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Muckle–Wells syndrome (MWS) is a rare autoinflammatory disorder. It is due to NLRP3 gene mutations, responsible for excessive caspase-1 activation and interleukin 1β processing. MWS is the intermediate phenotype of severity of cryopyrin-associated periodic syndrome. Urticarial rash, conjunctivitis, recurrent fever, arthralgia, and fatigue are the main clinical manifestations of MWS. Yet, sensorineural hearing loss and renal amyloidosis can occur after long term evolution. Patients’ quality of life has been drastically improved with the advent of IL-1 inhibitors. This review reports recent findings in MWS, particularly genotype/phenotype correlation, and discusses the clinical perspectives of this disease in a time of efficient treatment.
Muckle–Wells syndrome (MWS) is one of the three clinical forms of the cryopyrin-associated periodic syndrome (CAPS), a rare hereditary periodic fever syndrome due to genetic mutations in the NOD-like receptor 3 (NLRP3) gene. Chronic Infantile Neurological Cutaneous and Articular syndrome (CINCA) is the most severe form of CAPS with mental and physical disability; familial cold urticaria (FCAS) is the mild form, and MWS is the intermediate form. Urticarial rash, fever, arthralgia, and fatigue are the main clinical signs of CAPS. The NLRP3 gene mutation is responsible for overproduction of proinflammatory interleukin 1β (IL-1β), the driver of CAPS symptoms. Quality of life in MWS patients has been drastically improved since IL-1 inhibitors became available for treatment. This review first recalls the epidemiology, pathophysiology, and clinical presentation of MWS, then discusses the clinical perspectives of this disease now that efficient treatments exist, including the problems linked to their use, especially in very young children.
The prevalence of CAPS is estimated to be 1–10 cases per million (1/360,000 in France, with 150–200 cases).1 Caucasians seem to be affected more than other races and there is no male/female preponderance.
The three phenotypes of CAPS are caused by dominantly inherited or de novo gain-of-function mutations in the NLRP3 (also known as CIAS1) gene located on chromosome 1q44, with a variable penetrance.2 The NLRP3 gene encodes the NALP3 protein (cryopyrin) – a member of the intracellular nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) family. NLRs belong to the family of pattern- recognition receptors (PRRs). PRRs recognize different danger-associated molecular pattern molecules (DAMPs) and pathogen-associated molecular pattern molecules (PAMPs). All NLRs contain a NACHT domain that enables them to aggregate and oligomerize. Mutations in the NACHT domain of NALP3 may lead to increased inflammation.3 Two signals are necessary for IL-1β production. A first signal, response to the recognition of a PAMP by a PRR induces the production of the inactive form of IL-1β – pro-IL-1β – via the transcription factor NFκB. Upon activation by a second signal, triggered by a further PAMP or a DAMP, NALP3 oligomerizes and recruits other proteins such as Apoptose-associated speck-like protein (ASC) and caspase-1, creating a multi-protein assembly called inflammasome (Figure 1).4 The protease caspase-1 then cleaves IL-1β, releasing IL-1β from the cell. IL-1β is a proinflammatory cytokine that causes fever, vasodilatation, and systemic inflammation. IL-1β is potent at low concentrations, whereas its natural inhibitor, the IL-1 receptor antagonist (IL-1RA), needs very high concentrations to be effective. In CAPS patients, the inflammasome is activated even in absence of chronic infection. DAMPs may be IL-1 itself, specifically IL-1α, resulting in inflammasome activation.5 Thus, IL-1 induces a vicious IL-1β-producing cycle in an autocrine manner, and the IL-1RA concentrations that are reached in CAPS are not sufficient to inhibit IL-1β. Yet, this IL–1β-producing cycle can be interrupted by anakinra, which blocks both IL-1α and IL-1β.6,7 These different mutations display a strong genotype–phenotype correlation, although a specific mutation may be associated with different phenotypes of variable severity. Few patients with convincing CAPS profile have shown no mutation. Some of them have somatic mosaicism, suggesting a role of somatic mutations.
MWS is characterized by chronic or intermittent episodes of fever, headache, urticarial rash, arthralgia, or arthritis in the absence of a specific trigger.8 The febrile attacks start in early childhood with a median age of onset of 0.8 years.9 Between 40% and 80% of patients experience intense fatigue leading to social isolation.10,11 The attacks can increase nocturnally, accompanied by general malaise with chills, sweating, intense myalgia, and heaviness in lower limbs, sometimes with edema.12 Most attacks resolve within 24 hours (48%), but a substantial portion (36%) last >3 days.9 Half the patients suffer <12 attacks a year, but 40% of patients experience >24 attacks a year.9 Headache and irritability are present in 90% of cases due to migraine, intracranial hypertension, or chronic meningitis, and have a hugely detrimental impact on daily life.9,10 Patients may present a livedoid aspect on the skin, with a non-pruritic urticarial rash appearing during attacks. Histologically, the lesions correspond to neutrophilic urticarial.12,13 More rarely, the patient presents with oral ulcer, folliculitis, or erythema nodosum.13 Osteoarticular symptoms are mainly arthralgia and nail clubbing. Cartilaginous proliferation at growth plates and epiphyses, as well as arthritis are seen only in CINCA patients.14 Patients with MWS can develop progressive sensorineural hearing loss, which becomes apparent after age 10, probably secondary to chronic inflammation of the internal ear.12 Conjunctivitis is frequent while episcleritis and uveitis can also be seen in the severe forms. Amyloidosis leading to proteinuria and renal failure affect up to 25% of cases.9,12
During the attacks, levels of C-reactive protein (CRP) and serum amyloid A (SAA) in the blood, as well as absolute neutrophil count may be increased.12
Differential diagnoses include other periodic inflammatory disorders such as tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), hyperimmunoglobulinemia D with periodic fever syndrome (HIDS), juvenile systemic granulomatosis, juvenile idiopathic arthritis, familial Mediterranean fever (FMF), and Behçet disease.12 Fever, skin rash, arthralgia, and persistent inflammatory markers were common with Still disease. Other autoimmune diseases could also be evoked as hypocomplementemic vasculitis or systemic lupus.13 CAPS, in general, and MWS, in particular, share common symptoms with other auto-inflammatory diseases such as HIDS, TRAPS, or FMF.12 The hereditary recurrent fever disease which mimics MWS the most is the syndrome associated with NALP 12 mutations, with cold-triggered urticarial during 5–10 days, abdominal pain, oral ulcers, headache, adenomegaly, and, in some patients, deafness.15
A recent study of 287 CAPS patients, including 164 cases of MWS patients, has proposed the following model for the diagnosis of CAPS with a sensitivity of 81% and a specificity of 94%:16
Raised inflammatory markers (CRP/SAA) (mandatory criteria).
In addition to ≥2 of 6 CAPS typical signs/symptoms:
A recent survey of a large European registry showed that some NLRP3 mutations correlated with the clinical phenotype and could predict the outcome of CAPS.9 Nine subgroups were defined corresponding to each of the most frequent genetic variants (R260W, E311K, V198M, T348M, D303N, and A439V mutations, and the functional polymorphism Q703K), to rare variants and to the absence of mutation. The patient’s clinical characteristics were compared according to the presence or absence of each of these mutations. The main correlations between clinical characteristics and genotypes are summarized in Table 1.
The R260W variant was associated with cold-triggered symptoms, a positive family history, and a trend toward symptom onset after the age of 6 months. Patients carrying R206W and V198M did not differ in terms of phenotype or disease severity from patients with R260W mutation alone. The T348M variant was associated with disease onset before the age of 6 months, a chronic course, and hearing loss. The V198M, E311K, and A439V alleles were negatively associated with neurological involvement. Patients carrying the functional polymorphism Q703K were characterized by very mild, late-onset disease with no severe neurological or musculoskeletal involvement, no deafness, and no family history. Patients bearing a rare mutation had disease onset before the age of 6 months, neurological manifestations including severe ones, musculoskeletal involvement, and sporadic disease pattern. Furthermore, they had a trend toward a higher risk of sensorineural hearing loss.
In brief, V198M and Q703K alleles are not disease causing, and the A439V and R260W alleles have been variably associated with a less severe phenotype. Patients carrying the T348M and E311K alleles or no mutations may have increased risk for a severe phenotype with hearing loss and neurological disease.
Prior to the discovery of biological treatments, pain killers and antihistamines had been shown to be ineffective for reducing CAPS symptoms, although high-dose corticosteroids were partially efficient.17 Patients had decreased quality of daily life, with fatigue, chronic pain, hearing and visual handicaps, as well as learning difficulties.10 They had to face a lack of understanding in their school or professional milieus, leading to social and affective isolation. Progressively, they could develop various psychological problems such as drug addictions or severe depression leading to suicide.10 Understanding CAPS pathophysiology has allowed efficacious treatment targeting IL-1β.
Three IL-1 inhibitors have shown efficacy in CAPS: anakinra, a recombinant non-glycosylated form of the human IL-1RA; rilonacept, a chimerical protein consisting of the IL-1-binding domains of IL-1RI and IL-1R accessory protein fused to the Fc portion of human IgG1; and canakinumab, a fully human monoclonal IgG1 targeted at IL-1β. Both anakinra and canakinumab are approved for all CAPS phenotypes in Europe. In Japan, only canakinumab is approved for all CAPS phenotypes. In the USA, canakinumab is approved for adults, and children aged >2 years, with FCAS and MWS; anakinra is approved for CINCA; and rilonacept is approved for adults and children aged >12 years with FCAS and MWS.17
Daily subcutaneous injections of anakinra resulted in rapid regression of symptoms and normalization of CRP and SAA levels.18–21 Anakinra has approval in the USA and Europe to be used in infants from 8 months onward at a dose between 1 and 8 mg/kg/day according to clinical severity, and at a dose of up to 300 mg for adults.17 Anakinra has a very short half-life (6 hours); thus, symptoms rapidly reappear if the treatment is interrupted. Anakinra has significant benefits for the treatment of systemic symptoms and as it can penetrate into the cerebrospinal fluid (CSF), it could affect chronic features such as aseptic meningitis, uveitis, and cochlear inflammation.19,22 In a study in CINCA patients, central nervous system inflammation evaluated by CSF analysis and leptomeningeal enhancement on FLAIR MRI were significantly decreased with anakinra, with visual acuity and peripheral vision improvement or stabilization in most patients over age 5.11 Furthermore, anakinra was effective in secondary amyloidosis with stabilization of renal function. However, complete reversal of amyloidosis has only been documented once.19 Canakinumab, with a long half-life of 28 days, has been proven to be efficient and safe versus placebo in a pivotal study published in 2009.23 Thirty-five MWS pediatric and adult patients received 150 mg canakinumab for adults and 2 mg/kg for children every 8 weeks. The effectiveness of canakinumab was rapid and sustained in the long term for all clinical and biological symptoms if the treatment was not discontinued.23,24 Canakinumab is shown to stabilize or decrease hearing loss, but there are no reports on canakinumab concentration in CSF.25,26 In a 2-year long phase III multicenter, single treatment arm, open-label study of canakinumab in patients with FCAS (n=30 patients), MWS (n=103), and CINCA (n=32), repeat neurological assessments of canakinumab treatment showed normalization in 9/20 patients, improvement in two patients, and a new symptom in one patient.24 Abnormal audiograms at baseline (n=63) improved upon treatment in 13/63 patients and were unchanged for 29 patients. Ocular involvement normalized in 1/22 patients, improved in six, and remained unchanged in 15 patients. Three out of four patients with amyloidosis improved and one worsened. The quality of life of patients drastically improved when different assessment tools were used to evaluate it such as the functional assessment of chronic illness therapy fatigue (FACIT-F), the Medical Outcomes Survey 36-item Short Form (SF-36) standard version, the HAQ for adults, and the CHAQ Parent Form 28 (CHQ-PF28) for children.10 Most patients saw an improvement in their physical abilities and social activities.
Rilonacept was demonstrated to be efficient in decreasing the disease activity score compared to placebo at the dose of 160 mg/week administered subcutaneously.27 The effect was maintained during the 96-week follow-up.28
Adverse events due to anti-IL-1 were injection-site reactions, including pain, swelling, redness, and pruritus, for all three IL-1 antagonists; however, this was transient and most patients were able to continue the treatment.23,27–29 Increased incidence of mild infections of the respiratory tract was the main side effect of IL-1 antagonists.23,27–29
Weight gain was reported in 10%–30% of patients with long-term use of anakinra or rilonacept; however, the extent of the weight gain remains to be investigated to determine whether it was excessive.21 Other rare side effects of anakinra included urinary tract infections, leukopenia, hepatitis, and macrophage activation syndrome.29 Anakinra use during pregnancy was safe in a small series of nine women,30 with normal gestational outcome. One of the twin fetus carrying an NLRP3 mutation had renal agenesis and died in utero. Other reports of renal malformation in fetuses carrying CAPS mutations excluded the hypothesis of a causal link with anakinra treatment.11 There are no published data on canakinumab and pregnancy. Thus, a switch from monoclonal anti-IL-1 antibodies to anakinra during pregnancy is recommended and caution is warranted in terms of renal malformations.17 Two large international registries have been established to collect data for anti-IL-1: the Eurofever physician’s registry31 and the β confident Novartis registry on Canakinumab.32
Generally, according to expert opinions, patients presenting with the most severe phenotypes, those at risk of severe complications, and patients presenting continuous biological inflammation (elevated CRP and SAA levels) should receive treatment to avoid organ damage and AA amyloidosis.17 For other patients who do not fulfil these categories, the burden of disease and quality of life should be assessed before a final decision is made. The duration of treatment is theoretically lifelong. Early treatment as soon as the disease is diagnosed may change, at least in part, the natural history, thereby reducing the occurrence of secondary complications.17
In summary, treating patients with IL-1 blockers, regardless of the nature of the drug and the phenotype of CAPS, markedly improved their ability to function in normal society.
To prevent secondary complications and to give children the chance to lead as normal life as possible from birth, IL-1 antagonists should be started as soon as possible, potentially even in very young children and newborns.17 However, for this age group, drug pharmacokinetics and distribution into the tissues are not well studied. Very young children usually need higher doses (3–5 times the recommended doses) to be effective on general symptoms and especially if the aim is to impact neurological manifestations, as well as vision and hearing loss.19,22 For children aged <2 years, the risk of developing encapsulated bacterial infections is high and pneumococcal vaccination prior to starting treatment is strongly recommended.17
Furthermore, the choice of anti-IL-1 monoclonal antibodies in cases of neurological involvement must be further studied as too few data are currently available with regard to diffusion of these drugs into CSF.26 In addition, the long-term outcome of treated patients needs to be followed up to determine the consequences of lifelong blockade of IL-1.
With IL-1 antagonists, the lives of MWS patients normalize, raising the question of reproduction. We have reported a series of nine male MWS patients in whom five had oligozoospermia and three had azoospermia.33 Treatment with IL–1-targeting drugs had a moderate or no effect on spermatozoa counts. The original study of MWS in 1962 reported a case of male infertility in a man with loss of libido and abnormal testicles.8 The extent of infertility in the male MWS population needs to be assessed more precisely in an international study, and the mechanisms leading to infertility need to be explored. Possible mechanisms include inflammation, IL-1β overproduction, altered testosterone level, and/or amyloidosis. Early treatment may be beneficial to preserve normal spermatozoa counts. However, the consequence of complete IL-1 blockade during childhood or adolescence on normal sexual maturation may be problematic, as IL-1α and -1β are known to be required for the regulation of sperm maturation in mice. Sexual health and fertility should be assessed systematically in all male patients to preserve fertility, according to these observations.
Clinical profiles and outcomes of MWS patients have been drastically improved with the increased understanding of CAPS pathophysiology and intervention using anti-IL-1 treatment. Normal life is now possible for patients. Advanced studies are still needed to predict phenotype from genotype for early treatment. Data on pharmacokinetics and diffusion of the drugs into CSF in young children are still needed for better indication and use of anti-IL-1. Consequences on growth, development, and sexual maturation of long-term use of IL–1-antagonists need to be assessed in children treated very early in life.
The author thanks Pierre Corbeau and Sarah Kabani for editing the manuscript.
TA Tran has received consulting fees from Novartis, Sobi, and Abbvie. His institution has received research fees from Novartis. The author reports no other conflicts of interest in this work.