DISCUSSION

Systemic Juvenile Idiopathic Arthritis is the most cimmon rheumatic disease in children and one
of the more common chronic illnesses of childhood. SJIA represents a heterogeneous group of
disorders all sharing the clinical manifestation of arthrirtis
Epidemiology
The worldwide incidence of SJIA ranges from 0.8-2.6/100,00 children per year, with prevalence
ranges from 7-401/100,000. These wide ranging numbers reflect population differences,
particularly environmental exposure and immunogenetic susceptibility, along with variations in
diagnostic criteria, difficulty in case ascertainment, and lack of population-based data. It is
estimated that 300,000 children in the United States have arthritis, including 100,000 with
a form of JIA. Oligoarthritis is the most common subtype (40-50%), followed by
polyarthritis (25-30%) and systemic JIA (5-15%). T here is no sex predominance in
systemic JIA (sJIA), but more girls than boys are affected in both oligoarticular (3 : 1)
and polyarticular (5 : 1) JIA. The peak age at onset is between 2 and 4 yr for
oligoarticular disease. Age of onset has a bimodal distribution in polyarthritis, with peaks
at 2-4 yr and 10-14 yr. sJIA occurs throughout childhood with a peak between 1 and 5
yr.
Etiology and Pathogenesis
T he etiology and pathogenesis of JIA are not completely understood, though both
immunogenetic susceptibility and an external trigger are considered necessary. JIA is a
complex genetic trait in which multiple genes may affect disease susceptibility. Variants
in major histocompatibility complex (MHC) class I and class II regions have indisputably
been associated with different JIA subtypes. Non-HLA candidate loci are also associated
with JIA, including polymorphisms in the genes encoding protein tyrosine phosphatase
nonreceptor 22 (PTPN22), tumor necrosis factor (TNF)-α, macrophage inhibitory factor,
interleukin (IL)-6, and IL-1α. There is evidence that the IL-6 gene confers susceptibility to
sJIA, with increased transmission of the −174G allele in patients older than 5 yr.
Possible nongenetic triggers include bacterial and viral infections, enhanced immune
responses to bacterial or mycobacterial heat shock proteins, abnormal reproductive
hormone levels, and joint trauma.
JIA is an autoimmune disease associated with alterations in both humoral and cell-
mediated immunity. T lymphocytes have a central role, releasing proinflammatory
cytokines favoring a type 1 helper T-lymphocyte response. Studies of T-cell receptor
expression confirm recruitment of T lymphocytes specific for synovial non–self antigens.
B-cell activation, immune complex formation, and complement activation also promote
inflammation. Inheritance of specific cytokine alleles may predispose to upregulation of
inflammatory networks, resulting in systemic disease or more severe articular disease.
sJIA is characterized by dysregulation of the innate immune system with a lack of
autoreactive T cells and autoantibodies. It therefore may be more accurately classified as
an autoinflammatory disorder, more like familial Mediterranean fever, than the other
subtypes of JIA. This theory is also supported by work demonstrating similar expression
patterns of a phagocytic protein (S100A12) in sJIA and familial Mediterranean fever, as
well as the same marked responsiveness to IL-1 inhibitors. 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. Advanced and uncontrolled
disease leads to pannus formation and progressive erosion of articular cartilage and
contiguous bone.
Clinical Manifestation
Arthritis must be present to make a diagnosis of any JIA subtype. Arthritis is defined by
intraarticular swelling or the presence of 2 or more of the following signs: limitation in
range of motion, tenderness or pain on motion, and warmth. 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 and causes the affected limb to be longer, 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 1st 6 mo of disease onset, and
often only a single joint is involved. It predominantly affects the large joints of the lower
extremities, such as the knees and ankles. 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 after 6 mo changes the classification to extended oligoarticular JIA and is
associated with a worse prognosis. Polyarthritis is characterized by inflammation of ≥5
joints in both upper and lower extremities. Rheumatoid factor (RF)–positive polyarthritis
resembles the characteristic symmetric presentation of adult rheumatoid arthritis. Rheumatoid
nodules on the extensor surfaces of the elbows, spine, and over the Achilles tendons,
although unusual, are associated with a more severe course and almost exclusively
occur in RF-positive individuals. sJIA is characterized by arthritis, fever, rash, and
prominent visceral involvement, including hepatosplenomegaly, lymphadenopathy, and
serositis (pericarditis). The characteristic fever, defined as spiking temperatures to ≥39°C
(102.2°F), occurs on a daily or twice-daily basis for at least 2 wk, with a rapid return to
normal or subnormal temperatures. Macrophage activation syndrome (MAS) is a rare but
potentially fatal complication of sJIA that can occur at any time (onset, medication,
change, active or remission) during the disease course. It is also referred to as
secondary hemophagocytic syndrome or hemophagocytic lymphohistiocytosis (HLH).

Diagnosis
JIA is a clinical diagnosis without any diagnostic laboratory tests. The meticulous clinical
exclusion of other diseases and many mimics is therefore essential. Laboratory studies,
including tests for ANA and RF, are only supportive or prognostic, and their results may
be normal in patients with JIA. 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, although 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 sJIA. ANA seropositivity is associated with increased risk of chronic uveitis
in JIA. Approximately 5-15% of patients with polyarticular JIA are seropositive for RF.
Anti–cyclic citrullinated peptide 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 sJIA usually have striking elevations in inflammatory
markers and white blood cell and platelet counts. Hemoglobin levels are low, typically in
the range of 7-10 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 or normal
white blood cell count and/or platelet count in a child with active sJIA should raise
concerns for MAS.
Treatment
T he 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 manage-ment
also requires monitoring for potential medication toxicities. Children with oligoarthritis often show
partial response to nonste-roidal antiinflammatory drugs (NSAIDs), with improvement in
inflammation and pain. Those who have no or partial response after 4-6 wk of treatment with
NSAIDs or who have func-tional limitations, such as joint contracture or leg-length discrepancy,
benefit from injection of intraarticular 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, and therefore require treatment with disease-
modifying antirheumatic drugs (DMARDs), methotrexate, and, if no response, TNF inhibitor

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 preTNF-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 with extended oligoarticular disease 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 greatest risk for development of chronic
uveitis. T here is no association between the activity or severity of arthritis and uveitis.
Persistent, uncontrolled anterior uveitis (see Fig. 155-15) can cause posterior synechiae,
cataracts, glaucoma, and band keratopathy, with resultant blindness. Morbidity can be
averted with early diagnosis and implementation of systemic therapy.