Before the biologic era, treatment of juvenile idiopathic arthritis (JIA) was often highly unsatisfactory, with children forced to endure the ill effects of lifelong disease, including pain and stiffness, disability, and even increased risk of mortality. Thanks in large part to improved understanding of the underlying pathophysiology of the disease, multiple new biologic agents have been developed and applied to these disorders, with remarkable effects. However, much information remains to be learned about applying particular therapies to the distinct categories of JIA, and there is still considerable room for improvement in individual patients.
Key points
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Juvenile idiopathic arthritis (JIA) is a heterogeneous group of diseases, with potentially different treatment responses among the varying categories.
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Methotrexate continues to be widely used and effective in the management of JIA.
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Interleukin-1 and Interleukin-6 blockade are both highly effective in children with systemic JIA (sJIA).
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With the exception of sJIA, children with all categories of JIA generally respond well to tumor necrosis factor (TNF) inhibition; certain complications of JIA (uveitis and inflammatory bowel disease) respond better to anti-TNF monoclonal antibodies than to etanercept.
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Abatacept is safe and effective in children with polyarticular JIA, and may also have a role in the management of uveitis.
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Rituximab may be effective in JIA, although its precise role remains undefined.
Subtypes of juvenile idiopathic arthritis
Juvenile idiopathic arthritis (JIA) is a heterogeneous group, currently parsed into 7 distinct subtypes. Although a discussion of the clinical and pathophysiologic differences between the subtypes is beyond the scope of this review, a brief discussion of them is in order. It is likely that many of the JIA subtypes are genetically and pathophysiologically distinct, and may respond differently to the therapies currently available.
Oligoarticular
Oligoarticular JIA (oJIA) typically has onset in early childhood, with a peak age at onset of 2 to 3 years. Most patients are female and antinuclear antibody (ANA) positive, with an increased risk of asymptomatic uveitis. Some of these patients will never develop more than 5 involved joints and are thus said to have persistent oJIA; if 5 or more joints develop after at least 6 months of disease, the child is diagnosed with extended oJIA.
RF − Polyarticular
Rheumatoid factor (RF) − polyarticular JIA (pJIA) is diagnosed if a child has at least 5 involved joints within the first 6 months of disease, and if a test for RF is negative. This heterogeneous group includes children with similar demographic and clinical features as oJIA, as well as children with a symmetric course similar phenotypically to RF + disease. About 50% of these children test positive for ANA, and it has been argued that this ANA-positive subgroup of children with RF − pJIA, oJIA, and psoriatic JIA (psJIA; see later discussion) constitutes a homogeneous group.
RF + Polyarticular
Diagnosis of RF + pJIA requires only 5 swollen joints, plus at least 2 positive tests for RF 3 months apart within the first 6 months of the disease. In practice, meeting the serologic requirements within the specified time frame is often the most challenging aspect of diagnosis, given delays in referral. Clinically, these patients typically have far more than 5 affected joints, as they resemble their adult counterparts diagnosed with rheumatoid arthritis (RA). The similarities extend to shared genetics, additional laboratory studies, and extra-articular complications.
Psoriatic JIA
Diagnosis of psJIA requires frank psoriasis in the context of a child with arthritis, or the presence of 2 or more psoriatic-like findings, namely nail pits, dactylitis, and positive family history in a first-degree relative (in the absence of exclusion criteria). psJIA is a heterogeneous group, consisting of an early-onset cohort similar clinically to children with early-onset oJIA and pJIA; and a late-onset group that is more similar to adults with psoriatic arthritis (PsA) and to other children with spondyloarthritis (SpA).
Enthesitis-Related Arthritis
Enthesitis-related arthritis (ERA) constitutes juvenile SpA and best corresponds to the undifferentiated SpA category used in adult classification systems. Although it is rare for children to have frank ankylosis, many of these children have SpA features, including male predominance, enthesitis, evidence of sacroiliitis on magnetic resonance imaging, and positive test for HLA-B27.
Systemic JIA
Systemic JIA (sJIA) is defined by occurrence of systemic features, including high spiking fevers, rash, hepatosplenomegaly, lymphadenopathy, and serositis. Laboratory testing often reveals markedly elevated inflammatory markers, although some of the laboratory values can become spuriously normal in the setting of macrophage activation syndrome (MAS). Although arthritis is required for diagnosis as per the International League of Associations for Rheumatology (ILAR) criteria, it is not uncommon for the systemic features to predominate at first, before or simultaneously with the onset of arthritis.
Undifferentiated Arthritis
Undifferentiated arthritis is not a single diagnosis, but rather reflects a catch-all category of children who do not meet any or who meet 2 or more of the other ILAR categories. Examples include a child with clear features of sJIA, who has a parent with psoriasis; a child with RF + pJIA who, owing to referral delays, did not have 2 separate positive tests for RF within 6 months of onset of disease; and a child with both HLA-B27–positive axial spondyloarthritis and psoriasis. Because of its evident heterogeneity, this category is not discussed further herein.
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