Page 751 - Clinical Immunology_ Principles and Practice ( PDFDrive )

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Juvenile Idiopathic Arthritis

Randy Q. Cron, Peter Weiser, Timothy Beukelman

Juvenile idiopathic arthritis (JIA) is a collection of conditions Distinctions based on the types and location of joints manifesting
that manifest with chronic arthritis in childhood. By definition, arthritis may prove useful in identifying more homogeneous
JIA occurs prior to the 16th birthday (juvenile), has no known subtypes. Thus the criteria will likely continue to evolve and
causes (idiopathic), and has evident chronic (>6 weeks’ duration) benefit from more precise clinical, laboratory, and genetic distinc-
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swelling/inflammation of a joint or joints (arthritis). The tions. One such suggested reclassification of JIA categories is
nomenclature and subcategorization of JIA have been published, based on shared similarities among children with JIA who are
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with a second revision in 2004, partly in an attempt to unify the positive for antinuclear antibody (ANA) regardless of total joint
American (juvenile rheumatoid arthritis [JRA]) and European count, and a recent proposal used probabilistic principal com-
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(juvenile chronic arthritis [JCA]) classification schemes. Removal ponent analysis of a large set of biological and clinical data to
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of the word “rheumatoid” was also important to distinguish subdivide patients with JIA. Moreover, there have been several
these unique disorders from adult rheumatoid arthritis (RA) attempts to characterize the genetics of the JIA categories by
(Chapter 52). The new classification of JIA also includes the using a variety of approaches. 5
human leukocyte antigen (HLA)-B27–associated spondyloar-
thropathies (Chapter 57), which occur frequently during child- Polygenic Disorder
hood (Table 53.1). Like most autoimmune conditions, JIA is a polygenic disorder
Because JIA is a diagnosis of exclusion, other causes of child- with ≥20 potential genes contributing to the phenotypes of
hood chronic arthritis need to be ruled out. For example, sar- chronic arthritis presenting during childhood. An exception is
coidosis (Chapter 73), Sjögren disease (Chapter 54), systemic the systemic JIA (sJIA) category, which resembles an autoinflam-
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lupus erythematosus (SLE) (Chapter 51), Lyme disease (Chapter matory disorder rather than a solely autoimmune process. Unlike
28), dermatomyositis (Chapter 56), and a variety of vasculitides autoimmunity, which is believed to be the result of an imperfect
(Chapters 58 and 59) may all present as chronic arthritis in adaptive immune system, autoinflammatory conditions are
childhood. JIA, by definition, is idiopathic; however, chronic thought to result from genetic perturbations in the innate immune
arthritis as part of inflammatory bowel disease (IBD) (Chapter response. Many autoinflammatory recurrent fever syndromes
75) or associated with psoriasis (Chapter 64) is categorized under have been identified as resulting from single gene defects, such
the JIA umbrella. When considering the seven categories of JIA as pyrin in familial Mediterranean fever (FMF), and tumor
together, the estimated prevalence of JIA is roughly 1 in 1000 necrosis factor (TNF) receptor in TNFR1-associated periodic
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children, with rates varying in different regions of the world, syndrome (TRAPS) (Chapter 60). Whether sJIA is the result
likely because of genetic risk factors and/or environmental triggers. of a single gene defect or is one of many potential single gene
Moreover, the relative rates of JIA categories vary in different defects in the same immune pathway is currently unknown.
regions of the world (e.g., oligoarticular JIA is very common in However, a common complication of sJIA is the life-threatening
Scandinavia, and enthesitis-related JIA is more typical in Latin condition of macrophage activation syndrome (MAS), which
America). resembles familial hemophagocytic lymphohistiocytosis (fHLH)
(Fig. 53.1). MAS may be present in ≈50% of children with sJIA
ETIOLOGY AND PATHOGENESIS in either an overt or occult/subclinical fashion. Recently, genetic
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polymorphisms and heterozygous (single copy) mutations in
Genetic Contribution genes associated with fHLH when present as homozygous defects
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Because JIA is an eclectic group of disorders with joint inflam- have been identified in children with sJIA and overt MAS. Protein
mation, is far less common than RA, and is classified into unique products of these genes, including perforin 1 and MUNC 13-4,
categories based largely on subjective clinical phenotypes, are critical in the pathway mediating cytolysis by CD8 T cells
understanding its genetic causes is extremely difficult. Indeed, and natural killer (NK) cells (Chapter 17). This cytolysis is crucial
the relatively arbitrary distinction of having ≤4clinically arthritic to the ability to shut down an immune response following control
joints to be considered as oligoarticular JIA is influenced by of infection. Defects in this pathway can result in a hyperinflam-
whether temporomandibular joint (TMJ) arthritis (or in essence matory state (cytokine storm) leading to pancytopenia, coagu-
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any other suspected joint involvement) is screened for with lopathy, and multisystem organ failure. The most common
magnetic resonance imaging (MRI) because clinical examination condition resulting in MAS during childhood is sJIA. Therefore
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is neither sensitive nor specific for diagnosing TMJ arthritis. sJIA may be genetically related to fHLH but associated with
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