Is mechanical stress an important pathogenic factor in hidradenitis suppurativa?

Hidradenitis suppurativa (HS) is a chronic of recurrent, inflammatory, follicular disease that usually presents after puberty with painful deep-seated, inflamed lesions in the inverse skin areas of the body. It has been hypothesized that mechanical pressure or friction is a risk factor for HS. We describe the case of a man with a lower leg amputation who presented HS-like lesions on his leg stump after wearing a leg prosthesis. Although pilonidal sinus-like disease could not be excluded, we diagnosed him with HS-like lesions, induced by prosthesis-related friction. We argue that this case supports the concept that mechanical friction and a warm humid microclimate by occlusion contribute to HS development

Weekly adalimumab treatment decreased disease flare in hidradenitis suppurativa over 36 weeks: integrated results from the phase 3 PIONEER trials

Background: Hidradenitis suppurativa (HS) is a chronic skin disease characterized by inflammatory lesions that flare unpredictably. The impact of weekly adalimumab (ADAew) on HS flare is not well-characterized. Objective: To evaluate the impact of disease flare on health-related quality of life (HRQOL) in moderate-to-severe HS patients and to determine the effect of ADAew on disease flare using integrated data from two phase 3 trials over 36 weeks. Methods: In period A (12 weeks), Dermatology Life Quality Index (DLQI) score change from baseline was compared in patients who flared and those who did not, regardless of treatment. The proportion of patients experiencing flare, duration of flare and time to flare was evaluated for ADAew vs. placebo (PBO). In period B (24 weeks), proportion of patients experiencing flare who received continuous ADAew treatment through 36 weeks was assessed. Results: HRQOL was markedly improved among those who did not experience flare. In period A, the proportion of patients who experienced flare was significantly lower with ADAew vs. PBO (12.3% vs. 35.3%, P < 0.001). ADAew patients also had longer time to first flare (101 days vs. 57 days; P < 0.001) and shorter flare duration (18.9 days vs. 32.0 days, respectively; P = 0.001) vs. PBO. Through 36 weeks of treatment, 20.2% of ADAew patients flared, and for those who achieved at least a partial clinical response to ADAew at 12 weeks, only 5.7% flared. Conclusions: Flare reduction is an important measure in HS that correlates with clinically meaningful improvement in HRQOL. ADAew reduces HS flare through 12 and subsequent 36 weeks of treatment

A novel nicastrin mutation in a three-generation Dutch family with hidradenitis suppurativa: a search for functional significance

Background: Mutations in the γ-secretase enzyme subunits have been described in multiple kindreds with familial hidradenitis suppurativa (HS). Objective: In this study, we report a novel nicastrin (NCSTN) mutation causing HS in a Dutch family. We sought to explore the immunobiological function of NCSTN mutations using data of the Immunological Genome Project. Methods: Blood samples of three affected and two unaffected family members were collected. Whole-genome sequencing was performed using genomic DNA isolated from peripheral blood leucocytes. Sanger sequencing was done to confirm the causative NCSTN variant and the familial segregation. The microarray data set of the Immunological Genome Project was used for thorough dissection of the expression and function of wildtype NCSTN in the immune system. Results: In a family consisting of 23 members, we found an autosomal dominant inheritance pattern of HS and detected a novel splice site mutation (c.1912_1915delCAGT) in the NCSTN gene resulting in a frameshift and subsequent premature stop. All affected individuals had HS lesions on non-flexural and atypical locations. Wildtype NCSTN appears to be upregulated in myeloid cells like monocytes and macrophages, and in mesenchymal cells such as fibroblastic reticular cells and fibroblasts. In addition, within the 25 highest co-expressed genes with NCSTN we identified CAPNS1, ARNT and PPARD. Conclusion: This study reports the identification a novel NCSTN gene splice site mutation which causes familial HS. The associated immunobiological functions of NCSTN and its co-expressed genes ARNT and PPARD link genetics to the most common environmental and metabolic HS risk factors which are smoking and obesity

High prevalence of hidradenitis suppurativa in patients with perianal fistula

Abstract Background Perianal fistula is an abnormal communication between the anal canal and perianal skin. Hidradenitis suppurativa (HS) is a chronic, auto-inflammatory skin disease in the intertriginous body areas, presenting with recurring abscesses, inflammatory nodules, and sinus tracts. The aim of this study was to determine the prevalence of HS in patients with a perianal fistula. Methods All patients with perianal fistula visiting a specialized proctology clinic between July and September 2017 were included and asked a validated diagnostic question for HS. Subsequently, physical examination was performed to objectively assess the diagnosis and relevant patient characteristics. Results In 6.6% (8/122) of patients, HS was diagnosed outside the perianal region. Four of these patients were newly diagnosed. The fistulas in HS patients were classified as a superficial fistula (three), a blind ending fistula (two), and a transsphincteric fistula (two). One patient had more than one type of fistula. Conclusion The prevalence of HS in patients with a perianal fistula is at least 6.6%. This is higher than the prevalence reported in the general European population (1%) suggesting an association between perianal fistulas and HS. We stress the importance to screen for HS in patients with perianal fistulas in order to start appropriate anti-inflammatory treatment to reduce symptoms and disease progression

The anti-inflammatory potency of biologics targeting tumour necrosis factor-alpha, interleukin (IL)-17A, IL-12/23 and CD20 in hidradenitis suppurativa: an ex vivo study

Background Biologics targeting inflammatory mediators can achieve clinical improvements in hidradenitis suppurativa (HS). However, their clinical efficacy shows great interpatient variability in daily practice. Objectives To investigate the anti-inflammatory potency of a selection of currently available biologics and prednisolone for the treatment of HS in an ex vivo skin culture system using lesional HS biopsies. Methods Lesional skin samples from 10 patients with HS and skin samples from five healthy controls were cultured ex vivo and exposed to prednisolone or biologics targeting tumour necrosis factor (TNF)-a, interleukin (IL)-17A, IL-12/23p40 or CD20 (adalimumab, infliximab, secukinumab, ustekinumab and rituximab, respectively). Real-time quantitative polymerase chain reaction and cytokine bead arrays were used to measure the inhibitory effect of the biologics on cytokines and antimicrobial peptides (AMPs). Results The relative mRNA expression o

Apremilast for moderate hidradenitis suppurativa: no significant change in lesional skin inflammatory biomarkers

Background: Treatment with apremilast has recently demonstrated clinically meaningful improvement in moderate hidradenitis suppurativa (HS). Objective: To evaluate the change in expression of inflammatory markers in lesional skin of HS patients receiving apremilast 30 mg twice daily (n = 15) for 16 weeks compared with placebo (n = 5). Methods: At baseline, 5-mm punch biopsies were obtained from an index lesion (HSL) and non-lesional (HSN) skin in the same anatomical area. Subsequent HSL samples were taken as close as possible to the previously biopsied site at week 4 and week 16. After sampling, biopsies were split; one half was processed for in vivo mRNA analysis using real-time quantitative PCR; the other half was cultured for ex vivo protein analysis using a proximity extension assay (Olink). Linear mixed effects models were calculated to compare the levels of inflammatory markers in HSL skin between apremilast and placebo over time. Results: At baseline, 17 proteins with a fold change >2 in HSL vs. HSN skin were identified in 20 patients. The top five were IL-17A (5), S100A12, CST5, IL-12/23p40, CD6 (1) with fold changes ranging from 6.6 to 1638, respectively (FDR <0.044). Linear mixed effects models for 75 assays were calculated. Protein levels of S100A12 decreased during treatment in the apremilast group compared with the placebo group (p = 0.014, FDR = 0.186). None of the 14 genes exhibited significant changes in expression over time. However, an evident downward trend in relative mRNA expression of IL-17A and IL-17F was demonstrated in patients receiving apremilast. Conclusion: We did not detect statistically significant changes in inflammatory markers in HSL skin of HS patients receiving apremilast compared with placebo, despite clinical improvement in the apremilast group. Nonetheless, S100A12 and IL-17A were significantly elevated in HSL skin and showed a decrease i