in whom definite arthritis has developed to avoid premature treatment in a patient who may prove to have a disease other than JRA. Medication alone is not sufficient for most children with arthritis, who benefit from a team approach (see Consultations).

Drug Category: Nonsteroidal anti-inflammatory drugs (NSAIDs)

These agents are used in all children with JRA as the medication of first choice. Predicting which individual patient will respond to a particular NSAID is not possible; sometimes, after 1-2 months of treatment, those persons who do not respond may benefit from changing to a different NSAID. Most children with pauciarticular JRA and only a few with polyarticular JRA respond to NSAID treatment without needing the addition of second-line drugs (eg, MTX).

Administer NSAIDs with caution in any patient with renal or liver disease and avoid administering NSAIDs during pregnancy. NSAIDs have a variety of adverse effects (eg, gastritis, bone marrow suppression, hepatitis, interstitial nephritis, CNS changes), which should be monitored.

Drug Name	Ibuprofen (Motrin, Ibuprin)
Description	Inhibits inflammatory reactions and pain by decreasing prostaglandin synthesis.
Adult Dose	400 mg PO q4-6h, 600 mg q6h, or 800 mg q8h while symptoms persist; not to exceed 3.2 g/d
Pediatric Dose	30-50 mg/kg/d PO divided qid; not to exceed 2.4 g/d
Contraindications	Documented hypersensitivity; peptic ulcer disease; recent GI bleeding or perforation; renal insufficiency; high risk of bleeding
Interactions	Coadministration with aspirin increases risk of inducing serious NSAID-related side effects; probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effect of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; may increase PT when taking anticoagulants (instruct patients to watch for signs of bleeding); may increase risk of MTX toxicity; phenytoin levels may be increased when administered concurrently
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Pregnancy category D in third trimester of pregnancy; caution in congestive heart failure, hypertension, and decreased renal and hepatic function; caution in coagulation abnormalities or during anticoagulant therapy

Drug Name	Diclofenac (Voltaren, Cataflam)
Description	Inhibits prostaglandin synthesis by decreasing activity of enzyme COX, which in turn decreases formation of prostaglandin precursors.
Adult Dose	100-200 mg/d PO divided bid/qid; not to exceed 225 mg/d
Pediatric Dose	<12 years: 2-3 mg/kg/d PO divided bid/qid >12 years: Administer as in adults
Contraindications	Documented hypersensitivity; administration into CNS; peptic ulcer disease; recent GI bleeding or perforation; renal insufficiency; high risk of bleeding
Interactions	Coadministration with aspirin increases risk of inducing serious NSAID-related side effects; probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effect of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; may increase PT when taking anticoagulants (instruct patients to watch for signs of bleeding); may increase risk of MTX toxicity; phenytoin levels may be increased when administered concurrently
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Pregnancy category D in third trimester of pregnancy; acute renal insufficiency, hyperkalemia, hyponatremia, interstitial nephritis, and renal papillary necrosis may occur; increases risk of acute renal failure in patients with preexisting renal disease or compromised renal perfusion; low white blood cell counts occur rarely and usually return to the reference range in ongoing therapy; discontinuation of therapy may be necessary if persistent leukopenia, granulocytopenia, or thrombocytopenia occurs

Drug Name	Tolmetin (Tolectin)
Description	Inhibits prostaglandin synthesis by decreasing activity of enzyme COX, which in turn decreases formation of prostaglandin precursors.
Adult Dose	400 mg PO tid; typical dosage range is 600 mg/d to 1.8 g/d; not to exceed 2 g/d
Pediatric Dose	20 mg/kg/d PO divided tid/qid initially; then 15-30 mg/kg/d; not to exceed 30 mg/kg/d
Contraindications	Documented hypersensitivity; administration into CNS; peptic ulcer disease; recent GI bleeding or perforation; renal insufficiency; high risk of bleeding
Interactions	Coadministration with aspirin increases risk of inducing serious NSAID-related side effects; probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effect of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; may increase PT when taking anticoagulants (instruct patients to watch for signs of bleeding); may increase risk of MTX toxicity; phenytoin levels may be increased when administered concurrently
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Pregnancy category D in third trimester of pregnancy; acute renal insufficiency, hyperkalemia, hyponatremia, interstitial nephritis, and renal papillary necrosis may occur; increases risk of acute renal failure in patients with preexisting renal disease or compromised renal perfusion; low white blood cell counts occur rarely and usually return to the reference range in ongoing therapy; discontinuation of therapy may be necessary if persistent leukopenia, granulocytopenia, or thrombocytopenia occurs

Drug Name	Indomethacin (Indocin)
Description	Rapidly absorbed. Metabolism occurs in liver by demethylation, deacetylation, and glucuronide conjugation. Inhibits prostaglandin synthesis.
Adult Dose	25-50 mg PO bid/tid; not to exceed 200 mg/d ER product may be administered qd or bid
Pediatric Dose	1-2 mg/kg/d PO divided bid/qid; not to exceed 4 mg/kg/d or 150-200 mg/d
Contraindications	Documented hypersensitivity; GI bleeding; renal insufficiency
Interactions	Coadministration with aspirin increases risk of inducing serious NSAID-related side effects; probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effect of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; may increase PT when taking anticoagulants (instruct patients to watch for signs of bleeding); may increase risk of MTX toxicity; phenytoin levels may be increased when administered concurrently
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Pregnancy category D in third trimester of pregnancy; acute renal insufficiency, hyperkalemia, hyponatremia, interstitial nephritis, and renal papillary necrosis may occur; increases risk of acute renal failure in patients with preexisting renal disease or compromised renal perfusion; reversible leukopenia may occur (discontinue if persistent leukopenia, granulocytopenia, or thrombocytopenia occurs)

Drug Name	Celecoxib (Celebrex)
Description	Inhibits primarily COX-2. COX-2 is considered an inducible isoenzyme, induced by pain and inflammatory stimuli. Inhibition of COX-1 may contribute to NSAID GI toxicity. At therapeutic concentrations, COX-1 isoenzyme is not inhibited, thus incidence of GI toxicity, such as endoscopic peptic ulcers, bleeding ulcers, perforations, and obstructions, may be decreased when compared to nonselective NSAIDs. Seek lowest dose for each patient. Neutralizes circulating myelin antibodies through anti-idiotypic antibodies; down-regulates pro-inflammatory cytokines, including INF-gamma; blocks Fc receptors on macrophages; suppresses inducer T and B cells and augments suppressor T cells; blocks complement cascade; promotes remyelination; may increase CSF IgG (10%). Has a sulfonamide chain and is primarily dependent upon cytochrome P450 enzymes (a hepatic enzyme) for metabolism.
Adult Dose	100-200 mg PO bid
Pediatric Dose	<2 years: Not established >2 years: >10 kg to <25 kg: 50 mg PO bid >25 kg: 100 mg PO bid
Contraindications	Documented hypersensitivity
Interactions	CYP450 2C9 substrate; coadministration with fluconazole may cause increase in celecoxib plasma concentrations because of inhibition of celecoxib metabolism; coadministration of celecoxib with rifampin may decrease celecoxib plasma concentrations
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Pregnancy category D during third trimester; may cause fluid retention and peripheral edema; caution in compromised cardiac function, hypertension, conditions predisposing to fluid retention; caution in severe heart failure and hyponatremia because may deteriorate circulatory hemodynamics; NSAIDs may mask usual signs of infection; caution in the presence of existing controlled infections; evaluate therapy when symptoms or lab results suggest liver dysfunction

Drug Category: Immunosuppressive agents

Most children with polyarticular JRA and some with aggressive pauciarticular disease benefit from additional immunosuppressive agents (ie, in particular, MTX).

Drug Name	Sulfasalazine (Azulfidine, EN-tabs)
Description	Decreases the inflammatory response and systemically inhibits prostaglandin synthesis.
Adult Dose	500 mg PO qd initially; gradually increase by 500 mg/wk to 2-3 g/d PO divided bid
Pediatric Dose	<6 years: Not established >6 years: 10 mg/kg/d PO divided bid initially; increase by 10 mg/kg/d qwk; typical dose range is 30-50 mg/kg/d; not to exceed 2 g/d
Contraindications	Documented hypersensitivity; coadministration of sulfa drugs or any component; GI or GU obstruction
Interactions	Decreases effects of iron, digoxin, and folic acid; conversely, increases effect of PO anticoagulants, PO hypoglycemic agents, and MTX
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Do not use in pregnancy when near term; caution in patients with renal or hepatic impairment, blood dyscrasias, or urinary obstruction

Drug Name	Methylprednisolone (Solu-Medrol)
Description	Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability. Used temporarily for JRA until longer-term treatment provides effective relief.
Adult Dose	30 mg/kg/dose IV administered over 30 min q4-6h prn; administer high dose only for 2-3 d
Pediatric Dose	15-30 mg/kg IV qd administered over 30 min for 2-3 d
Contraindications	Documented hypersensitivity; viral, fungal, or tubercular skin infections
Interactions	Coadministration with digoxin may increase digitalis toxicity secondary to hypokalemia; estrogens may increase levels of methylprednisolone; phenobarbital, phenytoin, and rifampin may decrease levels of methylprednisolone (adjust dose); monitor patients for hypokalemia when taking medication concurrently with diuretics
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Hyperglycemia, edema, osteonecrosis, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, growth suppression, myopathy, and infections are possible complications of glucocorticoid use

Drug Name	Prednisone (Deltasone, Meticorten, Orasone, Sterapred)
Description	Immunosuppressant for treatment of JRA. May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and also suppresses lymphocytes and antibody production.
Adult Dose	7.5 mg PO qd for short-term treatment while waiting for efficacy of other antirheumatic drugs
Pediatric Dose	4-5 mg/m2/d PO; alternatively, 0.05-2 mg/kg PO divided bid/qid; taper over 2 wk, as symptoms resolve and other antirheumatic drugs take effect
Contraindications	Documented hypersensitivity; viral infection; peptic ulcer disease; hepatic dysfunction; connective tissue infections; fungal or tubercular skin infections; GI disease
Interactions	Coadministration with estrogens may decrease prednisone clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use

Drug Category: Tumor necrosis factor (TNF) inhibitors

TNF is a cytokine of which 2 forms have been identified with similar biological properties. TNF-alpha or cachectin is produced predominantly by macrophages, and TNF-beta or lymphotoxin is produced by lymphocytes. TNF is but one of many cytokines involved in the inflammatory cascade that contributes to symptoms.

Drug Category: Immunomodulator

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Inpatient Care

• Further inpatient care is required for persisting fevers of unknown origin or when children with known juvenile rheumatoid arthritis (JRA) have severe exacerbation of disease.
• Admit for evaluation any child who loses the ability to walk for unknown reasons.
• Development of pericarditis in children with systemic JRA is usually an indication for admission.

Further Outpatient Care

• Patients with JRA may have a gradually responsive disease (particularly those with pauciarticular JRA).
• A small number of patients with pauciarticular JRA develop aggressive arthritis confined to a single joint; such patients may require more intensive medical treatment and physical therapy.
• Some patients with polyarticular JRA demonstrate rapid response to treatment; however, most have prolonged courses, requiring frequent adjustments in medical and nonmedical therapy. Some have sufficient problems with activities of daily living, and they may benefit from courses of outpatient (and sometimes inpatient) rehabilitation.

In/Out Patient Meds

• See Medication.

Transfer

• Consider outpatient evaluation in a pediatric rheumatology center for all patients with known and suspected disease. Inpatient care for individuals with intercurrent illnesses may best be carried out at local hospitals; complications from JRA usually indicate transfer to a hospital with a pediatric rheumatology center.

Deterrence/Prevention

• No prevention of JRA is known. The best means of deterrence is compliance with recommended treatment. As many as one half of patients may not comply with every detail of recommended treatment. Persisting noncompliance is a problem that increases risk of morbidity. Parents of such patients often admit noncompliance only to the child's primary care physician, rather than to a pediatric subspecialty team. The continued monitoring of compliance by the primary care physician, together with continuing communication between the pediatric subspecialist and primary physician, is an important part of the treatment of children with JRA and any chronic illness.

Complications

• Systemic-onset JRA
• • Pericarditis (patients often presenting with orthopnea and responsive to intravenous corticosteroid treatment)
  • Hemolytic anemia
  • Disseminated intravascular coagulopathy (often present at a low level of activity): Levels of D-dimer and fibrinogen may be elevated; their return to reference range levels is observed with successful treatment.
  • Macrophage activation syndrome
  • • This is a rare, but important, complication, in which numbers of all 3 bloodlines become rapidly decreased. Hypofibrinogenemia, thrombocytopenia, and elevated aspartate aminotransferase levels are hallmarks.
    • Hypotension, central nervous system disease, and marked hepatosplenomegaly may be noted as complications of a release of massive amounts of cytokines.
    • Bone marrow aspiration finding histiocytic consumption of bone marrow precursors confirms the diagnosis and excludes malignancy.
    • Macrophage activation syndrome often responds to cyclosporin A.
  • Endarteritis resulting in circulatory compromise of the digits with threatened autoamputation
  • • This complication is even more rare than macrophage activation syndrome.
    • Central administration of prostaglandin E1 may be of potential benefit, similar to its use for patients with scleroderma and endarteritis.
• Pauciarticular JRA
• • Knee flexion contractures: This complication requires splinting at night, in addition to medical treatment, to restore range of motion, allow recovery of muscle strength, and avoid subluxation of the joint.
  • Uveitis
  • • Often asymptomatic, patients are typically young girls who have positive levels of ANA.
    • In such patients, evaluation using a slit-lamp examination by a pediatric ophthalmologist every 4 months can detect early disease.
    • Treatment with topical corticosteroid medication and with mydriatic agents (to prevent closed-angle glaucoma) often can prevent progression of disease to development of calcium deposition in the lens (band keratopathy) and adhesions of the iris to the lens (posterior synechiae), in which an irregular pupillary margin develops (see Media file 7).
    • Such complications may herald a chronic active disease, in which vision is threatened; immunosuppressive agents, such as methotrexate or cyclosporin, may help to control chronic uveitis. Infliximab can be effective in some patients who are resistant to immunosuppressive agents.
  • Leg length discrepancy (can result from neovascularization of growth plates of an affected knee)
  • • The problem may not be detected in patients with a knee flexion contracture until the contracture is corrected.
    • Treatment consists of a shoe lift on the nonaffected side.
• Polyarticular JRA
• • Skeletal abnormalities - Increased size of epiphyses, accelerated bone age, narrowed joint spaces, swan-neck and/or boutonniere deformities, and joint subluxation (see Media files 5-6).
• • Cervical spine involvement
  • • Difficulty flexing the spine may create a problem for intubation prior to surgery; inform anesthesiologists of the patient's diagnosis. Screening cervical spine radiography may help screen for potential difficulties during induction of anesthesia.
    • High-level subluxation is a potential complication.

Prognosis

• Some studies suggest that many children with JRA can lead productive lives. However, other studies suggest many patients, particularly those with polyarticular disease, may have problems with active disease throughout adulthood, with sustained remission attained in a minority of patients. Early hip or wrist involvement, symmetric disease (even in pauciarticular patients), presence of rheumatoid factor, and prolonged active disease have been associated with poor long-term outcomes.
• Children with systemic disease tend to have either complete responsiveness to medical therapy or development of a polyarticular course that tends to be refractive to medical treatment, with disease persisting into adulthood.
• Most children with pauciarticular disease demonstrate eventual permanent remission; a small number progress to persisting polyarticular disease.

Patient Education

• Educating the patient, family, and school personnel (eg, classroom teachers, physical education teachers, nurses) about JRA and its presentation, treatment, and potential effects is continually necessary. Members of the pediatric rheumatology team in pediatric rheumatology clinics are the best educators about JRA. Another important source of information is the American Juvenile Arthritis Organization, a council of the Arthritis Foundation.
• For excellent patient education resources, visit eMedicine's Arthritis Center. Also, see eMedicine's patient education articles Juvenile Rheumatoid Arthritis and Understanding Rheumatoid Arthritis Medications.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• The major medicolegal pitfall lies in diagnosing juvenile rheumatoid arthritis (JRA) when another problem exists (eg, infection, malignancy, orthopedic problem). Whenever possible, referral to a pediatric rheumatologist can help address this issue. Careful attention to presenting history and initial physical examination findings can lower the likelihood of such a pitfall. However, the chance of such a pitfall can never be eliminated completely. At the time of diagnosis, inform parents and/or caregivers of the possible need to revise the diagnosis of JRA should new symptoms, physical findings, or unusual laboratory results develop.

Special Concerns

• Chronic illness imposes burdens on families, who may vary in their abilities to cope. Social workers can help provide assessment and assist families in finding resources (including counseling). Remind parents and/or caregivers to bring all questions to the pediatric rheumatology team, who can often help. Any unusual symptom may signal a new complication of disease or adverse effect of medication. In the current health care environment, managed care can result in initial denial of services (eg, physical therapy), resulting in delays in treatment with subsequent morbidity. Advocacy by the primary care physician and pediatric rheumatologist can help point out the need for such services.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Patient with active pauciarticular disease. Note significant suprapatellar swelling (effusion) as well as loss of natural contour medial to the patella. Image courtesy of Barry L. Myones, MD.
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Media type:  Photo

Media file 2:  Patient with active polyarticular arthritis. Note swelling (effusions) of all proximal interphalangeal (PIP) joints in addition to boney overgrowth. Also note lack of distal interphalangeal joint (DIP) involvement. The patient has interosseus muscle wasting (observed on the dorsum of the hands), and subluxation and ulnar deviation of the wrists are present. Image courtesy of Barry L. Myones, MD.
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Media type:  Photo

Media file 3:  Wrist radiographs of the patient with active polyarticular arthritis shown in Image 2. Note severe loss of cartilage in the intercarpal spaces and the radiocarpal space of the right wrist. A large erosion is present in the articular surface of the ulnar epiphysis. The view of the left wrist shows boney ankylosis involving the lateral 4 carpal bones with sparing of the pisiform. Erosions are present in the distal radius and ulna. Almost a loss of cartilage has occurred between the radius and ulna and the carpus. Narrowing of the carpal/metacarpal joints is present. Image courtesy of Barry L. Myones, MD.
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Media type:  X-RAY

Media file 4:  Close-up of the proximal interphalangeal (PIP) effusions in the patient with active polyarthritis shown in Images 2 and 3. Synovial thickening and effusion, as well as boney overgrowth, are present at the PIP joints bilaterally. Image courtesy of Barry L. Myones, MD.
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Media type:  Photo

Media file 5:  Patient with inactive polyarticular arthritis. Long-term sequelae of polyarticular disease includes joint subluxation (note both wrists and thumbs), joint contractures (at proximal interphalangeal joints [PIPs] and distal interphalangeal joints [DIPs]), boney overgrowth (at all PIPs), and finger deformities (eg, swan-neck or boutonniere deformities). Image courtesy of Barry L. Myones, MD.
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Media type:  Photo

Media file 6:  Hand and wrist radiographs of the patient with inactive polyarticular arthritis shown in Image 5. Long-term sequelae of polyarticular disease includes periarticular osteopenia, generalized increase in the size of epiphyses, accelerated bone age, narrowed joint spaces (especially at the fourth and fifth proximal interphalangeal joints [PIPs] bilaterally), boutonniere deformities (at left third and fourth interphalangeal joints), and medial subluxation of the first metacarpophalangeal joints (MCPs) bilaterally. Flattening and erosion of the radial carpal articular surface is present in both wrists. Mild narrowing of the joint spaces exists at the carpometacarpal joints and intercarpal rows bilaterally, with sclerotic change of the intercarpal row (right > left). The trapezium and trapezoid may be fused bilaterally. Image courtesy of Barry L. Myones, MD.
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Media type:  X-RAY

Media file 7:  Sequelae of chronic anterior uveitis. Note the posterior synechiae (weblike attachments of the pupillary margin to the anterior lens capsule) of the right eye secondary to chronic anterior uveitis. This patient has a positive antinuclear antibodies (ANAs) and initially had a pauciarticular course of her arthritis. She now has polyarticular involvement but no active uveitis. Image courtesy of Carlos A. Gonzales, MD.
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Media type:  Photo

Media file 8:  One set of suggested algorithms for the treatment of patients with juvenile arthritis. This should not be considered dogmatic because treatment is not standardized and remains empiric and, at times, controversial.
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Media type:  Image

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

• Adams A, Lehman TJ. Update on the pathogenesis and treatment of systemic onset juvenile rheumatoid arthritis. Curr Opin Rheumatol. Sep 2005;17(5):612-6. [Medline].
• Alsufyani K, Ortiz-Alvarez O, Cabral DA, et al. The role of subcutaneous administration of methotrexate in children with juvenile idiopathic arthritis who have failed oral methotrexate. J Rheumatol. Jan 2004;31(1):179-82. [Medline].
• Arabshahi B, Dewitt EM, Cahill AM, et al. Utility of corticosteroid injection for temporomandibular ar