Juvenile idiopathic arthritis (JIA) encompasses a complex group of disorders with arthritis as a common feature. This article provides the pediatrician with a review of the epidemiology, classification, clinical manifestations, and complications of JIA. It also provides an update on the current understanding of the cause of JIA and recent developments in management and a recent review of the long-term outcome in JIA.
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Juvenile idiopathic arthritis (JIA) is defined as arthritis ≥6 weeks duration in child ≤16 years old without other known cause.
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Juvenile idiopathic arthritis is a diagnosis of exclusion; it is important to consider the potential mimickers of JIA.
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Early referral to pediatric rheumatology should be considered.
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Use of nonsteroidal antinflammatory drugs is appropriate before review with a pediatric rheumatology specialist.
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Surveillance for and prevention of complications of JIA is critical (eg, uveitis and growth disturbance).
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Aim for early detection and treatment of flares of disease.
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In patients on immune-modulatory and biologic medication:
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Monitor for side effects
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Beware of infections
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Avoid live vaccines.
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Goals of therapy: achieve remission, minimize medication toxicity, maximize function, optimize growth and development and improve quality of life.
An increased understanding of the underlying pathogenesis of JIA, the development of targeted biologic therapies and rigorous clinical trials studying these new therapies as well as increasing international collaborative efforts have seen major advances in the management and outcome of children with JIA.
Epidemiology
JIA remains an uncommon, but by no means rare, condition affecting children worldwide. It is the most common rheumatic disease of childhood. Estimates of incidence and prevalence have been difficult to ascertain because of variations in diagnostic criteria, differences in data ascertainment or study design, low disease frequency, and small study numbers.
Epidemiologic studies report prevalence rates between 0.07 and 4.01 per 1000 children and annual incidence between 0.008 and 0.226 per 1000 children. The large difference in reported rates is likely because of varying study characteristics. The highest prevalence was reported in community-based studies, in which children were examined in classrooms or homes. On the other hand, clinic-based studies seem to report lower prevalence rates, perhaps reflecting that many clinicians fail to recognize JIA and that these children therefore do not come to the attention of clinicians in large study centers, hence the true prevalence is underestimated.
There are few data outlining the prevalence of JIA in populations other than those of European descent. In the most heavily populated areas of the world, epidemiologic data are scarce. Lower frequencies of JIA have been reported in children in Japan and Costa Rica (annual incidence 0.0083 and 0.068 per 10000, respectively). Many of these studies are limited by small sample size and selection bias. One retrospective study reported lower frequency of JIA in Hawaiians of Filipino, Japanese, and Samoan descent compared with White Hawaiians.
One questionnaire-based study addressed ethnicity in a large multiethnic single-center cohort. European descent appeared to be an important predisposing factor for oligoarticular JIA and psoriatic JIA. Black and native North American patients were less likely to have oligoarticular JIA and more likely to have rheumatoid factor (RF)-positive polyarthritis.
Cause and pathogenesis
The underlying cause and pathogenesis of JIA remain unclear. JIA is a heterogeneous disorder, and the subtypes have varying clinical and laboratory features that may reflect distinct immunopathogenic processes. The pathogenesis for each subtype is undoubtedly multifactorial and likely triggered by environmental stimuli in genetically susceptible individuals.
Oligoarticular and RF-positive polyarticular JIA seem to be autoimmune diseases of the adaptive immune system. Positive antinuclear antibody (ANA) and RF are common and these subtypes are consistently associated with HLA genes.
Identified genetic susceptibility genes include genes in the HLA group and also non-HLA-related genes such as genes related to cytokines and other immune functions. The association of HLA class I and II alleles with JIA is well established and suggests the likely involvement of T cells and antigen presentation in the pathogenesis of JIA.
In the genetically susceptible individual, environmental triggers are considered important in the pathogenetic process of JIA. This trigger may cause an uncontrolled innate and adaptive immune response toward self-antigen, resulting in inflammation and disease. Autoantigens from cartilage and other joint tissues are believed to play important roles and to contribute to the activation of CD4+ T cells, leading to proliferation and the production of proinflammatory cytokines.
By contrast, there is increasing evidence to suggest that systemic JIA (sJIA) may be an autoinflammatory disease, primarily involving the innate immune system. sJIA does not have HLA gene associations and is not associated with autoantibodies. sJIA is characterized by uncontrolled activation of phagocytes (including macrophages, monocytes, and neutrophils) caused by unknown triggers and leads to increase of phagocyte secreted inflammatory cytokines such as interleukin 1 (IL-1), IL-6, and IL-18.
Distinct pathogenic processes seem to be involved within the subtypes of JIA, and further definition of these immunogenetic and inflammatory pathways may help explain the considerable clinical heterogeneity seen in patients with JIA and importantly help direct therapy.
Cause and pathogenesis
The underlying cause and pathogenesis of JIA remain unclear. JIA is a heterogeneous disorder, and the subtypes have varying clinical and laboratory features that may reflect distinct immunopathogenic processes. The pathogenesis for each subtype is undoubtedly multifactorial and likely triggered by environmental stimuli in genetically susceptible individuals.
Oligoarticular and RF-positive polyarticular JIA seem to be autoimmune diseases of the adaptive immune system. Positive antinuclear antibody (ANA) and RF are common and these subtypes are consistently associated with HLA genes.
Identified genetic susceptibility genes include genes in the HLA group and also non-HLA-related genes such as genes related to cytokines and other immune functions. The association of HLA class I and II alleles with JIA is well established and suggests the likely involvement of T cells and antigen presentation in the pathogenesis of JIA.
In the genetically susceptible individual, environmental triggers are considered important in the pathogenetic process of JIA. This trigger may cause an uncontrolled innate and adaptive immune response toward self-antigen, resulting in inflammation and disease. Autoantigens from cartilage and other joint tissues are believed to play important roles and to contribute to the activation of CD4+ T cells, leading to proliferation and the production of proinflammatory cytokines.
By contrast, there is increasing evidence to suggest that systemic JIA (sJIA) may be an autoinflammatory disease, primarily involving the innate immune system. sJIA does not have HLA gene associations and is not associated with autoantibodies. sJIA is characterized by uncontrolled activation of phagocytes (including macrophages, monocytes, and neutrophils) caused by unknown triggers and leads to increase of phagocyte secreted inflammatory cytokines such as interleukin 1 (IL-1), IL-6, and IL-18.
Distinct pathogenic processes seem to be involved within the subtypes of JIA, and further definition of these immunogenetic and inflammatory pathways may help explain the considerable clinical heterogeneity seen in patients with JIA and importantly help direct therapy.
Diagnosis and classification
The diagnosis of JIA requires the persistence of arthritis for more than 6 weeks in a child less than 16 years of age in whom there is no other identified cause for arthritis. The differential diagnosis for inflammatory arthritis is broad and should be considered in all patients presenting with arthritis. This subject is discussed by Roberta Berrard in detail elsewhere in this issue.
JIA is a complex, heterogeneous group of disorders without clearly defined cause; classifying the various subtypes in to distinct homogeneous groups has been problematic. The International League of Associations for Rheumatology (ILAR) criteria for classification of JIA were first proposed in 1993 and are now the commonly agreed on terminology. The aim of this classification system is to attempt to create homogeneous subtypes of JIA. The ILAR classification divides JIA into 7 subtypes: oligoarticular JIA, seropositive polyarticular JIA, seronegative polyarticular JIA, systemic-onset JIA (sJIA), enthesitis-related arthritis (ERA), psoriatic JIA (PsJIA), and undifferentiated JIA ( Table 1 ).
| ILAR JIA Subtype | Age, Sex, and % Total Patients with JIA | Typical Joint Involvement | Occurrence of Uveitis | Other Features |
|---|---|---|---|---|
| F>M Early childhood 40%–50% | ≤4 joints Large joints: knees, ankles, wrist Persistent disease: never >4 joints affected Extended disease: involves >4 joints after first 6 mo of disease | Common (30%) especially if ANA-positive Usually asymptomatic | ANA 60%–80% positive |
| Polyarticular (RF-negative) | F>M 2 peaks: 2–4 y and 6–12 y 20%–25% | ≥5 joints Symmetric | Common (15%) | ANA 25% positive ± C spine and TMJ |
| Polyarticular (RF-positive) | F>M Late childhood/early adolescence 5% | Symmetric small and large joints Erosive joint disease | Rare (<1%) | ANA 75% positive Rheumatoid nodules |
| Systemic | M = F Throughout childhood 5%–10% | Poly or oligoarticular | Rare (<1%) | Daily (quotidian) fever for ≥2 weeks Evanescent rash Lymphadenopathy Hepatosplenomegaly Serositis |
| Enthesitis-related arthritis | M>F Late childhood/ adolescence 5%–10% | Weight-bearing joint especially hip and intertarsal joints History of inflammatory back pain or sacroiliac joint tenderness | Symptomatic acute uveitis (∼7%) | Enthesitis HLA-B27-positive Axial involvement (including sacroiliitis) Family history of HLA-B27-associated disease |
| Psoriatic arthritis | F>M 2 peaks: 2–4 y and 9–11 y 5%–10% | Asymmetric or symmetric small or large joints | Common (10%) | Nail pits, onycholysis Dactylitis Psoriasis Family history psoriasis |
| Undifferentiated | 10% | Does not fulfill criteria for any above category or fulfills criteria for >1 category |
There continues to be much debate in the literature about the classification of JIA. The current classification criteria have allowed for international consistency; however, some problems continue to arise in assigning patients to particular subtypes, resulting in a substantial proportion of patients designated as undifferentiated. Advances in the understanding of the immunogenetic pathogenesis of JIA may help refine this classification further.
Clinical manifestations of JIA
Arthritis is clinically characterized by joint effusion, joint line tenderness and warmth, restricted range of movement, and limitation of movement secondary to pain.
The common feature of all the subtypes of JIA is arthritis. Joint inflammation results in pain, loss of function, and morning stiffness. The distribution of joint involvement varies between subtypes of JIA. Systemic symptoms typically occur in systemic and polyarticular subtypes and can include fatigue, weight loss, anemia, anorexia, or fever. Growth abnormalities can complicate JIA and result in short stature or localized growth disturbance such as bony overgrowth, prematurely fused epiphyses, and limb length discrepancies. Table 1 describes the common features of the subtypes of JIA.
Oligoarticular JIA
Oligoarticular JIA is defined as JIA involving 4 or fewer joints in the first 6 months of disease. This subgroup is further divided into persistent and extended disease based on the number of additional joints involved beyond the first 6 months. Children with persistent oligoarthritis often enter remission, although they remain at risk for disease flares. Approximately 50% of patients with oligoarthritis progress to develop extended disease and within 2 years of disease onset have polyarthritis. This group have a more guarded prognosis, because fewer children with extended oligoarthritis enter remission.
Oligoarticular JIA predominantly affects the large joints, most commonly the knees, ankles, wrists, and elbows ( Fig. 1 ). Uveitis may occur in up to 30% of children with oligoarthritis. Other extra-articular symptoms rarely occur.
Polyarticular JIA
Polyarticular JIA is defined as JIA involving 5 or more joints and is further divided into RF-positive and RF-negative polyarthritis, based on the presence or absence of RF.
RF-negative patients have a variable disease onset and course, which contribute to the heterogeneity in this JIA subgroup. The onset of joint involvement can be acute or insidious, and large or small joints may be involved. Other than the number of inflamed joints, patients with RF-negative ANA-positive polyarticular JIA are often difficult to distinguish clinically from patients with ANA-positive extended oligoarticular JIA. According to current ILAR criteria, these 2 groups of patients are classified separately. However, the joint count and the timing of joint involvement may not be the most appropriate criteria to aid in defining homogeneous groups of JIA, and future refinement of the classification criteria may be needed.
RF-positive patients share many clinical and immunogenetic characteristics with adult patients with rheumatoid arthritis. The disease onset occurs typically in adolescence and the arthritis is often erosive and symmetric, involving the wrists and small joints of the hands and feet ( Fig. 2 ). Systemic features such as fever and constitutional upset may occur at onset, and patients may have rheumatoid nodules.
Polyarticular JIA is a chronic disease, with many patients entering adulthood with active disease or functional disability.
s JIA
sJIA is characterized by arthritis and systemic features such as fever and rash. The arthritis is frequently polyarticular but can be limited to few joints, and large or small joints can be involved. The arthritis may be preceded by the systemic symptoms by months. The fever is typically high, spiking daily or twice daily, with rapid return to normal or subnormal temperatures in between ( Fig. 3 ). The fever is often accompanied by a well-circumscribed evanescent salmon-pink macular rash commonly present on the trunk and proximal extremities (see Fig. 3 ). Lymphadenopathy and hepatosplenomegaly are common features of sJIA. Cardiac disease is well described, and pericardial effusions occur in approximately 10% of children with sJIA. Myocarditis is less common.
Laboratory findings in sJIA reflect systemic inflammation and include leukocytosis, thrombocytosis, anemia, increased transaminase levels, and increased inflammatory markers. ANA is positive in only 5% to 10%, and RF is rarely seen.
In the absence of arthritis, the clinician should remain cognizant of the broad differential diagnosis of sJIA, including infection, malignancy, inflammatory bowel disease, acute rheumatic fever, and other rheumatic diseases such as vasculitis and systemic lupus erythematosus. Leukemia frequently presents with musculoskeletal symptoms at diagnosis and may mimic JIA. Information that may differentiate leukemia from sJIA includes low white cell count, low or normal platelet count, and the presence of nighttime pain. In contrast, positive ANA, high lactate dehydrogenase level, rash, and fever may not be helpful in discriminating between leukemia and JIA. See article elsewhere in this issue for a review of the differential diagnosis.
Heterogeneity also is evident amongst patients with sJIA as seen by the different disease course and severity. Approximately 40% of patients have a monophasic illness, whereas more than half have a chronically persistent disease course. A small group of patients have a relapsing polycyclic course. In general, systemic features subside over the initial months to years; however, they may recur with disease exacerbations. In many patients, the progressive and destructive arthritis is the most significant complication, leading to significant morbidity and functional impairment. Early predictors of destructive arthritis include polyarthritis, hip involvement, thrombocytosis, or presence of active systemic disease (fever or need for systemic corticosteroids) at 6 months after diagnosis.
Macrophage activation syndrome (MAS, see article elsewhere in this issue) is a potentially life-threatening complication of sJIA characterized by activation of T cells and macrophages, leading to an overwhelming inflammatory response. It is thought by some to be integral to the pathogenesis of sJIA. MAS can be difficult to distinguish from sJIA because it shares some features. MAS is characterized by sustained fever (compared with the quotidian fever of sJIA), hepatosplenomegaly, anemia, liver function abnormalities, rash, coagulopathy, and central nervous system dysfunction. Several laboratory features suggestive of MAS include decreasing white cell count and platelets, decreasing erythrocyte sedimentation rate, increased ferritin level, hypertriglyceridemia, hypofibrinogenemia, and evidence of hemophagocytosis on bone marrow aspirate. Preliminary guidelines for the diagnosis of MAS in association with sJIA have been suggested but are yet to be validated. Early diagnosis and aggressive treatment of MAS are necessary to avoid significant morbidity and mortality. High-dose corticosteroids and supportive care are the first-line therapies; however, agents such as cyclosporin, etoposide, and intravenous immunoglobulin have also been used.
Enthesitis-related JIA
As defined by the ILAR classification, ERA is characterized by the presence of arthritis or enthesitis. The arthritis in ERA typically involves the lower limb, especially the hip and intertarsal joints. The sacroiliac joint is frequently involved, although often not until later in the clinical course. ERA represents the undifferentiated forms of spondyloarthritis in children.
Enthesitis is the term used to describe inflammation at the insertion of tendons, ligaments, or joint capsules to the bone. It is characterized by tenderness, warmth, and swelling. The typical locations for enthesitis in ERA are in the lower limbs, in particular at the iliac crest, posterior and anterior superior iliac spine, femoral greater trochanter, ischial tuberosity, patella, tibial tuberosity, Achilles, and plantar fascia insertions. ERA should be considered in patients presenting with significant heel or foot pain. Other features of this category are outlined in Table 1 . Another unique feature of this subtype of JIA is the involvement of the axial skeleton, especially in the sacroiliac joints, with some children developing ankylosing spondylitis within 10 to 15 years of disease onset.
P s JIA
PsJIA is characterized by the presence of arthritis and psoriasis. Other common features ( Fig. 4 ) include dactylitis (defined as sausagelike swelling of the involved digits), nail changes (pitting or onycholysis), or a family history of relatives with psoriasis. PsJIA further clusters into 1 of 2 subgroups. The first group has similar characteristics to oligoarticular JIA, occurring typically in young ANA-positive girls with a high risk of asymptomatic anterior uveitis. However, unlike oligoarticular JIA, dactylitis and involvement of the small joints may occur. The second group, resembling ERA, occurs in older children and adolescents, has a male predominance, and has an increased risk of spondyloarthritis.
Psoriasis and arthritis may not occur concurrently, and arthritis may precede the development of psoriasis by many years. The psoriasis may be subtle and mandates a careful examination in children, in whom it may involve the extensor surfaces in the limbs, scalp, posterior auricular, axilla, umbilicus, or gluteal fold.
Complications of JIA
Uveitis
One of the most significant complications of JIA is anterior uveitis. This is a chronic nongranulomatous inflammation of the anterior chamber of the eye, affecting the iris and ciliary body. It is usually insidious in onset and asymptomatic, mandating frequent ophthalmologic surveillance. However, patients with ERA are more likely to present with acute symptomatic uveitis. The risk of uveitis is based on the JIA subtype, age at disease onset, and ANA status. The highest risk group of patients is oligoarticular JIA, especially if the patient is female, ANA-positive, and less than 4 years of age. Table 2 summarizes the recommended frequency of ophthalmologic screening in children with JIA. Uveitis disease activity does not necessarily correlate with the course of arthritis.
| ILAR JIA Subtype | ANA | Age at Onset of Disease | Duration of Disease | |
|---|---|---|---|---|
| ≤4 y | >4 y | |||
| Oligoarticular JIA, Polyarticular JIA, and ERA | Positive | ≤6 y | 3 monthly | 6 monthly |
| >6 y | 6 monthly | 12 monthly | ||
| Negative | ≤6 y | 6 monthly | 12 monthly | |
| >6 y | 12 monthly | 12 monthly | ||
| sJIA | Not applicable | Not applicable | 12 monthly | 12 monthly |
The management of uveitis should be supervised by an eye care expert (ophthalmologist or optometrist) in conjunction with a pediatrician or pediatric rheumatologist. Uveitis is usually managed with topical corticosteroids and a mydriatic agent. Oral, periocular, or intravenous corticosteroids may be required to achieve relief of inflammation, and children with disease that is difficult to control may require additional immunomodulatory medication such methotrexate or biologic agents. Complications of uveitis include band keratopathy and cataracts (occurring in 42%–58% patients), glaucoma (19%–22% patients), and blindness.
Abnormalities of Growth
JIA may be complicated by linear or localized growth disturbance. Linear growth abnormalities are particularly observed in patients with chronic active disease and are therefore most common in children with polyarticular or sJIA.
The mechanisms of poor linear growth in children with JIA are likely multifactorial. Chronic inflammation and high levels of circulating proinflammatory cytokines may play a role in growth suppression through effects on the growth plate and impairment on insulinlike growth factor 1 (IGF-1). Overexpression of IL-6, in particular, may play an important role in abnormal skeletal development, as shown in the murine model via several possible mechanisms such as a reduction of circulating IGF-1 levels, growth plate and ossification center abnormalities, and induction of osteoclast activity. Severe growth restriction is now uncommon, possibly as a result of more aggressive immunomodulatory therapy with disease-modifying antirheumatic drugs (DMARDs) and biologic agents ( Tables 3 and 4 ). When severe growth retardation does occur, growth hormone may be considered.
| DMARD | Action/Mechanism | Dosing | Common Side Effects | Precautions | Monitoring | Other Comments |
|---|---|---|---|---|---|---|
| Methotrexate | Inhibits purine synthesis. Multiple possible sites of action, including inhibition of dihydrofolate reductase and AICAR transformylase, adenosine deaminase | Weekly PO or SC | GI upset, mouth ulceration Transient liver enzyme abnormalities, hematologic abnormalities (rare) | Avoid sulfamethoxazole and trimethoprim (bone marrow suppression) Avoid pregnancy (fetal death and congenital abnormalities) Avoid alcohol consumption | CBC and LFTs 4-weekly to 12-weekly | Folate supplementation important to alleviate GI side effects and mouth ulcers Avoid live vaccines |
| Sulfasalazine | Not clearly understood, possibly multiple immunomodulatory and antiinflammatory effects | Twice a day PO | Rash, GI upset, myelosuppression, liver function abnormalities, hypersensitivities Hypogammaglobulinemia | Safe in pregnancy | CBC and LFTs 4-weekly to 12-weekly | Beware possible additive hepatotoxicity in conjunction with MTX |
| Leflunomide | Inhibits pyrimidine synthesis through inhibition of dihydro-orotate dehydrogenase | Daily PO | GI upset, rash Hypertension Liver enzyme abnormalities | Teratogenic | CBC and LFTs 4-weekly to 12-weekly | Cholestyramine can be used to enhance elimination |
| Biologic Class | Example of Drug | Administration | Common Side Effects | Precautions | Monitoring |
|---|---|---|---|---|---|
| TNF inhibitors | Etanercept Adalimumab Infliximab | Etanercept SC every week, adalimumab SC every 2 wk, infliximab IV every 2 wk to 8 wk | Hypersensitivity infusion reactions | For all biologic medication: Avoid in patients with active infection and hold biologic in event of active infection requiring treatment Avoid in presence of TB infection | For all biologic medication: Ensure negative TB test before commencement and annually Routine laboratory investigations including CBC, LFT, renal function |
| IL inhibition | Anakinra (IL-1) Canakinumab (IL-1β) Tocilizumab (IL-6) Rilonacept (IL-1) | Anakinra daily Canakinumab every 4 wk Rilonacept every week Tocilizumab every 2 wk | Injection site or infusion reactions | Avoid live vaccines | For rituximab consider measurement of B-cell subsets |
| B-cell depletion | Rituximab | Every week × 2 doses | Infusion reactions | Consider concomitant use of methotrexate to prevent development of immunogenicity | |
| T-cell costimulatory modulator | Abatacept | Weeks 0, 2, 4 then every 4 wk | Infusion reaction uncommon |
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