Effect of anakinra on arthropathy in CINCA/NOMID syndrome

CINCA/NOMID is an autoinflammatory disorder characterized by the triad of neonatal onset of cutaneous symptoms, chronic meningitis, and recurrent fever and it presents with distinctive osteoarthropathy, synovitis mainly of the large joints and overgrowth of epimetaphyseal cartilage, particularly of the long bones. The cartilage overgrowth eventually causes osseous overgrowth and deformity that persists beyond skeletal maturity and leads to limb length discrepancy, joint contracture, and early degenerative arthropathy. Autoinflammation in CAPS/NOMID has been proven to derive from excessive release of interleukin-1 (IL-1). It has been well documented that the IL-1 receptor antagonist anakinra (Kineret(R)) helps mitigate systemic inflammation in the disorder. However, a general consensus has not been reached on its beneficial effect on osteoarthropathy. The case of a girl with CINCA/NOMID syndrome who showed dramatic improvement of osteoarthropathy after anakinra treatment is reported. A 4-year-old girl suffered at the age of 10 months from a generalized urticarial skin lesion with recurrent episodes of fever and growth disorder. Blood examination revealed persistent massive neutrophilia, anemia and intense acute phase response. She manifested knee joint swelling with limited ROM when she was 20 months old and was diagnosed as being CINCA/NOMID based on characteristic findings of radiograph despite negative CIAS1 mutation. Radiological examination demonstrated metaphyseal fraying and cupping and widening of the growth plate in the distal femur. MR imaging showed mottled gadolinium enhancement at the chondrosseous junction. Neither significant joint effusion nor synovitis was identified. At 2 years and 7 months of age, anakinra, 2 mg/kg/day given by regular daily subcutaneous injections, was started. A few days after the initiation of the treatment, her clinical symptoms and laboratory findings of active inflammation were promptly alleviated. She was not able to walk unaided prior to the treatment, but she walked independently 1 month after the treatment. Follow-up radiographs and MR imaging showed that growth plate widening and gadolinium enhancement at the chondrosseous junction were less conspicuous. Furthermore, longitudinal growth of the femur and tibia was identified during 20 months of observation

Detection of Base Substitution-Type Somatic Mosaicism of the NLRP3 Gene with >99.9% Statistical Confidence by Massively Parallel Sequencing

Chronic infantile neurological cutaneous and articular syndrome (CINCA), also known as neonatal-onset multisystem inflammatory disease (NOMID), is a dominantly inherited systemic autoinflammatory disease and is caused by a heterozygous germline gain-of-function mutation in the NLRP3 gene. We recently found a high incidence of NLRP3 somatic mosaicism in apparently mutation-negative CINCA/NOMID patients using subcloning and subsequent capillary DNA sequencing. It is important to rapidly diagnose somatic NLRP3 mosaicism to ensure proper treatment. However, this approach requires large investments of time, cost, and labour that prevent routine genetic diagnosis of low-level somatic NLRP3 mosaicism. We developed a routine pipeline to detect even a low-level allele of NLRP3 with statistical significance using massively parallel DNA sequencing. To address the critical concern of discriminating a low-level allele from sequencing errors, we first constructed error rate maps of 14 polymerase chain reaction products covering the entire coding NLRP3 exons on a Roche 454 GS-FLX sequencer from 50 control samples without mosaicism. Based on these results, we formulated a statistical confidence value for each sequence variation in each strand to discriminate sequencing errors from real genetic variation even in a low-level allele, and thereby detected base substitutions at an allele frequency as low as 1% with 99.9% or higher confidence

Cold-induced urticaria with a familial transmission: a case report and review of the literature

Abstract Introduction Cryopyrin-associated periodic syndrome is a rare genetic disorder causing cold-induced urticaria, severe arthralgias, and (potentially) renal failure and hearing loss. Therapies that effectively control the symptoms and prevent the complications of this debilitating disorder are now available, making recognition of this disease important. Case presentation A 60-year-old Caucasian woman presented with complaints of rash and joint pains to a general medicine clinic. Her history showed that her symptoms were linked to cold exposure, but the results of a cold stimulation time test were negative. Several generations of her family had similar symptoms. Conclusions This case highlights the importance of considering cryopyrin-associated periodic syndrome in the differential diagnosis of cold-induced urticaria. Several medications targeting interleukin-1-beta are available, providing significant relief from symptoms and improvement in quality of life in affected patients.</p

Inflammasome and IL-1β-Mediated Disorders

The NLRP3 inflammasome is an intracellular complex that regulates the release of proinflammatory cytokines such as interleukin-1β in response to exogenous pathogens and endogenous danger signals. Evidence from studies involving human genetics, human ex vivo mononuclear cell responses, and in vivo and in vitro murine models confirms the importance of the inflammasome and interleukin-1β in the pathogenesis of several inherited and complex diseases. The availability of several effective interleukin-1β targeted therapies has allowed for successful proof-of-concept studies in several of these disorders. However, many other diseases are likely to be mediated by the inflammasome and interleukin-1β, providing additional targets in the future

Neonatal-onset multisystem inflammatory disease responsive to interleukin-1 beta inhibition

BACKGROUND:Neonatal-onset multisystem inflammatory disease is characterized by fever, urticarial rash, aseptic meningitis, deforming arthropathy, hearing loss, and mental retardation. Many patients have mutations in the cold-induced autoinflammatory syndrome 1 (CIAS1) gene, encoding cryopyrin, a protein that regulates inflammation.METHODS:We selected 18 patients with neonatal-onset multisystem inflammatory disease (12 with identifiable CIAS1 mutations) to receive anakinra, an interleukin-1-receptor antagonist (1 to 2 mg per kilogram of body weight per day subcutaneously). In 11 patients, anakinra was withdrawn at three months until a flare occurred. The primary end points included changes in scores in a daily diary of symptoms, serum levels of amyloid A and C-reactive protein, and the erythrocyte sedimentation rate from baseline to month 3 and from month 3 until a disease flare.RESULTS:All 18 patients had a rapid response to anakinra, with disappearance of rash. Diary scores improved (P<0.001) and serum amyloid A (from a median of 174 mg to 8 mg per liter), C-reactive protein (from a median of 5.29 mg to 0.34 mg per deciliter), and the erythrocyte sedimentation rate decreased at month 3 (all P<0.001), and remained low at month 6. Magnetic resonance imaging showed improvement in cochlear and leptomeningeal lesions as compared with baseline. Withdrawal of anakinra uniformly resulted in relapse within days; retreatment led to rapid improvement. There were no drug-related serious adverse events.CONCLUSIONS:Daily injections of anakinra markedly improved clinical and laboratory manifestations in patients with neonatal-onset multisystem inflammatory disease, with or without CIAS1 mutations