Metabolomic and lipidomic fingerprints in inflammatory skin diseases - Systemic illumination of atopic dermatitis, hidradenitis suppurativa and plaque psoriasis.

Auto-inflammatory skin diseases place considerable symptomatic and emotional burden on the affected and put pressure on healthcare expenditures. Although most apparent symptoms manifest on the skin, the systemic inflammation merits a deeper analysis beyond the surface. We set out to identify systemic commonalities, as well as differences in the metabolome and lipidome when comparing between diseases and healthy controls. Lipidomic and metabolomic LC-MS profiling was applied, using plasma samples collected from patients suffering from atopic dermatitis, plaque-type psoriasis or hidradenitis suppurativa or healthy controls. Plasma profiles revealed a notable shift in the non-enzymatic anti-oxidant defense in all three inflammatory disorders, placing cysteine metabolism at the center of potential dysregulation. Lipid network enrichment additionally indicated the disease-specific provision of lipid mediators associated with key roles in inflammation signaling. These findings will help to disentangle the systemic components of autoimmune dermatological diseases, paving the way to individualized therapy and improved prognosis.

Eosinophils in hidradenitis suppurativa patients exhibit pro-inflammatory traits, implicating a potential pathogenic role in the disease.

Hidradenitis suppurativa (HS) is an inflammatory skin disease characterized by painful nodules, abscesses and purulent secretions in intertriginous regions. Intense pruritus frequently accompanies HS lesions, adding further discomfort for patients. While Th17 pathway activation is implicated in HS pathogenesis, disease mechanisms are still not fully understood, and therapeutics are lacking. Previous reports raise a potential role for eosinophils in HS, showing a strong association of eosinophil levels with disease severity. To investigate eosinophils in HS, we recruited patients and matched healthy controls and then performed flow-cytometry studies, eosinophil stimulation assays, and lesional skin staining for eosinophils. We found that HS patients reported similar levels of pain and itch. Compared to matched controls, HS blood exhibited decreased mature eosinophils and increased numbers of immature eosinophils, coupled with a significant increase in dermal eosinophilic infiltrates. Additionally, IL-17RA+ eosinophils were highly and significantly correlated with multiple HS-related clinical scores. In both stimulated and unstimulated conditions, HS eosinophils showed an inflammatory phenotype versus controls, including an increase in costimulatory T- and B-cell markers (e.g. CD5 and CD40) following all stimulations (TNFα/IL-17A/IL-17F). These findings highlight the significance of pruritus in HS and suggest a higher turnover of eosinophils in HS blood, potentially due to the consumption of eosinophils in skin lesions. Our data delineate the features and functions of eosinophils in HS and suggest that eosinophils participate in disease pathogenesis, advancing Th17-related inflammation. Further studies are needed to investigate eosinophils' response to current HS treatments and their potential as a therapeutic target in the disease.

Setting the Stage for Standardized Reporting of Clinical and Demographic Information in Laboratory-Based Studies of Hidradenitis Suppurativa.

Hidradenitis suppurativa (HS) is a complex inflammatory skin condition affecting 0.1-4% of the population that leads to permanent scarring in the axilla, inframammary region, groin, and buttocks. Its complex pathogenesis involves genetics, innate and adaptive immunity, microbiota, and environmental stimuli. Specific populations have a higher incidence of HS, including females and Black individuals and those with associated comorbidities. HS registries and biobanks have set standards for the documentation of clinical data in the context of clinical trials and outcomes research, but collection, documentation, and reporting of these important clinical and demographic variables are uncommon in HS laboratory research studies. Standardization in the laboratory setting is needed because it helps to elucidate the factors that contribute mechanistically to HS symptoms and pathophysiology. The purpose of this article is to begin to set the stage for standardized reporting in the laboratory setting. We discuss how clinical guidelines can inform laboratory research studies, and we highlight what additional information is necessary for the use of samples in the wet laboratory and interpretation of associated mechanistic data. Through standardized data collection and reporting, data harmonization between research studies will transform our understanding of HS and lead to novel discoveries that will positively impact patient care.

Hidradenitis Suppurativa Found Associated With Cytokine Storm.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory disease that generates multiple cytokines. Here, we present an example of the cytokines forming a cytokine storm and its effects on the patient. CASE PRESENTATION: We report the case of a 55-year-old man who had severe but stable HS. Serum samples were collected from the patient and extraordinarily elevated cytokine concentrations were identified in the patient's serum.  Conclusion: Cytokine storms may be a condition associated with HS posing additional risk to patient survival. J Drugs Dermatol. 2024;23(5):e134-e136.     doi:10.36849/JDD.7860R1e.

An evaluation of secukinumab for the treatment of moderate-to-severe hidradenitis suppurativa.

INTRODUCTION: Until recently, biological therapy for hidradenitis suppurativa was limited to anti-tumor necrosis factor (TNF) blockade with adalimumab (ADA). However, not all patients respond to treatment with ADA. This highlighted the need for more therapeutic options. Interleukin (IL)-17/T-helper 17 (Th17) axis may play an important role in the pathophysiology of HS. Recently, the IL-17A inhibitor secukinumab, which targets IL-17A specifically and prevents it from interacting with the IL-17 receptor, has been FDA-approved for HS. AREAS COVERED: Secukinumab, represents a novel therapeutic strategy in HS management. An overview of structural and pharmacological characteristics is provided. Described efficacy in clinical trials and case reports and safety data from is presented. EXPERT OPINION: As response to anti-TNFas is lost over time, secukinumab has provided an alternative HS treatment option in clinical practice. Overall, secukinumab has shown good efficacy and a favorable side effect profile in HS clinical trials but may be avoided in patients with inflammatory bowel disease. Long-term and real-life data on the use of secukinumab are essential for improving decision-making in HS therapy.

Gram-negative anaerobes elicit a robust keratinocytes immune response with potential insights into HS pathogenesis.

Hidradenitis Suppurativa (HS) is a chronic autoinflammatory skin disease with activated keratinocytes, tunnel formation and a complex immune infiltrate in tissue. The HS microbiome is polymicrobial with an abundance of commensal gram-positive facultative (GPs) Staphylococcus species and gram-negative anaerobic (GNA) bacteria like Prevotella, Fusobacterium and Porphyromonas with increasing predominance of GNAs with disease severity. We sought to define the keratinocyte response to bacteria commonly isolated from HS lesions to probe pathogenic relationships between HS and the microbiome. Type strains of Prevotella nigrescens, Prevotella melaninogenica, Prevotella intermedia, Prevotella asaccharolytica, Fusobacterium nucleatum, as well as Staphylococcus aureus and the normal skin commensal Staphylococcus epidermidis were heat-killed and co-incubated with normal human keratinocytes. RNA was collected and analysed using RNAseq and RT-qPCR. The supernatant was collected from cell culture for protein quantification. Transcriptomic profiles between HS clinical samples and stimulated keratinocytes were compared. Co-staining of patient HS frozen sections was used to localize bacteria in lesions. A mouse intradermal injection model was used to investigate early immune recruitment. TLR4 and JAK inhibitors were used to investigate mechanistic avenues of bacterial response inhibition. GNAs, especially F. nucleatum, stimulated vastly higher CXCL8, IL17C, CCL20, IL6, TNF and IL36γ transcription in normal skin keratinocytes than the GPs S. epidermidis and S. aureus. Using RNAseq, we found that F. nucleatum (and Prevotella) strongly induced the IL-17 pathway in keratinocytes and overlapped with transcriptome profiles of HS patient clinical samples. Bacteria were juxtaposed to activated keratinocytes in vivo, and F. nucleatum strongly recruited murine neutrophil and macrophage migration. Both the TLR4 and pan-JAK inhibitors reduced cytokine production. Detailed transcriptomic profiling of healthy skin keratinocytes exposed to GNAs prevalent in HS revealed a potent, extensive inflammatory response vastly stronger than GPs. GNAs stimulated HS-relevant genes, including many genes in the IL-17 response pathway, and were significantly associated with HS tissue transcriptomes. The close association of activated keratinocytes with bacteria in HS lesions and innate infiltration in murine skin cemented GNA pathogenic potential. These novel mechanistic insights could drive future targeted therapies.

No seroconversion in a retrospective study analyzing QuantiFERON TB-gold testing in pediatric psoriasis and hidradenitis suppurativa patients taking biologic therapy at an academic center in New York City.

Guidelines are inconsistent regarding annual QuantiFERON® TB Gold (QFT) tests in children taking biologics for dermatological conditions, and there is limited research on seroconversion, especially in regions with high tuberculosis (TB) prevalence. A retrospective review of pediatric patients taking biologic treatment for psoriasis or hidradenitis suppurativa (HS) who had one baseline and at least one follow-up QFT test was conducted to assess for seroconversion during treatment. Thirty-two patients were included, with no instances of seroconversion. These findings suggest that routine annual TB rescreening for pediatric patients taking biologic therapy for dermatologic conditions may not be necessary without additional TB exposure risks or symptomatology.

Autoimmune, Autoinflammatory Disease and Cutaneous Malignancy Associations with Hidradenitis Suppurativa: A Cross-Sectional Study.

BACKGROUND: Hidradenitis suppurativa (HS) is a debilitating cutaneous disease characterized by severe painful inflammatory nodules/abscesses. At present, data regarding the epidemiology and pathophysiology of this disease are limited. OBJECTIVE: To define the prevalence and comorbidity associations of HS. METHODS: This was a cross-sectional study of EPICTM Cosmos© examining over 180 million US patients. Prevalences were calculated by demographic and odds ratios (OR) and identified comorbidity correlations. RESULTS: All examined metabolism-related, psychological, and autoimmune/autoinflammatory (AI) diseases correlated with HS. The strongest associations were with pyoderma gangrenosum [OR 26.56; confidence interval (CI): 24.98-28.23], Down syndrome (OR 11.31; CI 10.93-11.70), and polycystic ovarian syndrome (OR 11.24; CI 11.09-11.38). Novel AI associations were found between HS and lupus (OR 6.60; CI 6.26-6.94) and multiple sclerosis (MS; OR 2.38; CI 2.29-2.48). Cutaneous malignancies were largely not associated in the unsegmented cohort; however, among Black patients, novel associations with melanoma (OR 2.39; CI 1.86-3.08) and basal cell carcinoma (OR 2.69; CI 2.15-3.36) were identified. LIMITATIONS: International Classification of Diseases (ICD)-based disease identification relies on coding fidelity and diagnostic accuracy. CONCLUSION: This is the first study to identify correlations between HS with melanoma and basal cell carcinoma (BCC) among Black patients as well as MS and lupus in all patients with HS.

Neutrophilic granulocyte-derived B-cell activating factor supports B cells in skin lesions in hidradenitis suppurativa.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory disease characterized by painful inflamed nodules, abscesses, and pus-draining tunnels appearing in axillary, inguinal, and perianal skin areas. HS lesions contain various types of immigrated immune cells. OBJECTIVE: This study aimed to characterize mediators that support lesional B/plasma cell persistence in HS. METHODS: Skin samples from several cohorts of HS patients and control cohorts were assessed by mRNA sequencing, quantitative PCR on reverse-transcribed RNA, flow cytometry, and immunohistofluorescence. Blood plasma and cultured skin biopsy samples, keratinocytes, dermal fibroblasts, neutrophilic granulocytes (neutrophils), monocytes, and B cells were analyzed. Complex systems biology approaches were used to evaluate bulk and single-cell RNA sequencing data. RESULTS: Proportions of B/plasma cells, neutrophils, CD8+ T cells, and M0 and M1 macrophages were elevated in HS lesions compared to skin of healthy and perilesional intertriginous areas. There was an association between B/plasma cells, neutrophils, and B-cell activating factor (BAFF, aka TNFSF13B). BAFF was abundant in HS lesions, particularly in nodules and abscesses. Among the cell types present in HS lesions, myeloid cells were the main BAFF producers. Mechanistically, granulocyte colony-stimulating factor in the presence of bacterial products was the major stimulus for neutrophils' BAFF secretion. Lesional upregulation of BAFF receptors was attributed to B cells (TNFRSF13C/BAFFR and TNFRSF13B/TACI) and plasma cells (TNFRSF17/BCMA). Characterization of the lesional BAFF pathway revealed molecules involved in migration/adhesion (eg, CXCR4, CD37, CD53, SELL), proliferation/survival (eg, BST2), activation (eg, KLF2, PRKCB), and reactive oxygen species production (eg, NCF1, CYBC1) of B/plasma cells. CONCLUSION: Neutrophil-derived BAFF supports B/plasma cell persistence and function in HS lesions.

Altered Skin and Gut Microbiome in Hidradenitis Suppurativa.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease characterized by the formation of nodules, abscesses, and fistulae at intertriginous sites. The skin-gut axis is an area of emerging research in inflammatory skin disease and is a potential contributory factor to the pathogenesis of HS. A total of 59 patients with HS provided fecal samples and nasal and skin swabs of affected sites for analysis. A total of 30 healthy controls provided fecal samples, and 20 healthy controls provided nasal and skin swabs. We performed bacterial 16S ribosomal RNA gene amplicon sequencing on total DNA derived from the samples. Microbiome alpha diversity was significantly lower in the fecal, skin, and nasal samples of individuals with HS, which may be secondary to disease biology or related to antibiotic usage. Ruminococcus gnavus was more abundant in the fecal microbiome of individuals with HS, which is also reported in Crohn's disease, suggesting comorbidity due to shared gut microbiota alterations. Finegoldia magna was overabundant in HS skin samples relative to that in the healthy controls. It is possible that local inflammation is driven by F. magna by promoting the formation of neutrophil extracellular traps. These alterations in both the gut and skin microbiome in HS warrant further exploration, and therapeutic strategies, including fecal microbiota transplant or bacteriotherapy, could be of benefit.

Pilot study of fractional microneedling radiofrequency for hidradenitis suppurativa assessed by clinical response and histology.

BACKGROUND: Hidradenitis suppurativa (HS) is a devastating chronic inflammatory skin disease with frequent recurrences. Various systemic treatments and procedures have been used but the efficacy of fractional microneedling radiofrequency (FMR) has not been reported. AIM: To evaluate the clinical and histological efficacy of FMR in the treatment of HS lesions. METHODS: An 8-week, prospective, split-body, unblinded study was conducted, which enrolled 10 adult patients with mild to moderate HS to receive 3 sessions of FMR treatment biweekly. HS severity was assessed using the number and type of lesions, HS Physician Global Assessment (HS-PGA) and the modified Sartorius score (mSS). Skin biopsies were performed on participants to assess change in inflammation before and after FMR. RESULTS: Severity of HS was significantly reduced on the FMR-treated side of the body, but not on the control side. Inflammatory HS lesions were significantly reduced after 4 weeks, while HS-PGA and mSS were significantly decreased after 6 weeks. Immunohistochemistry staining showed decreased expression of inflammatory markers including neutrophil elastases, interleukin (IL)-8 and IL-17, tumour necrosis factor-α, transforming growth factor-ß1 and matrix metalloproteinases. CONCLUSION: FMR may be a viable treatment option for mild to moderate HS.