Query: Neonatal-onset multisystem inflammatory disease

title: A case of neonatal onset multisystem inflammatory disease supporting a role of interleukin 1b in moyamoya syndrome
abstract: Moyamoya syndrome (MMS) is a chronic progressive cerebrovascular condition characterized by bilateral stenosis/occlusion of the terminal internal carotid artery (ICA) often extending to neighboring cerebral arteries with prominent collateral circulation and increased risk of hemorrhage. Symptoms include stroke, TIA, and  MMS's etiology is unknown. However, experimental evidence from arterial smooth muscle cells (SMC) derived from patients with MMS has suggested that interleukin 1 beta (IL 1b) dependent prostaglandin overproduction plays a crucial role in its pathogenesis.2 Neonatal onset multisystem inflammatory disease (NOMID) is an autosomal dominantly inherited disease characterized by excessive IL 1b overproduction and autoinflammation. Accordingly, NOMID is treated with IL 1 receptor antagonists such as anakinra (Kineret, Swedish Orphan Biovitrum AB, Sweden, Stockholm) or IL 1 receptor antibodies such as canakinumab (Ilaris, Novartis, Basel, Switzerland).3 We here report the development of MMS in a NOMID patient. In this patient, escalation of IL 1 receptor antagonistic treatment led to a significant reduction of disease activity and TIAs. Both the occurrence of MMS in this NOMID patient and the clinical and laboratory improvement because of IL 1 receptor antagonism provide direct clinical evidence that IL 1b overproduction could play a pathophysiologic role in MMS.

title: Involvement of nuclear factor kappa B in development of neonatal onset multisystem inflammatory disease
abstract: The present study investigated the relationship between nuclear factor kB1 gene (NFkB1) and neonatal onset multisystem inflammatory disease (NOMID) among Chinese neonates. We therefore aimed to investigate whether nuclear factor kappa B involved in development of NOMID among Chinese neonates. Patients with confirm diagnosis of NOMID or healthy neonates was enrolled at Maternal and child health hospital of Hubei province, China. Involvement of poly (ADP ribose) polymerase 1 (PP 1) and nuclear factor kB1 was assessed using PCR techniques with the help of DNA sample. A total of 220 Chinese neonates with NOMID, and 220 healthy neonates were completed study. We note that the involvement of del/ins of NFkB1 gene in development of NOMID among Chinese neonates. GG and G SNPs of PP 1 were found responsible for developing NOMID and the individuals with GA SNPs protect responsible for protecting from NOMID. Thus, nuclear factor kB1 and PP 1 involved in cause of NOMID, and considering as risk of developing is approx. 2 times higher compared to healthy subjects. Our study result shown that polymorphism of nuclear factor kB1 and PP 1 is involved in development of NOMID in China. Our study suggested that NFkB1 and PP 1 is a possible target for treatment of NOMID; the treatment targeting nuclear NFkB1 and PP 1 is useful for effective patient care. Our study results encourage conducting large trial evaluating role of NFkB1and PP 1 polymorphism in NOMID.

title: Neonatal Onset Multisystem Inflammatory Disease.

title: Low Back and Buttock Pain in a NOMID/CINCA Syndrome Patient Under Canakinumab Therapy Time for Another Biologic?
abstract: NOMID/CINCA Syndrome (Neonatal Onset Multisystem Inflammatory Disease/ Chronic Infantile Neurologic Cutaneous and Articular Syndrome) is a rare inflammatory periodic fever syndrome responding to treatment with IL 1 antagonists. Axial Spondyloarthritides (axSpA) are a group of diseases responding to TNF (Tumor Necrosis Factor alpha) or IL 17 antagonists. Overlap syndromes of these two entities have, so far, not been described. Of importance, NOMID/ CINCA syndrome does not respond to treatment with TNF antagonists and only a small subgroup of axial spondyloarthritides may respond to IL 1 antagonists. Combination therapy of anakinra, an IL 1 antagonist, and the TNF antagonist etanercept, was associated with an increased rate of infections in RA patients.  A 25 year old woman with NOMID/CINCA syndrome successfully treated with canakinumab developed inflammatory back pain and was, subsequently, diagnosed with axial spondylarthritis. After an ineffective therapeutic approach with both initial intra articular spinal glucocorticoids injections and, subsequently, sulfasalazine, etanercept was initiated. Under this combined etanercept and canakinumab treatment both diseases, NOMID/CINCA syndrome and axial spondylarthritis, were controlled and no severe infection developed.  In summary, this case demonstrates a favorable response to treatment with canakinumab and etanercept in combination in a patient with an overlap syndrome of NOMID/ CINCA syndrome and axial spondylarthritis with an acceptable safety profile. Such a combination therapy should be given with care and after other therapeutic alternatives failed.

title: Off Label Studies on Anakinra in Dermatology: A Review.
abstract: Anakinra (Kineret(r) is an interleukin 1 receptor antagonist (IL 1Ra) FDA approved for use in rheumatoid arthritis and in neonatal onset multisystem inflammatory disease (NOMID) It has been used off label for a variety of dermatologic conditions. A review of the available studies and cases of these off label uses would be valuable to the dermatologist considering alternative treatments for these oftentimes poorly studied conditions. The PubMed/MEDLINE, EMBASE, Scopus, and ClinicalTrials.gov databases were searched with the term 'anakinra. Results were manually screened to identify published data on off label uses of anakinra in dermatologic conditions and systemic conditions with prominent dermatologic manifestations. Anakinra appears to show efficacy for numerous dermatologic conditions, with the strongest evidence for hidradenitis suppurativa, Bechet's disease, Muckle Wells syndrome, and SAPHO syndrome. Case reports and case series data are available for numerous other dermatologic conditions. Anakinra is a potential option for patients with certain difficult to treat dermatologic diseases, given its relatively benign adverse effect profile and its effectiveness in a wide array of conditions. Overall, anakinra appears to be a promising option in the treatment of numerous dermatologic inflammatory conditions refractory to first line therapies, but further and higher quality data is needed to clarify its therapeutic role.

title: Induced pluripotent stem cell derived monocytic cell lines from a NOMID patient serve as a screening platform for modulating NLRP3 inflammasome activity
abstract: Curative therapeutic options for a number of immunological disorders remain to be established, and approaches for identifying drug candidates are relatively limited. Furthermore, phenotypic screening methods using induced pluripotent stem cell (iPSC) derived immune cells or hematopoietic cells need improvement. In the present study, using immortalized monocytic cell lines derived from iPSCs, we developed a high throughput screening (HTS) system to detect compounds that inhibit IL 1b secretion and NLRP3 inflammasome activation from activated macrophages. The iPSCs were generated from a patient with neonatal onset multisystem inflammatory disease (NOMID) as a model of a constitutively activated NLRP3 inflammasome. HTS of 4,825 compounds including FDA approved drugs and compounds with known bioactivity identified 7 compounds as predominantly IL 1b inhibitors. Since these compounds are known inflammasome inhibitors or derivatives of, these results prove the validity of our HTS system, which can be a versatile platform for identifying drug candidates for immunological disorders associated with monocytic lineage cells.

title: Cryopyrin Associated Periodic Syndromes and Treatment Options
abstract: Cryopyrin associated periodic syndromes (CAPSs) are a growing family of autoinflammatory diseases, also known as periodic fever syndromes. There are three forms of CAPS: (1) Familial Cold autoinflammatory syndrome or familial cold urticaria, (2) Muckle wells syndrome, and (3) neonatal onset multisystem inflammatory disease or chronic infantile neurological cutaneous articular syndrome. Genetic mutations in the NLRP3 gene were found to be present in most patients. The foremost common findings between all the CAPS disorders are rash, fever which is sometimes present at birth or in early childhood, joint problems, and conjunctivitis. More extreme forms of CAPS include more persistent inflammation that can cause hearing loss and meningitis and can lead to mental and developmental delays. Drugs for CAPS target the source of inflammation which is the over production of interleukin 1s by modified cryopyrin inflammasomes. Three drugs are used to treat CAPS: Rilonacept, canakinumab, and anakirna. With these drugs, the prognosis is greatly improved, with most patients having less frequent episodes, decreased buildup of amyloid in the body, and extended life of severe cases up to adulthood.

title: SAT0510 LONG TERM EFFECTIVENESS OF CANAKINUMAB IN AID INTERIM ANALYSIS OF THE CAPS SUBGROUP FROM THE RELIANCE REGISTRY
abstract: In the treatment of monogenic autoinflammatory diseases (AID) a heterogeneous group of diseases with excessive interleukin (IL) 1b release and severe systemic and organ inflammation, the anti IL 1 inhibitor canakinumab (CAN) has been associated with rapid remission of symptoms in clinical trials as well as in real  3  The aim of the RELIANCE registry is to explore long term effectiveness and safety of CAN under routine clinical practice conditions in pediatric and adult patients with CAPS (cryopyrin associated periodic syndromes, including Muckle Wells syndrome [MWS] familial cold autoinflammatory syndrome [FCAS] neonatal onset multisystem inflammatory disease [NOMID]/chronic infantile neurological cutaneous and articular syndrome [CINCA] FMF (familial Mediterranean fever) TRAPS (tumor necrosis factor receptor associated periodic syndrome) and HIDS/MKD (hyperimmunoglobulinemia D syndrome/mevalonate kinase deficiency)  This prospective, non interventional, observational study is based in Germany with a 3 year follow up and enrolls pediatric =2 years and adult patients with clinically confirmed diagnoses of CAPS, FMF, TRAPS and HIDS/MKD routinely receiving CAN. In 6 monthly visits, clinical data and patient reported outcomes are assessed. Study endpoints are long term effectiveness and safety of CAN. Here, the CAPS cohort was analyzed.  This 18 month interim analysis includes 78 CAPS patients (49% females) enrolled by September 2019. Mean age at baseline was 25 years and mean duration of prior CAN treatment was 5.7 years. 64 patients (82% had MWS, 2 FCAS, 7 NOMID/CINCA, 3 atypical CAPS and 2 lacked subtype diagnosis. Disease activity, fatigue and social impairment by patients' assessment, days absent from school/work, inflammatory markers, and remission by physician assessment were evaluated at 6 monthly intervals starting at baseline with last update at 18 months of follow up (table 1) The results demonstrate sustained remission and disease control as evaluated parameters remained stable over time. Serious adverse events were reported for 9 patients including papillitis, pyrexia, tonsillitis (n=2) appendicitis, chest pain, circulatory collapse, skin disorders, and preterm delivery.Table 1. Patient and physician assessment of clinical CAPS disease activity and laboratory markers over time Baseline 6 months 12 months 18 months Number of patients, N 78 51 42 29 Mean age, years (SD) 25 (4; 79) 22 (4; 79) 20 (4; 58) 22 (4; 54) Patient's assessment of disease activity 0 10, mean (min; max) 2.2 (0; 7) 1.8 (0; 7) 2.4 (0; 7) 2.8 (0; 8) Patient's assessment of fatigue 0 10 2.9 (0; 9) 2.4 (0; 8) 2.8 (0; 8) 1.7 (0; 7) Number of patients without impairment of social life by disease 16 (49) 29 (76) 20 (61) 14 (67) Number of patients with days absent from school/work 25 (32.5) 11 (22) 14 (34) 15 (52) Inflammatory markers, CRP/SAA, mean (mg/dL) 0.43.2 0.42.1 0.30.8 0.20.5 Number of patients in disease remission (physician assessment) 55 (72) 38 (76) 29 (71) 22 (76)  The 18 month interim analysis of the RELIANCE study, the longest running real life CAN registry, demonstrates that long term CAN treatment is safe and effective in CAPS patients.

title: OP0286 PROTEOMICS AND RNA SEQUENCING APPROACHES HIGHLIGHT THE ROLE OF ENDOTHELIAL CELL DYSREGULATION IN IL 1 AND IFN MEDIATED AUTOINFLAMMATORY DISEASES, NOMID AND CANDLE
abstract: Systemic Autoinflammatory diseases present with sterile inflammation. NOMID (Neonatal Onset Multisystem Inflammatory Disease) is caused by gain of function mutations in NLRP3 and excess IL 1 production, presents with fever, neutrophilic dermatosis, aseptic meningitis, hearing loss and eye inflammation; CANDLE (Chronic Atypical Neutrophilic Dermatosis, Lipodystrophy and Elevated Temperature) is caused by loss of function mutations in proteasome genes that lead to type 1 interferon signaling, characterized by fever, panniculitis, lipodystrophy, cytopenia, systemic and pulmonary hypertension and basal ganglia calcification. IL 1 blockers are approved for NOMID and JAK inhibitors show efficacy in CANDLE treatment.  We used proteomic analysis to compare differentially expressed proteins in active NOMID and CANDLE compared to healthy controls before and after treatment, and whole blood bulk RNA seq to identify the immune cell signatures.  Serum samples from active NOMID (n=12) and CANDLE (n=7) before and after treatment (table 1) and age matched healthy controls (HC) (n=7) were profiled using the SomaLogic platform (n=1125 proteins) Differentially expressed proteins in NOMID and CANDLE were ranked after non parametric tests for unpaired (NOMID p  Compared to control, 205 proteins (127 upregulated, 78 downregulated) were significantly different at baseline in NOMID, compared to 163 proteins (101 upregulated, and 62 downregulated) in CANDLE. 134 dysregulated proteins (85 upregulated, 49 downregulated) overlapped in NOMID and CANDLE  Pathway analysis identified neutrophil and monocyte chemotaxis signature in both NOMID and CANDLE. NOMID patients had neutrophilia and active neutrophils. CANDLE patients exhibited active neutrophils in whole blood RNA. Endothelial cell activation was the most prominent non hematopoietic signature and suggest distinct endothelial cell dysregulation in NOMID and CANDLE. In NOMID, the signature included neutrophil transmigration (SELE) endothelial cell motility in response to angiogenesis (HGF, VEGF) while in CANDLE the endothelial signatures included extracellular matrix protein deposition (COL8A) suggesting increased vascular stiffness. CANDLE patients had higher expression of Renin, 4 out of 7 had hypertension, NOMID patients did not have hypertension. Treatment with anakinra and baricitinib normalized 143 and 142 of dysregulated proteins in NOMID and CANDLE respectively.  Differentially expressed proteins in NOMID and CANDLE are consistent with innate immune cell activation. Distinct endothelial cell signatures in NOMID and CANDLE may provide mechanistic insight into differences in vascular phenotypes. Treatment with anakinra and Baricitinib in NOMID and CANDLE leaves 30% and 13% of the dysregulated proteins unchanged.  This work was supported by Intramural Research at National Institute of Allergy Immunology and Infectious Diseases of National Institutes of Health, Bethesda, Maryland, the Center of Human Immunology and was approved by the IRB. Disclosure of Interests: None declared

title: Computational Modeling of NLRP3 Identifies Enhanced ATP Binding and Multimerization in Cryopyrin Associated Periodic Syndromes
abstract: Cyropyrin associated periodic syndromes (CAPS) are clinically distinct syndromes that encompass a phenotypic spectrum yet are caused by alterations in the same gene, NLRP3. Many CAPS cases and other NLRP3 autoinflammatory diseases (NLRP3 AIDs) are directly attributed to protein coding alterations in NLRP3 and the subsequent dysregulation of the NLRP3 inflammasome leading to IL 1b mediated inflammatory states. Here, we used bioinformatics tools, computational modeling, and computational assessments to explore the proteomic consequences of NLRP3 mutations, which potentially drive NLRP3 inflammasome dysregulation. We analyzed 177 mutations derived from familial cold autoinflammatory syndrome (FCAS) Muckle Wells Syndrome (MWS) and the non hereditary chronic infantile neurologic cutaneous and articular syndrome, also known as neonatal onset multisystem inflammatory disease (CINCA/NOMID) as well as other NLRP3 AIDs. We found an inverse relationship between clinical severity and the severity of predicted structure changes resulting from mutations in NLRP3. Bioinformatics tools and computational modeling revealed that NLRP3 mutations that are predicted to be structurally severely disruptive localize around the ATP binding pocket and that specific proteo structural changes to the ATP binding pocket lead to enhanced ATP binding affinity by altering hydrogen bond and charge interactions. Furthermore, we demonstrated that NLRP3 mutations that are predicted to be structurally mildly or moderately disruptive affect protein protein interactions, such as NLRP3 ASC binding and NLRP3 NLRP3 multimerization, enhancing inflammasome formation and complex stability. Taken together, we provide evidence that proteo structural mechanisms can explain multiple mechanisms of inflammasome activation in NLRP3 AID.