Arici, ZS

Berard, R.

Demirkaya, E.

Durrant, K.

Gattorno, M.

Goldbach-Mansky, R.

Jones, O.

Piskin, D.

Romano, M.

English

Scholarship@Western

Western University Scholarship@Western Paediatrics Publications Paediatrics Department 6-2020 A Systematic Review for the Management of the Genetically Defined Il-1-Mediated Autoinflammatory Diseases, Caps, Traps, Mkd and Dira R. Berard M. Romano ZS Arici D. Piskin O. Jones See next page for additional authors Follow this and additional works at: https://ir.lib.uwo.ca/paedpub  Part of the Pediatrics Commons Authors R. Berard, M. Romano, ZS Arici, D. Piskin, O. Jones, K. Durrant, R. Goldbach-Mansky, M. Gattorno, and E. Demirkaya 838 Friday, 05 June 2020 Scientific Abstractspresent work aims to obtain clinical and analytical data that can guide us to an etiological diagnosis.Objectives: To describe and identify the differences between HPS secondary to AID and HOD during their admission to a tertiary hospital between 2005 and 2019.Methods: This is a retrospective observational study. We include patient meet-ing the diagnostic criteria for HLH proposed by Henter JI. (1), or who presented haemophagocytic cells (HC) in the bone marrow biopsy (BMB), or who had HPS in the hospital discharge report. Demographic, clinical, analytical, etiolog-ical, underlying disorders and prognosis variables were collected. Continuous variables are described with the mean or median according to the degree of normality. Kruskal Wallis, Fisher test and Mann-Whitney U test were used for the bivariate analysis, and also a multivariate logistic regression analysis was performed.Results: We found 30 patients with secondary HPS, 22 of which corresponded to the AID [Systemic Lupus Erythematosus (n=5), Adult Still’s Disease (n=3), Rheumatoid arthritis (n=1) and IgG4 Sclerosing Disease (n=1)] and HOD [Non-Hodgkin’s Lymphoma (n=3), Myelodysplastic syndrome (n=3), Acute leu-kemia (n=3), Extranodal NK cell lymphoma (n=1), Multiple Myeloma (n=1) and probable lymphoproliferative process (n=1)]. The coincidence of an infectious disease with HPS was observed in 8 of the 22 cases [AID: 5 cases (2 Cytomeg-alovirus, 2 viral respiratory infections and 1 bacterial infection) and HOD: 3 cases (2 Epstein Barr virus and 1 bacterial infection)]. In two patients with HPS sec-ondary to HOD (acute leukemia), allogeneic transplantation was associated as a possible trigger. In a patient with myelodysplastic syndrome, HPS was associ-ated with the development of graft versus host disease. The age at diagnosis was lower in the AID [40 (26.5 - 56.3); p 0.001]. The HOD had more severe cytopenias [platelets 4500 (650 - 15,750; p 0.009), leukocytes 2050 (20 - 728; p 0.0001) and neutrophils 0 (0 - 280; p 0.002)]. Overall mortality (n=30 patients) was 43.3% (HOD: 66.7%; p 0.029) (table 1). In the final multivariate model according to AID and HOD, the following independent associations were observed: age (p 0.002), platelets (p 0.031), GOT (p 0.012), GPT (p 0.015), total proteins (p 0.007) and mortality (p 0.007).Conclusion: The HOD presented higher mortality and severe cytopenias. The AID presented a higher elevation of transaminases and better prognosis.References: [1] Henter JI, et al. HLH-2004: Diagnostic and therapeutic guidelines for HLH.Pediatr Blood Cancer. 2007;48:124.Disclosure of Interests: César Antonio Egües Dubuc: None declared, Andrea De Diego: None declared, Patricia Cabrera Miranda: None declared, Nerea Alcorta Lorenzo: None declared, Jesús Alejandro Valero Jaimes: None declared, Jose Ramon Furundarena Salsamendi: None declared, Luis Maria Lopez Dominguez: None declared, Jorge Jesús Cancio Fanlo: None declared, Olga Maiz-Alonso: None declared, Esther Uriarte Isacelaya: None declared, Jaime Calvo Grant/research support from: Lilly, UCB, Consult-ant of: Abbvie, Jansen, Celgene, Joaquin Maria Belzunegui Otano: None declaredDOI: 10.1136/annrheumdis-2020-eular.4688FRI0482 A SYSTEMATIC REVIEW FOR THE MANAGEMENT OF THE GENETICALLY DEFINED IL-1-MEDIATED AUTOINFLAMMATORY DISEASES, CAPS, TRAPS, MKD AND DIRAR. Berard1, M. Romano2, Z. S. Arici3, D. Piskin1, O. Jones4, K. Durrant5, R. Goldbach-Mansky6, M. Gattorno7, E. Demirkaya1. 1Western University, London, Canada; 2Istituto Ortopedico Gaetano Pini, Milano, Italy; 3Sanliurfa Education and Research Hospital, Sanliurfa, Turkey; 4Walter Reed Army Medical Center, Washington, United States of America; 5Autoinflammatory Alliance, San Francisco, United States of America; 6NIH Clinical Center, Bethesda, United States of America; 7Istituto Giannina Gaslini,  Genova, ItalyBackground: Ultra-rare genetically defined IL-1 mediated autoinflammatory diseases (AIDs) include mevalonate kinase deficiency (MKD), tumor necro-sis 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 inflamma-tion; 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 sci-ence 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 remis-sion, 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).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 including inflammatory 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.Table 1. Characteristics and comparative analysis of HPS secondary to AID and HOD Total AID HODn 30 10 12 *p<0,05Age (x ± s) 55,5 ±18,3 40 26,5-56,3 68 57,5-73,8 0,001Gender, male 14 46,7% 3 30% 9 75% 0,084Spenomegaly 16 53,3% 5 50% 8 66,7% 0,666Hepatomegaly 10 33,3% 4 40% 4 33,3% 1,000Hb (g/dL) 7,1 6,4-7,9 7,2 6,6-8,4 6,5 5,9-7,3 0,05Pt (x109/L) 13 500 5 000-52 50031 650 11 000-100 2504 500 650-15 750 0,004Leu (x109/L) 1 250 238-3 153 1 985 1 350-3 382 185 20 – 728 0,000Neu (x109/L) 615 0-1 550 948 633-1 808 0 0-280 0,001Fb (mg/dL) (n=24) 171 111-358 212 90-450 167 114-354 1,00Fer (ng/mL) (n=28) 15 330 5 434-38 28414 263 4 254-14 263 16 796 8 287 - 56 9690,314Tg (mmol/L) 341 226-438 411,5 234-572 321 233,8-403,8 0,314GOT (U/L) 139 78-406 457 289-1 140 106 71-193 0,003GPT (U/L) 162 46-388 432 174-599 109 54-263 0,017T.P. (n=29) 4,8 ±,1,04 5,0 4,5-5,8 4,3 3,9-4,5 0,003Hospital stay 35,5 20,0-60,8 30,5 9,5-53,3 61,5 29,3-93,3 0,036Hospital stay pre-dx 16,5 8,5-29,8 10 5,0-16,5 26 10-39 0,038Mortality 13 43,3% 1 10% 8 66,7% 0,011Hb: hemoglobin, Pt: platelets, Leu; leukocytes, Neu, neutrophils, Fb: fibrinogen, Fer: ferritin, Tg: triglycerides, GOT: aspartate aminotransferase, GPT: alanine aminotransferase, T.P.: total proteins, pre-dx: prior to the diagnosis of HPS according to BMO. *Analysis between AID and HOD. on July 14, 2021 by guest. Protected by copyright.http://ard.bmj.com/Ann Rheum Dis: first published as 10.1136/annrheumdis-2020-eular.6023 on 2 June 2020. Downloaded from Scientific Abstracts Friday, 05 June 2020 839References: [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-Desch-ner 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-Man-sky: None declared, Marco Gattorno Consultant of: Sobi, Novartis, Speakers bureau: Sobi, Novartis, Erkan Demirkaya: None declaredDOI: 10.1136/annrheumdis-2020-eular.6023FRI0483 SUBCLINICAL INFLAMMATION AND RELATED PARAMETERS IN PATIENTS WITH FAMILIAL MEDITERRANEAN FEVERM. T. Duruöz1, N. Öz1, A. Ozer1, H. H. Gezer1, D. Erdem Gürsoy1, S. Acer Kasman1. 1Marmara University Pendik Training and Research Hospital, Physical Treatment and Rehabilitation Rheumatology, Istanbul, TurkeyBackground: Familial Mediterranean Fever (FMF), which is more common in groups in the Mediterranean basin, is a monogenic autoinflammatory disease characterized by recurrent attacks of febrile peritonitis, pleuritis and arthritis.Objectives: In this study, we aimed to investigate the clinical, demographic and genotypic features that may be associated with subclinical inflammation in FMF and to determine the related parameters with subclinical inflammation.Methods: FMF patients according to the Tel-Hashomer criteria were included into the study. The demographic characteristics of the patients, duration of the disease, concomitant diseases, MEFV genotype mutation, colchicine use and resistance were collected. Acute-phase reactants such as white blood cell count, erythrocyte sedimentation rate, and C-reactive protein levels during the attacks and attack-free periods were noted. Subclinical inflammation was defined as the continuation of the acute phase response (CRP) between epi-sodes. We divided study population into two groups as; patients with or without subclinical inflammation (Group 1 and Group 2, respectively) and these group were compared with the parameters described above. Patients with infectious disease (viral or bacterial) in the past two months were excluded from the studyResults: Eigthy patients (72.5% female) with mean age 37.1 SD 11.2 years were recruited into the study. Twenty-three (28.7%) patients were determined with subclinical inflammation. Group 1 had significantly higher rate of concomi-tant rheumatic disease(i.e spondyloarthropathy), erythrocyte sedimentation rate and MEFV homozygous mutation compared with Group 2 (p<0.05, for each). Disease duration, months PRASS score, FMF quality of life, age at onset of symptoms, family history of FMF, response to colchicine, attack time, attack in the last 6, delay in diagnosis parameters were not significantly different between groups (p> 0.05).Conclusion: FMF patients whose elevated erythrocyte sedimentation rate and MEFV homozygous mutation should be closely monitored for subclinical inflam-mation even during attack-free periods. Concomitant disease should be detected in FMF patients with subclinical inflammation.References: [1] Shinawi M, Brik R, Kepten I, Berant M, Gersoni B. Familial Mediterranean fever: high gene frequency and heterogenous disease among Israeli-Mos-lem Arab population. J Rheumatol 2000;27:1492–5[2] Bayram MT, Çankaya T, Bora E, Kavukçu S, Ülgenalp A, Soylu A, Türkmen M. Risk factors for subclinical inflammation in children with Familial Mediter-ranean fever. Rheumatol Int. 2015 Aug;35(8):1393-8.Table 1: Demographic and clinical features of the patients with familial Mediterranean fever Without Subclinical inflamationn= (57)With Subclinical inflamationn= (23)P valueAge (years; mean SD) 37,78 SD 13,22 36,82 SD 10,49 0.987Female, gender, n (%) 45(%78) 13(%56) 0.055Disease duration(month; mean SD)255,3 SD 195,1 180,2 SD 121,1 0.191PRASS score(mean SD)6,08 SD 2,15 5,36 SD 1,59 0.147BMİ, kg/m2 26,12 SD 4,8 32,13 SD 28,48 0.629Current smoking status (%) 17(%29) 3(%13) 0.067Age at onset of symptoms (month;  mean SD)15,69 SD 9,41 17,28 SD 10,34 0.54Family history of FMF(%) 37(%64) 18(%78) 0.295Response to colchicine(%) 6(%10) 4(%17) 0.462Attack time(day; mean SD)1,9 SD 1,1 2,26 SD 1,4 0,523Attack in the last 6 months (mean SD) 2,79 SD 3,1 4,56 SD 5,5 0,184FMF quality of life(mean SD)31,5 SD 13,6 25.7 SD 16,4 0,130Delay in diagnosis(month; mean SD) 12,29 SD 10,9 14,3 SD 14,9 0,840Disclosure of Interests: None declaredDOI: 10.1136/annrheumdis-2020-eular.4801FRI0484 SAFETY PROFILE, CLINICAL AND RADIOLOGICAL EFFICACY OF ANAKINRA, TARGETED AND COMBINED TREATMENT IN ERDHEIM-CHESTER DISEASEN. Farina1, C. Campochiaro1, A. Tomelleri1, G. De Luca1, G. Cavalli1, L. Dagna1. 1IRCCS San Raffaele Hospital, Unit of Immunology, Rheumatology, Allergy and Rare Diseases, Milan, ItalyBackground: Erdheim-Chester disease (ECD) is a rare non-Langerhans histio-cytosis. Combined treatment with anakinra (ANK) and targeted MAPK-inhibiting therapies (vemurafenib – VMF - or cobimetinib - CBM) has been recently used to treat severe cases of ECD.Objectives: To evaluate the safety and the clinical and radiological efficacy of ANK, targeted and combined treatments in ECD patients in a real-world setting.Figure 1. Flow-charts of systematic review for CAPS, TRAPS and MKD.Table 1. Disease characteristics and therapy-related adverse reactions of Erdheim-Chester patients treated with vemurafenib, cobimetinib and/or anakinra. Vemurafenib (n=19) Cobimetinib (n=10) Anakinra (n=12)Clinical Manifestations     Cardiovascular 79% 70% 75% Retroperitoneal 84% 60% 42% Pleuropulmonary 63% 80% 42% Neurological and/or orbital 90% 90% 92%Adverse reactions 74% 60% 25% Renal 26% 10% 0% Cutaneous 26% 30% 17% Systemic Inflammation 11% 10% 0% Cardiovascular 11% 10% 0% Gastrointestinal 0% 30% 0% Haematological 0% 10% 0% Herpes Zoster 0% 0% 8% on July 14, 2021 by guest. Protected by copyright.http://ard.bmj.com/Ann Rheum Dis: first published as 10.1136/annrheumdis-2020-eular.6023 on 2 June 2020. Downloaded from 

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

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

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