Genome-wide mapping of gene–microbiota interactions in susceptibility to autoimmune skin blistering

Susceptibility to chronic inflammatory diseases is determined by immunogenetic and environmental risk factors. Resident microbial communities often differ between healthy and diseased states, but whether these differences are of primary aetiological importance or secondary to the altered inflammatory environment remains largely unknown. Here we provide evidence for host gene–microbiota interactions contributing to disease risk in a mouse model of epidermolysis bullosa acquisita, an autoantibody-induced inflammatory skin disease. Using an advanced intercross, we identify genetic loci contributing to skin microbiota variability, susceptibility to skin blistering and their overlap. Furthermore, by treating bacterial species abundances as covariates with disease we reveal a novel disease locus. The majority of the identified covariate taxa are characterized by reduced abundance being associated with increased disease risk, providing evidence of a primary role in protection from disease. Further characterization of these putative probiotic species or species assemblages offers promising potential for preventative and therapeutic treatment development

Thermal Ablation for Treating Tumor-induced Osteomalacia in a Patient With IV Phosphate Dependency

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome associated with tumors secreting fibroblast growth factor 23 that can be cured with complete surgical resection of the tumor. However, when these tumors are at difficult locations, less invasive modalities such as thermal ablation (TA) might be a good alternative. A 40-year-old woman was seen for a second opinion because of severe hypophosphatemia with complaints of fatigue, myalgia, and muscle weakness for which she needed IV phosphate for 15 to 18 hours per day in addition to oral alfacalcidol and phosphate. Initial laboratory results revealed hypophosphatemia (0.59 mmol/L [1.83 mg/dL]; reference range, 0.90-1.50 mmol/L [8.40-10.2 mg/dL]), increased fibroblast growth factor 23 levels (137 RU/mL; reference range, &lt;125 RU/mL), and a reduced TmP-GFR (0.47 mmol/L; reference range, 0.8-1.4 mmol/L). Gallium-positron emission tomography/computed tomography (CT) showed moderately increased uptake at thoracic vertebra (Th) 8 and mildly increased uptake at Th7, suggestive of TIO. Complete tumor removal would have required resection of at least 1 vertebral body. Therefore, CT-guided TA was performed at Th8. No complications were observed, and in the months after, treatment with IV phosphate could be discontinued, indicating a satisfying result from the procedure. This extreme TIO case demonstrates that CT-guided TA can be an alternative to extensive or risky classical surgery.</p

Oral administration of the selective GPR120/FFA4 agonist compound A is not effective in alleviating tissue inflammation in mouse models of prototypical autoimmune diseases

ω3-polyunsaturated free fatty acids (ω3-PUFAs), particularly docosahexaenoic (DHA) and eicosapentaenoic acid (EPA), are thought to exert health promoting effects in metabolic and in inflammatory diseases. The molecular mechanisms of these beneficial effects are only partially understood. DHA and EPA activate Free Fatty Acid receptor 4 (GPR120/FFA4). Recently, the first orally available, synthetic ligand of FFA4, 3-[2-chloro-5-(trifluoromethoxy)phenyl]-3-azaspiro[5.5]undecane-9-acetic acid ("compound A"; cpd A) has been developed. Cpd A exhibits distinctly higher potency, efficiency, and selectivity at FFA4 than ω3-PUFAs and ameliorates insulin resistance and adipose tissue inflammation in the mouse. With GPR120/FFA4 activation believed to also attenuate tissue inflammation in autoimmune diseases, cpd A may also have a beneficial effect in these diseases. We have therefore addressed the therapeutic potential of cpd A in mouse models of three prototypical autoimmune diseases, specifically psoriasis, rheumatoid arthritis, and bullous pemphigoid. The effect of cpd A on the course of Aldara™-induced psoriasis-like dermatitis, K/BxN serum transfer arthritis, and antibody transfer pemphigoid disease-like dermatitis was scrutinized. Cpd A did not alter the course of Aldara-induced psoriasis-like dermatitis, K/BxN serum transfer arthritis, or antibody transfer pemphigoid disease-like dermatitis. Our results suggest that therapeutic regimens solely relying on FFA4 activation do not bear the potential to treat inflammatory diseases. With cpd A distinctly more potent in activating GPR120/FFA4 than ω3-PUFAs, this also suggests that GPR120/FFA4 activation by ω3-PUFAs does not significantly contribute to the health-promoting effects of ω3-PUFAs in autoimmune diseases

Skin autofluorescence, reflecting accumulation of advanced glycation end products, and the risk of dementia in a population-based cohort

Conditions such as hyperglycemia and oxidative stress lead to the formation of advanced glycation end products (AGEs), which are harmful compounds that have been implicated in dementia. Within the Rotterdam Study, we measured skin AGEs as skin autofluorescence, reflecting long-term accumulation of AGEs, and determined their association with the risk of dementia and with brain magnetic resonance imaging (MRI) measures. Skin autofluorescence was measured between 2013 and 2016 in 2922 participants without dementia. Of these, 1504 also underwent brain MRI, on which measures of brain atrophy and cerebral small vessel disease were assessed. All participants were followed for the incidence of dementia until 2020. Of 2922 participants (mean age 72.6 years, 57% women), 123 developed dementia. Higher skin autofluorescence (per standard deviation) was associated with an increased risk of dementia (hazard ratio 1.21 [95% confidence interval 1.01–1.46]) and Alzheimer’s disease (1.19 [0.97–1.47]), independently of age and other studied potential confounders. Stronger effects were seen in apolipoprotein E (APOE) ε4 carriers (1.34 [0.98–1.82]) and in participants with diabetes (1.35 [0.94–1.94]). Participants with higher skin autofluorescence levels also had smaller total brain volumes and smaller hippocampus volumes on MRI, and they had more often lacunes. These results suggest that AGEs may be involved in dementia pathophysiology.</p

Skin autofluorescence, reflecting accumulation of advanced glycation end products, and the risk of dementia in a population-based cohort

Conditions such as hyperglycemia and oxidative stress lead to the formation of advanced glycation end products (AGEs), which are harmful compounds that have been implicated in dementia. Within the Rotterdam Study, we measured skin AGEs as skin autofluorescence, reflecting long-term accumulation of AGEs, and determined their association with the risk of dementia and with brain magnetic resonance imaging (MRI) measures. Skin autofluorescence was measured between 2013 and 2016 in 2922 participants without dementia. Of these, 1504 also underwent brain MRI, on which measures of brain atrophy and cerebral small vessel disease were assessed. All participants were followed for the incidence of dementia until 2020. Of 2922 participants (mean age 72.6 years, 57% women), 123 developed dementia. Higher skin autofluorescence (per standard deviation) was associated with an increased risk of dementia (hazard ratio 1.21 [95% confidence interval 1.01–1.46]) and Alzheimer’s disease (1.19 [0.97–1.47]), independently of age and other studied potential confounders. Stronger effects were seen in apolipoprotein E (APOE) ε4 carriers (1.34 [0.98–1.82]) and in participants with diabetes (1.35 [0.94–1.94]). Participants with higher skin autofluorescence levels also had smaller total brain volumes and smaller hippocampus volumes on MRI, and they had more often lacunes. These results suggest that AGEs may be involved in dementia pathophysiology.</p

Inhibition of phosphodiesterase-4 significantly decreases oral mucosa lesions in experimental anti-laminin 332 mucous membrane pemphigoid

Mucous membrane pemphigoid (MMP) is characterized by autoantibodies against the dermal-epidermal-junction and a mucosal disease predominating over skin involvement. As the treatment of MMP patients still relies on high-dose corticosteroids, there is an unmet need for new and more specific therapies. Here, we made use of a recently established experimental model that recapitulated major clinical and immunopathological characteristics of human MMP by the injection of IgG against the murine alpha3 chain of laminin 332 (Lam332) into adult mice. In a prophylactic approach, the specific PDE4 inhibitor roflumilast (ROF) led in 2 independent, blinded experiments, to the reduction of oral lesions compared to vehicle-treated mice as quantified by endoscopy (p¼0.029). In contrast, an increase in skin lesions was observed in ROF-treated mice (p<0.0001). In a quasi-therapeutic approach, i.e. when ROF/vehicle was not used until mice had developed first skin lesions, ROF-treated mice showed significantly less oral lesions compared to vehicle-treated mice, while skin lesions did not differ. To investigate the discrepant effect of ROF on oral and skin lesions, a transcriptome analysis of both tissues in ROF- and vehicle-treated anti-Lam332 MMP mice as well as mice injected with normal rabbit IgG was performed. An up-regulation of IL-6 and an impact of CXCL2 were found by Gene Set Enrichment and STRING analysis, respectively, in both the skin and buccal mucosa of vehicle-treated mice. The subsequent incubation of murine keratinocytes with anti-mLam332 IgG resulted in a dose-dependent release of IL-6 and CXCL2, which was inhibited by the addition of ROF. Our data propose IL-6 and CXCL2 as relevant pathogenic factors in MMP and suggest PDE4 inhibition as potential novel treatment options for MMP patients with severe oral lesions

Genetic Architecture of Plasma Adiponectin Overlaps With the Genetics of Metabolic Syndrome–Related Traits

OBJECTIVE - Adiponectin, a hormone secreted by adipose tissue, is of particular interest in metabolic syndrome, because it is inversely correlated with obesity and insulin sensitivity. However, it is not known to what extent the genetics of plasma adiponectin and the genetics of obesity and insulin sensitivity are interrelated. We aimed to evaluate the heritability of plasma adiponectin and its genetic correlation with the metabolic syndrome and metabolic syndrome-related traits and the association between these traits and 10 ADIPOQ single nucleotide polymorphisms (SNPs). RESEARCH DESIGN AND METHODS - We made use of a family-based population, the Erasmus Rucphen Family study (1,258 women and 967 men). Heritability analysis was performed using a polygenic model. Genetic correlations were estimated using bivariate heritability analyses. Genetic association analysis was performed using a mixed model. RESULTS - Plasma adiponectin showed a heritability of 55.1%. Genetic correlations between plasma adiponectin HDL cholesterol and plasma insulin ranged from 15 to 24% but were not significant for fasting glucose, triglycerides, blood pressure, homeostasis model assessment of insulin resistance (HOMA-IR), and C-reactive protein. A significant association with plasma adiponectin was found for ADIPOQ variants rs17300539 and rs182052. A nominally significant association was found with plasma insulin and HOMA-IR and ADIPOQ variant rs17300539 after adjustment for plasma adiponectin. CONCLUSIONS - The significant genetic correlation between plasma adiponectin and HDL cholesterol and plasma insulin should be taken into account in the interpretation of genome-wide association studies. Association of ADIPOQ SNPs with plasma adiponectin was replicated, and we showed association between one ADIPOQ SNP and plasma insulin and HOMA-IR

Denosumab compared with risedronate in postmenopausal women suboptimally adherent to alendronate therapy: Efficacy and safety results from a randomized open-label study

Denosumab has been shown to reduce new vertebral, nonvertebral, and hip fractures in postmenopausal women with osteoporosis. In subjects who were treatment-naive or previously treated with alendronate, denosumab was associated with greater gains in bone mineral density (BMD) and decreases in bone turnover markers when compared with alendronate-treated subjects. This trial was designed to compare the efficacy and safety of denosumab with risedronate over 12 months in postmenopausal women who transitioned from daily or weekly alendronate treatment and were considered to be suboptimally adherent to therapy. In this randomized, open-label study, postmenopausal women aged ≥55 years received denosumab 60 mg subcutaneously every 6 months or risedronate 150 mg orally every month for 12 months. Endpoints included percentage change from baseline in total hip BMD (primary endpoint), femoral neck, and lumbar spine BMD at month 12, and percentage change from baseline in sCTX-1 at months 1 and 6. Safety was also assessed. A total of 870 subjects were randomized (435, risedronate; 435, denosumab) who had a mean (SD) age of 67.7 (6.9) years, mean (SD) BMD T-scores of -1.6 (0.9), -1.9 (0.7), and -2.2 (1.2) at the total hip, femoral neck, and lumbar spine, respectively, and median sCTX-1 of 0.3 ng/mL at baseline. At month 12, denosumab significantly increased BMD compared with risedronate at the total hip (2.0% vs 0.5%), femoral neck (1.4% vs 0%), and lumbar spine (3.4% vs 1.1%; p<0.0001 at all sites). Denosumab significantly decreased sCTX-1 compared with risedronate at month 1 (median change from baseline of -78% vs -17%; p<0.0001) and month 6 (-61% vs -23%; p<0.0001). Overall and serious adverse events were similar between groups. In postmenopausal women who were suboptimally adherent to alendronate therapy, transitioning to denosumab was well tolerated and more effective than risedronate in increasing BMD and reducing bone turnover

BP180-specific IgG is associated with skin adverse events, therapy response and overall survival in non-small cell lung cancer patients treated with checkpoint inhibitors

BACKGROUND: Anti-PD1/PD-L1 therapy frequently entails immune-related adverse events (irAEs) and biomarkers to predict irAEs are lacking. While checkpoint inhibitors have been found to re-invigorate T-cells, the relevance of autoantibodies remains elusive. OBJECTIVE: Our aim was to explore whether IgG autoantibodies directed against co-expressed antigens by tumor tissue and healthy skin correlate with skin irAEs and therapy outcome. METHODS: We measured skin-specific IgG via ELISA in non-small cell lung cancer (NSCLC) patients, who received anti-PD1/PD-L1 treatment between July 2015 and September 2017 at the Kantonsspital St. Gallen. Sera were sampled at baseline and during therapy after 8 weeks. RESULTS: Analysis of publicly available tumor expression data revealed that NSCLC and skin co-express BP180, BP230 and type VII collagen. Of 40 recruited patients, 16 (40%) developed a skin irAE. Only elevated anti-BP180 IgG at baseline significantly correlated with the development of skin irAEs (P=.04), therapy response (P=.01) and overall survival (P=.04). LIMITATIONS: The patients were recruited in a single tertiary care center. CONCLUSIONS: Our data suggest that the level of anti-BP180 IgG of NSCLC patients at baseline is associated with better therapy response, overall survival and a higher probability to develop skin irAEs during anti-PD1/PD-L1 treatment