Aberrant expression of interleukin-17A in mast cells contributes to the pathogenesis of hidradenitis suppurativa.

BACKGROUND: Hidradenitis suppurativa (HS) significantly diminishes the quality of life for patients. Delayed diagnosis represents a significant challenge in effectively managing HS. OBJECTIVES: To identify and characterize the key mediator in HS. METHODS: Bioinformatic transcriptomic analysis was applied to identify potential candidates contributing to the disease process of HS. Skin samples from 40 patients with HS, four with psoriasis and 29 with normal skin were included. The expression of interleukin (IL)-17A was evaluated and compared among samples of normal skin, psoriatic skin and skin from different stages of HS by immunohistochemistry or dual-colour immunofluorescence. In vitro experiments and RNA sequencing analysis were also conducted to validate the expression of IL-17A and its pathogenic effect in HS. RESULTS: Transcriptomic database analyses identified IL-17 signalling as a potential contributor to HS. In HS, the predominant IL-17A+ cell population was identified as mast cells. IL-17A+ mast-cell density was significantly elevated in HS, especially in samples with advanced Hurley stages, compared with normal skin and psoriasis samples. The close contact between IL-17A+ mast cells and IL-17 receptor A (IL-17RA)-expressing keratinocytes was demonstrated, along with the significant effects of IL-17A on keratinocyte cell proliferation and HS pathogenic gene expression. Treatment with biologics (brodalumab or adalimumab) reduced the severity of the disease and the number of IL-17A+ mast cells in affected tissues. CONCLUSIONS: The presence of high-density IL-17A+ mast cells may serve as a valuable pathological marker for diagnosing HS. Moreover, developing therapeutic drugs targeting IL-17A+ mast cells may provide a new approach to treating HS.

Taiwanese Dermatological Association (TDA) consensus recommendations for the definition, classification, diagnosis, and management of hidradenitis suppurativa.

Hidradenitis suppurativa (HS) is a chronic inflammatory follicular disease characterized by painful, recurrent, inflamed lesions most commonly occurring in the axillary, inguinal, and anogenital regions. HS can inflict immense physical and psychological impact on patients who suffer from this distressing disease. Management of HS generally requires combining various medical and procedural treatment modalities; however, the disease is often recalcitrant to conventional treatments. In light of recent evidence supporting the effectiveness of biologic agents in the treatment of HS, the Taiwanese Dermatological Association established an expert panel of nine dermatologists to develop consensus statements aimed to provide up-to-date evidence-based guidance in optimizing HS patient management in Taiwan. The recommendations described in the statements were summarized in a management algorithm in terms of general care, topical treatment, systemic treatment, and procedural treatment.

Variation of body regional responses to Ustekinumab and Secukinumab in psoriasis patients: A real-world retrospective study and literature review.

Psoriasis in different body regions displays varying therapeutic responses to biologics, whereas currently relevant studies remain scarce. We retrospectively reviewed the treatment responses of patients with moderate-to-severe psoriasis, who completed the two-year reimbursed ustekinumab or secukinumab treatment in two medical centers in Southern Taiwan. Demographic profiles and body regional PASI scores (head/neck, trunk, upper and lower limbs) along the treatment course were recorded. The proportions of patients attaining PASI 75, 90, 100 and the extent of body regional PASI score improvements were compared in biologic naïve or experienced patients. A total of 57 and 67 patients receiving ustekinumab and secukinumab injections, respectively, were included. Overall, patients receiving secukinumab showed higher degrees of PASI score improvements along the two-year treatment course. The lower limbs had the highest, and the upper extremities and head/neck had the lowest post-treatment PASI scores regardless of prior biologic use in the groups of ustekinumab and secukinumab. The upper limbs showed the highest, while the lower limbs had the lowest complete remission rate (regional specific PASI 100) in response to ustekinumab (upper limbs 48.7%, lower limbs 25.6%) and secukinumab (upper limbs 77.1%, lower limbs 42.8%) in biologic naïve groups. Our study demonstrated that lower limbs were the most treatment-refractory area in response to ustekinumab and secukinumab injections, while the upper limbs and head/neck region had a better response.

Hidradenitis suppurativa: Disease pathophysiology and sex hormones.

Hidradenitis suppurativa is a cutaneous chronic inflammatory disease that is estimated to affect about 1% of the population and caused pain, malodorous discharge, disfigurement, and poor quality of life with psychosocial problems. The typical features are recurrent painful nodules, abscesses, and sinus tracts on the axillae, groins, gluteal areas, and anogenital regions since postpuberty. Smoking and obesity are two major triggering factors of hidradenitis suppurativa. Women are prone to have hidradenitis suppurativa than men in Western countries, but the male-to-female ratio is reversed in oriental countries. The disease severity can be affected by menstruation, pregnancy, and menopause. Furthermore, the phenotypes are different among men and women with hidradenitis suppurativa. Men are prone to have buttock involvement while women are prone to have axillary, groins, and submammary lesions. This review introduces the skin appendages and pathophysiology of hidradenitis suppurativa and then focuses on the sex difference and the effects of sex hormones on hidradenitis suppurativa and current hormone-associated treatments.

Distribution and clinical features of lymphomas involving skin in Taiwan.

A wide variety of primary and secondary lymphoma types involves the skin. However, reports with comparisons between both groups are limited in Taiwan. We retrospectively enrolled all cutaneous lymphomas and evaluated their clinicopathologic features. There were 221 cases of lymphoma: 182 (82.3%) primary and 39 (17.7%) secondary. Mycosis fungoides was the most common primary T-cell lymphoma, 92 (41.7%) cases, followed by CD30-positive T-cell lymphoproliferative disorders including lymphomatoid papulosis (n = 33, 14.9%) and cutaneous anaplastic large cell lymphoma (n = 12, 5.4%). The most frequent primary B-cell lymphomas were marginal zone lymphoma (n = 8, 3.6%) and diffuse large B-cell lymphoma (DLBCL), leg type (n = 8, 3.6%). DLBCL including variants was the most common secondary lymphoma involving skin. Most primary lymphomas presented at low-stage (T-cell, 86%; B-cell, 75%), whereas the majority of secondary lymphomas presented at high-stage (T-cell, 94%; B-cell, 100%). Patients with secondary lymphomas had an older mean age, more frequent B symptoms, lower serum albumin and hemoglobin, and a higher frequency of atypical lymphocytes in blood than those with primary lymphomas. In primary lymphomas, older age, lymphoma types, decreased lymphocyte counts and atypical lymphocytes in blood were poorer prognostic factors. In secondary lymphoma patients, lymphoma types, high serum lactate dehydrogenase and low hemoglobin levels predicted poorer survival. We found that the distribution of primary cutaneous lymphomas in Taiwan mirrors that of other Asian countries but shows some differences as compared with Western countries. Primary cutaneous lymphomas have a better prognosis than secondary lymphomas. Histologic classification of lymphomas highly correlated with disease presentation and prognosis.

Gene expression profiling for analysis acquired oxaliplatin resistant factors in human gastric carcinoma TSGH-S3 cells: the role of IL-6 signaling and Nrf2/AKR1C axis identification.

Oxaliplatin treatment is a mainstay of treatment for advanced gastrointestinal tract cancer, but the underlying mechanisms of acquired oxaliplatin resistance remain largely obscured. We previously demonstrated that increased DNA repair capacity and copper-transporting ATPase 1 (ATP7A) level contributed to oxaliplatin resistance in the human gastric carcinoma cell line TSGH-S3 (S3). In the present study, we applied gene array technology to identify additional resistance factors in S3 cells. We found that interleukin-6 (IL-6), aldo-keto reductase 1C1 (AKR1C1), and AKR1C3 are the top 3 upregulated genes in S3 cells when compared with parent TSGH cells. Despite a higher level of endogenous IL-6 in S3, IL-6 receptor (IR-6R, gp-80, and gp-130) levels were similar between TSGH and S3 cells. The addition of exogenous IL-6, IL-6 targeted siRNA, or neutralizing antibodies neither affected Stat3 activation, a downstream target of IL-6, nor changed oxaliplatin sensitivity in S3 cells. However, manipulation of AKR1C activity with siRNA or AKR1C inhibitors significantly reversed oxaliplatin resistance. AKR1Cs are classical antioxidant response element (ARE) genes that can be transcriptionally upregulated by nuclear factor erythroid 2-related factor 2 (Nrf2). Knockdown of Nrf2 not only decreased the levels of AKR1C1, AKR1C2, and AKR1C3 mRNA and protein but also reversed oxaliplatin resistance in S3 cells. Taken together, these results suggest that activation of the Nrf2/AKR1C axis may contribute to oxaliplatin resistance in S3 cells but that the IL-6 signaling pathway did not contribute to resistance. Manipulation of Nrf2/AKR1Cs activity may be useful for management of oxaliplatin-refractory gastric cancers.