Key points

Introduction

The autoinflammatory syndromes comprise a clinically distinct set of disorders unified by recurrent febrile episodes accompanied by inflammatory cutaneous, mucosal, serosal, and osteoarticular manifestations. Although these rare disorders often have a striking onset and inflammatory features, they are without an infectious or autoimmune cause. Instead, many are unified by a genetically driven dysregulated innate immune response with resultant activation of the inflammasome and cytokine excess. Hence, these disorders respond to interleukin (IL)-1 or tumor necrosis factor (TNF)-α and generally not to immunosuppressives. Manifestations include periodic fevers, neutrophilic rashes or urticaria, serositis, hepatosplenomegaly, lymphadenopathy, elevated acute phase reactants, neutrophilia, and a long-term risk of secondary amyloidosis.

The identification of the genetic origins underlying certain disorders has rapidly advanced understanding of the immunopathogenesis of autoinflammatory disorders. Affected individuals often have first- or second-degree relatives with similar features. A monogenic defect has been identified for familial Mediterranean fever (FMF), TNF receptor–associated periodic syndrome (TRAPS), hyperimmunoglobulinemia D with periodic fever syndrome (HIDS), and cryopyrin-associated periodic syndromes (CAPS)—which include a spectrum of disorders: familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID). Additional disorders also fall under the autoinflammatory umbrella, because they manifest similar inflammatory features but may or may not have an identifiable genetic cause. Etiologic defects have been discovered for cyclic neutropenia; pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome; pyoderma gangrenosum, acne, and suppurative hidradenitis (PASH) syndrome; deficiency of the IL-1 receptor antagonist (IL-1Ra) (DIRA); and deficiency of the IL-36R antagonist (DITRA). Those without a known cause include systemic-onset juvenile idiopathic arthritis (SoJIA); adult-onset Still disease (AOSD); periodic fever, aphthous stomatitis, pharyngitis, and adenopathy (PFAPA) syndrome (or Marshall syndrome); and Schnitzler syndrome.

Although these disorders are often rare, some are more frequently seen than others. A federally funded German registry was established in 2009 and in a 9-month period they identified 117 patients (65 male and 52 female; ages 1–21 years) with a diagnosis of FMF (n = 84), SoJIA (n = 22), clinically confirmed AIDS (n = 5), TRAPS (n = 3), CAPS (n = 1), HIDS (n = 1), and PFAPA (n = 1). This review focuses on the distinguishing clinical features, onset, fever/flare duration, etiology, and effective treatments—each of which is crucial to establishing an accurate diagnosis.

Introduction

The autoinflammatory syndromes comprise a clinically distinct set of disorders unified by recurrent febrile episodes accompanied by inflammatory cutaneous, mucosal, serosal, and osteoarticular manifestations. Although these rare disorders often have a striking onset and inflammatory features, they are without an infectious or autoimmune cause. Instead, many are unified by a genetically driven dysregulated innate immune response with resultant activation of the inflammasome and cytokine excess. Hence, these disorders respond to interleukin (IL)-1 or tumor necrosis factor (TNF)-α and generally not to immunosuppressives. Manifestations include periodic fevers, neutrophilic rashes or urticaria, serositis, hepatosplenomegaly, lymphadenopathy, elevated acute phase reactants, neutrophilia, and a long-term risk of secondary amyloidosis.

The identification of the genetic origins underlying certain disorders has rapidly advanced understanding of the immunopathogenesis of autoinflammatory disorders. Affected individuals often have first- or second-degree relatives with similar features. A monogenic defect has been identified for familial Mediterranean fever (FMF), TNF receptor–associated periodic syndrome (TRAPS), hyperimmunoglobulinemia D with periodic fever syndrome (HIDS), and cryopyrin-associated periodic syndromes (CAPS)—which include a spectrum of disorders: familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID). Additional disorders also fall under the autoinflammatory umbrella, because they manifest similar inflammatory features but may or may not have an identifiable genetic cause. Etiologic defects have been discovered for cyclic neutropenia; pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome; pyoderma gangrenosum, acne, and suppurative hidradenitis (PASH) syndrome; deficiency of the IL-1 receptor antagonist (IL-1Ra) (DIRA); and deficiency of the IL-36R antagonist (DITRA). Those without a known cause include systemic-onset juvenile idiopathic arthritis (SoJIA); adult-onset Still disease (AOSD); periodic fever, aphthous stomatitis, pharyngitis, and adenopathy (PFAPA) syndrome (or Marshall syndrome); and Schnitzler syndrome.

Although these disorders are often rare, some are more frequently seen than others. A federally funded German registry was established in 2009 and in a 9-month period they identified 117 patients (65 male and 52 female; ages 1–21 years) with a diagnosis of FMF (n = 84), SoJIA (n = 22), clinically confirmed AIDS (n = 5), TRAPS (n = 3), CAPS (n = 1), HIDS (n = 1), and PFAPA (n = 1). This review focuses on the distinguishing clinical features, onset, fever/flare duration, etiology, and effective treatments—each of which is crucial to establishing an accurate diagnosis.

Etiology

Immune responses are either innate or adaptive. The adaptive immune response recognizes self from nonself and generates antigen-specific cellular and cytokine responses, and, with activation-driven autoantibody production, the adaptive responses can establish immunologic memory or immune tolerance. By contrast, the innate immune response acts with immediacy to danger or pathogen signals, termed pathogen-associated molecule patterns ( PAMPs ) and endogenous damage-associated molecular patterns ( DAMPs ). PAMPs and DAMPs activate intracellular inflammasomes to set forth an inflammatory cascade of effector molecules. For example, the NLRP3 inflammasome is a cytosolic scaffold of proteins triggered by PAMPs (microbial pathogens, monosodium urate, and toxins) and DAMPs (ATP, membrane disruption, oxygen radicals, and hypoxia). A disrupted, dysregulated innate immune system yields a proinflammatory state, with the final common pathway being activation of the NLRP3 gene and the inflammasome, with resultant unopposed cytokine excess. Activation of the inflammasome yields increased production of proinflammatory cytokines, such as IL-1, IL-18, TNF-α, IL-6, IL-17, type 1 interferons (IFN-α and IFN-β), and the complement system. The inflammasome is a complex of proteins that activates caspase-1, leading to cleavage of inactive pro-IL-1β to active IL-1β. The critical role of the inflammasome in these disorders has led some to refer to the autoinflammatory disorders as inflammasomopathies .

TRAPS

TRAPS is also known as familial Hibernian fever, owing to a higher frequency of this syndrome in those of Irish, Scottish, or Austrian or Northern European dissent. Nevertheless, it has been described in other ethnic groups, including Mediterraneans. TRAPS differs from FMF and HIDS by having febrile attacks that last 1 to 3 weeks and occasionally up to 6 weeks. Characteristic features include fever, arthralgia, myalgia, migratory rash, abdominal pain, pleuritis, conjunctivitis, periorbital edema, oral ulcers, and scrotal swelling. Skin manifestations include migratory macular erythematous rash or patches, ecchymoses, edematous dermal plaques, serpiginous or annular lesions, and periorbital edema. Limited skin biopsies showed perivascular and interstitial lymphocytic and mononuclear infiltrates without evidence of granulomatous or vasculitic change.

The genetics underlying this disorder was clarified by studies of a large Irish multiplex family who demonstrated an autosomal dominant syndrome characterized by recurrent fever, rash, and abdominal pain. Fevers last more than 5 days and less than 6 weeks. The vast majority (75%–88%) has childhood onset, usually as toddlers at approximately age 3 years and most occurring before age 10 years. Adult onset may occur. Manifestations of TRAPS depend on the mutations for the gene encoding p55 TNF receptor type I (CD120a). There are 46 known missense mutations involving TNF receptor type I, all of which are localized to distal chromosome 12p. The R92Q and P46L mutations are seen in 4% and 1% of the population, respectively, and tend to have low penetrance and less severe disease. The R92Q and T61I polymorphisms may be found with an adult onset and are often associated with rheumatoid arthritis, lupus, or multiple sclerosis. There is effective treatment with etanercept, which has been shown to reduce the frequency and severity of flares. There are reports of efficacy with anakinra and worsening with infliximab.

Hyper IgD syndrome

HIDS is a rare disorder that begins early in life, usually before 2 years of age. Most reports have been seen in those of northern European, Dutch, or French ancestry. HIDS has inflammatory symptoms lasting 3 to 7 days with recurrent fever, chills, cervical lymphadenopathy, abdominal pain, hepatosplenomegaly, diarrhea, arthralgia or arthritis, aphthous ulcers, skin rash (usually palmar/plantar), and headaches. Vaccinations may precipitate in inflammatory attacks in some patients. High levels of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and serum amyloid A are seen, and IgD levels greater than 100 IU/dL are sensitive but not specific for HIDS. In 1999, mevalonate kinase (MVK) gene mutations were found in patients with HIDS. Currently, tests for the MVK gene are the gold standard in diagnostic testing. HIDS is an autosomal recessive disorder, with defects in the gene encoding MVK, an enzyme central to cholesterol synthesis. Although colchicines and steroids are sometimes effective, anakinra has become the drug of choice because it has been more uniformly beneficial in observational reports.

Familial mediterranean fever

FMF is the most common of the ancestral or monogenic autoinflammatory disorders. FMF preferentially affects Sephardic Jews, Armenians, Turks, North Africans, Arabs, Moroccans, and others whose familial origins can be traced to the Mediterranean basin. Although the vast majority of cases have Mediterranean roots, ancestry should not exclude this diagnosis or the need for genetic testing if the clinical picture is suggestive, because many non-Mediterraneans have been diagnosed with FMF. The disorder often begins in childhood or adolescence, and up to 20% may have their first attack after the age of 20 years. Younger cases usually have more striking features, and severity lessens with age. FMF is characterized by febrile episodes accompanied by cutaneous, serosal, or synovial/tenosynovial inflammation. Fevers are usually 38°C or higher and last 1 to 3 days, ending as abruptly as they begin. Bouts are unpredictable in their frequency and are usually without known triggers but may be provoked by infection, stress, exercise, or surgery. Cutaneous features are distinctive, if not pathonomonic, and manifest as unilateral, more so than bilateral, erysipelas-like erythema that is often painful and located on the extensor surface of the arms, legs, or dorsum of feet. Also distinctive is the occurrence of recurrent inflammatory, sterile, monarticular inflammatory joint effusions or tenosynovial swelling. Less commonly, myalgia, migratory arthritis, and destructive/erosive arthritis may occur. Serositis manifests as either pleuritis or peritonitis with abdominal pain and, less frequently, as pericarditis or scrotal swelling. Rare manifestations include aseptic meningitis, orchitis, and vasculitis. Laboratory findings include leukocytosis and marked elevations of the ESR and CRP during the attacks. Amyloidosis may complicate FMF with serum amyloid A deposition in the kidney or other organs. Amyloidosis is more common with M694V homozygocity, male patients, and the alpha/alpha serum amyloid A1 gene. Amyloidosis is unrelated to the severity of FMF and can be diagnosed by biopsy of the rectum, kidney, abdominal fat, or bone marrow.

FMF results from a recessive mutation of the MEFV or Mediterranean Fever gene 16p13. This recessive mutation is located on the short arm of the chromosome 16. The zygosity and type of mutation determines the severity of the disorder and age of onset in many. In FMF, there are more than 80, mostly missense, mutations with the 5 most common genotypes (M694V, M6941, M680I, V726A, and E148Q) accounting for nearly 80% of cases. The dominant mutation depends on the population: V726A is common among Ashkenazi and Iraqi Jews, Druzes, and Armenians; M680I is frequent in Armenians and Turks; M694I and A744S in Arabs; and R761H in Lebanese patients. MEFV is found in neutrophils and myeloid cells and encodes an 86-kDa protein, called pyrin (or marenostrin). Defective pyrin function leads to uncontrolled inflammation with elevated levels of IFN-γ and circulating proinflammatory cytokines, including TNF-α, IL-1, IL-6, and IL-8.

Many patients with FMF respond favorably to colchicine. Colchicine is effective in both aborting and preventing attacks and, when used chronically, decreases the risk of amyloidosis. Most patients respond well with only a minority refractory to colchicine—either because of dose-limiting gastrointestinal toxicity or more-aggressive disease. Steroids may be effective but are seldom needed. Refractory cases respond well to IL-1 inhibition (with anakinra, canakinumab, or rilonacept).

The diagnosis of FMF should be a largely clinical one, based on recurrent 1- to 4-day bouts of fever with synovial, serosal, or skin inflammation and high acute-phase proteins. Confirmation by MEFV testing may be necessary in atypical cases and those evidently not of Mediterranean ancestry.

Cryopyrin-associated periodic syndromes (cryopyrinopathies)

The CAPS are a distinct subset of autosomal dominant disorders etiologically connected by mutations of the NACHT domain of NLRP3, previously known as cryopyrin. NLRP3 (which stands for NOD-like receptor family pyrin domain 3) includes the cold-induced autoinflammatory syndrome 1 (CIAS1) gene and, as such, much of the literature suggests that these disorders are related to defects in CIAS1. CIAS1 encodes for cryopyrin, a protein similar to pyrin that is also expressed primarily in neutrophils and monocytes. CAPS include familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal onset multisystem inflammatory disease (NOMID) also known as chronic infantile neurologic cutaneous and articular syndrome (CINCA). The severity of disease is milder in FCAS and MWS but tends to be the most severe in NOMID, with often devastating neurologic complications. Common features of CAPS, regardless of the specific clinical entity, include fever, urticarial-like rash, conjunctivitis, bone and joint symptoms, and elevated inflammatory markers, such as CRP. There is little/no risk of amyloidosis with chronicity. CAPS patients have uniformly responded well to IL-1 inhibition (anakinra, rilonacept, and canakinumab).

FCAS begins in infancy and is unique by being provoked by cold exposure, with brief episodes (lasting <24 h) of urticarial-like rash, fever, conjunctivitis, and joint/limb pain. Although some patients have significant disability related to these attacks, long-term prognosis is favorable for most.

MWS has an older onset (adolescents and young adults), with fevers lasting up to 7 days. Frequent attacks and chronicity may be accompanied by sensorineural hearing loss or deafness and a long-term risk of amyloidosis.

NOMID is the most severe form of CAPS and differs from FCAS and MWS by being chronic, rather than episodic, in its manifestations. It is characterized by a neonatal or infantile onset of chronic urticarial rash, low-grade fever, otolaryngologic findings, sensorineural hearing loss, tinnitus, and, later, chronic aseptic meningitis, which may result in cerebral atrophy, seizures, hearing and vision loss, and mental retardation. NOMID patients may develop a distinctive overgrowth of the epiphyses in the long bones, with resultant deformity, leg length discrepancy, joint contractures, or premature degenerative arthritis. Late closure of the fontanel leads to frontal bossing. Amyloidosis is a known risk and mortality may be as high as 20%. Before administration of IL-1 antagonistic therapy, the prognosis for patients with NOMID was poor.