Chronic Infantile Neurologic, Cutaneous, Articular Research Articles

Aseptic Μeningitis in Hereditary Autoinflammatory Diseases

Autoinflammatory diseases (ADs) refer to a group of disorders of the innate immune system, mainly monogenic, marked by episodes of systemic inflammation. Aseptic meningitis is a rare neurological manifestation of ADs characterized by meningeal inflammation, negative routine cultures in the cerebrospinal fluid and identical signs and symptoms of bacterial meningitis. Herein, the aim of this review article is to describe the association between aseptic meningitis and ADs, especially in patients with familial Mediterranean fever (FMF) and chronic infantile neurological cutaneous articular (CINCA) syndrome. We will discuss the emerging role of proinflammatory cytokines, such as interleukin 1 (IL-1), interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-α), in the pathogenesis of aseptic meningitis in ADs, and will explore recent treatment developments, such as the use of biological agents.

Cryopyrinopathies

Cryopyrin-associated periodic syndromes (CAPS) are linked to one single gene mutations, however they are associated with 3 syndromes, which are, from the mildest to the most severe phenotype familial cold urticaria, Muckle-Wells syndrome and chronic, infantile, neurologic, cutaneous, articular (CINCA) syndrome also called neonatal-onset multisystem inflammatory disease (NOMID). Autosomic dominant inheritance is present in most cases but in CINCA/NOMID syndrome where neomutations are more common. Mutations in the gene encoding cryopyrin, NLRP3, are associated with deregulation of caspase-1 activity, excessive interleukin-1 production and an autoinflammatory syndrome, which in familial cold urticaria and Muckle-Wells syndrome may be triggered or worsened by exposure to coldness. More and more mutations are described and even somatic mutations that can explain some clinical signs beginning in adulthood. Patients disclose a pseudo-urticarial rash, arthralgia, headaches, sometimes fever, biological inflammation but also, in severe forms of the disease, neurologic inflammation with central deafness, ophthalmologic inflammation, chronic meningitis. Some CINCA/NOMID patients also develop growth cartilage pseudo-tumoral hypertrophy. Natural disease history is usually benign in familial cold urticarial but severe in the other forms, particularly regarding neuro-sensorial involvement. In addition, secondary AA amyloidosis may develop in all forms in the absence of control of chronic inflammation. Anti-interleukin-1 treatment with anakinra, rilonacept or canakinumab induces in most cases complete remission, however sequelae may be present, particularly if central deafness or cartilage bone hypertrophy have already developed. This treatment is also important to prevent secondary amyloidosis or stabilize and even sometimes allow improvement of amyloidosis lesions.

Successful kidney transplantation during anakinra treatment without complications

Although the incidence of end stage renal failure in patients with autoinflammatory diseases has decreased since the introduction of the interleukin-1 (IL-1)-receptor antagonist anakinra, it is still relatively common. Cessation of anti-IL-1 therapy during and after kidney transplantation will not be possible in most patients because of the risk of recurrence of inflammation. The effect of continued anti-IL-1 therapy on transplantation-related complications is currently unknown. Recently, we have performed kidney transplantation in two patients while on anakinra therapy. The first patient is a 70 year old male, who suffered from febrile episodes since 2004 and was diagnosed with adult onset Still's disease in 2010. He had been using anakinra ever since. Chronic renal insufficiency due to thrombotic microangiopathy had been present since 2005. In September 2014 he received a kidney transplant of a living related donor, under standard immunosuppression (tacrolimus, prednisone and mycophenolate mofetil (MMF)), while anakinra was continued. Kidney function improved rapidly and he could be discharged from the hospital 7 days post transplantation. Until March 2015, he has been readmitted two times: once for a single day because of drainage of a wound abscess, and for 5 days 1 year post-transplantation because of sepsis with unknown cause. He now has adequate and stable transplant function. The other patient is a 20 year old woman with mutation-negative Chronic Infantile Neurologic Cutaneous Articular (CINCA) syndrome. She had been using anakinra since 2004, which was switched to canakinumab in 2012. She was known with chronic renal insufficiency with proteinuria, probably due to recurrent urinary tract infections, vesico-urethral reflux and chronic use of NSAIDs since 2009. Kidney biopsy was contra-indicated. Because of rapidly progressive renal function loss, she received a pre-emptive kidney transplant of a healthy related donor in September 2014, under standard immunosuppression. Canakinumab was switched to anakinra just before transplantation, because of shorter half-life, making it easier to cease in case of complications. Kidney function increased rapidly and she could be discharged 6 days post-transplantation. She had been readmitted a single time for two days because of a primo-EBV and influenza infection in December 2014. She now has normal kidney function. In these two cases we did not find an increase of transplantation-related complications or post-transplantation infectious complications, when kidney transplantation with a standard immunosuppresive regimen was performed during anakinra therapy. It is important to adapt the dosing of anakinra to the kidney function before and after transplantation. Written informated consent for publication of their clinical details was obtained from the patient/parent/guardian/relative of the patient.

PReS13-SPK-1588: Recurrent fevers

Fevers are common in childhood, usually due to infections. Some children however experience recurrent episodes of seemingly unprovoked fevers. These so-called periodic fever syndromes are rare diseases. Clinically they are characterized by generalized inflammation and different combinations of localized tissue inflammation. Skin and joints are often affected in these patients and the long-standing inflammation can lead to irreversible organ damage due to tissue deposition of inflammatory amyloid proteins. Especially the kidney is vulnerable tot his so-called AA-amyloidosis. The spontaneous sterile inflammation in the absence of autoantibodies places the periodic fever syndromes in the same category as systemic juvenile idiopathic arthritis: the group of autoinflammatory diseases. Often these are genetically determined. Over the past 15 years genetic defects have been identified underlying more than twenty such genetic autoinflammatory diseases. These are disorders like Familial Mediterranean Fever, caused by mutations in the MEFV gene, TNF-receptor associated periodic syndrome (TRAPS), caused by mutations in the TNFRSF1A gene and the Chronic Infantile Neurological Cutaneous Articular (CINCA) syndrome, caused by mutations in the NLRP3 gene. Identification of the responsible genes has led to understanding of the pathophysiology and hence to effective targeted therapy. Interleukin-1 has proved to be the central mediator in many of these disorders. This finding in the congenital autoinflammatory diseases has led to novel therapies in more common disorders like interleukin-1 blockade in systemic Juvenile Idiopathic Arthritis. The rarity of the periodic fever syndromes hampers evidence based therapy. International collaboration in the EUROFEVER network has enabled us to better define the clinical picture of these disorders and to select targets for therapeutic research. However, many children currently defy genetic diagnosis. Next generation genetic sequencing efforts will hopefully identify the cause of inflammation in this group of patients. The functional consequences of autoinflammatory diseases are primarily related to the unpredictable fever episodes. However irreversible sequelae, such as hypertrophic arthropathy, chronic renal failure, impaired vision or hearing do occur. Since these are largely preventable by adequate control of inflammation, effective therapy is essential.

PReS-FINAL-2240: Serum amyloid protein a concentration in CAPS patients treated with anti IL1Β

Although all patients with chronic inflammatory conditions are at risk for developing type AA amyloidosis, the incidence varies widely between the different Autoinflammatory syndromes. The reported incidence is about 35% of patients with CAPS (cryopyrin-associated periodic syndrome) which comprises familial cold auto-inflammatory syndrome (FCAS), Muckle-Wells syndrome and CINCA (chronic infantile neurological cutaneous, articular inflammatory syndrome). CAPS is associated with mutations in NLRP3/CIAS1 on chromosome 1q44, found only in about 50% of patients. Previous studies have demonstrated that IL-1β inhibitors are able to induce complete remission of clinical manifestations and suppression of markers of inflammation in the majority of patients.

PW02-026 - Low frequency variants of NLRP3 in CAPS patients

Somatic mosaicism of NLRP3 has been identified in a high percentage of “mutation-negative” patients suffering from chronic infantile neurologic, cutaneous, articular (CINCA) syndrome.

The schedule of administration of canakinumab in cryopyrin associated periodic syndrome is driven by the phenotype severity rather than the age

IntroductionInterleukin-1 (IL-1) blockade is the treatment of choice of cryopyrin associated periodic syndromes (CAPS). Anti-IL-1 monoclonal antibody (canakinumab) was recently registered. However no clear data are available on the optimal schedule of administration of this drug. The aim of the present study was to analyse the impact of canakinumab on CAPS patients in daily clinical practice and to identify the best schedule of administration according to age and phenotype.Methods13 CAPS patients (10 children and 3 young adults) treated with canakinumab were followed for 12 months. Clinical and laboratory parameters were collected at each visit. Health-related quality of life (HRQoL) was recorded at month 12. Complete response was defined as absence of clinical manifestations and normal examinations. Clinical and laboratory variables at last follow-up were compared with those registered at the moment of anakinra discontinuation.Resultsseven patients with chronic infantile neurological cutaneous articular (CINCA) syndrome, four patients with Muckle-Wells syndrome (MWS) and two patients with an overlapping MWS/CINCA phenotype were analysed. CINCA patients experienced a higher number of modifications of the treatment (increased dosage or decreased dosing interval) in respect to MWS patients. At the end of the follow-up CINCA patients displayed a higher frequency of administration with a median dose of 3.7 mg/kg (2.1 mg/kg for MWS patients). Canakinumab was withdrawn in a patient with CINCA for incomplete response and poor compliance. The effect of canakinumab on HRQoL was similar to that observed during treatment with anakinra, with the exception of an improvement of the psychosocial concepts after the introduction of canakinumab.ConclusionsThe use of canakinumab in daily practice is associated with persistent satisfactory control of disease activity but needs progressive dose adjustments in more severe patients. The clinical phenotype, rather than the age, represents the main variable able to determine the need of more frequent administrations of the drug at higher dosage.

High incidence of NLRP3 somatic mosaicism in patients with chronic infantile neurologic, cutaneous, articular syndrome: Results of an international multicenter collaborative study

Chronic infantile neurologic, cutaneous, articular (CINCA) syndrome, also known as neonatal-onset multisystem inflammatory disease (NOMID), is a dominantly inherited systemic autoinflammatory disease. Although heterozygous germline gain-of-function NLRP3 mutations are a known cause of this disease, conventional genetic analyses fail to detect disease-causing mutations in ∼40% of patients. Since somatic NLRP3 mosaicism has been detected in several mutation-negative NOMID/CINCA syndrome patients, we undertook this study to determine the precise contribution of somatic NLRP3 mosaicism to the etiology of NOMID/CINCA syndrome. An international case-control study was performed to detect somatic NLRP3 mosaicism in NOMID/CINCA syndrome patients who had shown no mutation during conventional sequencing. Subcloning and sequencing of NLRP3 was performed in these mutation-negative NOMID/CINCA syndrome patients and their healthy relatives. Clinical features were analyzed to identify potential genotype-phenotype associations. Somatic NLRP3 mosaicism was identified in 18 of the 26 patients (69.2%). Estimates of the level of mosaicism ranged from 4.2% to 35.8% (mean ± SD 12.1 ± 7.9%). Mosaicism was not detected in any of the 19 healthy relatives (18 of 26 patients versus 0 of 19 relatives; P < 0.0001). In vitro functional assays indicated that the detected somatic NLRP3 mutations had disease-causing functional effects. No differences in NLRP3 mosaicism were detected between different cell lineages. Among nondescript clinical features, a lower incidence of mental retardation was noted in patients with somatic mosaicism. Genotype-matched comparison confirmed that patients with somatic NLRP3 mosaicism presented with milder neurologic symptoms. Somatic NLRP3 mutations were identified in 69.2% of patients with mutation-negative NOMID/CINCA syndrome. This indicates that somatic NLRP3 mosaicism is a major cause of NOMID/CINCA syndrome.

Autoinflammatory syndromes: report on three cases

Autoinflammatory syndromes are diseases manifested by recurrent episodes of fever and inflammation in multiple organs. There is no production of autoantibodies, but interleukins play an important role and acute-phase reactants show abnormalities. Our aim was to report on three cases of autoinflammatory syndromes that are considered to be rare entities. The authors describe the clinical features of three patients whose diagnosis were the following: tumor necrosis factor receptor-associated periodic syndrome (TRAPS), chronic infantile neurological cutaneous articular (CINCA) syndrome and familial Mediterranean fever (FMF). All of the patients presented fever, joint or bone involvement and increased acute phase reactants. The genetic analysis confirmed the diagnoses of two patients. The great diversity of manifestations and the difficulties in genetic analyses make the diagnosing of these diseases a challenge.

Síndrome CINCA: presentación de un caso con exacerbación febril de sus lesiones cutáneas

Chronic infantile neurologic cutaneous articular (CINCA) syndrome is a serious chronic systemic inflammatory disease that presents at a young age and that is characterized by skin, joint, and central nervous system disease. Skin symptoms are the first to appear, in the form of a longstanding nonpruritic urticarial rash, with exacerbations coinciding with episodes of fever, arthritis, and enlarged lymph nodes. The findings of biopsy of skin lesions are extremely variable but characterized by perivascular neutrophilic infiltrate.With the discovery of mutations in the CIAS1 gene, which encodes a protein known as cryopyrin, this entity has been classified as one of the cryopyrin-associated autoinflammatory diseases, along with familial cold urticaria and Muckle-Wells syndrome. This discovery has also made available new therapeutic options. We present the case of a boy diagnosed with CINCA syndrome who presented with an outbreak of painful skin lesions and fever. These lesions were thought to be an exacerbation of underlying lesions during an episode of fever.

Exacerbation of Skin Lesions During Fever in a Patient With Chronic Infantile Neurologic Cutaneous Articular Syndrome

Chronic infantile neurologic cutaneous articular (CINCA) syndrome is a serious chronic systemic inflammatory disease that presents at a young age and that is characterized by skin, joint, and central nervous system disease. Skin symptoms are the first to appear, in the form of a longstanding nonpruritic urticarial rash, with exacerbations coinciding with episodes of fever, arthritis, and enlarged lymph nodes. The findings of biopsy of skin lesions are extremely variable but characterized by perivascular neutrophilic infiltrate. With the discovery of mutations in the CIAS1 gene, which encodes a protein known as cryopyrin, this entity has been classified as one of the cryopyrin-associated autoinflammatory diseases, along with familial cold urticaria and Muckle-Wells syndrome. This discovery has also made available new therapeutic options. We present the case of a boy diagnosed with CINCA syndrome who presented with an outbreak of painful skin lesions and fever. These lesions were thought to be an exacerbation of underlying lesions during an episode of fever.

New CIAS1 mutation and anakinra efficacy in overlapping of Muckle-Wells and familial cold autoinflammatory syndromes

Muckle-Wells syndrome (MWS) and familial cold autoinflammatory syndrome (FCAS) are rare periodic fevers associated with CIAS1 mutations. A third entity, the chronic infantile neurological, cutaneous, articular (CINCA) syndrome was also recently associated with mutation in the same gene. A phenotypic and genotypic continuum seems to exist from the most benign (FCAS) to the most severe forms (CINCA). Although a CIAS1 mutation can be associated with two different phenotypes. We report a family of three patients exhibiting the MWS and FCAS phenotypes. These phenotypes were associated with a novel missense mutation in CIAS1. Anakinra controlled inflammatory flares in the three patients. FCAS, MWS and CINCA could be different phenotype expressions of the same disease.

Pattern of interleukin‐1β secretion in response to lipopolysaccharide and ATP before and after interleukin‐1 blockade in patients with CIAS1 mutations

To examine the synthesis, processing, and secretion of interleukin-1beta (IL-1beta), as well as the clinical and biologic effects of IL-1 blockade, in patients with chronic infantile neurologic, cutaneous, articular (CINCA) syndrome and Muckle-Wells syndrome (MWS), in an effort to understand the molecular mechanisms linking mutations of the CIAS1 gene and IL-1beta hypersecretion, and the underlying response to IL-1 receptor antagonist (IL-1Ra). Six patients with CINCA syndrome or MWS were treated with IL-1Ra and followed up longitudinally. Monocytes obtained from the patients and from 24 healthy donors were activated with lipopolysaccharide (LPS) for 3 hours, and intracellular and secreted IL-1beta levels were determined by Western blotting and enzyme-linked immunosorbent assay before and after exposure to exogenous ATP. LPS-induced IL-1beta secretion was markedly increased in monocytes from patients with CIAS1 mutations. However, unlike in healthy subjects, secretion of IL-1beta was not induced by exogenous ATP. Treatment with IL-1Ra resulted in a dramatic clinical improvement, which was paralleled by an early and strong down-regulation of LPS-induced IL-1beta secretion by the patients' cells in vitro. Our results showed that the requirements of ATP stimulation for IL-1beta release observed in healthy individuals are bypassed in patients bearing CIAS1 mutations. This indicates that cryopyrin is the direct target of ATP and that the mutations release the protein from the requirement of ATP for activation. In addition, the dramatic amelioration induced by IL-1Ra treatment is at least partly due to the strong decrease in IL-1beta secretion that follows the first injections of the antagonist. These findings may have implications for other chronic inflammatory conditions characterized by increased IL-1beta.

Clinical and genetic characterization of Italian patients affected by CINCA syndrome

We report the experience of the Italian Registry of patients affected by chronic infantile neurological, cutaneous, articular (CINCA) syndrome. The clinical and genetic features of 12 unrelated Italian patients with CINCA syndrome are described, focusing on the possible influence of the presence of CIAS1/cryopyrin mutations on the phenotype of the disease and on its prognosis. The clinical features of 12 Italian CINCA patients were evaluated. Genomic DNA of the patients was sequenced using specific primers for CIAS1 and ASC genes. Our patients shared typical CINCA characteristics and, sometimes, remarkable perinatal events, peculiar of CIAS1-mutated patients. Seven patients carried CIAS1 missense mutation, localized within the nucleotide binding domain of cryopyrin. Four previously described mutations and three new heterozygous CIAS1 missense mutations were identified. ASC gene, encoding for a direct interactor of cryopyrin, was not mutated in Italian CINCA patients. Finally, we reported the efficacy and safety of anti-IL1 therapy (Anakinra) in seven patients with a particularly severe CINCA phenotype. Despite some common signs-used as syndrome hallmarks-we observed a high variability in symptoms, genetic results and outcomes in Italian CINCA patients. In contrast with other authors, we cannot find out any correlation between mutations in CIAS1 and CINCA severity, but we underlined the concomitance of perinatal events and mental retardation only in CIAS1 mutated subjects. Finally, we confirmed the efficacy of Anakinra treatment, both in CIAS1-mutated and non-mutated patients.

A severe case of chronic infantile neurologic, cutaneous, articular syndrome treated with biologic agents

In this report we describe a case of severe chronic infantile neurologic, cutaneous, articular (CINCA) syndrome with a novel G307V cryopyrin mutation and all of the characteristic clinical and laboratory features of this autoinflammatory disease. There was no clear response to standard therapies, including human interleukin-1 (IL-1) receptor antagonist (anakinra) and soluble tumor necrosis factor receptor (etanercept). The patient finally had a partial clinical response (reduction in fever and irritability) and complete laboratory response (improved C-reactive protein and serum amyloid A levels) to humanized anti-IL-6 receptor antibody (MRA), but died from congestive heart failure and interstitial pneumonia 2 months after initiation of therapy. We serially measured the serum cytokine levels and expression of NF-kappaB activation in the patient's peripheral blood mononuclear cells before and during consecutive therapies. Pathologic examination of autopsy specimens was also performed. This case illustrates the continued difficulty in management of patients with CINCA syndrome and the complexity of the inflammatory pathways in this disorder.

Hydrocephalus in CINCA syndrome treated with anakinra

Chronic infantile neurologic, cutaneous, articular (CINCA) syndrome is a rare congenital autoinflammatory disease characterized by neonatal-onset chronic meningitis, hydrocephalus, sensorineural hearing loss, persistent urticarial rash, deforming arthritis, and recurrent fever. This clinical entity is believed to result from dysregulation of cytokine production. No recommended treatment protocol exists so far for CINCA syndrome. We report a 7-year-old child affected with CINCA syndrome in whom no therapy had resulted effective. Anakinra, an interleukin-1-receptor antagonist, was administered in a 1-year period with complete inflammatory symptom remission and dramatically ameliorated laboratory tests. This optimal response has been supported by the demonstration of a stabilized hydrocephalus upon magnetic resonance imaging and by an overall improvement of the neurodevelopmental issues. This paper emphasizes and discusses the medical approach with anakinra in CINCA syndrome presenting with hydrocephalus in which a consistent control of the neurological picture can be obtained.

Anakinra in mutation-negative CINCA syndrome

Chronic infantile neurological cutaneous articular (CINCA) syndrome is a rare congenital inflammatory disorder with variable clinical manifestations but devastating in a great majority of the cases. The syndrome is characterized by a generalized, wandering palpable rash eruption of neonatal onset, chronic arthropathy characterized by abnormal proliferation of cartilage and an abnormal ossification, and a progressive neurological impairment as the result of a chronic meningitis caused by polymorphonuclear cell infiltration [1, 2]. Nevertheless, many other manifestations are described, including fever, generalized lymphadenopathy, hepatosplenomegaly, developmental retardation, hydrocephalus, cerebral atrophy, ocular involvement in the form of uveitis and papilitis, and perceptive deafness. Recently, the syndrome has been associated with mutations in the CIAS1 gene [3]. These mutations will imply a higher level of interleukin-1 (IL-1) and a good response with the recombinant human IL-1 receptor antagonist anakinra [4, 5]. Nevertheless, CINCA syndrome has not always been associated with CIAS1 mutations, but in these cases, patients can also respond well to the treatment with anakinra [6], as in the case of the patient we present. Case report

Molecular and Genetic Characteristics of Hereditary Autoinflammatory Diseases

Autoinflammatory diseases are defined as recurrent "unprovoked" inflammatory events which do not produce high-titer autoantibodies or antigen-specific T cells. There are currently eight hereditary forms of these diseases: Familial Mediterranean fever (FMF), hyperimmunoglobulinemia D with periodic fever syndrome (HIDS), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), chronic infantile neurologic cutaneous articular (CINCA) syndrome or neonatal-onset multisystem inflammatory disease (NOMID), pyogenic sterile arthritis, pyoderma gangrenosum, acne (PAPA) and Blau syndrome. Apart from FMF (which has a prevalence of about 0.1 percent among non-Ashkenazi Jews, Armenians, Turks and Arabs), they are very rare disorders. FMF and HIDS are autosomal recessive diseases, all the other members of the family are autosomal and dominantly transmitted. Their common clinical features are recurrent and usually short attacks of synovitis and various skin eruptions; abdominal pain and fever are also frequently observed. The genes of all of these diseases have been discovered and, with the exception of HIDS, it was found that the proteins they encode share certain domains taking part in innate immunity and apoptosis. Thus it was evident that hereditary autoinflammatory diseases may help us understand better a number of important and prevalent pathologic events. We have reviewed the recent and rapidly accumulating knowledge on the molecular aspects of these disorders.

Clinical and genetic heterogeneity among Spanish patients with recurrent autoinflammatory syndromes associated with the CIAS1/PYPAF1/NALP3 gene

To investigate the involvement of the CIAS1/PYPAF1/NALP3 gene in 7 unrelated Spanish families with recurrent autoinflammatory diseases characterized by early onset, recurrent fever, and a chronic urticarial rash, in whom a clinical diagnosis of cryopyrin-associated periodic syndromes (CAPS) is suspected. Clinical symptoms, results of laboratory analyses, and data on previous treatments in members of the 7 families were recorded on a questionnaire specific for hereditary autoinflammatory diseases. All coding regions and intronic flanking boundaries of the CIAS1/PYPAF1/NALP3 gene were amplified by polymerase chain reaction and sequenced. Five different missense mutations, including 2 de novo and 1 previously unreported mutation (R488K), were identified in exon 3 of the CIAS1/PYPAF1/NALP3 gene in 5 of the 7 affected families. Expanded genetic analysis among the healthy individuals identified incomplete penetrance in 2 families. No mutations were found in 2 of the 3 patients with chronic infantile neurologic, cutaneous, articular (CINCA) syndrome/neonatal-onset multisystem inflammatory disease (NOMID). The clinical data suggested a diagnosis of familial cold-induced autoinflammatory syndrome in 3 families, CINCA/NOMID syndrome in 3 others, and a possible Muckle-Wells syndrome, whereas mutational analysis showed different CIAS1/PYPAF1/NALP3 missense mutations in 5 families. These data are consistent with a common molecular basis of these diseases and highlights the phenotypic heterogeneity among CIAS1/PYPAF1/NALP3 gene-associated syndromes. The previously unreported mutation and the incomplete penetrance found in 2 families expand the genetic basis underlying these autoinflammatory syndromes. These findings should alert clinicians to the possible genetic basis of these conditions, even in the absence of a family history, in their attempts to establish an accurate diagnosis and the optimal therapeutic approach.

Spectrum of clinical features in Muckle-Wells syndrome and response to anakinra.

Mutations in the NALP3/CIAS1/PYPAF1 gene are associated with the autoinflammatory diseases Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), and neonatal-onset multisystem inflammatory disease (NOMID), which is also known as chronic infantile neurologic, cutaneous, articular (CINCA) syndrome. Molecular studies suggest that NALP3 is involved in the processing of interleukin-1beta (IL-1beta), prompting us to investigate whether IL-1 blockade may be therapeutic in patients with MWS. We reviewed the clinical features of 3 members of a family, all of whom had MWS associated with the NALP3 variant V200M (also designated V198M), and evaluated the response of their inflammatory disease to treatment with the recombinant human IL-1 receptor antagonist anakinra. The subjects kept a diary of symptoms and underwent fortnightly clinical and laboratory assessments, including measurement of the serum amyloid A protein concentration. Each subject had fever, rashes, arthralgia, conjunctivitis, sensorineural deafness, and an intense acute-phase response characteristic of MWS. However, additional features were identified, including exacerbation of their disease by cold and neurologic manifestations, that have hitherto been described only in FCAS and NOMID, respectively. Clinical and serologic evidence of active inflammatory disease resolved rapidly and completely during treatment with anakinra. The remarkable response of MWS to anakinra suggests that IL-1beta has a fundamental role in the pathogenesis of inflammation associated with mutations in the NALP3 gene, and supports study of IL-1 inhibition in patients with NOMID/CINCA syndrome or FCAS. The clinical features of the various syndromes associated with mutations in the NALP3 gene may overlap to a greater extent than has previously been recognized.