Page 96 - The Netter Collection of Medical Illustrations - Integumentary System_ Volume 4 ( PDFDrive )

Plate 4-11 Integumentary System

CLINICAL MANIFESTATIONS OF AUTOINFLAMMATORY SYNDROMES
AUTOINFLAMMATORY Cutaneous findings
SYNDROMES (Continued)

TRAPS patients. Skin findings are characteristic and
consist of migratory, pink to red patches and macules.
Periorbital swelling may be prominent.
Histology: Each of the autoinflammatory skin lesions
has a unique histology. The diagnosis cannot be made
on the basis of histology alone, but histologic findings
are used to rule out other conditions in the differential
diagnosis and to help confirm the diagnosis of an auto-
inflammatory disease. Skin biopsies should be taken
during acute attacks, when a rash is present.
Cutaneous biopsy specimens from patients with
HIDS typically show a neutrophilic vasculitis. Neutro-
phils are found throughout the dermis. A skin biopsy
from a patient with one of the cyropyrinopathies shows
a neutrophilic perivascular infiltrate associated with
diffuse dermal edema. NOMID and CINCA also Classic TRAPS rash The rash in HIDS can Typical appearance Typical appearance
exhibit a perivascular infiltrate of lymphocytes scattered that migrates in a be variable, including of urticaria-like rash of erysipelas-like
within the neutrophilic infiltrate. FMF skin biopsies centrifugal pattern maculopapular and of the cryopyrinopathies FMF rash, often on
show a diffuse population of dermal neutrophils. urticarial forms. lower extremities
TRAPS skin biopsies are nondescript and show a bland Joint and central nervous system findings
lymphocytic infiltrate in a dermal perivascular location.
Biopsy of the periorbital edema shows a perivascular
lymphocytic infiltrate and dermal edema.
Pathogenesis: Remarkable success has been achieved
in deciphering the pathogenesis of these disease states,
which are all interconnected through the innate
immune system. The defective genes and the proteins
that they encode have been determined. These proteins
play a critical role in regulation of the innate immune
system’s inflammatory response. If they are defective,
they cause varying amounts of dysregulation of neutro-
phils and other inflammatory cells. The innate immune
system is nonspecific in nature and does not rely on Optic fundus with papillederma
antibody production. Various innate pattern recogni-
tion receptors (e.g., Toll-like receptors) are able to rec-
ognize foreign molecules and directly activate the
innate immune system. The normal activation of the
innate immune system allows for prompt recognition
of foreign elements and a proper immune reaction to Joint enlargement seen in NOMID
those elements. The autoinflammatory conditions have
been discovered to involve defects in various compo-
nents of the innate immune system.
HIDS is caused by a mutation in the MVK gene,
located on chromosome 12, which encodes the protein
mevalonate kinase. This gene helps regulate cholesterol
synthesis, but it is also important for production of
precursors that will ultimately be isoprenylated. The
lack of these isoprenylated proteins leads to dysregula-
tion of IL-1β and ultimately to the clinical findings of
HIDS. All of the cryopyrinopathies are caused by a
genetic defect of the NLRP3 gene located on chromo-
some 1. This gene, which is also called CIAS1, encodes
the protein cryopyrin. The defect allows for a gain in
function of the cryopyrin protein, which results in Arthritis/periarthritis Headache
hyperactivity of the inflammasome. The inflammasome
is a cytoplasmic soluble conglomeration of various pro-
teins that is part of the innate immune system and is
constantly identifying foreign material. Its stimulation signaling due to serum TNF activation of the antagonist, anakinra. The cryopyrinopathies have been
ultimately increases the activity of the caspase 1 protein receptor. treated with cold avoidance in the case of FCAS, and
and the production of IL-1β. FMF has been found to Treatment: Therapy is specific to each syndrome. NSAIDs, oral steroids, anakinra, and other immuno-
be caused by a defect in the MEFV gene, which encodes The molecular understanding of the pathogenesis suppressants have been tried. FMF has been treated
the pyrin protein. Pyrin is also a regulator of the inflam- has led to specific therapies. Because of their rarity, with good success with colchicine, taking advantage of
masome, and defects in pyrin result in increased levels no randomized studies have been performed on the its antineutrophil effect. TRAPS has been successfully
of IL-1β. TRAPS is caused by a defective gene on treatment of these conditions. HIDS has been success- treated with etanercept or anakinra. Etanercept is
chromosome 12 named TNFRSF1A. This gene encodes fully treated with nonsteroidal antiinflammatory drugs believed to remove the soluble TNF that is responsible
the 55-kd TNF receptor. The defect leads to excessive (NSAIDs), statin medications, and the interleukin for activating the mutated receptor.

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