What causes hidradenitis suppurativa ?—15 years after

Zouboulis, Christos C.; Benhadou, Farida; Byrd, Angel As; Chandran, Nisha Ns; Giamarellos‐Bourboulis, Evangelos J.; Fabbrocini, Gabriella; Frew, John W.; Fujita, Hideki; González‐López, Marcos A.; Guillem, Philippe; Gulliver, Wayne; Hamzavi, Iltefat; Hayran, Yıldız; Hórvath, Barbara; Hüe, Sophie; Hunger, R. M.; Ingram, John R.; Jemec, Gregor B. E.; Qiang, Jun; Kimball, Alexa B.; Kirby, Joslyn S.; Konstantinou, Maria Mp; Lowes, Michelle Ma; MacLeod, Amanda S.; Martorell, A.; Marzano, Angelo Valerio; Matusiak, Łukasz; Nassif, Aude; Nikiphorou, Elena; Nikolakis, Georgios; Costa, André Nogueira da; Okun, Martin; Orenstein, Lauren A V; Pascual, José C.; Paus, Ralf; Périn, B; Prens, Errol P.; Röhn, Till Ta; Szegedi, Andrea; Szepietowski, Jacek C.; Tzellos, Thrasyvoulos; Wang, Baoxi; Zee, Hessel H. van der

doi:10.1111/exd.14214

Cited by 103 publications

(72 citation statements)

References 199 publications

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“…Genes encoding koebnerisin and calprotectin have been demonstrated to be upregulated in HS lesional skin by means of microarray‐based gene expression analysis, 5 suggesting a hyperactivation of the innate immunity leading to HS hyperinflammation 49 . S100 antimicrobial peptides also behave as damage‐associated molecular pattern (DAMP) molecules triggering the inflammasome activation and contributing to the autoinflammatory signalling in HS 1 …”

Section: S100a Proteinsmentioning

confidence: 99%

“…Skin is considered steroidogenic factory, capable to produce most sex steroids de novo from cholesterol and catalyse more or less potent steroids from their precursors, contributing to skin homeostasis 65,66 . Sex hormones were linked with HS: the documented increased prevalence in women, the manifestation of the disease immediately after puberty, its rare postmenopausal occurrence and the effect of pregnancy in disease flares indicate a role of hormones for the pathogenesis of the disease 1 . On the other hand, HS patients demonstrate an increased prevalence of components of the metabolic syndrome, 67 diabetes mellitus type II 68 and showed improvement of disease severity after weight loss 69 .…”

Section: Hormones and Metforminmentioning

confidence: 99%

“…The rapidly increasing interest on hidradenitis suppurativa/acne inversa (HS) and the ongoing elucidation of its pathogenesis 1 intensify the search for target molecules of future HS treatment, which still remains though inconclusive. The total of 113 clinical studies currently documented in ClinicalTrials.gov indicates the wide range of ongoing target search 2 .…”

Section: Introductionmentioning

confidence: 99%

“…To date, however, many molecules have been identified in histologic samples, 11,12 but the sequence of the pattern and the key initiators are still work in progress. In the meantime, the inhibition of tumour necrosis factor (TNF)‐α, IL‐1 and IL‐17 has been validated in clinical trials as relevant 1 . This article, which summarizes the data of the homonymous scientific symposium, which took place during the 10th European Hidradenitis Suppurativa Foundation (EHSF) e.V.…”

Section: Introductionmentioning

confidence: 99%

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Target molecules for future hidradenitis suppurativa treatment

Zouboulis

Frew

Giamarellos‐Bourboulis

et al. 2021

Experimental Dermatology

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The registration of the tumour necrosis factor‐α inhibitor adalimumab in 2015 was a major step forward in the treatment of hidradenitis suppurativa/acne inversa (HS). However, it soon became evident that the effectiveness of adalimumab in daily practice was highly variable. A significant unmet medical need of HS patients remained, and the search for novel therapeutic targets was intensified. During the 10th European Hidradenitis Suppurativa Foundation (EHSF) e.V. Conference, reknown international HS investigators virtually presented and discussed the published data on these potential target molecules for future HS treatment. This article addresses the most promising molecules currently under investigation from a pathophysiological and clinical point of view. With phase III trials ongoing, the anti‐ interleukin (IL)‐17 biologics bimekizumab and secukinumab are in the most advanced stage of clinical development showing promising results. In addition, targeting IL‐1α with bermekimab has shown encouraging results in two clinical trials. Directing treatment at neutrophil recruitment and activation by targeting IL‐36 with spesolimab fits well in the pathogenic concept of HS and clinical phase II trial results are pending. In contrast to in situ evidence, Complement 5a (C5a) and C5a receptor blockade have only shown greater clinical benefit in patients with severe HS. Inhibition of Janus kinase (JAK) 1 signalling in HS showed clinical efficacy only in the highest dosage, highlighting that careful surveillance of the balance between safety and efficacy of JAK inhibition is warranted. Overall, clinical efficacies of all novel treatments reported so far are modest. To guide drug development, more and better‐defined translational data on the pathogenesis of this severe and enigmatic inflammatory skin disease are required.

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Section: S100a Proteinsmentioning

confidence: 99%

Section: Hormones and Metforminmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Target molecules for future hidradenitis suppurativa treatment

Zouboulis

Frew

Giamarellos‐Bourboulis

et al. 2021

Experimental Dermatology

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“…Both the EOfAD-like and fAI-like mutations caused very statistically significant changes in the gene sets KEGG_CYTOKINE_CYTOKINE_RECEPTOR _INTERACTION and KEGG_RIBOSOME. The former gene set reflects that both mutations appear to affect inflammation that is a characteristic of the pathologies of both EOfAD [93] and fAI (reviewed in [94]). Like oxidative phosphorylation, we have also observed effects on ribosomal protein genes sets for every EOfAD-like mutation we have studied [39][40][41]43].…”

Section: Discussionmentioning

confidence: 99%

PRESENILIN 1mutations causing early-onset familial Alzheimer’s disease or familial acne inversa differ in their effects on genes facilitating energy metabolism and signal transduction

Barthelson

Dong

Newman

et al. 2021

Preprint

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BackgroundThe most common cause of early-onset familial Alzheimer’s disease (EOfAD) is mutations in PRESENILIN 1 (PSEN1) allowing production of mRNAs encoding full-length, but mutant, proteins. In contrast, a single known frameshift mutation in PSEN1 causes familial acne inversa (fAI) without EOfAD. The molecular consequences of heterozygosity for these mutation types, and how they cause completely different diseases, remains largely unexplored.ObjectiveTo analyse brain transcriptomes of young adult zebrafish to identify similarities and differences in the effects of heterozygosity for psen1 mutations causing EOfAD or fAI.MethodsRNA sequencing was performed on mRNA isolated from the brains of a single family of 6-month-old zebrafish siblings either wild type or possessing a single, heterozygous EOfAD-like or fAI-like mutation in their endogenous psen1 gene.ResultsBoth mutations downregulate genes encoding ribosomal subunits, and upregulate genes involved in inflammation. Genes involved in energy metabolism appeared significantly affected only by the EOfAD-like mutation, while genes involved in Notch, Wnt and neurotrophin signalling pathways appeared significantly affected only by the fAI-like mutation. However, investigation of direct transcriptional targets of Notch signalling revealed possible increases in γ-secretase activity due to heterozygosity for either psen1 mutation. Transcriptional adaptation due to the fAI-like frameshift mutation was evident.ConclusionWe observed both similar and contrasting effects on brain transcriptomes of the heterozygous EOfAD-like and fAI-like mutations. The contrasting effects may illuminate how these mutation types cause distinct diseases.

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