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Year: 2018

Comparison of gangrenosum and hypertensive ischemic leg Martorell in a Swiss cohort

Kolios, Antonios G A ; Hafner, Jürg ; Luder, C ; Guenova, Emmanuella ; Kerl, K ; Kempf, Werner ; Nilsson, J ; French, L E ; Cozzio, A

Abstract: Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis presenting with painful and sterile skin ulcerations (1). Its aetiology remains largely unknown although an autoinflammatory back- ground seems possible. Several comorbidities as well as triggering factors such as surgery, trauma or pharmacological therapies have been associated with the development of PG (2). Different topical and systemic treatments are recommended for PG, most commonly topical steroids or calcineurin inhibitors as well as systemic steroids, dapsone, and others, as well as by our group and others and ustekinumab (3, 4). This article is protected by copyright. All rights reserved.

DOI: https://doi.org/10.1111/bjd.15901

Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-140535 Journal Article Accepted Version

Originally published at: Kolios, Antonios G A; Hafner, Jürg; Luder, C; Guenova, Emmanuella; Kerl, K; Kempf, Werner; Nilsson, J; French, L E; Cozzio, A (2018). Comparison of pyoderma gangrenosum and hypertensive ischemic leg ulcer Martorell in a Swiss cohort. British Journal of Dermatology, 178(2):e125-e126. DOI: https://doi.org/10.1111/bjd.15901 Accepted Article 1 This by is protectedarticle reserved. Allrights copyright. doi: 10.1111/bjd.15901 lead to differences between this version and the throughbeen the copyediting, pagination typesetting, which process, may and proofreading hasThis article been accepted publicationfor andundergone peerfull but review not has Kolios A.G.A. cohort Swiss a in Martorell ulcer leg ischemic hypertensive and gangrenosum pyoderma of Comparison Article type : Research Letter 2 3 4 Short title Short § University Hospital, Gloriastrasse 23, 8091 Zurich, Switzerland, Tel.+41 255 44 11 11, author * Corresponding CRP neutrophilia, Keywords: Kolios, French. Cozzio, thedataanalysis. of accuracy thedataand the of integrity the for responsibility access toall hadfull Allauthors contribution: Author’s [email protected]

Kerl, Kempf, Hafner, Nilsson and French.

Department of Dermatology, Zurich University Hospital, Zurich, Switzerland Department of Zurich Immunology, University Hospital, Zurich, Switzerland these authors contribute equally last to this this work. to equally last contribute these authors Department of Dermatology, Venerology and Allergology, Kantonsspital Venerology andAllergology, St. Department St.Gallen, Gallen, Dermatology, of Kempf und Pfaltz Histologische Diagnostik, Zürich, Switzerland Zürich, Diagnostik, Kempf Histologische undPfaltz

: PG :HYTILU PG Switzerland Pyoderma gangrenosum, hypertensive ischemic leg ulcer Martorell, systemic , inflammation, systemic leg Martorell, ulcer ischemic hypertensive gangrenosum, Pyoderma 1,2, * , J. Hafner , J. Critical revision of the manuscript for important intellectual content intellectual important for the manuscript revisionof Critical

: Antonios G. A. Kolios, Department of Immunology and Dermatology, Zurich Zurich Dermatology, Immunology and of G. Department A.Kolios, : Antonios 1 , C.Luder

1 , E. Guenova , E. Study supervision 1,3

, K. Kerl of the data in the case. Dres. Kolios and Cozzio take and Cozzio Dres. Kolios case. inthe data the of Version of Record. Please Version as this cite ofRecord. article : French. 1 , W. Kempf

1,4 , J.Nilsson Switzerland Drafting of the manuscript 2 ,French L.E.

Fax +41 44-255 Fax 4403, : Luder, Guenova, 1,§ , A.Cozzio :

3,§

Accepted Article This by is protectedarticle reserved. Allrights copyright. Other were analysed for both cohorts in order to identify features which support clinical distinction ( clinicaldistinction support which features identify to order in cohorts both for analysed were findings laboratory and records Medical at period. theUSZ same the during diagnosed time 32 HYTILU patients (7). These PG study in our included and were al. by Su et analysis. these patients further The remaining from four to exclu , ofHYTILU leading one and with signs with three identified histopathological patients and patients these 38 of re-assessment ahistopathological PG.We performed as werediagnosed patients 31.12.2012. 179 patients wereidentified an with initial suspected differenti an 01.01.2002 between hospitalized were who allpatients for conducted was “gangrenosum” and/or Sankt Gallen (KSSG), and in the private practice of Prof. Werner K ( Zurich of Hospital University Dermatology, of theDepartment files of In the patient diseases. both clues for diagnostic develop to comorbidities and findings laboratory data, clinical on focus and cohort aHYTILU with PG our compare we study strongly it as HYTILU fatal in could be immunosuppression This (5, 6). ulcer borders inflamed necrosis and purple cent mellitus. with lower is leg HYTILU of Typical ulceration apresentation latero-dorsal clinical hypertensi arterial showing allpatients and arteriolosclerosis subcutaneous HYTILUis (5). haveto HYTILU werefound PG of diagnosis areferral with the patients of was (HYTILU) Martorell ulcer leg ischemic Hypertensive initial manifestation. at misdiagnosed often and exclusion of adiagnosis is gangrenosum Pyoderma 4). (3, ustekinumab and canakinumab others and group well by our as as and others, infliximab dapsone, syste aswellas inhibitors calcineurin or steroids topical commonly most PG, for recommended therapies have thedevelopment associated with been of as astriggering well comorbidities Severalpossible. backgr anautoinflammatory although largely unknown remains aetiology (1). Its ulcerations skin sterile and painful with presenting dermatosis aneutrophilic israre(PG) Pyoderma gangrenosum Prism® 7.0b, 2016, and Microsoft Excel® 14.3.2, 2011, were used. study was approvedlocal ethics by the committee (KEK-ZH 2014-0432). For stat disease, metabolic syndrome and more microbial superinfection ( microbial superinfection more and syndrome disease, metabolic arterialsuch as mellitus, diabetes perip comorbidities cardiovascular hypertension, higher CRP but lower levels of blood leukocytes and neut Compared to PG, HYTILUappeared less frequent in women,at

: Conflict of interest: non-related to the article. / Funding: not applicable. not / Funding: article. tothe non-related interest: of : Conflict previously investigated by our group showing that 50% that showing byour group investigated previously patients were retrospectively compared to a cohort of of cohort toa compared retrospectively were patients pharmacological or trauma surgery, as such factors appearance can clinically be misleading for PG and and PG for misleading be clinically can appearance rophils, lesion localization only at the lower leg, more more leg, lower at the localization lesion only rophils, 34 patients fulfilled the criteria for PG as established as PG 34 patients for established fulfilled the criteria PG (2). Different topical and systemic treatments are are treatments Differenttopical systemic and PG (2). increases the risk of septicaemia. (5) In the current the In (5) of septicaemia. risk the increases empf (USZ) a keyword search for “pyoderma” Table 1

laterage, more often in smokers, showed ). aldiagnosis PG, of which of 38

on and up to 58% diabetes diabetes 58% to and up on USZ), Cantonal Hospital of Hospital USZ), Cantonal isticalanalysis GraphPad heral artery occlusive heral artery occlusive caused by ischemic byischemic caused Table 1 mic steroids, mic steroids, ound seems seems ound ral black sion of sion ). The d Accepted Article This by is protectedarticle reserved. Allrights copyright. PG and HYTILU Comparison 1: Table findings. these to confirm international registri or PG.studies Largerof prospective aspect proven formally but not expected an is which PG patients, our of proportion considerable ina markers inflammat increased also We identified these disorders. accurately differentiate to be in order utilized co comorbidities of andpresence parameters laboratory localization, inlesion that suggest differences (subcutaneous stenotic arteriolosclerosis in 100% and medialcalcificatio missing and visualizingfeatures infiltration features“the of neutrophilic typical “PG-like of to is HYTILUtaken and in PG the biopsy if In particular carefully considered. be should differ and HYTILU are important gangrenosum Pyoderma findings. our confirm to needed are and largercohorts small rather arehowever cohorts Both 4%). head 5%, limb upper 24%, trunk 67%, leg (lower PG of diagnose the favouring hint clinical further a be could leg the lower HYTILU patients in our cohort had an ulcer located on th allofthe Furthermore, (5). studies in bigger confirmed be needs to this however population, normal Swiss t seems in our small cohort PG cardiovascular comorbidities of prevalence the adjustment age as inPG. Upon has group, also previously which our significantly been by in HYTILU, more reported arteryhypertension, occlusive peripheral disease, lesions could beexplained by the exacerbated response.C isby increasingly field(8). the also suggested Additional inPG andneutrophilia CRP of anelevated findings Our Laboratory (mean) Alcohol Smoking BMI (kg/m2) (years) manifestation at Age Female gender ns 12.5% 11.8% ns 25% 20.6% * 28.3 24.1 *** 73.5 61.2 ns 50.0% 61.8% (n=32) HYTILU metabolic syndrome and metabolic syndrome mellitusdiabetes appear indicates the presence of systemic inflammation, which which inflammation, systemic thepresence of indicates e leglower asand such, a lesion localization of outside ly the reduced likelihood of pathogenic bacteria in PG inPG bacteria pathogenic lyof likelihood thereduced es on these rare ulcerative skin diseasesrareulcerative are onthese skin needed es ential diagnosis for ulcerative skin disorders and and disorders skin ulcerative for ential diagnosis (n=34) PG ardiovascularcomorbidities likearterial n in 71% cases)of n inis high. 71% Our findings value p o small, the chance of o chanceof small, the o correspond theto o correspond HYTILU HYTILU uld also also uld ory ory -

Accepted Article This by is protectedarticle reserved. Allrights copyright. 3.5-9.6 x 10^9/L, referencevalue: 1.4-8.0 x 10^9/L, ns = not significa leuk =milligram,G/L = = <5mg/L,= value: reference meter, mggiga/liter CRP 10^9/L, index, BMI kg = = = CRP disease, mass C-reactive body protein, PAOD Ki occlusive = peripheral artery comorbidities. localization, values, laboratory data, demographic by patients PG 34 and Martorell) legulcer ischemic HYTILU (hypertensive patients 32 of Comparison PG and HYTILU Comparison 1: Table

p Microbiological swabpositive Renal insufficiency comorbidities Cardiovascular leg lower localization Lesion ≤ 0.01, *** = ***0.01, p Thrombosis mellitus Diabetes syndrome Metabolic Cerebrovascular infarction Other cardiopathy infarction Myocardial disease heart Hypertensive PAOD hypertension Arterial (G/L) Neutrophils (G/L) Leukocytes CRP (mg/L) ≤ 0.001, ****= p ≤ 0.0001). Statistics: unpaired t test with Welch's correction. correction. withWelch's test t unpaired Statistics: 0.0001). 06 41 **** 90.6% 44.1% ns 28.1% 20.6% ** 79.4% *** 67% 100% 100% .%88 ns 3.1% 8.8% **** 53.1% 8.8% **** 65.6% 2.9% * 21.9% 2.9% ns **** 12.5% 2.9% 5.9% * **** 25.0% 5.9% 29.4% ** 40.6% 11.8% * 62.5% 8.4 ns 100% 10.5 ns 14.5 7.9 9.9 31.5 nt nt / p>0.05, * = p ocytes reference value: value: ocytes reference ≤ logram, m logram, 0.05, ** = Accepted Article This by is protectedarticle reserved. Allrights copyright. Literature gangrenosum.Dermatol JDtsch2016;14(10):1023-30. Ges. Jockenhofer F, Herberger K, Schaller Hohaus J, KC, Stoffels-Weindorf M, Ghazal PA, et al. Tricenter analysis cofactors of and comorbidity within patients pyoderma 8. 2004;43(11):790-800. Perry Powell gangrenosum: DavisMD, FC, Su RH, Weenig Pyoderma HO. WP, clinicopathologic correlationand proposed IntJDermatol.diagnostic criteria. 7. Weenig Davis RH, MD, Dahl PR, Su SkinWP. ulcers asmisdiagnosed pyoderma gangrenosum. N Engl J Med. 2002;347(18):1412-8. 6. 2010;146(9):961-8.Dermatol. Nobbe S, Lauchli J, Hafner Partsch Mayer H, S, Amann-Vesti D, etal. B, Martorell leg ischemic subcutaneous arteriolosclerosis.hypertensive ulcer: of a ischemic model Arch 5. ustekinumab. Arch 2011;147(10):1203-5. Dermatol. Guenova Teske E, A, Fehrenbacher B, Hoerber Adamczyk S, A, Schaller M, et al. Interleukin 23 expression in gangrenosum andtargeted pyoderma therapywith 4. 23. Canakinumab al. Traidl-HoffmannKerl HertlM,et B, K, C, Kolios Meier Maul AG, JT, in steroid-refractory adults with gangrenosum. Br pyoderma JDermatol. 2015;173(5):1216- 3. Powell Perry SuFC, and WP, gangrenosum: classification HO.Pyoderma management. JAm Acad1996;34(3):395-409; Dermatol. quiz10-2. 2. Meier MaulJT, B, FrenchLE.[Pyoderma gangrenosumand Sweet's syndrome : Cutaneous autoinflammatory of manifestations disorders]. 2016. Hautarzt. 1.