The etiology of JRA is unknown. It likely does not represent a single disorder but rather a spectrum of diseases of diverse pathogenesis. An immunogenetic predisposition is present in certain children: the HLA antigens DR5 (DRB1*1104), DRw6, DRw8, DQw1 (DQA1*0501), and DPw2.1 (DPB1* 0201) are associated with the development of persistent oligoarthritis at an early age in young girls with ANA seropositivity, and DR4 (DRB1*0401 and 0404) is increased in frequency in older children with polyarthritis who are seropositive for RFs. The risk associated with these immunogenetic profiles appears to be age-related. A JRA-like arthritis is a manifestation of
immunodeficiency in children with selective IgA deficiency, agammaglobulinemia or hypogammaglobulinemia, and C2 complement component deficiency. In children with oligoarthritis, T-lymphocyte proliferative responses to heat-shock protein 60 are associated with a remission of the inflammatory disease. A study of 144 families has established the association of several tumor necrosis factor-alpha (TNFα) single nucleotide polymorphisms (SNPs) with juvenile oligoarthritis. Interleukin-6 (IL-6) is increased in the circulation of children with systemic-onset disease. In systemic-onset disease, IL-6-174G is over-represented in the transcriptional regulation of the IL-6 gene and is associated with resistance to glucocorticoid therapy. Also in systemic-onset disease, high levels of macrophage inhibitory factor (MIF) in serum and synovial fluid are associated with a G to C SNP at position-173 of the MIF gene that leads to glycocorticoid resistance, persistence of arthritis, and a relatively poor outcome.

The synovial membrane in JRA is characterized by villous hypertrophy and hyperplasia of the synovial lining layer. Edema and hyperemia are present, along with vascular endothelial hyperplasia and the infiltration of lymphocytes and plasma cells. Pannus formation eventually occurs in severely affected joints and leads to the destruction of articular cartilage and contiguous bone.

Infiltrates of inflammatory cells occur also in parenchymal organs, such as the liver, and along serosal surfaces of the pericardium, pleura, and peritoneum. Rheumatoid nodules result from a small-blood-vessel vasculitis but are rare findings in affected children. The rash of JRA is characterized histologically by a neutrophilic perivasculitis and infiltration of round cells surrounding capillaries and subdermal venules.

Although the onset of JRA occurring before a child reaches 6 months of age is unusual, the mean age at onset characteristically is young (1 to 3 years), with a substantial number of cases beginning throughout childhood and young adolescence. Girls are affected at least twice as frequently as are boys.

Fatigue, low-grade fever, anorexia, weight loss, and failure to grow are common findings at onset of the disease in moderate to severely affected children. Morning stiffness, musculoskeletal gelling after inactivity, and night pain often are associated with incompletely controlled disease. Affected children may not, however, always communicate these symptoms to their parents. Instead, the child may present with increased irritability, a posture of guarding the joints, a limp, or refusal to walk.

Tenosynovitis also is a component of active disease. A stenosing synovitis of the flexor tendon sheaths may lead to loss of extension of the fingers or to a trigger finger. Rheumatoid nodules may occur on the tendons or subcutaneously over pressure points. They are found particularly in children who have widespread polyarthritis, are older at onset, and have prominent small-joint disease, an unrelenting course with early development of bony erosions, and RF seropositivity.

The classification criteria for JRA of the American College of Rheumatology (ACR) and for juvenile idiopathic arthritis of the International League for Arthritis and Rheumatism (ILAR) are compared in Table 434.5. JRA was defined by the ACR as onset of arthritis in a child younger than 16 years. Arthritis is defined clinically by swelling or effusion or the presence of two or more of the following signs: limitation of range of motion, tenderness or pain on motion, and increased heat in one or more joints. JRA often is a diagnosis of exclusion and, therefore, similar diseases must be considered (see Table 434.2). The differential diagnosis generally includes other rheumatic
and connective tissue diseases, especially acute rheumatic fever, SLE, and ankylosing spondylitis. In our experience, other forms of arthropathy, such as reactive and psoriatic arthritis, are uncommon findings. Particular attention must be accorded, however, to infectious arthritis, serum sickness, Henoch-Schönlein purpura, the enteropathies such as ulcerative colitis and regional enteritis, and hematologic diseases such as leukemia, sickle-cell anemia, and hemophilia. The concurrence of arthritis and immunodeficiency already has been mentioned. Certain viral illnesses, especially rubella, mumps, and Lyme disease, have an associated arthritis. Tumors, especially neuroblastoma in young children, may present as bone pain or arthritis. Although the onset of JRA in the hip is an uncommon occurrence, transient synovitis, Legg-Calvé-Perthes disease, and slipped capital femoral epiphysis may mimic JRA, especially if the pain is referred to the knee, as it often is.

Conservative management attempts to control the clinical manifestations of the disease and prevent or minimize deformity. Ideally, this approach involves a multidisciplinary team that follows the affected child throughout the course of the illness. Management should be family-centered, community-based, and coordinated. The long-term therapeutic program must be accepted by the child and family and judged to have a favorable risk-benefit ratio by the pediatric rheumatologist.

Prognosis is reasonably satisfactory for most children with JRA, so the philosophy of management initially should stress the simplest, safest, and most conservative measures. If this program of treatment proves inadequate, other therapeutic modalities should be chosen (Table 434.6).

NSAIDs are moderately effective in suppressing inflammation and fever. Aspirin seldom is used in North America at this time, and drugs such as naproxen, ibuprofen, and tolmetin are preferred. The first two drugs can be prescribed also as a suspension, which is particularly useful for younger children. All children with JRA should receive yearly influenza vaccines and should be immune to varicella.

Hydroxychloroquine is a useful adjunctive agent for treating the child with more progressive disease. Because of concern over retinopathy as a toxic reaction, a relatively low dose is chosen, (e.g., 5 mg/kg/day), and every 6-month ophthalmologic examinations, especially for color vision, are monitored during its administration. Intramuscular gold compounds and D-penicillamine were used previously for children whose polyarthritis was unresponsive to conservative management. Toxicities from these drugs primarily are hematologic, renal, or hepatic.

Methotrexate has become the most accepted approach to the advanced drug treatment of severe or resistant polyarthritis. In a large, multinational, double-blind, randomized trial, a dose of 10 mg/m² once a week markedly reduced the articular severity index, compared with placebo. This drug is attractive for pediatric use because it is given only once a week orally as a pill or liquid, and it has no proven oncogenic potential or untoward risk of causing sterility. Toxicity is monitored clinically and by periodic complete blood cell counts and liver enzyme determinations.

Additional therapy can include etanercept, a TNFα blocker. It consists of two TNFα receptor monomer chains fused to the Fc domain of human IgG₁. The drug binds TNFα in the vascular and extracellular compartments and inhibits its activity. A controlled trial of etanercept in children with polyarticular JRA who had failed therapy with methotrexate indicated that 74% demonstrated improvement at 3 months on a subcutaneous dose of 0.4 mg/kg twice a week. A 2-year follow-up indicated that the overall rate of improvement was 79% and remissions occurred in 37%.

Infliximab is a monoclonal antibody that has the capacity to bind TNFα in both the extracellular and vascular compartments, and also on the cell surface. A pediatric trial is currently in progress to evaluate the safety and efficacy of this drug in JRA. Another biologic response modifier is anakinra (r-metHuIL-1ra), which interferes with the actions of IL-1 in the inflammatory response.

The long-term safety of cytokine blockade is unknown. Potentially, it is associated with an increased frequency of systemic infection and should not be used in children with recurrent or chronic infections. Tuberculosis always should be excluded before beginning therapy.

Glucocorticoid drugs should be reserved for treatment of the severely involved child who is recalcitrant to more conservative therapeutic regimens or for those with life-threatening disease and its complications, such as pericarditis. Many toxicities (e.g., Cushing syndrome) and growth retardation are associated with their use. Ophthalmic administration is indicated for treatment of chronic uveitis. Intra-articular steroid often is used to achieve the specific goals of a physical therapy program or for persistent monarticular or oligoarticular involvement.

Other immunosuppressive agents seldom are required in the long-term treatment of JRA. However, some children have failed to improve on all other therapies and are candidates for experimental protocols involving agents such as azathioprine or cyclophosphamide. Critical considerations are the oncogenic potential of these agents, potential sterility, and bone marrow suppression. Intravenous immunoglobulin, cyclosporin A, and other biologic response modifiers are additional approaches to experimental therapy.

In general, more than half of the children who develop JRA have a satisfactory recovery from their disease and enter adult life without serious functional disability, although as many as 45% may have continuing low-grade activity for some years. A small percentage of patients whose disease has gone into remission will have a recurrence of arthritis during the adult years. As many as 15% of children with JRA, however, enter adulthood with significant functional disability. The child most at risk has had polyarthritis of later age of onset, early symmetric involvement of the small joints of the hands or feet, unremitting activity of the joint disease, early appearance of erosions, prominent systemic manifestations, and development of RF seropositivity and subcutaneous nodules. Progressive hip disease also is a major cause of long-term disability.

Serious functional disability is an uncommon development in children who have oligoarthritis and pursue a course of limited joint disease. The prognosis for sight in children with chronic uveitis has improved dramatically, a development probably related to earlier detection and better management of this complication. Blindness, however, still occurs in as many as 15% of affected eyes.

Approximately one-half of children with systemic onset eventually will recover completely; however, most JRA-related deaths in the United States have been associated with this type of disease. Death occurs in fewer than 1% of children with JRA, and it often is a result of overwhelming infection. In Europe, renal failure secondary to amyloidosis is a leading cause of death. Amyloidosis seldom occurs as a complication of JRA in North America.

Estimates of prognosis should remain optimistic, and, in many children, prognosis is excellent. Of importance is that both the child and parents understand the disease and share in its long-term management. The nature of JRA, the goals of therapy, and the expected course of the disease should be discussed in detail. A carefully selected program of coordinated care, initiated by the pediatric rheumatologist, must be reinforced constantly by the team nurse and social worker. Some families of children with JRA display psychiatrically important disruptions (e.g., divorce, separation, and depression). Thus, a priority in the management of a child with this chronic illness is to foster normal psychological and social development and peer group activities. A child’s unceasing potential for physical and psychological growth is a critical factor working in favor of the therapeutic program and team management. This natural endowment for future physical and psychological development is what enables so much to be accomplished in most children with JRA.

Numerous environmental, hereditary, and immunogenetic factors are implicated in the pathogenesis of this autoimmune disorder. The F1 hybrid of New Zealand white and black mice develops an SLE-like disease with early onset of renal failure that is more marked in females than in males. Household dogs also develop an SLE-like illness and, identical to their mouse counterparts, have circulating antibodies to native DNA and immune-complex deposition in tissues.

Environmental triggers, such as excessive exposure to the sun, a drug reaction, or an infection, may precipitate the onset of SLE. The basic pathogenesis of SLE appears to be immunologic abnormalities of homeostatic control affecting nuclear and cytoplastic antigens. Antibodies found in children with SLE include those that are tissue-specific as well as those related to nuclear antigens. These antibodies participate in specific manifestations of the disease, such as acute hemolytic anemia, thrombocytopenia, leukopenia, and thrombosis, and in the antigen–antibody complex deposition that results in systemic vasculitis and lupus nephritis, as well as impaired cell-mediated immunity and T-suppressor cell dysfunction.

Another connective tissue disease or an abnormal marker of immunologic function (e.g., ANA) is present in approximately 10% of family members. SLE has occurred in identical twins (concordance 24%). It is associated with sporadic or familial immunodeficiency, such as selective IgA deficiency, and inherited disorders of complement components, such as homozygous C2, C1q, C1r, or C1 esterase inhibitor deficiency. In many affected children, a marked immunogenetic predisposition is evident in the extended haplotype for genes located on chromosome 6: HLA-B8, DR2 or DR3, DQw1 or DQw2, and C4A null.

An immune-complex vasculitis with fibrinoid necrosis is the basic inflammatory lesion. Vascular lesions are widespread throughout the parenchymal organs, in subdermal tissues, and on the mucosal and serosal surfaces. Soluble immune complexes can be demonstrated beneath the vascular endothelium and along the dermal-epidermal junction in the lupus-band test.