Version May 2024
INTRODUCTION — Three clinically overlapping interleukin (IL) 1-associated autoinflammatory disorders are known collectively as the cryopyrin-associated periodic syndromes (CAPS) or cryopyrinopathies: familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disorder (NOMID, also known as chronic infantile neurologic cutaneous and articular [CINCA] syndrome). The cryopyrinopathies are rare, with an estimated prevalence of 1 in 360,000 in a French study [1]. A related but distinct autoinflammatory disorder is due to deficiency of the IL-1 receptor antagonist (DIRA).
There are multiple other autoinflammatory disorders that present with periodic fever. These disorders are discussed separately. (See "The autoinflammatory diseases: An overview".)
CRYOPYRIN-ASSOCIATED PERIODIC SYNDROMES
Genetics — All three cryopyrinopathies arise from pathogenic variants in a single gene, NLRP3, at chromosome 1q44, encoding a protein called cryopyrin (also known as nacht domain-, leucine-rich repeat- and pyrin domain-containing protein 3 [NALP3] or pyrin domain-containing apoptotic protease activating factor 1-like protein [PYPAF1]; cryopyrin is derived from the Greek words for icy cold and fire) [2,3]. The mode of inheritance is autosomal dominant with variable penetrance.
Pathogenesis — Cryopyrin is important in innate immunity as part of the multiprotein NALP3 inflammasome complex [4]. It belongs to a family of nucleotide-binding domain and leucine-rich repeat-containing (NLR) proteins that respond to intracellular pathogens and other danger signals.
Cryopyrin serves as a scaffold for assembly of the NALP3 inflammasome, one of multiple distinct inflammasome complexes with distinct triggering mechanisms but shared downstream effector function [4]. These inflammasomes are responsible, through a cascade of interactions involving caspase 1, for activation of the potent proinflammatory cytokines interleukin (IL) 1 beta and IL-18 by cleavage of their inactive precursors. The inflammasome also cleaves and activates a protein called "gasdermin D" that forms pores in the cell membrane to enable release of these cytokines into the environment and, under some conditions, also to trigger a form of cell death termed "pyroptosis" [4,5]. In addition to its intracellular function, the NALP3 inflammasome can be released from activated macrophages, where it can amplify inflammation by continuing to activate IL-1-beta in the extracellular milieu and in neighboring phagocytes [6,7].
Signals for cryopyrin activation include the various pathogen-associated molecular patterns (PAMPs; such as bacterial toxins and viral ribonucleic acid [RNA]); danger-associated molecular patterns (DAMPs; such as uric acid crystals, adenosine triphosphate [ATP], low intracellular concentrations of potassium, skin irritants, ultraviolet B radiation); and alum, the commonly used vaccine adjuvant [4,8,9].
Point mutations in NLRP3 in the cryopyrinopathies are thought to promote aberrant formation of the inflammasome and inappropriate production of active IL-1 beta, either due to defective self-inhibition by the mutant cryopyrin protein or to resistance of the established inflammasome to negative regulatory signals [10-12]. Murine studies suggest that aberrant production of IL-18 and caspase 1-driven pyroptosis plays roles in these diseases, although the efficacy of IL-1 antagonists in patients with CAPS suggests that excess IL-1 beta retains a primary pathogenic role [13]. (See 'Treatment of cryopyrinopathies' below.)
Phenotypic differences among the CAPS probably reflect in large part the differential impact of mutations on the activity of the inflammasome, modulated by individual genetic background. Not surprisingly, the boundaries among these three syndromes are not sharp, and patients may have features of more than one disorder or may not be classic for any of them [10,14,15].
Clinical features of specific disorders — The clinical features of the three types of CAPS are reviewed below.
Familial cold autoinflammatory syndrome — Familial cold autoinflammatory syndrome (FCAS), formerly called familial cold urticaria, is the mildest of the cryopyrin-associated disorders. It is an unusual condition in which exposure to generalized cold, such as an air-conditioned room, results in a stereotyped systemic inflammatory response including fever, an urticarial rash, conjunctival injection, and substantial arthralgias (picture 1).
Symptoms usually develop in the first year of life, occasionally in the newborn period upon exposure to cold in the delivery room. Urticaria followed by fever starts approximately seven hours after cold exposure. Leukocytosis, sometimes to above 30,000 cells/microL, starts approximately 10 hours after cold exposure and begins to subside 12 to 14 hours later [16,17].
Attacks usually resolve within 24 hours, though considerable variability is observed between individuals and also depends on the extent and duration of cold exposure. The presence of conjunctivitis and triggering by cold help to discriminate FCAS from other periodic fever disorders [18]. Patients may experience daily rashes, fatigue, headache, and myalgias, particularly toward afternoon and evening, even in the absence of cold exposure.
Histologically, the rash in these patients is characterized by a marked infiltration of neutrophils, in contrast to other causes of urticaria. (See "Chronic spontaneous urticaria: Clinical manifestations, diagnosis, pathogenesis, and natural history".)
Uncommonly, chronic untreated FCAS leads to secondary amyloidosis [19-21]. Treatment of FCAS and other cryopyrinopathies is discussed below. (See 'Treatment of cryopyrinopathies' below.)
Muckle-Wells syndrome — Muckle-Wells syndrome (MWS) is a rare condition characterized by the following triad [2,19,22,23]:
●Intermittent episodes of fever, headache, urticarial rash, and joint pain (arthralgias or arthritis)
●Progressive sensorineural hearing loss
●Secondary (AA) amyloidosis with nephropathy
Febrile episodes occur at irregular intervals every few weeks, lasting 12 to 36 hours before resolving spontaneously. Age of onset is variable. Precipitating factors vary and cannot always be identified, but they may include both heat and cold [22,23]. The sensorineural hearing loss, presumably related to inflammation within the cochlea or the leptomeninges, begins in childhood and may be profound [24-26].
Amyloidosis occurs in a subset of patients [19,21,27,28]. The signs and symptoms of amyloidosis in the cryopyrinopathies are similar to those observed with secondary amyloidosis in other disorders. (See "Overview of amyloidosis", section on 'Clinical manifestations'.)
NLRP3 pathogenic variants implicated in MWS may be distinct or overlap those causing FCAS [14]. (See 'Familial cold autoinflammatory syndrome' above.)
Neonatal-onset multisystem inflammatory disease — Neonatal-onset multisystem inflammatory disorder (NOMID), also known as chronic infantile neurologic cutaneous and articular (CINCA) syndrome, is the most severe of the autoinflammatory cryopyrinopathies [10,29].
Clinical features, including a migratory, erythematous rash resembling urticaria, fever, impaired growth, abnormal facies with frontal bossing, protruding eyes, and saddle-shaped nose, are characteristic and generally develop at or near the time of birth [14]. Other manifestations are chronic meningitis, sensorineural hearing loss, cerebral atrophy, uveitis, lymphadenopathy, and hepatosplenomegaly [26]. Limb and joint pain is common, and focal exuberant cartilaginous proliferation at growth plates and epiphyses resemble tumors. NOMID may cause premature death, and chronic inflammation may lead to secondary amyloidosis. Images and links to additional images of the rash and other findings associated with these conditions can be found on the website of the Autoinflammatory Alliance.
Diagnosis — The diagnosis should be suspected in patients with recurrent episodes of unexplained systemic inflammation, with fever present in most, but not all, patients. Urticaria is a hallmark manifestation that occurs in almost all patients and rarely in other autoinflammatory syndromes. Sensorineural hearing loss is also essentially restricted to CAPS among the autoinflammatory disorders [18]. A family history is common since these diseases are autosomal dominant, but sporadic cases may occur.
Diagnostic criteria include raised inflammatory markers (C-reactive protein [CRP] and serum amyloid A) plus at least two of six typical CAPS manifestations [30]:
●Urticaria-like rash
●Cold-triggered episodes
●Sensorineural hearing loss
●Musculoskeletal symptoms
●Chronic aseptic meningitis
●Skeletal abnormalities
The diagnosis of CAPS is confirmed by genetic testing for NALP3 mutations. In an analysis of over 800 samples sent for NALP3 mutation testing, a positive test was unlikely in a patient with fewer than three episodes, age at presentation ≥20 years, and normal CRP levels [1]. Patients with low-penetrance NALP3 variants (Q703K, R488K, V198M) may present atypically [31]. Some CAPS patients may appear negative for NALP3 mutation on conventional testing but are found to exhibit somatic mosaicism for a pathogenic variant using next-generation sequencing, which has superior ability to detect mosaicism compared with conventional Sanger sequencing [32-34].
Treatment of cryopyrinopathies — A central role for IL-1 beta in these disorders is confirmed by the effectiveness of therapies directed against IL-1 in preventing and alleviating symptoms and substantially reducing levels of inflammatory indices, including serum amyloid A and associated risk of amyloidosis [35,36]. (See 'Pathogenesis' above.)
Anakinra — Anakinra (starting dose 1 to 2 mg/kg daily, typical maximum dose 8 mg/kg daily, given subcutaneously), an IL-1 receptor antagonist, is approved by the US Food and Drug Administration (FDA) for treatment of NOMID [37]. It is also used for other forms of CAPS (FCAS and MWS) and for deficiency of the IL-1 receptor antagonist (DIRA). (See 'Deficiency of the IL-1-receptor antagonist (DIRA)' below.)
In patients with FCAS, treatment with anakinra can prevent cold-induced attacks and markedly reduce daily symptoms [38-40]. Among patients with renal secondary amyloidosis due to CAPS, anakinra has led to marked reductions in proteinuria and stabilization of serum creatinine [20,40]. (See "Renal amyloidosis".)
Treatment with anakinra can also control systemic inflammation in MWS, potentially with an effect on amyloid risk mediated through normalization of levels of serum amyloid A protein. The impact on hearing loss remains uncertain, but partial recovery has been reported [23,41-44]. Measurement of intrathecal inflammatory markers suggests that anakinra may be superior to the monoclonal anti-IL-1 beta canakinumab (see 'Canakinumab' below) for control of central nervous system (CNS) inflammation given its ability to penetrate the blood-brain barrier [45].
In NOMID/CINCA, treatment with anakinra has improved signs and symptoms related to inflammation in some [46-51], but not all [49], cases. Bone and joint abnormalities are less responsive to this agent [51].
Rilonacept — Rilonacept (given subcutaneously, loading dose 4.4 mg/kg, maximum dose 320 mg; weekly maintenance dose 2.2 mg/kg, maximum dose 160 mg), an IL-1 trap, is approved by the US FDA for treatment of patients 12 years of age and older with CAPS, including FCAS and MWS [52]. Treatment with rilonacept can markedly reduce symptoms and inflammatory markers, including serum CRP and serum amyloid A [53,54]. Two double-blind, placebo-controlled trials of 6 and 18 weeks duration examined the effects of rilonacept in 41 patients with FCAS and 3 with MWS. The treated patients experienced a significant reduction in symptom scores compared with placebo (84 versus 13 percent) [54]. The drug was well tolerated, and the most common adverse effects were injection-site reactions (36 versus 13 percent).
Canakinumab — Canakinumab is a human anti-IL-1 beta monoclonal antibody that does not react with other members of the IL-1 family. Subcutaneous administration of canakinumab to 35 patients with CAPS resulted in a complete response in 34 [55]. Of the responders, 31 were randomly assigned to receive canakinumab or placebo every 8 weeks for up to 24 weeks. Treated patients were more likely to remain in remission (100 versus 19 percent) and to normalize their serum CRP and serum amyloid A protein levels.
Benefit was sustained in an open-label extension. The median time to flare in the placebo-treated patients was approximately 22 weeks after the initial dose of canakinumab given prior to randomization. The incidence of suspected infections was significantly higher in the canakinumab-treated patients during the randomized phase of the trial (67 versus 25 percent) [55]. Follow-up data as long as six years support the safety of canakinumab in CAPS patients [56].
Clinical response may be less complete in patients with the most severe cryopyrinopathy, NOMID, despite dose escalation to 8 mg/kg every four weeks, which is double the conventional dose [57]. In addition, studies of cerebrospinal fluid (CSF) showed that canakinumab was not as effective as anakinra at reducing leukocyte counts and cytokine levels, potentially because of the superior CSF penetration of anakinra, suggesting that the latter may be preferable for the treatment of CNS inflammation in NOMID [45].
Other agents — Case reports suggest that other drugs may be effective in patients with NOMID/CINCA, including thalidomide [58] and the anti-IL-6 receptor antibody, tocilizumab [49]. In one case, a patient with CAPS and coincident leukemia exhibited resolution of her CAPS following allogenic hematopoietic cell transplantation [59].
Vaccination in CAPS — Exacerbations of inflammation in CAPS have been reported following vaccination against pneumococcus with either the polysaccharide or the conjugate vaccine [60,61]. Flare of disease has also been reported after vaccination against Neisseria meningitidis (meningococcus) [62]. The benefit of this vaccination must therefore be balanced against the risk in this population.
KERATOENDOTHELIITIS FUGAX HEREDITARIA — Patients with this rare condition exhibit repeated attacks of unilateral conjunctival injection, photophobia, and pain, typically one to six times per year, sometimes resulting in corneal scarring [63]. Topic corticosteroid therapy is typically sufficient for control. No other organ systems are involved. This condition segregates with a variant in NLRP3, c.61G>C and appears to be a mild focal cryopyrinopathy [63,64].
DEFICIENCY OF THE IL-1-RECEPTOR ANTAGONIST (DIRA)
Clinical presentation — An autoinflammatory syndrome distinct from the cryopyrinopathies is characterized by the neonatal onset of sterile multifocal osteomyelitis, periostitis, and a neutrophilic pustulosis [65-67]. The disease presents at birth or within two months postpartum. Other clinical findings include periarticular swelling from epiphyseal overgrowth, oral mucosal lesions, and vasculitis. Untreated patients may die from multiorgan failure. Marked elevations of the erythrocyte sedimentation rate and serum C-reactive protein (CRP) are present, but fever is not.
Genetics — The 10 patients described in the two initial reports all exhibited deficiency of the interleukin (IL) 1-receptor antagonist (IL-1RN) due to homozygous germline pathogenic variants in IL1RN [65,66]. Eight of these patients had single point mutations, and two had deletions within the sequence encoding IL-1RN. Two additional patients, both Puerto Rican, were reported with a homozygous microdeletion of IL1RN and five adjacent, related genes, a deletion common in this population [67,68]. The clinical syndrome is thought to be due to hyperresponsiveness to IL-1 beta stimulation because of failure of the defective protein to be secreted. Heterozygous carriers are asymptomatic.
Diagnosis — The diagnosis is made by genetic testing for mutations involving IL1RN. The differential diagnosis includes infantile pustulosis (neonatal-onset pustulosis), infantile pustular psoriasis, and SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis) syndrome [67-69]. (See "Neutrophilic dermatoses".)
Treatment — Treatment with nonsteroidal antiinflammatory drugs, disease-modifying antirheumatic drugs, and glucocorticoids was only partially effective. IL-1 inhibitors including anakinra, a recombinant human IL-1 receptor antagonist, and rilonacept, an IL-1 trap, are approved by the US Food and Drug Administration (FDA) for treatment of DIRA [37,52]. As expected from the pathophysiology, anakinra was highly effective in most patients, with complete resolution of symptoms and skin and bone lesions in small case series [65,66,68]. In a study of six children who had responded to anakinra and were switched to rilonacept (2.2 mg/kg subcutaneously weekly), five had recurrence of micropustular rash during the first three months of the study and underwent dose escalation (4.4 mg/kg weekly), and one patient remained on the starting dose [70]. All patients were in remission at six months and remained in remission for the duration of the two-year study. Growth was normal, quality-of-life scores improved, and no serious adverse events were reported.
SUMMARY AND RECOMMENDATIONS
●Types of CAPS – Three clinically overlapping autoinflammatory disorders are known collectively as the cryopyrin-associated periodic syndromes (CAPS) or cryopyrinopathies: familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disorder (NOMID, also known as chronic infantile neurologic cutaneous and articular [CINCA] syndrome). (See 'Introduction' above and 'Cryopyrin-associated periodic syndromes' above.)
●Genetics and pathogenesis – The CAPS all arise from point mutations in a single gene, NLRP3 (nacht domain-, leucine-rich repeat- and pyrin domain-containing protein 3 [NALP3]), which encodes the cryopyrin protein. Cryopyrin is important in innate immunity as part of the multiprotein inflammasome complex. Inheritance of these disorders is autosomal dominant with variable penetrance. NLRP3 mutations promote aberrant formation of the inflammasome and inappropriate production of active interleukin (IL) 1 beta. Phenotypic differences among CAPS are thought to largely reflect the differential impact of mutations on the activity of the inflammasome, modulated by individual genetic background. The syndromes may overlap, and patients may have features of more than one disorder. (See 'Genetics' above and 'Pathogenesis' above.)
●Familial cold autoinflammatory syndrome – FCAS, formerly called familial cold urticaria, is the mildest of the cryopyrin-associated disorders. It is an unusual condition in which exposure to generalized cold, such as an air-conditioned room, results in a stereotyped systemic inflammatory response including fever, an urticarial rash, conjunctival injection, and substantial arthralgias. Symptoms usually develop in the first year of life. Attacks usually resolve within 24 hours, though considerable variability is observed. The presence of conjunctivitis helps to discriminate FCAS from other periodic fever disorders. (See 'Familial cold autoinflammatory syndrome' above.)
●Muckle-Wells syndrome – MWS is a rare condition characterized by the triad of intermittent episodes of fever, headache, urticarial rash, and joint pain (arthralgias or arthritis); progressive sensorineural hearing loss; and secondary amyloidosis with nephropathy. Febrile episodes occur at irregular intervals every few weeks, lasting 12 to 36 hours before resolving spontaneously. Age of onset is variable. Precipitating factors vary and cannot always be identified, but they may include both heat and cold. (See 'Muckle-Wells syndrome' above.)
●Neonatal-onset multisystem inflammatory disorder – Abnormalities in cryopyrin are responsible for NOMID, which is also known as CINCA syndrome. Clinical features, including a migratory, erythematous rash resembling urticaria, fever, impaired growth, abnormal facies with frontal bossing, protruding eyes, and saddle-shaped nose, are characteristic and generally develop at or near the time of birth. Other manifestations affecting the brain, eyes, joints, liver, and spleen may also be present, and AA amyloidosis can occur. NOMID may cause premature death. (See 'Neonatal-onset multisystem inflammatory disease' above.)
●Treatment – A central role for IL-1 beta in these disorders is confirmed by the effectiveness of therapies directed against IL-1 in preventing and alleviating symptoms and in substantially reducing levels of inflammatory indices, including serum amyloid A. These therapies include anakinra, rilonacept, and canakinumab. Anakinra may be superior to the other agents for central nervous system (CNS) inflammation. Vaccination against pneumococcus should be pursued with caution because of the potential for increased CAPS-associated inflammatory response. (See 'Treatment of cryopyrinopathies' above and 'Anakinra' above and 'Rilonacept' above and 'Canakinumab' above.)
●Deficiency of the IL-1RN (DIRA), a related disorder – An autoinflammatory syndrome distinct from the cryopyrinopathies is characterized by the neonatal onset of sterile multifocal osteomyelitis, periostitis, a neutrophilic dermatosis, and elevated acute-phase reactants without fever. Untreated patients may die from multiorgan failure. The patients have a deficiency of the IL-1-receptor antagonist (IL-1RN) due to homozygous germline mutations, which may result in hyperresponsiveness to IL-1-beta stimulation and the clinical syndrome. The most effective treatment has been with the IL-1 receptor antagonist, anakinra. (See 'Deficiency of the IL-1-receptor antagonist (DIRA)' above and 'Clinical presentation' above and 'Genetics' above and 'Treatment' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges E Richard Stiehm, MD, who contributed as a Section Editor to earlier versions of this topic review.
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