Zbornik 24. mednarodne multikonference • INFORMACIJSKA DRUZBA Zvezek J Proceedings of the 24th International Multiconference INFORMATION SOCIETY Volume J I S S 0 S I Delavnica projekta BATMAN BATMAN Project Workshop Urednika • Editors: Sergio Crovella, Anton Gradišek 4. oktober 2021 Ljubljana, Slovenija • 4 October 2021 Ljubljana, Slovenia • http://is.ijs.si Zbornik 24. mednarodne multikonference INFORMACIJSKA DRUŽBA – IS 2021 Zvezek J Proceedings of the 24th International Multiconference INFORMATION SOCIETY – IS 2021 Volume J Delavnica projekta BATMAN BATMAN Project Workshop Urednika / Editors Sergio Crovella, Anton Gradišek http://is.ijs.si 4. oktober 2021 / 4 October 2021 Ljubljana, Slovenia Urednika: Sergio Crovella Department of Biological and Environmental Sciences, College of Arts and Sciences Qatar University, Doha, State of Qatar. Anton Gradišek Department of Intelligent Systems Jožef Stefan Institute, Ljubljana Založnik: Institut »Jožef Stefan«, Ljubljana Priprava zbornika: Mitja Lasič, Vesna Lasič, Lana Zemljak Oblikovanje naslovnice: Vesna Lasič Dostop do e-publikacije: http://library.ijs.si/Stacks/Proceedings/InformationSociety Ljubljana, oktober 2021 Informacijska družba ISSN 2630-371X Kataložni zapis o publikaciji (CIP) pripravili v Narodni in univerzitetni knjižnici v Ljubljani COBISS.SI-ID 85974531 ISBN 978-961-264-223-5 (PDF) PREDGOVOR MULTIKONFERENCI INFORMACIJSKA DRUŽBA 2021 Štiriindvajseta multikonferenca Informacijska družba je preživela probleme zaradi korone v 2020. Odziv se povečuje, v 2021 imamo enajst konferenc, a pravo upanje je za 2022, ko naj bi dovolj velika precepljenost končno omogočila normalno delovanje. Tudi v 2021 gre zahvala za skoraj normalno delovanje konference tistim predsednikom konferenc, ki so kljub prvi pandemiji modernega sveta pogumno obdržali visok strokovni nivo. Stagnacija določenih aktivnosti v 2020 in 2021 pa skoraj v ničemer ni omejila neverjetne rasti IKTja, informacijske družbe, umetne inteligence in znanosti nasploh, ampak nasprotno – rast znanja, računalništva in umetne inteligence se nadaljuje z že kar običajno nesluteno hitrostjo. Po drugi strani se je pospešil razpad družbenih vrednot, zaupanje v znanost in razvoj. Se pa zavedanje večine ljudi, da je potrebno podpreti stroko, čedalje bolj krepi, kar je bistvena sprememba glede na 2020. Letos smo v multikonferenco povezali enajst odličnih neodvisnih konferenc. Zajema okoli 170 večinoma spletnih predstavitev, povzetkov in referatov v okviru samostojnih konferenc in delavnic ter 400 obiskovalcev. Prireditev so spremljale okrogle mize in razprave ter posebni dogodki, kot je svečana podelitev nagrad – seveda večinoma preko spleta. Izbrani prispevki bodo izšli tudi v posebni številki revije Informatica (http://www.informatica.si/), ki se ponaša s 45-letno tradicijo odlične znanstvene revije. Multikonferenco Informacijska družba 2021 sestavljajo naslednje samostojne konference: • Slovenska konferenca o umetni inteligenci • Odkrivanje znanja in podatkovna skladišča • Kognitivna znanost • Ljudje in okolje • 50-letnica poučevanja računalništva v slovenskih srednjih šolah • Delavnica projekta Batman • Delavnica projekta Insieme Interreg • Delavnica projekta Urbanite • Študentska konferenca o računalniškem raziskovanju 2021 • Mednarodna konferenca o prenosu tehnologij • Vzgoja in izobraževanje v informacijski družbi Soorganizatorji in podporniki multikonference so različne raziskovalne institucije in združenja, med njimi ACM Slovenija, SLAIS, DKZ in druga slovenska nacionalna akademija, Inženirska akademija Slovenije (IAS). V imenu organizatorjev konference se zahvaljujemo združenjem in institucijam, še posebej pa udeležencem za njihove dragocene prispevke in priložnost, da z nami delijo svoje izkušnje o informacijski družbi. Zahvaljujemo se tudi recenzentom za njihovo pomoč pri recenziranju. S podelitvijo nagrad, še posebej z nagrado Michie-Turing, se avtonomna stroka s področja opredeli do najbolj izstopajočih dosežkov. Nagrado Michie-Turing za izjemen življenjski prispevek k razvoju in promociji informacijske družbe je prejel prof. dr. Jernej Kozak. Priznanje za dosežek leta pripada ekipi Odseka za inteligentne sisteme Instituta ''Jožef Stefan'' za osvojeno drugo mesto na tekmovanju XPrize Pandemic Response Challenge za iskanje najboljših ukrepov proti koroni. »Informacijsko limono« za najmanj primerno informacijsko potezo je prejela trditev, da je aplikacija za sledenje stikom problematična za zasebnost, »informacijsko jagodo« kot najboljšo potezo pa COVID-19 Sledilnik, tj. sistem za zbiranje podatkov o koroni. Čestitke nagrajencem! Mojca Ciglarič, predsednik programskega odbora Matjaž Gams, predsednik organizacijskega odbora i FOREWORD - INFORMATION SOCIETY 2021 The 24th Information Society Multiconference survived the COVID-19 problems. In 2021, there are eleven conferences with a growing trend and real hopes that 2022 will be better due to successful vaccination. The multiconference survived due to the conference chairs who bravely decided to continue with their conferences despite the first pandemic in the modern era. The COVID-19 pandemic did not decrease the growth of ICT, information society, artificial intelligence and science overall, quite on the contrary – the progress of computers, knowledge and artificial intelligence continued with the fascinating growth rate. However, COVID-19 did increase the downfall of societal norms, trust in science and progress. On the other hand, the awareness of the majority, that science and development are the only perspectives for a prosperous future, substantially grows. The Multiconference is running parallel sessions with 170 presentations of scientific papers at eleven conferences, many round tables, workshops and award ceremonies, and 400 attendees. Selected papers will be published in the Informatica journal with its 45-years tradition of excellent research publishing. The Information Society 2021 Multiconference consists of the following conferences: • Slovenian Conference on Artificial Intelligence • Data Mining and Data Warehouses • Cognitive Science • People and Environment • 50-years of High-school Computer Education in Slovenia • Batman Project Workshop • Insieme Interreg Project Workshop • URBANITE Project Workshop • Student Computer Science Research Conference 2021 • International Conference of Transfer of Technologies • Education in Information Society The multiconference is co-organized and supported by several major research institutions and societies, among them ACM Slovenia, i.e. the Slovenian chapter of the ACM, SLAIS, DKZ and the second national academy, the Slovenian Engineering Academy. In the name of the conference organizers, we thank all the societies and institutions, and particularly all the participants for their valuable contribution and their interest in this event, and the reviewers for their thorough reviews. The award for lifelong outstanding contributions is presented in memory of Donald Michie and Alan Turing. The Michie-Turing award was given to Prof. Dr. Jernej Kozak for his lifelong outstanding contribution to the development and promotion of the information society in our country. In addition, the yearly recognition for current achievements was awarded to the team from the Department of Intelligent systems, Jožef Stefan Institute for the second place at the XPrize Pandemic Response Challenge for proposing best counter-measures against COVID-19. The information lemon goes to the claim that the mobile application for tracking COVID-19 contacts will harm information privacy. The information strawberry as the best information service last year went to COVID-19 Sledilnik, a program to regularly report all data related to COVID-19 in Slovenia. Congratulations! Mojca Ciglarič, Programme Committee Chair Matjaž Gams, Organizing Committee Chair KONFERENČNI ODBORI CONFERENCE COMMITTEES International Programme Committee Organizing Committee Vladimir Bajic, South Africa Matjaž Gams, chair Heiner Benking, Germany Mitja Luštrek Se Woo Cheon, South Korea Lana Zemljak Howie Firth, UK Vesna Koricki Olga Fomichova, Russia Mitja Lasič Vladimir Fomichov, Russia Blaž Mahnič Vesna Hljuz Dobric, Croatia Klara Vulikić Alfred Inselberg, Israel Jay Liebowitz, USA Huan Liu, Singapore Henz Martin, Germany Marcin Paprzycki, USA Claude Sammut, Australia Jiri Wiedermann, Czech Republic Xindong Wu, USA Yiming Ye, USA Ning Zhong, USA Wray Buntine, Australia Bezalel Gavish, USA Gal A. Kaminka, Israel Mike Bain, Australia Michela Milano, Italy Derong Liu, Chicago, USA Toby Walsh, Australia Sergio Campos-Cordobes, Spain Shabnam Farahmand, Finland Sergio Crovella, Italy Programme Committee Mojca Ciglarič, chair Bogdan Filipič Dunja Mladenič Niko Zimic Bojan Orel, Andrej Gams Franc Novak Rok Piltaver Franc Solina, Matjaž Gams Vladislav Rajkovič Toma Strle Viljan Mahnič, Mitja Luštrek Grega Repovš Tine Kolenik Cene Bavec, Marko Grobelnik Ivan Rozman Franci Pivec Tomaž Kalin, Nikola Guid Niko Schlamberger Uroš Rajkovič Jozsef Györkös, Marjan Heričko Stanko Strmčnik Borut Batagelj Tadej Bajd Borka Jerman Blažič Džonova Jurij Šilc Tomaž Ogrin Jaroslav Berce Gorazd Kandus Jurij Tasič Aleš Ude Mojca Bernik Urban Kordeš Denis Trček Bojan Blažica Marko Bohanec Marjan Krisper Andrej Ule Matjaž Kljun Ivan Bratko Andrej Kuščer Boštjan Vilfan Robert Blatnik Andrej Brodnik Jadran Lenarčič Baldomir Zajc Erik Dovgan Dušan Caf Borut Likar Blaž Zupan Špela Stres Saša Divjak Janez Malačič Boris Žemva Anton Gradišek Tomaž Erjavec Olga Markič Leon Žlajpah iii iv KAZALO / TABLE OF CONTENTS Delavnica projekta BATMAN / BATMAN Project Workshop ................................................................................... 1 PREDGOVOR / FOREWORD ................................................................................................................................. 3 PROGRAMSKI ODBORI / PROGRAMME COMMITTEES ..................................................................................... 4 Identification Of Novel Genetic Variants In Hidradenitis Suppurativa Patients Through The Investigation Of Familial Cases / Tricarico Paola Maura, Moura Ronald, Gratton Rossella, dos Santos Silva Carlos André, Brandão Lucas, Crovel a Sergio ......................................................................................................................... 5 Generation Of Animal And Human 3D Models Of Acne Inversa / Boufenghour Wacym, Flacher Vincent ............ 9 Development Of New Cellular Models To Identify Molecular Mechanisms In Hidradenitis Suppurativa / Nait- Meddour Cecile, Matar Rola, Boniotto Michele ................................................................................................ 11 Hidradenitis Suppurativa: From Clinic To Bench And Back / Marzano Angelo, Moltrasio Chiara, Genovese Giovanni ........................................................................................................................................................... 14 Disease Burden Of Hidradenitis Suppurativa And Assessment Of A Non-Invasive Treatment Option / von Stebut Esther .................................................................................................................................................... 17 An Overview of the BATMAN Platform / Vuk Zdenko, Bizjak Jani, Dovgan Erik, Gams Matjaž, Gradišek Anton .......................................................................................................................................................................... 19 Indeks avtorjev / Author index ................................................................................................................................ 23 v vi Zbornik 24. mednarodne multikonference INFORMACIJSKA DRUŽBA – IS 2021 Zvezek J Proceedings of the 24th International Multiconference INFORMATION SOCIETY – IS 2021 Volume J Delavnica projekta BATMAN BATMAN Project Workshop Urednika / Editors Sergio Crovella, Anton Gradišek http://is.ijs.si 4. oktober 2021 / 4 October 2021 Ljubljana, Slovenia 1 2 PREDGOVOR Na delavnici sodelujejo partnerji projekta ERA PerMed BATMAN in drugi zainteresirani znanstveniki. BATMAN je akronim za “Biomolecular Analyses for Tailored Medicine in Acne iNversa”, biomolekularne analize za personalizirano zdravljenje Acne Inversa. Cilj projekta, ki se je začel leta 2019, je priti do novih spoznanj in boljšega razumevanja mehanizmov kronične bolezni Acne Inversa, imenovane tudi Hidradenitis Suppurativa, in razviti ciljane metode zdravljenja. To bo pripomoglo k boljšemu življenju pacientov. Raznoliki konzorcij projekta sestavljajo partnerji s področij medicine, genetike, modelov tkiv in informacijskih tehnologij. Delavnica je tudi del letnega sestanka partnerjev konzorcija. Predsednika delavnice se distancirata od nagrad, ki so bile podeljene med Multikonferenco. Sergio Crovella in Anton Gradišek, predsednika delavnice FOREWORD This Workshop brings together the partners that collaborate on the ERA PerMed project BATMAN, as well as other interested parties. BATMAN stands as the acronym for “Biomolecular Analyses for Tailored Medicine in Acne iNversa”. The aim of the project that started in 2019 is to find new knowledge and better understanding of mechanisms of the chronic disease Acne Inversa, also called Hidradenitis Suppurativa, and to provide tailored treatment for the patients, thus improving their quality of life. The consortium is heterogeneous and brings together partners with experiences in the field of medicine, genetics, tissue models, and information technologies. This Workshop is also a part of the annual consortium meeting of the partners. Workshop chairs distance themselves from the awards that were handed out during the Multiconference. Sergio Crovella and Anton Gradišek, workshop chairs 3 PROGRAMSKI ODBOR / PROGRAMME COMMITTEE Sergio Crovella Anton Gradišek Paola Maura Tricarico 4 Identification of novel genetic variants in Hidradenitis Suppurativa patients through the investigation of familial cases Paola Maura Tricarico † Rossella Gratton Lucas Brandão Laboratory of Genetic Laboratory of Genetic Laboratory of Genetic Immunology, Institute for Immunology, Institute for Immunology, Institute for Maternal and Child Health – Maternal and Child Health – Maternal and Child Health – IRCCS “Burlo Garofolo”, Trieste, IRCCS “Burlo Garofolo”, Trieste, IRCCS “Burlo Garofolo”, Trieste, Italy; tricaricopa@gmail.com Italy; Italy; lucabrand@gmail.com rossella.gratton@burlo.trieste.it Ronald Moura † Sergio Crovella Laboratory of Genetic Carlos André dos Santos Department of Biological and Immunology, Institute for Silva Environmental Sciences, College Maternal and Child Health – Laboratory of Genetic of Arts and Sciences, University IRCCS “Burlo Garofolo”, Trieste, Immunology, Institute for of Qatar, Doha, Qatar Italy; Maternal and Child Health – sgrovella@qu.edu.qa ronald.rodriguesdemoura@burlo.t IRCCS “Burlo Garofolo”, Trieste, rieste.it Italy; carlos.biomedicina@gmail.com † These authors contributed equally to this article. ABSTRACT Hidradenitis suppurativa (HS), a chronic autoinflammatory refractory disease with recurrent skin lesions and wounds of Hidradenitis Suppurativa (HS) familial cases represent 40% of difficult resolution, currently represents an area of high-unmet the total cases observed. Current knowledge on the etio-clinical need. HS has multifactorial etiology that involves a pathogenesis of these cases is still poor; for this reason, we strict interplay between genetic factors, immune dysregulation, decided to investigate the genetic variants associated to this hormonal influence, bacterial colonization, impaired wound disease in 5 HS families. In 3 families we found single healing and environmental risk factors [1, 2]. Approximately nucleotide variation (SNV) in genes never associated with HS: 40% of patients with HS report a family history of the ZNF318, DCD, DSC3. In one family we found a new SNV in condition, and amongst these only about 10% present mutations in genes involved in the gamma NCSTN gene, one of the few genes already associated with HS. -secretase pathway, namely NCSTN, PSENEN and PSEN1 genes [3]. In another family, due to the low number of individuals The study of HS familial cases represents a tool identify novel analyzed, we did not find with certainty the SNV associated genetic factors, other than the genes of the gamma-secretase with the disease but we found three SNVs in PADI3, DSP and pathway, involved in the etio-pathogenesis of this complex KRTAP10-4 genes. Deepening knowledge on the genetic disease. Unfortunately, analyzing HS familial cases can be variants associated with these familial HS cases is a necessary sometimes difficult due to delayed diagnosis, absence of first step to unravel the disease etio-pathogenesis; in fact, to personal and family health history investigation, incomplete better understand the disease an integrated approach involving penetrance of the disease and also unwillingness to participate different OMICs is the right path to be followed. in the genetic study of other family members. Here we investigated 5 HS families aimed at identifying genetic KEYWORDS variants associated with the disease, using whole exome sequencing (WES). Hidradenitis suppurativa, familial cases, genetic variants, WES Patients with a positive family history of HS were recruited analysis. from January 2019 to May 2021 at the Dermatology Unit of the University of Milan (Italy) and at the Dermatology Service of “Hospital das Clinicas”, Recife, Brazil. All study participants signed a written informed consent after the approval by the Single Regional Ethical Committee of Friuli Venezia Giulia Permission to make digital or hard copies of part or all of this work for personal or (CEUR) (CEUR-2018-Sper-127-BURLO and CEUR-2020-Em-classroom use is granted without fee provided that copies are not made or 380) by the Area B Milan Ethics Committee (protocol no. distributed for profit or commercial advantage and that copies bear this notice and 487_2020) and by Ethical Committee of the Federal University the full citation on the first page. Copyrights for third-party components of this work must be honored. For all other uses, contact the owner/author(s). of Pernambuco (n. 3.048.719; 30/11/2018). Information Society 2021, 4-8 October 2021, Ljubljana, Slovenia Genomic DNAs have been extracted from saliva by using the © 2021 Copyright held by the owner/author(s). Oragene-DNA (Ottawa, Canada) kit following the manufacturer’s protocols. WES, with 100X of expected coverage, has been performed in outsourcing by Macrogen 5 Information Society 2021, 4-8 October 2021, Ljubljana, Slovenia P.M. Tricarico et al. (Seoul, Korea). WES analysis has been performed using the particularly highlighted by the increased flexibility of its C-InterOMICs Genome Pro software, as described in our previous terminal region. study [4]; WES results have been validated by Sanger In HS, a dysbiosis-driven aberrant activation of the innate Sequencing. immune system leading to excessive inflammatory responses, is thought to be partially induced by a marked dysregulation in In family 1 (11 HS patients and 36 healthy subjects) we found a antimicrobial peptides production, in particular DCD [6, 7]. rare missense single nucleotide variation (SNV) in the exon 4 of Indeed, in the skin of HS patients a significant down-regulation ZNF318 gene in heterozygosis (rs767801219). The SNV was of DCD expression has been observed [8, 9]. detected in heterozygosis in 17 family members comprising all In family 3 (4 HS patients and 1 control) we found a rare of the 11 individuals who initially declared to be affected by HS missense SNV at exon 10 of DSC3 gene in heterozygosis and additional 6 individuals that haven't been mentioned to (rs114245564) in all 4 HS patients (Figure 3). possess any sign of the disease (Figure 1). This identified SNV shows an autosomal dominant inheritance pattern with incomplete penetrance. Figure 1: Pedigree of the Family 1. 47 individuals adhered to the study, 11 of which declared to be affected by HS, and the genotype of the selected variant in ZNF318 gene (rs767801219). ZNF318 gene encodes the zinc finger 318 (ZNF318) protein Figure 3: Pedigree of the Family 3. 5 individuals adhered to involved in the regulation of the androgen receptor by acting the study, 4 of which declared to be affected by HS, the both as a co-repressor or co-activator in AR transactivation genotype of the selected variant in DSC3 gene (rs114245564) function. To date the effect of the SNV in the protein structure is hard to predict in silico due to the dimension of the protein DSC3 gene encodes Desmocollin-3 a desmosomal cadherin and the lack of a clearly defined structure, but the role of superfamily member, component of the transmembrane core of androgens in HS is well known and has been explored in desmosomes required for maintaining cell adhesion in the numerous observational and some interventional studies [5]. epidermis. The critical role of these desmosomal cadherins in In family 2 (2 HS patients and 1 control and 1 child) we found a epithelial integrity has been illustrated by their disruption in rare frameshift insertion in exon 4 of DCD gene in mouse models and human diseases. Alterations in the heterozygosis (rs538180888) in all 2 HS patients; this variant is expression and function of the desmosomal cadherins have been also present in the daughter, an 11-year-old child who begins to observed in severe autoimmune skin disease pemphigus, manifest relapsing inguinal furuncles (Figure 2). epidermolysis bullosa and hypotrichosis and recurrent skin vesicles [10, 11]. In family 4 (4 HS patients, 3 controls and 2 children), enrolled in Brazil, so with individuals showing a different genetic background when compared to the other Italian members of the analyzed families, we found a SNV in NCSTN gene exon 2 in heterozygosis (NM_015331:exon2:c.T131A) encoding a premature stop codon [NP_056146 1:p.(L44*)], in all 4 HS patients and also in the 2 children (11- and 16-year-old). To date, these 2 children do not show the disease, probably due to their young age (Figure 4). Figure 2: Pedigree of the Family 2. 4 individuals adhered to the study, 2 of which declared to be affected by HS, the genotype of the selected variant in DCD gene (rs538180888). DCD gene encodes Dermcidin, the most abundant antimicrobial peptide (AMP) present in human sweat. The identified frameshift variant disrupts the ORF of DCD and results in a 33 amino acid peptide having a completely altered sequence, if compared to the wild- type DCD-1(L) peptide. This affects both the N-terminal and the C-terminal partitions, hence impairing the activity of DCD. This mutant is characterized by a less Figure 4: Pedigree of the Family 4. 9 individuals adhered to compact structure and by an increased solvent accessibility, the study, 4 of which declared to be affected by HS, the genotype of the selected variant in NCSTN gene. 6 The investigation of familial cases allows the identification of Information Society 2021, 4-8 October 2021, Ljubljana, Slovenia novel genetic variants in Hidradenitis Suppurativa patients This genetic variant was not present in the Genome residues into citrullines. Deimination is implicated in many Aggregation Database (gnomAD) and therefore it was never physiological processes including keratinocyte biology and skin associated with HS; despite this, the NCSTN gene is one of the homeostasis. One example of deiminated protein is the fillagrin, few genes already associated with HS [3]. a key protein in the epidermal barrier function, expressed in the In family 5 (2 HS patients and 1 control) we found 25 SNVs in hair follicle. In addition to this, PADI3 gene may also play a genes expressed in the skin or by the immune system (Table 1). role in the cornification-related autophagy process of the epidermis. Uncombable Hair Syndrome 1 and Central Centrifugal Cicatricial Alopecia are diseases associated with Table 1: List of single nucleotide variations (SNVs) genes PADI3 gene [12]. expressed in the skin or by the immune system, found in 2 DSP encodes for Desmoplakin, an obligate and the most HS patients and not in the control of the family 5 abundant component of functional highly specialized adhesive intercellular junctions known as desmosomes. Desmosomes are Gene SNV Ref Alt abundant in districts that are continuously subjected to AQP9 rs1439722664 T C mechanical solicitations such as the epidermis and hair follicles, PHYKPL because they confer strong mechanical strength to tissues and rs559406393 C G ACSS2 contributing to the maintenance of tissue architecture and rs371982555 C T cohesiveness [13, 14]. Alopecia, palmo-plantar keratoderma, ARSK rs754905227 T A skin fragility woolly-hair syndrome, erythrokeratodermia, CRIP1 rs200883038 C A dilated cardiomyopathy, arrhythmogenic right ventricular MYH14 rs371244397 C T cardiomyopathy/dysplasia are disorders also connected to SMYD5 rs61755313 G A alteration in the expression and function of Desmoplakin [15]. VEGFA vi6.43777526 T G KRTAP10-4 encodes for Keratin Associated Protein 10-4, DHFR2 rs772191447 T C which are essential for the formation of a rigid and resistant hair TRPS1 rs61745721 T C shaft through their extensive disulfide bond cross-linking with HSPBP1 rs150486738 G A abundant cysteine residues of hair keratin. This gene plays an MAP3K4 important role in the keratinization pathway [16]. rs1477003192 T C Unfortunately, perhaps due to the low number of family PADI3 rs142129409 T A individuals analyzed, to date we do not have the ability to PPP1R3D rs377580619 G A identify with certainty the SNV associated with this HS familial SYNE1 rs34028822 G A case. ZNF692 rs201441689 C T ADPRHL2 rs139736291 A G Considering the findings obtained by analyzing some HS PTCD1 rs35556439 G A families, one with different genomic background with respect to COPB2 vi3.139379091 C T the others, we can state that HS familial cases are extremely DSP rs78652302 A T useful to investigate novel actors involved in this complex KRTAP10-4 rs782312294 G T disease, so the first need is to augment the number of families PRSS1 to be analyzed; secondly, to more deeply and precisely evaluate rs757111793 G A SCFD2 the role of the identified genetic factors, at least an integration rs79025139 C A with transcriptome is needed. To this end it is important to TRIM16 rs143877253 C A recall that when families are diagnosed and recruited, it should TTLL12 rs369903948 T C be envisaged, when possible and permitted by the ethical committee, a skin biopsy of lesional, pre-lesional and healthy Among these genes, the ones considered as possibly related to skin of the patients, to allow RNA extraction and consequent dermatologic disorders based on their functions are: PADI3, transcriptome analysis. DSP and KRTAP10-4 (Figure 5). As conclusive remarks, we should bear in mind that HS is a complex disease and that the genetics by itself is not able to completely unravel the disease etio-pathogenesis; an integrated approach involving different OMICs, such as genomics, transcriptomics and microbiomics etc. is the path to be followed to better understand the disease and consequently design possible tailored treatments. ACKNOWLEDGMENTS This work was supported by a Biomolecular Analyses for Tailored Medicine in AcneiNversa (BATMAN) project, funded by ERA PerMed, by a grant from the Institute for Maternal and Figure 5: Pedigree of the Family 5. 3 individuals adhered to Child Health IRCCS ‘Burlo Garofolo/Italian Ministry of the study, 2 of which declared to be affected by HS, the Health’ (RC16/ 2018), by a grant Interreg Italia-Slovenia, ISE-genotype of the selected variants in PADI3, DSP and EMH 07/2019 and by CNPq (311415/2020-2). KRTAP10-4 genes. REFERENCES PADI3 encodes for a member of the peptidyl arginine [1] Schell SL, Schneider AM, Nelson AM. Yin and Yang, 2021. A disrupted deiminase family of enzymes, which catalyze the post-skin microbiome and an aberrant host immune response in hidradenitis translational deimination of proteins by converting arginine 7 Information Society 2021, 4-8 October 2021, Ljubljana, Slovenia P.M. Tricarico et al. suppurativa. Exp Dermatol. (May, 2021). 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Int J Mol Androgens and Estrogens in Hidradenitis Suppurativa - A Systematic Sci. 2020 (Jan, 2020), 21:566. DOI: Review. Acta Dermatovenerol Croat. (Dec, 2016), 24:239-249. PMID: https://doi.org/10.3390/ijms21020566. 28128074. [13] Garrod D and Chidgey M, 2008. Desmosome structure, composition and [6] Schlapbach C, Yawalkar N and Hunger RE, 2009. Human beta-defensin-function. Biochim Biophys Acta. (Mar, 2008), 1778:572-587. DOI: 2 and psoriasin are overexpressed in lesions of acne inversa. J Am Acad https://doi.org/10.1016/j.bbamem.2007.07.014. Dermatol. (Jul, 2009), 61:58-65. DOI: [14] Kurzen H, Moll I, Moll R, Schäfer S, Simics E, Amagai M, Wheelock https://doi.org/10.1016/j.jaad.2008.12.033. MJ and Franke WW, 1998. Compositionally different desmosomes in the [7] Wolk K, Warszawska K, Hoeflich C, Witte E, Schneider-Burrus S, Witte various compartments of the human hair follicle. Differentiation. (Sep, K, Kunz S, Buss A, Roewert HJ, Krause M, Lukowsky A, Volk HD, 1998), 63:295-304. DOI: https://doi.org/10.1046/j.1432- Sterry W and Sabat R, 2011. Deficiency of IL-22 contributes to a chronic 0436.1998.6350295.x. inflammatory disease: pathogenetic mechanisms in acne inversa. J [15] Paller AS, Czarnowicki T, Renert-Yuval Y, Holland K, Huynh T, Sadlier Immunol. (Jan, 2011), 186:1228-1239. DOI: M, McAleer MA, Tran G, Geddes GC, Irvine AD and Guttman-Yassky https://doi.org/10.4049/jimmunol.0903907. E, 2018. The spectrum of manifestations in desmoplakin gene (DSP) [8] Shanmugam VK, Jones D, McNish S, Bendall ML and Crandall KA, spectrin repeat 6 domain mutations: Immunophenotyping and response to 2019. Transcriptome patterns in hidradenitis suppurativa: support for the ustekinumab. J Am Acad Dermatol. (Mar, 2018), 78:498-505.e2. DOI: role of antimicrobial peptides and interferon pathways in disease https://doi.org/10.1016/j.jaad.2017.10.026. pathogenesis. Clin Exp Dermatol. (Dec, 2019), 44:882-892. DOI: [16] https://www.genecards.org/cgi-bin/carddisp.pl?gene=KRTAP10- https://doi.org/10.1111/ced.13959. 4&keywords=KRTAP10%5C-4 [9] Coates M, Mariottoni P, Corcoran DL, Kirshner HF, Jaleel T, Brown DA, Brooks SR, Murray J, Morasso MI and MacLeod AS, 2019. The 8 Generation of animal and human 3D models of Acne Inversa Wacym Boufenghour Dr. Vincent Flacher Laboratory I2CT / CNRS UPR3572 Laboratory I2CT / CNRS UPR3572 Institut de Biologie Moléculaire et Institut de Biologie Moléculaire et Cellulaire Cellulaire Strasbourg, France Strasbourg, France w.boufenghour@cnrs-ibmc.unistra.fr v.flacher@cnrs-ibmc.unistra.fr ABSTRACT human skin cells. Our objective is to repurpose this skin model by either using keratinocytes from AI patients producing a Acne Inversa (AI; Verneuil’s Disease, Hidradenitis Suppurativa) defective desmoplakin, or HaCaT genetically modified through is a chronic inflammatory condition affecting the hair follicles in CRISPR-Cas9 to carry mutations for the gamma-secretase moist areas of the body (inguinal folds, scrotum, pubic area). As complex. We expect those mutated epithelial cells to produce an currently understood, AI is triggered by a hair canal obstruction, epidermis and influence MoDCs introduced in the scaffold. The leading to follicle bursting and entry of cellular debris and final purpose is to induce an inflammatory response close to AI bacteria into the dermis, resulting in a powerful and persistent ex vivo. inflammation [1]. Over time, some patients develop severe scarring of the inflamed areas, leading to surgical removal of the We tested different scaffold seeding conditions using healthy affected skin areas. These events might be triggered or human fibroblasts, keratinocytes and MoDCs. We also evaluated exacerbated by bacterial infection or epithelial barrier non-modified HaCaT cells instead of keratinocytes. The weakening. Thus far, only mutations in genes encoding the resulting models were frozen after up to 6 weeks of culture, gamma-secretase) have been found to underlie familial forms of sliced and stained with various epithelial and immune markers. AI. Despite promising results, cell seeding and fibroblast Our laboratory aims at creating ex vivo and in vivo models to proliferation were inconsistent. We assume this to result from the better study AI pathogenesis, which are still lacking. To achieve scaffold manufacturing process, which we are currently seeking this, we are developing full-thickness skin models built from to optimize. cells of healthy donors and patients, as well as murine models bearing AI-related defects for autophagy in hair follicles. In 2 Reproducing auto-inflammatory addition, we participate in an effort to unravel the potential characteristics of acne inversa in a mouse involvement of B cells, a specific yet poorly studied aspect of AI. model. KEYWORDS Acne inversa, human 3D skin model, mouse, hair follicle, Dr. Michele Boniotto (Créteil, France) found that AI patient inflammation, immunology, autophagy, B cells mutations of the gamma secretase complex results in autophagy impairment in vitro. This prompted us to breed a mouse model to investigate this matter further in vivo, by crossing 1 Human reconstructed skin model with Sox9creERT2 and Atg5flox/- strains. Since Sox9 is an important primary fibroblasts and epidermal cells from transcription factor driving hair follicle stem cells (HFSC) either healthy donors or immortalized cell development and function [4, 5], the resulting strain is expected lines (HaCaT) to lack functional autophagy in the infundibulum of the hair follicle. We expect that autophagy loss of function in HFSC to produce a barrier defect and a stronger immune infiltrate, as a Previous work from our team allowed the creation of an immunocompetent skin model based on a collagen scaffold [2, result of impaired processing of apoptotic hair follicle cells 3], monocyte-derived dendritic cells (MoDCs) and primary (efferocytosis) [6]. Two consecutive depilations were performed in the course of two Permission to make digital or hard copies of part or all of this work for personal or weeks, which may lead to hair occlusions. Skin samples were classroom use is granted without fee provided that copies are not made or distributed for profit or commercial advantage and that copies bear this notice and the full harvested and studied by flow cytometry and immunochemistry citation on the first page. Copyrights for third-party components of this work must staining. Total skin digestion six hours after the second be honored. For all other uses, contact the owner/author(s). Information Society 2021, 4-8 October 2021, Ljubljana, Slovenia depilation showed a stronger infiltration of neutrophils and © 2021 Copyright held by the owner/author(s). monocytes in the dermis of knock-out mice (Sox9creERT2 Atg5flox/-) compared to wild-type (Atg5flox/+) and littermates 9 Information Society 2021, 4-8 October 2021, Ljubljana, Slovenia W. Boufenghour et al. (Sox9creERT2 Atg5flox/+). Infiltration was resolved after one REFERENCES week in all animals. Further interpretation requires confirmation [1] Vossen Allard R. J. V., van der Zee Hessel H., Prens Errol P. (2018), of these preliminary results by additional experiments. Next, we Hidradenitis Suppurativa: A Systematic Review Integrating Inflammatory Pathways Into a Cohesive Pathogenic Model, Frontiers plan to directly inhibit gamma secretase and autophagy function in Immunology, 9:1664-3224. individually or simultaneously in C57BL/6 mice. https://doi.org/10.3389/fimmu.2018.02965 [2] Bechetoille, N., Vachon, H., Gaydon, A., Boher, A., Fontaine, T., Schaeffer, E., Decossas, M., André-Frei, V. and Mueller, C.G. (2011), A new organotypic model containing dermal-type macrophages. 3 B cell populations in blood samples from Experimental Dermatology, 20: 1035-1037. https://doi.org/10.1111/j.1600-0625.2011.01383.x families affected by acne inversa [3] Muller, Q., Beaudet, M. J., De Serres-Bérard, T., Bellenfant, S., Flacher, V., & Berthod, F. (2018). Development of an innervated tissue-engineered skin with human sensory neurons and Schwann cells Dr. Sergio Crovella (Trieste, Italy) has identified a familial differentiated from iPS cells. Acta biomaterialia, 82, 93–101. https://doi.org/10.1016/j.actbio.2018.10.011 mutation of the transcription factor Znf318 in AI patients of an [4] Nowak, J. A., Polak, L., Pasolli, H. A., & Fuchs, E. (2008). Hair Italian family (unpublished data). It was previously published follicle stem cells are specified and function in early skin that Znf318 is necessary for IgD expression by B cells in mouse morphogenesis. Cell stem cell, 3(1), 33–43. https://doi.org/10.1016/j.stem.2008.05.009 models [7, 8]. Interestingly, AI is among the few dermatological [5] Vidal, V. P., Chaboissier, M. C., Lützkendorf, S., Cotsarelis, G., Mill, conditions that show prominent B cell infiltrates in lesions [9, P., Hui, C. C., Ortonne, N., Ortonne, J. P., & Schedl, A. (2005). Sox9 Is Essential for Outer Root Sheath Differentiation and the Formation 10]. of the Hair Stem Cell Compartment. Current Biology, 15(15), This prompted us to investigate the role of B cells in AI 1340‑1351. https://doi.org/10.1016/j.cub.2005.06.064 pathogenesis. As a preliminary work, we intend to identify [6] Mesa, K. R., Rompolas, P., Zito, G., Myung, P., Sun, T. Y., Brown, S., Gonzalez, D. G., Blagoev, K. B., Haberman, A. M., & Greco, V. variations in B cell subsets among PBMCs from patients with (2015). Niche-induced cell death and epithelial phagocytosis regulate familial or sporadic forms of AI. Our cytometry panel allows us hair follicle stem cell pool. Nature, 522(7554), 94‑97. https://doi.org/10.1038/nature14306 to study the naive, memory and plasmablast B cell populations [7] Enders, A., Short, A., Miosge, L. A., Bergmann, H., Sontani, Y., in patient blood. Bertram, E. M., Whittle, B., Balakishnan, B., Yoshida, K., Sjollema, G., Field, M. A., Andrews, T. D., Hagiwara, H., & Goodnow, C. C. (2014). Zinc-finger protein ZFP318 is essential for expression of IgD, Covid-19 crisis prevented blood sampling from Italian patients, the alternatively spliced Igh product made by mature B lymphocytes. who may show B-cell related defects related to their Znf318 Proceedings of the National Academy of Sciences, 111(12), 4513‑4518. https://doi.org/10.1073/pnas.1402739111 mutation. Yet, we analyzed healthy and diseased individuals of [8] Pioli, P. D., Debnath, I., Weis, J. J., & Weis, J. H. (2014). Zfp318 affected families from Innsbruck, Austria, for which whole-exon Regulates IgD Expression by Abrogating Transcription Termination within theIghm/IghdLocus. The Journal of Immunology, 193(5), sequencing is not yet available. So far, blood B cells of 7 patients 2546‑2553. https://doi.org/10.4049/jimmunol.1401275 from 3 different families have been studied. Currently [9] Hoffman, L. K., Tomalin, L. E., Schultz, G., Howell, M. D., Anandasabapathy, N., Alavi, A., Suárez aggregated data identified patients that deviate from usual -Fariñas, M., & Lowes, M. A. (2018). Integrating the skin and blood transcriptomes and serum population percentages, although we require additional proteome in hidradenitis suppurativa reveals complement unaffected people from the same families to confirm our dysregulation and a plasma cell signature. PLOS ONE, 13(9), e0203672. https://doi.org/10.1371/journal.pone.0203672 analyses. Raw PBMCs have also been frozen, which will be [10] Musilova, J., Moran, B., Sweeney, C., Malara, A., Zaborowski, A., assayed for T cell responses and used to produce MoDC for our Hughes, R., Winter, D., Fletcher, J., & Kirby, B. (2020). Enrichment of Plasma Cells in the Peripheral Blood and Skin of Patients with 3D skin models. Hidradenitis Suppurativa. Journal of Investigative Dermatology, 140(5), 1091–1094.e2. https://doi.org/10.1016/j.jid.2019.08.453 DISCUSSION Despite significant delays related to COVID-19 for animal breeding and interruption of cell cultures for more than 3 months, we have improved our 3D scaffold production method and achieved successful seeding with human-derived cells, including MoDCs. We managed to establish protocols and produce preliminary results on the in vivo studies in the mice, and have plans to go more in depth in the future by studying systemic gamma-secretase inhibition. Finally, our analyses of AI patients in Austria will be interpreted in the light of their upcoming whole exome sequencing data, and extended by samples from Italian patients with Znf318 mutation. ACKNOWLEDGMENTS The authors would like to thank Dr. Michele Boniotto (Créteil, Frnce), Dr. Sergio Crovella, Dr. Paola Tricarico (Trieste, Italy) Pr. Mathias Schmuth, Dr. Gudrun Ratzinger, Wolfram Jaschke (Innsbruck Hautklinik, Austria), Layal Doumard, Delphine Lamon and Fabien Lhericel (Strasbourg, France). 10 Development of new cellular models to identify molecular mechanisms in Hidradenitis Suppurativa Cecile Nait-Meddour † Rola Matar Michele Boniotto IMRB Team Leboyer IMRB Team Leboyer IMRB Team Leboyer UPEC/IMRB UPEC/IMRB UPEC/IMRB Creteil France Creteil France Creteil France cecile.nait-meddour@inserm.fr rola.matar@inserm.fr michele.boniotto@inserm.fr ABSTRACT distribution and hair follicle anatomy, but important genes such as DCD identified in a HS family by our consortium doesn’t have No satisfactory in-vivo and in-vitro models to recapitulate a homologous in the mouse. Hidradenitis Suppurativa (HS) hallmarks have been developed so far. The first transgenic Ncstn KO mice model, engineered Ex vivo models using patients lesional skins have also been after the finding that g-secretase mutations were associated with developed [4]. In fact, Vossen et al. [5] cultured punch biopsies HS in several families, lacked important HS features such as skin from HS patients showing a major contribution of IL-1 in skin inflammation, abscess formation, fistulas, and scarring. In -vitro, inflammation in HS. Moreover, these Authors were able to test the use of skin explants has helped in the identification of the IL-different drugs to tame skin inflammation showing the 1 contribution to HS skin inflammation in HS, but this technique effectiveness of the anti-TNF-a therapy. depends on skin biopsies availability. Even if this ex-vivo model can be used to test a candidate For these reasons we have developed different models to obtain treatment, specific limitations make this model useless for skin cells and skin organoids from Induced Pluripotent Stem cell precision medicine. In fact, different genetic variants seem to lines carrying HS-associated mutations cause the disease, so a skin model for each patient (or family) should be developed. Our Team is developing new cellular models to identify the main biological pathways affected in HS and 3D models to be used to KEYWORDS test novel candidate drugs. We are making use of hair follicle CRISPR/Cas9, Induced Pluripotent Stem Cells, Outer root epithelial cells isolated from selected patients to build 3D sheath epithelial cells, Skin Organoids, keratinocytes, sebocytes reconstituted immunocompetent skins in collaboration with Dr. Flacher: these models will allow the study of the cross-talk among skin cells and immune cells 1 INTRODUCTION AND RESULTS At the same time, we have developed skin organoids bearing hair Hidradenitis suppurativa (OMIM#142690; HS) is a chronic follicles from Induced Pluripotent Stem cells obtained from inflammatory disease involving hair follicles that presents with patients with specific candidate mutations (Figure 1). By using painful nodules, abscesses, fistulae, and hypertrophic scars, the CRISPR/Cas9 methodology we have been able to correct the typically occurring in apocrine gland bearing skin [1]. Adequate candidate mutation and obtain isogenic cell lines differing only models reflecting hallmarks of HS pathogenesis are a for the selected mutation. IPSCs have been differentiated in prerequisite to not only better characterize the molecular activity CD200+/ITGA6+ hair follicle stem cells that could be further of genetic mutations in HS, but also to allow the discovery and differentiated in TP63+/CK14+ keratinocytes or of therapeutic targets in personalized approaches to cure the CK7+/MUC1+/PPARG+ sebocytes. disease. About 10% of HS patients present mutations in three of the four components of the gamma-secretase complex, namely NCSTN, PSEN1 and PSENEN with most of the mutations found in NCSTN [2]. These findings led to the analysis of the NCSTNflox/flox;K5-Cre mice that showed some HS hallmarks such as follicular hyperkeratosis and inflammation [3]. Unfortunately, mica and humans differ not only in hair Permission to make digital or hard copies of part or all of this work for personal or classroom use is granted without fee provided that copies are not made or distributed for profit or commercial advantage and that copies bear this notice and the full citation on the first page. Copyrights for third-party components of this work must be honored. For all other uses, contact the owner/author(s). Information Society 2021, 4-8 October 2021, Ljubljana, Slovenia © 2021 Copyright held by the owner/author(s). 11 Information Society 2021, 4-8 October 2021, Ljubljana, Slovenia C. Nait-Meddour et al. As we have already shown a defect in lysosomes in NCSTN deficient HaCaT cells, we are studying the lysosome structures in TP63+/CK14+ keratinocytes derived from mutated and corrected using lysosomal markers (Figure 3). Figure 1: Skin organoids bearing hair follicles from IPSCs IPSCs obtained from an HS patient with a novel mutation in NCSTN and presenting with HS and DDD were cultivated as Figure 3: Lysosome distribution in KC obtained from skin described by Lee et al. [6] for 140 days and skin organoids organoids bearing hair follicles obtained from a mutated and corrected clone. Study of lysosome distribution in mutated and corrected From the skin organoids, thanks to a collaboration with StemCell keratinocytes using lysosomal markers CD63, LAMP1 and Technologies, we have been able to isolate and cultivate melanosomes degradation (Pigment) TP63+/CK14+ keratinocytes (Figure 2) 2 OUTLOOK TP63 CK14 Skin organoids will be analyzed by immunofluorescence and DAPI immunohistochemistry. In addition, we plan to understand the activity of NCSTN mutation in skin organoids maturation by performing single cell RNA sequencing (Sc-RNAseq). Our hypothesis is that a g-secretase impaired activity skews the differentiation of hair follicle stem cells towards the epithelial keratinocytes. We do expect to see smaller or absent sebaceous glands in our skin organoids and an enlarged population of outer root and inner root Figure 2: TP63+/CK14+ Keratinocytes isolated from skin sheath keratinocytes. organoids We plan to carry on the same experiments with IPCSs cell from a patient with a novel ZNF318 mutation. ZNF318 is Keratinocytes were obtained after dispase I digestion of skin involved in Androgen Receptor (AR) signaling [7, 8], that has a organoids and cultivated in StemCell Technologies major role in sebocytes differentiation [9]. We do expect that a Keratinocyte Medium. perturbed AR signaling will skew the differentiation of hair follicle stem cells towards the keratinocyte population, still affecting sebaceous gland development. IPSCs will be differentiated in 2D in CD200+/ITGA6+ hair follicle stem cells and treated to become CK7+/MUC1+/PPARG+ sebocytes (Figure 4) to understand what the activity of the novel ZNF318 mutation is. IPSCs-derived keratinocytes and sebocytes will be provided to Dr. Flacher’s team to build 3D immunocompetent skins. 12 Development of new cellular models Information Society 2021, 4-8 October 2021, Ljubljana, Slovenia REFERENCES [1] G. B. Jemec, “Clinical practice. Hidradenitis suppurativa,” N Engl J Med, vol. 366, no. 2, pp. 158-64, Jan 12, 2012. [2] S. Duchatelet, S. Miskinyte, M. Delage, M. N. Ungeheuer, T. Lam, F. Benhadou, V. Del Marmol, A. Vossen, E. P. Prens, O. Cogrel, M. Beylot-Barry, C. Girard, J. Vidil, O. Join-Lambert, M. Parisot, P. Nitschke, S. Hanein, S. Fraitag, H. H. Van der Zee, D. Bessis, G. Damiani, A. Altomare, Y. H. Liao, G. Nikolakis, C. C. Zouboulis, A. Nassif, and A. Hovnanian, “Low Prevalence of GSC Gene Mutations in a Large Cohort of Predominantly Caucasian Patients with Hidradenitis Suppurativa,” J Invest Dermatol, Mar 3, 2020. [3] J. Yang, L. Wang, Y. Huang, K. Liu, C. Lu, N. Si, R. Wang, Y. Liu, and X. Zhang, “Keratin 5-Cre-driven deletion of Ncstn in an acne inversa-like mouse model leads to a markedly increased IL-36a and Sprr2 expression,” Front Med, vol. 14, no. 3, pp. 305-317, Jun, 2020. [4] C. C. Zouboulis, “Ex vivo human models of hidradenitis suppurativa/acne inversa for laboratory research and drug screening,” Br J Dermatol, vol. 181, no. 2, pp. 244-246, Aug, 2019. [5] A. Vossen, K. R. van Straalen, E. F. Florencia, and E. P. Prens, “Lesional Inflammatory Profile in Hidradenitis Suppurativa Is Not Solely Driven by IL-1,” J Invest Dermatol, vol. 140, no. 7, pp. 1463-1466 e2, Jul, 2020. [6] J. Lee, C. C. Rabbani, H. Gao, M. R. Steinhart, B. M. Woodruff, Z. E. Pflum, A. Kim, S. Heller, Y. Liu, T. Z. Shipchandler, and K. R. Koehler, Figure 4: CK7+/MUC1+/PPARG+ sebocytes differentiated “Hair-bearing human skin generated entirely from pluripotent stem cells,” from IPSCs. Sebocytes were obtained from IPSCs after 22 Nature, vol. 582, no. 7812, pp. 399-404, 2020. days in Sebocyte Culture Medium. [7] M. Ishizuka, H. Kawate, R. Takayanagi, H. Ohshima, R. H. Tao, and H. Hagiwara, “A zinc finger protein TZF is a novel corepressor of androgen receptor,” Biochem Biophys Res Commun, vol. 331, no. 4, pp. 1025-31, ACKNOWLEDGMENTS Jun 17, 2005. [8] R. H. Tao, H. Kawate, K. Ohnaka, M. Ishizuka, H. Hagiwara, and R. This work was supported by a Biomolecular Analyses for Takayanagi, “Opposite effects of alternative TZF spliced variants on Tailored Medicine in Acne iNversa (BATMAN) project, funded androgen receptor,” Biochem Biophys Res Commun, vol. 341, no. 2, pp. by ERA PerMed and by a “Starting Grant” from IMRB. 515-21, Mar 10, 2006. [9] C. Barrault, J. Garnier, N. Pedretti, S. Cordier-Dirikoc, E. Ratineau, A. Deguercy, and F. X. Bernard, “Androgens induce sebaceous differentiation in sebocyte cells expressing a stable functional androgen receptor,” J Steroid Biochem Mol Biol, vol. 152, pp. 34-44, Aug, 2015. 13 Hidradenitis suppurativa: from clinic to bench and back Angelo Marzano Chiara Moltrasio Giovanni Genovese Dermatology Unit Dermatology Unit Dermatology Unit Fondazione IRCCS Ca’ Granda Fondazione IRCCS Ca’ Granda Fondazione IRCCS Ca’ Granda OMP, Milan, Italy OMP, Milan, Italy OMP, Milan, Italy angelo.marzano@unimi.it moltrasiochiara@gmail.com giovgenov@gmail.com ABSTRACT and gluteal ones [1]. More recently, Van der Zee et al. proposed six different phenotypes, including the regular, frictional Hidradenitis suppurativa (HS) is a chronic inflammatory furuncle, scarring folliculitis, conglobata, syndromic and ectopic disease presenting with nodules, abscesses, and fistulas on the types [2]. Additional clinical phenotypes and cluster apocrine gland-bearing skin. HS may be classified as sporadic, classifications have also been reported [3-5], but a definitive familial or syndromic (PASH, PAPASH, PASH/SAPHO consensus has not been reached and any of these classifications overlapping), the latter one being rare and characterized by a addresses a prediction of therapeutic outcome. IHS4 constellation of conditions regarded as autoinflammatory in (International Hidradenitis Suppurativa Severity Score System) their origin. is a validated tool for the severity assessment of HS and is arrived at by the number of nodules BAT2021 aims to bring together medical, genetic, experimental and lifestyle data to create holistic health records (HHR), which (multiplied by 1) plus the number of abscesses (multiplied by 2) will allow us to build a tailored approach of each patient. plus the number of draining tunnels (multiplied by 4). A total score of 3 or less signifies mild, 4-10 means moderate and 11 or The inclusion criteria for patient enrollment are the compliance higher correspond to severe disease [6]. to the diagnostic criteria for HS; patient’s demographics, HS has a profound impact on patients and their family life, clinical signs, anatomic phenotype classification, lifestyle leading to a high extent of emotional and physical distress, with habits, severity classification and treatment (former and current) social embarrassment, isolation, and depression [7]. With a are documented. prevalence in Europe varying between 0.3% and 1% [8], and a diagnosis often underestimated and usually delayed for 7.2 ± DNA/RNA obtained from biological samples (predominantly 8.7 years [9], HS is not a rare disease. saliva and skin biopsies) of HS patients will be analysed by HS is associated with several other disorders: i) autoimmune or whole exome sequencing, whole genome genotyping SNPs inflammatory comorbidities, particularly inflammatory bowel arrays and transcriptomics. Clinical and molecular data will be diseases, ii) rheumatologic diseases, such as seronegative stored into a special platform developed for the purpose of the spondyloarthropathies and Adamantiades– Behçet disease project and will be analysed using advanced algorithms of spondylarthritis and iii) malignancies, where the most severe artificial intelligence to propose a novel stratification method complication is the development of squamous cell carcinoma in that clinicians can use in daily clinical practice. areas of chronically diseased HS skin. Other comorbidities associated with HS include obesity, dyslipidemia, diabetes KEYWORDS mellitus, metabolic syndrome, hypertension, cardiovascular disease, secondary amyloidosis, lymphedema, polycystic ovary Hidradenitis suppurativa, clinical practice, research workflow, syndrome and sexual dysfunction. Finally, HS is also associated whole-exome sequencing, whole genome genotyping SNPs with mental comorbidity and psychosocial impairments [10]. HS arrays, transcriptomic, stratification, genotype-phenotype is usually a sporadic disease but may more rarely occur as a correlation, therapeutic outcomes familial disorder [11]. In a minority of patients, HS can present in combination with other diseases as a complex clinical syndrome. The main autoinflammatory syndromes characterized 1 Clinical background by the presence of HS are pyoderma gangrenosum (PG), acne Hidradenitis suppurativa (HS), also known as acne inversa, is a and suppurative hidradenitis (PASH), pyogenic arthritis, PG, chronic, inflammatory, recurrent, debilitating skin disease (of the acne and suppurative hidradenitis (PAPASH), psoriatic arthritis, terminal hair follicle), clinically characterized by inflammatory PG, acne and suppurative hidradenitis (PsAPASH), pustular nodules that progress into abscesses and draining tunnels with psoriasis, arthritis, PG, synovitis, acne and suppurative foul smelling. Three main clinical HS phenotypes have been hidradenitis (PsAPSASH) and PG, acne, suppurative proposed, namely the classic or axillary- mammary, follicular hidradenitis, and ankylosing spondylitis (PASS) [12]. However, HS can also occur in the context of complex syndromes such as Permission to make digital or hard copies of part or all of this work for personal or Familial Mediterranean Fever (FMF), synovitis, acne, pustulosis, classroom use is granted without fee provided that copies are not made or distributed hyperostosis and osteitis (SAPHO), follicular occlusion for profit or commercial advantage and that copies bear this notice and the full syndrome, Down syndrome, Keratitis-ichthyosis-deafness (KID) citation on the first page. Copyrights for third-party components of this work must syndrome, Dowling-Degos disease and Bazex-Dupré- Christol be honored. For all other uses, contact the owner/author(s). Information Society 2021, 4-8 October 2021, Ljubljana, Slovenia syndrome [13]. © 2021 Copyright held by the owner/author(s). Risk factors such as smoking, obesity and other lifestyle triggers have been linked to HS onset, while genetic factors are considered to play a crucial role in HS etiopathogenesis [14]. 14 Information Society 2021, 4-8 October 2021, Ljubljana, Slovenia A. Marzano et al. 30% of HS patients report a family history of HS; mutations in member affected is very useful for determining the patterns of γ-secretase genes (NCSTN, PSENEN and PSEN1) have been disease inheritance. identified as the most common genetic changes involved in HS All biological samples are collected, stored, and used in familial cases and these variants lead to an impairment of Notch agreement with the ethical and research guidelines set. Currently, signaling. Notch signaling pathway dysregulation results in an we have collected saliva from 200 HS patients through Oragene alteration in the proliferation and differentiation of keratinocytes DNA collection Kit (for human DNA) that allows for a high-leading to disruption of the normal hair follicle cycle and the quality human DNA to assess biomarkers and genetic variants formation of follicular cysts, typical for HS [15]. Our group associated to HS, its severity and response to biologic therapy. In recently hypothesized HS as a member of neutrophilic collaboration with IRCCS Burlo Garofolo of Trieste, we have dermatoses based on the elevated concentration of the cytokines analyzed through Whole Exome Sequencing, 12 syndromic IL-1β and IL-17 in skin lesions [16]. Moreover, some of our patients (PASH, PAPASH, PASH/SAPHO collaborators deeply involved in this project have also identified patients with HS occurring in the context of autoinflammatory overlapping) and in the first report, we have demonstrated syndromes, showing that PASH and PAPASH patients bear genetic variants involving genes regulating the keratinization genetic variants in genes coding for proteins of the process and vitamin D metabolism, suggesting that a inflammasomes such as PSTPIP1, MEFV, NOD2 and NLRP3 dysregulation of these two pathways may contribute to the HS [17]. Moreover, the up regulation of pro- inflammatory pathogenesis. Vitamin D has been predicted as able to regulate cytokines/chemokines in both lesional skin and serum are skin homeostasis by controlling proliferation and differentiation involved in the multifactorial HS pathogenesis [18]. With several of hair follicle and the low levels of vitamin D observed in all new gene mutations coming into play, such as those involved in studied patients support the idea that vitamin D insufficiency the keratinization pathways [19], on the background of a could be involved in PASH and PAPASH pathogenesis. dysregulated innate immune response to commensal microbes We have also recruited 9 familial cases of HS, two of which in and alterations in the skin microbiome as well, HS can be collaboration with IRCCS Burlo Garofolo of Trieste and the regarded as a multifactorial, polygenic autoinflammatory disease Italian Association of HS patients, respectively. Genetic analyses [18]. of HS familial cases and their family members are ongoing. Medical treatments in HS are aimed at reducing incidence and Our group has collected HS skin biopsies from lesional, flares thus improving HS patients’ quality of life. Mild cases are perilesional and unaffected tissue (approximately 2 cm from the usually treated by topical antibiotics having anti- inflammatory lesional skin) from the same anatomical region. Important is i) to properties. Widespread disease is treated by systemic antibiotics take biopsies from different kind of HS lesions, including and most severe cases by biologics such as adalimumab (anti-abscesses, plaques and fistulae (in the same patient, if it is TNFα), currently the only biologic approved by the United States possible); ii) smaller lesions (up to 1 cm in diameter) such as Food and Drug Administration [20] and by European Medicines cysts and inflammatory and non-inflammatory nodules, should Agency for treatment of HS [20,21]. be completely excised while a deep biopsy (extending to Surgical resection of irreversibly damaged skin is often required, subcutaneous tissue) should be made from abscesses and fistulae but often leads to functional impairments [20]. Different clinical and iii) typical sites, such as axillary or inguinal folds as well as trials for biologics targeting IL-17, IL-1 (alpha and beta), IL-36 anogenital area should be chosen for taking biopsy but and Janus kinase (JAK) 1 signaling response are currently having samples also from atypical sites, i.e. dorsum or cervical ongoing, but simple outcome measures or novel biological region as well as foruncles on different areas of the body, could models are demands to measure the efficacy of treatments [22]. be of interest. Skin samples has been subdivided into two parts, one of which for conventional histology (formalin-fixed, paraffin- embedded) 2 Patient’s enrollment and biological samples and the other one frozen for additional studies collection (immunohistochemistry, protein array, real - time PCR). An additional skin samples is taken and stored in Rna ladder for Acting as one of the clinical partners of the project, Fondazione transcriptomic analyses. IRCCS Ca’ Granda Ospedale Maggiore Policlinico of Milan has For functional and validation studies, we have performed hair a large outpatient clinic with specialization in HS. The inclusion follicle pick up according to the following procedure: a firm pull criteria for patient enrollment are the compliance to the motion with forceps must be performed at the base of the hair. diagnostic criteria for HS [23]. Patient’s demographics, clinical Only plucked hair in the anagen phase (minimum of five from signs, anatomic phenotype classification, lifestyle habits, each subject) contain enough keratinocytes for a successful severity classification and treatments (former and current) are culture initiation. The hair has been plucked from the occipital documented. For the data documentation, the REDCap platform and temporal scalp regions but facial hair types like beard, is used. eyebrow, or hair from the nose can be used. The hair shaft has The study population include approximately 300 patients with been cutted slightly behind the follicle with sterile scissors moderate-to-severe HS, of which most are sporadic. 6% of resulting in an approximate 5 mm long piece consisting mainly patients have a HS positive family history and 14 patients present of the follicle. The plucked hairs were stored in a tube filled with a HS syndromic form (4 PASH patients, 3 PAPASH, 5 5 mL Defined keratinocytes-SFM medium (DKSFM; Gibco – PASH/SAPHO overlapping, 1 SAPHO and 1 patient with Thermo Fisher Scientific, Switzerland) at room temperature [24]. PASS). Before biological samples collection, all patients and their relatives provide written informed consent for genomic analysis 3 Conclusions (protocol no. 487_2020) and receive pre-test genetic counselling in accordance with guidelines; indeed, the occurrence of the The comparison of the results obtained from DNA/RNA same condition among family members is a key factor to sequencing between patients and controls will highlight consider. Pedigree analysis of the families with more than one possible causative genes and signalling pathways. The possible detection of genotype-phenotype correlations will allow a more 15 Hidradenitis suppurativa: from clinic to bench and back Information Society 2021, 4-8 October 2021, Ljubljana, Slovenia exhaustive and precise clinical patient stratification which, in [13] Garcovich S, Genovese G, Moltrasio C, Malvaso D, Marzano AV. PASH, PAPASH, PsAPASH, and PASS: The autoinflammatory syndromes of addition to the existing pharmacogenetic data banks, will help hidradenitis suppurativa. (2021). Clin Dermatol, 39(2):240-247. doi: the development of new effective drugs and a future 10.1016/j.clindermatol.2020.10.016. individualized treatment of HS patients. [14] Sabat R, Jemec GBE, Matusiak Ł, Kimball AB, Prens E, Wolk K. Hidradenitis suppurativa. (2021). Nat Rev Dis Primers, 6(1):18. doi: 10.1038/s41572-020-0149-1 ACKNOWLEDGMENTS [15] Wang Z, Yan Y, Wang B. γ-Secretase Genetics of Hidradenitis Suppurativa: A Systematic Literature Review. (2020). Dermatology, 1-7. The authors would like to thank Prof. Sergio Crovella and Dr. doi: 10.1159/000512455. Epub ahead of print. Paola Tricarico (Trieste, Italy), Dr. Michele Boniotto (France), [16] Marzano AV, Ortega-Loayza AG, Heath M, Morse D, Genovese G, Prof. Mathias Schmuth (Austria), Prof. Ester Von-Stebut-Cugno M. Mechanisms of Inflammation in Neutrophil-Mediated Skin Diseases. (2019). Front Immunol, 10:1059. doi: Borschitz (Cologne), Dr. Vincent Flaher (France), Matjaž Gams 10.3389/fimmu.2019.01059 and Anton Gradišek (Slovenia). [17] Marzano AV, Damiani G, Ceccherini I, Berti E, Gattorno M, Cugno M. (2017). Autoinflammation in pyoderma gangrenosum and its syndromic form (pyoderma gangrenosum, acne and suppurative hidradenitis). Br J REFERENCES Dermatol, 176(6):1588-1598. doi: 10.1111/bjd.15226 [1] Canoui-Poitrine F, Le Thuaut A, Revuz JE, Viallette C, Gabison G, Poli [18] Marzano AV. (2016). Hidradenitis suppurativa, neutrophilic dermatoses F, et al. (2013). Identification of three hidradenitis suppurativa and autoinflammation: what's the link?. Br J Dermatol, 174(3):482-3. doi: phenotypes: latent class analysis of a cross-sectional study. J Invest 10.1111/bjd.14364 Dermatol, 133(6):1506-11. doi: 10.1038/jid.2012.472 [19] Brandao L, Moura R, Tricarico PM, Gratton R, Genovese G, Moltrasio C, [2] Van der Zee HH, Jemec GB. (2015). New insights into the diagnosis of et al. (2020). Altered keratinization and vitamin D metabolism may be key hidradenitis suppurativa: Clinical presentations and phenotypes. pathogenetic pathways in syndromic hidradenitis suppurativa: a novel JAMA, 73: S23-6. doi: 10.1016/j.jaad.2015.07.047 whole exome sequencing approach. J Dermatol Sci, 99(1):17-22. doi: [3] Martorell A, Jfri A, Koster SBL, Gomez-Palencia P, Solera M, Alfaro- 10.1016/j.jdermsci.2020.05.004 Rubio A, et al. (2020). Defining hidradenitis suppurativa phenotypes [20] Folkes AS, Hawatmeh FZ, Wong A, Kerdel FA. Emerging drugs for the based on the elementary lesion pattern: results of a prospective study. J treatment of hidradenitis suppurativa. (2020). Expert Opin Emerg Drugs, Eur Acad Dermatol Venereol, 34(6):1309-1318. doi: 10.1111/jdv.16183 25(3):201-211. doi: 10.1080/14728214.2020.1787984. [4] Naasan H, Affleck A. (2015). Atypical hidradenitis suppurativa. Clin Exp [21] Marzano AV, Genovese G, Casazza G, Moltrasio C, Dapavo P, Micali G, Dermatol, 40:891-3. doi: 10.1111/ced.12655 et al. (2021). Evidence for a 'window of opportunity' in hidradenitis [5] Cazzaniga S, Pezzolo E, Bettoli V, Abeni D, Marzano AV, Patrizi A, et al. suppurativa treated with adalimumab: a retrospective, real-life multicentre (2021). Characterization of Hidradenitis Suppurativa Phenotypes: A cohort study. Br J Dermatol, 184(1):133-140. doi: 10.1111/bjd.18983. Multidimensional Latent Class Analysis of the National Italian Registry [22] Zouboulis CC, Frew JW, Giamarellos-Bourboulis EJ, Jemec GBE, Del IRHIS. J Invest Dermatol, 141(5):1236-1242.e1. doi: Marmol V, Marzano AV, et al. (2021). Target molecules for future 10.1016/j.jid.2020.08.032 hidradenitis suppurativa treatment. Exp Dermatol, 30 Suppl 1:8-17. doi: [6] Zouboulis CC, Tzellos T, Kyrgidis A, Jemec GBE, Bechara FG, 10.1111/exd.14338. PMID: 34085329. Giamarellos-Bourboulis EJ, et al. (2017). Development and validation of [23] Zouboulis CC et al. (2015). Hidradenitis suppurativa/acne inversa: Criteria the International Hidradenitis Suppurativa Severity Score System (IHS4), for diagnosis, severity assessment, classification and disease evaluation. a novel dynamic scoring system to assess HS severity. Br J Dermatol, Dermatology, 231:184- 90. doi: 10.1159/000431175 177(5):1401- 1409. doi: 10.1111/bjd.15748. [24] Re S, Dogan AA, Ben-Shachar D, Berger G, Werling AM, Walitza S, et al. [7] Matusiak Ł. (2020). Profound consequences of hidradenitis suppurativa: a (2018). Improved Generation of Induced Pluripotent Stem Cells From review. Br J Dermatol, 183(6): e171-e177. doi: 10.1111/bjd.16603 Hair Derived Keratinocytes - A Tool to Study Neurodevelopmental [8] Ingram JR. (2020) The epidemiology of hidradenitis suppurativa. Br J Disorders as ADHD. Front Cell Neurosci, 12:321. doi: Dermatol, 183(6):990-998. doi: 10.1111/bjd.19435 10.3389/fncel.2018.00321. [9] Saunte DM, Boer J, Stratigos A, Szepietowski JC, Hamzavi I, Kim KH, et al. (2015). Diagnostic delay in hidradenitis suppurativa is a global problem. Br J Dermatol, 173(6):1546- 9. doi: 10.1111/bjd.14038 [10] Preda-Naumescu A, Ahmed HN, Mayo TT, Yusuf N. (2021) Hidradenitis suppurativa: pathogenesis, clinical presentation, epidemiology, and comorbid associations. Int J Dermatol. doi: 10.1111/ijd.15579. Epub ahead of print. [11] Zouboulis CC, Benhadou F, Byrd AS, Chandran NS, Giamarellos-Bourboulis EJ, Fabbrocini G, et al. (2020). What causes hidradenitis suppurativa?-15 years after. Exp Dermatol, 29(12):1154-1170. doi: 10.1111/exd.14214. [12] Genovese G, Moltrasio C, Garcovich S, Marzano AV. (2020) PAPA spectrum disorders. G Ital Dermatol Venereol, 155(5):542-550. doi: 10.23736/S0392-0488.20.06629-8. 16 Disease burden of hidradenitis suppurativa and assessment of a non-invasive treatment option Esther von Stebut Department of Dermatology University of Cologne Cologne, Germany esther.von-stebut@uk-koeln.de ABSTRACT ASSESSMENT OF HS DISEASE BURDEN Hidradenitis suppurativa (HS) is a chronic inflammatory skin To contribute to the development of a validated tool for the disease of intertriginous body areas. Due to an often delayed (objective, physician-based) assessment of disease diagnosis and various symptoms, disease burden is often under severity/activity, we participated in a consensus towards the estimated. In the present work, we summarize our results development of an International HS Severity Score System obtained from several studies aiming at a better description of (IHS4) initiated by members of the European Hidradenitis disease activity and an improved assessment of patient-related Suppurativa Foundation (EHSF) [2]. Within the IHS4, a variety symptoms. of clinical signs were rated by 11 centers including and assessing Treatment options for HS are limited; treatment ranges from 236 patients. The resulting IHS4 score is arrived at by the number medical to surgical options. However, despite numerous of nodules (multiplied by 1) plus the number of abscesses treatment options for HS, efficacious and noninvasive treatment (multiplied by 2) plus the number of draining tunnels (multiplied options resulting in long-term remission and management of by 4). A total score of 3 or less signifies mild, 4-10 signifies symptoms of the disease are still needed. We present a meta-moderate and 11 or higher signifies severe disease. The IHS4 was analysis of topical treatment options and discuss the need of real developed and published in 2017 and since then, a variety of world data for estimation of treatment efficacy. studies have utilized the score to assess disease severity both in real-life, as well as within clinical trials [3]. As such, the baseline KEYWORDS IHS4 score has proven to be a meaningful predictor for Acne inversa, Hidradenitis suppurativa, human, disease burden, recurrences during adalimumab therapy of HS [3]. DLQI, treatment options, topical treatment, medical device, Using a German data base with information on ~1800 HS IHS4 patients, the patients’ quality of life (QoL) was assessed [4]. The aim of this study was to present more robust data on patients’ QoL using the Dermatology Life Quality Index (DLQI). Overall, INTRODUCTION within this large cohort, the mean DLQI was 13.2±8.1 again Hidradenitis suppurativa (HS) as a chronic inflammatory disease stressing the strong burden of HS on affected patients and a of the skin characteristically manifests in inguinal, axillary and severely impaired quality of life. QoL correlated with pain, submammary body areas. HS patient suffer severely from the disease severity as assessed by the IHS4 sore, as well as Hurley disease due to pain, stigmatization and often delayed diagnosis, score. since the disease is often misinterpreted as repeated abscesses for Pain is one of the important aspects affecting QoL in HS patients. a long time. Consultation of a dermatologist early after disease Pain was assessed by a numerical rating scale (0= no pain to 10= onset is important. severe pain) by affected HS patients (1,795 individuals) [5]. Pain Treatment of HS is often frustrating, since the options are limited. was reported by 84% of patients with the majority reporting mild Medical treatments including antibiotics, hormones, and anti-pain (78%). Interestingly, females and smokers experienced TNF ) can successfully control symptoms, but more intense pain. Pain levels correlated with the number of discontinuation is often associated with relapses. Surgical affected areas and disease severity, as expected. interventions can induce long-term symptom control, but may To gain further insights into the frequency of familial cases not be useful for all patients due to long remission times and within 1795 German patients, we performed a patient survey in scarring tissue. 4 independent, patient network-run social media platforms within Germany. Within 7 days, a cumulative number of 642 responses was acquired. Out of these responses, 249 (38%) of the Permission to make digital or hard copies of part or all of this work for personal or classroom use is granted without fee provided that copies are not made or distributed patients confirmed that at least one first-degree relative (parents, for profit or commercial advantage and that copies bear this notice and the full children, siblings) are also affected by the disease. This citation on the first page. Copyrights for third-party components of this work must be honored. For all other uses, contact the owner/author(s). complements already existing data from the literature stating Information Society 2021, 4–8 October 2021, Ljubljana, Slovenia hereditary HS in 5-40% of cases [6]. Earlier reports described © 2021 Copyright held by the owner/author(s). hereditary HS to be more severe; studies analyzing the 17 Information Society 2021, 4–8 October 2021, Ljubljana, Slovenia von Stebut pathomechanism in these families involving gamma-secretase DISCUSSION and inflammasome activation are underway [6,7]. HS is a chronic inflammatory disease of the skin, which requires raising better awareness, good scoring tools and more TOPICAL AND DEVICE-BASED THERAPY (outpatient) treatment alternatives. Although the disease was previously treated using surgery, new treatment modalities FOR MILD HS allowing for an effective treatment of mild and moderate cases in Treatment options for HS are often unsatisfactory. We recently an ambulatory setting are currently developed. studied the effect of a combination therapy of intense pulsed light (IPL) and radiofrequency (RF). To this aim, the first study with HS appears to present as a disease with a variety of different 47 patients was performed as a prospective, monocentric, mutations and pathways involved in its pathogenesis. Assessing randomized, three-arm parallel-group design trial with a prior 12 these familial cases of HS will aid in a better understanding of weeks observation period (NICE study) [8,9]. Treatment arms the disease and open avenues for therapeutic modification. were IPL and RF monotherapies or IPL + RF combination therapy. After 12 weeks, all patients received IPL + RF for ACKNOWLEDGMENTS additional 12 weeks (cross-over). After 12 weeks, active lesion The authors would like to thank Michele Boniotto (Créteil, counts of the IPL + RF group decreased by 50% in 50% of France), Sergio Crovella, Paola Tricarico (Trieste, Italy) Mathias patients, in 33% even by 75% (Hurley I/II patients, less effective Schmuth, (Innsbruck Hautklinik, Austria), Matjaž Gams and in Hurley III) correlating with an even better improvement in Anton Gradišek (Ljubljana, Slovenia) and Vincent Flacher DLQI. A controlled follow up trial (RELIEVE study) compared (Strasbourg, France) within the ERA PerMed funded consortium topical clindamycin with topical clindamycin plus IPL + RF in BatMan for helpful discussions. 88 patients [10]. After 16 weeks of treatment, the IHS4 score was improved by 60% in the combination therapy group compared to REFERENCES 18% improvement in clindamycin-treated patients. Secondary [1] Marzano AV, et al. Evidence for a 'window of opportunity' in hidradenitis endpoints (e.g. DLQI) showed similar results. suppurativa treated with adalimumab: a retrospective, real-life multicentre cohort study. Br J Dermatol. 2021;184(1):133-140. doi: The aim of a follow-up study was to perform a meta-analysis on 10.1111/bjd.18983 [2] Zouboulis CC, Tzellos T, Kyrgidis A, et al R; Development and validation the effectiveness of local and instrument-based therapies under of the International Hidradenitis Suppurativa Severity Score System the prism of their efficacy and safety profile [11]. We thus (IHS4), a novel dynamic scoring system to assess HS severity. Br J performed a literature search and analyzed clinical evidence for Dermatol. 2017 Nov;177(5):1401-1409. doi: 10.1111/bjd.15748. [3] Chiricozzi A, Giovanardi G, Garcovich S, et al (2020) Clinical and the various therapeutic options. Effective treatments for out-ultrasonographic profile of adalimumab-treated hidradenitis suppurativa patient care of HS patients exist including topical clindamycin, patients: A real-life monocentric experience. Acta Derm Venereol 100:adv00172. resorcinol, and intralesional corticosteroids. New devices such as [4] Krajewski PK, Matusiak Ł, von Stebut E, Schultheis M, Kirschner U, LAight therapy (combining IPL with radiofrequency) are Nikolakis G, Szepietowski JC. Quality-of-Life Impairment among Patients with Hidradenitis Suppurativa: A Cross-Sectional Study of 1795 available, which can be used as monotherapy or adjunct therapy Patients. Life (Basel). 2021 Jan 8;11(1):34. doi: 10.3390/life11010034 in combination with systemic treatment and/or surgery for the [5] Krajewski PK, Matusiak Ł, von Stebut E, Schultheis M, Kirschner U, management of HS patients. All topical treatment options are Nikolakis G, Szepietowski JC. Pain in Hidradenitis Suppurativa: A Cross-sectional Study of 1,795 Patients. Acta Derm Venereol. 2021 Jan best suited for mild to moderate HS and aid to control disease 5;101(1):adv00364. doi: 10.2340/00015555-3724. activity. [6] Frew JW. Differential profiles of gamma secretase Notch signalling in hidradenitis suppurativa: the need for genotype-endotype-phenotype analysis. Br J Dermatol. 2021 Jan 9. doi: 10.1111/bjd.19805. [7] Zouboulis CC, Benhadou F, Byrd AS, et al What causes hidradenitis REQUIREMENT FOR REAL WORLD DATA suppurativa ?-15 years after. Exp Dermatol. 2020 Dec;29(12):1154-1170. doi: 10.1111/exd.14214. ON TREATMENT EFFICACY [8] Wilden S, Friis M, Tuettenberg A, Staubach-Renz P, Wegner J, Grabbe S, von Stebut E. Combined treatment of hidradenitis suppurativa with intense Publication of real world data on the results of treatment with pulsed light (IPL) and radiofrequency (RF). J Dermatolog Treat. 2021 (approved) drugs and/or medical devices is important to allow Aug;32(5):530-537. doi: 10.1080/09546634.2019.1677842. for a reasonable judgement about the efficacy of a medication, [9] Zimmer S, Basien K, von Stebut E. [Impact of LAight therapy on hidradenitis suppurativa care]. Hautarzt. 2021 Jul;72(7):586-594. doi: especially since due to the nature of controlled clinical studies 10.1007/s00105-021-04843-z. certain patient groups, who in daily clinical routine would best [10] Schultheis M, Staubach P, Nikolakis G, Grabbe S, Ruckes C, von Stebut E, Kirschner U, Matusiak L, Szepietowsk IF. LAight® therapy benefit from such new treatments, are excluded from study significantly enhances treatment efficacy of 16 weeks of topical inclusions. Real world data on the treatment of HS was clindamycin solution in Hurley I and II hidradenitis suppurativa: Results from period A of RELIEVE, a multicenter randomized, controlled trial. summarized [12]. Adalimumab, the only approved biological Dermatology 2021, manuscript accepted. treatment so far, represents a cost-efficient and effective therapy. [11] Nikolakis G, von Stebut E [Topical and novel device-based therapies for mild hidradenitis suppurativa]. Hautarzt. 2021 Aug;72(8):676-685. doi: Additional publications about real world data with high(er) 10.1007/s00105-021-04849-7. [12] Zouboulis CC, von Stebut E. Need for real-world data studies on numbers of patients, including those with different risk factors, hidradenitis suppurativa/acne inversa treatment. Hautarzt. 2021 are required. Real world data will help to really assess the Aug;72(8):700-705. doi: 10.1007/s00105-021-04847-9. developing therapeutic spectrum of HS in our daily routine. 18 An Overview of the BATMAN Platform Zdenko Vuk Jani Bizjak Erik Dovgan Department of Intelligent Systems Department of Intelligent Systems Department of Intelligent Systems Jožef Stefan Institute Jožef Stefan Institute Jožef Stefan Institute Jamova cesta 39 Jamova cesta 39 Jamova cesta 39 Ljubljana, Slovenia Ljubljana, Slovenia Ljubljana, Slovenia zdenko.vuk@ijs.si jani.bizjak@ijs.si erik.dovgan@ijs.si Matjaž Gams Anton Gradišek Department of Intelligent Systems Department of Intelligent Systems Jožef Stefan Institute Jožef Stefan Institute Jamova cesta 39 Jamova cesta 39 Ljubljana, Slovenia Ljubljana, Slovenia matjaz.gams@ijs.si anton.gradisek@ijs.si ABSTRACT This paper presents an overview of the platform used in the project BATMAN. We look at the architecture and at the interactions between the components, namely the website, the smartphone app, and the server, and how these components are used by the medical doctors, patients and data scientists. KEYWORDS BATMAN platform, web platform, smartphone application, questionnaires 1 INTRODUCTION In recent years, the use of smartphone applications related to health has expanded substantially. Smartphones and other wearable sensors have become being daily companions for a majority of the population in developed countries. Probably the most Figure 1: The basic schema showing the interactions of the commonly-known health-related applications focus on aspects platform users with the technical components. such as exercise (i.e., fitness trackers) or nutrition and are typically independent of involvement of a medical doctor. On the other hand, there is ongoing research dealing with the use of data from the wearables to assist the clinicians in improving treat-The rest of the paper is organized as follows. Section 2 presents ment of patients. An example of such research is the ERA PerMed the BATMAN platform. The smartphone application is described project BATMAN [1] that aims at improving the understanding in Section 3. Finally, Section 4 concludes the paper with summary of the chronic dermatological condition Hidradenitis Suppura-and future plans. tiva (HS), also called Acne Inversa. HS is a chronic inflammatory disease involving hair follicles that presents with painful nodules that release pus. Within the framework of the BATMAN project, 2 THE BATMAN PLATFORM AND ITS we aim in bringing together medical, genetic, experimental, and USERS lifestyle data to build a truly personalized model of each patient In this section, we present an overview of the BATMAN platform, in order to tailor specific treatments. namely how its components work and how they are used by the This paper presents the overview of the platform developed participants in the project, i.e., medical doctors, patients, and within the BATMAN project. This platform collects data from data scientists. The basic schema of the interactions is shown patients, such as answers to questionnaires, and enable doctors in Figure 1. The patient and the doctor input the patient data to follow the patient’s state and assign additional questionnaires through a website. Patients also use a smartphone app for activ-when appropriate. The gathered data are anonymized and further ity tracking. The information collected via the website and the processed by data scientists by building models for HS patients smartphone app are stored on a server where it is then available and seeking for new knowledge. to data scientists. The BATMAN platform website has a double functionality: it Permission to make digital or hard copies of part or all of this work for personal serves as the main information point about the BATMAN project or classroom use is granted without fee provided that copies are not made or distributed for profit or commercial advantage and that copies bear this notice and and it is also the entry point to the platform. Users can log in the full citation on the first page. Copyrights for third-party components of this with their usernames and passwords. Depending on their role, work must be honored. For all other uses, contact the owner/author(s). they can see different types of content. To ensure the security Information Society 2021, 4–8 October 2021, Ljubljana, Slovenia © 2021 Copyright held by the owner/author(s). and to prevent any unauthorized access, the user accounts are created by the platform administrators and assigned to users. 19 Information Society 2021, 4–8 October 2021, Ljubljana, Slovenia Zdenko Vuk, Jani Bizjak, Erik Dovgan, Matjaž Gams, and Anton Gradišek Figure 3: User interface for editing a questionnaire. Figure 2: Online form for doctors to upload the patient’s EHRs. 2.1 Doctors Medical doctors can view and manage the patients’ files. They are also able to manually upload the patients’ medical records (see Figure 2). If convenient, patients can be assigned to different groups. The doctors have the possibility to create new questionnaires (see Figure 3) and to assign questionnaires to their patients (see Figure 4). There are three types of general questionnaires: • Major Depression Inventory • Dermatology Quality of Life • Food preferences The food preferences questionnaire has been split to several forms with a small number of questions since the list of food preferences includes around 200 items, which makes it tiresome for the patient to fill in one sitting. Figure 4: User interface for assigning questionnaires. Depending on the preferences, each questionnaire can be as- signed to a patient more than once, which is relevant especially for the Depression and Quality of life questionnaires. On the other hand, the food preferences typically do not change frequently thus this questionnaire can be assigned only once. The doctor gets the list of available user accounts for patients from the administrator. Then the doctor then assigns accounts to patients. This procedure enables us to keep the identity of the patients anonymous for all other participants. 2.2 Patients Figure 5: Patient’s view of the platform to see the com- Each patient obtains the user account information from his/her pleted part of the food preferences questionnaire. medical doctor. Patients interact with the platform either through the website or via the smartphone application. On the website, they can view their data (see, for example, Figure 5) and they can also use it as the interface with which they can fill in the 2.3 Data Scientists questionnaires. In addition, they can also fill in the question-Data scientist can access all the data that the medical doctors naires through the smartphone application, which we describe and the patients enter into the platform. The data available to in Section 3. the data scientists is anonymized. 20 An Overview of the BATMAN Platform Information Society 2021, 4–8 October 2021, Ljubljana, Slovenia Figure 6: Login dialog and home screen of the smartphone Figure 7: Questionnaire menu and an example of a ques- application. The home screen shows the summary of daily tionnaire, in this case the Dermatology Quality of Life. activities and the pending questionnaires. The data is currently being collected in the pilot study and will be then used to build models for HS patients and to seek for new knowledge. 2.4 Administrators The highest level of access belongs to the administrator. Regard-ing the platform functionality, the administrator can access pages for managing users, groups, and for making changes on questionnaires. 3 SMARTPHONE APPLICATION The smartphone application is available for Android-based phones only. It can be accessed through Play Store [2], or found with search for “Biomolecular Analyses for Tailored Medicine”. Patients log in the smartphone application using the same Figure 8: Example of the data that the smartphone appli- account as to the platform. The login and home screen for a cation sends to the server. sample patient are shown in Figure 6. There are two main functionalities of the smartphone appli- cation: to monitor the daily activity of the patient, and to help In order to keep the application transparent to the users, the them to fill in the questionnaire, which is likely easier on the patients can access the data log showing all information that smartphone than requiring to log in to a separate website just the application has communicated to the server (see Figure 8). for that purpose. Additional functionality of the application is a pedometer, which The application uses the Google Fit [3] plug-in to trace the pa-allows the user to track steps when activated (as opposed to the tient’s steps and calories burned. The activity summary updates integrated step counter that tracks the steps during the entire in real time based on the patient’s activity. The collected daily day). activity serves as a reasonable proxy for the patient’s wellbeing, e.g., if the HS condition is bad at a given time, the patient is likely 4 CONCLUSION to move less because of the pain, while if the patient starts mov-In this paper, we presented an overview of the components of the ing more after a treatment, this likely implies that the treatment BATMAN platform. The platform is currently used to collect the has been successful. heterogeneous patient data, including medical, genetic, activity, As for the questionnaires, the application allows the patient and self-reported data. to easily fill in the forms using the screen. An example of the In the last stage of the project, the collected data will allow us questionnaire is shown in Figure 7. to find novel knowledge about the patients suffering from HS and 21 Information Society 2021, 4–8 October 2021, Ljubljana, Slovenia Zdenko Vuk, Jani Bizjak, Erik Dovgan, Matjaž Gams, and Anton Gradišek will allow the doctors to create personalized treatments that could Science, and Sport (MIZŠ). We would also like to thank the stu-turn out to be more effective. This will be specially supported dents who participated in the project. by the data scientists who will develop AI-based approaches for automatic knowledge extraction. REFERENCES [1] Batman project’s website. 2021. https://batman-project.eu/ ACKNOWLEDGMENTS en. The authors acknowledge the funding from the ERA PerMed [2] Batman app on Google Play Store. 2021. https://play.google. project BATMAN, contract number C3330-20-252001. On Slove- com/store/apps/details?id=si.ijs.batman&hl=en. nian side, the project is funded by the Ministry of Education, [3] Google Fit. 2021. https://developers.google.com/fit. 22 Indeks avtorjev / Author index Bizjak Jani .................................................................................................................................................................................... 19 Boniotto Michele .......................................................................................................................................................................... 11 Boufenghour Wacym ..................................................................................................................................................................... 9 Brandão Lucas ................................................................................................................................................................................ 5 Crovella Sergio ............................................................................................................................................................................... 5 dos Santos Silva Carlos André ....................................................................................................................................................... 5 Dovgan Erik ................................................................................................................................................................................. 19 Flacher Vincent .............................................................................................................................................................................. 9 Gams Matjaž ................................................................................................................................................................................ 19 Genovese Giovanni ...................................................................................................................................................................... 14 Gradišek Anton ............................................................................................................................................................................ 19 Gratton Rossella ............................................................................................................................................................................. 5 Marzano Angelo ........................................................................................................................................................................... 14 Matar Rola .................................................................................................................................................................................... 11 Moltrasio Chiara ........................................................................................................................................................................... 14 Moura Ronald ................................................................................................................................................................................. 5 Nait-Meddour Cecile .................................................................................................................................................................... 11 Tricarico Paola Maura .................................................................................................................................................................... 5 von Stebut Esther ......................................................................................................................................................................... 17 Vuk Zdenko .................................................................................................................................................................................. 19 23 24 Delavnica projekta BATMAN BATMAN Project Workshop Sergio Crovella, Anton Gradišek Document Outline 02 - Naslovnica - notranja - J - TEMP 03 - Kolofon - J - TEMP 04 - IS2021 - Predgovor - TEMP 05 - IS2021 - Konferencni odbori 07 - Kazalo - J 08 - Naslovnica - notranja - J - TEMP 09 - Predgovor podkonference - J 10 - Programski odbor podkonference - J 01 - TEMP 02 - Boufenghour 03 - Nait-Meddour 04 - Marzano 05 - Stebut 06 - Vuketal Abstract 1 Introduction 2 The BATMAN platform and its users 2.1 Doctors 2.2 Patients 2.3 Data Scientists 2.4 Administrators 3 Smartphone Application 4 Conclusion Acknowledgments 12 - Index - J Blank Page Blank Page Blank Page Blank Page 06 - Vuketal.pdf Abstract 1 Introduction 2 The BATMAN platform and its users 2.1 Doctors 2.2 Patients 2.3 Data Scientists 2.4 Administrators 3 Smartphone Application 4 Conclusion Acknowledgments Blank Page