The autoinflammatory disorder, Neonatal-onset Multisystem Inflammatory Disease (NOMID) is the most severe phenotype of disorders caused by mutations in CIAS1 that result in increased production and ...secretion of active IL-1β. NOMID patients present with systemic and organ-specific inflammation of the skin, central nervous system and bone, and respond dramatically to treatment with IL-1 blocking agents. We compared the cellular infiltrates and transcriptome of skin biopsies from patients with NOMID (n = 14) before treatment (lesional (LS) and non-lesional (pre-NL) skin) and after treatment (post-NL) with the IL-1 blocker anakinra (recombinant IL-1 receptor antagonist, Kineret®, Swedish Orphan Biovitrum AB, SOBI), to normal skin (n = 5) to assess tissue responses in the context of untreated and treated disease. Abundant neutrophils distinguish LS skin from pre-NL and post-NL skin. CD11c(+) dermal dendritic cells and CD163(+) macrophages expressed activated caspase-1 and are a likely source of cutaneous IL-1 production. Treatment with anakinra led to the disappearance of neutrophils, but CD3(+) T cells and HLA-DR(+) cells remained elevated. Among the upregulated genes IL-6, IL-8, TNF, IL-17A, CCL20, and the neutrophil defensins DEFA1 and DEFA3 were differentially regulated in LS tissues (compared to normal skin). Important significantly downregulated pathways in LS skin included IL-1R/TLR signaling, type I and II cytokine receptor signaling, mitochondrial dysfunction, and antigen presentation. The differential expression and regulation of microRNAs and pathways involved in post-transcriptional modification were suggestive of epigenetic modification in the chronically inflamed tissue. Overall, the dysregulated genes and pathways suggest extensive "adaptive" mechanisms to control inflammation and maintain tissue homeostasis, likely triggered by chronic IL-1 release in the skin of patients with NOMID.
Inflammasomes are innate immune sensors that respond to pathogen- and damage-associated signals with caspase-1 activation, interleukin (IL)-1β and IL-18 secretion, and macrophage pyroptosis. The ...discovery that dominant gain-of-function mutations in NLRP3 cause the cryopyrin-associated periodic syndromes (CAPS) and trigger spontaneous inflammasome activation and IL-1β oversecretion led to successful treatment with IL-1-blocking agents. Herein we report a de novo missense mutation (c.1009A > T, encoding p.Thr337Ser) affecting the nucleotide-binding domain of the inflammasome component NLRC4 that causes early-onset recurrent fever flares and macrophage activation syndrome (MAS). Functional analyses demonstrated spontaneous inflammasome formation and production of the inflammasome-dependent cytokines IL-1β and IL-18, with the latter exceeding the levels seen in CAPS. The NLRC4 mutation caused constitutive caspase-1 cleavage in cells transduced with mutant NLRC4 and increased production of IL-18 in both patient-derived and mutant NLRC4-transduced macrophages. Thus, we describe a new monoallelic inflammasome defect that expands the monogenic autoinflammatory disease spectrum to include MAS and suggests new targets for therapy.
Autoinflammatory diseases manifest inflammation without evidence of infection, high-titer autoantibodies, or autoreactive T cells. We report a disorder caused by mutations of IL1RN, which encodes the ...interleukin-1-receptor antagonist, with prominent involvement of skin and bone.
We studied nine children from six families who had neonatal onset of sterile multifocal osteomyelitis, periostitis, and pustulosis. Response to empirical treatment with the recombinant interleukin-1-receptor antagonist anakinra in the first patient prompted us to test for the presence of mutations and changes in proteins and their function in interleukin-1-pathway genes including IL1RN.
We identified homozygous mutations of IL1RN in nine affected children, from one family from Newfoundland, Canada, three families from The Netherlands, and one consanguineous family from Lebanon. A nonconsanguineous patient from Puerto Rico was homozygous for a genomic deletion that includes IL1RN and five other interleukin-1-family members. At least three of the mutations are founder mutations; heterozygous carriers were asymptomatic, with no cytokine abnormalities in vitro. The IL1RN mutations resulted in a truncated protein that is not secreted, thereby rendering cells hyperresponsive to interleukin-1beta stimulation. Patients treated with anakinra responded rapidly.
We propose the term deficiency of the interleukin-1-receptor antagonist, or DIRA, to denote this autosomal recessive autoinflammatory disease caused by mutations affecting IL1RN. The absence of interleukin-1-receptor antagonist allows unopposed action of interleukin-1, resulting in life-threatening systemic inflammation with skin and bone involvement. (ClinicalTrials.gov number, NCT00059748.)
Objective: To describe the pregnancy course and outcome, and use of anakinra, a recombinant selective IL-1 receptor blocker, during pregnancy in patients with cryopyrin-associated periodic syndromes ...(CAPS), including familial cold auto-inflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and neonatal onset multi-system inflammatory disease (NOMID). Methods: Women currently enrolled in natural history protocols (NCT00059748, and/or NCT00069329 under IND) who have been pregnant were included. Subjects underwent a structured, standardized interview with regards to maternal health, pregnancy and fetal outcomes. Medical records were reviewed. Results: Nine women (four with FCAS, one with MWS and four with NOMID) reported one to four pregnancies, each resulting in a total of fifteen FCAS, three MWS, and six NOMID pregnancies. Six births from FCAS mothers and three births from NOMID mothers occurred while patients were receiving anakinra. If a woman became pregnant while taking anakinra, the pre-pregnancy anakinra dose was continued. Anakinra dose was increased during one twin pregnancy. No preterm births or serious complications of pregnancy were observed. One fetus of the twin pregnancy had renal agenesis and suffered fetal demise. Genetic testing showed the deceased twin carried the same NLRP3 c.785T>C, p.V262A mutation as the mother. The other twin is healthy and mutation negative. Conclusions: Anakinra was continued during pregnancy in women with CAPS and provided significant, persistent CAPS symptom relief while continuing to prevent the long-term sequelae of CAPS. Anakinra was well tolerated. Although a causal relation between anakinra and renal agenesis seems unlikely, further safety data are needed.
Objective
To describe the pregnancy course and outcome and the use of anakinra, a recombinant selective interleukin‐1 receptor blocker, during pregnancy in patients with cryopyrin‐associated periodic ...syndromes (CAPS), including familial cold autoinflammatory syndrome (FCAS), Muckle‐Wells syndrome (MWS), and neonatal‐onset multisystem inflammatory disease (NOMID).
Methods
Women with CAPS who were currently enrolled in natural history protocols and had been pregnant were included. Subjects underwent a structured, standardized interview with regard to maternal health, pregnancy, and fetal outcomes. Medical records were reviewed.
Results
Nine women (4 with FCAS, 2 with MWS/NOMID overlap, and 3 with NOMID) reported 1–4 pregnancies (a total of 15 pregnancies in women with FCAS, 3 in women with MWS, and 6 in women with NOMID). Six births to women with FCAS and 3 births to women with NOMID or MWS/NOMID overlap occurred while the patients were receiving anakinra. In women who became pregnant while taking anakinra, the anakinra treatment was continued; the prepregnancy dosage was maintained except in the case of 1 woman whose dosage was increased during a pregnancy with twins. No preterm births or serious complications of pregnancy were observed. One fetus of the twin pregnancy had renal agenesis and died in utero. Genetic testing showed that the deceased twin carried the same NLRP3 c.785T>C, p.V262A mutation as the mother. The other twin was healthy and mutation negative.
Conclusion
Anakinra was continued during pregnancy in women with CAPS and provided significant, persistent symptom relief while continuing to prevent the long‐term sequelae of CAPS. Anakinra was well tolerated. Although a causal relationship between anakinra and renal agenesis seems unlikely, further safety data are needed.
Cryopyrin-associated periodic syndromes (CAPS) represent a spectrum of CIAS1 gene-mediated autoinflammatory diseases characterized by recurrent systemic inflammation. The clinical spectrum of CAPS ...varies from mild to severe and includes the syndromes historically described as familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID). This article presents the largest cohort of patients with CAPS. The objective is to describe the pathogenesis, otolaryngologic, and audiologic manifestations of CAPS.
Prospective (2003-2009).
National Institutes of Health.
Fifty-seven patients with a diagnosis of CAPS were identified (31 NOMID, 11 NOMID/MWS, 9 MWS, and 6 FCAS). Comprehensive data regarding clinical manifestations, audiologic phenotype, and fluid attenuation inversion recovery MRI (FLAIR-MRI) of the brain and inner ear were obtained.
Complete audiologic data obtained on 70% of ears revealed conductive hearing loss in 4 (11%) NOMID ears and mixed hearing loss in 5 (13%) NOMID and 2 (14%) NOMID/MWS ears. Sensorineural hearing loss (SNHL), worse in higher frequencies, was the most common type of hearing loss and was present in 23 (61%) NOMID, 10 (71%) NOMID/MWS, and 4 (33%) MWS ears. All of the patients with FCAS had normal hearing except 2, who had SNHL from 4 to 8 kHz. On FLAIR-MRI sequence, cochlear enhancement was noted in 26 of 29 (90%) NOMID, 6 of 11 (55%) NOMID/MWS, 3 of 9 (33%) MWS, and 1 of 6 (17%) FCAS patients and was significantly associated with the presence of hearing loss. Maxillary sinus hypoplasia and mucosal thickening were found in 39% and 86% of the cohort, respectively.
CIAS1 pathway–mediated CAPS is associated with unregulated autoinflammation mediated by interleukin-1 in the cochlea and hearing loss. Timely diagnosis is crucial to initiate early treatment with interleukin-1 receptor antagonists.
Background/Purpose:
Neonatal‐onset multisystem inflammatory disease (NOMID) is an autoinflammatory disease characterized by fever, chronic urticarial rash, CNS manifestations, elevated acute phase ...reactants, and arthropathy. About 50% of patients with NOMID have de novo missense mutations in NLRP3/CIAS1, leading to constitutive inflammasome activation and IL‐1 production in monocytes, and caspase‐1 mediated persistence of osteoblast progenitor cells that are also found in other fibroblastoid tumors (). Poorly differentiated chondrocytes are seen with abnormal enchondral bone formation without inflammatory cells in NOMID arthropathy with bony overgrowth and premature fusion of physis. While blocking IL‐1 with anakinra reduces organ‐specific (central nervous system, inner ear, eye) and systemic inflammation (fever, rash, acute phase reactants), it has little effect on preexisting bone lesions.
Methods:
NOMID individuals with at least 5 months of follow up data (clinical, laboratory, and radiographic) on IL‐1 blocking treatment were included for review.
Results:
18 (36.7%) of the NOMID patients (n = 49; 21 male/28 female; age at study entry: 9.4 yo, 0.8–46.3 yo; duration of follow‐up: 4.6 yrs, 0.4–9.5 yrs) had bony involvement, most commonly the knee (16/49 = 32.7%, 12/49 = 24.5% with patellar involvement). 11/49 (22.4%) had multi‐joint involvement, typically asymmetric, including 4 elbows, 5 wrists, 6 ankles, 3 shoulders, and 2 hips. Ongoing abnormal enchondral bone formation continues until physeal fusion, which often occurs prematurely at involved sites, despite anaanakinra treatment. Lesions eventually ossify normally but may cause bone deformities. 3 patients had patellar subluxations (1 managed surgically) and 2 had patella resections. Leg length discrepancy (8/49 = 16.3%) and bowed leg deformities (9/49 = 18.3%) present due to premature, asymmetric fusion of physis required osteomy and/or stapling in 3. 2 developed long twisted fibula to accommodate shortened tibia, 1 surgically managed with stapling. One individual developed hip subluxation due to a longer left leg, which resulted in left hip avascular necrosis. 2 individuals had pseudofractures with development of horizontal linear defects noted in long‐bones consistent with residual changes from abnormal enchondral ossification rather than true fracture. 1 individual developed severe contractures with bilateral knee arthropathy and subsequently had bilateral total knee replacement.
Conclusion:
1. Unique bony findings in NOMID are due to persistence of immature osteoblast precursors with abnormal enchondral bone growth which continues until physeal fusion despite anakinra treatment, often with premature fusion at affected sites, with eventual normal ossification. 2. Surgical intervention can be safely considered for those with significant pain/disability from NOMID arthropathy. 3. Consideration of horizontal linear pseudofractures in long bones and risk of hip avascular necrosis is important in those with NOMID ().
Background/Purpose:
Neonatal onset multisystem inflammatory disease (NOMID) is a rare autoinflammatory disease caused by NLRP3 mutations that lead to constitutive NLRP3 inflammasome activation and ...IL‐1β release. Patients present with neutrophilic urticaria, chronic aseptic meningitis, and papilledema. IL‐1β inhibitors improve the inflammatory manifestations, normalize acute phase reactants, decrease CSF WBC and protein, and proinflammatory cytokine levels. We found that cytokine levels decrease with anakinra treatment, but do not normalize during clinical remission. The higher IL‐6 and IP‐10 levels in CSF than in the blood suggest local production in the brain/CSF. Our objective is to examine whether CSF cytokines, particularly IL‐6 and IP‐10, correlate with CSF subpopulations of immune cells and CSF characteristics.
Methods:
Immunophenotyping and cytokine data were available on 2 baseline and 16 anakinra treated patients, 9/16, fulfilled clinical remission criteria (ESR ≤25 mm/hr, CRP ≤0.5 mg/dl, CSF WBC ≤5 cells/μl and protein ≤40 mg/dl) and control patients (n = 7). Cytokines levels (IL‐1β, IL‐6, IL‐10, IP‐10, IL‐12 (p70) and (p40), IFN‐γ, TNF‐α, and IL‐18) were correlated to CSF WBC, protein, albumin quotient (AQ), and opening pressure at baseline, post‐treatment, and clinical remission. Correlation was assessed with Pearson and Spearman tests.
Results:
At baseline, monocytes, granulocyte, and T cells were higher in NOMID patients versus controls. Post‐treatment monocytes and granulocyte counts decreased but remained higher even in clinical remission, relative to control. Only IL‐6 and IP‐10 correlated with monocytes (r = .66, p = .051; r = .86, p = .002) respectively. A correlation of IP‐10 but not IL‐6 with granulocytes was weaker than with monocytes (r = .66, p = .058). IL‐6, IP‐10, and IL‐18 correlated with CSF protein, AQ, and WBC (except IL‐18). At baseline, IL‐6 and IL‐18 significantly correlated with CSF protein (r = .68, p = .027; r = .80, p = .0065) and AQ (r = .82, p = .011; r = .78, p = .029) respectively. At post‐treatment, IL‐18 significantly correlated and IL‐6 trend towards significance with CSF protein (r = .53, p = .022; r = .40, p = .096) and AQ (r = .83, p = .0002; r = .47, p = .087) respectively.
Conclusion:
1) Inflammatory cells significantly decrease in NOMID patients, especially monocytes which remain elevated even in patients in clinical remission, suggesting residual inflammation. 2) The correlation of monocytes with IL‐6 and IP‐10 suggests their contribution to IL‐6 and IP‐10 production, which may contribute to the recruitment of other inflammatory cells including granulocytes. 3) IL‐6, IP‐10, and IL‐18 may be a marker for blood brain barrier dysfunction in NOMID and their use in long term monitoring should be explored. 4) These results are consistent with the notion that NOMID is caused by dysfunction in innate immune cells, particularly monocytes.
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