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

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.     

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

OBJECTIVE: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.     

Hearing improvement in a patient with variant Muckle-Wells syndrome in response to interleukin 1 receptor antagonism

BACKGROUND: Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome, and neonatal onset multisystem inflammatory disease, also called chronic, infantile, neurological, cutaneous, and articular syndrome, are three hereditary autoinflammatory syndromes caused by mutations affecting the CIAS1/NALP3 gene on chromosome 1q44. The proinflammatory cytokine, interleukin 1beta, is believed to have a fundamental role in their pathogenesis. CASE REPORT: The case is described of a 59 year old white woman who presented with increasingly severe MWS-type features over a 15 year period. The response to interleukin 1beta inhibition with anakinra was dramatic, including a reduction in intracranial pressure with associated auditory improvement, as demonstrated by serial audiometry. CONCLUSIONS: The confirmed improvement in hearing after initiation of interleukin 1 receptor antagonism corroborates previous reports that specific blockade of this single cytokine reverses most of the symptoms of this group of CIAS1/NALP3 related autoinflammatory conditions, including the sensorineural deafness, which has not been previously reported.     

Primer: inflammasomes and interleukin 1beta in inflammatory disorders

Inflammasomes are large, multimeric protein complexes that link the sensing of microbial products and metabolic stress to the proteolytic processing of prointerleukin (pro-IL)-1beta to its active form. NALP1 and NALP2 are founding members of the Nod-like receptor family. Other Nod-like receptors, including NALP3 and NOD2, which are associated with inflammatory disorders, have also been described. The NALP1 and NALP3 inflammasomes are located in the cytoplasm and can, therefore, detect intracellular infection through recognition of microbial pathogen-associated molecular patterns. The inflammasome pathways cooperate with Toll-like receptor pathways to mediate a rapid and appropriate response to pathogens and genotoxic stress. Mutations in both pyrin and NALP3 components of inflammasomes are associated with innate-immune-mediated diseases (familial Mediterranean fever and the 'cryopyrinopathies'), and aberrant IL-1beta processing has been reported in several autoinflammatory conditions, including Muckle-Wells syndrome, chronic infantile neurologic, cutaneous and articular syndrome/neonatal onset multisystem inflammatory disease, and gout. The effectiveness of IL-1beta blockade in treating many of these conditions has transformed the understanding and management of these disorders and also highlighted the role of aberrant IL-1beta signaling in other conditions, such as adult-onset Still's disease and systemic juvenile idiopathic arthritis.     

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

Objective

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‐1β (IL‐1β), prompting us to investigate whether IL‐1 blockade may be therapeutic in patients with MWS.

Methods

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.

Results

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.

Conclusion

The remarkable response of MWS to anakinra suggests that IL‐1β 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.

     

Klinik der autoinflammatorischen Erkrankungen im Kindesalter

Autoinflammatory diseases are a group of monogenic inflammatory diseases with an early onset in childhood. Previously these diseases were summarized as“periodic fever syndromes.” Included in this spectrum are familial Mediterranean fever, mevalonate kinase deficiency, and tumor necrosis factor receptor-associated disease. They are characterized by periodic or recurrent episodes of systemic inflammation causing fever, accompanied by rash, serositis, lymphadenopathy, arthritis, and other clinical manifestations. The other large group of autoinflammatory diseases consists of the cryopyrin-associated periodic syndromes, which include the cryopyrinopathies. The mildest form is familial cold-associated syndrome, a more severe form is Muckle–Wells syndrome, and the most severe is neonatal-onset multisystem inflammatory disease/chronic infantile neurological cutaneous and articular syndrome. These are characterized by chronic or recurrent systemic inflammation associated with various clinical presentations, including urticaria-like rash, arthritis, sensorineural deafness, and central nervous system and bone involvement. In our review we focus on the clinical presentation of these diseases.     

The spectrum of monogenic autoinflammatory syndromes: Understanding disease mechanisms and use of targeted therapies

Monogenic autoinflammatory diseases encompass a distinct and growing clinical entity of multisystem inflammatory diseases with known genetic defects in the innate immune system. The diseases present clinically with episodes of seemingly unprovoked inflammation (fever, rashes, and elevation of acute phase reactants). Understanding the genetics has led to discovery of new molecules involved in recognizing exogenous and endogenous danger signals, and the inflammatory response to these stimuli. These advances have furthered understanding of innate inflammatory pathways and spurred collaborative research in rheumatology and infectious diseases. The pivotal roles of interleukin (IL)-1β in cryopyrin-associated periodic syndromes, tumor necrosis factor (TNF) in TNF receptor-associated periodic syndrome, and links to inflammatory cytokine dysregulation in other monogenic autoinflammatory diseases have resulted in effective therapies targeting proinflammatory cytokines IL-1β and TNF and uncovered other new potential targets for anti-inflammatory therapies.     

Mutations in NALP12 cause hereditary periodic fever syndromes

NALP proteins, also known as NLRPs, belong to the CATERPILLER protein family involved, like Toll-like receptors, in the recognition of microbial molecules and the subsequent activation of inflammatory and immune responses. Current advances in the function of NALPs support the recently proposed model of a disease continuum bridging autoimmune and autoinflammatory disorders. Among these diseases, hereditary periodic fevers (HPFs) are Mendelian disorders associated with sequence variations in very few genes; these variations are mostly missense mutations whose deleterious effect, which is particularly difficult to assess, is often questionable. The growing number of identified sporadic cases of periodic fever syndrome, together with the lack of discriminatory clinical criteria, has greatly hampered the identification of new disease-causing genes, a step that is, however, essential for appropriate management of these disorders. Using a candidate gene approach, we identified nonambiguous mutations in NALP12 (i.e., nonsense and splice site) in two families with periodic fever syndromes. As shown by means of functional studies, these two NALP12 mutations have a deleterious effect on NF-kappaB signaling. Overall, these data identify a group of HPFs defined by molecular defects in NALP12, opening up new ways to manage these disorders. The identification of these first NALP12 mutations in patients with autoinflammatory disorder also clearly demonstrates the crucial role of NALP12 in inflammatory signaling pathways, thereby assigning a precise function to this particular member of an emerging family of proteins whose putative biological properties are currently inferred essentially through in vitro means.     

Hereditary immunologic disorders caused by pyrin and cryopyrin

A new family of hereditary immunologic disorders known as the autoinflammatory diseases involves dysregulation of the innate immune system. Elucidation of the genetic basis of these disorders has resulted in improved understanding of the disease pathophysiology of systemic and tissue inflammation, and has also revealed novel nonpathologic innate immune mechanisms. These advances have also resulted in direct improvement in diagnosis and therapy for autoinflammatory disorders such as the cryopyrinopathies and familial Mediterranean fever and have implications for more common inflammatory diseases.     

The clinical continuum of cryopyrinopathies: novel CIAS1 mutations in North American patients and a new cryopyrin model

OBJECTIVE: The cryopyrinopathies are a group of rare autoinflammatory disorders that are caused by mutations in CIAS1, encoding the cryopyrin protein. However, cryopyrin mutations are found only in 50% of patients with clinically diagnosed cryopyrinopathies. This study was undertaken to investigate the structural effect of disease-causing mutations on cryopyrin, in order to gain better understanding of the impact of disease-associated mutations on protein function. METHODS: We tested for CIAS1 mutations in 22 patients with neonatal-onset multisystem inflammatory disease/chronic infantile neurologic, cutaneous, articular syndrome, 12 with Muckle-Wells syndrome (MWS), 18 with familial cold-induced autoinflammatory syndrome (FCAS), and 3 probands with MWS/FCAS. In a subset of mutation-negative patients, we screened for mutations in proteins that are either homologous to cryopyrin or involved in the caspase 1/interleukin-1beta signaling pathway. CIAS1 and other candidate genes were sequenced, models of cryopyrin domains were constructed using structurally homologous proteins as templates, and disease-causing mutations were mapped. RESULTS: Forty patients were mutation positive, and 7 novel mutations, V262A, C259W, L264F, V351L, F443L, F523C, and Y563N, were found in 9 patients. No mutations in any candidate genes were identified. Most mutations mapped to an inner surface of the hexameric ring in the cryopyrin model, consistent with the hypothesis that the mutations disrupt a closed form of cryopyrin, thus potentiating inflammasome assembly. Disease-causing mutations correlated with disease severity only for a subset of known mutations. CONCLUSION: Our modeling provides insight into potential molecular mechanisms by which cryopyrin mutations can inappropriately activate an inflammatory response. A significant number of patients who are clinically diagnosed as having cryopyrinopathies do not have identifiable disease-associated mutations.     

Current Status of Understanding the Pathogenesis and Management of Patients With NOMID/CINCA

Neonatal-onset multisystem inflammatory disease (NOMID)/chronic infantile neurologic, cutaneous, and arthritis (CINCA) syndrome is the most severe clinical phenotype in the spectrum of cryopyrin- (NLRP3/NALP3) associated periodic syndromes (CAPS). The study of patients with NOMID/CINCA has been instrumental in characterizing the extent of organ-specific inflammatory manifestations and damage that can occur with chronic interleukin (IL)-1β overproduction. Mutations in CIAS1/NLRP3 lead to constitutive activation of the “NLRP3 inflammasome,” an intracellular platform that processes and secretes increased amounts of IL-1β. The pivotal role of IL-1β in NOMID/CINCA has been demonstrated in several clinical studies using IL-1—blocking agents that lead to rapid resolution of the inflammatory disease manifestations. NOMID/CINCA is a monogenic autoinflammatory syndrome; and the discovery of the role of IL-1 in NOMID has led to the exploration in the role of IL-1 in other disorders including gout and Type II diabetes. The inflammation in NOMID/CINCA is continuous with intermittent flares, and organ manifestations encompus the central nervous system, eye, inner ear, and bones. This review discusses updates on the pathogenesis of NOMID/CAPS, emerging long term-outcome data regarding IL-1—blocking agents that have influenced our considerations for optimal treatment, and a monitoring approach tailored to the patient’s disease severity and organ manifestations.     

Autoinflammatorische Syndrome

In its strict sense, the term “autoinflammatory syndromes” comprises the hereditary periodic fever syndromes (HPF), which are caused by mutations of pattern-recognition receptors (PRR) and perturbations of the cytokine balance. These include the crypyrinopathies, familial Mediterranean fever, TNF-receptor associated periodic fever syndrome (TRAPS), hyper-IgD and periodic syndrome (HIDS), pyogenic sterile arthritis, pyoderma gangrenosum and acne (PAPA) syndrome, NALP12-HPF, and the Blau syndrome. The diseases are characterized by spontaneous activation of cells of the innate immunity in the absence of ligands. Autoantibodies are usually not found. HPF clinically present with recurrent fever episodes and inflammation, especially of serosal and synovial interfaces and the skin. Intriguingly, PRR-mediated autoinflammtory mechanisms also play a role in a number of chronic inflammatory and autoimmune diseases.     

Anakinra prevents symptoms of familial cold autoinflammatory syndrome and Raynaud's disease

OBJECTIVE: Familial cold autoinflammatory syndrome (FCAS) is a rare, hereditary disorder characterized by cold-induced inflammation. We describe the successful longterm treatment of a patient with FCAS with anakinra, an interleukin 1 receptor antagonist (IL-1Ra). The remarkable response of FCAS and associated Raynaud's disease in this patient suggests that IL-1 is an important mediator of these inflammatory diseases. Our report supports increasing evidence that anakinra plays an important role in the treatment of select chronic inflammatory diseases.     

Familial Mediterranean fever and the other autoinflammatory syndromes: evaluation of the patient with recurrent fever

PURPOSE OF REVIEW: The aim of this article is to summarize recent clinical, genetic and pathophysiologic findings of familial Mediterranean fever and several of the other systemic autoinflammatory diseases, a recently recognized group of disorders characterized by seemingly unprovoked inflammation but lacking high-titer autoantibodies. Genetic and clinical tools are improving the ability of the clinician to better approach patients with periodic fever and inflammation. RECENT FINDINGS: The spectrum of reported genetic mutations and susceptible ethnicities for the hereditary periodic fever subset of the autoinflammatory diseases has continued to expand. At the same time, the pathogeneses of many of these diseases are now understood to involve different aspects of a common pathway, largely affecting inflammatory cascades related to IL-1 or tumor necrosis factor-alpha. Three of these diseases which have been grouped as the cryopyrin-associated periodic syndromes result from defects in the same gene, and all three appear to respond well to anti-IL-1 therapy although controlled trials are still in progress. In addition, cytokine-based therapies are also now under investigation for hyperimmunoglobulinemia D with periodic fever syndrome and pyogenic sterile arthritis, pyoderma gangrenosum, and acne syndrome. SUMMARY: The identification of the genes and proteins mutated in many of the autoinflammatory diseases has broadened our understanding of the regulation of inflammation and the immune system, and provided the basis for the use of targeted therapies in these syndromes. We propose an algorithm for the evaluation of a patient with periodic fever, taking into account the patient's age, ethnicity, symptoms and signs, and results from laboratory and genetic testing.     

Interleukine-1, inflammasome et maladies auto-inflammatoires

Interleukin-1 is a major cytokine of innate immunity and inflammation. It exerts various systemic effects during the inflammatory response, such as fever induction, thrombopoiesis and granulopoiesis, or leukocyte recruitment. Its involvement has been demonstrated in many inflammatory-mediated diseases, such as diabetes or gout. Moreover, interleukin-1 plays a pivotal role in some autoinflammatory diseases, such as cryopyrinopathies or familial Mediterranean fever. In these diseases, a constitutional defect of the inflammasome, a protein complex responsible for the activation of interleukin-1, explains the hypersecretion of interleukin-1. Other autoinflammatory diseases have a more complex pathophysiology involving deregulation of the interleukin-1 pathway, upstream or downstream of the inflammasome, or through more complex mechanisms. In this review, we are detailing the synthesis, the activation, the signalling, and the regulation of interleukin-1. We then describe the autoinflammatory diseases or related-diseases where the pathological role of interleukin-1 has been demonstrated.     

The NOD2 defect in Blau syndrome does not result in excess interleukin‐1 activity

Objective

Blau syndrome is a rare, autosomal‐dominant, autoinflammatory disorder characterized by granulomatous arthritis, uveitis, and dermatitis. Genetics studies have shown that the disease is caused by single nonsynonymous substitutions in NOD‐2, a member of the NOD‐like receptor or NACHT–leucine‐rich repeat (NLR) family of intracellular proteins. Several NLRs function in the innate immune system as sensors of pathogen components and participate in immune‐mediated cellular responses via the caspase 1 inflammasome. Mutations in a gene related to NOD‐2, NLRP3, are responsible for excess caspase 1–dependent interleukin‐1β (IL‐1β) in cryopyrinopathies such as Muckle‐Wells syndrome. Furthermore, functional studies demonstrate that caspase 1–mediated release of IL‐1β also involves NOD‐2. The aim of this study was to test the hypothesis that IL‐1β may mediate the inflammation seen in patients with Blau syndrome.

Methods

IL‐1β release was measured in peripheral blood mononuclear cells cultured in vitro, obtained from 5 Blau syndrome individuals with a NOD2 (CARD15) mutation.

Results

We observed no evidence for increased IL‐1β production in cells obtained from subjects with Blau syndrome compared with healthy control subjects. Furthermore, we presented 2 cases of Blau syndrome in which recombinant human IL‐1 receptor antagonist (anakinra) was ineffective treatment.

Conclusion

Taken together, these data suggest that in contrast to related IL‐1β–dependent autoinflammatory cryopyrinopathies, Blau syndrome is not mediated by excess IL‐1β or other IL‐1 activity.

     

Disease-associated mutations in CIAS1 induce cathepsin B-dependent rapid cell death of human THP-1 monocytic cells

Mutations in the cold-induced autoinflammatory syndrome 1 (CIAS1) gene are associated with a spectrum of autoinflammatory diseases, including familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and chronic infantile neurologic, cutaneous, articular syndrome, also known as neonatal-onset multisystem inflammatory disease. CIAS1 encodes cryopyrin, a protein that localizes to the cytosol and functions as pattern recognition receptor. Cryopyrin also participates in nuclear factor-kappaB regulation and caspase-1-mediated maturation of interleukin 10. In this study, we showed that disease-associated mutations in CIAS1 induced rapid cell death of THP-1 monocytic cells. The features of cell death, including 7-AAD staining, the presence of cellular edema, and early membrane damage resulting in lactate dehydrogenase (LDH) release, indicated that it was more likely to be necrosis than apoptosis, and was effectively blocked with the cathepsin B-specific inhibitor CA-074-Me. CA-074-Me also suppressed induced by disease-associated mutation lysosomal leakage and mitochondrial damage. In addition, R837, a recently identified activator of cryopyrin-associated inflammasomes, induced cell death in wild type CIAS1-transfected THP-1 cells. These results indicated that monocytes undergo rapid cell death in a cathepsin B-dependent manner upon activation of cryopyrin, which is also a specific phenomenon induced by disease-associated mutation of CIAS1.