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Monday, April 12, 2021


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.


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.

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.

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