AUTOINFLAMMATORY SYNDROMES
The autoinflammatory syndromes are a rare group of diseases for which the
specific causes have been determined. The diseases in this category include
hyper-immunoglobulin D (hyper-IgD) syndrome (HIDS), the cryopyrinopathies,
familial Mediterranean fever (FMF), and tumor necrosis factor (TNF) receptor
associated periodic syndrome (TRAPS). The cryopyrinopathies are a group of
conditions made up of Muckle-Wells syndrome, familial cold autoinflammatory
syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID), and
chronic infantile neurological cutaneous and articular syndrome (CINCA). These
groupings were first proposed in the 1990s to bring together a collection of
inflammatory disorders that are distinct in nature and pathophysiology from
other forms of allergic, autoimmune, and immunodeficiency syndromes. Patients
with these auto-inflammatory diseases lack the autoreactive immune cells (T and
B cells) as well as autoantibodies. The identification of specific genes that
are defective and the roles played by those genes in the development of these
disorders has been critical in increasing understanding of these diverse
diseases. The common link in these conditions is the fact that they all
represent abnormalities of the innate immune system.
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| PATHOPHYSIOLOGY OF AUTOINFLAMMATORY SYNDROMES |
Clinical Findings: HIDS
is inherited in an autosomal recessive fashion. Patients present with fever,
arthralgias, abdominal pain, cervical adenopathy, and aphthous ulcers. Skin
findings are consistent with a cutaneous vasculitis with palpable purpura and
purpuric macules and nodules. Patients develop attacks of these symptoms with
some evidence of periodicity. The attacks can last from 3 to 7 days, and
typically the first attack occurs within the first year of life. As the child
ages, the frequency and the severity of the attacks lessen. No reliable trigger
has been found that initiates the attacks, and patients are completely normal
between attack episodes.
Within the group of cryopyrinopathies,
the distinctions among Muckle-Wells syndrome, FCAS, NOMID, and CINCA are not
clear, and many believe that they represent a phenotypic expression spectrum of
the same condition. These very rare syndromes are all inherited in an autosomal
dominant fashion. Patients present with recurrent fevers, arthralgias,
myalgias, and varying degrees of ophthalmic involvement with conjunctivitis and
anterior uveitis. The skin findings are typically generalized and consist of
red, edematous papules and plaques. The rash can appear urticarial but is less
pruritic. The attack episodes almost always last less than 24 hours. The
trigger for FCAS is cold exposure, but the other conditions have no known
precipitating factors. Twenty-five percent of patients with Muckle-Wells syn-
drome develop amyloidosis later in life, which may lead to chronic renal
failure. The other conditions also have been reported to lead to amyloidosis,
but much less commonly than Muckle-Wells syndrome. NOMID tends to be the most
severe of the cryopyrinopathies. Patients with NOMID can develop aseptic
meningitis and varying degrees of mental retardation along with
hepatosplenomegaly. These patients can develop a characteristic overgrowth of
cartilage around the knee that is quite noticeable on physical examination.
FMF is inherited in an autosomal
dominant fashion. It is the most common of all the autoinflammatory syndromes.
Patients experience attacks of fever and abdominal pain along with
monoarthritis. Occasionally, pleuritis and pericarditis are also present. The
skin findings consist of an erysipelas-like rash occurring almost exclusively
on the lower extremities. Lesions of palpable purpura may also be present,
indicating a cutaneous vasculitis. The attacks usually last less than 3 days,
with a variable length of time between attacks. Some adults develop renal
dysfunction due to amyloidosis.
TRAPS is inherited in an
autosomal dominant pattern and also can occur sporadically. Patients develop attacks
early in childhood, which consist of fever, abdominal pain, conjunctivitis,
arthralgias, and migratory myalgias. The attacks last longer than in the other
autoinflammatory syndromes. Each attack may last from days to weeks, with
frequent recurrences. Attacks may be precipitated by varying amounts of stress,
both physical and emotional. Again, the development of renal amyloidosis in
adulthood has profound effects on the prognosis and is estimated to occur in
10% of
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. Neutrophils 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 exhibit a perivascular infiltrate of
lymphocytes scattered within the neutrophilic infiltrate. FMF skin biopsies
show a diffuse population of dermal neutrophils. TRAPS skin biopsies are
nondescript and show a bland lymphocytic infiltrate in a dermal perivascular
location. Biopsy of the periorbital edema shows a perivascular lymphocytic
infiltrate and dermal edema.
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| CLINICAL MANIFESTATIONS OF AUTOINFLAMMATORY SYNDROMES |
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 neutrophils and other inflammatory cells. The innate immune
system is nonspecific in nature and does not rely on antibody production.
Various innate pattern recognition receptors (e.g., Toll-like receptors) are
able to recognize 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 those elements.
The autoinflammatory conditions have been discovered to involve defects in various
components 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 dysregulation
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 chromosome 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 hyperactivity of the inflammasome. The
inflammasome is a cytoplasmic soluble conglomeration of various proteins that
is part of the innate immune system and is constantly identifying foreign
material. Its stimulation ultimately increases the activity of the caspase 1
protein and the production of IL-1β. FMF has been found to be caused by a defect
in the MEFV gene, which encodes the pyrin protein. Pyrin is also a
regulator of the inflammasome, and defects in pyrin result in increased levels
of IL-1β. TRAPS is caused by a defective gene on chromosome 12 named TNFRSF1A.
This gene encodes the 55-kd TNF receptor. The defect leads to excessive signaling
due to serum TNF activation of the receptor.
Treatment: Therapy
is specific to each syndrome. The molecular understanding of the pathogenesis
has led to specific therapies. Because of their rarity, no randomized studies
have been performed on the treatment of these conditions. HIDS has been
successfully treated with nonsteroidal antiinflammatory drugs (NSAIDs), statin
medications, and the interleukin antagonist, anakinra. The cryopyrinopathies
have been treated with cold avoidance in the case of FCAS, and NSAIDs, oral
steroids, anakinra, and other immunosuppressants have been tried. FMF has been
treated with good success with colchicine, taking advantage of its
antineutrophil effect. TRAPS has been successfully treated with etanercept or
anakinra. Etanercept is believed to remove the soluble TNF that is responsible for
activating the mutated receptor.
