A Systematic Review for the Management of the Genetically Defined Il-1-Mediated Autoinflammatory Diseases, Caps, Traps, Mkd and Dira

Background:Ultra-rare genetically defined IL-1 mediated autoinflammatory diseases (AIDs) include mevalonate kinase deficiency (MKD), tumor necrosis factor receptor associated periodic syndrome (TRAPS), cryopyrinopathies (CAPS) and deficiency of the IL-1 receptor antagonist (DIRA). These disorders start perinatally, the clinical disease manifestations include systemic inflammation; and late diagnosis and inappropriate treatment cause irreversible organ damage. The varying skills of treating rheumatologists and paediatricians illustrate the need for management guidance, however criteria for validated methodology is geared towards common diseases with more heterogeneous pathogenesis.Objectives:The focus of this systematic review includes the evaluation of the existing literature and the evaluation of existing EULAR methodology for use in the ultra-rare diseases with defined pathomechanisms, CAPS, TRAPS, MKD and DIRAMethods:EULAR standardized operating procedures were followed during the review, including a meeting of experts to discuss key words, inclusion/exclusion criteria and PICO questions. Three fellows established the protocol of the review under the supervision of the EULAR methodologist and PubMed, Embase, and Cochrane databases were searched up to September 30, 2019.Results:We found 1582 articles for CAPS, 1109 articles for TRAPS,1741 articles for MKD and 557 articles for DIRA. Duplications, animal models and basic science studies, conference papers, systematic reviews/meta-analysis and articles not in English language is excluded. If we excluded case reports (n<4), then 72 articles for CAPS, 40 articles for TRAPS,44 articles for MKD and 1 article for DIRA should be included for full text evaluation and data extraction (Figure 1). However among the case reports, patients excluded achieved complete remission, assessed by clinical criteria and biomarkers. Of the studies included only few randomized studies for CAPS, TRAPS, MKD, and DIRA and would achieve higher level of evidence (Figure 1).Figure 1.Flow-charts of systematic review for CAPS, TRAPS and MKD.Conclusion:CAPS, TRAPS, MKD and DIRA are monogenic diseases with defined pathways and outcomes that include inflammatory remission based on clinical and biomarker data. Current methodological evaluations for genetically complex diseases undervalue the published evidence in case reports that report on remission and IL-1 biomarkers. We suggest that case studies that include hard outcomes includinginflammatory remission, and open label withdrawal studies that are both backed by biomarkers could be allowed to be included and be considered for a stronger evidence level.References:[1]van der Heijde D, Aletaha D, Carmona L, et al 2014 Update of the EULAR standardised operating procedures for EULAR-endorsed recommendations Annals of the Rheumatic Diseases 2015;74:8-13.[2]Gattorno M, Hofer M, Federici S, Vanoni F, Bovis F, Aksentijevich I, Anton J, Arostegui JI, Barron K, Ben-Cherit E, Brogan PA, Cantarini L, Ceccherini I, De Benedetti F, Dedeoglu F, Demirkaya E, Frenkel J, Goldbach-Mansky R, Gul A, Hentgen V, Hoffman H, Kallinich T, Kone-Paut I, Kuemmerle-Deschner J, Lachmann HJ, Laxer RM, Livneh A, Obici L, Ozen S, Rowczenio D, Russo R, Shinar Y, Simon A, Toplak N, Touitou I, Uziel Y, van Gijn M, Foell D, Garassino C, Kastner D, Martini A, Sormani MP, Ruperto N; Eurofever Registry and the Paediatric Rheumatology International Trials Organisation (PRINTO). Classification criteria for autoinflammatory recurrent fevers. Ann Rheum Dis. 2019 Aug;78(8):1025-1032.Disclosure of Interests:Roberta Berard: None declared, micol romano: None declared, Zehra Serap Arici: None declared, David Piskin: None declared, Olcay Jones: None declared, Karen Durrant: None declared, Raphaela Goldbach-Mansky: None declared, Marco Gattorno Consultant of: Sobi, Novartis, Speakers bureau: Sobi, Novartis, Erkan Demirkaya: None declare

The efficacy of anakinra in an adolescent with colchicine-resistant familial Mediterranean fever

Colchicine is the treatment of choice in familial Mediterranean fever (FMF) for the prevention of both attacks and secondary amyloidosis. The overall nonresponder rate is about 5–10%. Anakinra is known to have good effectiveness in a severe autoinflammatory syndrome [chronic infantile neurological cutaneous and articular (CINCA) syndrome] and other recurrent hereditary periodic fevers. Pyrin—the protein involved in FMF—has a role in activating the proinflammatory cytokine interleukin (IL)-1β. We report the effectiveness of the addition of an IL-1-receptor inhibitor (anakinra) to colchicine in controlling the febrile attacks and acute phase response in an adolescent with FMF resistant to colchicine

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

Proceedings from the 2\u3csup\u3end\u3c/sup\u3eNext Gen Therapies for Systemic Juvenile Idiopathic Arthritis and Macrophage Activation Syndrome symposium held on October 3-4, 2019

© 2020 The Author(s). For reasons poorly understood, and despite the availability of biological medications blocking IL-1 and IL-6 that have markedly improved overall disease control, children with Systemic Juvenile Idiopathic Arthritis (SJIA) are now increasingly diagnosed with life-threatening chronic complications, including hepatitis and lung disease (SJIA-LD). On October 3-4, 2019, a two-day meeting, NextGen Therapies for Systemic Juvenile Idiopathic Arthritis (SJIA) & macrophage activation syndrome (MAS) organized by the Systemic JIA Foundation (www.systemicjia.org/) in Washington, DC brought together scientists, clinicians, parents and FDA representatives with the objectives (1) to integrate clinical and research findings in MAS and SJIA-LD, and (2) to develop a shared understanding of this seemingly new pulmonary complication of SJIA. The current manuscript summarizes discussions and conclusions of the meeting

Diurnal secretion of growth hormone, cortisol, and dehydroepiandrosterone in pre- and perimenopausal women with active rheumatoid arthritis: a pilot case-control study

Rheumatoid arthritis (RA) is associated with neuroendocrine and immunologic dysfunction leading to rheumatoid cachexia. Although excess proinflammatory cytokines can decrease somatotropic axis activity, little is known about the effects of RA on growth hormone/insulin-like growth factor-1 (GH/IGF-I) axis function. We tested the hypothesis that patients with active RA exhibit decreased GH/IGF-I axis activity. To do so, we conducted a pilot case-control study at a clinical research center in 7 pre- and perimenopausal women with active RA and 10 age- and body mass index-matched healthy women. Participants underwent blood sampling every 20 minutes for 24 hours (8 a.m. to 8 a.m.), and sera were assayed for GH, cortisol, and dehydroepiandrosterone (DHEA). Sera obtained after overnight fasting were assayed for IGF-I, IGF-binding protein (IGFBP)-1, IGFBP-3, C-reactive protein (CRP), interleukin-6 (IL-6), glucose, insulin, and lipids. Body composition and bone mineral density were evaluated by DEXA (dual emission x-ray absorptiometry) scans. In patients with RA, mean disease duration was 7.6 ± 6.8 years, and erythrocyte sedimentation rate, CRP, and IL-6 were elevated. GH half-life was shorter than in control subjects (p = 0.0037), with no other significant group differences in GH deconvolution parameters or approximate entropy scores. IGF-I (p = 0.05) and IGFBP-3 (p = 0.058) were lower, whereas IGFBP-1 tended to be higher (p = 0.066), in patients with RA, with nonsignificantly increased 24-hour total GH production rates. There were no significant group differences in cortisol or DHEA secretion. Lean body mass was lower in patients with RA (p = 0.019), particularly in the legs (p = 0.01). Women with active RA exhibit a trend toward GH insensitivity and relatively diminished diurnal cortisol and DHEA secretion for their state of inflammation. Whether these changes contribute to rheumatoid cachexia remains to be determined