eMedicine Specialties > Pediatrics: General Medicine > Rheumatology

Juvenile Rheumatoid Arthritis

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

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

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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.
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    Systemic juvenile idiopathic arthritis (JIA) rash.

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

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

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    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.
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    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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    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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    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.

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    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.

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    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.

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    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.

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    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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    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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    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.

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

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

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    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).
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    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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    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.

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