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Learning objectives

Upon completion of this activity, participants should be able to:

1. Describe clinical features of Muckle–Wells syndrome (MWS).
2. Distinguish between familial cold autoinflammatory syndrome (FCAS) and the other 2 autoinflammatory syndromes.
3. Identify the most severe clinical features of chronic infantile neurological, cutaneous, and articular syndrome/neonatal-onset multisystemic inflammatory disease (CINCA/NOMID).
4. Identify the most common medication currently used for the autoinflammatory syndromes.

Competing interests

The authors, the Associate Publisher R Ashton and the CME questions author D Lie declared no competing interests.

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Familial cold autoinflammatory syndrome

FCAS, also known as familial cold urticaria, was first described in 1940 by Kile and Rusk.² This autosomal-dominant syndrome is characterized by recurrent, short, self-limited episodes of low-grade fever, rash and arthralgia that are precipitated by exposure to cold temperatures.^{3, 4, 5} Other commonly reported symptoms include conjunctivitis, muscle pain, profuse sweating, drowsiness, headaches, nausea and extreme thirst. Symptoms usually begin 1–2 h after generalized exposure to cold temperatures or to a considerable drop in temperature, and the duration of attacks is usually short (<24 h). In most patients with FCAS, the severity of the crisis correlates with the intensity of the cold trigger. Predictably, attacks are more frequent in winter, on damp and windy days, and following exposure to air conditioning. Patients frequently report a pattern of feeling well in the morning after a warm night, but symptoms develop after a cold trigger and worsen as the day progresses. Early onset of the disease, at birth or within the first 6 months of life, is common. Although late-onset renal amyloidosis was reported in several members of one family affected by FCAS, deafness and amyloidosis are not usually observed in FCAS, in contradistinction to MWS and CINCA (NOMID).^{3, 4, 5} Leukocytosis and increased plasma levels of acute-phase reactants are observed during episodes of inflammation.

Muckle–Wells syndrome

MWS was first described in 1962 by Muckle and Wells,⁶ in members of one family who presented with urticaria, deafness and renal amyloidosis. The disease is characterized by recurrent episodes of fever and rash associated with joint and eye manifestations, although fever is not always present. Precipitating factors cannot usually be identified, and triggering by cold is rarely observed. The course of the disease varies between individuals, from the typical recurrent attacks of inflammation to near-permanent symptoms. As with FCAS, patients with MWS often describe a pattern of worsening symptoms in the evening. Joint manifestations can be mild (i.e. short episodes of arthralgia), but recurrent episodes of joint swelling that predominantly affect the large joints have been observed⁷ and joint destruction has been reported in one family.⁸ As in FCAS, conjunctivitis is also frequently present. Episcleritis and iridocyclitis have been reported in several cases.⁹ Neurological involvement in MWS is usually not described, although headache and papilledema have been reported in some cases.^{9, 10} Perceptive deafness is common (occurring in approximately 70% of cases) and usually begins in childhood or early adulthood; the mechanism that leads to this sensorial involvement is not completely understood. Amyloidosis, caused by chronic inflammation, is the most serious complication of MWS and develops in adulthood in approximately 25% of cases; it manifests as proteinuria, followed by impaired renal function. Leukocytosis and increased plasma levels of acute-phase reactants are observed during episodes of inflammation, or near-permanently in severely affected individuals.

Chronic infantile neurological cutaneous articular syndrome

CINCA (NOMID) is associated with the most severe phenotype in this spectrum of diseases. This syndrome was first described by Prieur in the early 1980s^{11, 12} as a chronic inflammatory disease with rash, articular involvement and chronic, aseptic meningitis. First symptoms of CINCA (NOMID) occur at birth or in early infancy. Fever can be intermittent, very mild, or in some cases absent. The rash varies in intensity from patient to patient and with disease activity. Bone and joint inflammation also vary in severity: in approximately two-thirds of patients, joint manifestations are limited to arthralgia and transient swelling without effusion, and occur during flare-ups. In one-third of patients, however, severe and disabling arthropathy occurs as a result of overgrowth of the patella and the epiphyses of long bones (Figure 2). This arthropathy can cause gross deformity of the joints, with pain and a limited range of motion. Knees, ankles, wrists and elbows are the joints most commonly affected bilaterally, but small joints can also be involved. Radiological manifestations of the arthropathy associated with CINCA (NOMID) are distinctive; the most characteristic changes occur in the metaphysis and epiphysis, with overgrowth and irregular ossification.¹³ In very young children, bowing, shortening and widening of the long bones with a periosteal reaction can be observed. Abnormalities of the central nervous system (CNS) are present in almost all patients and are caused by a chronic, aseptic meningitis in which polymorphonuclear cells infiltrate the cerebrospinal fluid (CSF). Features of the disease phenotype related to CNS involvement vary in severity. Chronic headaches, vomiting and papilledema (seen on fundoscopy) are frequently observed consequences of chronic increased intracranial pressure. Spastic diplegia and epilepsy occasionally develop. Cognitive impairment occurs in severely affected patients. CSF examination shows variable hypercellularity of polymorphonuclear cells and/or hyperproteinorachia, and the CSF evinces an increased open pressure. CT findings can be normal or show mild ventricular dilatation and enlarged subdural fluid spaces, suggestive of mild cerebral atrophy. Leptomeningeal enhancement can be observed on MRI after gadolinium injection. Ocular disease consists of anterior uveitis in approximately 50% of patients with CINCA (NOMID) and posterior uveitis in another 20%.¹⁴ Optic atrophy can also develop. Ocular manifestations can progress to blindness, and 25% of patients have a major ocular disability in adulthood. Perceptive deafness is frequent and usually develops in late childhood or subsequently. Patients frequently have macrocrania, frontal bossing and saddle nose. Amyloid A amyloidosis develops with increasing age in some patients. Severe disabilities are frequent, and premature death is possible in severely affected patients. Prematurity and dysmaturity occur in one-third of patients. Umbilical-cord anomalies have been observed in a few cases.^{15, 16, 17} Leukocytosis and increased plasma levels of acute-phase reactants are both permanent symptoms in most cases.

Figure 2 Overgrowth arthropathy in a patient with CINCA (NOMID).

(A) Patellar overgrowth, which is characteristically observed in some patients who have CINCA (NOMID) with articular overgrowth. (B) Radiological image of a knee in a child with CINCA (NOMID) and articular overgrowth. Irregular ossification of the long-bone epiphyses, metaphysis and patella are evident. Abbreviations: CINCA (NOMID), chronic infantile neurological cutaneous articular syndrome (neonatal-onset multisystemic inflammatory diseases).

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Common overlapping symptoms

Careful examination of patients with cryopyrinopathies usually reveals an extensive overlap of clinical symptoms.^{10, 18, 19, 20} Patients with MWS might report symptoms that are consistent with FCAS, such as cold susceptibility (i.e. an increased frequency of attacks in winter), or symptoms consistent with mild CNS involvement, such as frequent headaches or asymptomatic papilledema, as seen in patients with CINCA (NOMID). Similarly, these signs can become increasingly obvious in patients as they age. Families with cryopyrinopathies can show mild phenotypic variability between affected individuals;²⁰ however, the most severe manifestations of CINCA (NOMID)—overgrowth arthropathy or severe neurological involvement—have never been reported in families whose affected members have relatively mild cryopyrinopathies.

Molecular basis of cryopyrinopathies

FCAS, MWS and CINCA (NOMID) are all caused by dominantly inherited or de novo mutations in CIAS1 (now known as NLRP3 [nucleotide-binding oligomerization domain, leucine-rich-repeat family, pyrin domain containing 3]). The official name for the protein encoded by this gene is NALP3 (NACHT, leucine-rich repeat and pyrin domains containing protein 3), but it has had several other names, including cryopyrin and PYPAF1 (pyrin-domain-containing Apaf1-like protein 1).^{21, 22} NALP3 belongs to the large family of NLR (nucleotide-binding domain and leucine-rich-repeat containing) proteins with 22 members in humans.²³ These proteins have key roles in innate immunity;²⁴ they are thought to be the intracellular equivalent of Toll-like receptors and activate various signaling cascades in response to metabolic stressors or microbial molecules that gain access to the cell.²⁵ Among the large family of NLR proteins, the NALPs are the largest subgroup with 14 members. All, including NALP3, have an amino-terminal pyrin domain, a central NACHT domain with a nucleotide-binding site and a carboxy-terminal leucine-rich repeat.²⁶

Function of NALP3

NALP3 interacts with other intracellular proteins to form a large complex called the inflammasome (Figure 3).²⁷ This complex is critically important in innate immunity, as it detects intracellular pathogens and other danger signals. Mechanisms of activation and regulation of the NALP3 inflammasome have been gradually elucidated. At rest, NALP3 is maintained in an inactive state in the cell cytoplasm. As shown by various in vitro and gene-knockout animal studies, NALP3 can be activated by a range of 'pathogen-associated molecular patterns',^{28, 29, 30} which include bacterial muramyl dipeptide, bacterial RNA or viral RNA, and by 'danger-associated molecular patterns'^{31, 32, 33, 34, 35} such as ATP, decreased intracellular potassium concentration, imidazoquinoline, monosodium urate crystals (which provoke inflammation and lead to gout), various skin irritants and ultraviolet B radiation. After activation via the leucine-rich-repeat domain, NALP3 interacts with ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain) and CARD8 (caspase recruitment domain containing protein 8; also known as CARDINAL).^{27, 36} When associated with the inflammasome, ASC can interact with procaspase 1 to mediate its conversion to caspase 1. Caspase 1, in turn, activates the interleukin (IL) precursors pro-IL-1 and pro-IL-18 to become proinflammatory IL-1 and IL-18, respectively.

Figure 3 The NALP3 inflammasome.

At rest, NALP3 is inactive in the cytoplasm. After being activated via its leucine-rich repeat by various PAMPs (such as muramyl dipeptides, bacterial or viral RNA) or DAMPs (such as uric acid crystals, ATP, low intracellular concentrations of potassium, skin irritants, ultraviolet B radiation), NALP3 is unfolded and interacts with ASC (by homotypic interaction between their pyrin domains) and CARD8. ASC then interacts with procaspase 1 through a homotypic interaction between their caspase recruitment domains, to mediate activation of caspase 1. Caspase 1 activates pro-IL-1 and pro-IL-18 become active IL-1 and IL-18, respectively. Abbreviations: ASC, apoptosis-associated speck-like protein containing a caspase recruitment domain; CARD8, caspase recruitment domain family, member 8; DAMP, danger-associated molecular pattern; FIIND, function to find domain; IL, interleukin; NACHT, an acronym derived from Nucleotide-binding oligomerization domain, leucine-rich-repeat family; Apoptosis inhibitory protein; Class II, major histocompatibility complex transactivator; Het-E incompatibility locus protein from Podospora anserina; Telomerase-associated protein 1; NAD, NACHT-associated domain; NALP3, NACHT, leucine-rich repeat, and pyrin domains containing protein 3; PAMP, pathogen-associated molecular pattern; PYD, pyrin domain.

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CIAS1 mutations

The mechanism by which CIAS1 mutations cause inflammatory diseases is still not completely understood, but in vitro studies suggest that these mutations have a gain-of-function effect, probably through the loss of a regulatory step associated with NALP3 activation.^{37, 38} The induction of inflammatory disease flares by exposure to cold in patients with FCAS also remains intriguing. New agents that target the IL-1 pathway have been proposed as potential treatments for patients with cryopyrinopathies as a result of these findings.

To date, approximately 60 disease-associated mutations in CIAS1 have been reported, almost all located in the region encoding the NACHT domain and its flanking structures (i.e. in exon three). In the past 5 years, four mutations have been identified in exons four and six within the region that encodes the leucine-rich repeat.^{31, 39, 40} Of the identified mutations, all but one are missense mutations.⁴¹ Some degree of genotype–phenotype correlation has been observed in the cryopyrinopathies; mutations found in patients with mild forms of cryopyrinopathy have not been identified in severely affected patients and vice versa. Additional genetic or environmental factors might also modulate the phenotypic expression of disease.^{18, 42} Few patients with FCAS and MWS, but approximately 40% of patients with CINCA (NOMID), do not carry any known CIAS1 mutations, which suggests that the cryopyrinopathies are genetically heterogeneous. Saito et al. have described three patients with CINCA (NOMID) who had somatic mosaicism; these patients carried a mutation in exon three of CIAS1 that occurred with different frequencies in whole blood and leukocytes.^{43, 44} This mechanism could account for some, but not all, patients classified as CIAS1-mutation negative.

Treatment of familial cold autoinflammatory syndrome and Muckle–Wells syndrome with anakinra

Anakinra was first used to treat two adult patients with a MWS phenotype; the drug was given daily by subcutaneous injection at a dose of 100 mg. The efficacy of this treatment was remarkable: all inflammatory symptoms (rash, fever and arthralgia) ceased a few hours after the first injection, and serum amyloid A protein levels normalized in a few days.⁴⁸ Hoffman et al. confirmed the striking efficacy of anakinra in prevention of acute inflammation in patients with FCAS,^{49, 50} and a number of studies confirmed the benefits of this treatment in patients with MWS, including improved hearing in selected cases.^{51, 52, 53} Anakinra very efficiently normalizes leukocytosis as well as levels of biologic inflammatory markers such as C-reactive protein and serum amyloid A protein. Some reports have also shown progressive improvement in amyloid-related proteinuria and nephritic syndrome if anakinra treatment is initiated before irreversible renal damage occurs.^{48, 54, 55} These benefits of IL-1 receptor antagonism in patients with FCAS and MWS are long-lasting (to date, the longest duration of continuous treatment reported in the literature is 3.5 years).⁵⁴ In adult patients, anakinra is usually initially prescribed at a dose of 100 mg per day, but maintenance doses can be reduced to 0.3–0.5 mg/kg daily in mild cases.⁵⁴

Anakinra in treatment of chronic infantile neurological cutaneous articular syndrome

The very encouraging results for anakinra in FCAS and MWS provided hope that this treatment would benefit severely affected patients with CINCA (NOMID), who might have serious, long-term disabilities that result from a broad range of symptoms that can include CNS involvement. Isolated case reports suggested anakinra was efficacious in this patient setting.^{10, 19, 56, 57} Goldbach-Mansky et al.⁵⁸ conducted an elegant, single-center study of 18 patients with CINCA (NOMID), mostly children, who had active disease. This study assessed the effects of anakinra on a broad range of symptoms. At baseline, all patients presented with CNS involvement and 11 had bony overgrowth. The starting dose of anakinra was 1 mg/kg per day, administered by subcutaneous injection, but was increased to 2 mg/kg per day in patients who had an incomplete response. All patients showed an immediate clinical improvement and rapid normalization of inflammatory biological markers. After 6 months, hearing had improved in one-third of the patients. Headache frequency, intracranial pressure and CSF protein levels decreased significantly compared with their baseline values, and cochlear and leptomeningeal enhancement (visible on patients' initial cerebral MRI scans) also improved in some individuals. Of note, in this study, 40% of the patients had no CIAS1 mutations; however, in terms of clinical manifestations of CINCA (NOMID) and response to anakinra, there were no differences between patients with or without CIAS1 mutations. Data on the long-term benefits of anakinra in patients with CINCA (NOMID) are still lacking. In our experience, the dose of anakinra required to control severe CINCA (NOMID), particularly if neurological involvement is severe, is higher than that recommended for patients with FCAS and MWS; we have successfully treated patients (median age at baseline 8.5 years, range 0.25–20 years) with up to 3 mg/kg per day of anakinra. Anakinra is well tolerated even at these high doses; we have not yet observed any adverse effects, apart from minor local pain and erythema at the injection site that tended to diminish gradually in most patients (B Neven et al., unpublished data).

New treatment perspectives

Interleukin 1 inhibition

Currently, a number of IL-1 inhibitors are in various stages of development. These include 'cytokine traps' and monoclonal antibodies to IL-1. The IL-1 trap (Rilonacept^®; Regeneron Pharmaceuticals, Inc., Tarrytown, NY) is a long-acting IL-1 blocker that comprises the extracellular domain of the human type 1 IL-1 receptor coupled to a human IgG₁ antibody. The safety and efficacy of weekly subcutaneous injections of Rilonacept^® (160 mg/week) were recently evaluated in 47 adult patients with FCAS and MWS.⁵⁹ After 1 year, Hoffman et al. confirmed that this treatment was effective (in terms of improved clinical symptoms and biological inflammatory markers); the most frequent adverse events reported were injection-site reactions (48%) and infections (most of which were upper respiratory tract infections). Overall, two patients died: a 70-year-old woman who had acute Streptococcus pneumoniae meningitis and a 37-year-old patient who had coronary atherosclerosis. Rilonacept^® has now been approved by the FDA for treatment of patients with MWS and FCAS who are older than 11 years. ACZ885 (Novartis International AG, Basel, Switzerland) is a new human IgG₁ monoclonal antibody directed against IL-1 that has a long half-life. ACZ885 is currently under investigation as a treatment for patients with cryopyrinopathies.^{60, 61}

Caspase 1 inhibition

Caspase 1 is another potential target of therapies for cryopyrinopathies. VX-765 (Vertex Pharmaceuticals, Cambridge, MA) is an orally active caspase 1 inhibitor that was able to block IL-1 secretion in vitro when peripheral blood mononuclear cells isolated from patients with FCAS were stimulated with lipopolysaccharide.⁶² A limited, open-label study of this drug has been conducted in six patients with MWS; these patients showed partial clinical and biological improvement with VX-765 treatment.⁶³

Practical considerations

Despite the promising results of anti-IL-1 agents in the treatment of patients with cryopyrinopathies, it is important to note that blockade of IL-1, especially with high-affinity, long-acting molecules, raises a potential risk of serious infections. This risk is particularly high in young children, in whom the immature immune response is less effective against polysaccharide-encapsulated bacteria. Moreover, safety data on these long-acting anti-IL-1 molecules are still lacking. Vaccination against S. pneumoniae should be updated before starting any anti-IL-1 therapy, especially in pediatric patients, and antibiotic prophylaxis should be considered in very young children treated with a high dose of anakinra. Cholesterol and triglyceride levels should also be monitored, especially in adults with other risk factors of coronaropathies.