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The occurrence of pruritus in psoriasis was previously underestimated but is a significant burden. Secukinumab (SEC), a monoclonal anti-interleukin-17A antibody, efficiently controls signs of psoriasis, but the effect on pruritus and cutaneous neuroanatomy remained unknown. The primary objective of this study (NCT02362789) was to evaluate the superiority of SEC treatment vs placebo on pruritus intensity (visual analogue scale; VAS). Furthermore, the treatment-dependent course of pruritus in association with absolute Psoriasis Area Severity Index (PASI) score, as well as cutaneous histopathology and neuroanatomy, was assessed. Open-label SEC 300 mg s.c. was administered regularly until week 16. Patients who reached a ≥ 98% PASI reduction (PASI ≥ 98) were randomized to receive either placebo or SEC up to week 32. Punch biopsies were collected from lesional psoriatic (baseline, weeks 16 and 32) and non-lesional (baseline) skin for histopathological and neuroanatomical analyses. VAS scores improved significantly after open-label SEC treatment but relapsed upon placebo (29.92 ± 33.8) compared with SEC (12.30 ± 22.6; p = 0.036). After SEC-dependent improvement in PASI, histopathology, marker expression and neuroanatomy, relapse was observed with treatment discontinuation in all parameters except neuroanatomy. SEC was superior to placebo by efficiently controlling reduced pruritus intensity, clinically normalizing skin lesions, and reversing histopathological abnormalities. The neuroanatomy recovered upon SEC and remained stable even after withdrawal.

Psoriasis is one of the most common immune-mediated inflammatory skin diseases. Expression and secretion of two pro-inflammatory molecules of the S100-alarmin family, S100A8 and S100A9, in keratinocytes is a hallmark of psoriasis, which is also characterized by an altered differentiation of keratinocytes. Dimers of S100A8/S100A9 (calprotectin) bind to Toll-like receptor 4 and induce an inflammatory response in target cells. Targeted deletion of S100A9 reduced the inflammatory phenotype of psoriasis-like inflammation in mice. A role of S100-alarmins in differentiation and activation of keratinocytes was suggested but has been never shown in primary keratinocytes. We now confirm that induction of S100-alarmins in an imiquimod-induced murine model of psoriasis-like skin inflammation was associated with an increased expression of interleukin (IL)-1α, IL-6, IL-17A, or TNFα. This association was confirmed in transcriptome data obtained from controls, lesional and non-lesional skin of psoriasis patients, and a down-regulation of S100-alarmin expression after IL-17 directed therapy. However, analyzing primary S100A9 -/- keratinocytes we found that expression of S100A8/S100A9 has no significant role for the maturation and inflammatory response pattern of keratinocytes. Moreover, keratinocytes are no target cells for the pro-inflammatory effects of S100A8/S100A9. However, different cytokines, especially IL-17A and F, highly abundant in psoriasis, strongly induced expression of S100-alarmins preferentially during early maturation stages of keratinocytes. Our data indicate that expression of S100A8 and S100A9 does not primarily influence maturation or activation of keratinocytes but rather represents the inflammatory response of these cells during psoriasis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Christmann, Zenker, Martens, Hübner, Loser, Vogl and Roth.)

Chronic pruritus is a bothersome symptom in psoriasis vulgaris and can profoundly reduce quality of life (QoL). In this exploratory analysis of the PSORITUS study, the impact of pruritus on QoL in 130 subjects with moderate-to-severe psoriasis was assessed using the ItchyQoL questionnaire. The majority of patients (n = 127) had to scratch their itchy skin regularly, which led to painful skin and frustration (mean ± standard deviation; SD ItchyQoL scores; 4.50 ± 0.56; 3.80 ± 1.09 and 4.20 ± 0.87, respectively). Changes in either temperature or season led to a worsening of itching in most of the patients (n = 126; mean ± SD ItchyQoL score; 3.80 ± 1.02). Many patients felt ashamed (n = 125) or embarrassed (n = 127) due to their itchy skin (mean ± SD ItchyQoL scores; 3.90 ± 1.26 and 3.40 ± 1.19, respectively). The results demonstrated the ItchyQoL questionnaire as a validated tool responsive to treatment for detailed insights into chronic pruritus in patients with psoriasis.

Psoriasis is a chronic inflammatory disease appearing as scaly erythematous cutaneous lesions, which are characterized by parakeratosis and acanthosis as well as the infiltration of immune cells, such as T helper-1 and T helper-17 cells. Here, we demonstrated that KdPT, a tripeptide structurally related to the C-terminal amino acids of alpha-melanocyte-stimulating hormone, which was previously shown to exhibit anti-inflammatory effects in intestinal inflammation, ameliorated ongoing disease in the mouse model of imiquimod-induced psoriasis-like skin inflammation and in the small xenotransplant mouse model of psoriasis. We could show that systemic KdPT treatment significantly reduced hyperkeratosis and acanthosis in murine as well as human skin. Moreover, KdPT upregulated Foxp3 in CD4 + T cells from mice and from peripheral blood of individuals with psoriasis and decreased the expression of type 1 inflammatory cytokines, indicating that the beneficial effect of KdPT was, at least in part, mediated by the induction of functional regulatory T cells that suppressed the activation of pathogenic CD4 + IFN-γ + and CD4 + IL-17 + T cells. Thus, these data might suggest KdPT as a potential novel therapeutic alternative for the treatment of psoriasis., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

We recently described an inducible human TNF transgenic mouse line (ihTNFtg) that develops psoriasis-like arthritis after doxycycline stimulation and analysed the pathogenesis of arthritis in detail. Here, we show that the skin phenotype of these mice is characterized by hyperproliferation and aberrant activation of keratinocytes, induction of pro-inflammatory cytokines, and infiltration with Th1 and Treg lymphocytes, particularly with macrophage infiltration into lesional skin, thus pointing to a psoriasis-like phenotype. To reveal the contribution of T cells and macrophages to the development of TNF-mediated psoriasis, ihTNFtg mice were crossbred into RAG1 KO mice lacking mature T and B cells. Surprisingly, the psoriatic phenotype in the double mutants was not reduced; rather, it was enhanced. The skin showed significantly increased inflammation and in particular, increased infiltration by macrophages. Consequently, depletion of macrophages in RAG1 KO or wild-type mice led to decreased disease severity. On the contrary, depletion of Treg cells in wild-type mice increased both psoriasis and the number of infiltrating macrophages, while adoptive transfer of Foxp3-positive cells into RAG1 KO or wild-type mice decreased both the development of psoriasis and macrophage infiltration. Thus, we conclude that Treg lymphocytes inhibit the pro-inflammatory activity of macrophages, which are the major immune effector cells in hTNF-mediated psoriasis. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

It is not clear whether TNF-α antagonists used in the treatment of psoriasis need to act systemically, or whether local inhibition of skin-produced TNF-α would be sufficient to silence skin inflammation. To answer this question, we conducted two multicentre, double-blinded, randomized, placebo-controlled clinical trials with the novel single-chain anti-TNF-α-PENTRA(®) -antibody DLX105. Upon intra-dermal injection, DLX105 induced a mean local PASI decrease of 33% over baseline after 2 weeks of treatment, while the placebo response was only 12% (P = 0.001). The clinical response was accompanied by changes in biomarkers such as reductions in K16, Ki67 and epidermal thickness as well as decreased mRNA levels of IL-17, TNF-α, IL-23p19, IL-12p40 and IFN-γ. Next, we applied the drug topically twice daily in a 0.5% hydrogel formulation. While the local PASI did not change, topical DLX105 mediated significant reductions of mRNA levels of key proinflammatory cytokines when compared to placebo, and this effect was further enhanced after weekly tape stripping of plaques to increase drug penetration. These results suggest that longer treatment periods and/or increased local drug concentrations might result in better therapeutic efficacy of topically applied DLX105. In sum, we can show for the first time that local inhibition of TNF-α is sufficient to mediate a biological response in psoriasis that translates into clinical efficacy., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The neuropeptide α-melanocyte-stimulating hormone (α-MSH) is a well-known mediator of skin pigmentation. More recently, it has been shown that α-MSH also exerts a strong anti-inflammatory and immunosuppressive activity. To elucidate the mechanisms underlying α-MSH-induced immunosuppression, we investigated whether α-MSH affects dendritic cell/T cell communication, as especially this interaction has an important role in the regulation of immune responses. Here, we show that α-MSH, by binding to MC-1R, induced tolerogenic dendritic cells, which were capable of expanding CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) in vitro, as well as in vivo. Notably, those α-MSH-induced Tregs were functional as they efficiently inhibited cutaneous contact allergy and ongoing psoriasis-like skin inflammation in mice. Furthermore, α-MSH induced tolerogenic dendritic cells capable of generating functional Tregs in human blood. Interestingly, human Tregs expanded via α-MSH-stimulated dendritic cells suppressed the proliferation and cytokine secretion of pathogenic T-helper-17 (Th17) cells from individuals with psoriasis. Taken together, these data indicate that α-MSH induced immunosuppressive Tregs in vitro and in vivo, which inhibited disease progression in a mouse model of psoriasis-like skin inflammation and suppressed the activation and proliferation of effector T cells from subjects with psoriasis.

In a CD18 hypomorphic polygenic PL/J mouse model, the severe reduction of CD18 (beta(2) integrin) to 2-16% of wild-type levels leads to the development of a psoriasiform skin disease. In this study, we analyzed the influence of reduced CD18 gene expression on T cell function, and its contribution to the pathogenesis of this disease. Both CD4(+) and CD8(+) T cells were significantly increased in the skin of affected CD18 hypomorphic mice. But only depletion of CD4(+) T cells, and not the removal of CD8(+) T cells, resulted in a complete clearance of the psoriasiform dermatitis. This indicates a central role of CD4(+) T cells in the pathogenesis of this disorder, further supported by the detection of several Th1-like cytokines released predominantly by CD4(+) T cells. In contrast to the CD18 hypomorphic mice, CD18 null mutants of the same strain did not develop the psoriasiform dermatitis. This is in part due to a lack of T cell emigration from dermal blood vessels, as experimental allergic contact dermatitis could be induced in CD18 hypomorphic and wild-type mice, but not in CD18 null mutants. Hence, 2-16% of CD18 gene expression is obviously sufficient for T cell emigration driving the inflammatory phenotype in CD18 hypomorphic mice. Our data suggest that the pathogenic involvement of CD4(+) T cells depends on a gene dose effect with a reduced expression of the CD18 protein in PL/J mice. This murine inflammatory skin model may also have relevance for human polygenic inflammatory diseases.

Novel Insights Into the Pathogenesis of Skin Autoimmune Diseases A complex interaction of genetics and environmental factors is one of the key underlying pathogenic mechanisms in skin autoimmune diseases. Keywords: skin; autoimmunity; pemphigus; pemphigoid; psoriasis; alopecia aerata (AA) EN skin autoimmunity pemphigus pemphigoid psoriasis alopecia aerata (AA) N.PAG N.PAG 6 04/09/21 20210325 NES 210325 The Spectrum of Skin Autoimmune Diseases According to the revised Witebsky's criteria by Rose and Bona, a disease is considered of autoimmune origin if (i) it can be transferred by pathogenic T cells or autoantibodies, (ii) it can be induced in experimental animals, or if (iii) autoimmunity is suggested by circumstantial evidence from clinical clues ([1]). Comorbidity in Skin Autoimmune Diseases With the availability of (relatively) effective treatments for chronic skin inflammation ([15]-[17]), comorbid diseases, mostly metabolic and cardiovascular, now significantly contributes to the morbidity of patients with skin autoimmune diseases. To guide the reading, we have classified the articles into the following subheadings: "Emerging" autoimmune diseases Novel insights into the pathogenesis of skin autoimmune diseases New diagnostic approaches in skin autoimmune diseases Comorbidity in skin autoimmune diseases Epidemiology of skin autoimmune diseases Novel treatment targets and therapeutic approaches for skin autoimmune diseases Characterization of patient biomaterials and model systems of skin autoimmune diseases "Emerging" Autoimmune Diseases In contrast to these more "classical" autoimmune diseases, fulfilling the revised Witebsky's criteria, there is an increasing evidence for a role of autoreactive T- and/or B-cells in chronic inflammatory skin diseases that have not been considered autoimmune so far ([7]). [Extracted from the article]

Chronic pruritus is a bothersome symptom in psoriasis vulgaris and can profoundly reduce quality of life (QoL). In this exploratory analysis of the PSORITUS study, the impact of pruritus on QoL in 130 subjects with moderate-to-severe psoriasis was assessed using the ItchyQoL questionnaire. The majority of patients (n = 127) had to scratch their itchy skin regularly, which led to painful skin and frustration (mean ± standard deviation; SD ItchyQoL scores; 4.50 ± 0.56; 3.80 ± 1.09 and 4.20 ± 0.87, respectively). Changes in either temperature or season led to worsening of itching in most of the patients (n = 126; mean ± SD ItchyQoL score; 3.80 ± 1.02). Many patients felt ashamed (n = 125) or embarrassed (n = 127) due to their itchy skin (mean ± SD ItchyQoL scores; 3.90 ± 1.26 and 3.40 ± 1.19, respectively). The results demonstrated the ItchyQoL questionnaire as a validated tool responsive to treatment for detailed insights into chronic pruritus in patients with psoriasis. [ABSTRACT FROM AUTHOR]

Psoriasis is a chronic inflammatory disease appearing as scaly erythematous cutaneous lesions, which are characterized by parakeratosis and acanthosis as well as the infiltration of immune cells, such as T helper-1 and T helper-17 cells. Here, we demonstrated that Kd PT, a tripeptide structurally related to the C-terminal amino acids of alpha-melanocyte-stimulating hormone, which was previously shown to exhibit anti-inflammatory effects in intestinal inflammation, ameliorated ongoing disease in the mouse model of imiquimod-induced psoriasis-like skin inflammation and in the small xenotransplant mouse model of psoriasis. We could show that systemic Kd PT treatment significantly reduced hyperkeratosis and acanthosis in murine as well as human skin. Moreover, Kd PT upregulated Foxp3 in CD4+ T cells from mice and from peripheral blood of individuals with psoriasis and decreased the expression of type 1 inflammatory cytokines, indicating that the beneficial effect of Kd PT was, at least in part, mediated by the induction of functional regulatory T cells that suppressed the activation of pathogenic CD4+ IFN-γ+ and CD4+ IL-17+ T cells. Thus, these data might suggest Kd PT as a potential novel therapeutic alternative for the treatment of psoriasis. [ABSTRACT FROM AUTHOR]