Epidemiology

The worldwide incidence of JIA ranges from 0.8 to 22.6/100,000 children per year, with prevalence ranges from 7 to 401/ 100,000. These wide-ranging numbers are attributable to population differences, particularly environmental exposure and immunogenetic susceptibility, along with difficulty in case ascertainment and lack of population-based data. It is estimated that 300,000 children in the USA have arthritis, including 100,000 with a form of JIA. Pauciarticular JIA (oligoarthritis) is the most common subtype (50-60%), followed by polyarticular (30-35%) and systemic-onset (10-20%). There is no sex predominance in systemic-onset JIA (SoJIA), but more girls than boys are affected in both pauciarticular (3 : 1) and polyarticular (5 : 1) JIA. The peak age at onset is between 2 and 4 yr for pauciarticular disease. Age of onset has a bimodal distribution in polyarthritis, with peaks at 2-4 yr and 10-14 yr. SoJIA occurs throughout childhood without a peak.

Etiology

The etiology and pathogenesis of JIA is not completely understood. At least 2 components are considered necessary: immunogenetic susceptibility and an external trigger. JIA is a complex genetic trait in which multiple genes may affect disease susceptibility. Various major histocompatibility complex regions (HLA) class I and class II alleles have been associated with different JIA subtypes. Several non-HLA candidate loci are also associated with JIA, including polymorphisms in the genes encoding tumor necrosis factor (TNF)-α, macrophage inhibitory factor (MIF), interleukin-6 (IL-6), and IL-1α. Possible nongenetic triggers include bacterial and viral infections (parvovirus B19, rubella, Epstein-Barr virus), enhanced immune responses to bacterial or mycobacterial heat shock proteins, abnormal reproductive hormone levels, and joint trauma.

Pathogenesis

JIA is an autoimmune disease associated with alterations in both humoral and cell-mediated immunity. T lymphocytes have a central role, releasing proinflammatory cytokines (e.g., TNF-α, IL-6, and IL-1). The cytokine profile favors type 1 helper T-lymphocyte response. Studies of T-cell receptor expression confirm recruitment of T lymphocytes specific for synovial non-self antigens. Complement consumption, immune complex formation, and B-cell activation also promote inflammation. Inheritance of specific cytokine alleles may predispose to upregulation of inflammatory networks, resulting in systemic-onset disease or more severe articular disease.

Systemic-onset JIA may be more accurately classified as an autoinflammatory disorder, more like familial Mediterranean fever (FMF), than the other subtypes of JIA. This theory is supported by work demonstrating similar expression patterns of a phagocytic protein (S100A12) in SoJIA and FMF, as well as the same marked responsiveness to IL-1 receptor antagonists.

All these immunologic abnormalities cause inflammatory synovitis, characterized pathologically by villous hypertrophy and hyperplasia with hyperemia and edema of the synovial tissue. Vascular endothelial hyperplasia is prominent and is characterized by infiltration of mononuclear and plasma cells with a predominance of T lymphocytes (Fig. 149-1). Advanced and uncontrolled disease leads to pannus formation and progressive erosion of articular cartilage and contiguous bone (Figs. 149-2 and 149-3).

Figure 149-1 Synovial biopsy specimen from a 10 yr old child with oligoarticular juvenile idiopathic arthritis. There is a dense infiltration of lymphocytes and plasma cells in the synovium.

Figure 149-2 Arthroscopy in the shoulder of a child with juvenile idiopathic arthritis showing pannus formation and cartilage erosions.

(Courtesy of Dr. Alison Toth.)

Figure 149-3 MRI with gadolinium of a 10 yr old child with juvenile rheumatoid arthritis (same patient as in Fig. 149-1). The dense white signal in the synovium near the distal femur, proximal tibia, and patella reflects inflammation. MRI of the knee is useful to exclude ligamentous injury, chondromalacia of the patella, and tumor.

Clinical Manifestations

Arthritis must be present for a diagnosis of any subtype of JIA to be made. Arthritis is defined by intra-articular swelling or the presence of 2 or more of the following signs: limitation in range of motion, tenderness or pain on motion, and increased heat or erythema. Initial symptoms may be subtle or acute and often include morning stiffness with a limp or gelling after inactivity. Easy fatigability and poor sleep quality may be associated. Involved joints are often swollen, warm to touch, and painful on movement or palpation with reduced range of motion but usually are not erythematous. Arthritis in large joints, especially knees, initially accelerates linear growth, causing the affected limb to be longer and resulting in a discrepancy in limb lengths. Continued inflammation stimulates rapid and premature closure of the growth plate, resulting in shortened bones.

Oligoarthritis is defined as involving ≤4 joints within the first 6 mo of disease onset, predominantly affecting the large joints of the lower extremities, such as the knees and ankles (Fig. 149-4). Often only a single joint is involved. Isolated involvement of upper extremity large joints is less common. Those in whom disease never develops in more than 4 joints are regarded as having persistent oligoarticular JIA, whereas evolution of disease in more than 4 joints over time changes the classification to extended oligoarticular JIA. The latter often portends a worse prognosis. Involvement of the hip is almost never a presenting sign and suggests a spondyloarthropathy (Chapter 150) or nonrheumatologic cause. The presence of a positive antinuclear antibody (ANA) test result confers increased risk for asymptomatic anterior uveitis, requiring periodic slit-lamp examination (Table 149-5).

Figure 149-4 Oligoarticular juvenile idiopathic arthritis with swelling and flexion contracture of the right knee.

Polyarthritis (polyarticular disease) is characterized by inflammation of ≥5 joints in both upper and lower extremities (Figs. 149-5 and 149-6). When rheumatoid factor (RF) is present, polyarticular disease resembles the characteristic symmetric presentation of adult rheumatoid arthritis. Rheumatoid nodules on the extensor surfaces of the elbows and over the Achilles tendons, although unusual, are associated with a more severe course and almost exclusively occur in RF-positive individuals. Micrognathia reflects chronic temporomandibular joint (TMJ) disease (Fig. 149-7). Cervical spine involvement (Fig. 149-8), manifesting as decreased neck extension, occurs with a risk of atlantoaxial subluxation and neurologic sequelae. Hip disease may be subtle, with findings of decreased or painful range of motion on exam (Fig. 149-9).

Figure 149-5 Hands and wrists of a girl with polyarticular juvenile idiopathic arthritis that is rheumatoid factor–negative. Notice the symmetric involvement of the wrists, metacarpophalangeal joints, and proximal and distal interphalangeal joints. In this photograph, there is cream with occlusive dressing on the patient’s right hand in preparation for placement of an intravenous line for administration of a biologic agent.

Figure 149-6 Progression of joint destruction in a girl with polyarticular juvenile idiopathic arthritis that is rheumatoid factor–positive, despite doses of corticosteroids sufficient to suppress symptoms in the interval between the radiographs shown in A and B. A, Radiograph of the hand at onset. B, Radiograph taken 4 yr later, showing a loss of articular cartilage and destructive changes in the distal and proximal interphalangeal and metacarpophalangeal joints as well as destruction and fusion of wrist bones.

Figure 149-7 CT scan of the temporomandibular joint of a patient with juvenile idiopathic arthritis exhibiting destruction on the right.

Figure 149-8 Radiograph of the cervical spine of a patient with active juvenile idiopathic arthritis, showing fusion of the neural arch between joints C2 and C3, narrowing and erosion of the remaining neural arch joints, obliteration of the apophyseal space, and loss of the normal lordosis.

Figure 149-9 Severe hip disease in a 13 yr old boy with active, systemic-onset juvenile idiopathic arthritis. Radiograph shows destruction of the femoral head and acetabula, joint space narrowing, and subluxation of left hip. The patient had received corticosteroids systemically for 9 yr.

Systemic-onset disease (SoJIA) is characterized by arthritis, fever, and prominent visceral involvement, including hepatosplenomegaly, lymphadenopathy, and serositis (pericarditis). The characteristic fever, defined as spiking temperatures to ≥39°C, occurs on a daily or twice-daily basis for at least 2 wk, with a rapid return to normal or subnormal temperatures (Fig. 149-10). The fever is often present in the evening and is frequently accompanied by a characteristic faint, erythematous, macular rash. The evanescent salmon-colored lesions classic for systemic-onset disease are linear or circular and are most commonly distributed over the trunk and proximal extremities (Fig. 149-11). The classic rash is nonpruritic and migratory with lesions lasting <1 hr. Fever, rash, hepatosplenomegaly, and lymphadenopathy are present in >70% of affected children. Koebner phenomenon, a cutaneous hypersensitivity to superficial trauma, is often present. Heat, such as from a warm bath, also evokes rash. Without arthritis, the differential diagnosis includes the episodic fever syndromes and a fever of unknown origin. Some children initially present with only systemic features, but definitive diagnosis requires presence of arthritis. Arthritis may affect any number of joints, but the course is classically polyarticular, may be very destructive, and includes hip, cervical spine, and TMJ involvement.

Figure 149-10 High-spiking intermittent fever in a 3 yr old patient with systemic juvenile idiopathic arthritis.

(From Ravelli A, Martini A: Juvenile idiopathic arthritis, Lancet 369:767–778, 2007.)

Figure 149-11 The rash of systemic-onset juvenile idiopathic arthritis. The rash is salmon-colored, macular, and nonpruritic. Individual lesions are transient and occur in crops over the trunk and extremities.

(Reprinted from the American College of Rheumatology: Clinical slide collection on the rheumatic diseases, Atlanta, copyright 1991, 1995, 1997, ACR. Used by permission of the American College of Rheumatology.)

Macrophage activation syndrome (MAS) is a rare but potentially fatal complication of SoJIA that can occur at anytime during the disease course. It is also referred to as secondary hemophagocytic syndrome or hemophagocytic lymphohistiocytosis (HLH) (Chapter 501). MAS classically manifests as acute onset of profound anemia associated with thrombocytopenia or leukopenia with high, spiking fevers, lymphadenopathy, and hepatosplenomegaly. Patients may have purpura and mucosal bleeding, as well as elevated fibrin split product values and prolonged prothrombin and partial prothromboplastin times. The erythrocyte sedimentation rate (ESR) falls because of hypofibrinogenemia and hepatic dysfunction, a feature useful in distinguishing MAS from a flare of systemic disease. The diagnosis is suggested by clinical criteria and is confirmed by bone marrow biopsy demonstrating hemophagocytosis (Table 149-6). Emergency treatment with high-dose intravenous methylprednisolone, cyclosporine, or anakinra may be effective. Severe cases may require therapy similar to that for primary HLH (Chapter 501).

Bone mineral metabolism and skeletal maturation are adversely affected in children with JIA, regardless of subtype. Children with JIA have decreased bone mass (osteopenia), which appears to be associated with increased disease activity. Increased levels of cytokines such as TNF-α and IL-6, both key regulators in bone metabolism, have deleterious effects on bone within the joint as well as systemically in the axial and appendicular bones. Osteoblast and osteoclast development and function have a central role in these negative bone changes. Abnormalities of skeletal maturation become most prominent during the pubertal growth spurt.

Diagnosis

JIA is a clinical diagnosis of exclusion with many mimics and without diagnostic laboratory tests. The meticulous clinical exclusion of other diseases is therefore essential. See Tables 149-1 to 149-4 for classification criteria. Laboratory studies, including tests for ANA and RF, are only supportive and their results may be normal in patients with JIA.

Differential Diagnosis

The differential diagnosis for arthritis is broad and a careful, thorough investigation for other underlying etiology is imperative. Findings of the history, physical exam, laboratory tests, and radiography help exclude other possible causes. Arthritis can be a presenting manifestation for any of the multisystem rheumatic diseases of childhood, including systemic lupus erythematosus (Chapter 152), juvenile dermatomyositis (Chapter 153), sarcoidosis (Chapter 159), and the vasculitic syndromes (Chapter 161) (Table 149-7). In scleroderma (Chapter 154), limited range of motion due to sclerotic skin overlying a joint may be confused with sequelae from chronic inflammatory arthritis. Acute rheumatic fever is characterized by exquisite joint pain and tenderness, a remittent fever, and a migratory polyarthritis. Autoimmune hepatitis can also be associated with an acute arthritis.

Many infections are associated with arthritis, and a recent history of infectious symptoms may help make a distinction. Viruses, including parvovirus B19, rubella, Epstein-Barr virus, hepatitis B virus, and HIV, can induce a transient arthritis. Arthritis may follow enteric infections (Chapter 151). Lyme disease (Chapter 214) should be considered in children with oligoarthritis living in or visiting endemic areas. Although a history of tick exposure, preceding flu-like illness, and subsequent rash should be sought, they are not always present. Monoarticular arthritis unresponsive to anti-inflammatory treatment may be the result of chronic mycobacterial or other infection such as Kingella kingae, and the diagnosis is established by synovial fluid analysis or biopsy. Acute onset of fever and a painful, erythematous, hot joint suggests septic arthritis. Isolated hip pain with limited motion raises the possibility of suppurative arthritis (Chapter 677), osteomyelitis, toxic synovitis, Legg-Calvé-Perthes disease, slipped capital femoral epiphysis, and chondrolysis of the hip (Chapter 670).

Tenderness over insertion of ligaments and tendons and lower extremity arthritis, especially in a boy, raises the possibility of a spondyloarthropathy (Chapter 150). Psoriatic arthritis can manifest as limited joint involvement in an unusual distribution (e.g., small joints of the hand and ankle) years prior to onset of cutaneous disease. Inflammatory bowel disease may manifest as oligoarthritis, usually affecting joints in the lower extremities, as well as gastrointestinal symptoms, elevations in ESR, and microcytic anemia.

Many conditions present solely with arthralgias (i.e., joint pain). Hypermobility may cause joint pain, especially in the lower extremities. Growing pains should be suspected in a child between the ages of 4 to 12 yr complaining of leg pain in the evenings with normal investigative studies and no morning symptoms. Nocturnal pain also alerts to the possibility of a malignancy. An adolescent with missed school days may suggest a diagnosis of fibromyalgia (Chapter 162).

Children with leukemia or neuroblastoma may have joint or bone pain resulting from malignant infiltration of the bone, synovium, or, more often, the bone marrow, sometimes months before demonstrating lymphoblasts on peripheral blood smear. Physical examination may reveal no tenderness or a deeper pain to palpation of the bone or pain out of proportion to exam findings. Malignant pain often awakens the child from sleep and may cause cytopenias. Because platelets are an acute-phase reactant, a high ESR with leukopenia and a low normal platelet count may also be a clue to underlying leukemia. In addition, the characteristic quotidian fever of JIA is absent in malignancy. Bone marrow examination is necessary for diagnosis. Some diseases, such as cystic fibrosis, diabetes mellitus, and the glycogen storage diseases, have associated arthropathies (Chapter 163). Swelling that extends beyond the joint can be a sign of lymphedema or Henoch-Schönlein purpura. A peripheral arthritis indistinguishable from JIA occurs in the humoral immunodeficiencies, such as common variable immunodeficiency and X-linked agammaglobulinemia. Skeletal dysplasias associated with a degenerative arthropathy are diagnosed from their characteristic radiologic abnormalities.

Laboratory Findings

Hematologic abnormalities often reflect the degree of systemic or articular inflammation, with elevated white blood cell and platelet counts and a microcytic anemia. Inflammation may also cause elevations in ESR and C-reactive protein (CRP), though it is not unusual for both to be normal in children with JIA.

Elevated ANA titers are present in 40-85% of children with oligoarticular or polyarticular JIA but are rare with SoJIA. ANA seropositivity is associated with increased risk of chronic uveitis in JIA. Approximately 5-10% of patients with polyarticular JIA are seropositive for RF. Anti–cyclic citrullinated peptide (CCP) antibody, like RF, is a marker of more aggressive disease. Both ANA and RF seropositivity can occur in association with transient events, such as viral infection.

Children with SoJIA usually have striking elevations in inflammatory markers and white blood cell and platelet counts. Hemoglobin levels are low, typically in the range of 7 to 10 g/dL, with indices consistent with anemia of chronic disease. The ESR is usually high, except in MAS. Although immunoglobulin levels tend to be high, ANA and RF are uncommon. Ferritin values are typically elevated and can be markedly increased in MAS (>10,000 ng/mL). In the setting of MAS, all cell lines have the potential to decline precipitously owing to the consumptive process. A low white blood cell count and/or platelet count in a child with active SoJIA should raise concerns for MAS.

Early radiographic changes of arthritis include soft tissue swelling, periarticular osteoporosis, and periosteal new-bone apposition around affected joints (Fig. 149-12). Continued active disease may lead to subchondral erosions and loss of cartilage, with varying degrees of bony destruction and, potentially, fusion. Characteristic radiographic changes in cervical spine, most frequently in the neural arch joints at C2-C3 (see Fig. 149-8) may progress to atlantoaxial subluxation. MRI is more sensitive than radiography to early changes (Fig. 149-13).

Figure 149-12 Early (6-mo duration) radiographic changes of juvenile idiopathic arthritis: Soft tissue swelling and periosteal new bone formation appear adjacent to the 2nd and 4th proximal interphalangeal joints.

Figure 149-13 MRI of the wrist in a child with wrist arthritis. Image on the left shows multiple erosions of carpal bones. Image on the right, obtained after administration of gadolinium contrast agent, reveals uptake consistent with active synovitis.

Treatment

The goals of treatment are to achieve disease remission, prevent or halt joint damage, and foster normal growth and development. All children with JIA need individualized treatment plans, and management is tailored according to disease subtype and severity, presence of poor prognostic indicators, and response to medications. Disease management also requires monitoring for potential medication toxicities. Please see Chapter 148 for a detailed discussion of the medications used in the treatment of rheumatic diseases.

Children with oligoarthritis often show at least partial response to nonsteroidal anti-inflammatory drugs (NSAIDs), with improvement in inflammation and pain (Table 149-8). Those who have no response after 4-6 wk of treatment with NSAIDS or who have functional limitations, such as joint contracture or leg length discrepancy, benefit from injection of intra-articular corticosteroids. Triamcinolone hexacetonide is a long-lasting preparation that provides a prolonged response. A minority of patients with oligoarthritis show no response to NSAIDs and injections, so require treatment with disease-modifying antirheumatic drugs (DMARDs), like patients with polyarticular disease.

NSAIDs alone rarely induce remission in children with polyarticular disease or SoJIA. Methotrexate is the oldest and least toxic of the DMARDs currently available for adjunctive therapy. It may take 6-12 wk to see the effects of methotrexate. Failure of methotrexate monotherapy may warrant the addition of a biologic DMARD. Biologic medications that inhibit proinflammatory cytokines, such as TNF-α and IL-1, have demonstrated excellent disease control. TNF-α antagonists (e.g., etanercept, adalimumab, infliximab) are used to treat children with an inadequate response to methotrexate, with poor prognostic factors, or with severe disease onset. Trials, however, are currently underway to evaluate the role of early and aggressive treatment in the management of JIA. Combination of TNF-α blockade and methotrexate may also be used in children with SoJIA and milder systemic symptoms. When systemic symptoms dominate, initiation of IL-1 receptor antagonist therapy often induces a dramatic and rapid response.

With the advent of newer DMARDs, the use of systemic corticosteroids can often be avoided. Systemic steroids are recommended only for management of severe systemic illness, for bridge therapy during the wait for therapeutic response to a DMARD, and for control of uveitis. Steroids should be avoided, as they impose risks of severe toxicities, including Cushing syndrome, growth retardation, and osteopenia, and they may not prevent joint destruction.

Management of JIA must include periodic slit-lamp ophthalmologic examinations to monitor for asymptomatic uveitis (see Table 149-5). Optimal treatment of uveitis requires collaboration between the ophthalmologist and rheumatologist. Initial management of uveitis may include mydriatics and corticosteroids used topically, systemically, or through periocular injection. DMARDs allow for a decrease in exposure to steroids, and methotrexate and monoclonal antibodies to TNF-α (adalimumab and infliximab) are effective in treating severe uveitis.

Dietary evaluation and counseling to ensure appropriate calcium, vitamin D, protein, and caloric intake are important for children with JIA. Physical therapy and occupational therapy are invaluable adjuncts to any treatment program. A social worker and nurse clinician can be important resources for families, to recognize stresses imposed by a chronic illness, to identify appropriate community resources, and to aid compliance with the treatment protocol.

Prognosis

Although the course of JIA in an individual child is unpredictable, some prognostic generalizations can be made on the basis of disease type and course. Studies analyzing management of JIA in the pre-TNF-α era indicate that up to 50% of patients with JIA have active disease persisting into early adulthood, often with severe limitations of physical function.

Children with persistent oligoarticular disease fare well, with a majority achieving disease remission. Those in whom more extensive disease develops have a poorer prognosis. Children with oligoarthritis, particularly girls who are ANA positive and with onset of arthritis earlier than 6 yr of age are at risk for development of chronic uveitis. There is no association between the activity or severity of the arthritis and the chronic uveitis. Persistent, uncontrolled anterior uveitis (Fig. 149-14) can cause posterior synechiae, cataracts, and band keratopathy, and can result in blindness. Many of these children do well with early diagnosis and implementation of therapy.

Figure 149-14 Chronic anterior uveitis, or iridocyclitis, of juvenile idiopathic arthritis. Extensive posterior synechiae have resulted in a small, irregular pupil. A well-developed cataract and early band keratopathy can be seen at the medial and lateral margins of the cornea.

The child with polyarticular JIA often has a more prolonged course of active joint inflammation and requires early and aggressive therapy. Predictors of severe and persistent disease include young age at onset, RF seropositivity or rheumatoid nodules, the presence of anti-CCP antibodies, and large numbers of affected joints. Disease involving the hip and hand and wrist is also associated with a poorer prognosis and may lead to significant functional impairment.

SoJIA in children is often the most difficult to control in terms of both articular inflammation and systemic manifestations. Poorer prognosis is related to polyarticular distribution of arthritis, fever lasting >3 mo, and increased inflammatory markers, such as platelet count and ESR, for >6 mo. Newer agents, such as the IL-1 and IL-6 receptor antagonists, hold promise for improving the outcomes for children with severe and prolonged systemic-onset disease.

Orthopedic complications include leg length discrepancy and flexion contractures, particularly of the knees, hips, and wrists. Discrepancies in leg length can be managed with a shoe lift on the shorter side to prevent secondary scoliosis. Joint contractures require aggressive medical control of arthritis, often in conjunction with intra-articular corticosteroid injections, appropriate splinting, and stretching of the affected tendons. Popliteal cysts may require no treatment if they are small or intra-articular injection with corticosteroids if they are more problematic.

Psychosocial adaptation may be affected by JIA. Studies indicate that, compared with control subjects, a significant number of children with JIA have problems with lifetime adjustment and employment. Disability not directly associated with arthritis may continue into young adulthood in as many as 20% of patients, together with continuing chronic pain syndromes at a similar frequency. Psychologic complications, including problems with school attendance and socialization, may respond to counseling by mental health professionals.