15 Years After

Home , Hidradenitis, Hidradenitis suppurativa

Received: 24 August 2020 | Accepted: 5 October 2020 DOI: 10.1111/exd.14214

REVIEW ARTICLE

What causes hidradenitis suppurativa ? — 15 years after

1European Hidradenitis Suppurativa Foundation e.V., Dessau, Germany 2Departments of Dermatology, Venereology, Allergology and Immunology, Dessau Medical Center, Brandenburg Medical School Theodor Fontane and Faculty of Health Sciences Brandenburg, Dessau, Germany 3Department of Dermatology, Hôpital Erasme, Universite Libre de Bruxelles, Bruxelles, Belgium 4Department of Dermatology, Howard University College of Medicine, Washington, DC, USA 5Division of Dermatology, Department of Medicine, National University Hospital, Singapore 64th Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, Athens, Greece 7Section of Dermatology, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy 8The Rockefeller University, New York, NY, USA 9Division of Cutaneous Science, Department of Dermatology, Nihon University School of Medicine, Tokyo, Japan 10Division of Dermatology, Hospital Universitario Marqués de Valdecilla, University of Cantabria, IDIVAL, Santander, Spain 11Department of Surgery, Clinique dew Val d’Ouest (Lyon), ResoVerneuil (Paris) and Groupe de Recherche en Proctologie de la Société Nationale Française de ColoProctologie, Paris, France 12Faculty of Medicine, Memorial University of Newfoundland, and NewLab Clinical Research Inc, St. John's, Canada 13Department of Dermatology, Henry Ford Hospital, Wayne State University, Detroit, MI, USA 14Department of Dermatology, Ankara Numune Training and Research Hospital, Ankara, Turkey 15Department of Dermatology University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands 16INSERM, Créteil, France 17Department of Dermatology, Inselspital, Bern University Hospital, Bern, Switzerland 18Department of Dermatology & Academic Wound Healing, Division of Infection and Immunity, Cardiff University, Cardiff, UK 19Department of Dermatology, Zealand University Hospital, Roskilde, Denmark 20Department of Dermatology, RenJi Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China 21Department of Dermatology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA 22Department of Dermatology, Penn State Milton S. Hershey Medical Center, Hershey, PA, USA 23Dermatology Department, Paul Sabatier University, University Hospital of Toulouse, Toulouse, France

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24Department of Dermatology, Department of Immunology, Department of Molecular Genetics and Microbiology, Duke University, Durham, NC, USA 25Department of Dermatology, Hospital of Manises, Valencia, Spain 26Dermatology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy 27Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy 28Department of Dermatology, Venereology and Allergology, Wrocław Medical University, Wrocław, Poland 29Institut Pasteur, Paris, France 30Centre for Rheumatic Diseases, King’s College London, and Department of Rheumatology, King’s College Hospital, London, UK 31Translational Science and Experimental Medicine, Early Respiratory and Immunology, Biopharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden 32Fort HealthCare, Fort Atkinson, WI, USA 33Department of Dermatology, Emory University School of Medicine, Atlanta, GA, USA 34Alicante University General Hospital, Alicante Institute for Health and Biomedical Research (ISABIAL-FISABIO Foundation), Alicante, Spain 35Dr. Phillip Frost Department of Dermatology & Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA 36Division of Dermatology, University of Washington, Seattle, WA, USA 37Department of Dermatology, Erasmus University Medical Center, Rotterdam, The Netherlands 38Autoimmunity, Transplantation and Inflammation, Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland 39Division of Dermatological Allergology, Department of Dermatology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary 40Department of Dermatology, Nordland Hospital Trust, Bodø, Norway 41Department of Dermatology, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

Correspondence Christos C. Zouboulis, Departments of Abstract Dermatology, Venereology, Allergology The 14 authors of the first review article on hidradenitis suppurativa (HS) pathogen- and Immunology, Dessau Medical Center, Brandenburg Medical School Theodor esis published 2008 in EXPERIMENTAL DERMATOLOGY cumulating from the 1st Fontane, Dessau, Germany, Auenweg 38, International Hidradenitis Suppurativa Research Symposium held March 30–April 06847 Dessau, Germany Email: [email protected] 2, 2006 in Dessau, Germany with 33 participants were prophetic when they wrote “Hopefully, this heralds a welcome new tradition: to get to the molecular heart of HS Funding information Medizinische Hochschule Brandenburg pathogenesis, which can only be achieved by a renaissance of solid basic HS research, as Theodor Fontane the key to developing more effective HS therapy.” (Kurzen et al. What causes hidradenitis suppurativa? Exp Dermatol 2008;17:455). Fifteen years later, there is no doubt that the desired renaissance of solid basic HS research is progressing with rapid steps and that HS has developed deep roots among inflammatory diseases in Dermatology and beyond, recognized as “the only inflammatory skin disease than can be healed”. This an- niversary article of 43 research-performing authors from all around the globe in the of- ficial journal of the European Hidradenitis Suppurativa Foundation e.V. (EHSF e.V.) and the Hidradenitis Suppurativa Foundation, Inc (HSF USA) summarizes the evidence of the intense HS clinical and experimental research during the last 15 years in all aspects of the disease and provides information of the developments to come in the near future.

KEYWORDS acne inversa, hair follicle, hidradenitis suppurativa, inflammatory skin diseases, pathogenesis

1 | 2005-2020: 15 YEARS OF review on “What causes hidradenitis suppurativa?” in this journal1 CONTINUOUS LEARNING—WHAT HAS and many new researchers have entered the field. In consequence, CHANGED IN OUR UNDERSTANDING the number of publications is growing exponentially. A global ap- OF DISEASE PATHOGENESIS IN-THE- preciation of the symptomatic impact of HS has emerged,2 along BETWEEN? with a quantitative understanding of the associated systemic comorbidities.3 The dysregulated gene pathways in lesional HS Substantial advances have been made in our understanding of skin have been mapped,4 and genetic5 and microbiome6 contri- hidradenitis suppurativa/acne inversa (HS) since the previous butions to disease pathogenesis have been explored. Much work 1156 | ZOUBOULIS et al.

24 remains to be done, but convincing evidence that proinflamma- involved in the γ-secretase complex and in the keratinization path- tory cytokines play a central role,7 that is opening the possibil- way25 on the background of alterations in the skin microbiome, HS ity of targeted treatment, has led to clinical trials8 and regulatory can be regarded as a multifactorial, polygenic, autoinflammatory dis- approval of adalimumab for treatment of HS. In turn, this has ease (Figure 1). spurred a flurry of new trials with different drugs.9 Trials need endpoints, and with fortuitous premonition, a structured search for evidence-based outcome variables has been performed by the 3 | MUTATIONS AND HS: WHAT IS VALID? European Hidradenitis Suppurativa Foundation (EHSF) e.V.10 and 11 is also on its way led by the HISTORIC group. Many other efforts Mutations of γ-secretase complex (GSC) genes PSENEN, PSEN1 and are underway to understand HS and optimize the management of NCSTN were first described in familial HS 10 years ago.26 Mutations this hitherto secret scourge. Expect the future to bring much good have since been reported in at least 41 patients or families world- for the many HS patients. wide, including 16 Chinese,27 4 Japanese,28 4 Jewish Ashkenazi,29 3 French,30 2 British,31 2 Indian,32 1 African American,33 1 American (Caucasian),34 1 German35 and 1 Dutch36 kindreds, 4 sporadic cases 2 | INFECTION, AUTOIMMUNITY OR (2 British, 1 Afro-Caribbean and 1 American)34,37 and 2 patients with BOTH? unknown familial history. The reported 41 mutations of GSC genes include 28 in NCSTN, 12 in PSENEN and one in PSEN1, of which 12 The role of bacterial infections per se as the primary cause of HS has are frameshifts, 11 result in nonsense mutations, 9 in missense mu- attracted a lot of controversy evolving knowledge as to the underly- tations and 9 are splice site mutations. GSC is an intramembrane ing pathogenesis. A wide range of bacteria, including Staphylococcus protease complex able to cleave more than 90 transmembrane pro- aureus, coagulase-negative staphylococci, Corynebacterium spe- teins. Mutations in GSC could affect activation of presenilin, prevent cies and anaerobic agents, such as Porphyromonas, Prevotella and substrate binding and hinder intramembrane cleavage of select pro- Fusobacterium, have been isolated from deep HS lesions.12,13 Indeed, teins. Most of the PSENEN gene mutations are associated with the bacteria may act in HS as pathogen-associated molecular triggers of “clinical subphenotype” of Dowling-Degos disease.5 In HS patients inflammation by creating patterns linking their receptors, including with NCSTN mutations, remarkable findings are the male predomi- the transmembrane toll-like receptors and intracellular Nucleotide nance (1.7:1 vs 1:3 in regular HS) and the characteristic phenotype. binding Oligomerization Domain (NOD)-like receptors.14 A down- Overall, GSC gene mutations occur only in around 6% of non-familial regulation of the alarmins/antimicrobial peptides S100A7 and HS. Several other mutations have been associated with (syndromic) S100A9 15 as well as an increased expression of antimicrobial cathel- HS including MEFV, POFUT1, PSTPIPP1 and FGFR2. An intriguing icidine LL-3716 has been detected in HS lesional skin, suggesting an question is what the functional consequences are of all these muta- innate immunity dysfunction leading to an altered host-microbiome tions and their causality. The GSC mutations were initially linked to crosstalk. decreased Notch signalling. Loss-of-function mutations would result Reports on the coexistence of HS with autoimmune diseases, in abnormal follicular differentiation, keratinization, occlusion and such as systemic lupus erythematous, and autoinflammatory condi- cyst formation. However, no significant differential expression of tions, such as Synovitis, Acne, Pustulosis, Hyperostosis and Osteitis Notch 1-4 was identified in HS lesional skin as well as other inflam- (SAPHO) syndrome,17 support the role of autoimmunity/autoinflammatory dermatoses including psoriasis, alopecia areata and atopic mation in HS pathogenesis. dermatitis.38 GSC-related proteases, ADAM10 and ADAM17, seem Interleukin (IL)-1β is a highly prominent cytokine in lesional skin more likely candidates. ADAM17 is associated with inflammatory of both classic HS18 and Pyoderma gangrenosum, Acne, Suppurative bowel disease and involved in epidermal, ductal and hair follicle for- Hidradenitis (PASH) syndrome, the main syndromic form of HS.19,20 mation, and production of matrix metalloproteinases. Furthermore, This cytokine plays a crucial role in autoinflammation,21 suggesting Nicastrin mutations interact with ADAM17 activity. Functional stud- that there is an important autoinflammatory component in the HS ies comprising GSC substrates other than Notch, including epige- pathogenesis.22 This view is further supported by genetic muta- netic, environmental and metabolic factors, should be considered. tions which are shared between HS and classic autoinflammatory Other genetic approaches in regular non-familial HS, such as GWAS diseases.20,21 The latter encompass a huge spectrum of conditions or exome-sequencing, are highly needed to discover new inflamma- characterized by episodes of neutrophil-driven, sterile inflammation tory pathways that may lead to novel therapeutic targets for this in the affected organs, including the skin.22 debilitating condition. As a consequence of these mutations, the inflammasome, which One large scale study using one Greek cohort and another is a protein complex in neutrophils and macrophages, activates the German cohort identified that carriers of more than six copy num- autoinflammatory process through an uncontrolled release of sev- bers of the β-defensin (hbD2) gene cluster of chromosome band eral proinflammatory cytokines such as IL-1, IL-17, IL-23 and Tumor 8p.23.1 had greater risk for the acquisition of HS (odds ratio 6.72). 18,23 Necrosis Factor (TNF)-α, all overexpressed in HS lesional skin. Carriage of more than six copy numbers was associated with less With several new gene mutations coming into play, such as those severe disease phenotype regarding the degree of purulence and ZOUBOULIS et al. | 1157

FIGURE 1 Genetic and environmental triggers have been implicated in the pathogenesis of hidradenitis suppurative (HS). These result in skin microbiome alterations and a cascade of inflammatory, immune-mediated responses that lead to up-regulated innate immunity. Associations with HS have been reported with cardio-metabolic diseases as well as autoimmune rheumatic diseases. Cardio- metabolic diseases include diabetes mellitus/insulin resistance, obesity, dyslipidaemia, hypertension. Autoimmune diseases in the rheumatic spectrum include Synovitis, Acne, Pustulosis, Hyperostosis and Osteitis (SAPHO) syndrome, psoriatic arthritis, rheumatoid arthritis, systemic lupus erythematosus. The overall outcome of uncontrolled autoinflammation/autoimmunity is an altered host-microbiome crosstalk. DC, dendritic cell; IL, interleukin; LTB4, leukotriene B4; MΦ, macrophage; PMN, polymorphonuclear cell; Th, T-helper cell; TNF, tumor necrosis factor. S100A7/ A8/A9 & LL-37 represent antimicrobial peptides.

the number of affected body areas. These patients were prone to antimicrobial peptide dermcidin and induction of proinflammatory high production of hbD2 from whole blood upon stimulation with cytokines IL-1, IL-17, TNF-α and interferons (Figure 2). Aberrant Staphylococcus aureus.39 adaptive immunity with marked increase in T and B cells and plasma cell signatures in HS could point to autoimmune causes or simply re- flect the result of chronic inflammation in late-stage HS. Importantly, 4 | SKIN TRANSCRIPTOME IN HS most of the previous transcriptomic studies were small and focused on moderate-severe HS limiting identification of potential HS disease HS personalized medicine relies on understanding the molecular drivers through early innate immune disease-associated molecules. taxonomy and heterogeneity among HS patients. With the fast- Large cohort transcriptomic studies including early and mini- evolving HS therapeutic landscape, defining the right drug for the mal HS disease in addition to moderate and severe cases and skin right patient at the right time is critical. Currently, only adalimumab, sample collection from lesional and anatomical site-matched non-le- a TNF-α inhibitor, is approved for treatment of HS moderate-severe sional skin are required to identify reliable and potentially predic- disease, but interest exists for targeting additional immune factors. tive biomarkers (Figure 2). Beyond microarray and whole-genome Great strides have been achieved through HS skin transcriptomic RNA sequencing, novel single cell sequencing and spatial resolution studies initiating an in-depth investigation of the molecular events of approaches are pivotal to the understanding of HS heterogeneity HS disease.4,40-43 The analysis of the HS transcriptome has provided and immunobiology aiming at defining specific endotypes. This unforeseen signatures of inflammatory, epithelial, hair follicle and will ultimately herald the development of personalized treatment sweat gland signalling molecules: Early innate immune responses approaches (Figure 2). Such approaches are currently pursued including the upregulation of the alarmins S100A7, S100A7A and through collaborative initiatives in other diseases and have shown S100A8/A9; downregulation of the eccrine sweat gland-specific success.44-46 1158 | ZOUBOULIS et al.

Healthy Skin Non-Lesional Hidradenis Suppurava Hidradenis Suppurava Skin (minimal to mild) (moderate to severe) -Follicular Clogging -Severe Inﬂammaon -Pilosebaceous and Sweat Gland Changes -Sinus Tracts and Abscesses -Inﬂammatory Nodules -Dysbiosis -Pain and Itch

LTB4

Non-Lesional Lesional

Targeted therapy against TNF-⍺ Adalimumab* Anbiocs Inﬂiximab IL-12/23 (p40) Ustekinumab Ansepcs IL23(p19) Guselkumab Risankizumab Hormonal Treatment IL17A Secukinumab IL17R Brodalumab Wound Management IL17A/F Bimekizumab IL-1R Anakinra Pain Killers IL-1⍺ Bermekimab LTB4 Intralesional Complement pathway JAK pathway Corcosteroids

FIGURE 2 Proposed key cells and mediators in the evolution of hidradenitis suppurativa (HS) and pathogenesis-based target therapies. HS is an inflammatory skin disease with a characteristic clinical presentation of recurrent or chronic painful, itching or suppurating lesions in the apocrine sweat gland–bearing regions of the body. Key processes during disease involve epidermal changes within the hair follicle infundibulum which culminate in follicular clogging and subsequent rupture and release of follicular content into the surrounding tissue triggering an inflammatory response. While the underlying inflammatory process is not fully understood, a multitude of immune cells infiltrate skin lesions and lead to tissue destruction of pilosebaceus and sweat gland units. Likely as a response to healing from the inflammatory process, tunnelling and tissue scarring can occur, worsening the clinical disease course. While early lesions have been reported to harbour normal bacterial flora for the skin region, dysbiosis and secondary infections with biofilm formation have been reported. Current non-biologic based therapies as well as targeted biologic therapies that are proposed or have been FDA-approved (adalimumab) or have been approved for clinical trials are shown. IFN, interferon; IL, interleukin; JAK, Janus kinase; LTB4, leukotriene B4; Th, T-helper cell; TNF, tumor necrosis factor. *Highlights the only FDA-approved biologic for hidradenitis suppurativa.

5 | RACIAL BACKGROUND AND HS Japan50-53 Turkey,54 Malta55 and Tunisia56 have observed higher prevalence in men. This male preponderance may be partially The role of race in HS pathogenesis is poorly understood. Observed confounded by the relatively higher frequency of smoking among differences in HS prevalence across epidemiologic studies are prob- Asian men compared to women.50 Gluteal distribution has been ably better explained by disparate study methodologies than by observed more frequently in Asian than in European and American true geographic and demographic differences. In the United States, HS cohorts, possibly related to male predominance in the Asian those of African American and biracial ancestry are disproportion- cohorts.50 Data regarding HS severity by race conflict with one ately affected by HS,47 and this difference is even greater among study suggesting that African American patients may have earlier adolescents.48 In Brazil, Amerindians are less likely to develop HS disease onset and are more likely to present with advanced dis- compared to other racial groups.49 ease compared to Whites.57,58 Several studies have highlighted racial differences in the clin- Genetic studies have identified several γ-secretase mutations ical characteristics of HS. In Western Europe and America, HS is linked to HS pathogenesis. Although these mutations were initially more common in women compared to men. However, studies from reported in Han Chinese families, the same mutations have subse- eastern nations including Singapore, South Korea, Malaysia and quently been detected in HS patients worldwide.59 It is unknown ZOUBOULIS et al. | 1159 whether the prevalence of these mutations differs by race 39; how- collaborative fashion with simultaneous collection of DNA for phe- 68 ever, known γ-secretase mutations explain the minority of familial notype-genotype comparison. HS cases.5 Much remains to be learned about the influence of race on the pathogenesis of HS. Unfortunately, the vast majority of HS studies 7 | SKIN MICROBIOTA AND HS have failed to report participants’ race or ethnicity.60 Adequate rep- resentation of diverse patients across all demographic groups in- Although HS was considered for many years to be purely inflammatory, cluding race and ethnicity is critical to enhancing our understanding recent extensive microbiology studies demonstrated the constant of disease pathogenesis and ensuring that treatments can meet the presence of commensal opportunistic bacterial flora within lesions, needs of all subgroups affected by this debilitating disease. isolated in 4-7 days by culture69 and confirmed by 16S-ribosomal- RNA-gene-amplicon-sequencing.6,13,70 16S-sequencing also demonstrated that microbiology correlates with Hurley's stage.12,71 In 6 | DO PHENOTYPES INDICATE half of Hurley stage I lesions, skin pathogens are isolated alone, ei- GENOTYPES? ther Staphylococcus lugdunensis (25%) or Cutibacterium spp (25%). In the other half of Hurley stage I lesions, in Hurley stages II and III The clinical presentation of HS, regardless of severity, is undeni- lesions, the flora is polymicrobial, with predominance of strictly an- ably heterogeneous. For instance, some patients form many cysts, aerobic species (Prevotella and Porphyromonas being the most abun- lesions at ectopic locations, other form mainly perianal heavily in- dant), but also includes aero-tolerant anaerobes: Actinomyces spp, flamed deep tunnels or superficial plaques on the body, while oth- Streptococcus anginosus group 6,69 and Corynebacterium spp, with lack ers form mainly superficial lesions resulting in ice-pick like scarring. of Staphylococcus epidermidis and Cutibacterium spp, usually present Because of this variety in presentation, different phenotypes are in control skin. Flora variety and richness increase with severity,12,69 very likely to exist. Identifying these phenotypes could be of clinical Fusobacterium, Campylobacter and Dialister being encountered al- relevance since different phenotypes could have variable progno- most exclusively in Hurley stage III lesions.13 Thus, clinical severity sis and require different treatment strategies. One example based phenotype correlates with microbiological phenotype, suggesting on geography is that Asian HS patients are more likely to be male different antimicrobial strategies according to severity. Using an- and have gluteal disease.61 Whether this relates to differences in tibiotic combinations targeted against isolated flora resulted in genotype, for example mutations in gamma secretase, remains to be complete remissions in Hurley stage I patients 71,72 and a dramatic investigated. improvement in patients with severe HS.73 In 2013, Canoui-Poitrine et al were the first to propose three Furthermore: phenotypes.62 However, it received little attention for a long period of time. Currently, the age of biologic HS treatment is fuelling HS re- • Two studies also demonstrated biofilm presence in HS lesions, search and phenotypes are more relevant than ever. More recently, mostly in severe forms,74,75 explaining constant relapses in previ- Martorell et al 63 as well as van der Zee et al 64 proposed a set of ous scars. phenotypes. However, there are still important obstacles to over- • Dysbiosis was confirmed in uninvolved HS skin by 3 teams.6,76,77 come. For instance, the Canoui-Poitrine types have only a modest • An immune deficiency towards commensal gut flora was reported interrater reliability and are therefore of limited use in clinical prac- in patients with Crohn's disease carrying a NOD2 mutation,78 tice and research settings. The clinical importance of the Martorell while some HS patients can present with both diseases. phenotypes has yet to be tested and the van der Zee types have not been statistically tested. All these data suggest a pathogenic role of the isolated flora, in- For future use to guide treatment, phenotypes must be clini- troducing a new concept of host-microbiome disease for HS. Instead cally distinctive and have a high inter- and intra-rater reliability. The of a purely autoinflammatory process with an unclear mechanism, importance of this was recently demonstrated when Frew et al at- HS could be considered as “auto-infectious,” due to a strictly cuta- tempted to retrospectively label phenotypes to previous genetic HS neous immune dysregulation. This deficiency would allow abnormal publications.65 A repeat of the process by another group resulted in bacterial proliferation with toxin production and an inappropriate a very different outcome.66 hyper-inflammatory host response, instead of bacterial elimination At the moment, the problem shared by all these phenotypic clas- from the dermis. This model could open avenues for novel treat- sifications is that they are based on analysis of relatively few cases ments and research for HS and associated diseases. Many questions and most are retrospective. The data do not always include all of the remain concerning HS microbiology. Is early microbial shift contrib- phenotypic features and comorbidities. An agreed minimum HS phe- uting to follicular occlusion? Could loss of the "microbial shield" be notype dataset67 may be needed to ensure that different datasets partially restored with immunomodulation or microbiota transplan- can be combined to increase statistical power. tation, as explored in inflammatory bowel disease? Over recent years, the HS community has grown and we support Future microbiology studies should aim at demonstrating an ab- efforts to study phenotypes in a prospective, large, international normal transcriptomic response of skin/immune cells, when put into 1160 | ZOUBOULIS et al. contact with HS lesional flora, with different levels of immune dys- of draining fistulas was significantly decreased, pointing towards a regulation/deficiency, potentially leading to different phenotypes role of C5a in HS fistulization. and personalized strategies (Figure 3). In recent months, we have witnessed the spread of the novel coronavirus, SARS-CoV-2, which resulted in a global health emer- gency. COVID-19 caused by SARS-CoV-2 is associated with an acute 8 | COMPLEMENT, COVID-19 AND respiratory illness that varies from mild to the acute respiratory dis- HS: WHAT WE LEARN FROM THIS tress syndrome (ARDS).83 Severe patients have complex immune ASSOCIATION? dysregulation dominated either by macrophage activation syndrome or IL-6 hyperfunction.84,85 Complement activation is a common if Complement split products, like complement 5a (C5a), mediate neu- not fixed feature of ARDS. C5a is elevated and has been proposed trophil chemotaxis and may play some role in HS pathogenesis.79,80 as a marker of ARDS associated with sepsis, cytokine storm and mul- Indeed, C1q, C2 and factor B were found to be up-regulated and tiorgan dysfunction.86,87 Accumulating evidence shedding light on factor H, factor D and C7 downregulated in HS. C5a is produced complement over-activation in severe COVID-19 turned attention through C5 cleavage which is mediated by C5 convertase. Activation to the therapeutic role of complement inhibitors.88 The PANAMO of C5 convertase is converging towards all classical, alternative and trial that investigates the efficacy of IFX-1 in severe COVID-19 is lectin pathways. C5a was significantly increased in the plasma of already under way.89,90 The reported beneficial responses of IFX-1 in patients with HS. Surprisingly, C5a was lower among patients with HS generate thoughts on the C5a kinetic interplay mediating ARDS Hurley stage III HS than Hurley stage I, driving the hypothesis that at acute activation and HS fistulization at chronic activation. At the C5a is consumed as HS worsens. Excess TNF-α was produced by the same time, COVID-19 pandemic did not seem to affect the manage- peripheral blood mononuclear cells of patients upon enrichment of ment of HS with biologics.91 growth medium with plasma; this was significantly attenuated upon addition of the selective C5a blocker IFX-1.81 Twelve Hurley III patients refractory to anti-TNFs were treated with IFX-1. Hidradenitis 9 | TISSUE T AND B CELLS IN HS Suppurativa Clinical Response (HiSCR) was achieved in 75% at day 50 of treatment, while treatment responses were maintained three Observational studies in moderate-to-severe HS have identified up- months after end of treatment in 83.3%.82 Remarkably, the number regulated numbers of Th1, Th17, B cells, plasma cells, monocytes,

FIGURE 3 A new vision of hidradenitis suppurativa (HS) including microbiology in the whole picture. The concept makes HS to appear as a host-microbiome syndrome, with different microbiologic phenotypes, which happen to correlate with severity, evolution mode and therapeutic strategies that have to be different according to microbiology and severity. The role of biofilms, recently unravelled, persisting in scars and waking up to produce flares in scars only, also justify the necessary surgical treatment and sounds important to be mentioned in the chronic inflammatory loop. ZOUBOULIS et al. | 1161 dendritic cells and neutrophils in lesional HS tissue 15,18,92,93 (Figure 4). and functional investigation. The chemokine signature of HS lesional The characteristics of cellular infiltrates in early and mild HS remain tissue and dermal inflammatory architecture is suggestive of the unclear. Transcriptomic studies (verified by immunohistochemistry, possibility of tertiary lymphoid organs developing in chronic HS le- immune fluorescence and reverse transcription-polymerase chain sions.101 This would fit with the known roles of complement, auto reaction) demonstrate dramatic upregulation of genes associated inflammation and autoantibody development.15,18,92,93 with B and plasma cells (CD19, 25, 86, 138), T cells (CD3, 25), mono- Overall, the characteristics of HS lesions are well-described cytes, dendritic cells (CD207, 303) and neutrophils.4,41 Inflammatory but their interactions and mechanistic roles in disease activity and cell trafficking cytokines including CXCL13, IL-6 and IL-8 are con- progression remains unclear. Priorities for future research into the sistently up-regulated in HS tissue.4,15,18,92-94 HS patients have been mechanism of T- and B-cell function in HS include translational stud- shown to also have autoantibodies against citrullinated and extra- ies utilizing targeted monoclonal antibodies and examining the role cellular matrix proteins.93 Immunoglobulin producing plasma cells of cells in mild and early disease. 95 and B cells 96 are major producers of IgD, IgG, IgM, ASCA and anti-CCP antibodies 92,94,95 characterized in HS. The mechanisms of B-cell-mediated activation of other cells and potential pathogenicity 10 | CYTOKINES, CHEMOKINES AND HS are yet to be determined. Th17 cells are identified in HS lesional tissue as associated with epidermal psoriasiform hyperplasia 15,18,92,94 The excessive inflammatory response seen in lesional skin of HS is and transepithelial neutrophil migration across tunnel epithelium.97 thought to be triggered by a combination of genetic, anatomical, Perifollicular and interfollicular mixed inflammatory cell infil- immunological and environmental factors.94,102 Thereby cytokines trates have been identified in the superficial dermis of mild lesions; play a crucial role. Several studies showed that T cells and dendritic however, these are major attractors to inflammatory infiltrates in cells are responsible for the secretion of IL-23 and IL-12, leading to HS, independent of lesional or perilesional status,97 different from a Th17 predominant immune response and keratinocyte hyperpla- the infiltrate found in mild disease. These observations suggest lim- sia.16,23,94,102 Especially IL-23 has been shown to induce IL-17 pro- itations to our knowledge and the importance of defining precise ducing T-helper cells, which infiltrate the dermis in HS lesions.103 sample collections for mechanistic and clinical trial studies.98 The The IL-17 family of cytokines has been shown to be important mechanistic roles of these cells also remain speculative given the rar- in the pathogenesis of many autoimmune and autoinflammatory ity of reliable in vitro, ex vivo 99 and in vivo 100 disease models. The diseases especially also in psoriasis. IL-17 also plays an essential interaction between cell types is an area requiring further molecular role in host defence against extracellular bacteria and fungi and

FIGURE 4 Comparison of observed cellular tissue infiltrates in (A) Normal skin; (B) Hidradenitis suppurativa (HS) Non-Lesional Skin; (C) HS Mild Disease; (D) HS with Tunnels and (E) HS Severe Disease. While little mechanistic evidence exists to support the linear progression of this model, it is assumed that mechanisms exist to link the individual observed conditions in HS Tissue although this needs further experimental exploration and confirmation. HS, hidradenitis suppurativa, Th, T-helper cell 1162 | ZOUBOULIS et al.

FIGURE 5 Metabolic factors promoting the development of hidradenitis suppurativa. BMI, body mass index; HS, hidradenitis suppurativa it has been shown to increase the expression of skin antimicrobial hormones and particularly androgens seem to play a role in the peptides/alarmins, such as hbD2 and psoriasin.104 Blocking IL-17 pathogenesis of the disease.110 HS related-premenstrual flares,111 seems therefore a valid therapeutic approach also for HS. rare postmenopausal occurrence,112 improvement during preg- During disease progression, many different cytokines have been nancy, post-partum flare-ups113 and association of the disease with shown to be expressed in increased levels. Especially TNF-α has contraceptive pills with low oestrogen/progesterone ratio suggest been shown to be elevated. These findings resulted in the introduc- an endocrine pathophysiologic variable for the disease.114 A current tion of anti-TNF-α antibodies in the therapy of HS. As HS progresses, systematic review analysed the therapeutic use of antiandrogens increased levels of TNF, IL-1, IL-17, S100A8, S100A9, caspase-1 and for HS, focusing on cyproterone acetate, spironolactone, finas- IL-10 appear in the tissue accompanied by a recruitment of neutro- teride and the antidiabetic drug metformin.115 The yielded case phils, mast cells and monocytes.7,15,94,102,105-108 Recent evidence series do not provide the evidence level for wide use of hormonal further points to autoinflammatory mechanism in HS. HS skin treatment for HS, which remains limited to female patients with shows increased formation of neutrophil extracellular traps (NET). menstrual abnormalities, signs of hyperandrogenism (seborrhoea, Intriguingly, immune responses to neutrophil and NET-related an- acne, hirsutism, androgenetic alopecia) and/or increased serum tigens have been linked to enhanced immune dysregulation and in- androgens.116,117 flammation.93 In combination with the strong type I interferon (IFN) Obesity is one of the cardinal factors which predispose to HS signature in HS skin, these findings suggest a key involvement of and there seems to be an endocrine background fuelling a latent the innate immune system in the pathogenesis of this disease.43,109 proinflammatory state. In a cohort study from Denmark childhood, As healing from the inflammatory process moves on, tissue scarring BMI was positively and significantly associated with risk of HS de- progresses.94,102,105 The development of scarring and sinus tracts velopment in adult age.118 Returning to normal weight before pu- is associated with metalloproteinase-2, tumor growth factor(TGF)-β berty was found to reduce risks of HS to levels of not overweight 119 and ICAM-1, with possible augmentation of TGF-β and ICAM-1 sig- children. Insulin resistance is common in HS. Current molecular nalling via specific components of the microbiome.94,102 studies focus on inflammation, while the correlation with hormonal treatments might be overlooked. The antidiabetic drug metformin exhibits an anti-inflammatory effect potentially reducing IL-6, TNF-α 11 | SEX HORMONES AND HS: WHAT‘S and IL-17 through decrease of Th17 cells, Treg and suppression of NEW? the NFκB complex. Prospective and retrospective case series and case reports provide evidence for its use.120,121 The role of hormones in HS remains to be elucidated (Figure 5). What is the window of opportunity for hormonal treatment of Gender predilections differ among races, as reported above. Sexual HS especially in the biologic era of HS? Could a major repurposing of ZOUBOULIS et al. | 1163 available hormonal medications for cutaneous diseases contribute Among the inflammatory mediators produced by adipocytes are to HS treatment? arachidonic acid-derived polyunsaturated fatty acids (PUFAs) of the Indeed, there are cases of HS, where patients have lost response ω6 class, the so-called eicosanoids. High-fat diet and in particular to antibiotics and still experience frequent flares of mild disease and western diet containing a high ω-6/ω-3 ratio can further enhance do not qualify for adalimumab treatment or for other upcoming bi- the release of arachidonic acid-derived lipid mediators by adipo- ologic treatments. In such cases, hormonal treatments might pro- cytes.132,133 Adipocytes are among the few non-leucocyte cell types vide a cost-effective alternative. Moreover, certain comorbidities, that possess the enzymatic machinery to produce the proinflam- such as severe heart insufficiency, do not allow the use of anti-TNF matory eicosanoid leukotriene B4 (LTB4), which confers not only treatment. In such cases, alternative hormonal therapies, such as the macrophage and neutrophil infiltration and activation but also con- diuretic spironolactone, which has antiandrogen properties, might tributes to insulin resistance and has been implicated with increased hold promise. cardiovascular risk.134,135 Interestingly, comprehensive PUFA lipid- omics analysis of HS skin lesions has recently identified LTB4 as the most dominantly up-regulated proinflammatory lipid mediator in HS 12 | CARDIOVASCULAR RISK FACTORS lesions, produced mainly by lesional macrophages.136 The potential AND THEIR POTENTIAL CONTRIBUTION TO contribution of proinflammatory LTB4 to dysregulated innate immu- THE PATHOMECHANISM OF HS nity in HS is currently investigated in clinical trials, and it is tempting to speculate that elevated levels of this inflammatory mediator may There is strong epidemiologic evidence that cardiovascular risk also contribute to metabolic syndrome-associated comorbidities in factors appear at a significantly higher rate in HS patients as com- HS. pared to healthy individuals. Among those risk factors, which are also commonly associated with metabolic syndrome, are obesity and in particular central obesity, insulin resistance, diabetes and 13 | SMOKING AND HS dyslipidaemia,122 as already highlighted above (Figure 5). HS is significantly related to presence of carotid plaques and increased HS is a tobacco-related skin disease.137 The role and mechanisms frequency of subclinical atherosclerosis and is associated with a of cigarette smoke (CS) in HS remain speculative. CS is composed significantly increased risk of adverse cardiovascular outcomes of numerous chemicals, whereas nicotine, benzopyrenes and dioxin- and all-cause mortality independent of measured confounders.123 like compounds are the most well-known. Notably, the risk of cardiovascular death is 58% higher in patients The natural ligands of nicotine are the nicotinic acetylcholine with HS than in patients with severe psoriasis.124 Obesity affects receptors (nAChRs), which are identified in skin keratinocytes, se- the overall morbidity and prognosis of patients with HS and weight bocytes and immune cells constituting the non-neuronal cholin- reduction can have a beneficial effect on HS prevalence and se- ergic system.138 Many HS patients are heavy smokers, since they verity and even lead to spontaneous resolution of disease.125,126 use tobacco to alleviate symptoms of anxiety and depression.139 Obesity elicits a low-grade systemic inflammation caused by adi- Variability in genes that encode nAChR subunits is associated with pocytes that secrete metabolically active proinflammatory media- multiple smoking phenotypes 140 and could explain a certain profile tors known as adipokines. The secretion of adipokines has been of HS smokers. Nicotine negatively impacts keratinocyte functions, found to be dysregulated in HS. These propagate the inflammatory including the stimulation of chemotaxis, cytokine release and oxida- cascade by recruiting macrophages to the adipose tissue, which tive stress 141 and also stimulates keratinocyte differentiation and release further proinflammatory mediators. In this regard, it has epithelial hyperplasia.142 In epidermis of patients with HS, there is been reported that the adipokines resistin and leptin were found a strong expression of nAChR around the pilosebaceous unit lead- increased in patients’ serum and adiponectin was decreased.127 ing to infundibular epithelial hyperplasia and follicular plugging.143 High systemic inflammatory burden may cause a state of insu- Furthermore, studies have revealed highly potent effects of the lin resistance in inflamed tissues which is causally linked to en- cholinergic system on sebocyte proliferation and lipid production in dothelial dysfunction and atherosclerosis.128 As a result, reduced vitro, but the role in HS is unclear.144 adiponectin and increased resistin serum levels have been iden- In addition, CS appears to further stimulate the dysbiosis-driven tified as surrogate biomarkers for insulin resistance in patients aberrant activation of the innate immune system in HS. Nicotine, with HS.129 Resistin and visfatin were proposed to be involved as an alkaloid, appears to promote growth of Staphylococcus aureus, in HS pathogenesis.130 Moreover, nutritional excess in metabolic thus modifying the microbiome145 and inhibits the synthesis of anti- syndrome can lead to adipose tissue expansion and adipocyte hy- microbial peptides, such as hbD2, rendering the follicle more suscep- pertrophy associated with increased release of inflammatory me- tible to bacterial invasion.146 diators. In subcutaneous adipose tissue, this can cause cutaneous Smokers in comparison with non-smokers exhibit higher serum 147 inflammatory responses but also spill-over of inflammatory media- levels of proinflammatory cytokines and TNF-α. Human bronchial tors into the systemic circulation contributing to progression of epithelial cells release IL-1β and express caspase-1 via stimulation the metabolic syndrome.129,131 of Toll-like receptors, after incubation with CS.148 In mouse models, 1164 | ZOUBOULIS et al. nicotine was found to activate NLP3 inflammasome.149 Smoking ad- a proinflammatory state that may underlie follicular instability and versely affects the Th17/Treg balance. It has been associated with promote the inflammatory response. increased expression of Th17 cells, IL-17 expression and impaired HS pathogenesis involves both hair follicle disruption and a numbers or function of Tregs.150 Furthermore, downregulation of robust immune response 163; however, the hfSCs at the bulge are Notch pathway gene expression has been reported in association immune privileged, lacking MHC I expression. It is theorized that al- with smoking.151 opecia areata (AA) is caused by the loss of immune privilege at the Finally, dioxin-like compounds and benzopyrenes of CS trigger in hair follicle either due to disruption of the hair follicle epithelium vivo and in vitro the aryl hydrocarbon pathway which is present on or a dysregulated immune response.164,165 HS has been associated keratinocytes, sebocytes and immune cells.152,153 Exposure to ex- with multiple inflammatory and autoimmune diseases, including tremely high concentrations of dioxins induces hyperkeratinization AA.166,167 In a Korean study, AA was more common in patients 166 of the pilosebaceous unit and a metaplastic response of the seba- with HS than in patients without HS (adjusted odds ratio = 1.35). ceous glands producing clinical lesions of chloracne,154 whose clin- Similarly, AA was also more common in patients with HS (adjusted 155 168 ical features are highly similar to the “smokers’ boils” in HS. The odds ratio = 1.99) in a US study. The lesions of HS and AA have possible actions of CS in HS are summarized in Figure 6. considerable overlap in inflammatory cytokines, including TNF- α, IL-17, IFNs, chemokine ligands 9 and 10, granzyme B, and oth- ers.43,164 It is not known yet if inflammatory phenotype of hfSC in 14 | HAIR FOLLICLE STEM CELL HS leads to the loss of hair follicle progenitor cells promoting AA; REPLICATION DISORDER VS. ALOPECIA however, investigating the association between these two diseases AREATA COMORBIDITY VS APOCRINE may help elucidate the pathogenesis of each. GLAND DISEASE: WHERE IS THE EVIDENCE? 15 | WHAT WE LEARN FROM “ECTOPIC” From its naming, the apocrine gland was implicated as a major AND “SYNDROMIC” HS? contributor in HS pathogenesis. In contrast, histopathologic and molecular studies indicate significant involvement of the hair fol- Recent attempts to classify HS phenotypes have distinguished “typi- licle with secondary apocrine gland injury.156-159 There are a num- cal” and “atypical” HS 169; syndromic and ectopic HS belong to the ber of changes in the hair follicle including an occluding spongiform latter. Autoinflammatory syndromes associated with HS and/or acne inflammation in the infundibulum with predominantly T cells and are rare.170 Their common pathogenic feature is an over-activation 157,160 infundibular disintegration in early lesions. Hair follicle ke- of innate immunity with aberrant activation of IL-1 and IL-17/TNF-α ratinocytes also produce more proinflammatory cytokines and axis resulting in the formation of neutrophilic infiltrate.171 The have an altered pattern of antimicrobial peptide production.15 onset of HS as part of their skin involvement raised the hypoth- Impaired hair follicular stem cells (hfSCs) homeostasis leading to esis to reconsider HS as a Th17-driven autoinflammatory disease. an increased proliferation induces stress replication and stimulates Interestingly, mutations in PSTPIP1 gene, that encodes for compo- type I IFN production which participates to the strong inflamma- nents of the inflammasome, a cytosolic multiprotein oligomers re- tory skin reaction.161 Dysregulation of the T reg/Th17 axis may sponsible for the IL-1 synthesis have been described in 2 forms of also impact hfSCs and subsequently lead to structural instability syndromic HS,19 the PASH syndrome 19,20,172 and the PAPASH syn- of the infundibulum.95,162 Thus, the follicle cells are altered towards drome defined by the PASH triad of pyoderma gangrenosum, acne

FIGURE 6 The possible actions of cigarette smoking in hidradenitis suppurativa. AhR, aryl hydrocarbon receptor; nAChRs, nicotinic acetylcholine receptors ZOUBOULIS et al. | 1165

173 and HS and the presence of pyogenic arthritis. The addition of burden. Soluble TNF-α receptor, IL-6, IL-17 and IL-23 have been either spondylarthritis (PASS) 174 or psoriatic arthritis (PsAPASH) 175 found to increase the blood-brain and blood-spinal cord barrier to the triad has also been described but associated mutations are not permeability, potentially aiding the infiltration of immune cells and identified. It is crucial to increase the awareness about syndromic inflammatory mediators into the central nervous system.190 Here, HS and the use of drugs that target IL1-TNF-α/IL-17 may represent these inflammatory cytokines may influence synaptic transmission attractive therapeutic options.176 analogous to locally released cytokines.185,187,189 Therefore, not In opposite, ectopic forms of HS do not develop regarding typical only analgesics or selective serotonin reuptake inhibitors, but also intertriginous and apocrine gland-bearing skin areas and may affect anti-inflammatory/immunomodulating therapies, could play an im- convex and/or apocrine gland-free areas (ear, chest, neck, nape, leg). portant role and significantly alleviate the intensity of pain and itch Local mechanical stress represents the main triggering factor 177,178 sensation.191 including friction, shearing and pressure. Mechanical follicular occlusion could be a mechanism by which local trauma would promote HS onset and molecular signalling underlying mechano-transduction 17 | PATHOGENESIS-ASSOCIATED should be explored. Interestingly, γ-secretase mutations causing im- FUTURE THERAPIES paired Notch pathway and thereby promoting Th17-driven inflammation have been reported in small numbers of HS cases.26 Whether Our modern understanding of the pathogenetic pathways that drive mechanical-induced alterations in the Notch pathway could also re- hidradenitis suppurativa is rapidly emerging. New tools that allow sult in apocrine metaplasia of eccrine glands could be discussed,179 the characterization of the microbiome, proteome and transcrip- since Notch has been identified as a regulator of skin stem cells tome are opening up new avenues of investigation.192 But perhaps fate.180 most interesting is the in vivo exploration of new targeted immunologic therapies. The use of new agents is likely to accelerate our understanding as they present the opportunity to use clinical effec- 16 | HOW ITCH AND PAIN OCCUR IN HS? tiveness to validate relevant patterns. Indeed, the pathogenetic patterns of HS are likely to be elucidated from bedside to bench, even It is obvious that pain accompanies HS, as the vast majority (95.2%- as they are from bench to bedside. Conducting inclusive, long-term, 97.1%) of patients, report it during the disease course.181,182 It is per- controlled multi-centre clinical trials investigating different biologi- ceived as the most troublesome symptom of HS.181 Although one cal agents or drugs with ancillary analyses of transcriptomes will leap decade ago HS was not considered a pruritic disease, itch is also a forward the HS patient journey. These will build the foundations to common HS-associated symptom (62.1%-77.5% of reporting pa- fully integrate our HS transcriptome knowledge with clinical records, tients) that adversely affects patients’ quality of life.181-183 Of note, epidemiologic and demographic factors.98 the co-occurrence rate of pain and itch in one location was surpris- To date, however, HS remains a “messy” immunologic disease. ingly high, as reported by 59.5%-74.9% of patients.181,182 Many cytokines have been identified in histologic samples, but the It could be assumed that both, acute pain observed during flare- sequence of the pattern and the key initiators are still a work in ups and itch frequently reported in the initial phase of HS (as a progress. A recent paper by Frew et al65 demonstrated no consistent prodrome) have a noci/-pruriceptive character, linked to the local cytokine patterns. However, the inhibition of TNF-α, IL-1 and IL-17 activation of cells of the innate and adaptive immune systems, with has been validated in clinical trials as relevant. Other transcriptomic pivotal roles for proinflammatory cytokines and various chemok- studies have reaffirmed their role and have additionally suggested ines, which can bind directly to their specific receptors on the pe- that androgen receptor, interferon-γ, IL-6, Growth Arrest-Specific ripheral terminals of the afferent nociceptive neurons.9,184-187 The 6, Glial Cell-Derived Neurotrophic Factor and Hepatocyte Growth unrestricted and chronic immune response observed in HS leads to Factor are viable targets using currently available agents (Table 1). pyroptosis resulting in irreversible tissue destruction and scar de- There is also early data suggesting that IL-23, C5a and Janus kinase velopment. This could alter the character of subjective symptoms inhibitors may be successful targets. and lead to the development of neuropathic pain and/or itch being As both targeted and multimodality approaches are tested, it will a consequence of the nervous system structures damage, or some- be interesting to see whether, given the high inflammatory load, a times of prolonged, unremitting nerve stimulation. Neuropathic multimodality approach is more effective for induction, and more pain and itch are often associated with each other, and hypersen- targeted approaches are useful for maintenance. Generally, effec- sitization to stimuli is present in both pain and itch of neuropathic tive treatment of HS with targeted anti-TNF agents has required origin.188 Recent considerations regarding chronic pain in HS tried higher doses than other skin diseases even with weight-based dos- to explain this phenomenon through the process of central sen- ing.193,194 Moreover, the cytokine profile of lesional skin suggests sitization, which is the effect of first-order afferent nociceptive tamping down other parts of the inflammatory cascade simultane- neuron repeated and increased activation during chronic and re- ously could be useful. In any event, the number of effective agents current inflammation.189 HS may promote the central sensitization currently under study is enormously encouraging and will lead us to development through its highly expressed systemic inflammatory better understand the disease and help our patients. 1166 | ZOUBOULIS et al.

TABLE 1 Association of drug Strength of existing clinical repurposing studies with clinical Agent Mechanism of Action Targets data supporting effect experience in HS Apremilast Phosphodiesterase-4 IFNγ + TNF/TNF-α ++ inhibitor

Gentamycin Antibiotic GAS6 + IL17/IL17A Spironolactone Antiandrogen AR + TNF/TNF-α ++ Thalidomide Immune modulator HGF + TNF/TNF-α Prednisone Immune suppressor NFκB +

18 | WHAT ARE WE EXPECTING IN THE Astellas, AxisShield, bioMérieux, InflaRx, ThermoFisher Brahms and FUTURE? XBiotech; and funding from the FrameWork 7 program HemoSpec (granted to the National and Kapodistrian University of Athens), Although a huge amount of knowledge has accumulated in the the Horizon2020 Marie-Curie Project European Sepsis Academy last 15 years, including simplified diagnostic criteria for early rec- (granted to the National and Kapodistrian University of Athens), ognition of the disease,195 we are just at the beginning of under- and the Horizon 2020 European Grant ImmunoSep (granted to standing HS and being able to treat it effectively. Future targets the Hellenic Institute for the Study of Sepsis). JWF was supported are emerging. Highly sophisticated molecular studies, such as next in part by a grant (no. UL1 TR001866) from the National Center generation sequencing analyses, will further increase the molecular for Advancing Translational Sciences (NCATS), National Institutes understanding of HS aetiology, which already has a solid basis due of Health (NIH) Clinical and Translational Science Award (CTSA) to current relevant studies.4,15,40-43 Through such reports, a clearer Program. HF has received honoraria for speaker and/or consultancy association of different clinical phenotypes 62-65 with relevant mo- from AbbVie, Boehringer-Ingelheim, Celgene, Eisai, Eli Lilly, Novartis, lecular expression patterns may be recognized, which will fulfil the Janssen-Cilag, Marho, Sanofi, Taiho, Tanabe-Mitubishi and UCB. PG requirements of personalized medicine in HS. Clinical and labora- received honoraria from AbbVie and Novartis as a consultant and tory biomarkers may accompany improved clinical outcome meas- provided lectures for AbbVie, Brothier, Cicaplus, Coloplast, Inresa ures 10,11,196 for better monitoring of the disease course. Robust ex and Novartis. MAG-L reports consultation fees/participation in com- vivo models might corroborate clinical data.197 Clearer documenta- pany-sponsored speaker's bureau from Abbvie. WPFG reports grants tion and newer diagnostic techniques, such as standardized photog- and research support by AbbVie, Amgen, Eli Lilly, Novartis, Pfizer; raphy, ultrasound and thermography 66,198-200 together with apps honoraria for invited talks and consultation by AbbVie, Actelion, for prospective evaluation of relevant patient outcome measures, Amgen, Arylide, Bausch Health, Boehringer, Celgene, Cipher, Eli lilly, such as daily assessment of pain,194 may lead towards the digitaliza- Galderma, Janssen, LEO, Novartis, PeerVoice, Pfizer, Sanofi, Tribute, tion and objectification of clinical follow-up. Ultimately, successful UCB, Valeant; and study fees from clinical trials by AbbVie, Asana, early HS treatment will aim to spare HS patients from progression Astellas, Boehringer-Ingleheim, Celgene, Corrona/National Psoriasis of the disease and preventing large surgical excisions, complications Foundation, Devonian, Eli Lilly, Galapagos, Galderma, Janssen, LEO, and recurrence. Novartis, Pfizer, Regeneron, UCB. IH reports consultation fees/ participation in advisory board of AbbVie; grant/research funding ACKNOWLEDGMENT from AbbVie, Allergan, Bayer, Bristol-Myers Squibb, Clinuvel, Estee Open access funding enabled and organized by ProjektDEAL. Lauder, Ferndale, Galderma, GE, Incyte, Janssen-Cilag, Johnson & Johnson, Lenicura, L’Oreal, LP, Merck, PCORI, Pfizer, Unigen; and CONFLICT OF INTEREST consulting fees from Incyte. BH reports fees from AbbVie, Akari, All authors declare that none of the mentioned conflicts of interest Celgene, Janssen-Cilag, Novartis and UCB for advisory boards, had any influence to this manuscript. CCZ has received thematically AbbVie, Janssen-Cilag, LEO, Novartis, Philips, Roche, Regeneron, relevant honoraria from AbbVie as advisor and conference speaker Sanofi and UCB for consultations; AbbVie, Akari, Celgene, Janssen- and from Idorsia, Incyte, Inflarx, Janssen-Cilag, Novartis, Regeneron Cilag, Novartis and Solenne for investigator initiative studies, and and UCB as advisor. His departments have received grants from AbbVie and Janssen-Cilag for educational grants, which fees were AbbVie, AOTI, Astra Zeneca, Galderma, Inflarx, Naos-Bioderma, payed to the institution. REH has received thematically relevant Novartis, PPM and UCB for his participation as clinical investiga- honoraria from AbbVie and Novartis. JRI is a consultant to Kymera tor. NSC has received fees from AbbVie, Johnson & Johnson and Therapeutics, Novartis, UCB and Viela Bio, and has received a Sanofi for participation in advisory boards, investigator fees for speaker's honorarium from UCB and travel expenses from AbbVie clinical trials from AbbVie, Novartis and Sanofi and speaker hono- and UCB. GBEJ has received honoraria from AbbVie, Chemocentryx, raria from Galderma, Johnson & Johnson and LEO. EJG-B has re- Coloplast, Incyte, Inflarx, Kymera Therapeutics, LEO, Novartis and ceived honoraria from Abbott, Angelini, bioMérieux, InflaRx, MSD UCB for participation on advisory boards, and grants from Abbvie, and XBiotech; independent educational grants from AbbVie, Abbott, Astra-Zeneca, Inflarx, Janssen-Cilag, LEO, Novartis, Regeneron and ZOUBOULIS et al. | 1167

Sanofi for participation as an investigator, and received speaker hon- AUTHOR CONTRIBUTION oraria from AbbVie, Boehringer-Ingelheim, Galderma and Novartis. Christos C. Zouboulis, Farida Benhadou, Angel S. Byrd, Nisha He has also received unrestricted departmental grants from LEO S. Chandran, Evangelos J. Giamarellos-Bourboulis, Gabriella and Novartis. JSK reports fees from AbbVie, Incyte, Viela Bio for Fabbrocini, John W. Frew, Hideki Fujita, Marcos A. González-López, advisory boards, AbbVie, ChemoCentryx, Incyte, Novartis, Bayer, Philippe Guillem, Wayne P. F. Gulliver, Iltefat Hamzavi, Yildiz Hayran, UCB for consultations and AbbVie as speaker. MPK is investiga- Barbara Hórvath, Sophie Hüe, Robert E. Hunger, John R. Ingram, tor for Abbvie, Boehringer-Ingelheim, Celgene, Eli Lilly, Janssen, Gregor B. E. Jemec, Qiang Ju, Alexa B. Kimball, Joslyn S. Kirby, Maria Novartis, Pfizer and UCB and has received honoraria from AbbVie, P. Konstantinou, Michelle A. Lowes, Amanda S. MacLeod, Antonio Eli Lilly, LEO and Novartis. ABK is consultant and Investigator for Martorell, Angelo V. Marzano, Łukasz Matusiak, Aude Nassif, Elena Abbvie, Eli Lilly, Janssen-Cilag, Novartis, Pfizer and UCB, consult- Nikiphorou, Georgios Nikolakis, André Nogueira da Costa, Martin ant for Kymera Therapeutics, investigator for ChemoCentryx and M. Okun, Lauren A. V. Orenstein, José Carlos Pascual, Ralf Paus, Board of Directors for Almirall and received fellowship funding Benjamin Perin, Errol P. Prens, Till A. Röhn, Andrea Szegedi, Jacek from AbbVie and Janssen-Cilag. MAL has served on the advisory C. Szepietowski, Thrasyvoulos Tzellos, Baoxi Wang and Hessel H. boards for Abbvie, Janssen-Cilag, and Viela Bio, and consulted for van der Zee wrote a part of the manuscript, read and approved the Almirall, BSN, Incyte, Janssen-Cilag, Kymera Therapeutics, and final manuscript. XBiotech. ASM is supported by funds from the National Institute of Health (R01AI139207) and the Department of Dermatology of DATA AVAILABILITY STATEMENT Duke University. She reports fees from Silab (consultancy, grant, The authors confirm the absence of shared data. speaker honorarium). Silab had no involvement, influence or decision on the content of this manuscript or the decision to publish. ASM ORCID also reports fees from the LEO Foundation (Scientific Evaluation Christos C. Zouboulis https://orcid.org/0000-0003-1646-2608 Committee) and her spouse is employed at Precision Biosciences Evangelos J. Giamarellos-Bourboulis https://orcid. and holds stock and stock options in this company. AM has served org/0000-0003-4713-3911 as a consultant for and received speaker fees from AbbVie, Celgene, John W. Frew https://orcid.org/0000-0001-5042-3632 Eli Lilly, Isdin, Janssen-Cilag, LEO, MSD, Novartis, Pfizer and UCB. Marcos A. González-López https://orcid. ŁM reports personal fees from AbbVie, Amgen, Galapagos, InflaRx, org/0000-0003-2423-5800 Janssen-Cilag, LEO, Menlo, Novartis, Pfizer, Pierre Fabre, Regeneron, José Carlos Pascual https://orcid.org/0000-0001-8279-215X Trevi and UCB. ANdC is an AstraZeneca employee and owns Jacek C. Szepietowski https://orcid.org/0000-0003-0766-6342 AstraZeneca stocks. AstraZeneca had no involvement, influence or decision on the content of this manuscript. LAVO is supported by REFERENCES funds from the National Institute of Health (K12D085850). She is an [1] Kurzen H, Kurokawa I, Jemec GBE, et al. Exp Dermatol. 2008;17:455. investigator for ChemoCentryx. JCP reports honoraria from AbbVie [2] Garg A, Neuren E, Cha D, et al. J Am Acad Dermatol. 2020;82:366. [3] Reddy S, Strunk A, Garg A. JAMA Dermatol. 2019;155:797. for participation on advisory boards. MMO received honoraria from [4] Zouboulis CC, Nogueira da Costa A, Makrantonaki E, et al. 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TT reports fees from AbbVie, UCB and Sanofi (consultancy, speaker [16] Thomi R, Schlapbach C, Yawalkar N, Simon D, Yerly D, Hunger RE. honorarium). HHvdZ reports fees from AbbVie and InflaRx. FB, ASB, Exp Dermatol. 2018;27:172. GF, YH, SH, QJ, MPK, AVM, AN, EN, GN, BP and BW declare no [17] Constantinou CA, Fragoulis GE, Nikiphorou E. Ther Adv conflict of interest. Musculoskelet Dis. 2019;11:1759720X19895488. 1168 | ZOUBOULIS et al.

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