Sneddon syndrome is a rare disorder affecting small and medium-sized blood vessels that is characterized by the association of livedo reticularis and stroke. We performed whole-exome sequencing (WES) in 2 affected siblings of a consanguineous family with childhood-onset stroke and identified a homozygous nonsense mutation within the epidermal growth factor repeat (EGFr) 19 of NOTCH3, p.(Arg735Ter). WES of 6 additional cases with adult-onset stroke revealed 2 patients carrying heterozygous loss-of-function variants in putativeNOTCH3downstream genes,ANGPTL4,andPALLD. Our findings suggest that impairedNOTCH3signaling is one underlying disease mechanism and that bi-allelic loss-of-function mutation inNOTCH3is a cause of familial Sneddon syndrome with pediatric stroke.

Psoriasis is a chronic skin disorder driven by IL-23 and the downstream T-helper cell 17 (Th17) pathway. Tildrakizumab is a humanized monoclonal antibody selectively targeting the p19 subunit of IL-23, a key cytokine for Th17 cells. Here, we provide an overview of IL-23 in the context of psoriasis pathogenesis and review the results of the Phase I, II and III clinical trials for tildrakizumab in patients with moderate-to-severe chronic plaque psoriasis in order to assess its efficacy, safety and clinical usefulness. In all clinical trials, tildrakizumab demonstrated significant clinical improvement and a favorable safety profile. In Phase III trials, 75% of tildrakizumab-treated patients reached a Psoriasis Area and Severity Index 75 at week 28 demonstrating superior efficacy as compared with etanercept treatment. The tildrakizumab-induced reduction in skin inflammation proves the important pathogenic role of IL-23 in psoriasis and further supports the utility of drugs targeting the IL-23/Th17 pathway. Targeting IL-23p19 with tildrakizumab augments the therapeutic repertoire for patients with moderate-to-severe chronic plaque psoriasis.

BACKGROUND:It has recently been suggested that patients with moderate to severe atopic dermatitis (AD) may profit from anti-interleukin (IL)-12/-23 p40 therapy. OBJECTIVE:We sought to assess the immunologic effects of ustekinumab treatment on AD skin and to correlate them with the clinical efficacy of this drug. METHODS:We investigated the course of 3 patients with severe AD who were administered 45 mg of subcutaneous ustekinumab over a period of 16 weeks. Clinical scores and skin biopsy specimens, taken at baseline and at week 8, were used to assess changes in disease severity. RESULTS:All patients showed a gradual improvement of the disease, achieving a 50% reduction in the Eczema Area and Severity Index score by week 16. Immunohistology of skin biopsy specimens revealed a significant decrease in the degree of epidermal hyperplasia/proliferation and the number of infiltrating dermal T cells, dendritic cells, and mast cells after treatment. Using quantitative real-time polymerase chain reaction of lesional skin, we found a clear reduction of T-helper 2-/22-associated molecules after therapy. LIMITATIONS:The small number of patients (n = 3) limits efficacy analysis and warrants prospective placebo-controlled studies in larger patient cohorts. CONCLUSION:Blocking IL-12/-23 p40 could be beneficial for a subgroup of patients with severely infiltrated AD.

Background Impairment of gastric digestion due to pH elevation increases the risk for food allergy induction. As patients after Roux-en-Y gastric bypass (RYGB) surgery have lower gastric acidity and less gastric gland secretion, we aimed to analyse in a prospective study the effect of limiting gastric digestion capacity by surgical intervention on the immune response towards allergens. Methods Nine patients undergoing RYGB surgery for morbid obesity and one control patient having undergone surgery for treatment of an incisional hernia were enrolled in the study. Before and 1, 3, 6, 9 and 12 months after surgery, blood was collected for analysis of specific IgE antibodies, and patients were subjected to skin prick testing with 16 food and 18 aeroallergens. Results Skin prick test results revealed an increase of positive reactions indicating sensitisations towards the tested food and aeroallergens in 77.8 and 88.9 % of the patients, respectively, after surgical elimination of gastric digestion. These results were in line with elevated titers of food- and aeroallergen-specific IgE antibodies in 7 out of 9 (7/9) and 5/9 patients, respectively, after RYGB surgery. Serum cytokine levels revealed a mixed response for IFN-γ and were mostly beneath detection limit for IL-4. Conclusion A change of IgE reactivity pattern occurred after impairment of gastric digestion due to surgical elimination underlining the important gastric gatekeeping function during oral sensitisation. Even though this study indicates an increased allergy risk for gastric bypass patients, further studies are needed to investigate in-depth the immunological changes associated with RYGB surgery.

proof-of-concept phase I clinical trial demonstrates that targeting interleukin (IL)-23 with an antibody that binds to the p19 subunit leads to clinical improvement of disease in patients with moderate to severe psoriasis.

Psoriasis is a chronic in ammatory skin disorder that affects approximately 2-3% of the population worldwide and has severe effects on patients' physical and psychological well-being1-3.The discovery psoriasis is an immune-mediated disease has led to more targeted, effective therapies; recent advances have focused on the interleukin \(IL)-12/23p40 subunit shared by IL-12 and IL-23.Evidence suggests that speci c inhibition of IL-23 would result in improvement in psoriasis.Here we evaluate tildrakizumab, a monoclonal antibody that targets the IL-23p19 subunit, in a three-part, randomized, placebo-controlled, sequential, rising multiple-dose phase I study in patients with moderate-to-severe psoriasis to provide clinical proof that speci c targeting of IL-23p19 results in symptomatic improvement of disease severity in human subjects.

Several subtypes of APCs are found in psoriasis patients, but their involvement in disease pathogenesis is poorly understood. Here, we investigated the contribution of Langerhans cells (LCs) and plasmacytoid DCs (pDCs) in psoriasis. In human psoriatic lesions and in a psoriasis mouse model (DKO* mice), LCs are severely reduced, whereas pDCs are increased. Depletion of pDCs in DKO* mice prior to psoriasis induction resulted in a milder phenotype, whereas depletion during active disease had no effect. In contrast, while depletion of Langerin-expressing APCs before disease onset had no effect, depletion from diseased mice aggravated psoriasis symptoms. Disease aggravation was due to the absence of LCs, but not other Langerin-expressing APCs. LCs derived from DKO* mice produced increased IL-10 levels, suggesting an immunosuppressive function. Moreover, IL-23 production was high in psoriatic mice and further increased in the absence of LCs. Conversely, pDC depletion resulted in reduced IL-23 production, and therapeutic inhibition of IL-23R signaling ameliorated disease symptoms. Therefore, LCs have an anti-inflammatory role during active psoriatic disease, while pDCs exert an instigatory function during disease initiation.

BACKGROUND Recently, the two single nucleotide polymorphisms, rs7927894 on chromosome 11q13.5 and rs877776 within the region of the hornerin gene, were identified as novel susceptibility variants for atopic dermatitis in the first genome wide association study in atopic dermatitis. OBJECTIVE The aim of our study was to evaluate the influence of these two genetic variants on atopic dermatitis and disease-related phenotypes in the Austrian population. METHODS 275 atopic dermatitis patients and 243 controls were genotyped for the two variants rs7927894 and rs877776 by using Taqman based allelic discrimination assays. RESULTS When comparing patients with controls we found a significant association of the rs7927894 variant on chromosome 11q13.5 with atopic dermatitis (OR: 1.71; CI 1.14-2.59; p=0.010). Subgroup analysis revealed no significant association of rs7927894 with early age of onset of the disease, concomitant asthma and allergic rhinoconjunctivitis, total serum IgE levels and family history of atopy. The analysis of the rs877776 variant showed neither a relevant difference in the allelic distribution between patients and controls nor a statistically significant association with any of the analyzed atopic dermatitis phenotypes. CONCLUSIONS In summary our data show a statistically significant association of the rs7927894 variant on chromosome 11q13.5 with atopic dermatitis but not with other disease-related phenotypes. Therefore, we assume that the rs7927894 single nucleotide polymorphism selectively influences eczema development. More investigations in distinct study populations are needed to assess the role of this interesting polymorphism in atopic dermatitis.

The major house dust mite allergens Der p 1 and Der p 2 are prevalent inducers of eczema. Der p 1 is a cysteine protease disrupting epithelial barriers, whereas Der p 2 functionally mimics the LPS-binding compound MD-2 within the TLR4 complex. In this work, we tested the percutaneous sensitizing capacity of recombinant (r) Der p 1 and Der p 2 in BALB/c mice. Mice were sensitized by percutaneous application of low (10 mu g/application) and high dose (100 mu g) rDer p 1 or rDer p 2, or with rDer p 1 followed by rDer p 2. Allergen-specific and total IgE antibodies were determined by ELISA. Eczema of BALB/c was classified by the itching score and corresponded to erosions. Infiltrating immune cells were identified by haematoxylin/eosin and Giemsa staining for eosinophils or mast cells, CD3 staining for T lymphocytes. Percutaneous treatments with rDer p 1, but not rDer p 2-induced specific IgG1. However, cotreatment with rDer p 1 led to increase in anti-Der p 2 IgG titres. Both allergens elicited skin erosions because of scratching, thickening of the epidermis, and eosinophil and T-cell infiltration. Our data indicate that recombinant mite allergens in the absence of adjuvant are sufficient for inducing eczema in BALB/c mice. As the enzymatic activity of an allergen might be an important cofactor for specific sensitization via the skin, Der p 1 may act as adjuvant for other allergens too. The presented mouse model is suitable for investigating the mechanisms of allergic eczema.

Background: Topical pimecrolimus may maintain remissions of atopic dermatitis (AD) by inhibiting subclinical inflammation. Objective: To evaluate clinical and cytological effects of pimecrolimus in topical corticosteroid-treated and resolved AD lesions. Methods: Patients (n = 67) with resolved AD lesions were randomized to 3-week double-blind treatment with either pimecrolimus cream 1% or vehicle cream. Outcome measures were reduction in Eczema Area and Severity Index (EASI) and number of leukocytes in skin biopsies in all randomized patients who were evaluable at the end of study. Results: The proportion of patients with a localized EASI <2 at the end of study was higher with pimecrolimus cream 1% than with vehicle cream (73.5 vs. 39.4%, respectively). There was a significant decrease in the number of infiltrating CD45+ cells in pimecrolimus cream 1% compared with placebo cream (–88.2 vs. 43.2 cells/mm2, respectively, p = 0.047) and a slight but nonsignificant reduction in the number of dermal dendritic cells, Langerhans cells, T cells and macrophages with pimecrolimus versus vehicle cream. Limitations: This was an exploratory study. Conclusion: Topical pimecrolimus was effective at maintaining betamethasone-17α-valerate-induced AD remission by inhibiting recurrences of the inflammatory infiltrate in the skin.