Page 754 - Clinical Immunology_ Principles and Practice ( PDFDrive )

726 Part six Systemic Immune Diseases

KEY CONCEPts JIA category affecting boys more than girls—ERA, with inflam-
Macrophage Activation Syndrome (MAS) mation of the entheses, attachments of the tendons, and ligaments
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to bone (see Table 53.1). An important finding of recent years
• MAS is present in up to 50% of children with systemic juvenile idiopathic is that imaging (MRI and, in certain cases, ultrasonography) can
arthritis (sJIA) in a subclinical or overt (10%) form. identify ongoing inflammation in clinically asymptomatic joints.
• MAS manifests as fever, liver dysfunction, pancytopenia, central nervous This has led to screening for TMJ inflammation primarily with
system disturbance, hyperferritinemia, hemophagocytosis, and MRI, as arthritis of this joint is frequently clinically silent but
coagulopathy. capable of resulting in facial dysmorphism from micrognathia
• MAS resembles hemophagocytic lymphohistiocytosis (HLH) and is in all JIA categories, including oligoarticular JIA. 2
thought to result from defects in perforin-mediated cytolysis by CD8
T cells and natural killer (NK) cells.
• Patients with sJIA and MAS have been noted to have NK-cell defects Oligoarticular JIA
and mutations in perforin-1 and MUNC13-4 cytolytic pathway genes. Oligoarticular JIA is likely the most common category of JIA,
• MAS can be fatal if not recognized and treated early. Mainstays of affecting children who have 1–4 joints inflamed, most commonly
therapy include high-dose corticosteroids and cyclosporine. knees, ankles, the TMJ, and fingers. The archetype of this group
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• Recently, interleukin-1 (IL-1) blockade with biological therapies has is a preschool-aged, blonde-haired, blue-eyed girl who limps
been found to be quickly and dramatically beneficial in treating MAS
associated with sJIA. and has swollen knees. The diagnosis of arthritis may be delayed,
as it is often painless. Because of this, by the time she is seen in
the medical office, she may already have developed bony hyper-
trophy and limb length discrepancy, as chronic articular inflam-
that MAS may be inherent to sJIA disease pathology in up to mation stimulates the osteoblasts of the nearby growth plates.
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half of all patients with sJIA. MAS is likely part of the spectrum In addition, there is often notable muscle wasting around the
of HLH disorders. Primary HLH, or fHLH, typically presents arthritic joint that can last into adulthood. The oligoarticular
in infancy following infection and results from homozygous JIA category has the highest percentage of positive ANA blood
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mutations in genes involved in the cytolytic pathway employed tests and associated potentially damaging silent uveitis. Mono-
by NK cells and CD8 T cells. Recent evidence suggests that patients articular involvement calls for a careful differential diagnosis.
with sJIA who have MAS have heterozygous defects in these JIA rarely presents with isolated hip involvement; toxic synovitis,
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same cytolytic pathway genes. MAS can be triggered by a variety septic hip, and malignancy all need to be considered. Oligoar-
of infectious organisms, particularly members of the herpes virus ticular JIA is also quite uncommon in middle and high school
family, but the precise role of infectious triggers of MAS in aged children, where the diagnosis of reactive arthritis, IBD-related
children with sJIA remains unknown. Nevertheless, the inability arthritis, and Lyme disease should be entertained. The ILAR
to effectively shut down an immune response via cytolytic classification has a separate sub-category for children who develop
mechanisms results in a “storm” of proinflammatory cytokines, additional joint involvement after the first 6 months based on
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such as IL-1, IL-6, IL-18, TNF, and IFN-γ. Mouse models of clinical presentation, extended oligoarticular JIA, which might
MAS/HLH have suggested that IFN-γ is the pivotal cytokine in be a variant of the RF-negative polyarticular category. Wrist
MAS. In practical terms, inhibition of IL-1, and potentially of involvement is considered to be a bad prognostic factor, as is
IL-6, has proven rather effective at treating MAS in children the extended oligoarticular phenotype, and elevated laboratory
with sJIA. 1,7,18 It is quite remarkable how dampening of one indicators of inflammation.
critical cytokine can help restore the immune imbalance of
multiple proinflammatory cytokines and rapidly reverse the Polyarticular JIA
life-threatening clinical scenario of MAS. Arthritis of ≥5 joints includes two main JIA categories (see Table
53.1) based on the presence of serum RF, an IgM antibody against
JIA CLINICAL SUBTYPES the IgG Fc receptor.
RF-positive serum on two occasions at least 3 months apart
+
As already mentioned, JIA is a group of chronic inflammatory is required for a child to be diagnosed with RF polyarticular
joint diseases, which last for at least 6 weeks and commence JIA. Joint involvement is typically bilateral and symmetrical,
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prior to the age of 16 years with no identifiable cause. There is involving the small joints of hands and feet. However, large
+
heterogeneity of clinical presentation and progression of the joints and cervical involvement are often present. RF polyarticular
various subtypes, which is largely addressed by the International JIA usually presents in adolescent girls and is considered a form
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League Against Rheumatism (ILAR) classification schema (see of early-onset adult RA. It is a relatively infrequent category of
Table 53.1). Nevertheless, as more information about genetic JIA with <5 % of all patients with JIA classified in this category.
factors, response to medication, and subsequent outcomes Antibodies to CCP are much less common in children with
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becomes available from multicenter studies, revisiting the clas- polyarticular JIA than in adults, but affected children usually
sification in the near future seems inevitable. A recent elegant have active arthritis for many years. The presence of RF predicts
report has suggested five distinct groups of patients categorized more destructive/erosive disease calling for early aggressive
on the basis of clinical disease trajectories, all with subsets different therapy. As in adult RA, arthritis of the wrists and fingers can
from those defined by the ILAR classification. 4 lead to ulnar deviation and boutonniere and swan neck deformi-
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The current classification of JIA relies heavily on the number ties. Destructive TMJ involvement is also common. Similar to
+
of the joints involved (≤4in oligoarticular JIA; ≥5 in polyarticular adult RA, RF polyarticular JIA in children commonly has
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JIA, with or without the presence of RF). Other categories of JIA extraarticular manifestations, such as low-grade fever and
are also classified on the basis of associated symptoms and signs, occasionally rheumatoid nodules over bony surfaces.
including fever, rash, and laboratory indicators of inflammation in RF-negative polyarticular JIA usually presents as asymmetrical
sJIA, or associated diseases, such as psoriasis. There is a separate involvement of the large joints, mostly knees, wrists, and ankles.