Uniwersytet Jagielloński Collegium Medicum Wydział lekarski Katarzyna Kaleta Epidemiologia, czynniki ryzyka oraz nowe podejście immunohistochemiczne mające na celu poznanie patogenezy wybranych chorób mieszków włosowych (acne inversa i acne vulgaris). Epidemiology, risk factors, and novel immunohistochemical approach aiming to undercover the pathogenesis of selected diseases of the pilosebaceous units (acne inversa and acne vulgaris). Praca doktorska -cykl prac Promotor: prof. dr hab. n. med. Anna Wojas-Pelc Pracę wykonano: w następujących jednostkach: • Katedra i Klinika Dermatologii Colegium Medicum, Uniwersytet Jagielloński. Kierownik jednostki: prof. dr hab. n. med. Anna Wojas-Pelc • Departments of Dermatology, Venereology, Allergology and Immunology, Dessau Medical Center, Brandenburg Medical School Theodore Fontane, Dessau, Niemcy. Kierownik jednostki: Univ-Prof. Dr. med. Prof. h.c. Dr. h.c. Christos C. Zouboulis Kraków, 2021 Pragnę złożyć serdeczne podziękowania mojej promotor, Pani Profesor Annie Wojas-Pelc za umożliwienie rozwoju naukowego. Mojemu kierownikowi specjalizacji, Pani dr n. med. Monice Kapińskiej-Mrowieckiej za zaszczepienie we mnie pasji do dermatologii. Panu Profesorowi Christosowi Zouboulisowi za zaufanie, możliwość współpracy i przekazaną wiedzę. Rodzicom i wszystkim moim Najbliższym za wsparcie oraz wiarę we mnie. 2 Skróty AI (łac. acne inversa) -trądzik odwrócony AFA (ang. adult female acne) -trądzik kobiet dorosłych AhR (ang. aryl hydrocarbon receptor) -receptor węglowodorów aromatycznych AiKDs (ang. autoinflammatory keratinization disorders) -autozapalne zaburzenia keratynizacji AMP (ang. antimicrobial peptides) -peptydy antybakteryjne AV (łac. acne vulgaris) -trądzik pospolity BMI (ang. body mass index) -wskaźnik masy ciała C. acnes -Corynebacterium acnes DAB (ang. 3,3’-diaminobenzidine) -3,3’-diaaminobenzydyna EGFR (ang. epidermal growth factor receptor) -receptor naskórkowego czynnika wzrostu FNDC5 (ang. fibronectin type III domain-containing protein 5) -błona typu I zawierająca białko 5 domeny fibronektyny typu III HOMA-IR (ang. Homeostasis Model Assessment of Insulin Resistance) -model homeostazy oporności na insulinę HS (łac. hidradenitis suppurativa) -trądzik odwrócony IGF-1 (ang. insulin-like growth factor -1) -insulinopodobny czynnik wzrostu 1 IHC (ang. immunohistochemistry) -badanie immunohistochemiczne IL -interleukina IFNγ -interferon gamma miRNA -mikro RNA, kwas rybonukleinowy MRP 8 (ang. myeloid-related protein 8) -kalgranulina A mTORCH (ang. mammalian target of rapamycin complex 1) -kompleks 1 kinazy treoninowo-serynowej ssaczy cel rapamycyny NLRP3 (ang. NLR family pyrin domain containing 3) -domena pirynowa z rodziny NLR 3 OS (ang. obese, smoking) -otyli palacze PAPASH (ang. pyoderma gangrenosum, acne vulgaris, pyogenic arthritis, hidradenitis suppurativa) -piodermia zgorzelinowa, trądzik zwyczajny, ropne zapalenie stawów, trądzik odwrócony PASH (ang. pyoderma gangrenosum, acne vulgaris, hidradenitis suppurativa) -piodermia zgorzelinowa, trądzik zwyczajny, trądzik odwrócony PASS (ang. pyoderma gangrenosum, acne vulgaris, hidradenitis suppurativa, ankylosing spondylitis) -piodermia zgorzelinowa, trądzik zwyczajny, trądzik odwrócony, seronegatywne zapalenie stawów osiowych PCB -polichlorowane bifenyle PG (łac. pyoderma gangrenosum) -piodermia zgorzelinowa PPAR-γ (ang. peroxisome proliferator-activated receptor gamma) -receptor gamma aktywowany przez proliferator peroksysomów PsAPASH (ang. psoriatic arthritis, pyoderma gangrenosum, acne vulgaris, hidradenitis suppurativa) -łuszczycowe zapalenie stawów, piodermia zgorzelinowa, trądzik zwyczajny, trądzik odwrócony PRISMA (ang. preferred reporting items for systematic reviews and meta-analyses) PSTPIP 1 (ang. proline-serine-threonine phosphatase-interacting protein 1) -białko 1 reagujące z fosfatazą, zawierające strukturę prolina-seryna-treonina SAPHO (ang. synovitis, acne vulgaris, pustulosis, hyperostosis, osteitis) -zapalenie błony maziowej, trądzik zwyczajny, łuszczyca krostkowa, przerost oraz zapalenie kości TCDD -2,3,7,8-tetrachlorodibenzo-p-dioksyna Th (ang. T helper) -limfocyty T pomocnicze TLR (ang. toll -like receptor) -receptor toll podobny TNF-α (ang. tumor necrosis factor α) -czynnik martwicy nowotworów alfa NN (ang. non obese, non smokers) -osoby nieotyłe, niepalące 4 SPIS TREŚCI 1. WYKAZ PUBLIKACJI WCHODZĄCYCH W SKŁAD PRACY DOKTORSKIEJ ... 6 2. WSTĘP I UZASADNIENIE PRACY .................................................................................. 7 2.1. DEFINICJE I EPIDEMIOLOGIA ................................................................................................ 7 2.2. PATOFIZJOLOGIA, CZYNNIKI RYZYKA I ROLA STANU ZAPALNEGO...................................... 10 2.3. NOWE KIERUNKI BADAŃ Z INNEJ PERSPEKTYWY................................................................ 15 3. CELE PRACY .................................................................................................................... 17 4. METODOLOGIA PRAC SKŁADAJĄCYCH SIĘ NA DYSERTACJĘ ........................... 18 5. PODSUMOWANIE WYNIKÓW ...................................................................................... 20 6. WNIOSKI I IMPLIKACJE PRAKTYCZNE ..................................................................... 24 7. PIŚMIENNICTWO............................................................................................................. 28 8. STRESZCZENIE ................................................................................................................ 35 9. TEKSTY PUBLIKACJI WCHODZĄCYCH W SKŁAD ROZPRAWY DOKTORSKIEJ...................................................................................................................... 39 10. OŚWIADCZENIA WSPÓŁAUTORÓW………………………………………...……86 5 1. Wykaz publikacji wchodzących w skład pracy doktorskiej Publikacja nr 1 Tytuł: The Skin as a Mirror of Internal Disease: Comorbidities and Epidemiology of Acne Vulgaris and Adult Female Acne -A Cross-sectional Study and Current State of Knowledge. Autorzy: Katarzyna Kaleta, Anna Bogusławska, Anthanosios J. Stefanis, Agata Kłosowicz, Natalia Juśko, Monika Kapińska-Mrowiecka, Elżbieta Broniatowska, Anna Wojas-Pelc. Czasopismo: Acta Dermatovenerologica Croatica, 2020; 28(3): 133-140. PMID: 33422166. Impact Factor: 1,256. Punkty ministerialne: 40 Publikacja nr 2 Tytuł: Metabolic disorders/obesity is a primary risk factor in hidradenitis suppurativa: an immunohistochemical real-world approach. Autorzy: Katarzyna Kaleta, Georgios Nikolakis, Amir M. Hossini, Ottfried Balthasar, Daifallah Almansouri, Aristeidis G. Vaiopoulos, Jürgen Knolle, Anna Bogusławska, Anna Wojas-Pelc, Christos C. Zouboulis. Czasopismo: Dermatology, 2021; 22: 1-9. DOI: 10.1159/000517017. Impact Factor: 5,366. Punkty ministerialne: 100 Publikacja nr 3 Tytuł: Phenotypes and Pathophysiology of Syndromic Hidradenitis Suppurativa: Different Faces of the Same Disease? A Systematic Review. Autorzy: Georgios Nikolakis*, Katarzyna Kaleta*, Aristedis G. Vaiopoulos, Katja Wolter, Sumer Baroud, Anna Wojas-Pelc, Christos C. Zouboulis. * równorzędne pierwsze autorstwo Czasopismo: Dermatology, 2020; 17:1-25. DOI: 10.1159/000509873. Impact Factor: 5,366. Punkty ministerialne: 100 6 2. Wstęp i uzasadnienie pracy 2.1. Definicje i epidemiologia Trądzik pospolity (trądzik zwyczajny, acne vulgaris, AV) jest najczęstszą zapalną chorobą skóry, dotykającą 9,4% światowej populacji [1]. Klinicznie AV charakteryzuje się obecnością zmian niezapalnych (zaskórników otwartych i zamkniętych) oraz zapalnych (krostek, grudek, guzków, cyst), zlokalizowanych przeważnie w okolicach łojotokowych na twarzy i na plecach [2]. W 20% przypadków dochodzi do wytworzenia blizn [3]. Trądzik stanowi problem skórny, który potencjalnie może mieć trwałe skutki zdrowotne; ponadto pacjenci z ciężkimi postaciami AV mają też zwiększone ryzyko wystąpienia chorób somatycznych oraz psychiatrycznych [4]. Szacuje się, że na trądzik choruje 80-100% osób między 11. a 30. rokiem życia, ze szczytem zapadalności przypadającym na 14.-17. rok życia dla płci żeńskiej i na 16.-19. rok dla płci męskiej. W ostatnich latach średni wiek chorych uległ podwyższeniu; powyżej 25. roku życia wykwity na twarzy stwierdza się aż u 54% kobiet i 40% mężczyzn [2, 5]. Trądzik osób dorosłych, tj. występujący po 25. roku życia, stanowi aktualnie narastający problem kliniczny, lecz przyczyna tego zjawiska nie jest w pełni wyjaśniona. Na poniższych rycinach przedstawiono różne postacie trądziku (zbiory własne autorki). Ryc. 1 Postać grudkowo-krostkowa u 27-letniej kobiety. Należy zwrócić uwagę na lokalizację zmian trądzikowych w obrębie czoła i policzków oraz obecność blizn. 7 Ryc. 2 Ciężkie postacie trądziku: zajęcie pleców w przebiegu trądziku skupionego (acne conglobata) u 18-letniego mężczyzny (po stronie lewej); trądzik piorunujący (acne fulminans) u 15-letniego chłopca z obecnością nadżerek, strupów oraz zmian krwotocznych na twarzy i plecach (po stronie prawej). Hidradenitis suppurativa (HS, acne inversa, AI) jest z kolei wyniszczającą dermatozą mieszków włosowych, która zwykle rozpoczyna się po okresie dojrzewania płciowego [6]. Częstość występowania HS waha się od 0,0003% do 4,1%, przy czym schorzenie to przeważa u kobiet (stosunek kobiet do mężczyzn 1 : 2,7 do 1 : 3,3) [7-10]. Rozpoznanie HS wymaga spełnienia trzech kryteriów: 1) obecności typowych zmian skórnych (głębokie, bolesne guzki, ropnie, przetoki, mostkowate blizny, pseudozaskórniki) w 2) typowych, bogatych w gruczoły potowe apokrynowe i narażonych na mechaniczne tarcie lokalizacjach (pachy, pachwiny, krocze, okolica okołoodbytnicza, fałdy pod-i śródpiersiowe lub pośladki) oraz 3) choroba musi mieć przewlekły oraz nawracający przebieg, ze stwierdzeniem co najmniej dwóch nawrotów w okresie sześciu miesięcy [3, 6, 9]. Najpowszechniej stosowanym systemem klasyfikacyjnym HS jest ocena według skali Hurleya: stadium I, łagodne (dotyczy 68% pacjentów) polega na tworzeniu się ropni bez przetok i bliznowacenia; w stadium II, umiarkowanym 8 (28% pacjentów) występuje jeden lub większa liczba ropni z wytworzeniem blizn i przetok, natomiast w stadium III, ciężkim (4% pacjentów) liczne, połączone przetokami ropnie zajmują cały obszar danej okolicy anatomicznej [11]. Ryc 3. Powyższe fotografie przedstawiają zmiany guzkowe i przetoki w obrębie pach u 40-letniej pacjentki -HS w stadium II według skali Hurleya (ze zbiorów własnych autorki). AV i HS mogą współistnieć jako część tzw. tetrady trądzikowej, do której zalicza się także torbiel włosową oraz rozwarstwiające zapalenie mieszków włosowych (perifolliculitis capitis abscendens et suffodiens) [3]. Według metaanalizy z 2019 roku pacjenci z HS mają 3,4 razy większą szansę wystąpienia trądziku pospolitego w porównaniu z grupą kontrolną [12]. Wertenteil i in. ocenili częstość występowania AV wśród dorosłych z HS na 15,2% w porównaniu z 2,9% u osób niechorujących na HS (p = 0,001) [12]. Zarówno trądzik zwyczajny, jak i acne inversa w znaczący sposób obniżają jakość życia pacjentów [14-17]. W świetle powyższych przesłanek zasadne i wartościowe jest wspólne rozpatrywanie obu schorzeń w ramach niniejszej rozprawy doktorskiej. 9 2.2. Patofizjologia, czynniki ryzyka i rola stanu zapalnego Patogeneza acne vulgaris oraz acne inversa jest złożona i nie została jeszcze w pełni poznana. Obecnie w centrum zdarzeń patofizjologicznych umieszcza się stan zapalny: AV i HS zalicza się do tzw. AiKDs, czyli autozapalnych zaburzeń keratynizacji (ang. autoinflammatory keratinisation disorders) [18-20]. W ich powstawaniu bierze się pod uwagę m.in. zaburzenia genetyczne. Genetyka AV i HS jest odmienna. W rodzinnych postaciach HS badacze rozważają znaczenie wpływu mutacji podjednostek γ-sekretazy i genu PSTPIP1 (proline-serine-threonine phosphatase-interacting protein 1). Typowane są różne geny potencjalnie związane z omawianymi jednostkami, a według niektórych doniesień gen PSTPIP1 może stanowić wspólne ogniwo genetyczne trądziku zwyczajnego i odwróconego [21, 22]. Uważa się, że w skali światowej 24% wszystkich chorób jest wywoływanych przez przyczyny środowiskowe [23]. Wśród potencjalnie kluczowych czynników prowokujących lub zaostrzających stan zapalny w patogenezie trądziku zwykłego i odwróconego wymienia się otyłość, zaburzenia hormonalne oraz palenie tytoniu. Poniżej przedstawiono aktualne poglądy na temat AV i HS jako chorób zapalnych/autozapalnych, ich czynników ryzyka/czynników biorących udział w ich genezie oraz aktualnych obszarów badań z nimi związanych. Patofizjologia i czynniki ryzyka trądziku zwyczajnego Tradycyjnie do podstawowych procesów obserwowanych w trądziku zwyczajnym zalicza się: zaburzenie wydzielania i składu sebum (w tym nadmiar wolnych kwasów tłuszczowych), powstawanie biofilmu Corynebacterium acnes (C. acnes) oraz wzmożoną proliferację keratynocytów w obrębie acroinfundibulum [2, 24, 25]. Wykazano, że C. acnes aktywuje mechanizmy odporności wrodzonej (w tym inflamasom NLRP3), a tym samym indukuje uwalnianie IL-1β z sebocytów i z komórek prezentujących antygen [26]. Istotną rolę w rozwoju AV odgrywają także zaburzenia hormonalne androgenów oraz insuliny/insulinopodobnego czynnika wzrostu 1 (IGF-1) [25]. Na podstawie badań asocjacyjnych całego genomu w trądziku o ciężkim przebiegu zidentyfikowano sześć loci genowych zaangażowanych w metabolizm androgenów, procesy zapalne i tworzenie blizn [24]. Obecność androgenów jest warunkiem sine qua non do powstawania wykwitów trądzikowych. W przypadku trądziku dorosłych kobiet (adult female acne, AFA) można zaobserwować zwiększenie liczby i wrażliwości receptorów sebocytów i keratynocytów na krążące androgeny. Dochodzi do aktywacji enzymów 10 odpowiedzialnych za metabolizm tych hormonów, co prowadzi do zwiększonej konwersji prekursorów do aktywnych form, tj. do testosteronu i dihydrotestosteronu [15]. Znajomość powyższych mechanizmów nie wyjaśnia jednak, dlaczego inne cechy hiperandrogenizmu oraz hiperandrogenemię obserwuje się u niewielkiego odsetka pacjentek z trądzikiem zwyczajnym. Ryc. 4. 25-letnia pacjentka z podejrzeniem zespołu PCOS, bez innych niż trądzik skórnych cech hiperandrogenizmu. Zwracają uwagę nasilone zmiany trądzikowe w nietypowej lokalizacji -kończyny dolne. Twarz jest zajęta w mniejszym stopniu (zbiory własne autorki). Badania na temat roli nikotynizmu w trądziku zwyczajnym są nieliczne, a ich wyniki sprzeczne. Niektóre dane sugerują, że palenie zaostrza przebieg AV [27], inne nie potwierdzają tego związku [28] lub wręcz wskazują na efekt protekcyjny palenia [29]. 11 Patofizjologia i czynniki ryzyka trądziku odwróconego Najnowsze dane literaturowe na temat patofizjologii HS podają, że zaburzona biogeneza miRNA w jednostce włosowej sprzyja prozapalnej aktywacji keratynocytów [14]. Najbardziej prawdopodobnym scenariuszem jest nieprawidłowa odpowiedź immunologiczna w stosunku do bakterii obecnych na skórze [20]. Na skutek stanu zapalnego dochodzi do nadprodukcji cytokeratyny 16 w infundibulum oraz inwolucji gruczołów łojowych [14]. Antygeny przedostające się z pękniętych mieszków włosowych do skóry właściwej prowokują dalszą rekcję immunologiczną, mediowaną przez neutrofile, monocyty, limfocyty Th1 i Th17 [14]. IL-17 zwiększa ekspresję peptydów przeciwdrobnoustrojowych (AMP), które stanowią istotny element wrodzonych mechanizmów obronnych przed patogenami [30]. W jednym z badań Zouboulis i in. wykazali w skórze pacjentów z HS dysregulację następujących AMP: S100A8, S100A9 oraz S100A12. Silną ekspresję stwierdzono w przypadku kalgranuliny A tj. S100A8/MRP8; w keratynocytach mieszkowych, a także w warstwie kolczystej naskórka [31]. W innym opracowaniu Wieland i in. mierzyli surowicze stężenie S100A8 jako markera diagnostycznego/prognostycznego HS -nie zaobserwowano korelacji z ciężkością ocenianą w skali Hurleya [32]. W badaniu immunohistochemicznym (IHC) składającym się na niniejszą dysertację wybrano oznaczenie IL-17 i jej receptora wraz z S100A8/MRP8 w skórze pacjentów z HS w celu porównania stanu zapalnego u osób z obecnością/bez obecności środowiskowych czynników ryzyka. Czynniki środowiskowe, takie jak palenie czy otyłość, wydają się odgrywać istotniejszą rolę w rozwoju HS niż w AV [7, 14]. Pomimo licznych doniesień epidemiologicznych, mówiących o współwystępowaniu HS z otyłością/nikotynizmem, ich znaczenie pozostaje w sferze spekulacji, gdyż istnieje niewiele dowodów molekularnych wyjaśniających wpływ uwarunkowań środowiskowych na skórę pacjentów [33]. Ponadto brakuje opracowań, które brałyby pod uwagę sytuację spotykaną powszechnie w życiu codziennym, czyli łączne oddziaływanie obu powyższych czynników [14]. Szacuje się, że 75% palaczy z HS jest otyłych [34]. Około 80-90% pacjentów z HS to byli lub aktywni palacze, wykazano dwukrotnie częstsze występowanie HS w populacji osób palących w porównaniu z niepalącymi [34]. Z kolei od 12 do 88% pacjentów cierpi na otyłość i może ona o kilka lat poprzedzać rozwój dermatozy [17, 35, 36]. Porównanie wybranych cech HS i AV przedstawiono w tabeli 1. 12 Tabela 1. Porównanie wybranych cech patofizjologicznych i klinicznych HS i AV Rola procesu zapalnego Trądzik zwyczajny Trądzik odwrócony Nadmierne wydzielanie prozapalnych cytokin: TNF-α, IL-1, IL-17 i IL-36, wzrost ekspresji receptorów TLR 2,4 w zmianach skórnych oraz zwiększona aktywność inflamasomu NLRP3, zaburzenia migracji podosomów Zmiany patofizjologiczne w mieszku włosowym Hiperplazja nabłonka, niedrożność, rozszerzenie i przerwanie ciągłości mieszków Pierwotna lokalizacja procesu chorobowego Mieszek łojowy Mieszek terminalny Najczęstsza lokalizacja zmian skórnych Twarz, plecy Pachy, pachwiny, okolica krocza, okolica okołoodbytnicza, fałdy podpiersiowe, pośladki Średni wiek pacjentów w momencie początku choroby 14.-17. rok życia (kobiety) i 16.-20.-24. rok życia 19. rok (mężczyźni) Częstość występowania w populacji 9,4% 0,0003% do 4,1% Płeć K = M K > M Flora bakteryjna Corynebacterium acnes Kontaminacja pierwotnie sterylnego procesu; Staphylococcus lugdunensis (Hurley I). Bakterie beztlenowe, promieniowce, Streptococcus milleri (Hurley II, III) Wykwity chorobowe Łojotok; zaskórniki zamknięte i otwarte, grudki, krostki, guzki, cysty, blizny Brak łojotoku; pseudozaskórniki typu „płyty nagrobnej”, guzki, ropnie, przetoki, mostkowate blizny Rola palenia w patogenezie ? + Rola otyłości w patogenezie ? ++ Rola hormonów w patogenezie + ? Objaśnienie: „?” -sprzeczne dane literaturowe; „+” -dowody przemawiające za rolą czynnika, „++” -mocne dowody przemawiające za rolą czynnika Dowodów na zaangażowanie mechanizmów zapalnych w patogenezę trądziku zwykłego i odwróconego dostarcza analiza tzw. zespołów autozapalnych, w których to trądzik zwyczajny/odwrócony współistnieje z innymi chorobami, takimi jak piodermia zgorzelinowa (pyoderma gangrenosum, PG), zapalenia jelit (colitis ulcerosa, choroba Leśniowskiego-Crohna) czy zapalenia stawów. Termin „choroba autozapalna” oznacza uszkodzenie tkanek na skutek nadmiernej aktywacji wrodzonego układu odpornościowego i dysfunkcji inflamasomu, często genetycznie uwarunkowane [26, 37, 38]. Jest to obecnie szeroko badany temat w naukach medycznych. Omawiane zespoły charakteryzują się nawracającymi jałowymi stanami zapalnymi, przy braku wysokich mian autoprzeciwciał lub antygenowo swoistych limfocytów T. W skórze dochodzi do akumulacji neutrofilów, makrofagów i nadprodukcji IL-1β, która inicjuje uwalnianie TNF-α i INF-γ; synergistycznie działa też IL-17 [20]. Trądzik zwyczajny i HS wchodzą w skład następujących syndromów: PASH (PG, trądzik zwyczajny i HS, ang. pyoderma gangrenosum, acne vulgaris, hidradenitis suppurativa), PAPASH (cechy PASH z ropnym zapaleniem stawów, ang. pyoderma gangrenosum, acne vulgaris, pyogenic arthritis, hidradenitis suppurativa), PsAPASH (PASH z łuszczycowym zapaleniem stawów, ang. psoriatic arthritis, pyoderma gangrenosum, acne vulgaris, hidradenitis suppurativa) oraz PASS (PG, trądzik zwyczajny, seronegatywne zapalenie stawów kręgosłupa, z HS lub bez HS, ang. pyoderma gangrenosum, acne vulgaris, hidradenitis suppurativa, ankylosing spondylitis). Dodatkowo, wyróżnia się też syndrom SAPHO, w przebiegu którego może wystąpić HS (synovitis, acne vulgaris, pustulosis, hyperostosis, osteitis). Z uwagi na podobieństwo symptomatologii i terapii powyższych zespołów nasuwa się pytanie, czy nie stanowią one różnych odmian fenotypowych jednej wyjściowej jednostki chorobowej. Odpowiedzi może dostarczyć dokładna charakterystyka owych schorzeń, ze zwróceniem uwagi na nowe konstelacje objawów. 14 2.3. Nowe kierunki badań z innej perspektywy Niniejsza praca doktorska podejmuje zagadnienie przewlekłych chorób zapalnych jednostki włosowo-łojowej z nowej, szerokiej perspektywy. Dotychczas nie przeprowadzono systematycznego przeglądu literatury uwzględniającego łącznie zespoły z kręgu PASH/SAPHO. Ponadto nie jest znana ogólna częstość współwystępowania innych schorzeń systemowych z trądzikiem zwyczajnym, a dane literaturowe odnośnie trądziku dorosłych kobiet wciąż nie prowadzą do jednoznacznych wniosków. Kolejnym nowatorskim elementem pracy doktorskiej jest wykorzystanie badania immunohistochemicznego fragmentów skóry uzyskanych od pacjentów z HS. IHC jest najpowszechniej stosowaną techniką na poziomie białkowym w diagnostyce dermatologicznej, która służy lokalizacji antygenów w tkankach utrwalonych w formalinie i zatopionych w parafinie. Kompleks antygen-przeciwciało jest wizualizowany w mikroskopie świetlnym za pomocą sygnału kolorowego. Wyniki są podawane półilościowo i mają istotne znaczenie, szczególnie w przypadku nowotworów skóry czy wykrywania mikroorganizmów zakaźnych [39, 40]. Dotychczasowe prace wykorzystujące IHC w HS dostarczały sprzecznych wyników, a ich jakość nie była optymalna (próbki pobierano w trakcie aktywnej terapii, nie dobierano pacjentów na podstawie skali Hurleya, nie uwzględniono takich zmiennych jak palenie i otyłość) [41]. W ramach niniejszej pracy badano molekuły, których rola patofizjologiczna była już przedmiotem dociekań naukowych w HS, takie jak IL-17 i jej receptor (IL-17R) [42, 43], MRP8 [32], IGF-1R [42, 44], receptor gamma aktywowany przez proliferator peroksysomów (PPAR-γ) [45] i receptor naskórkowego czynnika wzrostu (EGFR) [46], ale uwagę poświęcono także nowym, dotychczas nieanalizowanym w HS molekułom.. Były nimi receptor węglowodorów arylowych (AhR) oraz iryzyna. Białka te zostały wybrane, ponieważ pojawia się coraz więcej doniesień na temat ich znaczenia w patogenezie zapalnych chorób skóry. Polichlorowane bifenyle (PCB) i 2,3,7,8-tetrachlorodibenzo-p-dioksyna (TCDD) są głównymi zanieczyszczeniami środowiska obecnymi w dymie papierosowym. Biologiczne efekty działania TCDD i PCB w organizmie człowieka zależą m.in. od cytozolowego czynnika transkrypcyjnego, receptora węglowodorów arylowych. Odpowiada on za metabolizm ksenobiotyków, indukując cytochrom p450 [47]. AhR ulega obfitej ekspresji w komórkach organów barierowych -w tym skóry: w keratynocytach naskórka i sebocytach, a także w komórkach Th17 i Th22. Jest on konieczny do produkcji interleukiny 22 (IL-22). W badaniu Fabroccini i in. wykazano aktywację receptora węglowodorów arylowych 15 w trądziku zwyczajnym [48]. Ponadto uważa się, że bezpośrednim wynikiem toksyczności dioksyn jest rozwój tzw. trądziku chlorowcowego [49]. Drugim nowym białkiem jest iryzyna, adipomiokina wydzielana głównie przez tkankę tłuszczową i mięśniową po rozszczepieniu domeny FNDC5 (fibronectin type III domaincontaining protein 5) w odpowiedzi na bodźce takie jak ekspozycja na zimno czy wysiłek fizyczny [50]. Adipokiny reprezentują grupę hormonów i cytokin wydzielanych przez tkankę tłuszczową. Iryzyna stymuluje konwersję białej tkanki tłuszczowej do brązowej, zwiększając tym samym termogenezę oraz wydatek energetyczny, co chroni przed otyłością i insulinoopornością [51]. Omawiana adipomiokina wykazuje właściwości przeciwzapalne, redukuje wydzielanie cytokin, takich jak IL-1β, TNF-α, IL-6 czy białko chemotaktyczne monocytów [51]. Wcześniejsze badania koncentrowały się głównie na roli adipokin w AV, łuszczycy, regulacji regeneracji włosów, gojeniu ran i starzeniu się skóry [52]. W HS stwierdzono obniżone stężenie adiponektyny [53]. Wykazano, że stężenie iryzyny w surowicy u pacjentów z AV było niższe niż w grupie kontrolnej: niskie stężenie iryzyny i wysoki HOMA-IR (Homeostasis Model Assessment of Insulin Resistance) stanowiły dobry marker prognostyczny dla ciężkiego trądziku zwyczajnego [52]. Dlatego też w niniejszej rozprawie zdecydowano o badaniu ekspresji iryzyny w skórze pacjentów z HS i skorelowaniu wyników z ekspresją innych molekuł związanych z otyłością, stanem zapalnym i paleniem tytoniu. 16 3. Cele pracy 1. Charakterystyka epidemiologiczna pacjentów z trądzikiem zwyczajnym, ze szczególnym uwzględnieniem podgrupy dorosłych kobiet (AFA); ocena częstości współwystępowania schorzeń systemowych (w tym endokrynologicznych) u pacjentów z trądzikiem zwyczajnym w krakowskiej populacji. 2. Ocena roli zaburzeń metabolicznych/otyłości, palenia tytoniu/toksyn środowiskowych i stanu zapalnego w patogenezie hidradenitis suppurativa poprzez wykorzystanie różnic w ekspresji wybranych cząsteczek w zmienionej chorobowo skórze pacjentów z HS, którzy są otyli i palą tytoń (OS; obese smokers) w porównaniu z ekspresją w populacji dotkniętej HS, lecz bez otyłości i niepalących (NN; non-obese, nonsmokers). 3. Ocena współwystępowania wraz z trądzikiem zwyczajnym oraz trądzikiem odwróconym schorzeń o podłożu autozapalnym poprzez przegląd systematyczny literatury -charakterystyka epidemiologiczna, kliniczna i genetyczna. 4. Metodologia prac składających się na dysertację 17 Badania podejmujące wyżej przedstawione problemy zostały przeprowadzone w Klinice Dermatologii Collegium Medicum Uniwersytetu Jagiellońskiego w Krakowie oraz na Oddziale Dermatologii, Wenerologii, Alergologii i Immunologii Uniwersytetu Medycznego Brandenburg Theodor Fontane w Desinau, w Niemczech (Departments of Dermatology, Venereology, Allergology and Immunology, Dessau Medical Center). Dysertacja składa się z trzech prac, poświęconych kolejno: epidemiologii trądziku zwyczajnego, czynnikom ryzyka trądziku odwróconego oraz zespołom autozapalnym, w przebiegu których obserwuje się zarówno trądzik zwyczajny, jak i trądzik odwrócony. Pierwsza z prac była badaniem obserwacyjnym przekrojowym (cross-sectional study) bazującym na dokumentacji medycznej 354 pacjentów leczonych z powodu trądziku zwyczajnego w Klinice Dermatologii CMUJ. Analizowano dane 323 pacjentów leczonych w Poradni Przyklinicznej w latach 2016-2018 oraz 31 pacjentów hospitalizowanych z powodu trądziku w latach 2013-2018. Zebrano informacje dotyczące wieku, płci, schorzeń współistniejących, morfologii zmian skórnych (obecność zaskórników, grudek, krost, cyst, blizn, przebarwień) oraz rozmieszczenia tychże zmian w obrębie poszczególnych obszarów ciała. W przypadku pacjentów hospitalizowanych dostępne były dodatkowe dane do analizy: czas trwania choroby (lata, które upłynęły przed przyjęciem na Oddział Kliniki Dermatologii) oraz wskaźnik masy ciała (BMI) definiowany jako iloraz waga/wysokość podniesiony do kwadratu. Przeprowadzono analizę statystyczną przy użyciu programu STATISTICA 12.0. Normalność danych sprawdzona została za pomocą testu Shapiro-Wilka. Wszystkie zmienne przedstawione zostały w postaci wartości liczbowych wraz z odsetkami procentowymi, median (Me) z przedziałami międzykwartylowymi (IQR) lub średnich wraz z odchyleniami standardowymi (SD). Do oceny zależności między zmiennymi zastosowano testy Chi-kwadrat Pearsona i U Manna-Whitneya, a za poziom istotności statystycznej przyjęto p<0,05. Druga praca oryginalna stanowiła analizę immunohistochemiczną materiału tkankowego zmian skórnych, pozyskanego w wyniku biopsji/operacji pacjentów z hidradenitis suppurativa. Grupę badaną stanowiły 22 osoby dorosłe, cierpiące na HS. Kryterium wykluczającym była udokumentowana w wywiadzie insulinooporność i cukrzyca oraz stosowanie leków biologicznych w ciągu 12 miesięcy poprzedzających zabieg operacyjny. Pacjenci zostali podzieleni na dwie grupy: 12 otyłych palaczy (BMI >30 kg/m2) oraz 10 niepalących pacjentów bez otyłości (BMI <30 kg/m2). Osoby badane były odpowiednio dobrane pod względem wieku, płci, rozmieszczenia oraz ciężkości zmian skórnych. Fragmenty 18 skóry utrwalone w formalinie i zatopione w parafinie zostały skrojone za pomocą mikrotomu na skrawki grubości 3,5 mikrometrów. Następnie wybarwiono je przeciwciałami skierowanymi przeciwko proteinom związanym z otyłością (przeciwko PPAR-γ, iryzynie, IGFR-1R), związanymi z paleniem i proliferacją naskórka (AhR i EGFR); oraz markerami stanu zapalnego (MRP8/S100A8, IL-17 i jej receptorowi (IL-17R)), zgodnie z protokołem dostarczonym przez producenta (barwienie 3,3‘-diaminobenzydyną, DAB-staining). Preparaty naskórka i skóry właściwej zostały sfotografowane w stukrotnym powiększeniu (mikroskop EVOS, AMG, Bothell, Washington). Do analizy obrazów mikroskopowych użyto komputerowego programu FIJI (Fiji Is Just ImageJ; NIH, Bethesda, USA) oraz półautomatycznej procedury (tzw. Andy’s algorithm) [54]. Metoda ta opiera się na tzw. dekonwolucji barwnej. Celem dekonwolucji jest rozbicie obrazu na komponenty, które odpowiadają poszczególnym barwieniom. Algorytm umożliwia określenie liczby, procentu, powierzchni i średniej intensywności pozytywnie wybarwiających się komórek: im niższy parametr średniej intensywności barwienia, tym więcej wybarwionych cząsteczek, a co za tym idzie, tym wyższa ekspresja białka. Z uwagi na brak normalności rozkładu, do analizy statystycznej użyto testów nieparametrycznych U Manna-Whitneya, a istotność statystyczną zdefiniowano jako p<0,05. W ostatniej pracy dokonano systematycznego przeglądu artykułów zgromadzonych w elektronicznych bazach MEDLINE, EMBASE i CENTRAL przy użyciu następujących haseł wyszukiwania: „hidradenitis”, „suppurativa”, „acne inversa”, „autoinflammatory”, „synovitis”, „acne”, „pustulosis”, „hyperostosis”, „osteitis”, „arthritis”, „pyoderma gangrenosum”, „spondylitis”, „colitis” oraz „psoriasis”. Kryterium włączenia do przeglądu spełniały badania kliniczne, przekrojowe, kohortowe oraz opisy przypadków, serie przypadków i listy do redakcji, w których trądzikowi zwykłemu/odwróconemu towarzyszyły co najmniej dwie inne choroby autozapalne. Analizowano artykuły w języku angielskim, polskim, niemieckim i greckim, opublikowane w latach 1980-2020. Wyłączone z przeglądu zostały prace dotyczące tylko spektrum tetrady trądziku. Wykluczono też przypadki opisujące paradoksalne reakcje na leki biologiczne oraz choroby z kręgu rodzinnej gorączki śródziemnomorskiej. Standaryzowany formularz ekstrakcji (zgodnie z wytycznymi PRISMA) został użyty przez dwoje niezależnych badaczy do wyodrębnienia informacji dotyczących danych demograficznych, fenotypów zespołów oraz wyników leczenia. Ekstrahowano i analizowano dane dotyczące wieku, płci, pochodzenia etnicznego pacjentów, kolejności pojawienia się objawów, nasilenia trądziku, palenia tytoniu, otyłości, historii rodzinne, znanych mutacji genetycznych oraz leczenia. 19 5. Podsumowanie wyników W pierwszej pracy, opublikowanej w Acta Dermatovenerologica Croatica dokonano charakterystyki demograficznej populacji pacjentów z trądzikiem zwyczajnym. Mediana wieku chorych wynosiła 24 lata (IQR 20-31), jednak zwraca uwagę znaczna liczba pacjentów w starszym wieku; ogółem 95 osób ≥30 roku życia wciąż cierpiało na trądzik, a pojedyncze przypadki odnotowywano nawet u osób w wieku 50-69 lat. Dominującą płeć stanowiły kobiety (61%), a 45,37% z nich spełniało kryteria AFA. Z kolei powikłania trądziku, takie jak blizny, notowano statystycznie częściej u mężczyzn. Ogółem, blizny występowały u 27,97% badanych. Wykwity chorobowe najczęściej zajmowały twarz (87,49% pacjentów), następnie kolejno plecy i klatkę piersiową. Dominował typ zmian grudkowo-krostkowy, a większość pacjentów miała ograniczoną postać dermatozy (tj. zajęte maksymalnie dwie okolice ciała). Analiza chorób towarzyszących pozwoliła stwierdzić, że najczęściej trądzik zwyczajny współwystępował ze schorzeniami endokrynologicznymi: dotyczyło to 15,25% badanych, głównie kobiet (87,5%), a większość endokrynopatii stanowiły zaburzenia czynności tarczycy (6,21% wszystkich badanych). Z kolei najczęstszymi dolegliwościami dermatologicznymi towarzyszącymi trądzikowi były skórne manifestacje hiperandrogenizmu, takie jak łysienie androgenowe, łojotok i łojotokowe zapalenie skóry. Stwierdzono je u 15,82% pacjentów, a ich obecność nie korelowała z rozległością choroby. W pracy wyodrębniono także cechy populacji dorosłych kobiet z trądzikiem: mediana wieku wynosiła 32,5 roku (IQR 28-38), rzadko obserwowano zmiany skórne na plecach (27%), a choroba nie odbiegała rozległością od pozostałych pacjentów z trądzikiem. W grupie AFA statystycznie częściej niż u innych pacjentów stwierdzano zaburzenia endokrynologiczne (inne niż choroba tarczycy, p = 0,002), a co ciekawe, rzadziej niż u pozostałych występowały choroby skóry związane z hiperandrogenizmem (p = 0,034). Dodatkowo w grupie pacjentów hospitalizowanych z powodu AV analizowano parametr BMI: okazało się, że pacjenci z ciężkimi, wymagającymi hospitalizacji formami trądziku nie cechowali się większą masą ciała niż pozostali, a średnie BMI wynosiło 21,64 kg/m2. Mediana czasu, jaki upłynął od rozpoznania trądziku do hospitalizacji to 3 lata. W drugim z badań, zamieszczonym na łamach czasopisma Dermatology (2021), podjęto próbę wykazania, jak poszczególne czynniki ryzyka oddziałują na poziomie molekularnym na skórę pacjentów z HS. Stwierdzono, że markery związane z zaburzeniami metabolicznymi/otyłością cechowały się wyraźnym zróżnicowaniem ekspresji między 20 badanymi grupami, natomiast markery związane z paleniem tytoniu charakteryzowało tylko ograniczone zróżnicowanie. Iryzyna, PPAR-γ i IGF-1R wykazywały silniejszą statystycznie ekspresję u pacjentów niepalących oraz nieotyłych (NN), natomiast słabszą u palących i otyłych (OS). Iryzynę uwidoczniono we wszystkich warstwach naskórka, najintensywniej zaś w strefie ponadpostawnej u chorych z grupy NN. W keratynocytach wewnętrznej i zewnętrznej pochewki mieszków włosowych iryzyna wykazywała umiarkowaną ekspresję w obu badanych grupach. PPAR-γ był obecny również w częściach suprabazalnych naskórka u pacjentów NN, międzymieszkowo oraz w znacznie mniejszym stopniu w warstwie podstawnej w grupie OS. Keratynocyty mieszkowe nie wykazywały wyraźnych różnic w ekspresji. Ponadto w mieszkach włosowych skóry NN stwierdzono nieznacznie zwiększone cytoplazmatyczne barwienie IGF1R w porównaniu z próbkami uzyskanymi od OS. IGF-1R wykazano w warstwie podstawnej i ponadpodstawnej naskórka (w stratum granulosum i spinosum) w porównywalnym stopniu u chorych OS oraz NN. Z kolei ekspresja AhR, który jest receptorem aktywowanym m.in. przez dym tytoniowy, nie wykazywała istotnej różnicy między pacjentami OS a NN. Barwienie cytoplazmatyczne o umiarkowanej intensywności wykryto we wszystkich warstwach naskórka i zewnętrznej osłonce mieszków włosowych w obu grupach, z ogniskowo zwiększonym barwieniem w skórze właściwej i komórkach przewodów gruczołów potowych. EGFR manifestował się silniej w grupie NN niż w grupie OS: dla pacjentów NN stwierdzono intensywną ekspresję w błonie komórkowej, zwłaszcza w warstwie podstawnej oraz kolczystej. W grupie OS wykazano jedynie umiarkowane zabarwienie podstawnych keratynocytów. Obwodowe obszary mieszków włosowych były wyraźnie wybarwione w obu grupach. W odniesieniu do markerów stanu zapalnego, pacjenci OS wykazywali wyższą ekspresję IL-17R niż pacjenci NN, podczas gdy nie różnili się oni istotnie pod względem ekspresji samej IL-17. Peptyd antybakteryjny S100A8/MRP8 wykazywał silną immunoreaktywność w obu grupach. Stwierdzono jego intensywne barwienie we wszystkich warstwach naskórka, w zewnętrznej i wewnętrznej pochewce mieszków włosowych oraz w gruczołach łojowych. Wartości median intensywności i istotności statystycznych dla barwień przedstawiono w tabeli 2. 21 Tabela 2. Porównanie median intensywności barwień między grupami OS i NN. Badane białko OS (mediana NN (mediana p intensywności intensywności barwienia) barwienia) Iryzyna 98,3 76,5 0,008 PPAR-γ 138,8 94,7 <0,001 IGF-1R 138,3 135,1 0,03 AhR 99,8 107 0,4 EGFR 132 123,1 0,003 IL-17 128 114,2 0,09 IL-17R 147,8 164,8 0,023 S100A8 90,9 101,3 0,6 Ostatnia praca stanowiła przegląd systematyczny schorzeń autozapalnych współistniejących z trądzikiem odwróconym. Zidentyfikowano 64 artykuły spełniające kryteria włączenia do analizy. Spośród nich 35 artykułów dotyczyło łącznie 56 pacjentów z jednym z następujących zespołów chorobowych: PASH, PAPASH, PsAPASH lub PASS; wyodrębniono też 13 artykułów opisujących HS jako element zespołu SAPHO u 21 osób. Jeden z pacjentów miał nakładające się cechy PASH i SAPHO. Ponadto w 17 artykułach opisano 30 pacjentów, u których HS towarzyszyły minimum dwie inne choroby zapalne, aczkolwiek nie spełniali oni kryteriów żadnego z powyższych zespołów. Łącznie do czasu publikacji pracy opisano 107 pacjentów z syndromicznym HS. Ich średni wiek był wyższy niż u pacjentów ze sporadycznym wariantem HS. Najczęściej raportowanym w literaturze zespołem był syndrom PASH: w zespole tym dominowali mężczyźni, a wiek w momencie diagnozy wynosił średnio 33,7 lat. Nie obserwowano zależności występowania tej choroby od BMI czy też nikotynizmu. Jedna czwarta doniesień mówiła o rodzinnym występowaniu zespołu, a najczęściej wykrywane mutacje dotyczyły regionu promotorowego genu PSTPIP1 (15%). W pojedynczych przypadkach opisywano też mutacje nikastryny (podjednostki γ-sekretazy). Zarówno trądzik zwyczajny, jak i odwrócony miały ciężki przebieg (w 62% przypadkach HS dominowały stadia II i III według Hurleya, w 56% obecne były ciężkie formy AV). W zespole PASH, podobnie jak w pokrewnych mu zespołach, zidentyfikowano sekwencję czasową 22 pojawiania się objawów: jako pierwsze wystąpienie trądziku pospolitego/HS, następnie PG, a wreszcie objawów mięśniowo-szkieletowych (obecne w 1/3 do 2/3 opisów PASH/PAPASH/PsAPASH/PASS) lub jelitowych. Pojedyncze opisy literaturowe obejmowały: zespół PASS (8 pacjentów; średni wiek 26 lat), PAPASH (6 pacjentów; średni wiek 33,5 lat), PsAPASH (3 pacjentów). We wszystkich tych zespołach skórne manifestacje poprzedzały zajęcie innych narządów w większości przypadków (53%). W przeglądzie zwrócono też uwagę na zajęcie narządu wzroku w syndromicznym HS pod postacią zapalenia przedniego odcinka błony naczyniowej, zapalenia nadtwardówki, zapalenia spojówek lub obustronnego wrzodziejącego zapalenia rogówki (wrzód Moorena). Podobnie jak zapalenia jelit, objawy oczne nie były dotychczas włączane do kryteriów diagnostycznych omawianych zespołów autozapalnych. Poprzez analizę efektów leczenia udało się zidentyfikować dla powyższych jednostek najbardziej skuteczną opcję terapeutyczną, którą były inhibitory TNF-α. Pewien stopień odpowiedzi klinicznej wykazywało 80% pacjentów, u których stosowano infliksymab lub adalimumab. Bardzo dobrą odpowiedź stwierdzono u 47%/59%, a częściową u 41%/24% pacjentów leczonych odpowiednio infliksymabem/adalimumabem. Wciąż jednak pewien odsetek wykazywał oporność na terapię, przy czym najbardziej oporną składową był hidradenitis suppurativa. Trądzik zwyczajny, piodermia zgorzelinowa i spondyloartropatie lepiej reagowały na leczenie. W zespole SAPHO również przeważała płeć męska, ze stosunkiem kobiet do mężczyzn wynoszącym 1 : 1,2; średni wiek to 38,7 lat. Tylko pięcioro z pacjentów było palaczami tytoniu. W dostępnych doniesieniach brakowało informacji dotyczących masy ciała/BMI. Zaobserwowano, że w 61% udokumentowanych przypadków SAPHO trądzik zwyczajny lub odwrócony poprzedzały objawy kostno-stawowe. Niesteroidowe leki przeciwzapalne były lekami pierwszego rzutu w leczeniu objawowym, mimo że w 50% przypadków zaostrzeń nie wystarczały do opanowania dolegliwości bólowych. Podobnie jak w zespołach z kręgu PASH w przypadkach opornych na leczenie stosowano leki anty-TNF-α, w tym infliksymab, etanercept lub adalimumab. Odpowiedź była zwykle szybka zarówno w przypadku objawów skórnych, jak i kostno-stawowych, konieczne bywało jednak skrócenie odstępów czasowych między podaniami leku lub zwiększenie jego dawki. 23 6. Wnioski i implikacje praktyczne Mimo że trądzik zwykły i odwrócony są znacznie rozpowszechnione w populacji, to wciąż potrzeba nowych metod terapii, gdyż efektywność dostępnych leków często pozostaje niewystarczająca. Stąd tak ważne są dalsze badania oparte o genomikę, transkryptomikę oraz proteomikę -aby coraz lepiej poznawać procesy zaangażowane w patogenezę, a także rozwijać nowe, dostosowane do konkretnego pacjenta metody leczenia i interwencje środowiskowe. Wyniki badań niniejszej dysertacji stanowią wkład w poznanie czynników ryzyka trądziku odwróconego, epidemiologii trądziku zwykłego ze szczególnym uwzględnieniem trądziku dorosłych kobiet oraz wskazują na HS/AV jako manifestacje chorób ogólnoustrojowych. Najważniejsze wnioski z pracy wyszczególniono poniżej. 1) W przypadku 38,7% wszystkich badanych z trądzikiem zwyczajnym stwierdzono minimum jedną towarzyszącą przewlekłą chorobę układową. Jest to ważna obserwacja, gdyż do tej pory ogólna częstość współistnienia trądziku z innymi dolegliwościami nie została ustalona. Schorzenia endokrynologiczne, a w szczególności zaburzenia funkcji tarczycy stanowiły najczęstszą chorobę towarzyszącą wśród wszystkich osób z trądzikiem zwyczajnym. W całej badanej zbiorowości częstość chorób tarczycy wynosiła 6,21%, a u pacjentek z AFA 10,2%, była więc zbliżona do częstości populacyjnej. Dla porównania rozpowszechnienie endokrynopatii tarczycowych w Polsce wynosiło 9,5% (dane z Głównego Urzędu Statystycznego, 2019). Potrzebne są szersze badania określające stężenia hormonów tarczycy w osoczu/tkankach pacjentów z trądzikiem w porównaniu z grupą kontrolną, gdyż wyniki istniejących na ten temat prac są sprzeczne. 2) Kryteria AFA spełniało 45,37% spośród kobiet w badaniu (27,6% wszystkich analizowanych pacjentów). Mediana ich wieku wynosiła 32,5 lat, co pozostaje w zgodzie z danymi literaturowymi, mówiącymi o obecności zmian trądzikowych w coraz bardziej zaawansowanym wieku. Istnieją kontrowersje dotyczące typowej morfologii trądziku w wieku dorosłym (dominacja zaskórników vs. zmian zapalnych) [55, 56]. W naszym opracowaniu kobiety z AFA cechowały się przewagą wykwitów zapalnych. W podgrupie AFA statystycznie istotnie częściej niż w całej populacji stwierdzano zaburzenia endokrynologiczne (nie uwzględniając endokrynopatii tarczycowych). Mimo iż hiperandrogenemię stwierdza się w mniejszości populacji osób z trądzikiem, sugerujemy oznaczenie podstawowego profilu hormonalnego u wszystkich pacjentek cierpiących na AFA, a nie tylko u tych, u których obserwuje się inne dermatologiczne manifestacje hiperandrogenizmu. Według 24 naszych danych w grupie AFA inne skórne cechy hiperandrogenizmu występowały wręcz rzadziej niż w pozostałej badanej populacji (tj. mężczyzn i kobiet <25 roku życia) -trądzik może być więc izolowanym objawem nadmiaru androgenów. 3) Pacjenci z ciężkimi postaciami trądziku zwyczajnego, wymagającymi hospitalizacji nie cechowali się podwyższoną wartością BMI (średnie BMI 21,64 kg/m2), co przemawia za mniejszą rolą otyłości jako czynnika zaostrzającego przebieg choroby. Jest to zgodne z wynikami jednego z dużych badań, obejmującego 600 404 nastolatków -wykazano w nim, że nadmierny wskaźnik masy ciała stanowi czynnik protekcyjny w stosunku do AV, a tłumaczy się to zjawisko zwiększoną aktywnością aromatazy odpowiadającej za konwersję testosteronu do estradiolu [57]. 4) Badanie odzwierciedla sytuację, z jaką mamy do czynienia w życiu codziennym, gdzie otyłość i palenie to dwa czynniki ryzyka HS występujące często u jednej osoby. Na podstawie naszej analizy immunohistochemicznej zidentyfikowano otyłość jako najistotniejszy czynnik środowiskowy ryzyka, natomiast rola palenia tytoniu w patogenezie choroby wydaje się być mniejsza. Nie wykazano istotnych statystycznie różnic dotyczących skórnej ekspresji AhR -głównego tkankowego sensora dymu tytoniowego; należy jednak wziąć pod uwagę możliwość błędu wynikającego z biernego palenia w grupie kontrolnej. Nie poznano jak dotąd dokładnych mechanizmów, za pośrednictwem których otyłość wywiera wpływ na skórę -proponuje się m.in. szlaki IGF-1, wpływ na kinazę mTORC1, adipokiny czy też przewlekły stan zapalny, lecz zasadne jest badanie nowych molekuł [58]. Nasi pacjenci nie mieli zdiagnozowanej współistniejącej choroby metabolicznej (jak np. cukrzyca), można więc stwierdzić, że zmiany skórne w HS stanowią czuły marker odzwierciedlający tkankowe stężenia hormonów bardziej niż ich stężenia w surowicy. Dzięki biopsji i badaniu immunohistochemicznemu skóry możliwa jest ocena ryzyka metabolicznego pacjenta zanim nastąpi zmiana poziomu odpowiednich białek/związków chemicznych w surowicy. 5) Nie wykazano różnic w ekspresji IL-17 między grupami otyłych palaczy z HS, a nieotyłych i niepalących pacjentów z HS, jednak pierwsza grupa cechowała się większą ekspresją receptora dla tej interleukiny. Wskazuje to na istotną rolę ścieżki sygnałowej IL-17 w patogenezie HS, niezależnie od obecności środowiskowych czynników ryzyka. Nasza praca ma więc ważne implikacje dotyczące terapii HS: mimo ugruntowanej pozycji inhibitorów TNF-α (obecnie w Polsce zarejestrowany w tym wskazaniu jest jedynie adalimumab) trwają poszukiwania nowych metod terapeutycznych. Na podstawie naszych oznaczeń 25 immunohistochemicznych uważamy, że inhibitory IL-17 (z powodzeniem stosowane w łuszczycy) mogą znaleźć ważne miejsce w terapii HS, jednakże pod warunkiem dostosowania ich dawkowania do masy ciała pacjenta/towarzyszącego nikotynizmu. U pacjentów otyłych i palących dawka antagonisty IL-17R powinna być podwyższona w porównaniu z osobami z prawidłowym BMI. 6) W badaniu IHC potwierdzono rolę kalgranuliny A (S100A8/MRP8) jako markera hidradenitis suppurativa: obserwowano silną ekspresję tego białka u wszystkich pacjentów, w każdej warstwie naskórka; niezależnie od masy ciała czy nikotynizmu. Warto wspomnieć, że pomiary stężenia S100A8 w stolcu znalazły już praktyczne zastosowanie w prognozowaniu zaostrzeń choroby Leśniowskiego-Crohna [32]. W acne inversa dotychczas nie dysponujemy biochemicznym markerem dla monitorowania/diagnozowania. Osoczowe lub tkankowe zakresy norm dla S100A8 powinny być ustalone w dalszych badaniach. 7) Sprawując opiekę nad pacjentem, należy pamiętać, że ciężkie postacie trądziku pospolitego (acne fulminans, acne conglobata) oraz hidradenitis suppurativa mogą wiązać się z występowaniem systemowych zespołów autozapalnych. W tej grupie pacjentów ważne jest szczegółowe zebranie wywiadu dotyczącego dolegliwości żołądkowo-jelitowych, kostno-stawowych, czy też ze strony narządu wzroku oraz w razie potrzeby szybkie skierowanie do lekarza odpowiedniej specjalizacji. Syndromiczny HS częściej notuje się u mężczyzn, w przeciwieństwie do jego sporadycznej postaci. Jest on mniej związany z czynnikami środowiskowymi jak otyłość i nikotynizm (co odnotowano w naszym przeglądzie dla zespołu PASH). W zespołach z kręgu PASH/SAPHO trądzik zwykły/odwrócony najczęściej występują jako pierwsze manifestacje, stąd niezwykle istotna rola dermatologa w rozpoznawaniu i leczeniu. Prawidłowe leczenie zmian skórnych we wczesnym etapie może zapobiec dalszemu „marszowi autozapalnemu”, w przebiegu którego z czasem rozwijają się neutrofilowe choroby skory, takie jak łuszczyca, piodermia zgorzelinowa czy też zapalne zajęcie innych niż skóra układów. Ma to istotne znaczenie, ponieważ zespoły autozapalne są często trudne do leczenia i mogą być oporne na monoterapię lekami biologicznymi. 8) W rezultacie systematycznego przeglądu literatury ustalono, że pomiędzy poszczególnymi zespołami PASH/PAPASH/PsAPASH/PASS/SAPHO dochodzi do nakładania się objawów. 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Hu, Y., Zhu, Y., Lian, N., Chen, M., Bartke, A., & Yuan, R. (2019). Metabolic Syndrome and Skin Diseases. Frontiers in Endocrinology, 10. https://doi.org/10.3389/fendo.2019.00788 32 33 34 8. Streszczenie Cel: Pierwszym celem pracy była charakterystyka epidemiologiczna pacjentów dotkniętych trądzikiem zwyczajnym (AV) oraz hidradenitis suppurativa (HS). Cele szczegółowe dotyczyły scharakteryzowania schorzeń towarzyszących AV w krakowskiej populacji pacjentów, wyodrębnienia cech szczególnych subpopulacji dorosłych kobiet (AFA) oraz oceny współwystępowania z AV/HS innych schorzeń autozapalnych w przeglądzie systematycznym literatury. Drugim celem była ocena roli otyłości, nikotynizmu i stanu zapalnego w patogenezie HS na podstawie immunohistochemicznej analizy ekspresji wybranych markerów białkowych w skórze otyłych palaczy (OS) w porównaniu do osób bez otyłości i niepalących (NN). Materiał i metody: Badania zostały przeprowadzone w Klinice i Katedrze Dermatologii Collegium Medicum Uniwersytetu Jagiellońskiego w Krakowie, gdzie wykonano retrospektywną analizę dokumentacji medycznej 354 pacjentów z trądzikiem zwyczajnym. Drugim elementem pracy było badanie immunohistochemiczne na skrawkach skóry 22 pacjentów (10 NN, 12 OS) leczonych operacyjnie z powodu HS w Dessau w Niemczech na Uniwersytecie Medycznym Brandenburg Theodor Fontane, na Oddziale Dermatologii, Wenerologii, Alergologii i Immunologii. Fragmenty skóry utrwalone w formalinie, zatopione w parafinie zostały skrojone za pomocą mikrotomu na skrawki grubości 3,5 mikrometrów, a następnie wybarwione przeciwciałami firmy Abcam (Berlin, Niemcy) skierowanymi przeciwko proteinom związanym z otyłością (PPAR-γ, iryzynie, IGFR-1R), z paleniem i proliferacją naskórka (AhR i EGFR) oraz markerami stanu zapalnego (IL-17 i jej receptor, S100A8/MRP8). Preparaty naskórka i skóry właściwej zostały sfotografowane w stukrotnym powiększeniu (mikroskop EVOS AMG, Bothell, Washington). Do analizy obrazów mikroskopowych użyto komputerowego programu FIJI (Fiji Is Just ImageJ; NIH, Bethesda, USA) oraz półautomatycznej procedury (tzw. Andy’s algorithm). Trzecia z prac to wykonany przez dwoje niezależnych badaczy systematyczny przegląd artykułów zgromadzonych w latach 1980-2020 w elektronicznych bazach MEDLINE, EMBASE CENTRAL celem identyfikacji opisanych dotychczas przypadków, gdzie trądzikowi zwykłemu/odwróconemu towarzyszyły co najmniej dwie inne choroby autozapalne. Wyniki: W pierwszym, retrospektywnym badaniu pacjentów z trądzikiem zwyczajnym 61% osób stanowiły kobiety, a 27,6% to pacjentki klasyfikowane jako AFA. Mediana wieku w badaniu wynosiła 24 lata, dla AFA było to 32,5 lat. Pacjentki z AFA rzadziej cechowały się zmianami skórnymi na plecach, najczęściej zajętą okolicą była twarz. We wszystkich grupach 35 dominował trądzik grudkowo-krostkowy. U 38,7% wszystkich badanych stwierdzono towarzyszącą przewlekłą chorobą układową, najczęściej (15,25%) były to zaburzenia endokrynologiczne, w 6,21% zaburzenia czynności tarczycy. U kobiet z AFA istotnie częściej niż u pozostałych chorych stwierdzano zaburzenia endokrynologiczne, rzadziej natomiast występowały skórne cechy hiperandrogenizmu. Z kolei w badaniu immunohistochemicznym skóry pacjentów z HS peptydy związane z otyłością wykazywały zróżnicowaną ekspresję między grupami, podczas gdy peptydy związane z paleniem nie różniły się istotnie między OS i NN. EGFR manifestował się silniej w grupie NN niż w grupie OS. IL-17R wykazywał większą immunoreaktywność w grupie otyłych palaczy, natomiast S100A8 cechował się znaczną ekspresją u wszystkich badanych. Wreszcie, w trzeciej z prac, w ramach przeglądu systematycznego literatury zakwalifikowano 64 artykuły dotyczące syndromicznego HS. Wśród zidentyfikowanych prac znalazły się te dotyczące już zdefiniowanych zespołów, jak również nowych, dotychczas nieopisywanych konstelacji objawów, w tym przypadki zajęcia narządu wzroku. Manifestacje skórne, włączając HS, zwykle poprzedzały inne zmiany narządowe i u znacznej części pacjentów okazały się oporne na konwencjonalną terapię. Wnioski: Wyniki powyższych prac wskazują, że zaburzenia metaboliczne (otyłość) odgrywają dominującą rolę w patogenezie trądziku odwróconego, natomiast rola palenia tytoniu jest mniejsza. Wyodrębniono szczególną grupę kobiet u których trądzik zwyczajny był obecny >25 roku życia, co stanowi współcześnie narastający problem zdrowotny: w tej populacji AV może stanowić izolowaną formę hiperandrogenizmu, zasadny jest więc screening w kierunku towarzyszących zaburzeń hormonalnych. Ciężkie postacie AV lub HS mogą być zwiastunem systemowych zespołów autozapalnych takich jak SAPHO, PASH, PAPASH, PsAPASH czy PASS stąd konieczne są wczesna diagnoza i leczenie, celem powstrzymania „marszu autozapalnego”. 36 Abstract Aim: The first aim of the study was to perform the epidemiological characteristics of patients affected by acne vulgaris (AV) and hidradenitis suppurativa (HS). Specifically, an attempt was made to determine the conditions accompanying AV in the Cracow’s population of patients, to distinguish specific features of the adult female acne subpopulation (AFA) and to assess the co-existence of other autoinflammatory conditions associated with AV/HS via a systematic review of the literature. The second aim was to evaluate the role of obesity, nicotinism, and inflammation in the pathogenesis of HS using an immunohistochemical analysis of expression of the selected protein markers in the skin of obese smokers (OS) compared to non-obese and non-smokers (NN). Material and methods: The study was conducted at the Department of Dermatology, Jagiellonian University Medical College in Cracow, where a retrospective analysis of medical records of 354 patients with acne vulgaris was performed. The second part of the research was an immunohistochemical study on skin sections of 22 patients (10 NN, 12 OS) surgically treated for HS in Dessau, Germany at the Brandenburg Theodor Fontane Medical University, Department of Dermatology, Venereology, Allergology and Immunology. Formalin-fixed, paraffin-embedded skin sections were sliced with a microtome into 3.5-micrometer cuts and then stained with antibodies against proteins associated with obesity (PPAR-γ, irisin, IGFR1R), smoking/proliferation (AhR, EGFR), and inflammatory markers (IL-17 and its’ receptor, S100A8/MRP8); antibodies delivered by Abcam, Berlin, Germany. Epidermis and dermis specimens were photographed (x100 magnification; EVOS AMG microscope, Bothell, Washington). The computer program FIJI (Fiji Is Just ImageJ; NIH, Bethesda, USA) and a semi-automatic procedure (Andy's algorithm) were used to analyze the microscopic images. Finally, a systematic review of articles collected in the electronic databases MEDLINE, EMBASE and CENTRAL in the period of 1980-2020 was performed by two independent investigators to identify the cases in which acne vulgaris/acne inversa was accompanied by at least two other autoinflammatory diseases. Results: In the first retrospective study of patients with acne vulgaris, 61% of individuals were female and 27.6 % of all patients classified as AFA. The median age in the study was 24 years, for AFA it was 32.5 years. Patients with AFA were less likely to have skin lesions on the back, and the face was the most commonly affected area. Papulopustular acne predominated 37 in the whole population studied. In 38.7% of all subjects at least one chronic systemic disease was present, with endocrine disorders being the most common (15.25%), and thyroid dysfunction present in 6.21%. Endocrine disorders were significantly more frequent in women with AFA than in other patients, while cutaneous features of hyperandrogenism were less frequent in AFA. Furthermore, in the immunohistochemical examination of the skin probes of HS patients, peptides associated with obesity showed differential expression between groups, whereas peptides associated with smoking were not significantly different between OS and NN. EGFR manifested stronger in the NN than OS group. IL-17R showed greater immunoreactivity in the OS group, whereas S100A8 staining showed a substantial, increased expression in all subjects. Finally, in our third study a systematic literature review identified 64 articles on syndromic HS. The articles included those regarding already well-defined syndromes as well as new, previously undescribed constellations of symptoms, for instance with ocular involvement. Cutaneous symptoms, including HS, usually preceded symptoms from other organs, and they proved resistant to conventional therapy in a significant proportion of patients. Conclusions: The results of the study indicate that metabolic disorders (obesity) play a pivotal role in the pathogenesis of acne inversa, while the impact of smoking is less prominent. A special subgroup of women with acne present >25 years of age was identified, which is a growing health problem nowadays: in this population acne may constitute an isolated manifestation of hyperandrogenism, therefore a screening for concomitant hormonal disorders is warranted. Severe forms of AV or HS can be a harbinger of systemic autoinflammatory syndromes such as SAPHO, PASH, PAPASH, PsAPASH, or PASS, hence early diagnosis and treatment are necessary to prevent the "autoinflammatory march". 38 9. Teksty publikacji wchodzących w skład rozprawy doktorskiej Publikacja nr 1 Tytuł: The Skin as a Mirror of Internal Disease: Comorbidities and Epidemiology of Acne Vulgaris and Adult Female Acne -A Cross-sectional Study and Current State of Knowledge. Autorzy: Katarzyna Kaleta, Anna Bogusławska, Anthanosios J. Stefanis, Agata Kłosowicz, Natalia Juśko, Monika Kapińska -Mrowiecka, Elżbieta Broniatowska, Anna Wojas -Pelc Czasopismo: Acta Dermatovenerologica Croatica. 2020; 28(3): 133-140. Impact Factor: 1,256. Punkty ministerialne: 40 39 Acta Dermatovenerol Croat 2020;28(3):133-140 CLINICAL ARTICLE The Skin as a Mirror of Internal Disease: Comorbidities and Epidemiology of Acne Vulgaris and Adult Female Acne - A Cross-sectional Study and Current State of Knowledge Katarzyna Kaleta12, Anna Bogusławska13, Athanasios J. Stefanis4, Agata KłosowiczNatalia Juśko2, Monika Kapińska-Mrowiecka2, Elżbieta Broniatowskas, Anna Wojas-Pelc1 'Department of Dermatology, Jagiellonian University Medical College, Krakow, Poland department of Dermatology, Stefan Żeromski Krakow Municipal Hospital, Krakow, Poland;department of Pediatric and Adolescent Endocrinology, Institute of Pediatrics, Jagiellonian University Medical College, Krakow, Poland;department of Dermatology, Third Faculty of Medicine, Charles University, Prague, Czech Republic;5Andrzej Frycz Modrzewski Krakow University, Faculty of Medicine and Health Sciences, Krakow, Poland Corresponding Author: Katarzyna Kaleta, MD Department of Dermatology Jagiellonian University Medical College 8 Skawińska St 30-066 Krakow Poland katarzyna.kaleta@o2.pl Received: December 1,2019 Accepted: July 15,2020 ABSTRACT Acne vulgaris is a common skin condition affecting an increasing number of adults and might be a clue to identifying systemic disease. Objective of this study is assessment of the demographic and clinical characteristic, including comorbidities, of patients with acne with a special focus on adult female acne (AFA). This cross-sectional study analyzed the medical records of 354 patients with acne (323 outpatients and 31 hospitalized). Data concerning patient age, sex, lesions morphology and distribution on body areas, duration of the disease, Body Mass Index, and dermatologie and systemic comorbidities were collected. 61% of all patients were female, 45.37% of women were classified as AFA. The median age of patients with acne was 24 years and 32.5 years for AFA. The face was the most commonly affected area; patients with AFA had lesions on their back than less frequently non-AFA. Predominant eruptions were pustules and papules. 38.7% of patients had concomitant systemic chronic disease, 15.25% had an endocrinologie disorder, and 6.21% had thyroid gland dysfunction. Women with AFA had endocrinologie disorders more frequently (P=0.002), whereas cutaneous signs of hyperandrogen-ism were observed less frequently than in the non-AFA group (P=0.034). AFA possess distinct clinical features and it should raise suspicion towards possible underlying endocrinologie disturbance. KEY WORDS: acne vulgaris, adult women, epidemiology, comorbidity, hormones ACTA DERMATOVENEROLOGICA CROATICA 133 40 Kaleta et al. Skin as a mirror of internal disease Acta Dermatovenerol Croat 2020;28(3):133-140 INTRODUCTION Acne vulgaris is a chronic inflammatory disease of the pilosebaceous units, clinically manifesting with the presence of comedones, papules, pustules, cysts, nodules, and sometimes leading to scarring (13). Acne occurs mainly on the face, neck, and upper trunk (1,2). Mild forms of the disease develop in approximately 85% of the population, with the remaining 15% being severe nodular forms that include acne conglobata (4). The disease pathophysiology includes four basic processes, namely: follicular hyperkeratinization, androgen-induced hypersecretion of sebum, colonization of the hair follicles by Cutibacterium acnes (C. acnes), together with immune and inflammatory responses (2,3). Despite advances in understanding of its pathogenesis, few epidemiological studies of acne have been carried out, not just in Poland but also in other European countries (5,6). Acne vulgaris is undoubtedly one of the most common dermatologie disorders, with an estimated global prevalence of9.4%andthe highest occurrence in adolescents; 85% of individuals between 12 and 24 years have acne at some point of their lives (6,7). Recent research has shown that acne also affects a significant number of adults (1). In the literature, adult acne is defined as acne present beyond the age of 25 and can be classified as either acne persistent from adolescence, responsible for 80% of the cases, or the late-onset type (8-10). The disease may have special features at older ages. For instance, in contrast to teenage acne, in which men tend to be affected more commonly and severely, post-adolescent acne mainly affects women and is usually mild to moderate in grade (9,11,12). We need to define whether adult female acne (AFA) should be regarded as a separate clinical entity from acne vulgaris and therefore require a different therapeutical approach. Data also suggest that patients with severe acne are at higher risk for many somatic and psychological comorbidities, as the elements engaged in acne pathogenesis may also have an influence on organs other than skin. A role of C. acnes is currently postulated in the development of many different diseases, such as endophthalmitis, endocarditis, meningitis, and sarcoidosis (13). Acne may be a clue to hormonal disturbances, including polycystic ovary syndrome (PCOS) or congenital adrenal hyperplasia (14). There is reason to subject acne comorbidities in different age groups to closer scrutiny. Objectives The aim of the study was to assess the demo- graphic and clinical characteristic of patients with acne vulgaris with a special regard to adult female acne. An attempt was made to establish the diseases most frequently associated with acne. PATIENTS AND METHODS This was an uncontrolled observational cross-sectional study that analyzed the medical records of 354 patients with acne vulgaris from Dermatology Clinic of Jagiellonian University Medical College. The data comprise 323 outpatients (from January 2016 until December 2018) and 31 hospitalizations that occurred due to acne (from January 2013 until December 2018). 10 people were included in both groups (outpatients and hospitalized). The discrepancy between the time of analysis for the groups was due to lack of electronic medical documentation for the outpatient department before January 2016. The estimated minimal sample size was 246 patients, assuming 80% prevalence of acne in the Polish population. Patients were men and women aged between 12 and 69 years old. Data concerning patient age, sex, lesions morphology (presence of comedones, papules, pustules, cysts, scars, hyperpigmentation), and their distribution on body areas were collected for all groups. For hospitalized patients, additional data were available for analysis: duration of the disease (years passed before admission to the hospital) and the patients' Body Mass Index (BMI) - defined as weight/height squared (kg/m2). Other forms of acne, such as rosacea, ance inversa, and infantile acne, are not discussed in this article. Statistical analysis Statistical analysisof collected data was performed using STATISTICA 12.0.The normality of data was analyzed using the Shapiro-Wilk Test. All numerical variables were presented as numbers with percentages, median (Me) with interquartile range (IQR) or mean ± standard deviation (SD). Pearson's Chi-squared and U-Mann Whitney tests were used to assess the relationship between variables, and statistical significance was defined as P<0.05. RESULTS Demographic and general characteristics The median age of the 354 people treated for acne vulgaris at our Clinic was 24 years (IQR 20-31). Cases from the outpatient department had a higher median age than cases from the hospital (24 years, IQR 20-31 versus 20 years, IQR 17-29; P=0.02). There 134 ACTA DERMATOVENEROLOGICA CROATICA 41 Kaleta et al Skin as a mirror of internal disease Acta Dermatovenerol Croat 2020;28(3):133-140 Table 1. Acne lesions localization and types of acne eruptions Total AFA Non-AFA P-value N (%) N (%) N (%) Lesions localization Face 292 (82.48) 84 (85.71) 208 (81.25) 0.28 Back 140 (39.55) 27 (27.55) 113 (44.14) 0.003 Chest 73 (20.62) 24 (24.49) 49 (19.14) 0.27 Neck 32 (9.04) 12 (12.24) 20 (7.81) 0.2 Shoulders 26 (7.34) 6 (6.12) 20 (7.81) 0.58 Head 23 (6.5) 4 (4.08) 19 (7.42) 0.25 Buttocks 5 (1.41) 1 (1.02) 4 (1.56) 0.99 Other 17 (4.8) 4 (4.08) 13 (5.07) 0.79 Lesions morphology Comedones 128 (36.16) 32 (32.65) 96 (37.5) 0.26 Pustulo-papular 276 (77.97) 77 (78.57) 199 (77.73) 0.55 Acne conglobata 64 (18.07) 19 (19.39) 45 (17.58) 0.81 Inflammatory acne-ONS 19 (5.37) 3 (3.06) 16 (6.25) 0.2 Hyperpigmentation 96 (27.11) 21 (21.43) 75 (29.3) 0.08 Other 40 (11.23) 15 (15.3) 25 (9.77) 0.17 AFA - adult female acne, ONS - other non-specified Missing data: for acne lesions localization on mean level 4.87%: for acne lesions morphology on mean level 7.32% was a significant number of older individuals in our study: 69 adults aged 30-39 years, 20 adults aged 4049 years, and 6 between 50 and 69 years. The median age for patients with AFA was substantially higher than for the remaining acne population, at 32.5 years (IQR 28-38 versus 22 years for non-AFA patients, IQR 19-25; P<0.001). Women suffered from acne more frequently than men, comprising 61% of all patients with acne, with 45.37% of them - 98 women in the study (27.6% of the analyzed population) - classified as AFA. Women constituted 62.3% of outpatients . In the inpatients group, there was a slightly higher prevalence of men (53.33%), but the differences were not statistically significant (P=0.13). One of the outpatients was in the middle of a gender change process, but was classified as female in our records. Median duration of the disease before admission to the hospital was 3 years (IQR 0.92-5.00). Acne morphology The three most frequently affected body areas in all the analyzed groups were the same: the face (affected in 87.49% of all patients), followed by the back and chest. Women with AFA had lesions less frequently on their back compared with non-AFA sub- jects (27% versus 44.14%; P=0.003). The vast majority (70.62%) of all patients had a limited form of acne (defined as presence of eruptions on a maximum of 2 different body areas). Women with AFA were not found to have more extensive disease compared with the rest of the population (P=0.12). As fa r as acne lesions morphology was concerned, most patients presented with more than one lesion type. The most frequent eruptions were pustules and papules (present in 276 patients; 77.97%). There was no difference in inflammatory lesion prevalence for the AFA group compared with non-AFA (for papulo-pustular acne: 78.57% vs 77.73%; P=0.55). Moreover, 27.97% of all our patients suffered from acne scars. Among all the patients with scars, 53 (53.5%) were men and 46 (46.5%) were women (P<0.001). Table 1 depicts the acne morphology results in detail. Acne comorbidities 38.7% of patients with acne suffered from at least one systemic chronic disease. The most frequent comorbidities were endocrinologie disorders, present in 54 individuals (15.25%), of which thyroid gland dys- ACTA DERMATOVENEROLOGICA CROATICA 135 42 Kaleta et al. Skin asa mirror of internal disease Acta Dermatovenerol Croat 2020;28(3):133-140 Table 2. Chronic systemic and dermatologie comorbidities Total Outpatients Hospital p-value AFA Non-AFA p-value N (%) N (%) N (%) N (%) N (%) Chronic systemic comorbidities Thyroid gland 22 (6.21) 21 (6.5) 1 (3.22) 0.71 10 (10.2) 12 (4.69) 0.08 disfunction Other than thyroid 32 (9.03) 27 (8.36) 5 (16.12) 0.18 16 (16.33) 16 (6.25) 0.003 endocrinologie disease* Hormonal disease 54 (15.25) 42 (13) 6 (19.35) 0.41 24 (24.49) 24 (9.3) 0.002 (total) Diagnosed towards 15 (4.24) 15 (4.64) 0 0 0.38 5 (5.1) 0 0 0.57 endocrinologie disorders Other chronic 83 (23.44) 68 (21.05) 15 (48.39) <0.001 27 (27.55) 56 (21.88) 0.26 disease** No systemic disease 74 (20.9) 59 (18.27) 15 (48.39) <0.001 14 (14.29) 60 (23.43) 0.06 reported Dermatologie comorbidities Hyperandrogenism 56 (15.82) 53 (16.4) 3 (9.68) 0.44 22 (22.44) 34 (13.28) 0.03 associated disorder*** Eczema 21 (5.93) 21 (6.5) 0 0 0.24 4 (4.08) 17 (6.64) 0.36 Other disorder 70 (19.78) 67 (29.74) 3 (9.68) 0.14 21 (21.42) 49 (19.14) 0.63 No dermatologie 222 (62.71) 196 (60.68) 26 (83.87) 0.01 56 (57.14) 166 (64.84) 0.18 disease reported ‘Including: diabetes mellitus, impaired glucose tolerance, insulin resistance, PCOS, biochemical hyperandrogenism, hyperprolactinemia, premature ovarian insufficiency “For hospitalized population: systemic lupus erythematosus, granulomatosis with polyangiitis, Crohn's disease, Still's disease, thrombocytosis, aplastic anemia, mitral valve incompetence, hypertension, depression, hyperlipidemia, SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, osteitis), chronic idiopathic meningitis, retrobulbar neuritis *** Including: seborrhea, seborrheic dermatitis, acne inversa and androgenetic alopecia function was most frequently reported, i.e. by 6.21% of all patients. There was no significant difference between the frequency of endocrine disorders between hospitalized patients and outpatients (P=0.32). Women constituted the majority of all patients with acne who had an underlying endocrinopathy (87.5% vs 12.5% men; P<0.001). Women with AFA had a concomitant endocrinologie disorder more frequently than patients without AFA (PcO.001), specifically other than thyroid hormonal disease, but not thyroid dysfunction alone (PcO.001, P=0.08 respectively). In the hospitalized population, comorbidities otherthan endocrinologie chronic diseases were reported significantly more often than in outpatients (P<0.001). Some patients reported having additional chronic dermatologie conditions. Predominantly, 15.82% of patients had androgen-associated disorders. There was no correlation between presence of hyperandrogenism and the disease extent (P=0.72). Interestingly, patients with AFA had cutaneous signs of hy- perandrogenism less frequently than the non-AFA group (P=0.03). We did not observe an increase in BMI in hospitalized patients. Mean BMI in the study was within a normal range (21.64 kg/m2, SD 3.40; minimum value 16.54 kg/m2, maximum 30.45 kg/m2). Mean BMI for both sexes was 22.08 kg/m2 (SD 3.14 for women, SD 3.66 for men, P=0.47). A summary of systemic and cutaneous comorbidities acne is presented in Table 2. DISCUSSION Acne vulgaris is ranked among top three most prevalent dermatologie conditions and is the eight most prevalent disease in the general population worldwide (7,15). Acne affects 80-100% of people aged between 11 and 30 years old, but recent studies have shown that acne is affecting an increasing number of adults, particularly woemn (2,4). There was a significant number of older participants in our study (total of 95 people >30 years old). 136 ACTA DERMATOVENEROLOGICA CROATICA 43 Kaleta et al. Skin as a mirror of internal disease Acta Dermatovenerol Croat 2020;28(3):133-140 Available data has shown acne prevalence for people aged 20-29 to be 64%; for those between 30 and 39 years old it is 43%, and between 40 and 49 years it is 3% for men and 5 % for women (6). Even for people over 59, acne incidence was as high as 13% (3). As far as adult female acne is concerned, its prevalence varies highly from 14% in clinical studies to 54% in surveys (12,16). The peak age of acne incidence ranges between 16 to 20 years of age, according to different studies (2,7). Over recent decades, the average age of people with acne has increased from 20.5 to 26.5 years (11,17).This finding is in accordance with our results, where the median age of patients was 24 years. On the other hand, individuals with more severe acne requiring hospitalization were younger (median 20 years old) than outpatients. 27.6% of our study population were classified as AFA, which is similar to a Chinese study (25%) (3). AFA mean age ranges from 26.5 to 33.9 years in the literature (18). In our study, the median age for this acne subtype was 32.5 years, which was therefore closer to the reported upper age range. Acne has been increasingly recognized as a chronic disease, especially regarding AFA chronicity, which may persist until the postmenopausal period (10,19).The median duration of acne before admission to the hospital was 3 years in our study, which is longer than the global average duration of the disease (mean 2 years, median 1 year) (7). The sex ratio of reported visits to a dermatologist due to acne was evaluated in literature to be 5:3 women to men (15). In our study, women constituted the majority (62.3%) of outpatients, but the most severe cases of acne that required hospitalization were predominantly men (53.33%). Studies evaluating sex have shown that women are more often affected at younger ages and in adult acne, whereas men are more frequently affected during adolescence and with more severe forms of the disease (4,7,20). Several aspects of acne morphology were assessed in our study. The distribution of the lesions was mostly in accordance with the available literature. The face was by far the most common site of acne involvement (up to 100 % of individuals according to some studies). The extrafacial areas are affected at slightly different rates depending on the study, with the second most common location being the upper back (52%), followed by the upper chest (30%), lower back (22%), shoulders (16%), and neck (8%) (7). The majority of our patients had a disease restricted to two body areas. Women aged more than 25 years in our study differed from the whole acne population, having acne eruptions less frequently on their back. In a study by Di Landro et ai, 96.8% of women with AFA had lesions on the face (mainly on the cheeks and chin) and 30.4% had lesions on the trunk (17). Recent studies have questioned the classic localization on the lower third of the face, instead reporting involvement of multiple facial areas and a 48.4% prevalence of truncal lesions vs 11.2 % on the mandibulum (10,11). Apart from the lesion distribution, we also analyzed their morphology. The probability of having inflammatory acne was postulated to increase with patient age, although in some studies up to 93.7% of AFA had comedones and patients with comedonal acne were older than those with the inflammatory type (1,2,10,17,21,22). In our study, inflammatory pa-pulo-pustular eruptions were the most frequent. This was true for all groups: younger patients, hospitalized and older patients, and outpatients. Furthermore, there was no difference in eruption type between the AFA group and the other patients. Scarring is the most concerning and disfiguring sequela of acne. The predominance of acne scars varies highly from study to study (from 26.1% to 95%) (23). A significant number of patients suffered from scarring in our study, but, in contrast to some data that suggest more frequent scarring in female patients (14% vs 11%), we noted that men predominated among all patients with scars (53.5% in men vs 46.5% in women) (24). To our knowledge, the global prevalence of concomitant diseases in acne patients has not yet been estimated. There are single studies available; for example, comorbidities were found in 4.3% of women with adult female acne (18). Acne might bean indicator of hormonal disturbances, including syndromes such PCOS or congenital adrenal hyperplasia, as well as other systemic disorders such as Behcet syndrome, Apert syndrome, or hypovitaminosis (14). Comor-bid disorders associated in the literature with severe forms of acne in children and adolescents also include sinopulmonary disorders (asthma, sore throat other than streptococcal infection) and upper gastrointestinal diseases (13). According to some studies, psychiatric comorbidities accompany acne, but the data are not consistent (13,15,17,25). In our study, 38.7% of the total population with acne suffered from at least one systemic chronic disease. Flospitalized patients had significantly more concomitant systemic diseases than outpatients. The presence of a severe comorbidity such as collective tissue disease, vasculitis, or inflammatory diseases as in our inpatient population, might be a factor con- ACTA DERMATOVENEROLOGICA CROATICA 137 44 Kaleta et al. Skin as a mirror of internal disease Acta Dermatovenerol Croat 2020;28(3):133-140 tributing to more severe acne course. Only endocrinological comorbidities were significantly frequently noted in patients records, present in 15.25% of individuals. The relationship between acne and hormonal disfunctions has been widely discussed in literature, but the findings are not fully clear. Although it is generally agreed that there is no underlying endocrine disease in most cases of AFA, more and more studies suggest that late-onset or persistent acne suggest hyperandrogenism (18,26). Up to 70% women with PCOS, the main cause of hyperandrogenism, do have acne and the postulated causative factor of AFA is hyperproliferation of kératinocytes due to an increase in insulin and Insulin Growth Factor 1 levels (10,15,18). In our study, the vast majority (87.5%) of all patients with acne who had an underlying endocrinologie disease were women. Furthermore, patients with AFA had a concomitant endocrinologie disorder more frequently compared with patients without AFA, although no particular hormonal disease was associated with AFA. As for dermatologie comorbidities, patients most frequently suffered from seborrhea, seborrheic dermatitis, and androgenetic alopecia, which are conditions that might be attributed to some extend to a disturbance in androgen metabolism (10,27). Surprisingly, women with AFA had cutaneous manifestations of hyperandrogenism less frequently than non-AFA patients, which is in contrast to available studies: it has been reported that one third of AFA cases present some clinical features of hyperandrogenism (1). The explanation for this discrepancy might be that an inflammatory AFA subtype was predominant in our study, which is said to be less frequently associated with hyperseborrhea than the retentional form in which hyperseborrhea is always present (8,10). In studies on the adult acne population, alopecia was present in 1.8-7.2% of patients, but raised laboratory markers of hyperandrogenism were observed in only 3.08% cases, among which slightly elevated levels of dehydroepiandrosterone sulfate were reported most often (1,8,9,18,28). In acne, there is an altered response of skin receptors to circulating androgenic hormones and increased peripheral conversion to active metabolites (18). Insulin resistance is associated with acne independently from hyperandrogenemia, according to some researchers (29). Some studies emphasize a positive relationship between the number of acne localizations and the presence of hyperandrogenism signs. At least two locations of acne (thorax, shoulders, jaw, neck, and cheeks) were correlated with irregular menstrual cycles and seborrhea (26). no such correlation was found in our study. Flowever, our study demonstrated that there might be a rationale for analyzing thyroid dysfunctions in patients with acne, as thyroid dysfunction was the most frequently reported comorbidity in our study group (6.21%). The available study results remain contradictory -Tsvetanova et ai showed an increased risk for thyroid gland dysfunction or autoimmunity in patients with acne compared with the control group (22.86% vs 1.43%), while other studies have failed to demonstrate significant changes in thyroid parameters in adults with acne (30). Thyroid-stimulating hormone and thyroxine increase sebum secretion together with testosterone. The role of pro-inflammatory cytokines (interleukin-1, interleukin-2, interferon-alpha, interferon-gamma) elevated in autoimmune thyroid inflammation is also postulated to activate sebaceous gland function (30-32). Finally, we did not observe an increase in BMI in hospitalized patients with acne above the normal range. Mean BMI in our study was 21.64 kg/m2, which is lower than the mean BMI value for Poland (26.4kg/ m2 P30 and smokers, n = 12 vs. BMI <30 and non-smokers, n = 10) were stained with antibodies raised against irisin, PPARy, and IGF-1R, which correlate with metabolic disorders/obesity, EGFR and AhR, associated with smoking, and IL-17, IL-17R, and SI 00A8, as markers of inflammation. Results: Metabolic disorders/obesity-related markers exhibited marked differential expression between the two groups, while smoking-associated markers a limited one. IL-17R expression was stronger in obese/smokers, and S100A8 staining exhibited intense strong immunoreactivity in both groups without significant difference. Conclusions: The notion that obesity plays a role in HS development appears to be supported by the prominent regulation of the associated lesional biomarkers. Tobacco smoking might contribute less to HS than previously suspected. ©2021 S. Karger AG, Basel Katarzyna P. Kaleta and Georgios Nikolakis contributed equally to the study. karger@karger.com wwwJcarger.com/drm 5 2021 S. Karger AG, Basel Correspondence to: Christos C. Zouboulis, christos.zouboulis@klinikum-dessau.de 93.159.169.1M -7/2a-202l 4:59:09 PM 49 Introduction Hidradenitis suppurativa/acne inversa (HS) is a chronic, recurrent inflammatory skin disease of the hair follicle, which manifests with deep-seated, painful nodules, abscesses, tunnel formation, and subsequent scarring, most commonly localized in the axillary, inguinal, and anogenital regions [1]. Its evidenced global prevalence has been calculated to be 0.4% with a wide variation from 0.03% to 1% in different studies [2-4]. The exact pathophysiology of the disease is not fully elucidated. Multiple genetic, environmental, and endocrinological factors may play a role, leading to pilosebaceous plugging and follicular rupture [5, 6]. Obesity/metabolic syndrome, also represented by increased body mass index (BMI), smoking, and an aberrant regulation of the innate immunity, is among the most commonly reported risk factors for the development of HS [7-11]. HS prevalence in obese patients has been reported to be up to 18.1 ± 4.8%, the probability of metabolic syndrome in HS patients is 4.5-fold higher than in non-HS individuals, and smoking is associated with HS with an odds ratio of 12.6 (95% confidence interval 8.6-18.4) [1214]. Moreover, the disease improves after weight loss [12, 15, 16]. Several efforts have been made to dissociate these comorbid disorders or rank their importance for the development of HS. However, these data might ignore the real-world situation, where obesity and smoking often cooccur in the same person and family members [17-19]. For these reasons, we conducted this study to assess the importance of metabo lie disorders/obesity, smoking/environmental toxins, and inflammation in HS by utilizing the differential expression of major relevant protein markers in lesional skin of obese/smoking versus non-obese/non-smoking HS patients. The results indirectly categorize the importance of HS risk factors in a real-world setting. Materials and Methods Study Population This pilot immunohistochemical study was conducted based on a retrospective chart review of HS patients, who underwent biopsy/surgery in our Departments. The data have been recorded according to the European Hidradenitis Suppurativa Foundation protocol [20], which was approved by the Ethics Committee of the Brandenburg Medical School Theodor Fontane, Brandenburg, Germany. The patients group included 22 adult HS patients with no documented diabetes mellitus type II and insulin resistance, who were divided into two groups: 12 obese (body mass index [BMI] >30), cigarette smoking patients (OS) and 10 non-obese (BMI <30), non-smoking patients (NN). The demographic characteristics of the population are summarized in Table 1. 2 Dermatology DOI: 10.1159/000517017 Table 1. Demographic characteristics of the study population Characteristics OS NN Age, years, median (IQR) 35(12) 31(8) Sex, F/M 8/4 6/4 BMI (kg/m2), median (range) 35.5 (30.7-45.6) 24.4(18.4-28.3) Hurley stage I, n 1 1 Hurley stage II, n 3 5 Hurley stage III, n 6 6 IQR, Interquartile range; F, female; M, male; BMI, body mass index. Immunohistochemistry Formalin-fixed, paraffin-embedded skin specimens of lesional skin after skin biopsy/surgery were collected and cut in 3.5-pm sections and were prepared for immunohistochemistry, which was performed as previously described [21]. The sections were stained with antibodies raised against irisin, peroxisome proliferator-acti-vated receptor y (PPARy), insulin growth factor-1 receptor (IGF-1R), aryl hydrocarbon receptor (AhR), epidermal growth factor receptor (EGFR), myeloid-related protein 8 (MRP8, S100A8), interleukin-17 (IL-17), and IL-17 receptor (IL-17R) (Abeam, Berlin, Germany), according to the manufacturer’s protocol. The technical details, concerning primary antibody dilution, incubation time and epitope retrieval method are included in the online supplementary material SI and Table SI (for all online suppl. material, see www.karger.com/doi/10.1159/000517017). Characteristics of Studied Proteins Irisin is a novel adipomyokine increasing thermogenesis and energy expenditure, therefore protecting against insulin resistance and obesity [22, 23]. In animal skin, irisin is expressed in the basal epidermal layer and the pilosebaceous unit [24]. Peroxisome proliferator-activated receptor y (PPARy) is a nuclear hormone receptor expressed in the pilosebaceous unit [25] and is connected with the pathophysiology of metabolic diseases. Its upregulation/activation is associated with anti-inflammatory mechanisms, glucose metabolism regulation, and adipocyte/se-bocyte differentiation [25-27]. IGF-1, also known as somatomedin C, is a protein hormone that mediates its functions via a cell surface receptor belonging to the tyrosine kinase family [28, 29]. The IGF system is ubiquitous, with paracrine and endocrine metabolic functions. Activation of IGF-1 R coordinates protein, carbohydrate, and fat metabolism, promotes mitosis and inhibits cell apoptosis [30, 31]. AhR, which is well known to be activated by benzopyrene in skin cells [32], is a major polyaromatic hydrocarbon in smoke fume used as a marker for smoking [33]. AhR is a latent cytoplasmic transcription factor of the Per-ARNT-Sim-basic helix protein family [34], expressed in skin, mucosal épithélia, and immune cells. It modulates keratinocyte and sebocyte differentiation [35]. EGFR serves as a tyrosine kinase receptor involved in skin homeostasis, proliferation, differentiation, adhesion, migration, apoptosis, and inflammatory responses [36]. Reduction of its expression in epithelial cells has been associated with environmental pollution [37]. IL-17 and tumor necrosis I Kaleta et al. if 1 50 factor-a are considered to play a pivotal role in mediating inflammation/immune response in HS and are both targets of current and potential novel therapies [38-41]. S100A8, also known as calgranulin A, which belongs to the family of antimicrobial peptides (AMPs), is produced by kératinocytes as part of the body innate response to pathogenic invasion and is upregulated in many chronic dermatoses [42]. S100A8 contributes to leukocyte extravasation, promotes neutrophil activation, and hyperproliferation of kératinocytes. Image Analysis and Statistical Evaluation Non-overlapping photos of the epidermis and dermis (including the pilosebaceous unit) of each specimen (magnification xlOO) were analysed with the open-source platform FIJI of Image} software (NIH, Bethesda, USA) [43], using Andy’s algorithm for automated digital image analysis [44]. For this, after applying specific filters, the images were converted via colour deconvolution to 8-bit grey-scale images, and an optimal automatic threshold [45] was set to subsequently convert them to binary images. This facilitated the calculation of stained particles and the mean intensity of the image. Higher mean intensity is reversely correlated with positive particles counted and thus, protein expression. As the data were not normally distributed, intensities were compared with non-parametric Mann-Whitney two-tailed U test, using IBM SPSS Statistics 23 (IBM, Armonk, NY, USA). The results are presented as median with interquartile range (IQR) and were considered statistically significant ifp < 0.05. Results The patients’ demographic and clinical characteristics were similarly distributed in the two groups (Table 1). The metabolic disorders/obesity-related markers irisin, PPARy, and IGF-1R were differentially regulated in the OS and NN groups. The median intensity of image analysis for the adipomyokine irisin indicated weaker expression in the HS-involved skin of OS patients (OS 98.3 [IQR 86.0-106.9]; NN 76.5 [64.9-90.0],p = 0.008). Irisin was expressed in the entire epidermis and more intensely in the suprabasal layers of NN patients, while the inner and outer root sheath follicular kératinocytes depicted moderate expression in both groups. Similarly to irisin, PPARy staining demonstrated a stronger expression in NN skin (OS 138.8 [128.8-150.9]; NN 94.7 [86.6-107.6],p < 0.001). PPARy demonstrated a strong expression in the suprabasal interfollicidar layers of the epidermis of NN patients and mostly in the basal layer of OS patients at a markedly reduced level. The expression in the follicular kératinocytes did not exhibit differences. IGF-1R expression was stronger in NN patients (OS 138.3 [134.8-157.1], NN 135.1 [123.6-146.0], p = 0.03). IGF- 1R was expressed in the basal and suprabasal epider- mal layers (stratum granulosum and spinosum) both in OS and NN patients. The staining was weaker in the OS group, while the hair follicles of NN skin showed a slightly increased cytoplasmatic expression of IGF-1 R in comparison to the OS specimens. The expression of AhR, which is a marker receptor for environmental pollution such as smoking, exhibited no difference between OS and NN patients (p = 0.4). Moderate cytoplasmic staining has been detected in all epidermal layers and outer root sheath of hair follicles of both groups, with a focally increased staining in the dermis and sweat gland duct cells. EGFR exhibited a stronger expression in the NN than the OS group (OS 132.0 [124.2-142.2], NN 123.1 [99.3128.1], p = 0.003). NN showed intense membrane staining, markedly seen in basal and spinous epidermal layers in comparison to OS with moderate basal kératinocytes staining; peripheral regions of hair follicles were distinctly stained in both groups. Regarding inflammatory markers, OS patients exhibited higher IL-17R expression than NN patients (OS 147.8 [137.8-160.3]; NN 164.8 [154.9-181.9], p = 0.023), while IL-17 expression was similar in the two groups (p = 0.09). The antimicrobial peptide S100A8 exhibited intense strong immunoreactivity in both groups (p = 0.6). Intense staining in all epidermal layers, outer and inner root sheaths of hair follicles along with sebaceous glands was detected. The summary of the findings is shown in F igures 1 and 2. Representative IHC photos are shown in Figure 3. Discussion The precise nature of the immune imbalance in HS is still poorly understood [46, 47]. In the current study, we investigated the expression of selected proteins, associated with metabolic syndrome/obesity, environmental pollution/smoking, and inflammation in order to evaluate the possible involvement of the major triggering factors of HS, obesity and smoking, in the development of skin lesions. Moreover, through comparing OS with NN, real-world data were taken into consideration. Smoking promotes HS and hinders the healing of HS lesions [48-50]; however, its role is less well established than obesity. Available data come mostly from epidemiological studies, based on questionnaires. The prevalence of HS is doubled among tobacco smokers [51], yet the estimated incidence of smokers among a population of patients with HS varies widely from 30 to 98% [49, 52- Metabolic Disorders/Obesity Is a Primary Risk Factor in HS Dermatology DOI: 10.1159/000517017 Downloaded by: K. Katela - 251936 93.159.169.103 - 7,'2X2021 4:59:09 PM 51 3 52 Fig. 1. Tukey box plots depict median intensities (IQR) deriving from digital xlOO magnification images of OS versus NN specimens after IHC staining with irisin, PPARy, IGF-1R, AhR, EGF, IL-17, IL-17R, and MRP8 (S100A8). Average intensity correlates reversely with protein expression. There was a significantly increased expression in NN versus OS skin for irisin, PPARy, IGF-1R, EGFR, and IL-17R;p < 0.05. No statistically significant differences were demonstrated for AhR, IL-17, and MRP8; p > 0.05. 57]. A population-based study described a link between noted and no significant differences in Hurley stage be- HS and current but not prior smoking [58], The data tween smokers and non-smokers were registered, about the relationship between smoking and HS severity Obesity and smoking are often concomitantly present are unequivocal [54, 57-59]. No correlation of the num- in HS patients; however, reports taking into account this ber of cigarettes smoked per day with HS severity was co-occurrence are scarce [58,60-62]. Therefore, to reflect I 11 4 Dermatology Kaleta et al. DOI: 10.1159/000517017 lg * 7 ŚS li ss Q o> Fig. 2. Localization of the examined proteins after inspection of the IHC slides. Differential expression in different epidermal and dermal compartments are presented. OS, obese smokers; NN, non-obese non-smokers. this real-life situation, we decided to analyze the population of both smoking and obese HS individuals in comparison to a control group of neither smoking nor obese individuals. An estimated 75% of tobacco smokers diagnosed with HS are obese [51]. A retrospective analysis by Revuz et al. [4] underlined the importance of the association of those two factors in HS progression. In a cross-sectional study, Theut Riis et al. [11] suggested that the pack-years may have a synergistic effect with obesity, but BMI was the most important risk factor in the low BMI group. In light of this concomitance, we investigated the potential influence of metabolic and environmental factors by focusing on cutaneous expression of proteins associated with metabolism/obesity, such as irisin, PPARy, and IGF- 1R along with AhR and EGFR, which are related to air pollution/smoking, in addition to established HS inflammatory markers (IL-17, IL-17R, S100A8) [5, 63]. All obesity-related markers were differentially expressed between OS and NN patients. In contrast, among air pollution/ smoking and inflammatory markers, only EGFR and IL-17R were differentially expressed. These findings point at the major importance of metabolic disorders/ obesity for HS development and at in situ metabolic pathways alterations, which should be therefore thoroughly investigated searching to elucidate disease pathogenesis. In situ expression of irisin, PPARy, and IGF-1R might serve as biomarkers for upcoming or existing metabolic disorders in HS patients. The fact that inflammatory markers (S100A8, IL-17) were similarly expressed in OS and NN patients indicates a common inflammatory pattern of the disease in real life, which is independent of comorbid conditions. On the contrary, the enhanced IL-17R expression in obese/smoking HS patients might be a first proof for the requirement of biologic treatment dose adaptation to body weight/smoking [64, 65]. Conclusion This is a pilot, comprehensive study reflecting a real world setting of patients with HS. The notion that obesity plays a role in HS development appears to be supported by the prominent regulation of the associated le- Metabolic Disorders/Obesity Is a Primary Risk Factor in HS Dermatology DOI: 10.1159/000517017 Downloaded by: K. Kalela - 251936 93.159.169.103 - 7123,2021 4:89:09 PM 53 5 Fig. 3. Representative IHC images of both the epidermis (columns 1 and 2) and dermis (columns 3 and 4) of OS (columns 1 and 3) versus NN (columns 2 and 4) HS skin (xlOO magnification). Dermatology DOI: 10.1159/000517017 Kaleta et al. 54 Downloaded by: K. Katela - 251936 93.150-169.103 - 7,'2312021 4:59:09 PM 6 sional biomarkers. Tobacco smoking might contribute less to HS than previously suspected. As a limitation, the possibility of passive smoking for HS patients living in an environment with active smokers should be addressed. The detected differences in selected proteins of the obese/smoker group imply that primary end-organ alterations might provide a different phenotype in comparison to non-obese/non-smoker patients, however, without differences in the inflammation profile. The fact that all our patients did not have a manifesting metabolic disease indicates that skin changes could be more “sensitive” to tissue hormone levels than to serum ones. At last, non-response to biologies may be associated with a missing dose adaptation to body weight/smoking [64, 65]. Statement of Ethics The Ethics Committee of the Brandenburg Medical School Theodor Fontane (Brandenburg, Germany) approved the study protocol. All patients provided written informed consent. The study was conducted in accordance with the Declaration of Helsinki on Ethical Principles for Medical Research. Conflict of Interest Statement Christos C. Zouboulis has received thematic honoraria - independent from this work - from AbbVie, Idorsia, Incyte, Inflarx, Janssen, Novartis, Regeneron, and UCB. His departments have received grants from AbbVie, Inflarx, Novartis, and UCB for his contribution as clinical investigator. All other authors declare no conflict of interest. Key Message The differential regulation of obesity-related proteins suggests a major role of metabolic disorders in HS pathogenesis. Funding Sources None. Author Contributions Acknowledgements The Departments of Dermatology, Venereology, Allergology and Immunology, Dessau Medical Center, Dessau, Germany are health care providers of the European Reference Network for Rare and Complex Skin Diseases (ERN Skin - ALLOCATE Skin group). 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Hi- 63 dradenitis suppurativa and associated factors: Still unsolved problems. J Am Acad Derma toi. 2009;61:362-5. 64 60 Kagan RJ, Yakuboff KP, Warner P, Warden GD. Surgical treatment of hidradenitis suppurativa: A10-year experience. Surgery. 2005; 138:734-1. 61 Rompel R, PetresJ. Long-term results of wide 65 surgical excision in 106 patients with hidradenitis suppurativa. Dermatol Surg. 2000;26: 638-43. 62 Heinig B, Wollina U, Langner D, Nowak A Comorbidities, treatment, and outcome in severe anogenital inverse acne (hidradenitis suppurativa): a 15-year single center report. Int J Dermatol. 2017;56:109-15. Zouboulis CC. Biomarkers of hidradenitis suppurativa/acne inversa. Exp Dermatol. 2019;28:5. Zouboulis CC, Hansen H, Caposiena Caro RD, Damiani G, Delorme I, Pascual JC, et al. Adalimumab dose intensification in recalcitrant hidradenitis suppurativa/acne inversa. Dermatology. 2020;236(1 ):25-30. Sânchez Martinez EM, Murray G, Alfageme Roldân F, Garcia Ruiz R, Tobin AM, Zouboulis CC. Adalimumab dose intensification in hidradenitis suppurativa: effectiveness and safety results of a multicenter study. Br J Der matol. 2021. doi: 10.111 l/bjd.20525. I Metabolic Disorders/Obesity Is a Primary Dermatology 9 »! Risk Factor in HS DOI: 10.1159/000517017 j 57 Metabolic disorders/obesity is a primary risk factor in hidradenitis suppurativa - an immunohistochemical real-world approach Katarzyna P. Kaletaa,b*, Georgios Nikolakisa,c*, Amir M. Hossinia, Ottfried Balthasara’d, Daifallah Almansouria, Aristeidis Vaiopoulosa,c, Jürgen Knolled, Anna Boguslawskae, Anna Wojas-Pelcb, Christos C. Zouboulisa,c aDepartments of Dermatology, Venereology, Allergology and Immunology, Dessau Medical Center, Brandenburg Medical School Theodor Fontane, Dessau, Germany, bDepartment of Dermatology, Jagiellonian University Medical College, Krakow, Poland, cEuropean Hidradenitis Suppurativa Foundation e.V., Dessau, Germany, dInstitute of Pathology, Dessau Medical Center, Dessau, Germany, eDepartment of Paediatric and Adolescence Endocrinology, Paediatric Institute, Jagiellonian University Medical College, Krakow, Poland *The authors contributed equally to the study Supplementary material S1 For the staining and in order to avoid potential variation in intensity as the result of separate experiments, all slides were stained simultaneously using the DAKO EnVisionTM Flex detection system (DAKO, Hamburg, Germany). In brief, slides were pre-heated at 59oC for 30 min and were deparaffinized following standard procedures. All following steps were conducted after washing of the slides with DAKO wash buffer. The slides were placed in heat-induced epitope retrieval solution, preheated to 95-99oC for 25 min and then are left to cool off for 15 min. The slides were treated with 3% H2O2 for 5 min. The primary antibody was then 58 applied (all rabbit antibodies from Abcam, Berlin, Germany; Table S1), incubated with the specimens for 30 min at room temperature. Afterwards they were treated with the “DAKO EnVisionTM FlexHRP” enzyme solution for 20 min. The diaminobenzidine (DAB) Chromogen concentrate, properly diluted in substrate buffer, was applied twice to each section for 5 min at room temperature. The sections were finally immersed in DAKO FLEX™ Hematoxylin for 5 min at room temperature and were mounted in aqueous mounting medium, covered with coverslips and observed under a digital microscope (EVOS AMG, Fischer Scientific GmbH, Schwerte, Germany). Table S1. Immunohistochemistry technical details Antibody Dilution Epitope retrieval method Molecular weight (kDA) Polyclonal anti-human - 1 : 500 HIER Method / Dako Target 22 FNDC -5 (C - terminal) Retrieval Soultion pH 9 Polyclonal anti-human IGF-1 1 : 100 HIER Method / Dako Target 155 receptor (phospho Y1161) Retrieval Soultion pH 6.1 Monoclonal anti-human 1 : 100 HIER Method / Dako Target 58 PPAR-y 1+2 Retrieval Soultion pH 9 Anti-Aryl hydrocarbon 1 : 2000 HIER Method / Dako Target 96 Receptor antibody Retrieval Soultion pH 9 Polyclonal anti-IL-17RA 1 : 1000 HIER Method / Dako Target N/A receptor antibody Retrieval Soultion pH 9 Monoclonal anti-human 1 : 500 HIER Method / Dako Target 11 MRP8 antibody Retrieval Soultion pH 9 Monoclonal anti-human 1 : 200 HIER Method / Dako Target 134 EGFR Retrieval Soultion pH 6 EGFR, epidermal growth factor receptor; FNDC-5, fibronectin type III domain containing protein 5 (irisin); HIER, heat-induced epitope retrieval, MRP8, Migration inhibitory factor-related protein 8 59 Publikacja nr 3 Tytuł: Phenotypes and Pathophysiology of Syndromic Hidradenitis Suppurativa: Different Faces of the Same Disease? A Systematic Review. Autorzy: Georgios Nikolakis*, Katarzyna Kaleta*, Aristedis G. Vaiopoulos, Katja Wolter, Sumer Baroud, Anna Wojas-Pelc, Christos C. Zouboulis * równorzędne pierwsze autorstwo Czasopismo: Dermatology. 2020; 17:1-25. doi: 10.1159/000509873. Impact Factor: 5,366. Punkty ministerialne: 100 60 Review Article Dermatology Dermatology DOI: 10.1159/000509873 Received: April 23,2020 Accepted: June 27,2020 Published online: September 17,2020 Phenotypes and Pathophysiology of Syndromic Hidradenitis Suppurativa: Different Faces of the Same Disease? A Systematic Review Georgios Nikolakis3-b Katarzyna P. Kaleta3C Aristeidis G. Vaiopoulosa,b Katja Wolter3 Sumer Baroud3' d Anna Wojas-Pelcc Christos C. Zouboulis3-b --Departments of Dermatology, Venereology, Allergology, and Immunology, Dessau Medical Center, Brandenburg Medical School Theodor Fontane, Dessau, Germany; bEuropean Hidradenitis Suppurativa Foundation e.V., Dessau, Germany; 'Department of Dermatology, Jagiellonian University Medical College, Krakow, Poland; dUniversity of Sharjah, Sharjah, United Arab Emirates Keywords Hidradenitis suppurativa • Acne inversa • Syndrome • Arthritis • Synovitis-acne-pustulosis-hyperostosis-osteitis • Inflammatory bowel disease • Autoinflammatory disorder • Pustulosis Abstract Background: There is growing evidence that (certain) hidradenitis suppurativa (HS) comorbidities comprise syndromes including HS as a key cutaneous manifestation. These apparently autoinflammatory syndromes and their diagnostic delay might have detrimental effects on affected patients. Methods: A systematic review was performed on the databases MEDLINE, EMBASE, and CENTRAL utilizing a standardized extraction form according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Results: Sixty-four eligible articles on syndromic HS were retrieved. The identified syndromes included already described ones (pyoderma gangrenosum-acne-suppurative hidradenitis, pyogenic arthritis-pyoderma gangrenosum-acne-suppurative hidradenitis, psoriatic arthritis-pyoderma gangrenosum-acne-suppurative hidradenitis, pyoderma gangrenosum-acne vulgaris-hidradenitis suppurativa-ankylosing spondylitis, synovitis-acne-pustulo-sis-hyperostosis-osteitis) and further novel symptom constellations. Cutaneous signs, including HS lesions, usually precede signs from other organs. The cutaneous signs of a considerable proportion of patients appear refractory to conventional treatment, and monotherapy with biologies does not suffice to sustain remission. Conclusion:The results are subsequently discussed with focus on the pathophysiology and treatment of the detected syndromes. The dermatologist's role in the precise diagnosis and early treatment administration of HS is pivotal. The purpose of the treatment should be the effective prevention or delay of the autoinflammatory march and its irreversible consequences. «2020 S. Karger AG, Basel Introduction Hidradenitis suppurativa (HS), or acne inversa, is a chronic inflammatory skin disease of the hair follicle characterized by painful, deep-seated, recurrent nodules and abscesses, mostly in the apocrine-bearing localiza- G. Nikolakis and K.P. Kaleta contributed equally to the manuscript. karger@kargcr.com wwwJcargcr.com/drm © 2020 S. Karger AG, Basel Georgios Nikolakis Departments of Dermatology, Venereology, Allergology, and Immunology Dessau Medical Center, Brandenburg Medical School Theodor Fontane Aucnweg 38, DE-06847 Dessau (Germany) nikolakisgeorgios@ gmaiL com 61 tions of the body, namely the axillary, inguinal, and anogenital regions (Dessau definition) [1, 2], The initial inflammatory lesions rupture and lead to scarring and/or sinus tract formation [3]. The detected prevalence of the disease varies between 0.03 and 0.53%, whereas a prevalence up to 1% has been suggested [4-6]. HS mostly manifests during or after puberty. In addition to its occurrence as a single disease, HS can also be a cardinal manifestation or an optional feature of certain syndromes recognized through their unique phenotypic constellation [7]. Syndromic HS has been included in the group of the so called autoinflammatory diseases. Autoinflammatory diseases are characterized by recurrent sterile inflammation with lack of high autoantibody titers or antigen-specific T lymphocytes. They are caused by a dysregulation of innate immunity [8-12] and involve a series of cutaneous and multiorgan diseases [13]. The cutaneous involvement in autoinflammation is usually marked by accumulation of neutrophils. Apart from the classic neutrophilic dermatoses, such as pyoderma gangrenosum (PG), Sweet’s syndrome, palmoplantar pustulosis, and erythema elevatum et diutinum, other dermatoses, including HS, share similarly increased levels of proinflammatory chemokines and cytokines with autoinflammatory diseases [14-19]. The majority of autoinflammatory disorders are characterized by overproduction of interleukin-1 ß (IL-lß), which triggers the release of tumor necrosis factor alpha (TNFa) and interferon gamma, being subsequently responsible for neutrophil recruitment and activation as well as evasion of apoptosis [20-23], IL-17 also contributes to neutrophil recruitment and activation and acts in synergy with other cytokines, such as TNFa [24]. A dysregulation of the regulatory T/T helper 17 cell ratio is believed to play a role in aggravating the autoinflammatory response and has been detected both in PG and HS independently [25-27], PG, HS, acne conglobata, acne fulminans, palmoplantar pustulosis, inflammatory bowel disease (IBD; including Crohn’s disease [CD] and ulcerative colitis [UC]), musculoskeletal disorders (arthritis, synovitis, osteitis, hyperostosis, axial spondyloarthropathy), and ocular symptoms are the most common diseases/clinical signs reported in syndromic HS cases. Combinations of the aforementioned diseases/clinical signs led to the description of HS-related autoinflammatory syndromes: pyoderma gangrenosum-acne-suppurative hidradenitis (PASH), pyogenic arthritis-pyoderma gangrenosum-acne-suppurative hidradenitis (PAPASH), pyoderma gan- 2 Dermatology DOI: 10.1159/000509873 grenosum-acne vulgaris-hidradenitis suppurativa-anky-losing spondylitis (PASS), and psoriatic arthritis-pyoderma gangrenosum-acne-suppurative hidradenitis (PsAPASH). Moreover, the syn ovitis-acne-pus tul os is-hyperostosis-osteitis (SAPHO) syndrome comprises a combination of cutaneous and articular symptoms including HS, although pustulosis is listed in the acronym as the main cutaneous sign. The purpose of this review is to detect common clinical denominators of the different HS-associated syndromes and their current treatment in order to further broaden the scientific clinical spectrum of dermatologists so that they can actively search, diagnose, and treat syndromic forms of HS. Moreover, it attempts to recognize demographic characteristics of prevalence, phenotype, and order of organ manifestations in order to provide the scientific basis over indicated therapy options before the development of the whole syndromic, sometimes irreversible, symptoms palette. Lastly, it underlines the effective role of dermatology experts as coordinators in the multidisciplinary approach to the patient. Methods The initial search was conducted in the electronic databases MEDLINE, EMBASE, and CENTRAL using a set of relevant search terms: “hidradenitis,” “suppurativa,” “acne inversa,” “autoinflammatory,” “synovitis,” “acne,” “pustulosis,” “hyperostosis,” “osteitis,” “arthritis,” “pyoderma gangrenosum,” “spondylitis,” and “psoriasis.” Subsequently, the references of the aforementioned articles were also screened for eligibility. Eligible studies were considered clinical trials, cross-sectional studies, cohort studies, case series, case reports, and letters to the editor, where HS was referred to manifest with at least two other organ systems involved (i.e., musculoskeletal and gastrointestinal) including but not limited to arthritis, synovitis, osteitis, hyperostosis, ankylosing spondylitis, PG, CD or UC, acne vulgaris, and dissecting folliculitis. Excluded were reports only describing cutaneous signs of the follicular tetrad (acne, HS, pilonidal sinus, dissecting folliculitis of the scalp); articles in languages other than English, German, Polish, or Greek, and articles concerning paradoxical reactions to biologic drugs, as symptom development could not be definitively attributed to the initial disease manifestations that reoccur due to a loss of response to the biologic compound. Cases of familial Mediterranean fever, although inflammatory in nature, were not included as familial Mediterranean fever comorbidity with HS is controversial [28-30]. A standardized and predetermined extraction form (decided by G.N., K.P.K., and C.C.Z.) was used to extract information from each eligible study by two independent reviewers (G.N. and K.P.K.). Demographic data, phenotype characteristics, and treatment outcomes were recorded and separately confirmed. A Preferred Reporting Items for Systematic Reviews and Meta-Analyses Nikolakis/Kaleta/V aiopoulos/Wolter/ Baroud/Wojas-Pelc/Zouboulis 62 PubMed (MEDLINE), EMBASE, CENTRAL incl. references (n = 463) -► Duplicates excluded (n = 23) Non-duplicate citations screened (n = 440) Excluded articles after title/abstract screening (n = 269) Full-text articles assessed for eligibility (n = 171) Excluded articles if HS was not reported -> or if HS was recorded with only 1 other comorbidity (n = 45) Excluded articles such as reviews, quizzes, conference abstracts (n = 23) I Excluded articles describing solety -> symptoms of the "follicular occlusion" tetrad (n = 18) Excluded articles as paradoxic reactions of biologists (n = 18) -> Excluded articles describing FMF as co morbidity (n = 3) 64 articles included in the study PASH, the "Leading" Player in a HS-Associated Autoinflammatory Syndrome Team with a Still Unsolved Genetic Background Fig. 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) chart describing the méthodologie approach. FMF, familial Mediterranean fever; HS, hidradenitis suppurativa. (PRISMA) chart describing the méthodologie approach is presented in Figure 1. A total of 64 articles were determined eligible and thus included in our study. Thirty-five articles concern 56 patients with one of the following syndromes: PASH, PAPASH, PsAPASH, or PASS. Additionally, 13 articles reporting HS as a part of SAPHO syndrome in 21 individuals were identified. One of those patients had overleaping features of PASH and SAPHO, for whom the article was included in both aforementioned categories, but not counted twice. Finally, 17 articles described 30 patients where HS was accompanied by a minimum of two other inflammatory diseases/organs involved. One of those articles described 1 additional patient who had PASH syndrome. According to our methodology, there have been 107 patients with syndromic HS reported so tar. Syndromic Hidradenitis Suppurativa Results The great majority (almost 40%) of the cases identified through the literature search is represented by patients diagnosed with PASH syndrome, with a mean age at the time of diagnosis of 33.7 years and a significant male predominance (64%). Body mass index data were only reported in 20 out of 39 patients with PASH, with equal numbers of patients exhibiting a body mass index <25 or >25 (10/10). Similarly, there were 10 smoking individuals Dermatology 3 DOI: 10.1159/000509873 63 with PASH, 2 former smokers, and 7 dedared nonsmokers. Familial occurrence of the syndrome was reported in one-fourth of the cases. The most common genetic abnormalities were an increased number of microsatellite repeats (CCTG >5) in the proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1) promoter region reported in 15% of the patients, alterations in the coding region of the PSTPIP1 gene in 3 cases, and y-secretase complex gene mutations (nicastrin) in 5 cases. Two of the nicastrin mutation-affected individuals were nonobese nonsmokers in Hurley stage III, and three belonged to an Iranian family, whose 24 members demonstrated various combinations of PG, HS, and acne [3133]. Regarding the Hurley dassification for sporadic HS patients, stage I was the most common one, whereas only 4% of patients were reported as stage III with diffuse or near-diffuse involvement [34], On the contrary, most cases diagnosed with PASH (62%) were assessed to have extended disease (Hurley stage >11), and among them Hurley stage III was deteded in approximately half of the patients (n = 13). The severity of clinical presentation also concerns acne: 22 (56%) of PASH patients had severe forms of the disease, such as acne nodulocystica, acne fiilminans, or acne conglobata. Acne was the most common first manifestation of PASH (36%), typically followed by HS and finally PG. Interestingly, although by definition PASH lacks arthritis, in three articles PASH either coexisted or was preceded by joint symptoms. An example of PASH/ SAPHO overlap was given in the paper by Marzano et al. [35], in which 1 patient was described to have coxitis in early childhood. PASH coexisting with rheumatoid arthritis was identified [36,37]. Discussion The characteristics of patients with PASH syndrome persist, in contrast to patients with sporadic, nonsyn-dromic HS. In a case series by Hsiao et al. [38], 10 out of 11 patients presenting with HS and concomitant PG were female. When encountering patients with severe acne and HS, awareness should be raised towards the possible coexistence of PG. The temporal sequence is in accordance with available studies on concomitant HS and PG; Hsiao et al. [38] demonstrated that PG always occurs after HS, and the median time interval varied between 2.5 [38] and 21 [39] years, suggesting that PG could be a late-onset manifestation of the same defect that causes autoinflammation in HS. PG itself can be associated with multiple oth- 4 Dermatology DOI: 10.1159/000509873 er comorbidities, including arthritis, IBD, HS, and acne conglobata [40], The cause of PASH syndrome remains currently unknown. In most cases no provoking factor was identified, apart from bowel bypass surgery for obesity [41] and colectomy for UC [42], suggesting an aberrant nonspecific immune response to bacterial antigens. The available data regarding potential environmental factors are scarce. In contrast to pyogenic arthritis-pyoder-ma gangrenosum-acne (PAPA) syndrome, no definite genetic background has been proven for PASH. Candidate genes can be divided into two groups: a y-secretase complex family gene and genes whose role has been previously highlighted in other autoinflammatory diseases, such as PSTPIP1. The increased number of microsatellite CCTG repeats in the PSTPIP1 promoter region had previously been observed in patients with “aseptic abscess syndrome,” in which IBD is a common comorbidity (66%) [43]. In a current study, PSTPIP1 promoter disturbances were harbored exclusively by PASH patients [32], Mutations in the coding region of the PSTPIP1 gene occur more rarely [44-47]: the p.R405C variation was demonstrated in a patient with aggressive PG and could be pathogenic [46,48]. In the study by Duchatelet et al. [32], HS and acne cosegregated in three generations. It was hypothesized that a maternal PSTPIP1 mutation could be responsible for acne and HS, while a second mutation might cause PG. An aberrant variant of PSTPIP1 increases pyrin binding and IL-1 ß production and leads to a migratory phenotype in phagocytes [10,46,49]. Co-occurrence of mutations in NOD2 and LPIN2 was reported in SAPHO syndrome [ 14, 50], The second genetic region in focus, y-secretase, encodes an endoprotease complex that catalyzes the cleavage of certain transmembrane proteins, such as amyloid precursor, E- and N-cadherin, and Notch receptors [33]. One of the y-secretase subunits is nicastrin [32, 51-53], Judging by the heterogeneity of clinical and genetic presentations, PASH may present as just one possible phenotype of a still undefined autoinflammatory condition, with incomplete gene penetrance and expression [32,54]. Low-penetrance variants or a polygenic distribution might contribute to the underestimation of the contribution of genetics in syndromic HS. Nikolakis/Kaleta/V aiopoulos/Wolter/ Baroud/W ojas-Pelc/Zouboulis 64 PAPASH, PsAPASH, PASS, and Beyond; Joint Involvement as a Common Feature of HS-Related Autoinflammatory Syndromes - the Concept of the "Autoinflammatory March" Results Eight cases of PASS, 6 cases of PAPASH, and 3 cases of PsAPASH syndrome were retrieved. The 6 PAPASH patients had a mean age of 33.5 years at the time of diagnosis, which is similar to the mean age of PASH cases detected. PASS patients were slightly younger (26 years). The 3 cases of PsAPASH identified so far were aged 22, 50, and 55 years. As far as each organ involvement is concerned, we identified arthritis in 35% of patients with PASH, PAPASH, PsAPASH, and PASS. Two patients developed UC (PAPASH and PASH) and one developed CD as a second or third consecutive manifestation of syndromic HS. In 53% of the detected cases with PAPASH, PsAPASH, and PASS, cutaneous manifestations usually preceded other organ involvement. We also detected an additional number of reports describing HS patients with two concomitant autoinflammatory conditions, but the diagnosis of a specific syndrome was not stated. The mean age of these HS patients without a defined syndrome was 36.6 years. Case reports included mouth and genital [55] or even corneal ulcerations [56], resembling a variation of PG. Sixty percent suffered from concomitant arthritis, while 6 patients developed CD. Cutaneous preceding symptoms were reported in 33% of cases. Discussion Syndromic HS could be more frequent than expected. The earliest report from the 1980s described a patient with concomitant HS, Adamantiades-Behçet disease and arthritis [55]. In a case series of 11 patients with coexisting HS and PG, 3 patients fulfilled the criteria of PASH before the acronym PASH was established [38]. The mean age of described cases is higher than the mean age of patients with sporadic disease, possibly reflecting an even higher diagnostic delay. “Adding” further symptoms to HS results in the more complex phenotypes of PAPASH, PASS, and PsAPASH syndromes (Table 1). A typical sequence was acne vulgaris/HS followed by PG and subsequently musculoskeletal/gastrointestinal symptoms, constituting an “autoinflammatory march.” PASS, PAPASH, and PsAPASH can be distinguished by different type of joint involvement, namely ankylosing spondylitis for PASS [57] and pyogenic arthritis for PAPASH [47], while PsAPASH is a PAPASH variant with concomitant psoriatic arthritis [58]. Overall, the prevalence of arthritis occurs within one-third to two-thirds ofPASH, PAPASH, PsAPASH, PASS, and uncategorized syndromic HS patients. In the largest cohort with joint involvement reported by Gottlieb et al. [59], 9 patients with HS (2 PAPASH, 1 PsAPASH, 6 PASS) and joint disease were described. HS was the initial entity in 6 patients. A multicenter, observational study on a population of 640 HS patients established a frequency of musculoskeletal symptoms of 29% [60]. Axial and peripheral arthropathy correlated with HS and acne conglobata is usually a reactive arthritis manifesting over the age of 22 years [60, 61]. The onset of arthritis tends to be insidious, 2-15 years after the onset of skin lesions, asymmetric and correlated with HS severity [62]. Arthritis observed as a comorbidity of HS shares certain common features with spondyloarthropathies but is not linked to the HLA-B27 histocompatibility antigen [62, 63]. The less frequent concomitant manifestation concerned IBD, although the latter is a bystander in HS diagnosis [13]. Twenty-three percent of 255 IBD patients were also diagnosed with HS, with IBD manifesting on average 4 years before HS [64]. In another study, the frequency of HS in 1,260 patients with IBD was estimated at 7-11 vs. 1-2% in the general population [65]. Interestingly, the activity in the two organ systems is not linked [66], Eye involvement in syndromic HS was sporadically reported: 6 patients, without a defined diagnosis for their syndrome, presented ocular signs. In 3 cases concomitant Adamantiades-Behçet disease could account for anterior uveitis or episcleritis; 2 patients suffered from conjunctivitis and 1 patient had bilateral ulcerative keratitis (Mooren’s ulcer) [55, 56, 62], In a study by Saygin et al. [67], the most common types of inflammatory eye involvement were uveitis (65%) followed by sderitis (30%) and peripheral ulcerative keratitis. These data suggest a common autoinflammatory pathophysiologic mechanism for cutaneous, joint, gastrointestinal, and ophthalmic manifestations. Thus, HS in combination with symptoms such as ocular pain, redness, or decreased vision requires not only a prompt referral to an ophthalmologist, but also diagnostic procedures for multiorgan involvement. Syndromie Hidradenitis Suppurativa Dermatology 5 DOI: 10.1159/000509873 65 Table 1. PASH, PAPASH, PsAPASH, and PASS: a review of published studies Ref Cases, Age Sex Origin Smoker BMI Hurley HS Arthri- Acne Syno¬ Oste- Hyper- PG UC CD Ankylos- Pustu- Pso- Other Syn- Family y-Secietase Other Treatment Outcome Limitations/ (first vulgaris vitis itis ostosis ingspon- losis riasis history mutations mutations bias author) dylarthri- tis 1 out 34 M Russian yes 31.1 211 >«S yes (1). AC (3) PASH N/A ÎCCTG ITR 40 mg/d PR small number Falco of2 (2) microsatellite (NR); ANA of patients, no [83], repeats in the 100 mg/d ± objective crite¬ 2012 PSTPIP1 CsA 200 ria for the promoter mg/d efficacy of region therapy 2 out 44 M German yes 33.82 211 yes yes (1), AC yes PASH N/A TCCTG mi¬ GC +AZA PR small number of2 (2) (2) crosatellite 1 y (200 mg/ of patients, no 183h repeats in d tapered to objective crite¬ 2012 the PSTPIP1 100 mg/d); ria for the promoter SG efficacy of region therapy Marza no 1 34 M N/A N/A >40 111 yes yes (2k no no no yes no no no no no no PASH N/A N/A MEFV: RIF, CTX PR no objective [41], (1) eruptions (2) 3293880 A>G p.a. 1 PM scales of dis¬ 2012 P.I591T; and MTZ ease activity, NOD2: i.V.; 1FX 5 no data about 50745926 mg/kg smoking sta¬ C>T tus, informa¬ P-R702W tion about the same patient indifferent publications Bruzzese 1 33 M stan N/A N/A HI yes yes (3), yes(l), (4) no no no no no positise PASS N/A N/A ETN50 PR (Rin lack of certa in [57], (2) axial AC Mantoux mg/w + INH PG. acne, demographic 2012 SpA 300 mg/d, PR in HS) data, lack of IFX 5 mg/kg gene testing, + INH no objective assessment of improvement forHS Aytekin 1 23 M N/A 15.6 211 yes yes (1), yes PASH N/A N/A GC and ABX R no genetic [102]. (2) severe (3) for 2 m tests, no objec¬ 2013 cystic tis« assess¬ ment of im- pros'ement Marzano 1 16 F Molda¬ N/A N/A 211 yes yes (3), yes (1). yes (3) yes PAPASH N/A N/A PSTPIP1: AZMp.a R lack of certa in [47], vian 0) periph- mild (2) CÜ31 G>T (PR acne. demographic 2013 eral, P-E277D NR HS). PG data and dis¬ pyogen¬ missen se developed ease impros'e- ic mutation, while on 1L1RN: DAP 100 113890284 mg/d (6 m); G>A PR induced P-A106T; by adding MEFV: GC to DAP; 3293407 T>C ANA 100 p.M694V, mg/d 3293310 A>G, V726A; NOD2: V955I Koshelev 1 16 M N/A N/A N/A 211 yes yes, AC yes no no no no no dissecting PASH N/A N/A N/A CLI and RIF PR lack of demo¬ [103], cellulitis of Lv. followed graphic data, 2014 the scalp by px>.; sur¬ no clear order gery (inci¬ ofsymptoms sion and gi\C HS activ- s&ssment of P.G908R, ity per- improvement, P268S; sisted) repeating IL1RN: information S52N about 2 pa¬ tients previ¬ ously de¬ scribed) Marzano 2 out 23 M N/A N/A N/A 111 no yes no no no yes yes no no no no PASH no MEFV: ADA 80 mg R (com¬ as above [35]. of 3 R202Q; at time 0 and plete 2014 NOD2: then 40 mg control of P268S; every 2 w cutaneo us NLRPI2: picture p.G39V within 4 w) Marzano 3 out 43 M N/A N/A N/A III yes yes, SpAyes no yes no yes PASH/ no PSMB8: IFX 5 mg/kg PR as above [35], of 3 SAPHO 32811752 at 0,2, and (almost 2014 overleap OT P-G8R; 6 w, reduced complete MEFV: to every healingof R202Q; 8-12 w both PC. NOD2: SpA P268S respond¬ ed well. HS activ¬ ity per¬ sisted) Murphy 1 26 F N/A N/A N/A yes no yes(l). no no no yes yes PASH N/A N/A ERY (NR); PR no BMI given, [42]. (1) cystic (2) (1) CPA (NR); (3-mFU) no genetic 2015 GC and IFX tests, no vali¬ (NR for UC): dated scoring surgical for HS debridement, CsA 2 X 250 mg/d, sys¬ temic ste¬ roids and 2 doses of IFX 5 mg/kg (PR); MIN 100 mg/d for flares: MTX 25 mg/w and ADA 40 mg S.C. every 2 w Murphy [42]. 2015 Syndromie Hidradenitis Suppurativa Dermatology 7 DOI: 10.1159/000509873 Table 1 (continued) Ref. Cases, Age Sex Origin Smoker BMI Hurle)- HS Arthri¬ Acne Syno- Oste- Hyper- PG UC CD Ankylos- Pustu- Pso- Other Syn¬ Family y-Secretase Other Treatment Outcome Limitations/ (first tis vulgaris vit is itis ing spon- losis drome history mutations mutations bias author) dylarthri- Staub 1 22 F Turkish 36.73 N/A (2) yes (1) no no no (1) no PASH N/A no mutations 5-y intermit - R (20 m no validated (104], in PSIPIPI tentABX of FU) scoring system 2015 gene treatment for severity ( PR); surgery assessment andSG.GC, DAP, CsA ± ETN/ADA/ FA/ANA (nonsus¬ tained PR), CR achieved with a com¬ bination of CsA 5 mg/kg, IFX 5 mg/kg i.v. every 8 w, and DAP 50 mg/d Garzorz 1 39 F N/A N/A N/A 211 yes yes. yes, mild no no yes no no no no yes no PAPASH N/A N/A no mutations several surgi- R no order of [72]. pyogen in PSTPIP1 dures for HS; symptoms 2016 gene CsA (PR); given, lack of ADA demographic data and data about duration of remiss ion Calderón- 1 48 M N/A yes N/A 111 yes yes (1), no no yes no PASH N/A Heterozygous CGfor2w PR no validated Castrat (2) severe (3) missense scoring system [46]. mutation for severity 2016 C.12I30T assessment, no p.R405Cin patient-re¬ exon 15 in the ported out- PSTPIP1 gene Ducha- lout 23 M N/A yes <25 N/A yes yes(l),AF no no yes no PASH positive no mutation homozygote N/A N/A no informa¬ telet of3 (“se¬ (2) (2) for acne in coding for the tion about [32]. vere”) sequence (CCTG)5 treatment. 2015 ofPSENEN, repeat in the Hurley staging PSEN1, PSrPIPl NCT promoter Ducha- 2 out 37 M N/A yes <25 N/A (1) yes (2), AF no no yes no PASH positive no muta- heterozygote N/A N/A as above telet of 3 (“se¬ (3) for acne, tion in for the [32]. vere") HS. and coding (CCTG)5 and 2015 PASH sequence of (CCTG)8 PSENEN, repeats in the PSEN1, PSIPIPI NCT promoter Ducha- 3 out 29 F N/A no <25 N/A yes no yes (2). no no no yes no no no no no no PASH N/A NCT: loss heterozygote N/A N/A as above telet of 3 (*mild")(l) severe (3) of function for the [32]. mutation-, (CCTG)5 and 2015 heterozy¬ (CCTG)8 gote for 8- repeats in the nudeotide PSTPIP1 deletion: promoter c.344_ 351del, p.Tl 15N*20 Saraceno 1 50 M N/A yes >30 11 yes yes. yes, com- no no yes yes diabetes melli- PsAPASH N/A N/A N/A DAP, ITR, R (remis¬ no order of [58]. psori- edopustu- tus 2,arterial R1F-CLI. sion after symptoms 2015 atic lous hypertension, TCN.CEP 2w, du¬ given, no hypertriglyceri¬ without rable over genetic tests demia, depres- effect; ADA 36m) 40 mgevery other week 8 Dermatology Nikolakis/Kal eta/Vaiopoulos/Wolter/ DOI: 10.1159/000509873 Baroud/Wojas-Pelc/Zouboulis 68 Table 1 (continued) 0\ VO Ref. Cases, Age Sex Origin Smoker BMI Hurle)- HS Arthri¬ Acne Syno- Oste¬ Hyper- PG UC CD Ankylos- Pustu- Pso- Other Syn- Family y-Secretase Other Treatment Outcome Limitations/ (first tis vulgaris vitis itis ing spon- losis riasis history mutations mutations bias author) dylarthri- lout 37 M N/A yes <25 III yes yes. AF no no yes PASH positive no mutations EOT + sur¬ R no precise Lambert of 4 forHS in PSTPIPI gery. after order of symp¬ 1311. gene failure of 4 toms given 2015 wide exci¬ sion surger- Join- 2 out 26 M N/A yes <25 11 yes yes, severe no yes PASH positive; no mutations ERT + sur¬ R (sus¬ as above Lambert of 4 brother in PSTPIP1 gery after tained [311. of gpne failure of over 9 m) 2015 patient 1 NSAIDs, 1TR. oral ABX, and 30 surgical drainages Join- 3 out 23 M N/A yes <25 111 yes yes. AF no no no yes no no no no no no PASH N/A no no mutations PTA + sur¬ R as above Lambert of 4 in PSTPIPI gery after [31]. gene failure of 2015 GC, NSAIDs. ABX. and several drainages Join- of 4 29 F N/A <25 111 yes yes, severe no no PASH N/A Ncr no mutations PTA + sur¬ R (sus¬ as above Lambert mutation. in PSTPIPI gery; after tained [31]. specified gene failure of over 4 m) 2015 GC NSAIDs. ITR, COL, ETN. ADA, Gracia- 1 45 M N/A N/A N/A 111 yes yes(l). no yes yo no no no no no no PASH N/A N/A no mutations TCN (PR); R lack of certain Cazaiha (2) nodulo- (3) in PSTPIPI RIF-CL1 demographic [85]. cystic gene both 2 X 300 data and dis¬ 2015 mg/d and ease improve¬ CsA 4 mg/kg ment scales (PR for PG, NR for HS); GC and P DT every 2 w i«T 1 out 32 M N/A ex¬ 25 N/A yes yes no yes PASH positive N/A N/A CTX 960 NR no genetic 2015 d 2 smoker forHS nig/d, A MX/ tests, no Hur¬ CL 2 g, 3x/d, ley staging MTX. sul- given, no fone, CsA, order of symp- FIN. surgery and biologi¬ cal therapies (IFX. ADA, UST), GC, ANA for 12 Menis 2 out 30 M N/A 19.9 N/A; yes no yes no no no no no yes no no no no not definedno N/A N/A CU300 PR as above [82]. of 2 PGA - mg/d.LVX 2015 4 2 X 500 mg/d, ITR 30 mg/d, IFX (PR); surgery (PR); ANA (NR), GC for lOd Syndromie Hidradenitis Suppurativa Dermatology 9 DOI: 10.1159/000509873 Table 1 (continued) Ref. Cases, Age Sex Origin Smoker BMI Hurle)- HS Arthri¬ Ac ne Syno- Oste- Hyper- PG UC CD Ankylos- Pustu- Pso- Other Syn¬ Family y-Secretase Other Treatment Outcome Limitations/ (first tis vulgaris vitis itis ing spon- losis drome history mutations mutations bias author) dylarthri- Marz ano lout 20 M N/A N/A N/A III yes yes no no no PASH N/A N/A MEFV: IFX R (com¬ lack of certain [14]. of 2 M680I; plete) demographic 2017 NOD2: data, no order V955I_h; of symptoms NLRP3: given, repeat¬ Q703K; ed description NLR12: of patients F402L described in previous pa¬ pers Marz ano 2out 25 F N/A N/A N/A 111 yes yes no no yes PASH N/A N/A MEFV: IFX R (com¬ as above [14]. of 2 R202Q; plete) 2017 NLRP12: G39V; IL 1RN: S52N Zivanovic 1 32 F Cauca- no 39 211 yes no >«es ( 1 ). no no no yes no no no no no PCOS PASH N/A N/A no mutations steroids, PR (CR in no criteria of [105]. (2) sew re (3) in PSTPIP1 DAP, RIF, PG, PR in remission 2017 nodular gene (exons and CIP p.o. HS) given lOandll) Mizutani 1 18 M N/A N/A N/A N/A yes yes. yes (3). no no no yes no no no PASH N/A no mutations GC (NR). PR no informa¬ [36]. (2) (4) in PSTPIP1. CsA, DAP, tion about 2017 IL1RN, MIN (NR), BMI, smoking MEFV, GMA weekly status. Hurley MVK, for 10 w + staging, treat¬ NLRP12, GC (PR), ment duration NLRP3, maintained NOD2. by A DA PSMB8, 40mgewry TNFRSFIA. other week NLRC4, increased to PLCG2, 80mgewry HMOX1 other week [106?. 1 24 M N/A N/A N/A 211 yes yes ( 1). no no yes no yes, anky- no no trismus PASH N/A N/A excisional PR no data about 2016 (1) nodular (2) losis of surgery with smoking sta¬ the bilat¬ SG; GC for tus, BMI, not eral tern- 6w (PR); clear swather dibular addition of IFX was ad¬ joints DOXand ministered AMX/CL p.o. (PR) [107], 1 44 M African- N/A N/A N/A yes, yes yes no yes yes PAPASH/ N/A N/A CL1 (po., PR no smoking 2016 Ameri- periph¬ PAC over¬ Lv.) (NR). status, BMI, eral, leap DOX; GC genetic testing, pyogen tapered 5 m Hurle)' stag¬ ic post dis¬ ing, order of charge (PR) symptoms Leuen- 1 32 M Congo- N/A N/A III yes yes, yes, nodu- no no no yes no yes no no dissecting PASS N/A no mutations SG; ETN PR no smoking berger lese SpA lopustular cellulitis in PSrPIP 1 (NR); ANA status, BMI, [10]. of scalp gpne 100 mg/d order of symp¬ 2016 (PR) toms given 10 Dermatology Nikolakis/Kal eta/Vaiopoulos/Wolter/ DOI: 10.1159/000509873 Baroud/Wojas-Pelc/Zouboulis 70 Table 1 (continued) 71 Re£ Cases, Age Sex Origin Smoker BMI Hurle)- HS Arthri¬ Acne Syno- Os te- Hyper- PG UC CD Ankylos- Pustu- Pso- Other Syn¬ Family y-Secreta se Other Treatment Outcome Limitations/ (first stage tis vulgaris vitis itis ostosis ingspon- losis riasi drome history mutations mutations bias dylarthri- tis [81]. 1 out 26 M Cauca¬ 27.5 211 yes yes. nodulo- PA PASH N/A no mutations systemic R no treatment 2016 of2 sian periph cystic inPSTPIPl ABX, reti¬ duration, no eral gene(exons noids and order of symp¬ 10 and 11) NSAIDs and toms given GC (NR); surgical. FLU. ANA 100 mg/d. followed by ANA 100 mg/d and H R 30 mg/d Faleri 2 out 26 M Arabic yes 24.5 211 yes yes, nodu- no no no yes no no no no no PASH no N/A >5 repeats in multiple R (5 m of no order of [81]. of2 locystic psrpipi surgical FU) symptoms 2016 promoter procedures, given systemic ABX (NR). FLU 3mg/d, GC, ANA 100 mg/d PsT" 1 out 25 F Iranian N/A N/A N/A yes yes no no no no PASH positive. c.I635C>C, no mutations N/A N/A no informa¬ 2016 of 24 23 other (p.Tyr545’) inPSTPIPl tion about family nonsense gene treatment, members variant in order of symp¬ affected the NCT toms, Hurley byacne gene staging, BMI- PC, and/ genetic corre¬ orHS lation not possible 2 out 52 M N/A N/A N/A yes aphthous PASH positive, C.16350G no mutations N/A N/A as above of 24 stomatitis 23 other (p.Tyr545') in PSTPIP1 S»"002 family nonsense gene 2016 members variant in affected the NCT by acne/ gene PG/HS Faraji 3 out 54 F N/A N/A N/A yes yes no no no yes PASH positive, c.1635C>G no mutations N/A N/A Zonooz of 24 23 other (p.Tyr545*) inPSTPIPl [33], family nonsense gene 2016 members variant in affected the NCT by acne/ gene PG/HS Niv 1 36 M N/A N/A N/A 211 yes yes. no no no yes no no no no no vasculitis PASH N/A N/A no mutations GC for LCV. R no BMI. [108]. generalized (LCV), IgG in PSTPIP1 DAP, COL. tus, order of 2017 and IgA gene MMF, CsA; symptoms and monoclonal GC and DAP treatment gammopathy 300 mg/d, duration given followed by 100 mg/d DAP alone Syndromic Hidradenitis Suppurativa Dermatology 11 DOI: 10.1159/000509873 Table 1 (continued) Ref. Cases, Age Sex Origin Smoker BMI Hurle)- HS Arthri¬ Acne Syno- Oste- Hyper- PG UC CD Ankylos- Pustu- Pso- Other Syn¬ Family y-Secretase Other Treatment Outcome Limitations/ (first tis vulgaris vit is itis ing spon- losis riasis drome hi stor)1 mutations mutations bias author) dylarthri- de Wet 1 42 M N/A >40 III yes yes(l) no no no (3) no no no no ESRD due PASH N/A NLRC4: R (com¬ no validated [109], to focal R547S; multiple plete scoring system 2017 segmental IL10RA: ABX and remission for severity glomeruloscle¬ R35IG; antifungals of PG assessment rosis MEFV: (NR): GC lesions G436R, and DOX and D424E; 2 X 100 mg/d HiSCR; NLRP7: (PR); GC. 8-wFU) G487E, RIF 600 V3911; CLI 2 X 300 NOD2: mg/d (NR); P268S, ADA 40 R702W; mg/w PSMB8: G8R Jennings 1 34 F N/A ex- N/A 211 yes yes, severe no no yes no no no no hepatitis B PASH N/A N/A homozy¬ prolonged PR (sus¬ no family [45], smoker (“high gosity for courses of tained history, no 2017 BMI”) PSTPI PI oral and Lv. over orderofsymp- gene ABX (NR). 12m) ANA 100 nig/d, and GC; followed by ANA 200 mg/d and GC Lamiaux 1 59 M N/A N/A N/A N/A yes no yes Cl). no no no yes no no no no no no PASH N/A N/A no mutations GC (NR). R ( 12-m lack of demo¬ [68]. (2) cystic (3) in PSTPI PI ETN 2x50 FU) graphic data 2017 mg/w for IOm(R); 2nd course of ETN 1 m (NR) + GC (lm) (PR); ANA 100 mg/d discon¬ tinued after 15ddueto side effects; GC discon¬ tinued after 3 m due to side effects; CL1/RIF - R Îm]° 1 37 F Japanese N/A N/A N/A (1) yes ( 1), no no yes PASH positive N/A PSTPI PI: GC and PR (PG lack of smok¬ 2018 sewre (2) for HS heterozygous DAP relapse ing status. and acne misse nse after BMI, Hurley mutation 13 m) staging C.1034 A>G P-Y345C in exon 15 Sonbol 1 42 M N/A N/A N/A N/A (2) yes(l). no no yes PASH tions in homozygote ADA with PR lack of demo¬ [54]. nodular (3) NCT. for (CCTG)5 PR; ANA (6-m FU) graphic data, 2018 PSENEN, repeat in the intolerance; Hurley staging or PSENI PSTPI PI human- promoter, derived Lv. with no in¬ IgG creased num¬ ber of CCTG repeats 12 Dermatology Nikolakis/Kaleta/Vaiopoulos/Wolter/ DOI: 10.1159/000509873 Baroud/Wojas-Pelc/Zouboulis 72 Table 1 (continued) U> Re£ Cases, Age Sex Origin Smoker BMI Hurley HS Arthri- Acne Syno- Oste- Hyper- PG UC CD Ankylos- Pustu- Pso- Other Syn¬ Family y-Secreta se Other Treatment Outcome Limitations/ (first stage tis vulgaris vitis itis ostosis ingspon- losis riasis drome history mutations mutations bias dylarthri- tis Ead 1 out 30 F Cauca¬ N/A >30 I yes no yes - no no no PASH N/A N/A N/A CEX.CIP PR no informa¬ [37], of2 sian severe (NR); DOX (2-m FU) tion about 2018 200 mg/d, smoking sta¬ Cl Pand tus, order of CEX100 symptoms, mg/d (PR); famfly history, MIN 50-100 or genetic mg/d alterations tad 2 out 30 F Cauca¬ yes N/A N/A yes yes. yes yes PASH N/A N/A N/A GC for 4 y plete) no informa¬ [37], of2 sian periph¬ due to RA tion about 2018 eral. (NR); CTX BMI, order of matoid (NR); DOX symptoms, 100 mg/d. family history, LVX 500 genetic altera¬ mg/d. and tions steroid (PR); DAP 100 mg/d and GC (PR). DOX 2 X 100 mg/d for PC, flare (3w); GCand MTX for RA Gottlieb 1 out 38 F N/A N/A N/A 111 yes yes (2). yes no no no no no no yes (3) no no PA PASH N/A PSENEN, no mutations N/A R incomplete 159], of9 (1) axial PSEN1, inNOD2, information 2019 and NCT.or PSTPIPI about treat - periph¬ APH1 formation eral, about tempo¬ undif¬ ral acne occur¬ ferenti¬ rence in rela¬ ated tion to other symptoms, lack of demo¬ graphic data, family history Gottlieb 2 out 38 M N/A N/A N/A 111 yes yes (2). yes no no no yes(l) no no PA PASH N/A no muta- no mutations IFX 7.5 mg/ R no informa¬ [59]. of9 (1) periph¬ PSŁNEN. in NOD2, kg every 6 w tion about 2019 eral, PSENI. PSTPIPI and MTX temporal acne undif¬ NCT.or occurrence in ferenti¬ A PHI relation to ated other symp¬ toms, lack of demographic data, family history Gottlieb 3 out 55 F N/A N/A N/A III yes yes (2). yes yes PsAPASH N/A PSENEN. no mutations ADA 40 R as a bow [59], of9 (1) periph¬ (3) PSENI, inNOD2. mg/w and 2019 eral, NCT.or PSTPIPI MTX psori- APHI Gottlieb 4 out 33 F N/A N/A N/A Ul yes yes (2), yes no no no yes (2) no no PASS N/A tions in no mutations ANA, UST. R as above [59]. of9 (1) axial, PSENEN. in NOD2, TCZ (NR); 2019 undif¬ PSENI, PSTPIPI ADA 40 ferenti¬ NCT. or mg/w and ated APHI SIR (R) Syndromie Hidradenitis Suppurativa Dermatology 13 DOI: 10.1159/000509873 Table 1 (continued) Ref. Cases, Age Sex Origin Smoker BMI Hurley HS Arthri- Acne Syno- Oste- Hyper- PG UC CD Ankylos- Pustu- Pso- Other Syn- y-Sec re ta se Other Treatment Outcome Limitations/ (first n stage tis vulgaris vitis itis ostosis ingspon- losis riasis drome history mutations mutations bias author) dylarthri- Gottlieb 5 out 19 F N/A N/A N/A Ul yes yes (1), yes no no no no no no no yes (2) no no PASS N/A tions in no mutations ADA 40 R as above [59], of9 (2) axial PSENEN. inNOD2, mg/w and 2019 PSEN1, PSTPIP1 MTX NCT, or APHI Gottlieb 6 out 22 M N/A N/A N/A II yes yes (1), yes no no no no no no no yes(l) no no PASS N/A no muta¬ no mutations IFX 10 mg/ R as above [59], of9 (1) axial tions in in NOD2, kg every 4 w 2019 PSENEN. PSTP1P1 PSEN1, NCT, or APHI Gottlieb 7 out 17 F N/A N/A N/A III yes yes (2), yes no no no no no no no yes(l) no no PASS N/A no mutations IFX 5 mg/kg R as above [59], of9 (1) periph¬ in NOD2, every 8 w 2019 eral, PSENEN. PSTP1P1 and systemic undif¬ PSEN1, steroids ferenti¬ NCT, or ated APHI Gottlieb 8 out 20 M N/A N/A N/A 111 yes yes(l), yes no no no no no no no yes (2) no no PASS N/A no muta¬ no mutations ADA 40mg/ R as above [59], of9 (3) axial tions in inNOD2, kg/w 2019 PSENEN. PSTPIP1 PSENI, NCT, or APHI Gottlieb 9 out 32 M N/A N/A N/A III yes yes (2), yes no no no yes no no no no no no PASS N/A no muta- no mutations IFX 5 mg/kg R as above [59], of9 (!) undif- (2) PSENEN. in NOD2, every 8 w 2019 PSENI, PSTPIP1 NCT. or APHI McCarthy 1 46 M Cauca- N/A 17.9 III yes no yes no yes no yes no no no no no no PASH N/A N/A N/A ETN, IFX R no genetic [110], sian (osteo¬ (PR). MEM tests, family 2019 myeli¬ 5 g Lv. for history, remis¬ tis) 1 w sustained sion duration, with ADA smoking sta¬ (R) tus, order of symptoms Mansouri 1 44 F Iranian N/A >30 all yes no yes (2) no no no yes no no no no no prolactinoma, PASH N/A N/A N/A ITR 40 mg/d R (sus- no genetic PH. (1) (3) hypothyroidism and systemic tained tests, family 2019 steroids remission history, smok¬ for 2 y) ing status Gadelha 1 22 F N/A N/A N/A III yes yes (2). yes (2) no no no yes no no no no yes no PsAPASH N/A N/A N/A GC NSAIDs R no demo¬ mu. (1) periph¬ (2) (2) (NR), ADA graphic data, 2020 eral, 40 mg/d at genetic test, psori¬ weekO, duration of atic 20 mg/d at treatment week 2, subsequently 10 mg/w 14 Dermatology Nikolakis/Kal eta/Vaiopoulos/Wolter/ DOI: 10.1159/000509873 Baroud/Wojas-Pelc/Zouboulis ABX, antibiotics; AC, aene conglobata; ADA, adalimumab; AF.acne fulminans; AMX, amoxicillin; ANA, anakinra; APHI,anterior pharynx-defective 1; AZA, azathioprine; AZM, azithromycin; BMI, body mass index;CD,Crohn's disease; CEP, cephalosporin; CEX, cephalexin;ClP,ciprofloxacin; CL,clavulanicacid; CL1,clindamycin;COL, colchicine;CPA, cyproteroneacetate;CR, complete response; CsA, cyclosporine; CTX, co-trimoxazole;d.day(s); DAP, dapsone;DOX,doxycycline;ERT,ertapenenv, ERY,erythromycin; ESRD, end-stage renal disease; ETN, etanercept; FA.fumaric acid; FIN, finasteride; FLU, flucloxacillin;FU, follow-up; GC, glucocorticosteroids; GMA, granulocyte and monocyte aphaeresis; HMOX1, heme oxygenase 1; HS, hidradenitis suppurativa; IFX, infliximab; INH, isoniazid; I PM, imipenem; UR, isotretinoin; LCV, leukocytoclastk vasculitis; LVX, levofloxacin; m, month(s); M EFV, Mediterranean fever, MEM, meropenem; M IN. minocycline; MMF, mycophenolate mofetil; MTX, methotrexate; MTZ, metronidazole; MVK, mevalonatc kinase; NCT, nicastrin;NLRC4,NLR family CARD do main-containing protein 4;NLRP. nucleotide-binding domain and leucine-rich repeat containing proteins; NOD2, nucleotide-binding oligomerization domain containing 2; NR, no response to treatment; NSAIDs, nonsteroidal anti-inflammatory drugs; PAC, pyoderma gangrenosum, acne, colitis ulcerosa; PAPASH, pyogenic arthritis-pyoderma gangrenosum-acne-suppurative hidradenitis; PASH, pyoderma gangrenosum-acne- suppurative hidradenitis; PASS, pyoderma gangrenosum-acne vulgaris- hidradenitis suppurativa-ankyiosing spondylitis; PCOS, polycystic ovary syndrome; PDT, photodynamic therapy, PG, pyoderma gangrenosum: PGA, Physician's Global Assessment; PLCG2, phospholipase C gamma 2; PR. partial response; PsAPASH, psoriatic arthritis-pyoderma gangrenosum-acne-suppurative hidradenitis; PSEN1, presenilin 1; PSENEN, presenilin enhancer; PSMB8, proteasome subunit beta type-8; PSTPIP1, proline-serine-threonine phosphatase-interacting protein I; PTA, prolonged therapy with antibiotics; R. response; RA, rlieumatoid arthritis; RIF, rifampicin; SAPHO, synovitis-acne-pustulosis-hyperostosis-osteitis; SG, skin graft; SIR sirolimus; SpA, spondyloarthropathy, TCN, tetracycline; TCZ, tocilizumab; IN FRSF1A, tumor necrosis factor receptor superfamily member 1A; UC ulcerative colitis; UST, ustekinumab; w, week(s);y, year(s). 74 Therapy of PASH, PAPASH, PsAPASH, and PASS Results and Discussion Due to the many common clinical features, suspected common pathogenesis, and therapeutic options shared between PASH, PAPASH, PsAPASH, and PASS and undefined syndromic HS, these syndromes are presented and discussed here collectively (for details see Tables 1, 2). The therapy of syndromic HS sets a challenge as the medication should be ideally simultaneously effective towards all signs of the syndrome. In the analyzed patient cohort, implemented drugs were systemic antibiotics, isotretinoin, classic immunosuppressive agents, and biologies with/without surgery for HS. Why some patients remain resistant to multiple biologies while others are successfully treated solely with antibiotics and systemic steroids remains unclear. In single cases HS was the most refractory entity. Clinical response documentation was subjective, not based on validated disease outcome measures (HiSCR, IHS4) or widely accepted patient-reported outcomes, which limits the quality of the conclusions. The severity of a specific organ manifestation and the medical specialty, which gets confronted with the treatment first, usually defines the orientation of the treatment of choice, with only certain aspects of the syndrome treated effectively. Antibiotics remain a widely implemented treatment modality. Attempts with tetracyclines were registered in 17% of patients, however 67% exhibited partial or no response. Tetracyclines were most frequently prescribed, followed by clindamycin/rifampicin and dapsone. The known anti-inflammatory properties of certain antibiotics can account for their frequent use [68]. A promising option may be prolonged targeted antibiotic therapy using antibiotics based on microbiological culture. Four severe PASH patients achieved clinical remission with ceftriaxone and oral metronidazole or intravenous ertape-nem [31]. Despite bacteria often being seen as bystanders in HS pathogenesis [69, 70], the authors postulated that treatment was effective primarily due to their antimicrobial and not to their anti-inflammatory properties [31]. Oral retinoids did not result in favorable effects in the majority of the reported cases (80%). In a single PASH case, isotretinoin in combination with oral steroids induced a 2-year remission [71]. Among the classic immunosuppressants, cyclosporine (14% of patients) and methotrexate (MTX) (7% of patients) were the most frequently reported treatments, and the patients who responded to them were 7 out of 12 and 4 out of 6, respectively. Both drugs were used as mono- and multitherapy, in the latter case particularly in combination with biologies (adalimumab, infliximab) [59]. Tapering of cyclosporine was connected to relapses [72]. The most commonly used biologic agents were infliximab and adalimumab (17 cases each), followed by anakinra (13 cases). Dinarello [16] suggested that, in contrast to autoimmune diseases, TNFa antagonists in autoinflammatory syndromes do not produce favorable outcomes and can even exacerbate symptoms. According to the authors, IL- lß blockade brings more benefit. The reason why some subjects respond to anti-IL-1 agents and some to anti-TNFa is yet to be elucidated. TNFa inhibitors might constitute the most effective treatment modality for syndromic HS. Eighty percent of patients treated with infliximab and adalimumab showed some degree of clinical response: very good response was noted in 47/59% and partial response in 41/24% of patients treated with infliximab/adalimumab, respectively. Single patients were resistant to treatment, with HS being the most resistant component; PG, acne, and spondyloarthropathy responded well [73]. Infliximab is approved for inflammatory syndromes such as CD, rheumatoid arthritis, psoriasis, Adamantia-des-Behçet disease, and PG [66], with its effectiveness demonstrated in randomized clinical trials. Fifty percent of 38 patients with moderate to severe HS showed partial response after 8 weeks in comparison to placebo [74]. In a case series of 30 patients with PG, the total response and complete remission rate were 69 and 21%, respectively [75]. When infliximab was first used for HS in the setting of CD, both of them improved [76, 77]. Adalimumab, a human monoclonal IgGl antibody specific for TNFa, is the only biologic approved for the treatment of HS [78, 79]. PAPASH treated with adalimumab resulted in IL-17 and IL-22 increases in serum. Taking into account the aforementioned TNFa/IL-17 synergy, a combination therapy with a biospecific anti-TNFa/IL-17 antibody would constitute a promising option [72], Finally, use of the IL-1 inhibitor anakinra has been reported in the treatment of PASH syndrome [81]. Three out of 7 patients responded to treatment with 100 mg anakinra/day, developing a substantial but not complete response, while in 4 patients therapeutic failure with intolerable side effects was documented [82,83]. Moreover, anakinra was used in 2 PAPASH patients, providing good control of the disease [47, 81]. In one of the reported PASS cases, anakinra was proven ineffective [59]. In contrast, in an open-label pilot study with 6 HS patients, excellent results with anakinra were shown [84]. No com- Syndromie Hidradenitis Suppurativa Dermatology 15 DOI: 10.1159/000509873 75 Table 2. HS with concomitant autoinflammatory diseases, no defined acronym for their syndromic form; a review on published studies Re£ Cases, Age Sex Origin Smoker BMI Hurley HS Arthritis Acne Syno¬ Oste- Hyper- PG UC CD Ankylosing Pustu- Pso- Other Syndrome Treatment Outcome Limitations/bias (first vulgaris vitis spondyl- losis riasis author) Raynor [55], 33 F African- N/A N/A N/A yes yes(l). no no no no yes no no no no no ABD; anterior COL 0.6 mg 2x/d, PR no validated 1980 1 American (1) rheumatoid (2) uveitis and systemic steroids - scoring episcleritis 3m assessment Rosner [62], lof 10 46 M N/A N/A N/A N/A yes yes, axial and yes - AC no erythema nodo¬ NSAIDs, N/A no precise charac¬ 1982 peripheral sum, dissecting prednisone, teristics of partic¬ cellulitis of the D-penicillamine ular patients re¬ garding treatment and ethnic origin, lacking demo¬ graphic data, no Hurle)' staging Rosner [62], 2 of 10 24 M N/A N/A N/A N/A *. yes, axial and yes - AC no no no rc no no no no no no as above N/A as above 1982 peripheral Rosner [62], 3 of 10 22 F N/A N/A N/A N/A yes yes, yes - AC no no no no no no no no no no as above N/A as above 1982 peripheral Rosner [62], 4 of 10 36 M N/A N/A N/A N/A yes yes, axial and yes - AC no no yes no no no no no xerophthalmia, as above N/A as above 1982 peripheral conjunctivitis, penile ulcers Rosner [62], 5 of 10 37 F N/A N/A N/A N/A yes yes, axial and yes - AC no no no no no no no no no conjunctivitis as above N/A as above 1982 peripheral Rosner [62], 6 of 10 36 M N/A N/A N/A N/A yes yes, axial and yes - AC no no no no no no no no no no as above N/A as above 1982 peripheral Boydand 1 28 M Latin N/A N/A N/A yes no yes (2). AC no no no yes no no no no no dissecting fulfils 1TR for acne for PR lacking data about Zemtsov American (2) (3) folliculitis of criteria of 8 m; GCandCXM smoking status, [112], 1992 the scalp (1) PASH 2 X 250 mg/d, DAP BMI, Hurley score 100 mg/d Ha moi r 1 48 M N/A N/A N/A N/A yes yes, yes no no no no no no no no no no N/A N/A lacking demo¬ [113], 1999 peripheral graphic data, no Hurle)' staging Abid [56], 1 44 M African- N/A N/A N/A yes yes (3). no yes (3) no no no no yes (2), Mooren's GC + ABX, cyclo- R lack of data con¬ 1999 American (1) peripheral ulcer phosphamide 100 cerning BMI, mg/d - 50 mg/d and smoking status, steroids; all symp¬ Hurle)' scoring toms were controlled by cyclophospha¬ mide monotherapy Leybishkis 1 40 M African- N/A N/A 211 yes )«s, axial and yes(l), no no no NSAIDs satisfac- lacking smoking [114].2001 American (1) peripheral (2) acneiform tor)' status and BMI, no eruptions reliefof information about joint course of cutane- symptoms ous symptoms Rousso- 1 29 F N/A N/A N/A 211 yes yes, axial and yes no no GC (PR); surgical R no information moustakaki (1) peripheral (2) (3) treatment + CLI p.o. about BMI, smok¬ [115], 2003 (PR). NSAIDs, ITR ing status, treat¬ (PR), SSZ, BUD.CIP ment duration + MTZ (PR); IFX 5 mg/kg + AZA 2.5 mg/kg (R) Thein [ 116], 1 40 M Afro- N/A N/A 1 yes yes(l) yes(1) no yes (1) no no no no no no GC. DOX PR no information 2004 Caribbean 0) 100 mg/d; about BMI, smok¬ SSZpo. ing status, treat¬ ment duration Ah-Weng 1 of 6 51 M N/A N/A N/A N/A no yes(l), no no no no no no no GC R lack of demo¬ [39], 2005 (2) severe (3) graphic data, Hurle)' staging 16 Dermatology Nikolakis/Kaleta/Vaiopoulos/Wolter/ DOI: 10.1159/000509873 Baroud/Wojas-Pelc/Zouboulis 76 Table 2 (continued) Ref. Cases. Age Sex Origin Smoker BMI Hurley HS Arthritis Acne Syno- Oste- Hyper- PG UC CD Ankylosing Pustu- Pso- Other Syndrome Treatment Outcome Limitations/bias (first stage vulgaris vitis itis ostosis spondyl- losis riasis author) arthritis Ah-Weng 2 of6 42 M N/A N/A N/A N/A yes no )*s(l). no no no yes no no no no no schizophrenia CsA 5 mg/kg/d N/A lack of demo¬ [39], 2005 (2) (3) graphic data, Hurley staging, treatment dura¬ tion, outcome Ah-Weng 3 of 6 44 M N/A N/A N/A N/A yes(l). yes no MIN 200 mg/d, N/A [39], 2005 1 45 M Caucasiar i N/A N/A N/A yes(l). (3) DAP 100 mg/d; ; R Talio [ 117], 1 36 F N/A N/A N/A N/A cystic yes no CsA 4 mg/kg/d 1 1991 1 24 F N/A N/A N/A N/A yea(l) (4) ABX for 3 w (NR) R (30 w Moschelia lofll 24 F N/A N/A N/A N/A yes no no VAN and GEN i.v of FU) [118J.2007 2 of 11 33 F N/A N/A >30 N/A yes yes no CIP p.o , and IBU, 1 R lack of smoking Sah in [119], 3 of 11 20 N N/A N/A <30 N/A yes (2) 5 w (PR); surgery, for status, BMI. 2007 1 39 F Caucasiar i smoker N/A II yes (2). yes no VAN i.v., RIF.anc /d Hurley staging Hsiao [38], 1 out 66 M African- N/A N/A N/A yes(l) (2) INDO - 3 w R lack of smoking 2010 of 5 American N/A N/A N/A yes no yes(l). yes no ABX, DAP. ITR ■Y. status, BMI. Hsiao [38], 2 out 29 M African- (2) acne (2) (NR); surgery (R); i- R Hurle)' staging 2010 of 5 American yes yes, keloidalis yes no prednisone and R lack of smoking Hsiao [38], (2) peripheral (2) AZA (PR); IFX 5 o- R (36-m status, BMI, 2010 (2) no no mg/kg every 8 w FU) Hurley staging, Baerveldt yes no COL2 X 500 mg/c R order of symp¬ [1201,2013 (2) (PR for ABD, NR R toms, lack of FU Urn [76], yes no HS). DOX 200 mg C lack of smoking 2013 yes no yes (2) no no fulfils TCN, norethin- status, BMI of all Urn [76], (1) no no no criteria of drone/ethinyl (NR patients. Hurley 2013 yes no no no no PASH fluconazole, cef- staging, order of (1) no no no adroxil. drospire- symptoms, lack of yes no yes (2) no no none/ethinyl estra FU (1) no no no diol, ILS, spironoL as above yes yes (5) fulfils IFX, 6-MP, mesah no information (3) criteria of mine, ADA (NR), about BMI yes yes, PASH ANA, CsA, ILS no information (1) peripheral fulfils thalidomide + GC about BMI, smok¬ (2) criteria of (NR); MIN ing status, Hurley yes yes (2) - PASH staging, no clear (1) peripheral 1) diclofenac/m isopr sequence of symp¬ and axial, stol, COL, ILS, toms; general migratory CsA - temporär)' information about effect, 45 mg UST cutaneous symp¬ every 12 w toms appearing GC, ERY, and first in each case yes no no no surgical excision; as above (3) no systemic and no no no no ABD intralesional no no no no :} Behçet disease (‘ steroids no no yes(l) yes(2 dissecting celluli ABX, DAP. blue no no no no tis of the scalp light, laser; SSZ; G Syndromie Hidradenitis Suppurativa Dermatology 17 DOI: 10.1159/000509873 Table 2 (continued) Ref. Cases, Age Sex Origin Smoker BMI Hurley HS Arthritis Acne Syno- Oste- Hyper- PG UC CD Ankylosing Pustu- Pso- Other Syndrome Treatment Outcome Limitations/bias (first n stage vulgaris vitis itis ostosis spondyl- losis riasis arthritis Lim [76], 3 out 56 M African- N/A N/A N/A yes yes (2), yes(l), no no no no no no no no no NSAIDs (PR); GC + R as above 2013 of 5 American (1) peripheral cystic DOX, ILS Kiithi [121], 1 out 32 F N/A smoker 27 yes no no no no no no no yes no no yes no anti-TNFa R Hurley stage was 2017 of 7 not determined for each patient; “CD had preceded the diagnosis of HS.bya median interval of 48 m,” but the order of all symptoms is not stated; anti-TNF treatment was not specified Kirthi [121], 2 out 31 F N/A ex- 40 yes no no no no no yes no yes no no yes no anti-TNFa R as above 2017 of 7 smoker Kiithi [121], 3 out 33 M N/A smoker 26 yes no no no no yes yes no no no anti-TNFa R as above 2017 of 7 6-MP, 6-mereaptopurine; ABD. Adamantia des- Behęet disease; ABX, antibiotics; AC, ac ne conglobata-, ADA, adalimumab; ANA.anakinra; AZA.azatliioprine; BMI, body mass index; BUD, budesonide;CD, Crohn's disease; CIP, ciprofloxacin; CL1, clindamycin; COL colchicine; CsA, cyclosporine; CXM, cefuroxime; d, day( s); DAP, dapsone; DOX, doxycycline; ERY, erythromycin; FU, follow-up; GC, glucocorticosteroids; GEN, gentamicin; HS, hidradenitis suppurativa; 1BU, ibuprofen; IFX, infliximab; ILS, intralesional steroids; INDO, indomethacin; ITR, isotretinoin; m, month(s); MIN, minocycline; MTZ, metronidazole; NR, no response to treatment; NSAIDs, nonsteroidal anti-inflammatory drugs; PASH, pyoderma gangrenosum-acne-suppurative hidradenitis; PG, pyoderma gangrenosum; PR, partial response; R, response; RIF, rifâmpicin; SSZ, sulfasalazine; TCN, tetracycline: TNFa, tumor necrosis factor alpha; UC, ulcerative colitis; UST, ustekinumab; VAN, vancomycin; w,week(s). 18 Dermatology Nikolaki s/Kal eta/V aiopoulos/Wolter/ DOI: 10.1159/000509873 Barotid/Wojas-Pelc/Zouboulis plete remission of symptoms in syndromic HS was noted while on anakinra monotherapy, suggesting its ranking as a biologic of second choice when TNFa inhibitors are ineffective or contraindicated. There are single reports describing the use of other biologies, such as etanercept (6 cases), ustekinumab (3 cases), or tocilizumab (1 case), mostly with limited effects [59], Taking into account the complexity of syndromic HS, a combination of biologic agents with two other medications such as classic immunosuppressive drugs, steroids, and/or antibiotics might be a viable therapeutic option (Table 1). Rarer and more complex methods to reduce the inflammatory load of such patients, such as granulocyte and monocyte adsorption apheresis [36], photodynamic therapy, and intravenous immunoglobulins have also been reported [54,85]. SAPHO Syndrome and Syndromic HS: An Underestimated Comorbidity? Results We managed to retrieve 10 case reports and a case series with SAPHO-related HS (Table 3). This included 21 patients, with a female:male ratio of 1:1.2 and a mean age of 38.7 years. The origins of the patients are only scarcely documented. Only 5 were reported as smokers, while extensive documentation on weight or body mass index was lacking. The order of organ or system involvement was described in only 13/21 cases. We observed that in 61% of the documented cases, HS preceded the osteoarticular symptoms, either alone or in combination with acne vulgaris or acne fulminans (Table 3). Discussion SAPHO syndrome as a term entails the association of cutaneous manifestations, namely palmoplantar pustulosis or pustular psoriasis, severe acne (fulminans or conglobata) and HS, with certain osteoarticular manifestations. Since dermatologists did not participate in all reports, HS was omitted from the most common acronym [86]. Osteoarticular symptoms can occur without affecting the absence or presence of cutaneous involvement. Still, dermatologie manifestations, among which HS is also included, very often precede bone lesions and might be forgotten until their development. The lesions can also develop long after the osteoarticular lesions. Our search underlined that HS, alone or together with acne, is mostly an initial symptom is such cases and might prophesize SAPHO [87]. The male predominance of SAPHO with 78 VO Table 3. HS with concomitant SAPHO syndrome Ref. Cases, Age Sex Origin Smok- BMI Hurley HS Arthri- Acne Syno¬ Oste- Hyper- PG UC CD Ankylosing Pus tu-Other Syn- Family y-Secretase Other Treatment Outcome Limitations/ (first stage tis vulgaris vitis «stasis spondyl¬ losis history mutations mutations bias author) arthritis özyemisci- 1 54 M Caucasian N/A N/A 211 3 no 1 2 (inflammatory acute SAPHO N/A N/A ITR 0.7 mg/ kg/d PR HS classifica¬ Taskiran [ 122], back pain) anterior (NR), followed by tion and treat¬ 2007 uwitis (4) MTX 10 mg/d and ment duration, steroid (20 mg/d) exact treatment regime and treatment dura¬ tion not docu¬ mented Crowley [98], 1 32 M Caucasian yes >30 211 1 no 2 2 2 2 no no no 1 no no SAPHO N/A N/A N/A ADA 40 mg/w s.c., PR (8-y no objective 2018 MTX 10 mg/ws.c, FU) documentation intralesional and (scoring) on the intraarticular steroid improvement injections, local of HS lesions excision of HS lesions De Souza [96], 1 22 M N/A N/A N/A 211 no no no no no SAPHO no N/A N/A IFX 5 mg/kg every PR (12-m basic demo¬ 2011 6 wand MTX 10 FU) graphic data are mg/w p.o. and DOX lacking, so 150 mg/d (12 m) systemic docu¬ mentation of the intervals and therapeutic strategies cho¬ sen, response according to a validated sys¬ tem is lacking Correia [ 1231, 1 47 M N/A yes N/A III 1 2 2 2 2 no no no no no no SAPHO N/A N/A N/A DOX 100 mg N/A insufficient 2019 followed by ADA data on dose and outcome Bho sale [124], 1 39 F N/A yes N/A N/A 1 1 N/A 1 1 1 no no no no no no SAPHO N/A N/A N/A surgical therapy N/A type of surgery 2001 and locali zation(s) not mentioned Cianci [94], 1 57 F N/A yes N/A 211 1 2 N/A 2 2 2 no 2 SAPHO N/A N/A N/A ABXand steroids R (2-y FU) no objective 2017 (non- 1 followed by cyclo¬ assessment of obese] phosphamide, CsA, improvement MTX, SSZ followed of skin lesions by ETN, ADA. IFX, and bone/joint abatacept.golimu- lesions docu¬ mab followed by mented COL 1 mg/d Genovese [99], 1 15 M N/A N/A N/A 1 2 3 1 3 3 3 SAPHO N/A N/A N/A oral prednisolone PRafter no validated 2019 1.2 mg/kg/d, MIX 6-m treat- scoring system 15 mg/w and ADA was used or 40 mg S.C. every 2 w, mentioned to followed by 40 mg/w document treatment effi- Li [125], 2018 1 44 M Asian N/A N/A II 2 1 2 1 1 1 no no no no no SAPHO no single- N/A N/A N/A (Chinese) nucleotide deletion mutation of a cytosine at position 278 (c.278delC) of the NCT gene Syndromie Hidradenitis Suppurativa Dermatology 19 DOI: 10.1159/000509873 Table 3 (continued) Ref Cases, Age Sex Origin Smok-BMI Hurley HS Arthri-Acne Syno- Oste-Hyper- PG UC CD Ankylosing Pustu-Other Syn- Family y-Secretase Other Treatment Outcome Limitations/ (first er stage tis vulgaris vitis itis ostosis spondyl- losis drome history mutations mutations bias arthritis Vekic [ 100], 1 26 M Arabic yes >30 àll 1 2 1 2 3 3 1 no no 2(HLA-B27 no no SAPHO no N/A no MTX 25 mg/w s.c„ R for no objective 2018 (Lebanese) positive) ketoprofen 200 arthritis scoring for mg/d and pantopra- after 14 m documentation zole 40 mg/d, addi¬ of MTX. R of HS improve - tion of ADA 40 mg ofHSafter ment s.c daily 1 m later 5 wof ADA and of PG after 5m Gmyrek [126], 1 of2 38 F N/A N/A N/A N/A 1 2 no no 2 no no no no no 2 no SAPHO N/A N/A N/A I TR 60 mg/d, 50 mg PR after improvement 1999 INDO 3x/d l-mtreat- documented with no vali¬ dated scoring Gmyrek [126], 2 of2 30 M N/A N/A N/A N/A 1 1 no 1 1 no no no no no 1 dissecting SAPHO N/A N/A N/A ITR 120 mg/d, 10 R (arthri- descriptive 1999 cellulitis of mg ketorolac 3x/d, tis and documentation the scalp 1 g/d CEX over 7 d pustulosis) ofimprove- Kundli [127], 1 of3 42 F N/A N/A N/A N/A 2 3 1 3 no no no no no 3 no no SAPHO N/A N/A N/A NSAIDs, SSZ PR? no detailed 2013 documentation of treatment dose and re¬ sponse Bürgern eister 1 of3 25 F N/A N/A N/A >11 1 1 no no no no no no no no 1 no SAPHO N/A N/A N/A surgery and AZM R(HSand not exact docu¬ [97], 2012 (NR). NSAIDs. arthritis) mentation of prednisolone ( NR), time of im¬ and IFX 5 mg/kg provement Burgemeister 3 of 3 37 F N/A N/A N/A N/A 2 3 no no 3 no no no no no 1 no SAPHO N/A N/A N/A IFX 5 mg/kg every R (skin no objective/ [97], 2012 8 w symptoms validated docu¬ and pelvic mentation of pain) response Steinhoff 7 of 38- F 6 African- N/A N/A N/A - 3 of no no no no no SAPHO N/A N/A N/A NSAIDs, predni¬ PR no objective/ [128],2002 12 56 (5/7) American, 7 sone, MTX, COL, validated docu¬ 1 Caucasian INDO. ABX (TCN. mentation of CIP, CEP), SSZ response ABX, antibiotics; ADA, adalimumab; AZM, azithromycin; BMI, body mass index; CD, Crohn’s disease; CEP, cephalosporin; CEX, cephalexin; C1P, ciprofloxacin; COL, colchicine; CsA, cyclosporine; d, day(s); DOX, doxyeycline; ETN, etanercept; FU, follow-up; HS, hidradenitis suppurativa; IFX, infliximab; INDO, indometliacin; ITR, isotretinoin; m, month(s); MTX, methotrexate; NCT, nicastrin; NR, no response to treatment; NSAIDs, nonsteroidal anti-inflammatory drugs; PG, pyoderma gangrenosum; PR, partial re¬ sponse; R, response; SAPHO, synovitis-acne-pustulosis-hyperostosis-osteitis; SSZ, sulfasalazine. TCN, tetracycline; UC, ulcerative colitis; w, week(s);y, year(s). 20 Dermatology Nikolakis/Kaleta/Vaiopoulos/Wolter/ DOI: 10.1159/000509873 Baroud/Wojas-Pelc/Zouboulis 80 HS was not confirmed in this study [87]. Palmoplantar pustulosis is considered the most common dermatologie manifestation (50-75%), affecting 60% of patients with extensive follow-up [88, 89], The osteoarticular involvement has an insidious onset but can manifest with debilitating pain, which is exacerbated by movement or pressure. In adults, the axial skeleton is most commonly involved, with the anterior chest wall primarily and the spine secondarily being the most commonly affected skeletal sites [90]. Bone scan reveals the pathognomonic “bull’s head sign” of the sternocosto-davicular region, with the manubrium sterni representing the skull and the inflamed sternoclavicular joint and the adjacent claviculae representing the horns. Interestingly, the affected joint could remain clinically “silent” [91], Conventional magnetic resonance imaging is more sensitive and computed radiography is also well suited for detailed imaging of the sternoclavicular region. Sacroiliitis can be seen in up to 52% of SAPHO patients. Hyperostosis and osteitis are chronic inflammatory reactions involving the cortical and medullary bone. Early lesions appear usually osteolytic, followed by mixed lytic/sclerotic lesions with disease progression and cortical thickening at the end stages of the disease [92]. The criteria of Benhamou et al. [93] are used for the diagnosis of the syndrome [86], Therapy of HS-Related SAPHO Syndrome Results and Discussion The therapeutic options for the 21 cases are summarized in Table 3. In brief, the order of organ involvement was usually dictated by the first specialty that encountered and thus treated the syndrome. Osteoarticular symptoms were treated with nonsteroidal anti-inflammatory drugs, sulfasalazine and MTX, while cutaneous symptoms were treated with antibiotics, such as tetracyclines, ciprofloxacin, and cephalosporins. Isotretinoin, cyclophosphamide, and cyclosporine achieved only partial remission of the lesions. In most cases, anti-TNFa treatment (infliximab, adalimumab, golimumab) had to be initiated with initial good control of both cutaneous and osteoarticular symptoms. In many recalcitrant cases, anti-TNFa treatment had to be combined with MTX, prednisolone, or tetracyclines alone or in combination with HS surgery to better control the HS symptoms. In recalcitrant osteoarticular manifestations, intraarticular steroid injections were necessary. In one case almost full remission was reported with colchicine 1 mg/day after a 2-year follow-up [94]. Syndromic Hidradenitis Suppurativa As previously mentioned, most therapeutic modalities are based on case series, case reports, and expert judgement. Nonsteroidal anti-inflammatory drugs are a first-line symptomatic treatment, reported to show insufficient pain relief during flares in 50% of patients [86, 89], Intraarticular corticosteroids are effective for patients with refractory osteoarticular symptoms [87, 88]. The use of steroid-sparing agents in refractory cases, including MTX, sulfasalazine, or azathioprine, was only reported as beneficial for noncutaneous symptoms [88, 95]. Anti-TNFa agents were ultimately used in refractory cases, including infliximab [94, 96, 97], etanercept [94], or adalimumab [80, 94, 98-100]. The response was usually rapid for both cutaneous and osteoarticular symptoms. However, shortening of the intervals or dose intensification was individually required. A recent review of 66 SAPHO cases identified anti-TNFa treatment as first choice after nonresponse to conventional treatment, while skin disease (57%) exhibited a more common response than osteoarticular symptoms (38%). In contrast, anti-IL-1 treatment was proven beneficial for musculoskeletal symptoms but not for cutaneous symptoms [101]. The co-occurrence of multiple autoinflammatory signs in patients with HS is clearly neither seen as a common comorbidity nor as an accidental association. Our report reviews systematic autoinflammatory clinical signs connected with HS, not only through collecting cases of established syndromes, but also through combination of HS with two other inflammatory diseases, which may constitute novel syndromic manifestations. The “autoinflammatory march” emphasizes the key role of dermatologists to remain alert for signs of systemic involvement when encountering a patient with severe HS/acne. The limitation of this review is the lack of large-scale studies on the topic. Validated scoring systems for both cutaneous and osteoarticular symptoms can increase the quality of evidence and provide the necessary tools for a guideline or interdisciplinary expert consensus for the treatment of such patients. Key Message Early diagnosis of HS is pivotal to prevent the irreversible consequences of autoinflammatory march. Dermatology 21 DOI: 10.1159/000509873 Conclusion 81 Statement of Ethics This report was written in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and the MOOSE proposal, where applicable. Funding Sources This research did not receive any funding. Author Contributions Conflict of Interest Statement C.C. Zouboulis has received thematically relevant honoraria from AbbVie, Incyte, Indorsia, Inflarx, Janssen, Novartis, Regen-eron, and UCB as advisor, which had no influence on the preparation of the manuscript. His departments have received grants from AbbVie, Inflarx, Novartis, and UCB for his participation as investigator. All other authors have no conflicts of interest to disclose. G. Nikolakis and K.P. Kaleta performed the research and wrote and critically reviewed the manuscript. A.G. Vaiopoulos and C.C. Zouboulis contributed to the study design and critically reviewed the manuscript. K. Wolter participated in the preliminary research. 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PAPASH, PsAPASH and PASS autoinflammatory syndromes: phenotypic heterogeneity, common biological signature and response to immunosuppressive regimens. Br J Dermatol. 2019 Oct;181(4):866-9. 60 Richette P, Molto A, Viguier M, Dawidowicz K, Hayem G, Nassif A, etal. Hidradenitis suppurativa associated with spondyloarthritis -results from a multicenter national prospective study. J Rheumatol. 2014Mar;41(3):490-4. 61 Miller IM, McAndrew RJ, Hamzavi I. Prevalence, Risk Factors, and Comorbidities of Hidradenitis Suppurativa. Dermatol Clin. 2016 Jan;34( 1):7—16. 62 Rosner IA, Richter DE, Huettner TL, Kuffner GH, Wisnieski JJ, Burg CG. Spondyloarthropathy associated with hidradenitis suppurative and acne conglobata. Ann Intern Med. 1982 Oct;97(4):520-5. 63 Fimmel S, Zouboulis CC. Comorbidities of hidradenitis suppurativa (acne inversa). Der matoendocrinol. 2010 Jan;2(l):9-16. 64 van der Zee HH, van derWoudeCJ, Florencia EF, Prens EP. Hidradenitis suppurativa and inflammatory bowel disease: are they associated? Results of a pilot study. Br J Dermatol. 2010 Jan;162(l): 195-7. Syndromie Hidradenitis Suppurativa Dermatology 23 DOI: 10.1159/000509873 83 65 Janse IC, Koldijk MJ, Spekhorst LM, Vila AV, Weersma RK, Dijkstra G, et al. Identification of Clinical and Genetic Parameters Associated with Hidradenitis Suppurativa in Inflammatory Bowel Disease. Inflamm Bowel Dis. 2016 Jan;22(l):106-13. 66 Rosi YL, Lowe L, Kang S. Treatment of hidradenitis suppurativa with infliximab in a patient with Crohn’s disease. ) Dermatolog Treat. 2005 Feb;16(l):58-61. 67 Saygin D, Syed AU, Lowder CY, Srivastava S, Maya JJ, Hajj-Ali RA. Characteristics of inflammatory eye disease associated with hidradenitis suppurativa. Eur J Rheumatol. 2018 Sep;5(3): 165-8. 68 Lamiaux M, Dabouz F, Wantz M, Lebas D, Lasek A, Courivaud D, et al. Successful combined antibiotic therapy with oral clindamycin and oral rifampicin for pyoderma gangrenosum in patient with PASH syndrome. JAAD Case Rep. 2017 Dec;4(l): 17-21. 69 Nikolakis G, Join-Lambert O, Karagiannidis I, Guet-Revillet H, Zouboulis CC, Nassif A. Bacteriology of hidradenitis suppurativa/ acne inversa: A review. J Am Acad Dermatol. 2015 Nov;73(5 Suppl l):Sl2-8. 70 Nikolakis G, Liakou AI, Bonovas S, Seltmann H, Bonitsis N, Join-Lambert O, et al. Bacterial colonization in hidradenitis suppurativa/acne inversa: A cross-sectional study of 50 patients and review of the literature. Acta Derm Venereol. 2017 Apr;97(4):493-8. 71 Mansouri P, Hesami Z, Hajiha N, Chalangari A, Chalangari KM, Azizian Z. PASH Syndrome. The First Case Report from Iran. J Skin Stem Cell. 2019;5(4):4-6. 72 Garzorz N, Papanagiotou V, Atenhan A, Andres C, Eyerich S, Eyerich K, et al. Pyoderma gangrenosum, acne, psoriasis, arthritis and suppurative hidradenitis (PAPASH)-syn-drome: a new entity within the spectrum of autoinflammatory syndromes? J Eur Acad Dermatol Venereol. 2016 Jan;30(l):141-3. 73 Gottlieb A, Menter A, Armstrong A, Ocampo C, Gu Y, Teixeira HD. Adalimumab Treatment in Women With Moderate-to-Severe Hidradenitis Suppurativa from the PlaceboControlled Portion of a Phase 2, Randomized, Double-Blind Study. J Drugs Dermatol. 2016 Oct; 15(10): 1192-6. 74 Grant A, Gonzalez T, Montgomery MO, Cardenas V, Kerdel FA. Infliximab therapy for patients with moderate to severe hidradenitis suppurativa: a randomized, doubleblind, placebo-controlled crossover trial. J Am Acad Dermatol. 2010 Feb;62(2):205-17. 75 Brooklyn TN, Dunnill MG, Shetty A, Bowden JJ, Williams JD, Griffiths CE, et al. Infliximab for the treatment of pyoderma gangrenosum: a randomised, double blind, placebo controlled trial. Gut. 2006 Apr;55(4):505-9. 76 Lim DT, James NM, Hassan S, Khan MA. Spondyloarthritis associated with acne conglobata, hidradenitis suppurativa and dissecting cellulitis of the scalp: a review with illustrative cases. Curr Rheumatol Rep. 2013 Aug; 15(8):346. 24 Dermatology DOI: 10.1159/000509873 77 Katsanos KH, Christodoulou DK, Tsianos EV. Axillary hidradenitis suppurativa successfully treated with infliximab in a Crohn’s disease patient. Am J Gastroenterol. 2002 Aug;97(8):2155-6. 78 Kimball AB, Okun MM, Williams DA, Gottlieb AB, Papp KA, Zouboulis CC, et al. Two phase 3 trials of adalimumab for hidradenitis suppurativa. N Engl J Med. 2016 Aug;375(5): 422-34. 79 Zouboulis CC, Okun MM, Prens EP, Gniadecki R, Foley PA, Lynde C, et al. Longterm adalimumab efficacy in patients with moderate-to-severe hidradenitis suppurativa/acne inversa: 3-year results of a phase 3 open-label extension study. J Am Acad Der matol. 2019 Jan;80(l ):60-69.e2. 80 Zouboulis CC. Adalimumab for the treatment of hidradenitis suppurativa/acne inversa. Expert Rev Clin Immunol. 2016 Oct; 12(10): 1015-26. 81 Faleri S, Feichtner K, Ruzicka T. Schwere Akne bei Autoinflammationskrankheiten. Hautarzt 2016 Nov;67(ll):897-901. 82 Menis D, Maroftas-Jiménez L, Delgado-Mar-quez AM, Postigo-Llorente C, Vanaclocha-Sebastiän F. Two cases of severe hidradenitis suppurativa with failure of anakinra therapy. Br I Dermatol. 2015 Mar;172(3):810-1. 83 Braun-Falco M, Kovnerystyy O, Lohse P, Ruzicka T. Pyoderma gangrenosum, acne, and suppurative hidradenitis (PASH) - a new autoinflammatory syndrome distinct from PAPA syndrome. J Am Acad Dermatol. 2012 Mar;66(3):409-15. 84 Leslie KS, Tripathi SV, Nguyen TV, Pauli M, Rosenblum MD. An open-label study of anakinra for the treatment of moderate to severe hidradenitis suppurativa. J Am Acad Dermatol. 2014 Feb;70(2):243-51. 85 Gracia-Cazańa T, Frias M, Roselló R, Vera-Alvarez J, Gilaberte Y. PASH syndrome associated with osteopoikilosis. Int J Dermatol. 2015 Sep;54(9):e369-71. 86 Chamot AM, Benhamou CL, Kahn MF, Bera-neck L, Kaplan G, Prost A. Acne-pustulosis-hyperostosis-osteitis syndrome. Results of a national survey. 85 cases. Rev Rhum Mal Os teoartic. 1987 Mar;54(3): 187-96. French. 87 Nguyen MT, Borchers A, Selmi C, Naguwa SM, Cheema G, Gershwin ME. The SAPHO syndrome. Semin Arthritis Rheum. 2012 Dec; 42(3):254-65. 88 Hayem G, Bouchaud-Chabot A, Benali K, Roux S, Palazzo E, Silber mann-Hoffman O, et al. SAPHO syndrome: a long-term follow-up study of 120 cases. Semin Arthritis Rheum. 1999 Dec;29(3): 159-71. 89 Colina M, Govoni M, Orzincolo C, Trotta F. Clinical and radiologic evolution of synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome: a single center study of a cohort of 71 subjects. Arthritis Rheum. 2009 Jun;61(6): 813-21. 90 Depasquale R, Kumar N, Lalam RK, Tins BJ, Tyrrell PN, Singh J, et al. SAPHO: what radiologists should know. Clin Radiol. 2012 Mar;67(3): 195-206. 91 Freyschmidt J, Sternberg A. The bullhead sign: scintigraphic pattern of sternocostocla-vicular hyperostosis and pustulotic ar-throosteitis. Eur Radiol. 1998;8(5):807—12. 92 Khanna G, Sato TS, Ferguson P. Imaging of chronic recurrent multifocal osteomyelitis. Radiographies. 2009 Jul-Aug;29(4):1159-77. 93 Benhamou CL, Chamot AM, Kahn MF. Sy-novitis-acne-pustulosis hyperostosis-osteo-myelitis syndrome (SAPHO). A new syndrome among the spondyloarthropathies? Clin Exp Rheumatol. 1988 Apr-Jun;6(2): 109-12. 94 Cianci F, Zoli A, Gremese E, Ferraccioli G. Clinical heterogeneity of SAPHO syndrome: challenging diagnose and treatment. Clin Rheumatol. 2017 Sep;36(9):2151-8. 95 Jansson A, Renner ED, Ramser J, Mayer A, Haban M, Meindl A, et al. Classification of non-bacterial osteitis: retrospective study of clinical, immunological and genetic aspects in 89 patients. Rheumatology (Oxford). 2007 Jan;46(l): 154-60. 96 De Souza A, Solomon GE, Strober BE. SAPHO syndrome associated with hidradenitis suppurativa successfully treated with infliximab and methotrexate. Bull NYU Hosp Jt Dis. 2011;69(2): 185-7. 97 Burgemeister LT, Baeten DL, Tas SW. Biologies for rare inflammatory diseases: TNF blockade in the SA PHO syndrome. Neth J Med. 2012 Dec;70(10):444-9. 98 Crowley EL, O’Toole A, Gooderham MJ. Hidradenitis suppurativa with SAPHO syndrome maintained effectively with adalimumab, methotrexate, and intralesional corticosteroid injections. SAGE Open Med Case Rep. 2018 Jun;6:2050313X18778723. 99 Genovese G, Caorsi R, Moltrasio C, Marzano AV. Successful treatment of co-existent SAPHO syndrome and hidradenitis suppurativa with adalimumab and methotrexate. J Eur Acad Dermatol Venereol. 2019 Oct; 33(Suppl 6):40-l. 100 Vekic DA, Woods J, Lin P, Cains GD. SAPHO syndrome associated with hidradenitis suppurativa and pyoderma gangrenosum successfully treated with adalimumab and methotrexate: a case report and review of the literature. Int J Dermatol. 2018 Jan;57(l): 10-8. 101 Daoussis D, Konstantopoulou G, Kraniotis P, Sakkas L, Liossis SN. Biologies in SAPHO syndrome: A systematic review. Semin Arthritis Rheum. 2019 Feb;48(4):618-25. 102 Aytekin S, Uçmak D, Ayhan E, Fidan V. A new patient with pyoderma gangrenosum, acne, and suppurative hidradenitis (PASH) syndrome: case report. Turki ye Klin Derma-toloji. 2013;23(2):73-6. Nikolakis/Kaleta/V aiopoulos/Wolter/ Baroud/Wojas-Pelc/Zouboulis 84 103 Koshelev MV, Garrison PA, Wright TS. Concurrent hidradenitis suppurativa, inflammatory acne, dissecting cellulitis of the scalp, and pyoderma gangrenosum in a 16-year-old boy. Pediatr Dermatol. 2014 Jan-Feb;31(l):e20-1. 104 Staub J, Pfannschmidt N, Strohal R, Braun-Falco M, Lohse P, Goerdt S, et al. Successful treatment of PASH syndrome with infliximab, cyclosporine and dapsone. ) Eur Acad Dermatol Venereol. 2015 Nov;29(l 1):2243-7. 105 Zivanovic D, Masirevic I, Ruzicka T, Braun-Falco M, Nikolic M. Pyoderma gangrenosum, acne, suppurative hidradenitis (PASH) and polycystic ovary syndrome: coincidentally or aetiologically connected? Australas J Dermatol. 2017 May;58(2):e54-9. 106 Wargo JJ, Emmer BT. Systemic Inflammation Gone Awry: PASH Syndrome and Temporomandibular Joint Ankylosis. Am J Med. 2016 Apr; 129(4):el-3. 107 Ursani MA, Appleyard J, Whiteru O. Pyogenic arthritis, pyoderma gangrenosum, acne, suppurative hidradenitis (PA-PASH) syndrome: an atypical presentation of a rare syndrome. Am J Case Rep. 2016 Aug; 17: 587-91. 108 Niv D, Ramirez JA, Fivenson DP. Pyoderma gangrenosum, acne, and hidradenitis suppurativa (PASH) syndrome with recurrent vasculitis. JAAD Case Rep. 2017 Feb;3(1): 70-3. 109 de Wet J, Jordaan HF, Kannenberg SM, Tod B, Glanzmann B, Visser WI. Pyoderma gangrenosum, acne, and suppurative hidradenitis syndrome in end-stage renal disease successfully treated with adalimumab. Dermatol Online J. 2017 Dec;23(12): 13030/ qt82d4m2zw. 110 McCarthy S, Foley CC, Dvorakova V, Quinlan C, Murphy M, Maher M. PASH syndrome with bony destruction. Clin Exp Dermatol. 2019 Dec;44(8):918-20. 111 Gadelha R de L, Paiva R da SR, Palitot EB, Costa JEF da. PsAPASH: a rare and recent autoinflammatory syndrome associated with hidradenitis suppurativa. An Bras Dermatol. Mar-Apr 2020; 95(2): 203-6. 112 Boyd AS, Zemtsov A. A case of pyoderma vegetans and the follicular occlusion triad. J Dermatol. 1992 Jan;19(l):61-3. 113 Hamoir XL, François RJ, Van den Haute V, Van Campenhoudt M. Arthritis and hidradenitis suppurativa diagnosed in a 48-year-old man. Skeletal Radiol. 1999 Aug;28(8): 453-6. 114 Leybishkis B, Fasseas P, Ryan KF, Roy R. Hidradenitis suppurativa and acne conglobata associated with spondyloarthropathy. Am J Med Sei. 2001 Mar;321(3): 195-7. 115 Roussomoustakaki M, Dimoulios P, Chatzi-costas C, Kritikos HD, Romanos J, Panay-iotides JG, etal. Hidradenitis suppurativa associated with Crohn’s disease and spondyloarthropathy: response to anti-TNF therapy. J Gastroenterol. 2003;38( 10): 1000-4. 116 Thein M, Hogarth MB, Acland K. Seronegative arthritis associated with the follicular occlusion triad. Clin Exp Dermatol. 2004 Sep;29(5):550-2. 117 Tallo R, Quinet R, Waxman J. Reactive arthritis due to hidradenitis suppurativa mimicking osteomyelitis. South Med J. 1991 Sep; 84(9): 1147-9. 118 Moschella SL. Is there a role for infliximab in the current therapy of hidradenitis suppurativa? A report of three treated cases. Int J Dermatol. 2007 Dec;46( 12): 1287-91. 119 Sahin MT, Oztürkcan S, Türel-Ermertcan A, Yurtman-Havlucu D, Bilaç C. Behçet’s disease associated with hidradenitis suppurativa. J Eur Acad Dermatol Venereol. 2007 Mar;21(3):428-9. 120 Baerveldt EM, Kappen JH, Thio HB, van Laar JA, van Hagen PM, Prens EP. Successful long-term triple disease control by ustekinumab in a patient with Behcet’s disease, psoriasis and hidradenitis suppurativa. Ann Rheum Dis. 2013 Apr;72(4):626-7. 121 Kirthi S, Hellen R, O’Connor R, Connolly M, Tobin AM, McNamara D. Hidradenitis Suppurativa and Crohn’s Disease: A Case Series. Ir Med J. 2017 Aug;110(7):618. 122 Özyemisci-Taskiran O, Bölükbasi N, Gögüs F. A hidradenitis suppurativa related SAPHO case associated with features resembling spondylarthropathy and proteinuria. Clin Rheumatol. 2007 May;26(5):789-91. 123 Correia CP, Martins A, Oliveira J, Andrade S, Almeida J. Systemic Amyloidosis with Renal Failure: A Challenging Diagnosis of SAPHO Syndrome. Eur J Case Rep Intern Med. 2019 Mar;6(4):001087. 124 Bhosale P, Barron B, Lamki L. The “SAPHO” syndrome: a case report of a patient with unusual bone scan findings. Clin Nucl Med. 2001 Jul;26(7):619-21. 125 Li C, Xu H, Wang B. Is SAPHO syndrome linked to PASH syndrome and hidradenitis suppurativa by nicastrin mutation? a case report. J Rheumatol.2018Nov;45(ll):1605-7. 126 Gmyrek R, Grossman ME, Rudin D, Scher R. SAPHO syndrome: report of three cases and review of the literature. Cutis. 1999 Oct; 64(4):253-8. 127 Kundu BK, Naik AK, Bhargava S, Srivastava D. Diagnosing the SAPHO syndrome: a report of three cases and review of literature. Clin Rheumatol. 2013 Aug;32(8): 1237-13. 128 SteinhoffJP, Cilursu A, Falasca GF, Guzman L, Reginato AJ. A study of musculoskeletal manifestations in 12 patients with SAPHO syndrome. J Clin Rheumatol. 2002 Feb;8(l): 13-22. Syndromie Hidradenitis Suppurativa Dermatology 25 DOI: 10.1159/000509873 85 10. Oświadczenia współautorów Kraków, dn. 30.08.2021 Prof. dr hab. n. med. Anna Wojas-Pelc Katedra i Klinika Dermatologii Uniwersytetu Jagiellońskiego Collegium Medicum w Krakowie (stopień/tytuł, imię i nazwisko, afiliacja) OŚWIADCZENIE Jako współautor prac pt. “The Skin as a Mirror of Internal Disease: Comorbidities and Epidemiology of Acne Vulgaris and Adult Female Acne -A Cross-sectional Study and Current State of Knowledge”,“Metabolic disorders/obesity is a primary risk factor in hidradenitis suppurativa -an immunohistochemical real-world approach” oraz artykułu „Phenotypes and Pathophysiology of Syndromic Hidradenitis Suppurativa: Different Faces of the Same Disease? A Systematic Review” oświadczam, iż mój własny wkład merytoryczny w przygotowanie, przeprowadzenie i opracowanie badań oraz przedstawienie prac w formie publikacji to: nadzór merytoryczny oraz krytyczna rewizja powstałych manuskryptów. Jednocześnie wyrażam zgodę na przedłożenie w/w prac przez lek. Katarzynę Kaletę jako części rozprawy doktorskiej w formie spójnego tematycznie zbioru artykułów opublikowanych w czasopismach naukowych. Oświadczam, iż samodzielna i możliwa do wyodrębnienia cześć w/w prac wskazuje na indywidulany wkład lek Katarzyny Kalety przy zaprojektowaniu badań, zbieraniu danych klinicznych, wykonywaniu części eksperymentalnej, opracowaniu i interpretacji wyników oraz przygotowaniu i sprawdzeniu powyższych manuskryptów …………………………………… (podpis współautora pracy) ANNA WOJAS-PELC 87 Dessau, 18.08.2021 Prof. Dr. Christos C. Zouboulis Departments of Dermatology, Venereology, Allergology and Immunology Dessau Medical Center Brandenburg Medical School Theodor Fontane Auenweg 38, 06847 Dessau, Germany (title, name and surname, affiliation) Co-autorship statement I am a co-author of publications: „Metabolic disorders/obesity is a primary risk factor in hidradenitis suppurativa -an immunohistochemical real-world approach” (Dermatology 2021;[online ahead of print]. DOI: 10.1159/000517017) and „Phenotypes and Pathophysiology of Syndromic Hidradenitis Suppurativa: Different Faces of the Same Disease? A Systematic Review” (Dermatology. 2020 Sep 17:1-25. doi: 10.1159/000509873) I declare that my own substantial contribution to these publications is that of a senior author and consists of: -Study design, -Clinical diagnosis and documentation of the lesions and -Revision of the manuscripts Hereby, I agree with the submission of the above-mentioned publications by MSc/ MD Katarzyna Kaleta as part of her doctoral dissertation in the form of a thematically coherent collection of articles published in scientific journals. I declare that an independent and identifiable part of the abovementioned publications shows individual contribution of MSc/ MD Katarzyna Kaleta consisting of: -Studies design, -Systematic review of the literature, -Retrospective search and documentation, -Immunohistochemistry, -Digital evaluation, -Statistical analysis, -Interpretation of the results -Preparation of the manuscript, -Revision of the manuscript. (co-author's signature) 88 Dessau, 23.08.2021 Aristeidis Vaiopoulos, MD, PhD Departments of Dermatology, Allergology, Venereology, and Immunology Dessau Medical Center Brandenburg Medical School Theodor Fontane Auenweg 38, 06847 Dessau, Germany (title, name and surname, affiliation) Co-autorship statement As a co-author of the publications: „Metabolic disorders/obesity is a primary risk factor in hidradenitis suppurativa -an immunohistochemical real-world approach” (Dermatology 2021;[online ahead of print]. DOI: 10.1159/000517017) and „Phenotypes and Pathophysiology of Syndromic Hidradenitis Suppurativa: Different Faces of the Same Disease? A Systematic Review” (Dermatology. 2020 Sep 17:1-25. doi: 10.1159/000509873), I declare that my own substantial contribution to these publications consists of: -Immunohistochemistry analysis, -Preparation and revision of manuscripts. Hereby, I agree with the submission of the above-mentioned publications by MSc/ MD Katarzyna Kaleta as part of her doctoral dissertation in the form of a thematically coherent collection of articles published in scientific journals. I declare that an independent and identifiable part of the abovementioned publications shows individual contribution of MSc/ MD Katarzyna Kaleta consisting of: -Studies design, -Systematic review of the literature, -Retrospective search and documentation, -Immunohistochemistry, -Digital evaluation, -Statistical analysis, -Interpretation of the results, -Preparation of the manuscripts, -Revision of the manuscripts. (co-author's signature) 89 90 Dessau, 23.08.2021 Georgios Nikolakis MD, PhD Departments of Dermatology, Allergology, Venereology, and Immunology Dessau Medical Center Brandenburg Medical School Theodor Fontane Auenweg 38, 06847 Dessau, Germany (title, name and surname, affiliation) Co-autorship statement As a co-author of the publications: „Metabolic disorders/obesity is a primary risk factor in hidradenitis suppurativa -an immunohistochemical real-world approach” (Dermatology 2021;[online ahead of print]. DOI: 10.1159/000517017) and „Phenotypes and Pathophysiology of Syndromic Hidradenitis Suppurativa: Different Faces of the Same Disease? A Systematic Review” (Dermatology. 2020 Sep 17:1-25. doi: 10.1159/000509873), I declare that my own substantial contribution to these publications consists of: -Systematic review of the literature (in particular regarding SAPHO syndrome) -Clinical diagnosis and documentation of hidradenitis suppurativa lesions -Statistical analysis -Preparation and revision of manuscripts Hereby, I agree with the submission of the above-mentioned publications by MSc/ MD Katarzyna Kaleta as part of her doctoral dissertation in the form of a thematically coherent collection of articles published in scientific journals. I declare that an independent and identifiable part of the abovementioned publications shows individual contribution of MSc/ MD Katarzyna Kaleta consisting of: -Studies design, -Systematic review of the literature, -Retrospective search and documentation, -Immunohistochemistry, -Digital evaluation, -Statistical analysis, -Interpretation of the results, -Preparation of the manuscripts, -Revision of the manuscripts. (co-author's signature) 91 23.03.2021 Sumer Baroud University of Sharjah, Sharjah, United Arab Emirates. Co-authorship statement As a co-author of the publication „Phenotypes and Pathophysiology of Syndromic Hidradenitis Suppurativa: Different Faces of the Same Disease? A Systematic Review.” (Dermatology. 2020 Sep 17:1-25. doi: 10.1159/000509873), I declare that my own substantial contribution to the publication consists of scientific and linguistic correction. Hereby, I agree with the submission of the above-mentioned publication by MSc/ MD Katarzyna Kaleta as part of her doctoral dissertation in the form of a thematically coherent collection of articles published in scientific journals. I declare that an independent and identifiable part of the abovementioned publication





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mbn. shows individual contribution of MSc/ MD Katarzyna Kaleta consisting of: -Study design, -Systematic review of the literature, -Data interpretation -Preparation of the manuscripts -Revision of the manuscripts (co-author's signature) 92 Kraków, 23.08.2021 Dr n. chem. Elżbieta Broniatowska Wydział Lekarski i Nauk o Zdrowiu Krakowska Akademia im. Andrzeja Frycza Modrzewskiego (stopień/tytuł, imię i nazwisko, afiliacja) OŚWIADCZENIE Jako współautor pracy “The Skin as a Mirror of Internal Disease: Comorbidities and Epidemiology of Acne Vulgaris and Adult Female Acne -A Cross-sectional Study and Current State of Knowledge” (Acta Dermatovenerol Croat. 2020 Dec;28(3):133-140. PMID: 33422166) oświadczam, iż mój własny wkład merytoryczny w przygotowanie, przeprowadzenie i opracowanie badań oraz przedstawienie pracy w formie publikacji polegał na przeprowadzeniu analizy statystycznej Jednocześnie wyrażam zgodę na przedłożenie w/w pracy przez mgr/lek Katarzynę Kaletę jako część rozprawy doktorskiej w formie spójnego tematycznie zbioru artykułów opublikowanych w czasopismach naukowych. Oświadczam, iż samodzielna i możliwa do wyodrębnienia część ww. pracy wykazuje indywidualny wkład lek Katarzyny Kalety polegający na -opracowaniu pomysłu badań -stworzeniu hipotezy badawczej -przeprowadzeniu części eksperymentalnej -zebraniu i analizie danych epidemiologicznych -opracowaniu i interpretacji wyników pracy (podpis współautora) 93 94 23.08.2021, Kraków Lek. Anna Bogusławska Katedra i Klinika Endokrynologii Collegium Medicum Uniwersytetu Jagiellońskiego w Krakowie (stopień/tytuł, imię i nazwisko, afiliacja) OŚWIADCZENIE Jako współautor prac “The Skin as a Mirror of Internal Disease: Comorbidities and Epidemiology of Acne Vulgaris and Adult Female Acne -A Cross-sectional Study and Current State of Knowledge” (Acta Dermatovenerol Croat. 2020 Dec;28(3):133-140. PMID: 33422166) oraz „Metabolic disorders/obesity is a primary risk factor in hidradenitis suppurativa -an immunohistochemical real-world approach” (Dermatology 2021;[online ahead of print]. DOI: 10.1159/000517017) oświadczam, iż mój własny wkład merytoryczny w przygotowanie, przeprowadzenie i opracowanie badań oraz przedstawienie prac w formie publikacji polegał na: -opracowaniu pomysłów badań -opracowaniu i interpretacji wyników prac Jednocześnie wyrażam zgodę na przedłożenie w/w pracy przez mgr/lek Katarzynę Kaletę jako część rozprawy doktorskiej w formie spójnego tematycznie zbioru artykułów opublikowanych w czasopismach naukowych. Oświadczam, iż samodzielna i możliwa do wyodrębnienia część ww. pracy wykazuje indywidualny wkład lek Katarzyny Kalety polegający na -opracowaniu pomysłu badań -stworzeniu hipotezy badawczej -przeprowadzeniu części eksperymentalnej -zebraniu i analizie danych -opracowaniu i interpretacji wyników pracy -przygotowaniu i krytycznej rewizji manuskryptu (podpis współautora) 95 Kraków, 23.08.2021 Lek. Agata Kłosowicz Katedra i Klinika Dermatologii Uniwersytetu Jagiellońskiego Collegium Medicum w Krakowie (stopień/tytuł, imię i nazwisko, afiliacja) OŚWIADCZENIE Jako współautor pracy “The Skin as a Mirror of Internal Disease: Comorbidities and Epidemiology of Acne Vulgaris and Adult Female Acne -A Cross-sectional Study and Current State of Knowledge” (Acta Dermatovenerol Croat. 2020 Dec;28(3):133-140. PMID: 33422166) oświadczam, iż mój własny wkład merytoryczny w przygotowanie, przeprowadzenie i opracowanie badań oraz przedstawienie pracy w formie publikacji polegał na zebraniu i analizie danych epidemiologicznych. Jednocześnie wyrażam zgodę na przedłożenie w/w pracy przez mgr/lek Katarzynę Kaletę jako część rozprawy doktorskiej w formie spójnego tematycznie zbioru artykułów opublikowanych w czasopismach naukowych. Oświadczam, iż samodzielna i możliwa do wyodrębnienia część ww. pracy wykazuje indywidualny wkład lek Katarzyny Kalety polegający na -opracowaniu pomysłu badania -stworzeniu hipotezy badawczej -przeprowadzeniu części eksperymentalnej -zebraniu i analizie danych -opracowaniu i interpretacji wyników pracy -przygotowaniu i krytycznej rewizji manuskryptu (podpis współautora) 96 97 98 99 100 101 Kraków, 23.08.2021 Lek. Katarzyna Kaleta Katedra i Klinika Dermatologii Uniwersytetu Jagiellońskiego Collegium Medicum w Krakowie (stopień/tytuł, imię i nazwisko, afiliacja) OŚWIADCZENIE Jako współautor prac: “The Skin as a Mirror of Internal Disease: Comorbidities and Epidemiology of Acne Vulgaris and Adult Female Acne -A Cross-sectional Study and Current State of Knowledge” (Acta Dermatovenerol Croat. 2020 Dec;28(3):133-140. PMID: 33422166), “Metabolic disorders/obesity is a primary risk factor in hidradenitis suppurativa -an immunohistochemical real-world approach” (Dermatology 2021;[online ahead of print]. DOI: 10.1159/000517017) oraz artykułu “Phenotypes and Pathophysiology of Syndromic Hidradenitis Suppurativa: Different Faces of the Same Disease? A Systematic Review.” (Dermatology. 2020 Sep 17:1-25. doi: 10.1159/000509873, oświadczam, iż mój własny wkład merytoryczny w przygotowanie, przeprowadzenie i opracowanie badań oraz przedstawienie pracy w formie publikacji polegał na: zaprojektowaniu powyższych badań, stworzeniu hipotez badawczych, zbieraniu danych klinicznych i ich analizie, przeprowadzeniu badania immunohistochemicznego oraz fotograficznej dokumentacji obrazów immunohistochemicznych, opracowaniu i interpretacji uzyskanych danych, wykonaniu przeglądu systematycznego literatury, przygotowaniu i krytycznej rewizji manuskryptów. Jednocześnie wyrażam zgodę na przedłożenie w/w prac jako część mojej rozprawy doktorskiej w formie spójnego tematycznie zbioru artykułów opublikowanych w czasopismach naukowych. (podpis współautora) 102 103