Gabapentin and oral antidepressants for chronic pruritus: a prospective cohort study evaluating efficacy and side effects in daily dermatological practice.

BACKGROUND: Chronic pruritus is frequently seen in daily dermatological practice and is associated with marked impact on quality of life. Research on the use of gabapentin and oral antidepressants in daily dermatological practice is scarce. OBJECTIVE: To evaluate the efficacy and safety of gabapentin and oral antidepressants in patients with chronic pruritus in daily clinical practice. METHODS: A prospective observational single-center cohort study was conducted including adult patients with chronic pruritus and an indication for systemic treatment between June 2016 and May 2019. RESULTS: Systemic treatment with gabapentin and/or antidepressants was initiated in 31 patients with severe chronic pruritus (median average pruritus NRS score 7.0), in which most cases no underlying origin was identified (83.9%). In patients treated with gabapentin 900-1800 mg/day (N = 25), median average pruritus NRS decreased to 5.5 (IQR 3.0) after 4 weeks and remained stable up to 24 weeks of treatment. Efficacy of antidepressants was variable, with the highest response after initiation of amitriptyline, nortriptyline, and mirtazapine. Side effects were frequently observed in both gabapentin and antidepressant treatments; however, were mostly mild and temporary. LIMITATIONS: This was a single-site observational study, with limited sample size. CONCLUSION: Treatment with gabapentin and antidepressants should be considered in patients with chronic pruritus unresponsive to conventional treatment.

Th2 and Th9 responses in patients with chronic mucocutaneous candidiasis and hyper-IgE syndrome.

BACKGROUND: STAT1 mutations cause chronic mucocutaneous candidiasis (CMC), while STAT3 mutations cause hyper-IgE syndrome (HIES). CMC and HIES patients have T helper (Th) 17 defects suffering from mucosal Candida infections, but only patients with HIES show an allergic phenotype with eczema, eosinophilia and high IgE levels. OBJECTIVE: We investigated whether differential Th2 and Th9 responses may explain the clinical differences. METHODS: Peripheral blood mononuclear cells of patients with CMC (n = 4), patients with HIES (n = 4), patients with atopic dermatitis (n = 4) and healthy volunteers (n = 13) were stimulated with Candida and Staphylococcus aureus, with and without IL-4. The cytokines IL-5, IL-13, IL-9, IL-17 and TGFß and regulatory T cells were measured in cell culture supernatants by ELISA or flow cytometry, respectively. RESULTS: Peripheral blood mononuclear cells of patients with CMC showed a significantly impaired production of the Th2 cytokines IL-5 and IL-13, especially in the presence of IL-4. Moreover, IL-9 production was significantly lower in patients with CMC compared to healthy controls. In contrast, patients with HIES and patients with AD showed normal IL-5 and IL-13 production, while IL-9 production was significantly lower in patients with HIES compared to healthy controls. Although TGFß was involved in the IL-4-induced IL-9 production, TGFß levels and the frequency of regulatory T cells did not differ between patients with HIES and controls. Flow cytometry analysis demonstrated an IL-9+ IL-17+ CD4+ subset in healthy controls after stimulation with Candida which was less present in patients with HIES. CONCLUSION: Patients with CMC have a general Th defect including Th2 and Th9, while patients with HIES have normal Th2 cytokines. These differences are in line with their clinical presentation. Surprisingly, the allergic cytokine IL-9 was deficient in both HIES and CMC, suggesting a Th-17-derived origin.

Expression profile of cornified envelope structural proteins and keratinocyte differentiation-regulating proteins during skin barrier repair.

BACKGROUND: Recent studies have emphasized the importance of heritable and acquired skin barrier abnormalities in common inflammatory diseases such as psoriasis and atopic dermatitis (AD). To date, no comprehensive studies on the effect of experimental barrier disruption on cornified envelope protein expression have been performed. OBJECTIVES: To analyse the effect of experimental skin barrier disruption on the expression of cornified envelope structural proteins and keratinocyte differentiation-regulating proteins. METHODS: We examined mRNA (day 1, 3 and 7) and protein (day 1, 2, 4 and 9) expression levels of structural proteins and regulatory molecules after sodium dodecyl sulphate (SDS) application on normal skin, and tape stripping of uninvolved epidermis of patients with psoriasis and AD and healthy controls. RESULTS: Upon tape stripping, several structural molecules were significantly downregulated (at the mRNA level as well as the protein level), including LCE5A, LCE2B, FLG, FLG2 and LOR, whereas others were upregulated: IVL, SPRR1, SPRR2, HRNR and most notably LCE3A. The epidermal crosslinking enzymes TGM1, TGM3 and TGM5 were all upregulated, whereas proteases involved in the desquamation process (CTSV, KLK5 and KLK7) were downregulated or unaffected. Most results were similar in SDS-instigated irritant contact dermatitis. There was no significant difference in response between normal epidermis and nonlesional skin of patients with psoriasis and AD. CONCLUSIONS: Skin barrier disruption induces a temporary barrier repair response composed of increased expression of several cornification-related proteins, and decreased expression of some structural and desquamation-related proteins.

Molecular diagnostics of psoriasis, atopic dermatitis, allergic contact dermatitis and irritant contact dermatitis.

BACKGROUND: Microarray studies on the epidermal transcriptome in psoriasis and atopic dermatitis (AD) have revealed genes with disease-specific expression in keratinocytes of lesional epidermis. These genes are possible candidates for disease-specific pathogenetic changes, but could also provide a tool for molecular diagnostics of inflammatory skin conditions in general. OBJECTIVES: To analyse if gene expression signatures as found in purified epidermal cells from AD are also present in other eczematous conditions such as allergic and irritant contact dermatitis. METHODS: We used real-time quantitative polymerase chain reaction, immunohistochemistry and bioinformatics to investigate gene expression in different forms of eczema. Normal epidermis and psoriatic epidermis were analysed for comparison. RESULTS: Carbonic anhydrase II was highly induced in epidermis from all forms of eczema but not in psoriasis. Remarkably, the presumed neuron-specific Nel-like protein 2 showed a strong induction only in AD epidermis. Interleukin-1F9, elafin, beta-defensin-2 and vanin-3 were strongly induced in psoriasis, but not in any type of eczema. High levels of the chemokines CCL17 and CXCL10 were predominantly found in epidermis of allergic contact dermatitis. The chemokine CXCL8 was highly expressed in psoriasis, AD and allergic contact dermatitis, but not in irritant contact dermatitis. Cluster analysis or multinomial logistic regression indicated that expression levels of a set of seven genes are a strong predictor of the type of inflammatory response. CONCLUSIONS: These observations contribute to molecular diagnostic criteria for inflammatory skin conditions.