Aldehyde dehydrogenase inhibition blocks mucosal fibrosis in human and mouse ocular scarring

Mucous membrane pemphigoid (MMP) is a systemic mucosal scarring disease, commonly causing blindness, for which there is no antifibrotic therapy. Aldehyde dehydrogenase (ALDH) family 1 is upregulated in both ocular MMP (OMMP) conjunctiva and cultured fibroblasts. Application of the ALDH metabolite, retinoic acid (RA), to normal human conjunctival fibroblasts in vitro induced a diseased phenotype. Conversely, application of ALDH inhibitors, including disulfiram, to OMMP fibroblasts in vitro restored their functionality to that of normal controls. ALDH1 is also upregulated in the mucosa of the mouse model of scarring allergic eye disease, used here as a surrogate for OMMP, in which topical application of disulfiram decreased fibrosis in vivo. These data suggest that progressive scarring in OMMP results from ALDH/RA fibroblast autoregulation, that the ALDH1 subfamily has a central role in immune-mediated ocular mucosal scarring, and that ALDH inhibition with disulfiram is a potential, and readily translatable, antifibrotic therapy

Evaluation of early and late presentation of patients with ocular mucous membrane pemphigoid to two major tertiary referral hospitals in the United Kingdom

PURPOSE: Ocular mucous membrane pemphigoid (OcMMP) is a sight-threatening autoimmune disease in which referral to specialists units for further management is a common practise. This study aims to describe referral patterns, disease phenotype and management strategies in patients who present with either early or established disease to two large tertiary care hospitals in the United Kingdom.\ud \ud PATIENTS AND METHODS: In all, 54 consecutive patients with a documented history of OcMMP were followed for 24 months. Two groups were defined: (i) early-onset disease (EOD:<3 years, n=26, 51 eyes) and (ii) established disease (EstD:>5 years, n=24, 48 eyes). Data were captured at first clinic visit, and at 12 and 24 months follow-up. Information regarding duration, activity and stage of disease, visual acuity (VA), therapeutic strategies and clinical outcome were analysed.\ud \ud RESULTS: Patients with EOD were younger and had more severe conjunctival inflammation (76% of inflamed eyes) than the EstD group, who had poorer VA (26.7%=VA<3/60, P<0.01) and more advanced disease. Although 40% of patients were on existing immunosuppression, 48% required initiation or switch to more potent immunotherapy. In all, 28% (14) were referred back to the originating hospitals for continued care. Although inflammation had resolved in 78% (60/77) at 12 months, persistence of inflammation and progression did not differ between the two phenotypes. Importantly, 42% demonstrated disease progression in the absence of clinically detectable inflammation.\ud \ud CONCLUSIONS: These data highlight that irrespective of OcMMP phenotype, initiation or escalation of potent immunosuppression is required at tertiary hospitals. Moreover, the conjunctival scarring progresses even when the eye remains clinically quiescent. Early referral to tertiary centres is recommended to optimise immunosuppression and limit long-term ocular damage.\ud \u

Genome-Wide Meta-Analysis of Five Asian Cohorts Identifies PDGFRA as a Susceptibility Locus for Corneal Astigmatism

Corneal astigmatism refers to refractive abnormalities and irregularities in the curvature of the cornea, and this interferes with light being accurately focused at a single point in the eye. This ametropic condition is highly prevalent, influences visual acuity, and is a highly heritable trait. There is currently a paucity of research in the genetic etiology of corneal astigmatism. Here we report the results from five genome-wide association studies of corneal astigmatism across three Asian populations, with an initial discovery set of 4,254 Chinese and Malay individuals consisting of 2,249 cases and 2,005 controls. Replication was obtained from three surveys comprising of 2,139 Indians, an additional 929 Chinese children, and an independent 397 Chinese family trios. Variants in PDGFRA on chromosome 4q12 (lead SNP: rs7677751, allelic odds ratio = 1.26 (95% CI: 1.16–1.36), Pmeta = 7.87×10−9) were identified to be significantly associated with corneal astigmatism, exhibiting consistent effect sizes across all five cohorts. This highlights the potential role of variants in PDGFRA in the genetic etiology of corneal astigmatism across diverse Asian populations

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Immunosuppressive Therapy for Ocular Mucous Membrane PemphigoidStrategies and Outcomes

Purpose: To evaluate the effectiveness and toxicity of a stepladder immunosuppression strategy, including the use of mycophenolate mofetil and combination therapy, in the treatment of ocular mucous membrane pemphigoid.Design: Retrospective, noncomparative, interventional case series.Participants: Two hundred twenty-three eyes of 115 patients.Methods: Patients with a diagnosis of ocular mucous membrane pemphigoid commencing immunosuppression between January 1994 and July 2005 were identified. A treatment episode was defined by the use of a particular therapy or combination of therapies.Main Outcome Measures: For each treatment episode, success of immunosuppressive therapy in controlling ocular inflammation was graded as a success (S), qualified success (QS), or failure (F). Initial and final visual acuities (VAs), stage of cicatrization (Foster, Mondino), grade of conjunctival inflammation, and side effects were recorded.Results: In 70% (80/115) of patients, inflammation was controlled by the end of the study. At least 6 months remission off treatment occurred in 16 patients (14%). Of the 388 treatment episodes, 50% were classified as S; 27%, QS; and 23%, F. The most successful therapies were based on cyclophosphamide (S, 69%; QS, 21%; F, 10%), followed by mycophenolate (S, 59%; QS, 22%; F, 19%), azathioprine (S, 47%; QS, 24%; F, 29%), dapsone (S, 47%; QS, 30%; F, 23%), and sulfapyridine (S, 38%; QS, 27%; F, 35%). Combination sulfa-steroid-myelosuppressive agent therapy increased the response from 73% with single-agent therapy to 87%. Side effects were the reason for 29% of changes in therapy. These were most prominent with azathioprine (40%) and least with mycophenolate (15%). Initial best-corrected VA (BCVA) was 6/60 or less in 17% (37/223) of eyes, pemphigoid being the cause in 13% (29/223). Final BCVA was 6/60 or less in 34% (76/223) of eyes, pemphigoid being the cause in 26% (57/223). By the end of the study, Mondino stage cicatrization had progressed in 41% (92/223) of eyes and 53% (61/115) of patients.Conclusions: Mycophenolate mofetil seems to be an effective and well-tolerated immunosuppressant for moderately active ocular mucous membrane pemphigoid. Combination sulfa-steroid-myelosuppressive agent therapy in a stepladder regimen is a useful strategy to improve disease control. Cicatrization and VA may still progress and worsen despite adequate control of inflammation

Editorial. The evil curse of ocular pemphigoid

Evaluation of early and late presentation of patients with ocular mucous membrane pemphigoid to two major tertiary referral hospitals in the United Kingdom