Familial Cold-induced Autoinflammatory Syndrome Research Articles

Canakinumab for the treatment of cryopyrin-associated periodic syndromes.

Familial cold-induced autoinflammatory syndrome, Muckle-Wells syndrome and neonatal-onset multisystem inflammatory disease make up cryopyrin-associated periodic syndromes (CAPS). These are autoinflammatory inherited disorders caused by autosomal dominant gain-of-function mutations in the NLRP3 gene, located on chromosome 1q44. Cryopyrin/NALP3/NLRP3 is an essential component of intracellular inflammasomes that activate caspase-1, which in turn converts interleukin-1beta (IL-1beta) to its active form. IL-1beta is a potent cytokine that activates diverse elements of the immune and inflammatory systems leading to the pathogenic changes characteristic of CAPS. There is therefore much interest in the development of IL-1beta blocking agents as novel biologic treatments for these conditions. Canakinumab (ACZ-885; Ilaris, Novartis Pharma) is a fully humanized monoclonal antibody (mAb) specific for IL-1beta and is indicated for a wide range of inflammatory disorders including CAPS. This review will assess the utility of canakinumab as a treatment for CAPS.

DIRA, DITRA, and New Insights Into Pathways of Skin Inflammation

Dermatology has a long-standing affinity for acronyms. From AGEP (acute generalized exanthematous pustulosis) to XP (xeroderma pigmentosum), acronyms have become a part of our dermatology lexicon, perhaps occasionally to the consternation of our colleagues in other specialties. In this issue, Brau-Javier et al1 describe a patient with a severe pustular skin disease called “DIRA”—an acronym for “deficiency of the interleukin 1 (IL-1) receptor antagonist,” which we first described in 9 pediatric patients in 2009.2 As its name suggests, DIRA is a new autoinflammatory disease linked to activation of the IL-1 pathway (Figure), joining the ranks of other IL-1–associated conditions with a prominent dermatologic component, foremost the cryopyrin-associated periodic fever syndromes (CAPS)—familial cold–induced autoinflammatory syndrome (FCAS), Muckle-Wells syndrome, and neonatal-onset multisystem inflammatory disease (NOMID).3 Figure The pathogenesis of DIRA (deficiency of the interleukin 1 [IL-1] receptor [IL-1R] antagonist) and DITRA (deficiency of the IL-36 receptor [IL-36R] antagonist). Loss of the IL-1R antagonist leads to unopposed proinflammatory signaling by IL-1α ... CAPS is caused by gain of function mutations that lead to oversecretion of the well-established fever causing cytokine IL-1Β, and all 3 disorders manifest in the skin as neutrophilic urticaria. In contrast, DIRA presents in the neonatal period with a severe neutrophilic “pustular” skin eruption, skin pathergy, and nail dystrophy, as well as elevated acute-phase reactants, sterile osteomyelitis, and periostitis. DIRA is caused by loss of function of the IL-1 receptor (IL-1R) antagonist, the first endogenous cytokine receptor antagonist identified that blocks IL-1 signaling (Figure). Absence of the IL-1R antagonist results in unopposed proinflammatory signaling via the cytokines IL-1α and IL-1β on the IL-1R type I (IL-1R1). DIRA is a rare condition that you may never encounter in your practice, so why bother filing away another acronym in the deep recesses of your dermatologic cortex? First, as Brau-Javier et al1 demonstrate, just as with CAPS, DIRA is exquisitely responsive to IL-1 blockade. Responses are similar to those seen following anti–IL-1 treatment for NOMID, the most severe form of CAPS; children who have been ill since infancy now feel well for the first time; others confined to wheelchairs because of disabling joint pain are able to walk; and growth curves begin to arc upward again for the first time in years. Interleukin 1–blocking therapy is now the standard of care for CAPS, and 3 Food and Drug Administration–approved agents, anakinra, rilonacept, and canakinumab, are currently available that provide targeted inhibition of IL-1 signaling.4 Second, understanding DIRA may yield new insights into the mechanism of other challenging pustular skin conditions. The cutaneous and systemic features of DIRA bear similarity to features seen in pustular psoriasis and SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, and osteitis), suggesting that IL-1 signaling may play a role in these conditions as well.

Clinical presentation and pathogenesis of cold-induced autoinflammatory disease in a family with recurrence of an NLRP12 mutation

ObjectiveNLRP12 mutations have been described in patients affected with peculiar autoinflammatory symptoms. This study was undertaken to characterize NLRP12 mutations in patients with autoinflammatory syndromes, particularly a novel missense mutation, p.D294E, affecting a protein sequence crucial for ATP binding, which was identified in a Caucasian family with familial cold-induced autoinflammatory syndrome in some family members.MethodsFifty patients were tested for NLRP12 mutations. A Caucasian family with the p.D294E missense mutation of NLRP12 in some family members was clinically characterized. In vitro analysis of the effects of the mutation on NF-κB activity was performed in HEK 293 cells after cotransfection of the cells with a luciferase NF-κB–responsive element and mutant or wild-type (WT) NLRP12 expression plasmids. NF-κB activity was also evaluated 24 hours after stimulation with tumor necrosis factor α in monocytes from individual family members carrying the mutation. Furthermore, secretion of interleukin-1β (IL-1β), production of reactive oxygen species (ROS), and activation of antioxidant systems in patient and healthy donor monocytes, under resting conditions and after stimulation with pathogen-associated molecular patterns (PAMPs), were also assessed.ResultsIn the family assessed, the p.D294E mutation segregated in association with a particular sensitivity to cold exposure (especially arthralgias and myalgia), but not always with an inflammatory phenotype (e.g., urticarial rash or fever). In vitro, the mutant protein maintained the same inhibitory activity as that shown by WT NLRP12. Consistently, NLRP12-mutated monocytes showed neither increased levels of p65-induced NF-κB activity nor higher secretion of IL-1β. However, the kinetics of PAMP-induced IL-1β secretion were significantly accelerated, and high production of ROS and up-regulation of antioxidant systems were demonstrated.ConclusionEven with a variable range of associated manifestations, the extreme sensitivity to cold represents the main clinical hallmark in an individual carrying the p.D294E mutation of the NLRP12 gene. Although regulation of NF-κB activity is not affected in patients, redox alterations and accelerated secretion of IL-1β are associated with this mild autoinflammatory phenotype.

Rilonacept in the treatment of chronic inflammatory disorders

Rilonacept (IL-1 Trap/Arcalyst) is a long-acting interleukin-1 (IL-1) blocker developed by Regeneron Pharmaceuticals. Initially, Regeneron entered into a joint development effort with Novartis to develop rilonacept for the treatment of rheumatoid arthritis (RA) but this was discontinued following the review of phase II clinical data showing that IL-1 blockade appeared to have limited benefit in RA. In February 2008, Regeneron received Orphan Drug approval from the Food and Drug Administration for rilonacept in the treatment of two cryopyrin-associated periodic syndromes (CAPS) disorders, namely, familial cold-induced autoinflammatory syndrome (FCAS) and Muckle-Wells syndrome (MWS), for children and adults 12 years and older. CAPS is a group of inherited inflammatory disorders consisting of FCAS, MWS, neonatal-onset multisystem inflammatory disease (NOMID), also known as chronic infantile neurologic, cutaneous and articular (CINCA) syndrome, all associated with heterozygous mutations in the NLRP3 (CIAS1) gene, which encodes the protein NLRP3 or cryopyrin. Prior to the discovery of the NLRP3 (CIAS1) mutations and the advent of IL-1-targeted therapy, treatment was aimed at suppressing inflammation but with limited success. The dramatic success of selective blockade of IL-1beta, initially with the IL-1 receptor antagonist (IL-1Ra; Kineret(R) or anakinra/ Amgen, Inc.), not only provided supportive evidence for the role of IL-1beta in CAPS but also demonstrated the efficacy of targeting IL-1beta for treatment of these conditions. A high-affinity protein called rilonacept has been produced by cytokine Trap technology and was developed by Regeneron. The desirable longer half-life of rilonacept offers potential alternatives to patients who do not tolerate daily injections very well or have difficulty with drug compliance. The initial evidence for the beneficial effects of rilonacept for MWS and FCAS suggests that it would also be a suitable treatment for CNICA/NOMID. It is yet to be determined whether rilonacept would be an effective treatment for other chronic inflammatory conditions such as gout, familial Mediterranean fever and systemic juvenile idiopathic arthritis.

Canakinumab for the treatment of cryopyrin-associated periodic syndromes

Familial cold-induced autoinflammatory syndrome, Muckle-Wells syndrome and neonatal-onset multisystem inflammatory disease make up cryopyrin-associated periodic syndromes (CAPS). These are autoinflammatory inherited disorders caused by autosomal dominant gain-of-function mutations in the NLRP3 gene, located on chromosome 1q44. Cryopyrin/NALP3/NLRP3 is an essential component of intracellular inflammasomes that activate caspase-1, which in turn converts interleukin-1beta (IL-1beta) to its active form. IL-1beta is a potent cytokine that activates diverse elements of the immune and inflammatory systems leading to the pathogenic changes characteristic of CAPS. There is therefore much interest in the development of IL-1beta blocking agents as novel biologic treatments for these conditions. Canakinumab (ACZ-885; Ilaris, Novartis Pharma) is a fully humanized monoclonal antibody (mAb) specific for IL-1beta and is indicated for a wide range of inflammatory disorders including CAPS. This review will assess the utility of canakinumab as a treatment for CAPS.

Long term management of patients with cryopyrin-associated periodic syndromes (CAPS): focus on rilonacept (IL-1 Trap)

Cryopyrin-associated periodic syndromes (CAPS) are a group of inherited inflammatory disorders consisting of familial cold-induced autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID; also known as chronic infantile neurologic, cutaneous, articular [CINCA] syndrome). These rare disorders are associated with heterozygous mutations in the NLRP3 (CIAS1) gene, which encodes the protein NALP3 or cryopyrin, and inflammation driven by excessive production of the cytokine interleukin-1beta (IL-1beta). Amyloidosis is a serious complication with 25% of MWS patients developing amyloidosis, with occasional fatal consequences, whilst up to 20% of CINCA/NOMID patients die from various complications, before reaching the early adulthood. In some CINCA/NOMID adult survivors amyloidosis can also occur. Prior to the discovery of the CIAS1 gene mutations and the advent of IL-1 targeted therapy, treatment was aimed at suppressing inflammation, with limited success. The selective blockade of IL-1beta, with anakinra (IL-1 receptor antagonist), not only provided supportive evidence for the role of IL-1beta in CAPS, but also demonstrated the efficacy of targeting IL-1beta for treatment of these conditions. In February, 2008, 'Orphan Drug' approval from the Food and Drug Administration (FDA) for rilonacept (IL-1 Trap/Arcalyst(), Regeneron Pharmaceuticals, Inc) was given for the treatment of two CAPS disorders, FCAS and MWS in adults and children 12 years and older, making rilonacept the first therapy approved for the treatment of CAPS.

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

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. 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. 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. 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.

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.