eMedicine Specialties > Pediatrics: General Medicine > Rheumatology

Juvenile Rheumatoid Arthritis

C Egla Rabinovich, MD, MPH,, Assistant Professor and Co-Division Director, Department of Pediatrics, Division of Pediatric Rheumatology, Duke University Medical Center

Updated: Nov 25, 2009

Introduction

Background

Juvenile rheumatoid arthritis (JRA) is the most common rheumatological disease in children and is one of the most common chronic diseases of childhood. It represents a group of disorders that all share the clinical manifestation of chronic joint inflammation. The etiology is largely unknown, and the genetic component is complex, making clear distinctions between the various subtypes difficult. As a result, various classification criteria are recognized, with different benefits and limitations. A new nomenclature, juvenile idiopathic arthritis (JIA), is increasingly used and is replacing the term juvenile rheumatoid arthritis.

The American College of Rheumatology classifies juvenile rheumatoid arthritis into 3 distinct subtypes: pauciarticular juvenile rheumatoid arthritis, polyarticular juvenile rheumatoid arthritis, and systemic JRA. Other childhood arthritis such as juvenile ankylosing spondylitis and psoriatic arthritis are classified under spondyloarthropathies.

In 1997, the International League of Associations for Rheumatology (ILAR) conducted a consensus conference during which they proposed the nomenclature juvenile idiopathic arthritis. The classification criteria include psoriatic arthritis and enthesitis-related arthritis, which encompasses juvenile ankylosing spondylitis, arthritis associated with inflammatory bowel disease, reactive arthritis, and spondyloarthropathies. This has resulted in some confusion in the literature; when reviewing existing literature, consider whether authors are referring to the juvenile rheumatoid arthritis or juvenile idiopathic arthritis nomenclature because this affects the population.

This article focuses on oligoarticular juvenile idiopathic arthritis (pauciarticular juvenile rheumatoid arthritis), polyarticular juvenile idiopathic arthritis, both rheumatoid factor positive and negative (polyarticular JRA), and systemic juvenile idiopathic arthritis (systemic JRA).

Table 1. Comparison of Classification Criteria for Chronic Childhood Arthritis

Classification	ACR (1977)	ILAR (1997)
Nomenclature	Juvenile rheumatoid arthritis	Juvenile idiopathic arthritis
Minimum duration	>6 wk	>6 wk
Age at onset	<16 y	<16 y
£4 joints in first 6 mo after presentation	Pauciarticular juvenile rheumatoid arthritis	Oligoarticular juvenile idiopathic arthritis: (A) Persistent <4 joints for course of disease; (B) Extended >4 joints after 6 mo
>4 joints in first 6 mo after presentation	Polyarticular juvenile rheumatoid arthritis	Polyarticular juvenile idiopathic arthritis rheumatoid factor negative Polyarticular juvenile arthritis rheumatoid factor positive
Fever, rash, arthritis	Systemic juvenile rheumatoid arthritis	Systemic juvenile idiopathic arthritis
Other categories included	Exclusion of other forms	Psoriatic juvenile idiopathic arthritis Enthesitis-related arthritis Undifferentiated: (A) Fits no other category; (B) Fits more than one category
Inclusion of psoriatic arthritis, inflammatory bowel disease, juvenile ankylosing spondylitis	No	Yes

Advances in treatment over the last 20 years has improved the prognosis for children, especially with the advent of biologic medications. Juvenile idiopathic arthritis is a chronic disease characterized by periods of remission and flare. Treatment is aimed at inducing remission with the least toxicity from medications with hopes of inducing a permanent remission.

Pathophysiology

The etiology and pathogenesis of juvenile idiopathic arthritis is not completely understood. An external trigger (eg, infection, trauma) that triggers an autoimmune reaction, leading to synovial hypertrophy and chronic joint inflammation along with the potential for extra-articular manifestations, is theorized to occur in genetically susceptible individuals. Juvenile idiopathic arthritis is a genetically complex trait in which multiple genes are important for disease onset and manifestations. The IL2RA/CD25 gene has recently been implicated as a juvenile idiopathic arthritis susceptibility locus, as has the VTCN1 gene.^{[1 ]}

Both humoral and cell-mediated immunity are involved in the pathogenesis of juvenile idiopathic arthritis. T-lymphocytes have a central role, releasing proinflammatory cytokines (eg, tumor necrosis factor-alpha [TNF–α], interleukin [IL]-6, IL-1) and favoring a type-1 helper T-lymphocyte response. A disordered interaction between type 1 and type 2 T-helper cells has been postulated. Studies of T-cell receptor expression confirm recruitment of T-lymphocytes specific for synovial nonself antigens. Evidence for abnormalities in the humoral immune system include the increased presence of autoantibodies (especially antinuclear antibodies), increased serum immunoglobulins, presence of circulating immune complexes, and complement activation.

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 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.^{[2 ]}

Systemic-onset juvenile idiopathic arthritis may be more accurately classified as an autoinflammatory disorder, such as familial Mediterranean fever (FMF) or cryopyrin-associated periodic fever syndromes, than other subtypes of juvenile idiopathic arthritis. This theory is supported by recent work demonstrating similar expression patterns of a phagocytic protein (S100A12) in systemic-onset juvenile idiopathic arthritis and FMF, as well as the same marked responsiveness to IL-1 receptor antagonists.^{[3 ]}FMF is associated with mutations in the MEFV gene. These mutations are associated with activation of the IL-1b pathway, resulting in inflammation. A study by Ayaz of Turkish children with diagnosed with systemic JIA found an increased frequency of MEFV mutations;^{[4 ]}this study has not been replicated in other populations.

Frequency

United States

Approximately 300,000 children in the United States are estimated to have some type of arthritis. The incidence rate estimates of juvenile rheumatoid arthritis ranges from 4-14 cases per 100,000 children per year, with prevalence rates ranging from 9-113 cases per 100,000 population. Juvenile idiopathic arthritis incidence and prevalence are even harder to determine. These wide-ranging numbers are attributable to population differences, including environmental exposure and immunogenetic susceptibility, along with difficulty in case ascertainment and lack of population based data. Oligoarticular Juvenile idiopathic arthritis is the most common subtype (about half of all juvenile rheumatoid arthritis cases), followed by polyarticular juvenile idiopathic arthritis (one third of juvenile rheumatoid arthritis cases), and systemic-onset juvenile idiopathic arthritis (10-20% of juvenile rheumatoid arthritis cases).

International

Juvenile rheumatoid arthritis 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 with incidence of 11 cases per 100,000 population. A study from Germany found a prevalence rate of 20 cases per 100,00 population, with an incidence rate of 3.5 cases per 100,000 population. Estimates from Norway include a prevalence rate of 148 cases per 100,000 population with an incidence rate of 22 cases per 100,000 population.

Mortality/Morbidity

Increased mortality in adults with a history of juvenile rheumatoid arthritis has been found in a population-based study from Olmsted County Minnesota, where deaths were associated with development of another autoimmune disorder (mortality rate of .27 deaths per 100,000 population compared to expected rate of .068 deaths per 100,000 population).^{[5 ]}An increased mortality rate was also found in a Scottish population-based cohort study, with standardized mortality ratios in males of 3.4 (95% CI, 2 and 5.5) and in females of 5.1 (95% CI, 3.2 and 7.8). The cause of death in this study was not elucidated.

Children with juvenile idiopathic arthritis may experience complications specific to their disease subset (see Clinical) along with morbidity from adverse effects of medications.

Significant psychologic morbidity (eg, situational depression, anxiety, problems functioning in school) can occur in all subtypes regardless of disease severity. Such problems may occur in children with all subtypes and may be the result of additional factors, such as socioeconomic status and family dynamics.

Race

Few studies examining racial differences are noted because most studies that have examined prevalence data are derived from American or European white populations. Schwartz and colleagues found that, compared to whites, blacks with juvenile rheumatoid arthritis were older and were less likely to test positive for antinuclear antibody (ANA) or to have uveitis; however, blacks were more likely to test positive for immunoglobulin-M rheumatoid factor.^{[6 ]}Incidence of juvenile rheumatoid arthritis in Japan has been reported to be low, and lower rates have also been reported in children of Japanese, Filipino, or Samoan origin compared with whites living in Hawaii.

Sex

Oligoarticular juvenile idiopathic arthritis and polyarticular juvenile idiopathic arthritis affect girls more often than boys. The ratio of girls to boys with polyarticular juvenile idiopathic arthritis is estimated to be 3.5-4.5:1; among patients with oligoarticular juvenile idiopathic arthritis, the ratio is 3:1. Systemic-onset disease occurs with equal frequency in boys and girls.

Age

Oligoarticular juvenile idiopathic arthritis has a peak incidence in children aged 2-4 years. Polyarticular juvenile idiopathic arthritis has a biphasic peak of onset; the first is at a young age (1-4 y), similar to oligoarticular juvenile idiopathic arthritis, and the second peak is at age 6-12 years. Systemic juvenile idiopathic arthritis is not characterized by a peak age of onset; it is spread across the childhood years. Rheumatoid factor–positive disease is more common in adolescents.

Clinical

History

The subset of juvenile idiopathic arthritis (JIA) is determined by disease characteristics in the first 6 months after onset. Oligoarticular juvenile idiopathic arthritis (pauciarticular juvenile rheumatoid arthritis [JRA]) is defined as arthritis that involves 4 or less joints in the first 6 months of disease. Those who then develop arthritis in more than 4 joints after the first 6 months are classified as extended oligoarticular juvenile idiopathic arthritis. Children with 5 or more joints involved without the presence of rheumatoid factor are classified as having polyarticular juvenile idiopathic arthritis, rheumatoid factor negative. Presence of rheumatoid factor changes the classification to polyarticular juvenile idiopathic arthritis, rheumatoid factor positive. Typical rash, fevers and arthritis are characteristic of systemic-onset juvenile idiopathic arthritis, independent of the number of joints involved.

Arthritis must be present for at least 6 weeks in the same joint in order to make a diagnosis of juvenile rheumatoid arthritis or juvenile idiopathic arthritis.

The general history of juvenile arthritis includes the following:
- Morning stiffness, or gelling phenomenon, is a frequent complaint. In younger children, the toddler may no longer stand in the crib in the morning or after naps; a morning limp that improves with time may be noted.
- Disease onset is either insidious or abrupt, with morning stiffness and arthralgia during the day.
- Individuals with juvenile idiopathic arthritis may have a history of school absences, and their ability to participate in physical education classes reflects severity of the disease or acute flares. Typically, children with juvenile idiopathic arthritis and their parents are concerned about missing school days; in contrast, when psychogenic factors predominate (eg, pain syndromes), patients are more likely to report missing school days, and families are more concerned about sending their children to school.
- Limping may be observed in children with involvement of their lower extremity.
- A preceding illness raises the possibility of infectious trigger for the arthritis or a self-limited postinfectious arthritis.
- Illness in pets with a history of enteritis raises the possibility of reactive arthritis.
- History of travel to an endemic area with exposure to ticks raises the possibility of Lyme disease.
- GI symptoms, microcytic anemia, and elevated inflammatory markers raise the possibility of inflammatory bowel disease.
- Severe joint pain raises the possibility of acute rheumatic fever (also suggested by migratory but not additive arthritis, with fevers), malignancy with bone marrow–occupying cancers (eg, neuroblastoma, acute lymphocytic leukemia [with metaphyseal pain upon examination and decrease in 2 or more cell lines]), septic arthritis, or osteomyelitis.
- Weight loss without diarrhea may be observed in individuals with active juvenile idiopathic arthritis and is sometimes associated with anorexia. This symptom is also observed in individuals with malignancy such as acute lymphocytic leukemia or inflammatory bowel disease.
- Photophobia may be observed in children with usually asymptomatic uveitis.
- Orthopnea suggests pericarditis in children with systemic juvenile rheumatoid arthritis; the differential diagnosis includes systemic lupus erythematosus (SLE) and viral pericarditis.
- Complaints of joint pain may not predominate the history; children often quit using joints normally (eg, contractures of joints, decreased wrist range, limp) rather than complain of pain.
Systemic-onset juvenile rheumatoid arthritis or juvenile idiopathic arthritis is characterized by spiking fevers, typically occurring once or twice each day, at about the same time of day, with temperature returning to the normal or below normal. The fever pattern is very useful because infections, Kawasaki disease, and malignancy do not have such a predictable pattern.
- Systemic-onset juvenile rheumatoid arthritis is usually accompanied by an evanescent rash (lasting a few hours), which is typically nonpruritic, macular, and salmon colored (as opposed to brightly erythematous) and affects the trunk and extremities. Occasionally, the rash is extremely pruritic, and the pruritis is resistant to antihistamine treatment.
- Arthralgia is often present.
- Children are systemically ill appearing.
- Some children may have a generalized myalgia.
- Chest pain or shortness of breath may be a sign of pericarditis or pleuritis.
Oligoarticular (pauciarticular) disease is defined by arthritis affecting 4 or fewer joints.
- Typically, larger joints (eg, knees, ankles, wrists) are affected.
- Children are well-appearing despite ambulating with a limp.
- Monoarticular arthritis in a hip is highly unusual; infections, malignancy, and orthopedic conditions must be suspected and evaluated in this presentation.
- For isolated hip arthritis, 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.
- Chronic involvement can result in atrophy of extensor muscles in the thigh, tight hamstring ligaments, and knee flexion contractures. Leg length discrepancies occur in the involved limb with asymmetric arthritis.
Polyarticular disease affects at least 5 joints.
- Both large and small joints can be involved, often in symmetric bilateral distribution.
- Low grade fevers can accompany the arthritis.
- Severe limitations in motion are usually accompanied by muscle weakness and decreased physical function.
- Presence of rheumatoid factors differentiates the two forms of polyarticular juvenile idiopathic arthritis.

Physical

A complete physical examination is a critical for the diagnosis of juvenile idiopathic arthritis. Physical findings are important to provide criteria for diagnosis and to detect abnormalities suggestive of alternative etiologies for arthritis. The diagnosis of juvenile idiopathic arthritis is based on the physical finding of arthritis in at least one joint that persists for at least 6 weeks, with other causes excluded, in an individual younger than 16 years. No diagnostic serological tests for juvenile idiopathic arthritis are noted.

Arthritis is defined as either intra-articular swelling on examination or the combination of limited motion of a joint associated with pain, warmth, or erythema of the joint. The hips and small joints in the spine do not demonstrate swelling when affected by synovitis but demonstrate the combination of loss of motion and pain.

A definite diagnosis of systemic-onset juvenile rheumatoid arthritis must await the development of arthritis, which may occur at onset of the fever and rash, or may lag by months.
- Evanescent salmon-pink macular rash, often linear, is found on predominantly on the trunk and the extremities; this rash is associated with fever spikes and is seen in the image below.
- Systemic juvenile idiopathic arthritis (JIA) rash.
- Hepatosplenomegaly is often present.
- Lymphadenopathy is sometimes present.
- Muscle tenderness to palpation may be observed.
- Serositis, including pleural and pericardial effusions may be present, as is noted in the image below.
- Child with pericardial effusion due to systemic onset juvenile idiopathic arthritis (JIA).
- Pericardial tamponade has been rarely reported.
In individuals with oligoarticular juvenile idiopathic arthritis, 4 or fewer joints are affected; often, only a single joint is affected.
- Typically, large weight-bearing joints, knees, and ankles are affected, such as is seen in the image below.
- Eighteen-month-old girl with arthritis in her right knee. Note the flexion contracture of that knee.
- Involvement of a few small joints in the hands is atypical and suggests eventual development of polyarticular juvenile idiopathic arthritis or psoriatic arthritis. Diffuse tenosynovitis of a finger or toe, called a "sausage digit," is more typical of psoriatic arthritis or enthesitis-related arthritis.
- Chronic arthritis in a knee or ankle may lead to overgrowth of that limb with subsequent leg length discrepancy.
- Muscle atrophy, often of extensor muscles (eg, vastus lateralis, quadriceps when knee affected), may be found.
- Flexion contractures in the knees and, less commonly, the wrists are found.
In children with polyarticular juvenile idiopathic arthritis, 5 or more joints are affected in the first 6 months after disease onset.
- Weight-bearing joints are affected, and symmetric involvement of small joints in the hands is often found, such as is seen in the images below.
- 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.
- Wrist radiographs of the patient with active polyarticular arthritis shown in Media file 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.
- Close-up of the proximal interphalangeal (PIP) effusions in the patient with active polyarthritis shown in Media files 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.
- 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.
- Hand and wrist radiographs of the patient with inactive polyarticular arthritis shown in Media file 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.
- Decreased extension of the cervical spine is often asymptomatic. It is indicative of arthritis of the cervical spine and can lead to subluxation, typically of C2 vertebrae on C3. Fusion of the posterior elements of the vertebra may occur (see the image below).
- Flexion and extension views of C-spine in child with poorly controlled polyarticular juvenile idiopathic arthritis (JIA).
- Arthritis of the temporal-mandibular joint (TMJ) may lead to micrognathia. TMJ arthritis may be asymptomatic; decreased mouth aperture or ausculatory abnormalities over the TMJ are signs of underlying arthritis (see the image below).
- Temporal-mandibular joint (TMJ) MRI postgadolinium infusion. Abnormal increased uptake indicative of synovitis in child with polyarticular juvenile idiopathic arthritis (JIA).
Other findings in persons with juvenile rheumatoid arthritis are as follows:
- Ocular: Anterior uveitis is present in as many as 10% of children with oligoarticular and polyarticular juvenile idiopathic arthritis, especially those who are ANA positive. It is typically asymptomatic at onset and must be screened for with an ophthalmologic slit lamp examination. Photophobia, band keratopathy, and synechiae (ie, irregular iris perimeter resulting from postinflammatory adhesions of iris to lens) may be found (see the image below).
- 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.
- 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 juvenile rheumatoid arthritis.

Causes

The specific causes of juvenile rheumatoid arthritis remain undefined.

Differential Diagnoses

Acute Lymphoblastic Leukemia	Neuroblastoma
Autoimmune Chronic Active Hepatitis	Osteomyelitis
Behcet Syndrome	Pericarditis, Viral
Celiac Disease	Rheumatic Fever
Crohn Disease	Sarcoidosis
Endocarditis, Bacterial	Serum Sickness
Fever in the Toddler	Somatoform Disorder: Pain
Infectious Mononucleosis	Systemic Lupus Erythematosus
Kawasaki Disease	Tularemia
Lyme Disease	Ulcerative Colitis

Workup

Laboratory Studies

No laboratory studies are diagnostic for juvenile idiopathic arthritis (JIA). All laboratory study findings may be normal in children with juvenile idiopathic arthritis. Diagnosis is based on the physical finding of arthritis. Laboratory studies help exclude other underlying diagnosis, classify the type of arthritis, and help evaluate for extra-articular manifestations of juvenile idiopathic arthritis. Initial evaluation should include the following:
- Inflammatory markers
  - Erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) are usually elevated in children with systemic juvenile rheumatoid arthritis (JRA) and may be elevated or normal in those with polyarticular disease; however, it is often within the reference range in those with pauciarticular disease.
  - When elevated, inflammatory markers 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 systemic lupus erythematosus (SLE) presenting with arthritis, as well as marrow occupying malignancies. Thrombocytosis reflects inflammatory state and often mirrors inflammatory markers in juvenile idiopathic arthritis.
  - Anemia may result from chronic active juvenile rheumatoid arthritis; 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 nonsteroidal anti-inflammatory drugs (NSAIDs) or methotrexate (MTX), which can cause hepatotoxicity.
- Urinalysis with microscopic examination: Perform a urinalysis to exclude the possibility of infection (as a trigger of juvenile rheumatoid arthritis or transient postinfectious arthritis) and nephritis (observed in individuals with SLE). Urinalysis should be monitored in children on chronic NSAIDs. Serum creatinine levels should be obtained prior to initiation of treatment with NSAIDs.
- Antinuclear antibody (ANA)
  - ANA is observed in as many as 50% of children with juvenile idiopathic arthritis, particularly in those with oligoarticular or polyarticular rheumatoid factor–negative subtypes.
  - A positive ANA is a marker for increased risk of anterior uveitis. Children younger than 6 years at arthritis onset with a positive ANA finding are in the highest risk category for development of uveitis and need slit lamp screening every 3-4 months.
  - 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
  - Rheumatoid factor is found to be present in less than 10% of children with juvenile idiopathic arthritis. It is very rarely found in those with systemic juvenile idiopathic arthritis. Rheumatoid factor is a marker for early erosive disease and persistence of arthritis into adulthood.
  - Rheumatoid nodules may be seen in those with rheumatoid factor–positive disease
  - Compared with adults who have rheumatoid factor, children are at less risk for rheumatoid lung involvement and vasculitis.
Other laboratory tests for systemic juvenile rheumatoid arthritis 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.
- A falling sedimentation rate, along with normalization or falling WBC, low platelets, elevated liver function test findings, increased ferritin and triglycerides with low fibrinogen and associated erratic fevers, hemorrhages (disseminated intravascular coagulation–like pattern) are indicative of development of macrophage activating syndrome (MAS) in particularly in those with systemic onset juvenile idiopathic arthritis.
Other laboratory tests to consider include the following:
- ACE elevation may be indicative of sarcoidosis.
- Antistreptolysin 0 (AS0) and anti-DNAse B elevations may indicate acute rheumatic fever or poststreptococcal arthritis.

Imaging Studies

Radiography of affected joints: 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 juvenile rheumatoid arthritis 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 juvenile rheumatoid arthritis.

Other Tests

Dual-energy radiograph absorptiometry (DXA) scanning: Perform DXA scanning to document osteopenia in children with polyarticular juvenile rheumatoid arthritis.

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 reveal synovial infiltration with plasma cells, mature B lymphocytes, and T lymphocytes, with areas of synovial thickening and fibrosis.

Treatment

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 juvenile rheumatoid arthritis, despite medical treatment, may benefit from intra-articular steroid injection. Such injections may also be effective in treating temporomandibular arthritis in children with polyarticular juvenile rheumatoid arthritis. Usually, delay joint replacement (often of the hips, in patients with polyarticular juvenile rheumatoid arthritis) 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 juvenile rheumatoid arthritis. However, because active juvenile rheumatoid arthritis 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 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 are as active as possible.

Medication

Classes of medications are suggested below, and specific drugs are covered in detail by category. See the therapeutic algorithm below.

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.

Nonsteroidal anti-inflammatory drugs (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 methotrexate (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, along with its association with Reye syndrome. 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 juvenile idiopathic arthritis are underway. 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 oral (PO) MTX. Subsequent studies have demonstrated that some children with polyarticular arthritis unresponsive to PO MTX benefit from subcutaneous (SC) or intramuscular (IM) administration. The use of high-dose intravenous (IV) steroids in selected patients has been beneficial in some patients, particularly during an early period before MTX may have a full therapeutic effect.

Etanercept, a biologic agent administered SC twice weekly and containing a receptor to tumor necrosis factor (TNF) ligated to an Fc portion of immunoglobulin, has been found to be effective in controlling polyarticular arthritis not controlled by conventional medical treatment. Adalimumab is another anti-TNF agent now approved for use in juvenile idiopathic arthritis. These medications are for those children treated by pediatric rheumatology centers who are unresponsive to treatment including conventional second-line drugs.

Finally, the treatment of systemic juvenile idiopathic arthritis 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 juvenile rheumatoid arthritis. Corticosteroids may be avoided with the use of anakinra, which is relatively new, inhibits interleukin (IL)-1 activity, and appears to have unique efficacy on the systemic signs and symptoms of systemic juvenile idiopathic arthritis. Medication alone is not sufficient for most children with arthritis, who benefit from a team approach (see Consultations).

Nonsteroidal anti-inflammatory drugs (NSAIDs)

These agents are often used in all children with JIA as the medication of first choice, often in combination with disease modifying drugs (DMARDs) to relieve pain and swelling. Predicting which individual patient will respond to a particular NSAID is not possible; sometimes, after 6 weeks of treatment, those persons who do not respond may benefit from changing to a different NSAID. Many children with oligoarticular JIA and only a few with polyarticular JIA 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.

Meloxicam

Member of the enolic class of NSAIDs, structurally related to piroxicam.

Dosing

Adult

7.5 to 15 mg PO qd

Pediatric

>2 years: 0.125 mg/kg/day up to 7.5 mg qd

Interactions

Increased risk of GI side effects when combined with corticosteroids.

Contraindications

Any history of meloxicam or salicylate hypersensitivity, use in patients undergoing coronary artery bypass surgery, use in caution in patients with history of gastrointestinal bleeding.

Precautions

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

Black box warning for increased risk of stroke, adverse cardiovascular events such as myocardial infarction in adults with long term use.

Naproxen (Aleve, Naprelan, Naprosyn)

Used for analgesic and anti-inflammatory properties, treating arthralgia and arthritis. Each brand is marketed with slightly different safety and efficacy profiles. Inhibits inflammatory reactions and pain by decreasing activity of COX, which is responsible for prostaglandin synthesis.

Dosing

Adult

500-1000 mg/d PO divided bid; available in SR formulation (ie, Naprelan) that is administered qd

Pediatric

7-20 mg/kg/d PO divided bid/tid; not to exceed 1 g/d

Interactions

Coadministration with aspirin increases risk of inducing serious NSAID-related adverse 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
Compared with other NSAIDs, increased likelihood of causing pseudoporphyria cutanea tarda, a photosensitive eruption that causes scarring, especially in fair-skinned young individuals; contraindicated in patients who have pseudoporphyria from this drug

Contraindications

Documented hypersensitivity; peptic ulcer disease; recent GI bleeding or perforation; renal insufficiency

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Category D in third trimester of pregnancy; acute renal insufficiency, interstitial nephritis, hyperkalemia, hyponatremia, and renal papillary necrosis may occur; patients with preexisting renal disease or compromised renal perfusion risk acute renal failure; leukopenia occurs rarely, is transient, and usually returns to normal during therapy; persistent leukopenia, granulocytopenia, or thrombocytopenia warrants further evaluation and may require discontinuation of drug

Ibuprofen (Advil, Motrin)

Inhibits inflammatory reactions and pain by decreasing prostaglandin synthesis.

Dosing

Adult

400 mg PO q4-6h, 600 mg q6h, or 800 mg q8h while symptoms persist; not to exceed 3.2 g/d

Pediatric

30-50 mg/kg/d PO divided qid; not to exceed 2.4 g/d

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

Contraindications

Documented hypersensitivity; peptic ulcer disease; recent GI bleeding or perforation; renal insufficiency; high risk of bleeding

Precautions

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

Diclofenac (Voltaren, Cataflam)

Inhibits prostaglandin synthesis by decreasing activity of enzyme COX, which in turn decreases formation of prostaglandin precursors.

Dosing

Adult

100-200 mg/d PO divided bid/qid; not to exceed 225 mg/d

Pediatric

<12 years: 2-3 mg/kg/d PO divided bid/qid
>12 years: Administer as in adults

Interactions

Contraindications

Documented hypersensitivity; administration into CNS; peptic ulcer disease; recent GI bleeding or perforation; renal insufficiency; high risk of bleeding

Precautions

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

Tolmetin (Tolectin)

Inhibits prostaglandin synthesis by decreasing activity of enzyme COX, which in turn decreases formation of prostaglandin precursors.

Dosing

Adult

400 mg PO tid; typical dosage range is 600 mg/d to 1.8 g/d; not to exceed 2 g/d

Pediatric

20 mg/kg/d PO divided tid/qid initially; then 15-30 mg/kg/d; not to exceed 30 mg/kg/d

Interactions

Contraindications

Documented hypersensitivity; administration into CNS; peptic ulcer disease; recent GI bleeding or perforation; renal insufficiency; high risk of bleeding

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Indomethacin (Indocin)

Rapidly absorbed. Metabolism occurs in liver by demethylation, deacetylation, and glucuronide conjugation. Inhibits prostaglandin synthesis.

Dosing

Adult

25-50 mg PO bid/tid; not to exceed 200 mg/d
ER product may be administered qd or bid

Pediatric

1-2 mg/kg/d PO divided bid/qid; not to exceed 4 mg/kg/d or 150-200 mg/d

Interactions

Contraindications

Documented hypersensitivity; GI bleeding; renal insufficiency

Precautions

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)

Celecoxib (Celebrex)

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.

Dosing

Adult

100-200 mg PO bid

Pediatric

<2 years: Not established
>2 years:
>10 kg to <25 kg: 50 mg PO bid
>25 kg: 100 mg PO bid

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

Contraindications

Documented hypersensitivity

Precautions

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

Immunosuppressive agents

Many children with polyarticular juvenile idiopathic arthritis and some with oligoarticular juvenile idiopathic arthritis, especially extended oligoarticular juvenile idiopathic arthritis, benefit from additional immunosuppressive agents (ie, MTX).

Methotrexate (Rheumatrex)

Unknown mechanism of action in treatment of inflammatory reactions; may affect immune function. The anti-inflammatory effects do not appear to be mediated by inhibition of dihydrofolate reductase. Ameliorates symptoms of inflammation (eg, pain, swelling, stiffness). Adjust dose gradually to attain satisfactory response. Consider SC route for patients who do not respond to PO methotrexate or who have GI intolerance to PO dosing.

Dosing

Adult

7.5 mg/wk PO/SC or 2.5 mg PO/SC q12h for 3 doses administered qwk; doses are uptitrated for clinical effectiveness to 20 mg weekly; once response is achieved, the dose is reduced to lowest effective weekly dose

Pediatric

10-25 mg/m²/wk PO/IM/SC as a single dose or divided into 2 doses qwk; many pediatric rheumatologists increase dose (not to exceed 30 mg/m², approximately equivalent to 1 mg/kg); administer with folic acid 1-2 mg PO qd or folinic acid 2.5-5 mg PO qwk

Interactions

Coadministration with etretinate may increase hepatotoxicity of MTX; indomethacin and phenylbutazone can increase MTX plasma levels; may decrease phenytoin serum levels; probenecid, salicylates, procarbazine, and sulfonamides, including TMP-SMZ, may increase effects and toxicity of MTX; may increase plasma levels of thiopurines

Contraindications

Documented hypersensitivity; alcoholism; hepatic insufficiency; documented immunodeficiency syndromes; preexisting blood dyscrasias (eg, bone marrow hypoplasia, leukopenia, thrombocytopenia, significant anemia); renal insufficiency

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Monitor CBCs q1-2mo and liver and renal function q1-3mo during therapy (monitor more frequently during initial dosing, dose adjustments, or when risk of elevated MTX levels, such as dehydration); MTX has toxic effects on hematologic, renal, GI, pulmonary, and neurologic systems; discontinue if significant drop in blood counts occurs; aspirin, NSAIDs, or low-dose steroids may be administered concomitantly with MTX (possibility of increased toxicity with NSAIDs, including salicylates, has not been tested); supplement folic acid to prevent deficiency; add daily folic acid or weekly folinic acid to ameliorate adverse effects

Sulfasalazine (Azulfidine, EN-tabs)

Decreases the inflammatory response and systemically inhibits prostaglandin synthesis.

Dosing

Adult

500 mg PO qd initially; gradually increase by 500 mg/wk to 2-3 g/d PO divided bid

Pediatric

<6 years: Not established
>6 years: Typical dose range is 30-50 mg/kg/d; to lessen GI irritation, start at one half to one third of maintenance dose, increasing dose weekly; not to exceed 2 g/d.

Interactions

Decreases effects of iron, digoxin, and folic acid; conversely, increases effect of PO anticoagulants, PO hypoglycemic agents, and MTX

Contraindications

Documented hypersensitivity to salicylate or sulfonamides; coadministration of sulfa drugs or any component; GI or GU obstruction; porphyria

Precautions

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; blood dyscrasias, including aplastic anemia, agranulocytosis, and hemolytic anemia, may occur and may be fatal; Steven-Johnson syndrome may rarely occur

Methylprednisolone (Solu-Medrol)

Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability. Used temporarily for JRA until longer-term treatment provides effective relief.

Dosing

Adult

30 mg/kg/dose IV administered over 30 min q4-6h prn; administer high dose only for 2-3 d

Pediatric

15-30 mg/kg IV qd administered over 30-60 min for 2-3 d

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

Contraindications

Documented hypersensitivity; viral, fungal, or tubercular infections

Precautions

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, glaucoma, cataracts, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, growth suppression, myopathy, and infections are possible complications of glucocorticoid use.

Prednisone (Deltasone, Sterapred)

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.

Dosing

Adult

7.5 mg PO qd for short-term treatment while waiting for efficacy of other antirheumatic drugs

Pediatric

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

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

Contraindications

Documented hypersensitivity; viral infection; peptic ulcer disease; hepatic dysfunction; connective tissue infections; fungal or tubercular infections; GI disease

Precautions

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

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.

Adalimumab

Recombinant human IgG1 monoclonal antibody specific for human TNF. Reduce inflammation and inhibit progression of structural damage.

Dosing

Adult

RA: 40 mg SC q2wk; may increase in some patients not taking MTX to 40 mg SC qwk if warranted

Pediatric

<4 years: Not established
>4years and >15 kg but less than 30 kg: 20 mg SC q2wk
>4 years and >30 kg: 40 mg SC q2wk

Interactions

May interfere with immune response to live virus vaccine (eg, MMR) and reduce efficacy; MTX decreases clearance (available data do not support adjusting dose of either adalimumab or MTX); coadministration with anakinra (an IL-1 antagonist that also blocks TNF) may cause additive adverse effects, particularly development of serious infections

Contraindications

Documented hypersensitivity; active infection

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Causes immunosuppression; may be associated with serious infections (some fatal) including reactivation of tuberculosis, sepsis, or opportunistic infections, discontinue if serious infection occurs; increases risk for lymphoma development; associated with CNS demyelination (rare); autoantibody development may occur causing lupus-like syndrome; may cause hypersensitivity reactions including anaphylaxis and hematologic adverse effects (ie, pancytopenia, aplastic anemia); exacerbation of CHF or new onset CHF has been observed with TNF-blocking agents

Etanercept (Enbrel)

Acts by binding and inhibiting TNF, a cytokine that contributes to inflammatory and immune response.

Dosing

Adult

25 mg SC 2 times qwk

Pediatric

<4 years: Not established
4-17 years: 0.4 mg/kg SC 2 times qwk (administered at least 72-96 h apart); not to exceed 25 mg/dose
>17 years: Administer as in adults

Interactions

Do not administer within 3 mo of live virus vaccines (eg, MMR)

Contraindications

Documented hypersensitivity; sepsis

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in impaired renal function and asthma; discontinue administration if a serious infection develops; adverse effects may include injection site pain, localized erythema, rash, URI symptomatology, GI upset, nausea, vomiting, rhinitis, and cough; adverse events in children and adults are similar in frequency and type, those reported more commonly include headache (19%), nausea (9%), abdominal pain (19%), and vomiting (13%); immunizations should be brought up-to-date prior to initiating; rare cases of lupuslike symptoms and heart failure have been reported (discontinue treatment if symptoms develop)

Immune Modulator

These agents interfere with cytokine actions responsible for inflammation.

Abatacept (Orencia)

Selective costimulation modulator that inhibits T-cell activation by binding to CD80 and CED86, thereby blocking CD28 interaction. CD28 interaction provides a signal needed for full T-cell activation that is implicated in RA pathogenesis. Indicated for reducing signs and symptoms of RA, slowing progression of structural damage and improving physical function in adults with moderate-to-severe RA who have inadequate response to DMARDs, methotrexate, or TNF antagonists. May be used as monotherapy or with DMARDs (other than TNF antagonists, because of increased risk of serious infections [4.4% vs 0.8%]). Not recommended for concomitant use with anakinra (insufficient experience).

Dosing

Adult

Dose according to body weight; after initial administration, repeat at 2 and 4 wk after first infusion, then q4wk; infuse over 30 min
<60 kg: 500 mg IV
60-100 kg: 750 mg IV
>100 kg: 1 g IV

Pediatric

<6 years: Not established
6-17 years: Dose according to body weight; administer on days 1, 15, and 29, then q4wk thereafter; infuse IV over 30 min
<74 kg: 10 mg/kg IV
75-100 kg: 750 mg IV
>100 kg: 1000 mg IV

Interactions

In clinical trials, coadministration with TNF antagonists resulted in increased risk of serious infections; do not administer concurrently with live virus vaccines (eg, MMR) or within 3 mo of discontinuation

Contraindications

Documented hypersensitivity

Precautions

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

Discontinue if serious infection occurs; patients with COPD developed adverse effects more frequently, including COPD exacerbations, cough, rhonchi, and dyspnea; serious adverse reactions include serious infections (3% vs 1.9% placebo); malignancy frequency was similar to that of placebo (1.3% vs 1.1% placebo), with the exception of lung cancer (0.2% vs 0% placebo); common adverse effects include headache, upper respiratory tract infection, nasopharyngitis, and nausea

Interleukin-1 Receptor Antagonist

These agents inhibit IL-1 binding leading to decreased inflammation.

Anakinra (Kineret)

Competitively and selectively inhibits IL-1 binding to type I receptor (IL-1RI). IL-1 is found in excess in rheumatoid arthritis patients and is produced in response to inflammatory stimuli. By blocking IL-1 binding, inflammation and pain associated with rheumatoid arthritis are inhibited. Indicated for rheumatoid arthritis in patients who have failed one or more DMARDs. Dose should be administered at approximately the same time every day.

Dosing

Adult

100 mg SC qd

Pediatric

Not established

Interactions

None reported; higher rate of serious infections and neutropenia are possible when coadministered with TNF blocking agents (eg, etanercept, infliximab, adalimumab); may decrease response to live virus vaccines

Contraindications

Documented hypersensitivity to product or E coli –derived products; active infections

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Serious infections may occur (discontinue treatment if serious infection develops); neutropenia may occur (especially if administered concomitantly with TNF blocking agents); most common adverse effect is local reaction at site of injection; caution if administered to nursing women

Follow-up

Further Inpatient Care

Further inpatient care is required for persisting fevers of unknown origin or when children with known juvenile idiopathic arthritis (JIA) 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 juvenile idiopathic arthritis is usually an indication for admission.

Further Outpatient Care

Patients may have a gradually responsive disease (particularly those with pauciarticular juvenile idiopathic arthritis).
A small number of patients with pauciarticular juvenile idiopathic arthritis develop aggressive arthritis confined to a single joint; such patients may require more intensive medical treatment and physical therapy.
Some patients with polyarticular juvenile idiopathic arthritis 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.

Inpatient & Outpatient Medications

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 juvenile idiopathic arthritis usually indicate transfer to a hospital with a pediatric rheumatology center.
Treatment of macrophage activation syndrome (MAS) is a medical emergency and should be done by physicians familiar with this complication.

Deterrence/Prevention

No prevention methods are 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 juvenile idiopathic arthritis and any chronic illness.

Complications

Systemic-onset juvenile idiopathic arthritis
- Pericarditis (patients often presenting with orthopnea and responsive to intravenous corticosteroid treatment)
- Hemolytic anemia
- Disseminated intravascular coagulopathy (DIC), often present at a low level of activity: The levels of D-dimer and fibrinogen may be elevated; their return to reference range levels is observed with successful treatment.
- MAS
  - 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, CNS disease, and marked hepatosplenomegaly may be noted as complications of a release of massive amounts of cytokines.
  - Bone marrow aspiration may reveal histiocytic consumption of bone marrow precursors, which confirms the diagnosis and excludes malignancy. One does not need to see the histiocytic consumption for diagnosis of MAS.
  - MAS often responds to cyclosporin A, and some case reports have detailed response to anakinra.
- Endarteritis resulting in circulatory compromise of the digits with threatened autoamputation
  - This complication is even more rare than MAS.
  - Central administration of prostaglandin E1 may be of potential benefit, similar to its use for patients with scleroderma and endarteritis.
Pauciarticular juvenile idiopathic arthritis
- 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. Intra-articular corticosteroid injection should be strongly considered.
- Uveitis
  - Often asymptomatic, patients are typically young girls who have positive levels of antinuclear antibody (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.
  - 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 juvenile idiopathic arthritis
- Skeletal abnormalities - Increased size of epiphyses, accelerated bone age, narrowed joint spaces, swan-neck and/or boutonniere deformities, and joint subluxation
- 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 (in both flexion and extension) 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 juvenile idiopathic arthritis 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 juvenile idiopathic arthritis 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 juvenile idiopathic arthritis. 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

Medicolegal Pitfalls

The major medicolegal pitfall lies in diagnosing juvenile idiopathic arthritis (JIA) 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 juvenile idiopathic arthritis 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

Media file 1: 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.

Media file 2: Wrist radiographs of the patient with active polyarticular arthritis shown in Media file 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.

Media file 3: Close-up of the proximal interphalangeal (PIP) effusions in the patient with active polyarthritis shown in Media files 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.

Media file 4: 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.

Media file 5: Hand and wrist radiographs of the patient with inactive polyarticular arthritis shown in Media file 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.

Media file 6: 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.

Media file 7: 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.

Media file 8: Systemic juvenile idiopathic arthritis (JIA) rash.

Media file 9: Child with pericardial effusion due to systemic onset juvenile idiopathic arthritis (JIA).

Media file 10: Flexion and extension views of C-spine in child with poorly controlled polyarticular juvenile idiopathic arthritis (JIA).

Media file 11: Temporal-mandibular joint (TMJ) MRI postgadolinium infusion. Abnormal increased uptake indicative of synovitis in child with polyarticular juvenile idiopathic arthritis (JIA).

Media file 12: Eighteen-month-old girl with arthritis in her right knee. Note the flexion contracture of that knee.

References

Hinks A, Ke X, Barton A, et al. Association of the IL2RA/CD25 gene with juvenile idiopathic arthritis. Arthritis Rheum. Jan 2009;60(1):251-7. [Medline].
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Keywords

juvenile rheumatoid arthritis, JRA, juvenile idiopathic arthritis, JIA, juvenile arthritis, immunoglobulin M rheumatoid factor, pauciarticular JRA, polyarticular JRA, systemic-onset JRA, rheumatoid factor-positive disease, treatment, diagnosis, symptoms

Contributor Information and Disclosures

Author

C Egla Rabinovich, MD, MPH,, Assistant Professor and Co-Division Director, Department of Pediatrics, Division of Pediatric Rheumatology, Duke University Medical Center
C Egla Rabinovich, MD, MPH, is a member of the following medical societies: American College of Rheumatology
Disclosure: Nothing to disclose.

Medical Editor

Barry L Myones, MD, Associate Professor, Departments of Pediatrics and Immunology, Pediatric Rheumatology Section, Baylor College of Medicine; Director of Research, Pediatric Rheumatology Center, Texas Children's Hospital
Barry L Myones, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Immunologists, American College of Rheumatology, American Heart Association, American Society for Microbiology, Clinical Immunology Society, and Texas Medical Association
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Thomas JA Lehman, MD, FAAP, FACR, Clinical Professor of Pediatrics, Department of Pediatrics, Division of Pediatric Rheumatology, Weill-Cornell University; Chief, Hospital for Special Surgery
Thomas JA Lehman, MD, FAAP, FACR is a member of the following medical societies: PM American Allergy Society
Disclosure: Nothing to disclose.

CME Editor

Daniel Rauch, MD, FAAP, Director, Pediatric Hospitalist Program, Associate Professor, Department of Pediatrics, New York University School of Medicine
Daniel Rauch, MD, FAAP is a member of the following medical societies: Ambulatory Pediatric Association, American Academy of Pediatrics, and Society of Hospital Medicine
Disclosure: Baxter Honoraria Consulting

Chief Editor

Lawrence K Jung, MD, Chief, Division of Pediatric Rheumatology, Children's National Medical Center
Lawrence K Jung, MD is a member of the following medical societies: American Association for the Advancement of Science, American Association of Immunologists, American College of Rheumatology, Clinical Immunology Society, and New York Academy of Sciences
Disclosure: Nothing to disclose.

Acknowledgments

The authors and editors of eMedicine gratefully acknowledge Michael L Miller, MD, to the original writing and development of this article.

Further Reading

eMedicine Specialties > Pediatrics: General Medicine > Rheumatology

Juvenile Rheumatoid Arthritis

Introduction

Background

Pathophysiology

Frequency

United States

International

Mortality/Morbidity

Race

Sex

Age

Clinical

History

Physical

Systemic juvenile idiopathic arthritis (JIA) rash.

Child with pericardial effusion due to systemic onset juvenile idiopathic arthritis (JIA).

Eighteen-month-old girl with arthritis in her right knee. Note the flexion contracture of that knee.

Close-up of the proximal interphalangeal (PIP) effusions in the patient with active polyarthritis shown in Media files 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.

Flexion and extension views of C-spine in child with poorly controlled polyarticular juvenile idiopathic arthritis (JIA).

Temporal-mandibular joint (TMJ) MRI postgadolinium infusion. Abnormal increased uptake indicative of synovitis in child with polyarticular juvenile idiopathic arthritis (JIA).

Causes

Differential Diagnoses

Other Problems to Be Considered

Workup

Laboratory Studies

Imaging Studies

Other Tests

Procedures

Histologic Findings

Treatment

Medical Care

Surgical Care

Consultations

Diet

Activity

Medication

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.

Nonsteroidal anti-inflammatory drugs (NSAIDs)

Meloxicam

Dosing

Adult

Pediatric

Interactions

Contraindications

Precautions

Pregnancy

Precautions

Naproxen (Aleve, Naprelan, Naprosyn)

Dosing

Adult

Pediatric

Interactions

Contraindications

Precautions

Pregnancy

Precautions

Ibuprofen (Advil, Motrin)

Dosing

Adult

Pediatric

Interactions

Contraindications

Precautions

Pregnancy

Precautions

Diclofenac (Voltaren, Cataflam)

Dosing

Adult

Pediatric

Interactions

Contraindications

Precautions

Pregnancy

Precautions

Tolmetin (Tolectin)

Dosing

Adult

Pediatric

Interactions