Amy C. Foulkes

Pharmacogenomics and the Resulting Impact on Psoriasis Therapies

Psoriasis is a model disease for the development of pharmacogenomic markers of treatment response, with ready access to diseased tissue and objective validated outcome measures. With the application of state-of-the-art technologies and investment in careful experimental design, the goal of stratified medicine in psoriasis may be possible. Current pharmacogenomic studies in psoriasis show excellence in many areas, including the investigation of a broad range of psoriasis therapies. To facilitate the advent of stratified medicine in psoriasis, uniformity of study design is required, with high quality, consistent phenotyping strategies for participants; definitions of outcome; and the publication of reproducible methodologies.

Methotrexate Toxicity During Treatment of Chronic Plaque Psoriasis: A Case Report and Review of the Literature

Methotrexate continues to be one of the most widely used systemic immunosuppressive agents in dermatology. In addition to the important, well-characterized adverse effects such as hepatotoxicity and myelosuppression, methotrexate may induce a number of rare cutaneous adverse events including methotrexate-induced ulceration. We present a case of methotrexate-induced cutaneous ulceration in a patient with chronic plaque psoriasis occurring during long-standing methotrexate therapy. Withdrawal of the drug and appropriate skin care led to rapid healing of the ulceration and the agent was later safely reintroduced for the ongoing management of the patient’s chronic plaque psoriasis. Review of the literature demonstrates cases of this important rare adverse event, primarily occurring in patients with chronic plaque psoriasis, induced by triggers such as accidental overdose or introduction of an interacting agent. Cutaneous ulceration typically precedes other markers of toxicity. Active treatment with folinic acid (calcium leucovorin) may be required. Early recognition, prompt cessation of methotrexate, and appropriate treatment minimizes morbidity. Dermatologists need to be alert to the possibility of cutaneous adverse events associated with methotrexate therapy, aware of potential drug interactions, and confident in the management of methotrexate toxicity.

What's new in psoriasis? An analysis of guidelines and systematic reviews published in 2009-2010.

This review summarizes key clinical findings from 5 guidelines and 21 systematic reviews on psoriasis published or indexed in the period November 2009 to October 2010. The highlights include the British Association of Dermatologists guidelines on the use of biological interventions in psoriasis, and guidelines on the efficacy and use of acitretin. Biological therapies were reviewed for use in specific patient groups (such as those with hepatitis C) and from a health‐economics perspective. Another systematic review focused on outcome measures used to assess the severity of psoriasis. Finally, comorbidities including cardiovascular risk were the topic of four systematic reviews.

Research Techniques Made Simple: Bioinformatics for Genome-Scale Biology

High-throughput biology presents unique opportunities and challenges for dermatological research. Drawing on a small handful of exemplary studies, we review some of the major lessons of these new technologies. We caution against several common errors and introduce helpful statistical concepts that may be unfamiliar to researchers without experience in bioinformatics. We recommend specific software tools that can aid dermatologists at varying levels of computational literacy, including platforms with command line and graphical user interfaces. The future of dermatology lies in integrative research, in which clinicians, laboratory scientists, and data analysts come together to plan, execute, and publish their work in open forums that promote critical discussion and reproducibility. In this article, we offer guidelines that we hope will steer researchers toward best practices for this new and dynamic era of data intensive dermatology.

Development of chronic inflammatory demyelinating polyneuropathy in a patient receiving infliximab for psoriasis

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Palmoplantar contractures in childhood: a rare complication of vascular Ehlers-Danlos syndrome.

Although catastrophic vascular complications in vascular Ehlers–Danlos Syndrome (EDS) are well recognized, other complications such as flexion contractures and tendon nodules are rarely reported and poorly characterized. We report a young man with vascular EDS, who developed flexion contractures and tendon nodules, causing considerable disability. Limited management strategies are available for these complications, which have continued to prove a challenge to management.

A Framework for Multi-Omic Prediction of Treatment Response to Biologic Therapy for Psoriasis

Biologic therapies have shown high efficacy in psoriasis, but individual response varies and is poorly understood. To inform biomarker discovery in the Psoriasis Stratification to Optimise Relevant Therapy (i.e., PSORT) study, we evaluated a comprehensive array of omics platforms across three time points and multiple tissues in a pilot investigation of 10 patients with severe psoriasis, treated with the tumor necrosis factor (TNF) inhibitor, etanercept. We used RNA sequencing to analyze mRNA and small RNA transcriptome in blood, lesional and nonlesional skin, and the SOMAscan platform to investigate the serum proteome. Using an integrative systems biology approach, we identified signals of treatment response in genes and pathways associated with TNF signaling, psoriasis pathology, and the major histocompatibility complex region. We found association between clinical response and TNF-regulated genes in blood and skin. Using a combination of differential expression testing, upstream regulator analysis, clustering techniques, and predictive modeling, we show that baseline samples are indicative of patient response to biologic therapies, including signals in blood, which have traditionally been considered unreliable for inference in dermatology. In conclusion, our pilot study provides both an analytical framework and empirical basis to estimate power for larger studies, specifically the ongoing PSORT study, which we show as powered for biomarker discovery and patient stratification.

What’s new in psoriasis treatment? An analysis of systematic reviews published in 2015

This review provides a summary of key findings from 27 systematic reviews of 51 articles first published or indexed during 2015, focusing on the treatment of psoriasis and on precision medicine in psoriasis. The evidence supports weight‐loss interventions by dieting and exercise for improvement in disease severity in overweight and obese patients with psoriasis. No significant increased risk of serious infections was reported for the biologic therapies adalimumab, etanercept and ustekinumab compared with appropriate comparators. Evidence could not provide reliable estimates of rare adverse events, emphasizing the need for large prospective registries. Polymorphisms in the tumour necrosis factor (TNF)‐α gene may confer improved responses to TNF inhibitor (TNFI) therapy, but the studies to date lack power to detect a true association. From the limited available evidence, multidisciplinary management is both more effective and more satisfactory for patients with psoriasis and psoriatic arthritis than conventional consultations. This summary of reviews provides a succinct guide for clinicians and patients wishing to remain up to date with high‐quality evidence for the treatment of psoriasis.

Bioinformatics for dermatology: why we should learn about code

DEAR EDITOR, The era of high-throughput sequencing (HTS; otherwise known as next-generation sequencing) has revolutionized dermatological research. New publications describing successful translational research based on interpretation of omics data from dermatological sources appear each month. Bioinformatics refers to the tools used to collect, classify and analyse such datasets. Reviewing, digesting and replicating HTS studies requires not only expertise in bioinformatic techniques, but also the raw sequencing data, the associated clinical data and the complete code used to derive those findings. Meta-analyses have found an alarming lack of reproducibility in modern research. Many factors contribute to this problem, perhaps none so prominently as the widespread – and inexplicable – failure to publish scripts used to perform analysis. Although some inroads have been made towards establishing best practices in molecular biology, code sharing remains contentious. Publishers, including Nature Publishing Group, allow some discretion in publication of analysis scripts. Specifically, they state it is best practice to ‘release custom computer code in a way that allows readers to repeat the published results’. We argue from our work in genomics and stratified medicine that results vary greatly depending on subtle, unstated analytic choices that are invisible without access to both the raw data and the complete analysis script. Every HTS study is therefore ‘custom’. Sharing code, ideally in structured repositories such as GitHtub (github.com), can also assist the peer-review process, enabling precise debate on the appropriateness of particular methods. As HTS costs continue to fall over the coming decade, dermatological researchers will find themselves working on datasets of unprecedented size and resolution. In this era of ‘big data’, it is crucial that we standardize best practices for HTS research. We encourage dermatologists and skin scientists to familiarize themselves with the basic principles and tools of computational biology. We and others have highlighted paths into bioinformatics, from basic web-based platforms to coding courses. We furthermore urge our publishers to not just ensure review of code but to publish it along with omic and clinical data in order to facilitate fully reproducible research in dermatology and beyond. Acknowledgments

Genetic prediction of treatment response in psoriasis is still a work in progress

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