Autoinflammatory diseases mediated by inflammasomes and related IL-1 family cytokines (inflammasomopathies)

INTRODUCTION — 

Autoinflammatory diseases are conditions of pathogenic chronic or recurrent inflammation mediated by aberrant antigen-independent activation of the immune system. A broad spectrum of autoinflammatory diseases is now recognized, differing markedly from one another in pathogenesis and clinical manifestations. This topic covers autoinflammatory diseases that originate in aberrant activation of the inflammasome, sometimes termed "the inflammasomopathies." A general discussion of autoinflammatory diseases is available separately. (See "The autoinflammatory diseases: An overview".)

Additional topics cover other specific autoinflammatory diseases:

●(See "Familial Mediterranean fever: Epidemiology, genetics, and pathogenesis" and "Clinical manifestations and diagnosis of familial Mediterranean fever" and "Management of familial Mediterranean fever".)

●(See "Cryopyrin-associated periodic syndromes and related disorders".)

●(See "Hyperimmunoglobulin D syndrome: Pathophysiology" and "Hyperimmunoglobulin D syndrome: Clinical manifestations and diagnosis" and "Hyperimmunoglobulin D syndrome: Management".)

●(See "Tumor necrosis factor receptor-1 associated periodic syndrome (TRAPS)".)

●(See "Autoinflammatory diseases mediated by interferon production and signaling (interferonopathies)".)

●(See "Autoinflammatory diseases mediated by NFkB and/or aberrant TNF activity".)

●(See "Autoinflammatory diseases mediated by miscellaneous mechanisms".)

●(See "Deficiency of adenosine deaminase 2 (DADA2)".)

OVERVIEW OF THE INFLAMMASOME — 

Inflammasomes are cytoplasmic protein complexes whose triggered assembly unleashes a set of highly proinflammatory consequences, including but not limited to activation and release of interleukin (IL) 1-beta and other proteins (figure 1) [1,2].

●Inflammasomes are activated by a range of pathogen-derived or environmental signals. Detection of these stimuli triggers formation of a large cytoplasmic multimolecular complex that serves to activate a protease that in turn activates effector molecules such as IL-1-beta. The result is release of IL-1-beta and IL-18 and sometimes a proinflammatory form of cell death termed pyroptosis [3].

●The three major elements of an inflammasome are a scaffold protein that regulates its assembly; the protease caspase 1, also called IL-1-converting enzyme; and the linker/adaptor protein apoptosis-associated speck-like protein containing a C-terminal caspase-recruitment domain (ASC) that connects these molecules together, enabling molecules of caspase 1 to activate each other via proteolysis. Many ASC molecules form part of a single inflammasome, providing a large surface area for caspase 1 activation. A video model of inflammasome assembly is available.

●There are at least six different inflammasomes that contain all three archetypal components, distinguished by the scaffold protein that regulates their assembly. These scaffold proteins are pyrin, cryopyrin (also called nucleotide-binding oligomerization domain-like receptor family, caspase recruitment domain-containing [NLRC] 3), NLRC4, nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing (NLRP) 1B, NLRP12, and absent in melanoma (AIM) 2. Each protein resides in an inactive form in the cytoplasm until exposed to specific triggers, whereupon conformational changes enable it to initiate inflammasome formation. A further inflammasome, called the noncanonical inflammasome, is triggered by intracellular bacterial lipopolysaccharide, recognized directly by caspases 4 and 5 without an intermediate scaffold protein [2]. The noncanonical inflammasome preferentially cleaves pro-IL-18 [4,5].

●Upon activation, caspase 1 can remain associated with the inflammasome or diffuse away into the cytoplasm. Caspase 1 cleaves inactive pro-IL-1-beta into IL-1-beta. It also cleaves other IL-1 family cytokines, converting inert pro-IL-18 to active IL-18 and deactivating IL-33. Generation of IL-1-beta requires transcription of procytokine followed by processing through an active inflammasome, a two-step regulatory system that provides tight control of this potent proinflammatory mediator. By contrast, pro-IL-18 is expressed constitutively, with further production induced by inflammatory stimuli [6].

●IL-1-beta and IL-18 lack signal sequences required for release through conventional mechanisms. Instead, the inflammasome enables their secretion by cleaving another protein termed gasdermin D [7]. Cleaved gasdermin D inserts into the cell membrane, forming pores that allow cytokine exit, selecting preferentially for mature IL-1-beta and IL-18 on the basis of charge [8]. Inflammasome activation may also enable release of IL-1-alpha [9]. These pores also disrupt transmembrane electrolyte gradients, potentially triggering a proinflammatory form of cell death termed pyroptosis that can entrap intracellular pathogens [10].

●Inflammasomes can be "turned off" by encapsulation in an intracellular vacuole, a process termed autophagy [11]. Intact inflammasomes can be released from cells, although the biologic importance of extracellular inflammasomes is unknown [12,13].

DISEASES RELATED TO INFLAMMASOME ACTIVATION — 

The inflammasome-mediated diseases can be grouped according to inflammasome affected (table 1).

The pyrin inflammasome — The inflammasome scaffold protein pyrin is encoded by the gene MEFV, a name that reflects its role as the gene responsible for familial Mediterranean fever (FMF) [14,15]. Pyrin is normally maintained in an inactive state due to phosphorylation by the kinase Ras homolog gene family, member A (RhoA), a protein also involved in cell migration. Many pathogens seek to evade the immune system by producing toxins that inactivate RhoA; these toxins thereby also release pyrin from inhibition, facilitating host defense through formation of the pyrin inflammasome [2,16]. Microtubules participate in normal pyrin inflammasome assembly, potentially helping to explain the therapeutic value of the microtubule inhibitor colchicine [17]. Genetic defects affecting the pyrin inflammasome are implicated in several autoinflammatory diseases.

Familial Mediterranean fever — FMF (MIM #249100) is the most common of the monogenic autoinflammatory syndromes. FMF arises from gain-of-function pathogenic variants in MEFV, resulting in accelerated formation of the pyrin inflammasome. Specifically, as a defense against the pyrin inflammasome, Yersinia pestis (the plague bacterium) evolved a toxin termed YopM that bridges pyrin with its phosphorylating enzymes to keep pyrin in its inactive phosphorylated state, even when RhoA is inactivated. Human mutations in MEFV that cause FMF are relatively resistant to this toxin and so provide some degree of protection against plague, helping to explain why there are multiple founder mutations and why FMF gene carriage rates are high in regions where plague is endemic [18,19].

Most patients with FMF have pathogenic variants in both alleles, but a substantial minority have only one pathogenic variant. Indeed, mice rendered deficient in pyrin remain largely well, while those rendered transgenic for an FMF-associated pyrin variant develop inflammatory disease [20]. Thus, it is the presence of hyperfunctional pyrin that is the cause of inflammation in FMF, reflecting escape from regulatory mechanisms that normally constrain assembly of the pyrin inflammasome [2]. Accordingly, although historically considered to be autosomal recessive, FMF is now commonly regarded as autosomal dominant with limited penetrance and a gene-dose effect.

FMF is characterized by episodic attacks of fever lasting one to three days. Most patients also experience abdominal pain, pleurisy, and arthralgias or arthritis, the result of accompanying serositis and synovitis. Attacks are accompanied by an elevation in peripheral white blood cell count and acute-phase markers, while fluid from inflamed joints exhibits a neutrophil-predominant leukocytosis. Persistent inflammation can lead to secondary (amyloid A [AA]) amyloidosis.

The diagnosis may be strongly suggested by patient ethnicity. Sephardic Jews; Armenians; North Africans; Turks; and, to a lesser extent, Ashkenazi Jews, Greeks, and Italians are potential carriers [21]. However, persons outside of these groups have also been affected. (See "Familial Mediterranean fever: Epidemiology, genetics, and pathogenesis", section on 'Epidemiology'.)

The pathophysiology, clinical manifestations, diagnosis, and management of FMF are discussed separately. (See "Familial Mediterranean fever: Epidemiology, genetics, and pathogenesis" and "Clinical manifestations and diagnosis of familial Mediterranean fever" and "Management of familial Mediterranean fever".)

Pyrin-associated autoinflammation with neutrophilic dermatosis — Pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND; MIM #608068) is caused by pathogenic variants in MEFV that disrupt its phosphorylation by RhoA, resulting in constitutive assembly of the pyrin inflammasome [22,23]. Cell activation that induces production of pro-IL-1-beta, for example by bacterial lipopolysaccharide, thereby becomes sufficient to trigger generation and release of the highly potent inflammatory mediator IL-1-beta. Patients with PAAND may have prolonged episodes of fever lasting up to a few weeks and characteristically exhibit severe neutrophil skin inflammation, including cystic acne, hidradenitis suppurativa, and pyoderma gangrenosum, in addition to arthralgia/arthritis and myalgia/myositis. Like FMF, the familial pattern is autosomal dominant with limited penetrance. IL-1-beta antagonism may be effective, but some patients respond better to tumor necrosis factor (TNF) inhibition [22,23]. (See "Neutrophilic dermatoses".)

Other pyrin-associated autoinflammatory syndromes — A range of additional syndromes have been reported in patients bearing MEFV mutations, including neuroinflammation and hypereosinophilia; these patients respond to typical FMF treatments [24].

Hyperimmunoglobulin D syndrome — Hyperimmunoglobulin D syndrome (HIDS; MIM #260920, mevalonate kinase deficiency) is an autosomal recessive periodic fever syndrome usually associated with pathogenic variants in the MVK gene that encodes mevalonate kinase, a key enzyme in the nonsterol isoprenoid biosynthesis pathway. These pathogenic variants reduce, but do not abolish, mevalonate kinase activity. This defect impairs phosphorylation of pyrin, resulting in inflammation mediated through the pyrin inflammasome [25,26].

More than two-thirds of patients with HIDS present within the first year of life, typically with episodic attacks of fever lasting three to seven days, accompanied, in most cases, by chills, cervical lymphadenopathy, abdominal pain, and vomiting or diarrhea. Some patients experience headache, arthralgias or arthritis, aphthous ulceration, a pleomorphic rash, and, occasionally, splenomegaly. Attacks may be precipitated by vaccination, viral infection, trauma, and stress.

Many patients have characteristic abnormalities in immunoglobulins, including elevated levels of immunoglobulin D (IgD; >100 international units/mL) and elevated immunoglobulin A (IgA), although both can be within the normal range, and both lack specificity, limiting their utility for diagnosis. (See "Hyperimmunoglobulin D syndrome: Clinical manifestations and diagnosis", section on 'Laboratory findings'.)

Pathogenic variants in MVK that abolish enzyme activity result in mevalonic aciduria (MIM #610377), an autosomal recessive disease characterized by developmental delay, hepatosplenomegaly, dysmorphic features, and failure to thrive in addition to episodic fevers.

The clinical manifestations, diagnosis, pathophysiology, and management of HIDS are discussed in detail elsewhere. (See "Hyperimmunoglobulin D syndrome: Clinical manifestations and diagnosis" and "Hyperimmunoglobulin D syndrome: Pathophysiology" and "Hyperimmunoglobulin D syndrome: Management".)

PAPA syndrome — The syndrome of pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA; MIM #174200) is a rare, autosomal dominant condition resulting from pathogenic variants affecting the gene PSTPIP1, encoding the protein proline/serine/threonine phosphatase-interacting protein 1 [27]. PSTPIP1 and pyrin interact to promote development of a pyrin inflammasome independent of pyrin dephosphorylation [28-30]. Patients with PAPA typically exhibit very elevated levels of circulating IL-18, unlike patients with FMF, who exhibit either normal or modestly elevated levels of this cytokine [31]. IL-18 induces interferon gamma, which in turn induces pyrin, suggesting a pyrin inflammasome-positive feedback loop localized to inflamed tissues [30].

PAPA presents in the first decade of life with oligoarticular, destructive arthritis, typically involving the elbow, knee, and/or ankle [32]. Severe cystic acne develops in most patients in early adolescence, while pyoderma gangrenosum and pathergy-like sterile abscesses at injection sites occur in a subset of patients. Bone marrow suppression in the event of exposure to sulfonamide medications may also be observed. Some patients may manifest PAPA together with hidradenitis suppurativa (PAPASH syndrome) [33].

Treatment of PAPA syndrome often requires multiple agents. Glucocorticoids can be employed for short-term disease control, and some patients exhibit excellent response to anti-TNF therapy [34]. Patients frequently respond to IL-1 blockade, but these responses may be partial [35-37]. The postulated role of interferon gamma as part of a pyrin inflammasome positive feedback loop led to the observation that Janus kinase (JAK) inhibitors can provide substantial relief in refractory disease, either as monotherapy or coupled with IL-1 blockade [30]. (See "Pyoderma gangrenosum: Pathogenesis, clinical features, and diagnosis" and "Pyoderma gangrenosum: Treatment and prognosis" and "Pathogenesis, clinical manifestations, and diagnosis of acne vulgaris".)

PAMI syndrome — PSTPIP1 is implicated in a related autoinflammatory disease, PSTPIP1–associated myeloid-related proteinemia inflammatory (PAMI) syndrome (formerly called hyperzincemia and hypercalprotectinemia, Hz/Hc; MIM #194470) [38-40]. Patients with this disease exhibit prominent systemic inflammation, with manifestations that may include skin inflammation, arthritis, lymphadenopathy, hepatosplenomegaly, and cytopenias including neutropenia, anemia, and thrombocytopenia. Associated mutations in PSTPIP1 are distinct from those in PAPA and further increase the affinity between PSTPIP1 and pyrin. Compared with PAPA patients, persons with PAMI exhibit markedly elevated concentration of S100 protein complex migration inhibitory factor-related protein (MRP) 8/14 and of zinc, which binds MRP8/14. Response to IL-1-beta blockade, TNF blockade, and cyclosporine is observed but inconsistent, and some patients have required allogenic hematopoietic cell transplantation, which was successful [38,40].

Periodic fever, immunodeficiency, and thrombocytopenia (PFIT) — Patients with PFIT, which is caused by homozygous missense mutations in WD40 repeat domain 1 (WDR1), a protein involved in disassembly of the actin cytoskeleton [41], develop thrombocytopenia and a spontaneous autoinflammatory disease characterized by neutrophilic infiltration of multiple tissues [42]. Neutropenia and neutrophil dysfunction are also observed [43]. In mice bearing a hypomorphic mutation in the Wdr1 gene, the pyrin inflammasome interacts with the cytoskeleton, and inflammation is mediated largely through pyrin and the monocyte-derived IL-18, although not by IL-1-beta, a divergence that may reflect the different priming and activation signals governing generation of these mediators [44]. Some but not all patients bearing mutations in WDR1 exhibit elevation of circulating IL-18 [41,43]. Two siblings with PFIT presented in the first weeks of life with recurrent systemic inflammation [41]. Fevers lasting three to seven days recurred every 6 to 12 weeks, with accompanying elevation in erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and circulating IL-18. Other features included oral ulcers with scarring, perianal ulcers, thrombocytopenia, and immunodeficiency with susceptibility to bacterial and fungal (Pneumocystis jirovecii) pathogens. Glucocorticoids, colchicine, and IL-1 blockade had modest effects. One patient died, and the other recovered with allogenic hematopoietic cell transplantation.

NOCARH syndrome — Patients with mutations in cell division cycle 42 (CDC42) can develop a syndrome characterized by Neonatal Onset of panCytopenia, Autoinflammation, Rash, and episodes of Hemophagocytic lymphohistiocytosis (NOCARH) [45]. CDC42 is a GTPase that functions as an intermediary in multiple intracellular processes, including pyrin inflammasome assembly [46,47]. As a result of mutant protein mistrafficking, patient peripheral blood mononuclear cells produce abundant IL-1-beta and IL-18 [45,46]. Mutant CDC42 alters Golgi trafficking, resulting in failure of stimulator of interferon genes (STING) to translocate properly to the endoplasmic reticulum, leading to its activation and production of high levels of type I interferons in CDC42 variants associated with inflammatory disease, not in variants associated only with developmental delay and dysmorphology (Takenouchi-Kosaki syndrome) [48]. Correspondingly, patients exhibit an interferon transcriptional signature [48,49]. Nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB) overactivation is also reported [50]. Whereas IL-1 antagonists partially ameliorate the phenotype, recurrent hemophagocytic lymphohistiocytosis (HLH) proved fatal except in a patient treated with interferon gamma blockade as a bridge to allogenic bone marrow transplantation, which appeared curative [45]. The JAK inhibitor ruxolitinib was effective in one patient with NOCARH, suggesting a key role for the interferon pathway in disease pathogenesis [49].

The cryopyrin inflammasome — Diseases resulting from pathogenic variants in the cryopyrin gene NLRP3 were the first autoinflammatory diseases recognized to reflect aberrant inflammasome assembly. The cryopyrin scaffold protein is normally activated in response to triggers including adenosine triphosphate (ATP); bacterial and viral components; and crystals of uric acid, calcium pyrophosphate, and cholesterol [2]. Recognition that the cryopyrin inflammasome is also activated by crystals has led to recognition that the common diseases gout (monosodium urate crystals), pseudogout (calcium pyrophosphate dihydrate crystals), and even atherosclerotic cardiovascular disease (cholesterol crystals) could potentially be considered autoinflammatory [51,52].

Cryopyrin-associated periodic syndromes — Gain-of-function pathogenic variants in NLRP3 result in a family of autosomal dominant syndromes termed the cryopyrin-associated periodic syndromes (CAPS), reflecting principally the overproduction of IL-1-beta. Patients with CAPS typically fall into one of three clinical syndromes with overlapping clinical features:

●Familial cold autoinflammatory syndrome (FCAS1; MIM #120100), the mildest cryopyrinopathy, is manifested by brief (usually <24 hours) episodes of fever and maculopapular or urticarial rashes triggered by exposure to cold, such as entering an air-conditioned building. Cold is also a trigger for inflammation in other autoinflammatory syndromes including FCAS2 (mutation in NLRP12) and FCAS3 (mutation in phospholipase C, gamma 2 [PLCG2], also called PLCG2-associated antibody deficiency and immune dysregulation [PLAID]) [32,36]. (See 'The NLRP12 inflammasome' below and "Autoinflammatory diseases mediated by miscellaneous mechanisms", section on 'PLAID/APLAID'.)

●Muckle-Wells syndrome (MWS; MIM #191900) is associated with fevers and urticarial rashes that are not typically cold associated. Over time, some patients develop hearing loss and systemic amyloidosis.

●Neonatal-onset multisystem inflammatory disorder (NOMID, also called chronic infantile neurologic cutaneous and articular syndrome [CINCA]; MIM #607115), the most severe cryopyrinopathy, is characterized by persistent fevers and rashes, essentially from birth, associated with chronic meningitis and cartilaginous/bony deformities.

The genetics, clinical manifestations, pathogenesis, prognosis, and treatment of CAPS are discussed in detail elsewhere. (See "Cryopyrin-associated periodic syndromes and related disorders".)

Majeed syndrome — Majeed syndrome (MIM #609628) is an autosomal recessive disease caused by biallelic mutations in the lipin 2 gene (LPIN2), which is involved in lipid metabolism [53]. Defects in LPIN2 disrupt normal regulation of the NALP3 inflammasome, resulting in excess IL-1-beta production by mutant cells [54]. Features of Majeed syndrome include sterile osteolytic lesions, congenital dyserythropoietic anemia, and neutrophilic dermatosis [55]. Most patients present before the age of two years with additional features that include fever and marked elevation of inflammatory markers. Compared with patients with chronic nonbacterial osteomyelitis, patients typically present at a younger age and exhibit a more severe and prolonged course. Patients may respond to IL-1 blockade [56,57]. (See "Chronic nonbacterial osteomyelitis (CNO)/chronic recurrent multifocal osteomyelitis (CRMO) in children".)

The NLRC4 inflammasome — Nucleotide-binding oligomerization domain-like receptor family, caspase recruitment domain-containing (NLRC) 4 is a scaffold protein that forms an inflammasome upon recognition of bacterial virulence factors such as flagellin. Gain-of-function pathogenic variants in NLRC4 result in a condition termed autoinflammation with infantile enterocolitis (AIFEC), characterized by systemic autoinflammation with recurrent fever, malaise, splenomegaly, vomiting, intermittent rash, and enterocolitis [58,59]. Additional hallmarks are episodes of macrophage activation syndrome (MAS) and extremely high levels of IL-18, even after clinical improvement with IL-1 blockade. The prevalence of enterocolitis in this condition mirrors the predominantly intestinal expression of NLRC4 in an animal model [60]. Improvement in NLRC4-mediated disease has been reported after IL-18 blockade [61]. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis", section on 'Rheumatologic disorders'.)

The NLRP1 inflammasome — Nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 1 (NLRP1) was the scaffold protein first noted to mediate inflammasome assembly [1]. Unlike the other scaffold proteins, NLRP1 appears to be activated via proteolysis, including by bacterial virulence factors such as anthrax lethal toxin [2]. NLRP1 is expressed primarily in keratinocytes, such that aberrant activation manifests mainly as skin disease, including multiple self-healing palmoplantar carcinoma (MSPC) and familial keratosis lichenoides chronica (FKLC) [62]. Several families with dyskeratosis and arthritis have also been described, a condition termed NLRP1-associated autoinflammation with arthritis and dyskeratosis (NAIAD) [63]. NLRP1 is inhibited by dipeptidyl peptidase 9 (DPP9), and patients with mutations affecting this protein exhibited a syndrome of recurrent fevers, failure to thrive, skin manifestations (petechiae, abnormally pigmented macules), pancytopenia, and susceptibility to infections, responding to hematopoietic cell transplantation [64]. A further patient bearing a de-novo mutation in DPP9 developed florid HLH, accompanied by very high levels of IL-18 [65].

The NLRP12 inflammasome — Pathogenic variants in nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 12 (NLRP12) result in FCAS2, a disease that presents similarly to FCAS resulting from mutations in NLRP3 (the cryopyrin inflammasome) [66] (see 'Cryopyrin-associated periodic syndromes' above). Exposure to generalized cold results in fevers lasting between one and seven days, accompanied by elevation in circulating inflammatory markers, urticaria, arthralgia, and myalgias. Sensorineural hearing loss, optic neuritis, and amyloidosis reminiscent of the cryopyrinopathy spectrum have been reported. However, the phenotypic spectrum of NLRP12-associated diseases appears to be broad, with cold triggering reported in only 10 of 33 pediatric cases (30 percent); more common features were fevers (100 percent), polyarthralgia/arthritis (55 percent), abdominal pain/diarrhea (48 percent), and rash (45 percent, typically urticarial) [67]. NLRP12 also suppresses the noncanonical pathway activating the proinflammatory transcription factor complex NFkB, illustrating the tendency of autoinflammatory disorders to engage multiple proinflammatory pathways [68]. (See "Autoinflammatory diseases mediated by NFkB and/or aberrant TNF activity".)

The AIM2 inflammasome — The absent in melanoma 2 (AIM2) scaffold protein recognizes a broad range of pathogens, including double-stranded deoxyribonucleic acid (DNA) viruses [2]. Implicated in both immune defense and in the pathophysiology of cancer and psoriasis, and also in the stability of regulatory T cells [69,70], no autoinflammatory disease mediated by pathogenic variants affecting AIM2 has yet been described.

The noncanonical inflammasome — Caspase 4 and caspase 5 (both homologous with caspase 11 in mice) directly recognize intracellular lipopolysaccharide, thereby enabling caspase 4 to activate both pro-IL-18 and gasdermin D (as well as other proteins) in the absence of a large inflammasome-like multimolecular complex [71]. This noncanonical inflammasome is considered important for defense against gram-negative pathogens, but no related autoinflammatory disease has yet been described.

DISEASES RELATED TO OTHER IL-1 FAMILY PROTEINS — 

The IL-1 family includes not only IL-1-beta and IL-18 but also the proinflammatory cytokine IL-36 and the antiinflammatory cytokine blocker IL-1 receptor antagonist (IL-1RA). Deficiency of IL-1RA (DIRA) or of a related inhibitor of IL-36 also causes autoinflammatory disease.

Deficiency of the IL-1 receptor antagonist (DIRA) — DIRA (also called osteomyelitis, sterile multifocal, with periostitis and pustulosis [OMPP]; MIM #612852) is a syndrome that presents in early infancy with a diffuse pustular skin rash, sterile osteomyelitis, and periostitis with articular pain in the setting of markedly elevated inflammatory markers but no fever. This rare, autosomal recessive condition is due to pathogenic variants in IL1RN, the gene encoding the IL-1RA. Treatment with recombinant IL-1RA, anakinra, results in marked improvement. DIRA is discussed in greater detail separately. (See "Cryopyrin-associated periodic syndromes and related disorders", section on 'Deficiency of the IL-1-receptor antagonist (DIRA)'.)

Deficiency of the IL-36 receptor antagonist (DITRA) — DITRA (MIM #614204), an IL-1 family member, manifests as diffuse pustular psoriasis [72]. Generalized pustular psoriasis is covered in greater detail separately. (See "Pustular psoriasis: Pathogenesis, clinical manifestations, and diagnosis", section on 'Generalized pustular psoriasis'.)

DIAGNOSIS — 

As with other autoinflammatory diseases, the diagnosis of an inflammasomopathy is considered in patients who present with inflammatory episodes that recur or persist over months or years in the absence of another cause. Unusual infections, systemic juvenile idiopathic arthritis (sJIA; or adult-onset Still's disease [AOSD] in older patients, now collectively called Still's disease), chronic autoimmune conditions such as inflammatory bowel disease (IBD), and malignancy are first excluded. The evaluation then proceeds with an attempt to identify a clinical pattern consistent with one of the major autoinflammatory disorders. Clinical criteria, in the absence of genetic testing, have been developed for the diagnosis and classification of cryopyrin-associated periodic syndromes (CAPS) and familial Mediterranean fever (FMF) (table 2) [73]. However, genetic testing remains the mainstay of diagnosis for the inflammasomopathies, either targeted to a single gene or more commonly to a panel of autoinflammation-associated diseases. Classification criteria incorporate the results of such genetic testing, considering both unambiguously pathogenic mutations and variants of indeterminate significance, although these newer criteria are intended to be classification criteria rather than diagnostic criteria (table 3) [74]. Pending the results of genetic testing, IL-1 blockade (typically with anakinra) may be used for treatment. IL-18-blocking agents are under development but are unavailable for routine clinical use. (See 'Treatment' below.)

For diseases that present with fever, the most useful discriminators are the duration and periodicity of febrile episodes; ethnicity (eg, Mediterranean descent in FMF); family history of a similar syndrome, which suggests a heritable disorder (although recessive or de novo mutations will often lack such a history); and presence of associated clinical features.

Measurement of serum IL-18 is useful diagnostically. While all canonical inflammasomes are believed to activate pro-IL-1-beta and pro-IL-18, marked elevation of circulating IL-18 is reported with pathogenic variants in PSTPIP1, WDR1, CDC42, NLRC4, and DPP9; modest elevation is also observed in some patients with FMF and in patients with inborn error of immunity-related mutations in X-linked inhibitor of apoptosis (XIAP) and prolidase D (PEPD) [31,75,76]. The basis for this selectivity is incompletely understood but likely reflects differential availability of pro-IL-1-beta and pro-IL-18 in cells expressing the dysregulated inflammasome. High levels of IL-18 are also noted in Still's disease (comprising sJIA and AOSD), especially with active macrophage activation syndrome (MAS) [60,77]. Of note, IL-18 as measured by commercially available assays comprises both free IL-18 and IL-18 bound to its antagonist, IL-18-binding protein; free IL-18, as measured by research laboratories, is detectable largely in conditions where total IL-18 levels are highest, such as in nucleotide-binding oligomerization domain-like receptor family, caspase recruitment domain-containing 4 (NLRC4) related disease and active Still's-associated MAS [60]. (See "Systemic juvenile idiopathic arthritis: Clinical manifestations and diagnosis", section on 'Laboratory findings' and "Adult-onset Still's disease: Clinical manifestations and diagnosis", section on 'Immunologic studies' and "Systemic juvenile idiopathic arthritis: Complications", section on 'Macrophage activation syndrome'.)

Diagnosis is important because of potential implications for therapy, monitoring for the development of secondary (amyloid A [AA]) amyloidosis, and the need for genetic counseling. Despite advances in diagnostic testing, many patients still defy diagnostic classification [78-80]. In such cases, reconsideration of the full differential diagnosis is essential. If an autoinflammatory disease still appears likely, empiric therapy patterned on that employed in other clinically similar autoinflammatory diseases is often warranted, including colchicine and/or anakinra (recombinant IL-1 receptor antagonist [IL-1RA]) [81]. Referral to a center with appropriate expertise to perform exome/genome sequencing, including evaluation for mosaicism (presence of a mutant gene in some cells but not others) (see "The autoinflammatory diseases: An overview", section on 'Mosaicism'), or other targeted investigations should be considered and may lead to a definitive diagnosis. (See "Genetic testing in patients with a suspected primary immunodeficiency or autoinflammatory syndrome" and "Next-generation DNA sequencing (NGS): Principles and clinical applications".)

DIFFERENTIAL DIAGNOSIS — 

The differential diagnosis includes unusual infections such as relapsing fever, malignancy and premalignant states (Schnitzler syndrome), VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic), cyclic neutropenia, inflammatory bowel disease (IBD), and systemic juvenile idiopathic arthritis (sJIA)/adult-onset Still's disease (AOSD). (See "Fever of unknown origin in children: Etiology" and "Fever of unknown origin in children: Evaluation" and "Fever of unknown origin in adults: Etiologies" and "Fever of unknown origin in adults: Evaluation and management".)

●Relapsing fever – Relapsing fever is similar in name to periodic fever syndromes. However, relapsing fever is an arthropod-borne infectious disease caused by spirochetes of the Borrelia genus, not an autoinflammatory disease. It is also characterized by recurrent episodes of fever. (See "Clinical features, diagnosis, and management of relapsing fever".)

●Cyclic neutropenia – Other than periodic fever with aphthous stomatitis, pharyngitis, and adenitis (PFAPA), fever in autoinflammatory disorders is episodic rather than truly periodic. Thus, the presence of a predictable recurrent fever pattern should trigger consideration of cyclic neutropenia, which may be of childhood or adult onset. (See "Cyclic neutropenia".)

●Schnitzler syndrome – Schnitzler syndrome is an acquired autoinflammatory syndrome that presents with chronic urticaria associated with monoclonal immunoglobulin M (IgM) gammopathy (most often IgM kappa). Additional features may include bone pain, skeletal hyperostosis, arthralgias, lymphadenopathy, and intermittent fevers. Patients are at increased risk of hematologic malignancies. There is no specific test for Schnitzler syndrome, and clinicians must maintain a high index of suspicion in patients with chronic urticaria and a monoclonal IgM gammopathy. Most patients respond well to inhibition of the IL-1 pathway. Schnitzler syndrome is discussed in greater detail separately. (See "Urticarial vasculitis", section on 'Differential diagnosis'.)

●VEXAS syndrome – VEXAS syndrome is an inflammatory disease arising from acquired somatic mutations in the X-linked gene ubiquitin-activating enzyme 1 (UBA1), resulting in selective expansion of myeloid cells exhibiting dysregulated release of proinflammatory mediators [82,83]. Patients are typically over the age of 50 years and present with clinical features including fever, systemic inflammation, neutrophilic rashes, macrocytic anemia, lung infiltrates, and deep venous thrombosis; rarely, females are also affected, typically reflecting acquired X monosomy. (See "Autoinflammatory diseases mediated by NFkB and/or aberrant TNF activity", section on 'Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome'.)

●Systemic juvenile idiopathic arthritis/adult-onset Still's disease – A further diagnostic consideration is the febrile-onset arthritis known in childhood as sJIA and in adults as AOSD. Patients with these conditions present with features including high, spiking fevers; rash; serositis; and lymphadenopathy. Arthritis is often evident at onset but may sometimes lag for weeks or months. These clinical features, as well as brisk response to IL-1 antagonism in many patients, suggest that sJIA/AOSD may have autoinflammatory features, although important differences remain [84]. These diseases are discussed in detail separately. (See "Systemic juvenile idiopathic arthritis: Clinical manifestations and diagnosis" and "Adult-onset Still's disease: Clinical manifestations and diagnosis".)

●Inflammatory bowel disease – Crohn disease and ulcerative colitis typically present as abdominal pain, diarrhea, weight loss, fatigue, and elevated acute-phase reactants. Untreated disease is typically chronic, although intermittent exacerbations may mimic recurrent conditions. Particularly in Crohn disease, common signs and symptoms may be absent, and extraintestinal inflammation may be present in joints, bones, muscles, and even blood vessels. IBD is considerably more prevalent than inflammasomopathies. A careful personal and family history, physical exam, laboratory tests, and imaging studies should help identify IBD in patients with an undiagnosed inflammatory condition. (See "Clinical presentation and diagnosis of inflammatory bowel disease in children" and "Clinical manifestations and complications of inflammatory bowel disease in children and adolescents" and "Clinical manifestations, diagnosis, and prognosis of ulcerative colitis in adults" and "Clinical manifestations, diagnosis, and prognosis of Crohn disease in adults" and "Clinical manifestations and diagnosis of arthritis associated with inflammatory bowel disease and other gastrointestinal diseases" and "Dermatologic and ocular manifestations of inflammatory bowel disease" and "Growth faltering and pubertal delay in children with inflammatory bowel disease".)

●PFAPA syndrome – PFAPA syndrome is a relatively common entity compared with the other periodic fever syndromes. The etiology of PFAPA has not been defined, and further investigation may ultimately identify it as autoinflammatory.

Briefly, PFAPA is characterized by febrile episodes beginning in early childhood that recur approximately every three to four weeks. These episodes are associated with typical clinical features, and another cause is not identifiable. Episodes are abrupt in onset, last three to six days, and may be accompanied by one or more of the following: pharyngitis (exudative or nonexudative), mild aphthous ulcerations, lymphadenopathy, chills (rigors), fatigue, headache, and mild abdominal pain.

Despite its acronym, recurrent fevers are the only prominent clinical finding in many patients. Leukocytosis and elevation of inflammatory markers occur acutely during episodes and return to normal between episodes. Patients are healthy between episodes of fever and grow normally, even if they are anorectic and lose weight during the febrile episodes. Most patients with PFAPA outgrow the febrile episodes with time, and no long-term consequences have been identified. PFAPA syndrome is discussed in greater detail separately. (See "Periodic fever with aphthous stomatitis, pharyngitis, and adenitis (PFAPA syndrome)".)

●Hemophagocytic lymphohistiocytosis – Patients with defects in inflammasomopathy-associated genes including NLRC4, NLRP12, and CDC42 (as well as related genes not yet unambiguously implicated in autoinflammation) can present with manifestations of hemophagocytic lymphohistiocytosis (HLH), including fevers and cytopenias [85]. Accordingly, inflammasome-related diseases should be considered in patients with HLH, while other causes of HLH (primary or secondary) should be in the differential diagnosis of the inflammasomopathies. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis".)

TREATMENT — 

Inflammation in the inflammasomopathies is commonly mediated at least in part through IL-1-beta, and so blockade of this cytokine can be markedly effective [86-89]. Colchicine is highly effective in familial Mediterranean fever (FMF), both for prevention of clinical symptoms and for prevention of AA amyloidosis. IL-1 blockade is effective in colchicine-refractory FMF [88]. Blockade of IL-18 is effective in nucleotide-binding oligomerization domain-like receptor family, caspase recruitment domain-containing (NLRC) 4-mediated autoinflammation, but this agent (tadekinig alpha, a recombinant IL-18 binding protein) is available only in the context of a clinical trial or related compassionate use protocols [61]. A bispecific antibody against IL-1-beta and IL-18 is in development [90,91]. Janus kinase (JAK) inhibition can be helpful where disease mechanisms engage type I interferons (NOCARH [Neonatal Onset of panCytopenia, Autoinflammation, Rash, and episodes of Hemophagocytic lymphohistiocytosis] syndrome) or type II interferons (PAPA [pyogenic arthritis, pyoderma gangrenosum, and acne] syndrome). Nonsteroidal antiinflammatory drugs (NSAIDs) and glucocorticoids may play important ancillary roles. Bone marrow transplantation may be an option for severe, refractory disease [85]. Treatment of the most common inflammasomopathies is discussed in greater detail separately. (See "Management of familial Mediterranean fever" and "Hyperimmunoglobulin D syndrome: Management" and "Cryopyrin-associated periodic syndromes and related disorders".)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Familial Mediterranean fever".)

SUMMARY

●Definition – The autoinflammatory diseases constitute a family of disorders characterized by aberrant antigen-independent activation of inflammatory pathways. (See 'Introduction' above.)

●Pathogenesis – Autoinflammatory diseases mediated by pathogenic variants affecting the inflammasome are called the inflammasomopathies. The inflammasome is an intracellular protein complex responsible for proteolytic activation of interleukin (IL) 1-beta, IL-18, and the pore-forming protein gasdermin D (figure 1). There are at least six canonical inflammasomes, defined by the scaffold protein responsible for their assembly: pyrin, cryopyrin (nucleotide-binding oligomerization domain-like receptor family, caspase recruitment domain-containing [NLRC] 3), NLRC4, nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing (NLRP) 1, NLRP12, and absent in melanoma (AIM) 2. Pathogenic variants in each of these proteins, with the exception of AIM2, have been shown to cause human autoinflammatory disease. (See 'Overview of the inflammasome' above.)

●Types of inflammasomopathies – The most well-known inflammasomopathies are familial Mediterranean fever (FMF) due to mutations in pyrin and the cryopyrin-associated periodic syndromes (CAPS; familial cold autoinflammatory syndrome [FCAS], Muckle-Wells syndrome [MWS], and neonatal-onset multisystem inflammatory disease [NOMID]) caused by mutations in NLRP3. (See 'The pyrin inflammasome' above and 'The cryopyrin inflammasome' above.)

Other diseases related to excess activity of IL-1-family cytokines include deficiency of the IL-1RA and of the IL-36 receptor antagonist (DIRA and DITRA). (See 'Diseases related to other IL-1 family proteins' above.)

●Diagnosis – Inflammasome-mediated autoinflammatory diseases should be suspected when a patient presents with recurrent episodes of inflammation over months or years unexplained by another cause. Most patients develop their first disease manifestations in childhood. Features can include fevers, urticarial rashes, meningitis, bone overgrowth, and enterocolitis. Disorders of the NLRP1 inflammasome present with disease localized to skin. Genetic testing is typically employed to confirm a clinically suspected entity. (See 'Diagnosis' above.)

●Differential diagnosis – The differential diagnosis includes unusual infections such as relapsing fever, malignancy, cyclic neutropenia, inflammatory bowel disease (IBD), systemic juvenile idiopathic arthritis (sJIA)/adult-onset Still's disease (AOSD), and hemophagocytic lymphohistiocytosis (HLH). Periodic fever with aphthous stomatitis, pharyngitis, and adenitis (PFAPA) is a common syndrome of recurrent unexplained fever in children. Schnitzler syndrome and VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome are differential diagnostic considerations in adults. (See 'Differential diagnosis' above.)

●Treatment – Treatment of the inflammasomopathies varies with etiology and may include colchicine, IL-1 blockade, nonsteroidal antiinflammatory drugs (NSAIDs), and glucocorticoids. Janus kinase (JAK) inhibitors have proven helpful in case where disease is accompanied also by excess production of type I or II interferons. IL-18 blockade is experimental. (See 'Treatment' above.)