The analysis of an unparalleled resource revealed key clinical and genetic differences between patients with PPP and those with GPP.

Prominent skin involvement is a defining characteristic of autoinflammatory disorders caused by abnormal IL-1 signaling. However, the pathways and cell types that drive cutaneous autoinflammatory features remain poorly understood. We sought to address this issue by investigating the pathogenesis of pustular psoriasis, a model of autoinflammatory disorders with predominant cutaneous manifestations. We specifically characterized the impact of mutations affecting AP1S3, a disease gene previously identified by our group and validated here in a newly ascertained patient resource. We first showed that AP1S3 expression is distinctively elevated in keratinocytes. Because AP1S3 encodes a protein implicated in autophagosome formation, we next investigated the effects of gene silencing on this pathway. We found that AP1S3 knockout disrupts keratinocyte autophagy, causing abnormal accumulation of p62, an adaptor protein mediating NF-κB activation. We showed that as a consequence, AP1S3-deficient cells up-regulate IL-1 signaling and overexpress IL-36α, a cytokine that is emerging as an important mediator of skin inflammation. These abnormal immune profiles were recapitulated by pharmacological inhibition of autophagy and verified in patient keratinocytes, where they were reversed by IL-36 blockade. These findings show that keratinocytes play a key role in skin autoinflammation and identify autophagy modulation of IL-36 signaling as a therapeutic target.

Background: Spondyloarthritis (SpA), a chronic inflammatory, rheumatic disease, and hidradenitis suppurativa (HS) share several clinical en pathophysiological features, such as the association with inflammatory bowel disease and elevated cytokine levels IL-17 and TNF-a. Recently, SpA was reported to be more prevalent (2.3-28.2%) in HS patients than in the general population. Conversely, the prevalence of HS in SpA is not exactly known. Objective: To determine the prevalence of HS in patients with axial SpA, a SpA subtype primarily affecting the axial skeleton. Secondly, to identify patient characteristics associated with the presence of HS in axial SpA. Methods: Cross-sectional study. A self-screening questionnaire based on validated diagnostic HS questions was sent to patients from the Groningen Leeuwarden Axial Spondyloarthritis cohort fulfilling the ASAS axial SpA criteria. Self-reported HS symptoms were confirmed by previous medical diagnosis or verification by phone using highly specific validated questions. Results: In total, 75.6% (449/592) questionnaires were eligible for analyses. HS diagnosis could be confirmed in 41 (9.1%) patients. In comparison to patients without a positive history of HS, these patients were more often female (54% vs. 35%, p¼0.02), showed higher axial SpA disease activity (mean BASDAI 4.5 vs 3.6, p¼0.01 and ASDAS CRP 2.6 vs. 2.2 p¼0.003) and worse quality of life (QoL) (median ASQoL 9.0 vs 4.0, p<0.001). Also, a history of heel enthesitis and dactylitis was more prevalent (34% vs 19%, p¼0.03 and 15% vs 6%, p¼0.05, respectively). Multivariable analysis showed that a higher score on ASDAS CRP was independently associated with HS (OR 1.639, 95% CI 1.176-2.284). Conclusion: In our cohort of axial SpA patients, HS is more prevalent than in the general population (9.1% versus 0.053-4.1%). HS is associated with female gender, lower QoL, and especially higher axial SpA disease activity.

Recessive dystrophic epidermolysis bullosa (RDEB), a rare skin blistering disorder, is caused by loss-of-function mutations in the gene encoding type VII collagen (C7), COL7A1. The main phenotype in RDEB is compromised skin architecture and fragility, resulting in constant wounding and excessive scarring. Nonfunctional C7 results in defective anchoring fibrils, which provide adhesion between the epidermis and dermis. In this study we are interested in premature termination codon (PTC) mutations in COL7A1. PTCs are associated with mRNA instability and nonsense mediated mRNA decay (NMD) as well as early termination of protein translation, thus leading to non-functional protein. We evaluate a read-through approach for overcoming PTC mutations in COL7A1 as potential therapy for RDEB. Reading-through PTCs allows for insertion of an amino acid at the mutation site and synthesis of full-length protein. Several drugs have been reported for their read-through ability but their efficacy is gene dependent. Here we evaluate an FDA approved drug-amlexanox-and demonstrate that it induces full-length C7 synthesis in patient derived RDEB keratinocytes and fibroblasts in a codon sequence specific manner. From six mutant alleles tested, four responded to amlexanox treatment. Treated RDEB cells showed 3-to 14-fold increase of C7 synthesis by western blot and 2-to 5-fold upregulation of COL7A1 mRNA levels, measured by qPCR. In our system read-through correlated with UPF1 phosphorylation state e the main factor in NMD. In conclusion, our study shows that amlexanox induces PTC read-through and synthesis of fulllength C7 in RDEB cells and upregulates COL7A1 transcript levels. Our results suggest amlexanox as potential therapy for RDEB patients harboring PTC mutations.

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