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.

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.

High inflammation in hidradenitis suppurativa extends to perilesional skin and can be subdivided by lipocalin-2 expression.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease presenting with diverse manifestations ranging from nodules and abscesses to draining tunnels. Whether the underlying inflammation from lesions extends to relatively healthy-appearing adjacent perilesional and distant nonlesional skin has not been systematically evaluated. OBJECTIVE: We sought to characterize lesional, perilesional, and nonlesional skin in patients with HS. METHODS: Skin biopsy samples were collected under ultrasound guidance from patients with active, untreated moderate-to-severe HS. Site-matched control biopsy samples from healthy volunteers were used for comparison. RESULTS: RNA sequencing demonstrated that HS skin clustered separately from healthy control skin, with perilesional and lesion skin clustering together and away from nonlesional skin. Immunohistochemistry analysis identified psoriasiform hyperplasia with keratin 16 positivity in both perilesional and lesional skin, with comparable levels of CD3+, CD11c+, and neutrophil elastase-positive cellular infiltration. There was a marked upregulation of IL-17 signaling in perilesional and lesional skin. HS samples clustered on the basis of expression of lipocalin-2 (LCN2), with samples characterized by high LCN2 expression in the skin exhibiting a differing transcriptomic profile with significantly higher overall inflammation than that of skin characterized by low LCN2 levels. CONCLUSIONS: Perilesional HS skin has a transcriptomic and molecular profile comparable to that of lesional skin. HS can be grouped into 2 distinct subtypes based on molecular levels of LCN2 in the skin, with the LCN2-high subtype exhibiting an overall higher inflammatory burden and an upregulation of targetable cytokines. To our knowledge, this is the first study to characterize a unique HS subtype (and a potential endotype) that may guide future therapeutic targets.

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.

Hidradenitis suppurativa and rheumatoid arthritis: evaluating the bidirectional association.

Despite some common pathogenic themes, the association of hidradenitis suppurativa (HS) and rheumatoid arthritis (RA) has been poorly investigated. We aimed to evaluate the bidirectional association between HS and RA. A population-based study was conducted to compare HS patients (n = 6779) with age-, sex- and ethnicity-matched control subjects (n = 33,260) with regard to the incidence of new-onset and the prevalence of preexisting RA. Adjusted hazard ratios (HRs) and adjusted odds ratios (ORs) were estimated. The prevalence of preexisting RA was greater among patients with HS relative to controls (0.5% vs 0.3%. respectively; p = 0.019). The odds of being diagnosed with HS were 1.6-fold higher in patients with a history of RA (fully-adjusted OR, 1.66; 95% CI, 1.11-2.49; p = 0.014). The incidence rate of new-onset RA was estimated at 4.3 (95% CI, 2.5-6.8) and 2.4 (95% CI, 1.8-3.2) cases per 10,000 person-years among patients with HS and controls, respectively. The risk of RA was comparable between patients with HS and controls (fully-adjusted HR, 1.45; 95% CI, 0.77-2.72; p = 0.249). Compared to other patients with HS, those with HS and comorbid RA were older, had a higher prevalence of diabetes mellitus, hypertension, and hyperlipidemia, and had a comparable risk of all-cause mortality. In conclusions, a preexisting diagnosis of RA predisposes individuals to develop HS. Clinicians managing patients with HS and RA should be aware of this association. Further research is required to delineate the underlying pathomechanism of this observation.

Hidradenitis suppurativa: A folliculotropic disease of innate immune barrier dysfunction?

The innate immune system of human skin consists of a multi-layered barrier consisting of cells and soluble effector molecules charged with maintaining homeostasis and responding to insults and infections. It has become increasingly clear that these barrier layers become compromised in skin diseases, especially in disorders of an (auto)inflammatory nature. In the case of hidradenitis suppurativa, great strides have been made in recent years in characterizing the underlying breakdown in homeostatic innate immunity, including an increasing understanding of the central role of the hair follicle in this process. This breakdown appears to occur at multiple levels: the pilosebaceous unit, associated epithelium, the cutaneous microbiome, alteration of immune cell function and local molecular events such as complement activation. This review seeks to summarize, contextualize and analyse critically our current understanding of how these innate immune barriers become dysregulated in the early stage(s) of hidradenitis suppurativa, and to speculate on where potential hidradenitis suppurativa research could be most fruitful.

Anti-COVID-19 measurements for hidradenitis suppurativa patients.

The reported incidence of COVID-19 among cohorts of patients with inflammatory bowel and skin diseases under treatment with biologicals is low. Treatment may further modify disease severity as some biological modifiers, such as anakinra, are also proposed for the management of COVID-19 patients potentially providing HS patients with an advantage. The above preliminary evidence suggests that hidradenitis suppurativa (HS) does probably not provide an increased susceptibility for COVID-19 and that any susceptibility is unlikely to be modified negatively by treatment with biologicals. On the occasion of its 10th International Conference, experts of the European Hidradenitis Suppurativa Foundation e.V. have prepared a consensus statement regarding anti-COVID-19 measurements for HS patients. Based on the available knowledge, patients with HS may be vaccinated against SARS-CoV2 and patients affected by metabolic syndrome constitute a high-risk group for COVID-19 and should be vaccinated at the earliest convenient point in time. HS patients on treatment with adalimumab can be vaccinated with non-living virus anti-SARS-CoV2 vaccines. A possible suboptimal effect of the vaccine may be suspected but might not be expected universally. The management of the biological treatment in HS patients is at the discretion of the dermatologist / responsible physician.

Yin and Yang: A disrupted skin microbiome and an aberrant host immune response in hidradenitis suppurativa.

The skin microbiome plays an important role in maintaining skin homeostasis by controlling inflammation, providing immune education and maintaining host defense. However, in many inflammatory skin disorders the skin microbiome is disrupted. This dysbiotic community may contribute to disease initiation or exacerbation through the induction of aberrant immune responses in the absence of infection. Hidradenitis suppurativa (HS) is a complex, multifaceted disease involving the skin, innate and adaptive immunity, microbiota and environmental stimuli. Herein, we discuss the current state of HS skin microbiome research and how microbiome components may activate pattern recognition receptor (PRR) pathways, metabolite sensing pathways and antigenic receptors to drive antimicrobial peptide, cytokine, miRNA and adaptive immune cell responses in HS. We highlight the major open questions that remain to be addressed and how antibiotic therapies for HS likely influence both microbial burden and inflammation. Ultimately, we hypothesize that the two-way communication between the skin microbiome and host immune response in HS skin generates a chronic positive feed-forward loop that perpetuates chronic inflammation, tissue destruction and disease exacerbation.

Impact of the COVID-19 pandemic on the course and management of chronic inflammatory immune-mediated skin diseases: What's the evidence?

Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, medical professionals have been overwhelmed by questions beyond the infection itself. In dermatology practice, clinicians have been facing difficulties about the management of chronic immune-mediated skin diseases. Issues arose, such as the grade of immunosuppression or immunomodulation, discontinuation or modification of treatment, and initiation of new treatments. In this comprehensive review, we present the current evidence about the course and management of chronic inflammatory dermatoses during the COVID-19 pandemic, focusing on psoriasis, atopic dermatitis, and hidradenitis suppurativa.

In-Depth Analysis of the Hidradenitis Suppurativa Serum Proteome Identifies Distinct Inflammatory Subtypes.

Hidradenitis suppurativa is a chronic inflammatory dermatosis with presentations ranging from painful nodules and abscesses to draining tunnels. Using an unbiased proteomics approach, we assessed cardiovascular-, cardiometabolic-, and inflammation-related biomarkers in the serum of patients with moderate-to-severe hidradenitis suppurativa. The serum of patients with hidradenitis suppurativa clustered separately from that of healthy controls and had an upregulation of neutrophil-related markers (Cathepsin D, IL-17A, CXCL1). Patients with histologically diagnosed dermal tunnels had higher serum lipocalin-2 levels compared with those without tunnels. Consistent with this, patients with tunnels had a more neutrophilic-rich serum signature, marked by Cathepsin D, IL-17A, and IL-17D alterations. There was a significant serum‒skin correlation between proteins in the serum and the corresponding mRNA expression in skin biopsies, with healthy-appearing perilesional skin demonstrating a significant correlation with neutrophil-related proteins in the serum. CSF3 mRNA levels in lesional skin significantly correlated with neutrophil-related proteins in the serum, suggesting that CFS3 in the skin may be a driver of neutrophilic inflammation. Clinical significantly correlated with the levels of lipocalin-2 and IL-17A in the serum. Using an unbiased, large-scale proteomic approach, we demonstrate that hidradenitis suppurativa is a systemic neutrophilic dermatosis, with a specific molecular signature associated with the presence of dermal tunnels.

Is There a Role for Therapeutic Drug Monitoring in Patients with Hidradenitis Suppurativa on Tumor Necrosis Factor-α Inhibitors?

Tumor necrosis factor-α inhibitors, adalimumab and infliximab, are at the forefront of biologic therapy for the management of moderate-to-severe hidradenitis suppurativa, with adalimumab as currently the only approved medication for this condition. In treating patients, primary or secondary lack of response (also termed suboptimal response) is a major burden for both patients and healthcare systems and is a challenge with biologics in part owing to the development of anti-drug antibodies following treatment. To overcome this, therapeutic drug monitoring may be conducted proactively or reactively to a patient's suboptimal response guided by measurements of trough serum drug concentrations and levels of anti-drug antibodies. While strong evidence to support the utility of therapeutic drug monitoring exists in patients with inflammatory bowel disease, current information is limited in the context of hidradenitis suppurativa. We sought to summarize the available evidence and to present the role of therapeutic drug monitoring and other dose optimization strategies in improving clinical response in patients with hidradenitis suppurativa treated with tumor necrosis factor-α inhibitors.

Hidradenitis suppurativa is associated with acne keloidalis nuchae: a population-based study.

The association between acne keloidalis nuchae (AKN) and hidradenitis suppurativa (HS) is yet to be investigated. To determine the link between AKN and HS using a large computerized health maintenance database. A cross-sectional study design was used to assess the prevalence of HS in patients with AKN and in control participants matched by age, sex, and ethnicity. A total of 2677 participants with AKN and 13,190 control participants were studied. An increased prevalence of HS was observed in the AKN group compared to the control group (1.0% vs. 0.3%, respectively; OR, 3.6; 95% CI 2.2-5.8; P < 0.001), especially among those younger than 20 years (OR, 10.2; 95% CI 3.1-34.2; P < 0.001), and females (OR, 15.7; 95% CI 3.1-78.8; P < 0.001). After adjusting for confounding factors, the multivariate analysis demonstrated a persistent association of AKN with HS (adjusted OR, 3.6; 95% CI 2.1-5.9; P < 0.001). This study demonstrated a significant association between AKN and HS in an Israeli population. The threshold for diagnosis of HS among patients with AKN must be lowered in patients presenting with concerning symptoms. Further observational studies in other patient populations will help confirm this relationship.