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Background: Targeting immunometabolism has shown promise in treating autoimmune and inflammatory conditions. Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease involving painful lesions in apocrine gland-bearing skin. Therapeutic options for HS are limited and often ineffective; thus, there is a pressing need for improved treatments. To date, metabolic dysregulation has not been investigated in HS. As HS is highly inflammatory, we hypothesized that energy metabolism is dysregulated in these patients. Metformin, an antidiabetic drug, which is known to impact on cellular metabolic and signalling pathways, has been shown to have anti-inflammatory effects in cancer and arthritis. While metformin is not licensed for use in HS, patients with HS taking metformin show improved clinical symptoms., Objective: To assess the effect and mechanism of action of metformin in HS., Methods: To assess the effect of metformin in vivo, we compared the immune and metabolic profiles of peripheral blood mononuclear cells (PBMCs) of patients with HS taking metformin vs. those not taking metformin. To examine the effect of metformin treatment ex vivo, we employed a skin explant model on skin biopsies from patients with HS not taking metformin, which we cultured with metformin overnight. We used enzyme-linked immunosorbent assays, multiplex cytokine assays and quantitative real-time polymerase chain reaction (RT-PCR) to measure inflammatory markers, and Seahorse flux technology and quantitative RT-PCR to assess glucose metabolism., Results: We showed that metabolic pathways are dysregulated in the PBMCs of patients with HS vs. healthy individuals. In metformin-treated patients, these metabolic pathways were restored and their PBMCs had reduced inflammatory markers following long-term metformin treatment. In the skin explant model, we found that overnight culture with metformin reduced inflammatory cytokines and chemokines and glycolytic genes in lesions and tracts of patients with HS. Using in vitro assays, we found that metformin may induce these changes via the NLR family pyrin domain containing 3 (NLRP3) inflammasome and the AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR) pathway, which is linked to glycolysis and protein synthesis., Conclusions: Our study provides insight into the mechanisms of action of metformin in HS. The anti-inflammatory effects of metformin support its use as a therapeutic agent in HS, while its effects on immunometabolism suggest that targeting metabolism is a promising therapeutic option in inflammatory diseases, including HS., Competing Interests: Conflicts of interest R.H. has received honoraria from AbbVie, Janssen and UCB; and has acted as a subinvestigator in clinical trials for AbbVie and UCB. N.K. has received honoraria from AbbVie, Janssen, Lilly and UCB; and has acted as a subinvestigator in clinical trials for AbbVie, Moonlake and UCB. B.K. has received grants and/or honoraria from AbbVie, Almirall, Astra Zeneca, Biogen, Bristol Myers Squibb, Celgene, Janssen, Lilly, LEO Pharma, Merck, Moonlake, Novartis, Pfizer and UCB Pharma.​ J.M.F. has received honoraria from Novartis and Moonlake. A.P., C.M.S., E.K.P., J.M.M., A.M.O’R., M.I., P.A.B., J.P.A., C.K., A.Z., S.M. and D.W. declare no conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Background: Treatment for the debilitating disease hidradenitis suppurativa (HS) is inadequate in many patients. Despite an incidence of approximately 1%, HS is often under-recognized and underdiagnosed, and is associated with a high morbidity and poor quality of life., Objectives: To gain a better understanding of the pathogenesis of HS, in order to design new therapeutic strategies., Methods: We employed single-cell RNA sequencing to analyse gene expression in immune cells isolated from involved HS skin vs. healthy skin. Flow cytometry was used to quantify the absolute numbers of the main immune populations. The secretion of inflammatory mediators from skin explant cultures was measured using multiplex and enzyme-linked immunosorbent assays., Results: Single-cell RNA sequencing analysis identified a significant enrichment in the frequency of plasma cells, T helper (Th) 17 cells and dendritic cell subsets in HS skin, and the immune transcriptome was distinct and more heterogeneous than healthy skin. Flow cytometry revealed significantly increased numbers of T cells, B cells, neutrophils, dermal macrophages and dendritic cells in HS skin. Genes and pathways associated with Th17 cells, interleukin (IL)-17, IL-1β and the NLRP3 inflammasome were enhanced in HS skin, particularly in samples with a high inflammatory load. Inflammasome constituent genes principally mapped to Langerhans cells and a subpopulation of dendritic cells. The secretome of HS skin explants contained significantly increased concentrations of inflammatory mediators, including IL-1β and IL-17A, and culture with an NLRP3 inflammasome inhibitor significantly reduced the secretion of these, as well as other, key mediators of inflammation., Conclusions: These data provide a rationale for targeting the NLRP3 inflammasome in HS using small-molecule inhibitors that are currently being tested for other indications., Competing Interests: Conflicts of interest: R.H. has received honoraria from AbbVie, Janssen and UCB, and has acted as a subinvestigator in clinical trials for AbbVie and UCB. K.H.G.M. is the co-founder of and a shareholder in a startup biotechnology company involved in the development of anti-inflammatory therapeutics. B.K. has received grants and/or honoraria from AbbVie, Almirall, AstraZeneca, Biogen, Bristol Myers Squibb, Celgene, Janssen, Lilly, LEO Pharma, Merck, Moonlake, Novartis, Pfizer and UCB Pharma.​ J.M.F. has received honoraria from Novartis and Moonlake. M.R. is a former employee of AbbVie. B.M., C.M.S., A.Z., J.K., R.W.D., K.M.S., J.M., A.P., A.F., M.O’D., K.H., W.J.H. and D.C.W. declare no conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Hidradenitis suppurativa (HS) is a common cutaneous and systemic inflammatory disease with a significant impact on mental health and quality of life. It is associated with obesity, insulin resistance, metabolic syndrome, cardiovascular (CV) disease, and increased all-cause mortality. Metformin is used frequently in HS treatment and is effective for some patients. The mechanism of action of metformin in HS is unknown. A case-control study of 40 patients with HS (20 on metformin and 20 controls) was conducted to assess differences in metabolic markers, inflammation (C-reactive protein [CRP], serum adipokines, and CV risk biomarkers), and serum immune mediators. Body mass index (BMI), insulin resistance (77%), and metabolic syndrome (44%) were high overall, but not significantly different between the groups. This highlights the need for co-morbidity screening and management. A significant reduction in fasting insulin and a trend towards a reduction in insulin resistance were identified in the metformin group compared with pre-treatment levels. CV risk biomarkers were significantly favourable in the metformin group (lymphocytes, monocyte-lymphocyte ratio, neutrophil-lymphocyte ratio, and platelet-lymphocyte ratio). CRP was lower in the metformin group but was not statistically significant. Adipokines were dysregulated overall but were not different between the two groups. Serum IFN-γ, IL-8, TNF-α, and CXCL1 trended lower in the metformin group but did not reach significance. These results suggest that metformin improves CV risk biomarkers and insulin resistance in patients with HS. When the results of this study are considered alongside other studies in HS and related conditions, it is likely that metformin also has beneficial effects on metabolic markers and systemic inflammation in HS (CRP, serum adipokines, and immune mediators), warranting further research.

Hidradenitis suppurativa (HS) is a chronic relapsing inflammatory skin disease manifested as painful inflamed lesions including deep-seated nodules, abscesses and sinus tracts. The exact aetiology of HS is unclear. Recent evidence suggests that immune dysregulation plays a crucial role in pathogenesis and disease progression. Innate lymphoid cells (ILC) are a recently identified immune cell subset involved in mediating immunity, however their role in HS has not yet been investigated. Three distinct subsets of ILC- ILC1, ILC2 and ILC3 have been described, and these are involved in skin tissue homeostasis and pathologic inflammation associated with autoimmunity and allergic diseases. In this study, we analysed by multiparameter flow cytometry the frequencies of ILC subsets in skin and peripheral blood mononuclear cells (PBMC) of HS patients and compared these to healthy control subjects and psoriasis patients. The absolute numbers of total ILC and subsets thereof were significantly reduced in the blood of HS patients relative to healthy controls. However, when patients were stratified according to treatment, this reduction was no longer observed in patients undergoing anti-TNF treatment. In HS lesional skin the absolute numbers of ILC were significantly increased relative to control skin. Furthermore, the frequencies of total ILC as well as ILC2 and ILC3 were significantly higher in non-lesional than lesional HS skin. This study analysed for the first time the presence of ILC subsets in the blood and skin of HS patients. Our findings suggest that ILC may participate in HS pathogenesis., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: RHa received support for attendance at meetings from AbbVie and Janssen. OM received support for attendance at meetings from Novartis. BM received support for attendance at meetings from Miltenyi. AM received support for attendance at meeting from AbbVie. BK has received research support/principal investigator (clinical trials) from AbbVie, Alimirall, Janssen, Merck Sharpe Dolme, Moonlake, Novartis,Pfizer and UCB; been a consultant for AbbVie, Amgen, Almirall, Cel-gene, Janssen, Merck Sharpe Dolme, Moonlake, Novartis, Pfizer and UCB; received honoraria from AbbVie, Amgen, Alimrall, Celgene, Janssen, Lilly, Moonlake, Novartis, Pfizer and UCB; and been on scientific advisory boards for AbbVie, Almirall, Celgene, Janssen, Lilly, Moonlake Novartis, Pfizer and UCB. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Petrasca et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Competing Interests: Conflicts of interest: R. Hambly has received honoraria from AbbVie, Janssen and UCB and has acted as a subinvestigator in clinical trials for AbbVie and UCB. B.K. has received research support from or been a principal investigator (clinical trials) for AbbVie, Almirall, Janssen, Merck Sharpe & Dohme, Novartis, Pfizer and UCB; has been a consultant for AbbVie, Almirall, Celgene, Janssen, Merck Sharpe & Dohme, Novartis, Pfizer and UCB; has received honoraria from AbbVie, Almirall, Celgene, Janssen, Lilly, Novartis, Pfizer and UCB; and been on scientific advisory boards for AbbVie, Almirall, Celgene, Janssen, Lilly, Novartis, Pfizer and UCB.

Background: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disorder with significant morbidity. The pathogenesis remains incompletely understood although immune dysregulation plays an important role. It is challenging to treat and approximately 50% of patients respond clinically to adalimumab, the only licensed treatment., Objectives: To examine differences between lesional and nonlesional HS skin at baseline using bulk RNA sequencing, and to compare the transcriptome in the skin before and after 12 weeks of treatment with adalimumab. To examine transcriptomic differences between adalimumab responders and nonresponders using Hidradenitis Suppurativa Clinical Response and the International Hidradenitis Suppurativa Severity Score System (IHS4); and to compare transcriptomic differences based on disease severity (Hurley stage and IHS4)., Methods: We completed bulk RNA sequencing on lesional and nonlesional skin samples of patients before and after 12 weeks of treatment with adalimumab., Results: Baseline differentially expressed genes and pathways between lesional and nonlesional skin highlighted chemokines and antimicrobial peptides produced by keratinocytes; B-cell function; T-cell-receptor, interleukin-17 and nuclear factor-κB signalling; and T-helper-cell differentiation. Transcriptomic differences were identified in lesional skin at baseline, between subsequent responders and nonresponders. Patients with severe HS who did not respond to adalimumab had enriched complement and B-cell activation pathways at baseline. In addition, logistic regression identified CCL28 in baseline lesional HS skin as a potential biomarker of treatment response., Conclusions: This highlights the potential for targeting B-cell and complement pathways in HS treatment and the potential of stratifying patients at baseline to the most suitable treatment based on the skin transcriptome. CCL28 has not previously been identified in HS skin and has potential clinical relevance due to its antimicrobial function and homing of B and T cells at epithelial surfaces. Our results provide data to inform future translational and clinical studies on therapeutics in HS., Competing Interests: Conflicts of interest: R. Hambly has received honoraria from AbbVie, Janssen and UCB and has acted as a subinvestigator in clinical trials for AbbVie and UCB. B.K. has received research support from or been a principal investigator (clinical trials) for AbbVie, Almirall, Janssen, Merck Sharp & Dohme, Moonlake, Novartis, Pfizer and UCB; has been a consultant for AbbVie, Almirall, Celgene, Janssen, Merck Sharp & Dohme, Moonlake, Novartis, Pfizer and UCB; has received honoraria from AbbVie, Almirall, Celgene, Janssen, Lilly, Moonlake, Novartis, Pfizer and UCB; and has been on scientific advisory boards for AbbVie, Almirall, Celgene, Janssen, Lilly, Moonlake, Novartis, Pfizer and UCB., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Hidradenitis suppurativa (HS) is a chronic debilitating inflammatory disease, associated with metabolic syndrome, obesity and insulin resistance. Metformin, an oral hypoglycaemic agent, may play an important role in delaying or preventing the onset of diabetes and metabolic syndrome. Metformin has been reported as having efficacy in HS. It may have a role in the treatment of HS and its associated co-morbidities. Objective: To evaluate metformin use, response and tolerability in a HS population. Methods: A retrospective chart review of patients attending a specialist Dermatology HS clinic over 12 months. All patients treated with metformin were included. Results: Fifty-three HS patients received metformin; 85% female; mean age was 37 years and mean weight was 102 kg. The mean duration of metformin was 11.3 months and mean dose was 1.5 g/days. The 6- and 12-month drug survival were 61% and 39%, respectively. Metformin was well tolerated. Gastrointestinal side effects were experienced by 11%. Subjective clinical response was seen in 68% ( n  = 36) with 19% (7/36) of these having quiescent disease with metformin monotherapy. 25% had no improvement. Insulin resistance was seen in 75%. Its presence did not predict clinical response to metformin. Conclusion: Metformin is an effective, well tolerated and inexpensive treatment that represents a viable treatment option for HS. Key message: Metformin is an effective; well tolerated and inexpensive treatment in the management of HS.