The Inherited Autoinflammatory Syndrome: A Decade of Discovery

Abstract

The hereditary autoinflammatory diseases arise from mutations of genes regulating the innate immune system. These rare disorders are well characterized, both clinically and in terms of their molecular pathogenesis. The recurrent attacks of febrile polyserositis of Familial Mediterranean Fever (FMF) are due to defective pyrin, a protein that down-regulates inflammation. The Hyperimmunoglobulinemia D Syndrome (HIDS), which mimics FMF, results from a genetically conferred deficiency of mevalonate kinase. TRAPS (TNF Receptor Associated Periodic Syndrome), formerly known as Familial Hibernian Fever, is caused by a defective membrane receptor for TNF. Three other hereditary disorders which overlap in their clinical expression - Familial Cold Autoinflammatory Syndrome, the Muckle Wells syndrome, and Neonatal Onset Multisystem Inflamatory Disease (NOMID) - are a consequence of gain-of-function mutations of the gene encoding cryopyrin, the scaffolding protein of the inflammasome. The PAPA syndrome (Pyogenic Arthritis, Pyoderma gangrenosum, Acne) results from mutations of a gene that increases the binding of its product (PSPSTPIP1) to pyrin, thereby blunting the inhibitory effect of pyrin on inflammasome activation.

The past decade has witnessed tremendous growth in our knowledge of an expanding number of hereditary auto-inflammatory diseases. These advances relate to both their clinical characteristics and to our understanding of the molecular basis for many of them. In each of these diseases, inflammatory episodes recur, often with minimal or no evidence of a provocative event. Inflammation is triggered by the innate immune system. Patients do not evidence high titer auto-antibodies or antigen-specific T cells that might serve as mediators.

FAMILIAL MEDITERRANEAN FEVER

Familial Mediterranean fever (FMF) is the most widely known and the most prevalent of these inherited disorders The cardinal feature of FMF is recurrent attacks of fever with associated serosal inflammation (¹). The latter most often takes the form of sterile peritonitis but pleuritis, arthritis and rarely, pericarditis may be part of the clinical picture. In addition, a few FMF patients develop an erysipelas-like rash over their lower legs. The inflammatory episodes usually last one to three days, and they subside spontaneously. The patient returns to full, robust health during interim periods. The attacks may occur anywhere from once every ten days to as infrequently as once or twice a year. The most dreaded complication of untreated FMF is amyloidosis, which eventuates in renal failure in as many as 20% of patients in some populations. However the advent of daily colchicine therapy, introduced in the early 1970's, has provided complete protection against the development of amyloidosis, as well as the known effect of this hoary drug in abolishing or markedly attenuating the inflammatory episodes (²). The recommended dosage is 1.2 mg/day; it may be doubled in patients who do not achieve satisfactory remission on this regimen. Colchicine is generally very well tolerated. Some patients may experience mild diarrhea that is easily controlled by over-the-counter preparations. The drug's effect is probably mediated by its property of disaggregating the microtubular elements of neutrophils, thus impairing their participation in the inflammatory cycle. The gene for FMF, MEFV, was cloned in 1997 (³). It encodes a 781 amino acid protein known as pyrin. Pyrin is believed to have both intranuclear and cytoplasmic actions. Within the nucleus it acts via NF-β to either down regulate pro-inflammatory cytokines or conversely, up regulate anti-inflammatory cytokines. Within the cytoplasm, pyrin most likely modulates the cytoskeletal events in neutrophils. It also attenuates the production of IL-1β by inflammasomes.

HYPERIMMUNOGLOBULINEMIA D SYNDROME

Hyperimmunoglobulinemia D syndrome (HIDS) is a much rarer disease than FMF. It has been described mainly in European populations. It is inherited in autosomal recessive manner. The defective gene resides on chromosome 12q and encodes the enzyme mevalonate kinase (⁴). Attacks may be triggered by vaccinations or minor infections and last longer than those seen in FMF, the usual duration being between 3 and 7 days. Along with abdominal pain, patients may experience headaches, cervical lymphadenopathy, arthritis and diarrhea (⁵). Amyloidosis has been reported only rarely in HIDS. The deficiency in mevalonate kinase in HIDS patients is less severe than that occurring in mevalonic aciduria, which is characterized by ataxia, mental retardation, fevers and early death. Mevalonic kinase activity in HIDS patients is generally in the range of 5–15% of normal as compared to 0–4% in mevalonic aciduria. The mevalonic kinase deficiency is believed to predispose to inflammatory attacks due to diminished amounts of downstream anti- inflammatory isoprenylated proteins such as farnesylpyrophosphate. Most, but not all patients have elevated levels of immunoglobulin D. Despite its prominence in the nomenclature of this syndrome, there is no evidence that increased levels of immunoglobulin D contribute to its pathogenesis. HIDS does not respond to colchicine; anakinra has been reported to be a useful therapy.

TNF Receptor Associated Periodic Fever

TNF Receptor Associated Periodic Fever (TRAPS), formerly known as Familial Hibernian fever, results from a defective gene on chromosome 12p that encodes the cellular membrane receptor protein for TNF (⁶). Most of the 46 known mutations are at the extracellular portion of the protein. One proposed mechanism for TRAPS-associated inflammation is sustained TNF stimulation of target cells due to impaired shedding of the p55 component of this receptor protein. A rare disorder, TRAPS was originally described as occurring among individuals of Irish and Scottish descent but patients of other ancestries have since been reported. Febrile episodes last anywhere from 1 to 6 weeks and as in FMF, sterile peritonitis, pleuritis and arthritis form part of the clinical constellation. Quite distinctive of TRAPS is the concurrence of severe myalgias and migratory lymphedema during attacks as a consequence of a monocytic fasciitis. Other unusual features of this disorder are conjunctivitis and the development of inguinal hernias in males. TRAPS patients also may evidence erythematous rashes during attacks. A small minority of patients develop amyloidosis. There are no diagnostic laboratory tests for TRAPS. Anti-inflammatory drugs, NSAIDs and glucocordicoids are used to terminate attacks. Etanercept is recommended as a form of chronic therapy to prevent attacks. Anakinra has also been reported to suppress ongoing attacks.

THE CRYOPYRINOPATHIES

These three disorders, which overlap in their clinical expression, arise from gain-of-function mutations of the gene encoding cryopyrin, an essential component of the inflammasome. As a result of these mutations, hyperactivation of the inflammasome results in increased caspase-1 generation leading to hypersecretion of IL-1 Another proinflammatory event, activation of IL-6, is mediated via NF-β. The phenotypic differences among the three cryopyrinopathies are related to variation in the biological effects of the 41 known mutations of the cryopyrin gene. The cryopyrinopathies are inherited as autosomal dominants (^{7, 8}).

Familial Cold Autoinflammatory Syndrome:

Familial Cold Autoinflammatory Syndrome (FCAS) is the mildest of the three cryopyrinopathies. Symptoms often develop in childhood and tend to worsen with age. Approximately 150 cases of FCAS have been identified in the United States. Patients tend to live in the mid-southern states, south of winter freezing and north of constant exposure to air conditioning in the summertime. Exposure to cold typically brings on a pruritic, painful rash (⁹). Conjunctivitis, fever, joint symptoms, fatigue and headache may be part of clinical syndrome. Hearing loss, a more constant feature of the more severe cryopyrinopathies, is rare. Amyloidosis develops in fewer than 5% of patients. Anakinra is the agent of choice in treating FCAS.

Muckle-Wells Syndrome:

Muckle-Wells Syndrome (MWS) is encountered mainly in Europe. Its onset occurs during the first two decades of life. Triggers to inflammatory attacks other than exposure to cold include stress and exercise. In addition to episodes of fever, rash, arthralgias, abdominal pain and conjunctivitis, MWS patients develop progressive sensi-neural sensorineural deafness. As many as 25% of them will be burdened with the nephropathy of amyloidosis. Again, anakinra is the current choice of drug to control the inflammatory attacks. It may also play a role in protecting against amyloid deposition (^{10, 11}).

Neonatal Onset Multisystem Inflammatory Disease:

Neonatal Onset Multisystem Inflammatory Disease (NOMID) bears an alternate complex descriptive name, CINCA (Chronic Infantile Neurological Cutaneous and Articular syndrome). It is the most severe of the cryopyrinopathies (¹²). Along with fevers, rash, and hearing loss, NOMID patients experience major deforming joint disease, uveitis, chronic meningitis, cerebral atrophy and delayed development. They, too, are susceptible to amyloidosis. Death within the first two decades occurs in 20% of NOMID patients. In addition to anakinra, other therapies that may suppress disease progression include steroids, etanercept, possibly thalidomide, as well as a newly developed humanized anti IL-6 receptor monoclonal antibody.

Pyogenic Arthritis, Pyoderma Gangrenosum Acne (PAPA) Syndrome:

The metabolic lesion causing the PAPA syndrome is alteration of the protein PSTPIP-1 (proline, serine, threonine, phosphatase interactive protein). PSTPIP-1 co-localizes with pyrin in neutrophils. Mutations in its encoding gene produces a hyperphosphorylated product. The hyperphosphorylated PSTPIP-1 binds more avidly to pyrin, and in so doing, reduces pyrin's braking on inflammasome activation. Inherited as an autosomal dominant, the PAPA syndrome is characterized by sterile pyogenic arthritis, pyoderma gangrenosum and acne (¹³). The onset of acne coincides with puberty. Sterile skin abscesses may also be encountered

THE FUTURE

These periodic inflammatory syndromes and their correlation with mutated genes that encode mediators with inflammation is a fascinating story to date. However, it is by no means complete, for there may be even more syndromes to be discovered. The Amyloidosis Center of the Royal Free Hospital recently reported on the results of 1,003 patients with periodic fevers referred for genetic screening. Only 27% of this group proved to be positive for known mutations in genes encoding for the known hereditary inflammatory disorders.