Project description:ImportanceLinear porokeratosis features linear and whorled configurations of keratotic papules and plaques, with coronoid lamellae present on histologic examination. Because linear porokeratosis manifests in the lines of Blaschko representing the dorsoventral migration patterns of keratinocyte precursors, it has been suggested that postzygotic somatic mutation underlies the disease. However, no genetic evidence has supported this hypothesis to date.ObjectiveTo identify genetic mutations associated with linear porokeratosis.Design, setting, and participantsPaired whole-exome sequencing of affected skin and blood/saliva samples from 3 participants from 3 academic medical centers with clinical and histologic diagnoses of linear porokeratosis.Interventions or exposuresWhole-exome sequencing of paired blood/saliva and affected tissue samples isolated from linear porokeratosis lesions.Main outcomes and measuresGermline and somatic genomic characteristics of participants with linear porokeratosis.ResultsOf the 3 participants, 2 were male. Participant ages ranged from 5 to 20 years old. We found a combination of a novel germline mutation and a novel somatic mutation within affected tissue in all cases. One participant had a germline heterozygous PMVK c.329G>A mutation and a somatic copy-neutral loss of heterozygosity confined to the lesional skin, while a second had a germline heterozygous PMVK c.79G>T mutation and an additional PMVK c.379C>T mutation in the lesional skin. In a third participant, there was a germline splice-site mutation in MVD (c.70 + 5G>A) and a somatic deletion in MVD causing frameshift and premature codon termination within the lesional skin (c.811_815del, p.F271Afs*33 frameshift).Conclusions and relevanceOur findings suggest that linear porokeratosis is associated with the presence of second-hit postzygotic mutations in the genes that encode enzymes within the mevalonate biosynthesis pathway, and provide further evidence that the mevalonate pathway may be a potential target for therapeutic intervention in porokeratosis.

Project description:BackgroundThe association between psoriasis vulgaris and bullous pemphigoid (BP) remains largely unknown.ObjectivesTo investigate whether there is a causal effect between psoriasis vulgaris and BP.MethodsTwo-sample bidirectional Mendelian randomization (MR) analyses were conducted using publicly released genome-wide association studies (GWAS) summary statistics. The GWAS summary statistics for BP were downloaded online from FinnGen Biobank Documentation of the R12 release, which includes 219 BP cases and 218,066 controls. The GWAS data for psoriasis vulgaris were extracted from Sakaue et al., which comprises 5072 cases and 478,102 controls. Single-nucleotide polymorphisms (SNPs) associated with exposure were selected as instrumental variables by performing additional quality control steps. The inverse-variance-weighted (IVW) method was used for the primary MR analyses, and the MR-Egger regression, weighted mode method, weighted median method, and simple mode were employed for sensitivity analyses. The MR-Egger intercept test and "leave-one-out" sensitivity analysis were performed to evaluate the horizontal pleiotropy and the potentially influential SNPs, respectively.ResultsGenetically determined log odds of psoriasis vulgaris were associated with an increased risk of BP (IVW: odds ratio (OR) = 1.263, 95% confidence interval (CI): 1.013-1.575, P=0.038). Sensitivity analyses by the weighted mode (OR=1.255, 95%CI: 0.973-1.618, P=0.106), MR Egger (OR=1.315, 95%CI: 0.951-1.817, P=0.126), simple mode (OR=1.414, 95%CI: 0.823-2.429, P=0.234) and weighted median method (OR=1.177, 95%CI: 0.889-1.559, P=0.254) derived directionally consistent relationship between the genetically predicted log odds of psoriasis vulgaris and risks of developing BP. On the contrary, we found that genetically predicted BP had no significant effect on psoriasis vulgaris (IVW: OR=0.996, P= 0.707), indicating the unidirectionality of the relationship. MR-Egger intercept tests showed no evidence of horizontal pleiotropy. No influential SNP driving the results was detected by the leave-one-out sensitivity analysis.ConclusionsOur results suggested that psoriasis vulgaris causally increases the risk of BP, highlighting the need for potential strategies for the prevention and early diagnosis of comorbid BP in patients with psoriasis vulgaris. Further researches into this association and underlying mechanisms are warranted.

Project description:BackgroundBullous pemphigoid (BP) is the most common autoimmune blistering disease in the West. Oral steroids are the standard treatment.This is an update of the review published in 2005.ObjectivesTo assess treatments for bullous pemphigoid.Search strategyIn August 2010 we updated our searches of the Cochrane Skin Group Specialised Register, the Cochrane Central Register of Controlled Trials (Clinical Trials), MEDLINE, EMBASE, and the Ongoing Trials registers.Selection criteriaRandomised controlled trials of treatments for participants with immunofluorescence-confirmed bullous pemphigoid.Data collection and analysisAt least two authors evaluated the studies for the inclusion criteria, and extracted data independently.Main resultsWe included 10 randomised controlled trials (with a total of 1049 participants) of moderate to high risk of bias. All studies involved different comparisons, none had a placebo group. In 1 trial plasma exchange plus prednisone gave significantly better disease control at 1 month (0.3 mg/kg: RR 18.78, 95% CI 1.20 to 293.70) than prednisone alone (1.0 mg/kg: RR 1.79, 95% CI 1.11 to 2.90), while another trial showed no difference in disease control at 6 months.No differences in disease control were seen for different doses or formulations of prednisolone (one trial each), for azathioprine plus prednisone compared with prednisone alone (one trial), for prednisolone plus azathioprine compared with prednisolone plus plasma exchange (one trial), for prednisolone plus mycophenolate mofetil or plus azathioprine (one trial), for tetracycline plus nicotinamide compared with prednisolone (one trial). Chinese traditional medicine plus prednisone was not effective in one trial.There were no significant differences in healing in a comparison of a standard regimen of topical steroids (clobetasol) with a milder regimen (RR 1.00, 95% 0.97 to 1.03) in one trial. In another trial, clobetasol showed significantly more disease control than oral prednisolone in people with extensive and moderate disease (RR 1.09, 95% CI 1.02 to 1.17), with significantly reduced mortality and adverse events (RR 1.06, 95% CI 1.00 to 1.12).Authors' conclusionsVery potent topical steroids are effective and safe treatments for BP, but their use in extensive disease may be limited by side-effects and practical factors. Milder regimens (using lower doses of steroids) are safe and effective in moderate BP. Starting doses of prednisolone greater than 0.75 mg/kg/day do not give additional benefit, lower doses may be adequate to control disease and reduce the incidence and severity of adverse reactions. The effectiveness of adding plasma exchange, azathioprine or mycophenolate mofetil to corticosteroids, and combination treatment with tetracycline and nicotinamide needs further investigation.

Project description:ImportanceThe association between the use of medications and the development of bullous pemphigoid (BP) is unclear.ObjectiveTo assess the associations between previous exposure to certain medications and BP.Data sourcesFor this systematic review and meta-analysis, PubMed, the Cochrane Central Register of Controlled Trials, and Embase were searched for relevant studies from inception to February 20, 2020.Study selectionCase-control or cohort studies and randomized clinical trials that examined the odds or risk of BP in patients with previous medication use were included. No geographic or language limitations were imposed.Data extraction and synthesisThe Meta-analysis of Observational Studies in Epidemiology (MOOSE) guideline was followed. The Newcastle-Ottawa Scale was used to evaluate the risk of bias of included observational studies; Cochrane Collaboration's tool was used for randomized clinical trials. Aggregate data were used to conduct a random-effects model meta-analysis if the included studies were sufficiently homogenous. Subgroup analyses were performed for use of various medications of the same category.Main outcomes and measuresOdds ratio (OR), hazard ratio, and risk ratio of bullous pemphigoid in association with medication use.ResultsThis meta-analysis included 13 case-control studies, 1 cohort study, and 1 randomized clinical trial with a total of 285 884 participants. The meta-analysis of case-control studies showed a significant association of BP with previous use of aldosterone antagonists (pooled OR, 1.75; 95% CI, 1.28-2.40), dipeptidyl peptidase 4 inhibitors (pooled OR, 1.92; 95% CI, 1.55-2.38), anticholinergics (pooled OR, 3.12; 95% CI, 1.54-6.33), and dopaminergic medications (pooled OR, 2.03; 95% CI, 1.34-3.05). One cohort study found an increased risk of BP among patients receiving dipeptidyl peptidase 4 inhibitors (hazard ratio, 2.38; 95% CI, 1.16-4.88; P = .02). One trial found a higher occurrence of BP in patients with diabetes receiving linagliptin (0.2% in diabetes group vs 0% in the placebo group).Conclusions and relevanceThe findings of this systematic review and meta-analysis suggest that aldosterone antagonists, dipeptidyl peptidase 4 inhibitors, anticholinergics, and dopaminergic medications are associated with BP. These medications should be judiciously prescribed, particularly in high-risk patients who are elderly and have disabling neurologic disorders.

Project description:Bullous pemphigoid (BP) is a rare autoimmune skin blistering disease, characterized by the presence of autoantibodies against hemidesmosomal autoantigens. Cytokine expression is altered in BP patients, and several of these differently expressed cytokines, including IL-1α, IL-1β, IL-8, and TNF-α, contribute to disease pathogenesis. Since genetic polymorphisms in the genes of these cytokines might be implicated in susceptibility to BP disease, we aimed at testing this implication in susceptibility to BP in an Iranian cohort. Blood samples were collected from the subjects and genomic DNA was extracted. To detect the single nucleotide polymorphisms (SNPs), IL-1α (rs1800587), IL-1β (rs1143627, rs16944, rs1143634), IL-8 (rs4073), and TNF-α (rs1799964, rs1800630, rs1799724, and rs361525) genes were genotyped in BP patients and healthy controls as well as IL-8 (rs4073) in pemphigus vulgaris (PV) patients. Quantitative gene expression was evaluated by RT-PCR analysis. A significant difference was observed in the distribution of genotypes or alleles of IL-8 SNP between the BP patients and controls. The A-allele of IL-8 SNP is significantly more prevalent in the control individuals compared to the BP patient. To further validate this observation, we included PV patients as an additional control. Again, the A-allele of IL-8 SNP is significantly more prevalent in the PV compared to the BP patients. While we observed a trend toward significant differences regarding alleles of TNF-α rs1799724 as well as alleles of TNF-α rs1799964, this difference was, however, not evident after correction for multiple analysis. There was no significant difference in all other studied SNPs. In contrast to IL-1α, IL-1β, and TNF-α, IL-8 gene expression levels were significantly higher in the patients than that of controls. The minor allele in IL-8 SNP might play a protective role in susceptibility to BP in Iranian patients. Although higher expression levels of IL-8 gene was found in the patients compared with healthy controls, these levels, however, suggest no association with the examined polymorphism. Moreover, further investigation revealed an elevation in gene expression between wild and polymorphic genotypes of IL-1α rs1800587 and TNF-α rs361525 in the patient group and these SNPs are therefore associated with altering the levels of gene expression.

Project description:ImportanceDupilumab is a theoretically novel therapy for bullous pemphigoid (BP). However, its effectiveness and safety have yet to be confirmed in a large-scale study.ObjectiveTo assess the efficacy and safety of dupilumab in patients with BP and evaluate factors that potentially affect short-term and long-term outcomes.Design, setting, and participantsA retrospective cohort study was conducted from January 1, 2021, to July 31, 2022. The median (IQR) follow-up period was 24.6 (11.5-38.4) weeks. This multicenter study was performed in 6 dermatology departments of the National Autoimmune Bullous Diseases Cooperative Group of China. Adult patients with BP that received 300 mg of dupilumab every 2 weeks following an initial dose of 600 mg were included. Patients were eligible if they had a clinical presentation of BP combined with immunological or pathological evidence. Patients with drug-induced BP, with less than 4 weeks of follow-up, and who received dupilumab or any other biologics within 6 months were excluded.Main outcomes and measuresThe primary outcome was the proportion of patients who achieved disease control within 4 weeks. Disease control was defined as the absence of new lesions and pruritus, combined with the healing of existing lesions. Complete remission rates, relapse rates, changes in Bullous Pemphigoid Disease Area Index (BPDAI) scores, itching numerical rating scale (NRS) scores, laboratory results within 64 weeks, and adverse events (AEs) were also assessed.ResultsAmong 146 patients (median [IQR] age, 73 [64-85] years; 86 [58.9%] male patients) included in the study, 127 (87.0%) patients achieved disease control within 4 weeks, with a median (IQR) time of 14 (7-14) days. A total of 52 (35.6%) patients achieved complete remission, and 13 (8.9%) patients relapsed during the observation period. The complete remission rate and cumulative relapse rate at week 64 were 62.5% (5 of 8) and 30.9%, respectively. There was rapid and sustained improvement in clinical indicators and laboratory examination results after dupilumab treatment, including BPDAI scores, itching NRS scores, serum anti-BP180 and anti-BP230 antibodies, total IgE levels, and eosinophil count. Of these 146 patients, 107 (73.3%) did not report any AEs. The most common AEs were infections and eosinophilia. Serum anti-BP180 antibody levels of greater than 50 relative units (RU)/mL (OR, 3.63; 95% CI, 0.97-12.61; P = .045) were associated with 4-week disease control, and male patients were more likely to relapse (HR, 10.97; 95% CI, 1.42-84.92; P = .02).Conclusions and relevanceIn this retrospective cohort study, dupilumab treatment was associated with improved clinical symptoms in patients with BP. The safety profile was favorable, although concurrent infection and eosinophilia might pose potential concerns. This study suggests that patients with anti-BP180 antibody levels of at least 50 RU/mL and female sex may respond better.

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Two Cases of Porokeratosis with MVD Mutations, in Association with Bullous Pemphigoid.

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Two Cases of Porokeratosis with MVD Mutations, in Association with Bullous Pemphigoid.

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