The present data confirm the genetic basis of the combined DDD-HS phenotype and suggest that Notch signalling may play a central role in the pathogenesis of this rare condition.

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IgA pemphigus (IGAP) is a rare, distinct variant of pemphigus, currently classified, depending upon the histological features, immunofluorescence staining pattern and autoantibody profile, into two types: subcorneal pustular dermatosis (SPD) and intraepidermal neutrophilic IgA dermatosis. In a patient with a widespread blistering disease of the skin resembling SPD-type IGAP, we demonstrate the coexistence of IgA reactivity to both epidermal (desmocollins 2 and 3) and basement membrane-associated (BP180) proteins, suggesting the coexistence of atypical IGAP and linear IgA bullous dermatosis, respectively. This case, together with 20 previous reports of atypical IGAP, underscores the limitations of current classification schemes. Therefore, we suggest reclassifying these cases under the general term 'IGAP spectrum'.

Background Hidradenitis suppurativa (HS), a chronic, recurrent, debilitating skin disease, is characterized by painful, inflammatory, subcutaneous lesions of the axilla, inguinal and anogenital regions. Overall prevalence of HS is ˜1%, and the impact of disease on patient quality of life (QoL) and healthcare resource utilization (HRU) is high.Objectives To estimate the real-world effectiveness of adalimumab (Humiraâ) treatment in patients with moderate-tosevere HS on disease severity, pain, QoL, work productivity and HRU.Methods HARMONY (Effectiveness of Adalimumab in Moderate to Severe HidrAdenitis SuppuRativa Patientsa Multi-cOuNtry studY in Real Life Setting) is a multicentre, postmarketing observational study in adult patients with moderate-to-severe HS. Disease severity and QoL parameters were evaluated using validated measures at 12-week intervals over 52 weeks of treatment. The primary endpoint was the proportion of patients achieving a Hidradenitis Suppurativa Clinical Response (HiSCR: ≥50% reduction in abscess and inflammatory nodule count, with no increase in abscess and draining fistula counts relative to baseline) at 12 weeks. Secondary endpoints were HiSCR at 24, 36 and 52 weeks and changes in QoL parameters and work productivity assessments. Analyses were conducted using asobserved data. ResultsThe proportion of patients reaching the primary HiSCR endpoint was 70.2% (n = 132/188 enrolled) and remained ≥70% until study completion. There were statistically significant (P < 0.0001) reductions in worst and average skin pain. All of the QoL measures evaluated improved significantly (P < 0.0001) by 12 weeks of adalimumab treatment, as did work productivity assessments (P < 0.05), and there was a ˜50% decrease in HRU between baseline and week 52. Adalimumab was well tolerated.Conclusions In this real-world setting, adalimumab treatment of moderate-to-severe HS resulted in decreased disease severity and improvements in QoL and productivity. Response to adalimumab was rapid (within 12 weeks) and sustained (52 weeks). No unexpected safety signals were reported.

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and 3 Tel Aviv Med Ctr,Tel Aviv, Israel Dowling-Degos disease (DDD) is a rare disorder featuring reticulate pigmentation and hair follicular involvement and resulting from mutations in KRT5, POFUT1 and POGLUT1. Hidradenitis suppurativa (HS) is a chronic inflammatory disease of the hair follicle unit which can be caused by mutations in four genes (including PSENEN) encoding the -secretase complex. Both HS and DDD typically involve the flexural areas of the body. During the past 10 years, we encountered 4 patients who presented with clinical features consistent with both DDD and HS and aimed at identifying the genetic cause of coexisting DDD and HS. We initially excluded KRT5, POGLUT1 and POFUT1 mutations in all 4 patients. We then screened PSENEN for pathogenic mutations using Sanger sequencing since this gene was recently reported to be associated with the double phenotype displayed by our patients. We identified in all 4 affected individuals an hitherto unreported heterozygous c.168T>G, p.Y56X mutation in PSENEN. Haplotype analysis confirmed a common ancestral origin for the mutation in all 4 patients. Using qPCR and RNA extracted from patient keratinocytes, we observed a significant decrease in the expression of PSENEN as well as POFUT1 which had previously been implicated in DDD. DDD as well as HS-associated genes have been shown to encode important regulators of Notch signaling. Accordingly, using a reporter assay, we demonstrated decreased Notch activity in patient's keratinocytes. The present data confirm the genetic basis of the combined DDD-HS phenotype and suggest that Notch signaling may play a central role in the pathogenesis of this rare condition. 776TNFa suppressed IL-33 expression induced by STAT1 and STAT3 dependent signal H Tsuda, M Komine and M Ohtsuki Jichi Medical University, Shimotsuke-shi, Tochigi, Japan Many cytokines including TNFa and IFNg are involved in pathogenesis of skin inflammation diseases such as atopic dermatitis and psoriasis. Interleukin-33 (IL-33) is one of the IL-1 family cytokines and activates many immune cell types including ILC2s, eosinophils and mast cells. Serum IL-33 level is elevated in these diseases, and correlated with disease severity. IL-33 is mainly expressed in nucleus of epithelial and endothelial cells including epidermal keratinocytes. We previously demonstrated that IFNg and Oncostatin M (OSM) induced IL-33 expression both at RNA and protein levels in normal human epidermal keratinocytes (NHEKs), and this expression was dependent on dose and time, as well as on STAT1 and STAT3 signal pathways. TNFa also induced IL-33 in NHEKs, however, this induction was temporally at early time point after stimulation and IL-33 expression was rather suppressed at 24hr after stimulation. Combination of TNFa and IFNg or OSM indicated IL-33 in a similar manner to TNFa alone. We investigated the effect of TNFa on STAT1/3 signal. Presence of TNFa did not affect STAT1/3 phosphorylation induced by IFNg or OSM. In addition, TNFa did not suppress expression of STAT1, STAT3, JAK1 a...

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Summary 道林‐德戈斯病是一种罕见的遗传病,在青春期就会开始出现症状,表现为皮肤色素异常(色素沉着),常见于皮肤褶皱处,称为肢端曲侧。家族性化脓性汗腺炎也是一种罕见的遗传病,表现为肢端曲侧出现再生疖。通常在青春期就会开始出现症状。有时,患者身上会同时存在这两种疾病。最近,同时患有化脓性汗腺炎和道林‐德戈斯病的患者被发现名为PSENEN的同一基因存在缺陷。PSENEN的产物是一种蛋白质,它是名为NOTCH的合成物的一部分,后者在皮肤和其他器官发育的过程中起着重要的作用。在此项研究中,我们报告了4个德系犹太人家庭,他们具有两种疾病的临床表现特征。我们发现所有的患者都具有相同的PSENEN基因缺陷,此前这种缺陷从未被发现过。我们检查了该基因周围的区域,发现所有患者的情况都一样。这意味着,所有的患者都拥有来自同一祖先的突变。在研究项目的下一步中,我们希望展示对NOTCH产生实际影响的PSENEN基因缺陷。我们将一位患者的细胞与一位健康人员的细胞进行了对比。我们发现,患者细胞中的PSENEN较少,而当我们在细胞中注入一种当NOTCH处于活跃状态时使细胞发光的特殊元素时,我们发现患者细胞的发光程度要低于健康人员的细胞。总之,在现阶段研究中,我们发现了PSENEN中的一种新型基因缺陷,可能会同时引起两种疾病:道林‐德戈斯病和化脓性汗腺炎。我们还发现,NOTCH在两种疾病中都起着重要的作用。