Juvenile Idiopathic Arthritis 

Juvenile rheumatoid arthritis (JRA) is the most common chronic rheumatologic disease in children and is one of the most common chronic diseases of childhood. It represents a group of disorders that share the clinical manifestation of chronic joint inflammation.

The etiology is unknown, and the genetic component is complex, making clear distinctions between the various subtypes difficult. As a result, the various sets of classification criteria that have been recognized have different benefits and limitations. A new nomenclature, juvenile idiopathic arthritis (JIA), is being increasingly used in order to better define subgroups.

Go to Osteoarthritis, Pediatric Osteoarthritis, and Rheumatoid Arthritis for complete information on these topics.

Criteria and classification

Three groups have developed sets of criteria to classify children with arthritis: the American College of Rheumatology (ACR), the European League Against Rheumatism (EULAR), and the International League of Associations for Rheumatology (ILAR).^{[1, 2, 3]}

The ACR criteria define juvenile rheumatoid arthritis (JRA) by age limit (< 16 y) and the duration of disease (>6 weeks). (See Table.) The organization recognizes the following 3 subtypes:

• Polyarticular
• Pauciarticular
• Systemic

Other forms of childhood arthritis, such as juvenile ankylosing spondylitis and psoriatic arthritis, are classified under spondyloarthropathies.

The ILAR classification of JIA includes the following categories:

• Systemic-onset JIA
• Persistent or extended oligoarthritis
• Rheumatoid factor (RF)–positive polyarthritis
• RF-negative polyarthritis
• Psoriatic JIA
• Enthesitis-related arthritis
• Undifferentiated - The disease does not meet criteria for any of the other subgroups, or it meets more than 1 criterion (and therefore could be classified in a number of subgroups).

The EULAR proposed the term juvenile chronic arthritis (JCA) for the heterogeneous group of disorders that manifest as juvenile arthritis. The diagnosis requires that the arthritis begins before age 16 years and lasts for at least 3 months. The EULAR criteria for JCA recognize the following subtypes, based on characteristics at onset:

• Pauciarticular (1-4 joints)
• Polyarticular (≥5 joints)
• Presence of RF
• Systemic onset with characteristic features
• Positivity for rheumatoid factor
• Juvenile ankylosing spondylitis
• Juvenile psoriatic arthritis

This article will use the ILAR nomenclature unless differentiation is required between JIA and JRA or JCA.

Table. Comparison of Classification Criteria for Chronic Childhood Arthritis (Open Table in a new window)

The etiology and pathogenesis of JIA are not completely understood. Genetic susceptibility plays a major role, but there is significant overlap between loci associated with JIA and those associated with other autoimmune diseases.^[4]

JIA is a genetically complex disorder in which multiple genes are important for disease onset and manifestations. The IL2RA/CD25 gene has been implicated as a JIA susceptibility locus, as has the VTCN1 gene.^[5] Associations have been found between specific HLA alleles and clinical subtypes of JIA (eg, HLA-A(*)02:06 with susceptibility to JIA accompanied by uveitis, and HLA-DRB1(*)04:05 with polyarticular JIA, in a Japanese cohort).^[6]

Humoral and cell-mediated immunity are involved in the pathogenesis of JIA. 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, the 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 ribonucleic acid (mRNA) for vascular endothelial growth factor and angiopoietin 1, as well as for their receptors, suggesting that induction of angiogenesis by products of lymphocytic infiltration may be involved in persistence of disease.^[7]

Some pediatric rheumatologists view systemic-onset JIA as an autoinflammatory disorder, such as familial Mediterranean fever (FMF) or cryopyrin-associated periodic fever syndromes, rather than a subtype of JIA. This theory is supported by work demonstrating similar expression patterns of a phagocytic protein (S100A12) in systemic-onset JIA and FMF, as well as the same marked responsiveness to IL-1 receptor antagonists.^[8]

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 et al found an increased frequency of MEFV mutations in Turkish children who were diagnosed with systemic JIA^[9] ; this study has not been replicated in other populations.

United States statistics

Approximately 300,000 children in the United States are estimated to have some type of arthritis. The incidence rate estimates for JIA range from 4-14 cases per 100,000 children annually; for JRA, the prevalence has ranged from 1.6 to 86.1 cases per 100,000.^[10] These wide-ranging numbers are attributable to differing definitions and criteria for childhood arthritis; population differences, including environmental exposure and immunogenetic susceptibility; and difficulty in case ascertainment and lack of population based data.

International statistics

Worldwide, JIA appears to occur more frequently in certain populations (eg, indigenous peoples) from such disparate areas as British Columbia and Norway. A study in Sweden found the prevalence of JIA there to be similar to that in Minnesota, approximately 85 cases per 100,000 population, with an incidence of 11 cases per 100,000 population. A study from Germany found a prevalence rate of 20 cases per 100,000 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. The incidence of JIA in Japan has been reported to be low.

Disease-associated mortality for JIA is difficult to quantify, but it is estimated to be less than 1% in Europe and less than 0.5% in North America. Most deaths associated with JIA in Europe are related to amyloidosis, and most in the United States are related to infections.

The approximate frequencies of the various forms of JRA are as follows:

• Oligoarticular - 30%
• Polyarticular RF negative - 20%
• Polyarticular RF positive – 5%
• Systemic-onset – 5%
• Psoriatic - 5%
• Enthesitis Related – 25%
• Undifferentiated – 10%

Sexual differences in frequency

Girls with an oligoarticular onset outnumber boys by a ratio of 3:1. In children with uveitis, the ratio of girls to boys is 5-6.6:1, and in children with polyarticular onset, girls outnumber boys by 2.8:1. In striking contrast, systemic-onset occurs with equal frequency in boys and girls. Boys outnumber girls with enthesitis-related arthritis.^[11]

Age-related differences in frequency

Although JIA is defined as arthritis beginning before age 16 years, the age at onset is often much lower, with the highest frequency occurring in children aged 1-3 years.^[12] This age distribution is most evident in girls with oligoarticular JIA and psoriatic arthritis.

Polyarticular RF-negative JIA has a biphasic peak of onset; the first is at a young age (1-4 y), similar to oligoarticular JIA, and the second peak is at age 6-12 years. RF-positive disease is more common in adolescents. Systemic-onset JIA is not characterized by a peak age of onset; it is spread across the childhood years. The usual age of onset of enthesitis-related arthritis is 10-12 years.^[11]

Advances in treatment over the last 20 years—especially the introduction of early use of intra-articular steroids, methotrexate, and biologic medications—have dramatically improved the prognosis for children with arthritis. Almost all children with JIA lead productive lives. However, 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, symmetrical disease, the presence of RF, and prolonged active systemic disease have been associated with poor long-term outcomes. Compared with adults with RF-positive rheumatoid arthritis, however, children are at less risk for rheumatoid lung involvement and vasculitis.

Children with systemic-onset disease tend to either respond completely to medical therapy or develop a severe polyarticular course that tends to be refractory to medical treatment, with disease persisting into adulthood.

Most children with oligoarticular disease demonstrate eventual permanent remission, although a small number progress to persisting polyarticular disease.

Concern has been raised that the use of biologics may increase cancer risk among patients with JIA; however, lack of data on the baseline risk of cancer in this population has made it difficult to determine whether the concern is justified. A review of a large cohort of patients from the Swedish registry found an increased risk of cancer in patients who had not been on biologic therapies and had been diagnosed with JIA in the last 20 years. However, this risk was not found if the analysis was extended to patients diagnosed between 1969 and 1987.^[13]

The results of this study were not statistically significant. Nevertheless, they may have implications for interpretation of cancer signals in patients with JIA, particularly those who are on ongoing therapy with biologic agents, such as TNF-alpha inhibitors.

Educating the patient, family, and school personnel (eg, classroom teachers, physical education teachers, nurses) about JIA 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 JIA. Another important source of information is the American Juvenile Arthritis Organization, a council of the Arthritis Foundation.

For patient education information, see the Arthritis Center, as well as Juvenile Rheumatoid Arthritis and Juvenile Rheumatoid Arthritis Treatment.