The role of 39 psoriasis risk variants on age of psoriasis onset.

Recent genome-wide association studies (GWAS) have identified multiple genetic risk factors for psoriasis, but data on their association with age of onset have been marginally explored. The goal of this study was to evaluate known risk alleles of psoriasis for association with age of psoriasis onset in three well-defined case-only cohorts totaling 1,498 psoriasis patients. We selected 39 genetic variants from psoriasis GWAS and tested these variants for association with age of psoriasis onset in a meta-analysis. We found that rs10484554 and rs12191877 near HLA-C and rs17716942 near IFIH1 were associated with age of psoriasis onset with false discovery rate < 0.05. The association between rs17716942 and age of onset was not replicated in a fourth independent cohort of 489 patients (P = 0.94). The imputed HLA-C∗06:02 allele demonstrated a much stronger association with age of psoriasis onset than rs10484554 and rs12191877. We conclude that despite the discovery of numerous psoriasis risk alleles, HLA-C∗06:02 still plays the most important role in determining the age of onset of psoriasis. Larger studies are needed to evaluate the contribution of other risk alleles, including IFIH1, to age of psoriasis onset

"I don't want to manage it, I want to get rid of it" : a narrative analysis of living with chronic plaque psoriasis, and an investigation into vitamin D as a treatment : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Nutritional Science at Massey University, Albany, New Zealand

As a chronic skin disease, plaque psoriasis can cause significant psychosocial, emotional and physical burden. Psoriasis sufferers perceive others as lacking understanding around what it is like to live with this condition, and there has been little research exploring the experience of psoriasis in depth. The burden of psoriasis can be compounded by the difficulty of treating it, and the inconveniences, side effects and risks of available treatments, suggesting the importance of finding a safe, effective and convenient treatment for psoriasis. Vitamin D and psoriasis have a long-standing relationship, with topical vitamin D analogues used to treat mild-tomoderate disease, and observational studies suggesting an association between higher systemic vitamin D (serum calcidiol) concentrations and less severe psoriasis. These findings suggest vitamin D3 supplements, which raise serum calcidiol concentrations, might improve psoriasis. In this thesis, two studies were conducted to address the limited in-depth understanding of the experience of psoriasis, and the need for a safe, effective treatment, respectively. The aims were 1) to gain a deeper understanding of the experience of living with psoriasis; and 2) to investigate whether oral vitamin D3 supplements can effectively treat psoriasis. For 1), data from semi-structured interviews with 10 men and women with psoriasis was analysed using narrative analysis. Narrative trajectories involving three predominant narrative forms shaped participants’ stories: restitution, where the focus was on overcoming psoriasis through trying to find an effective treatment or cure; chaos, where psoriasis was experienced as overwhelming and brought about a sense of hopelessness, and resignation, which was centred on begrudgingly accepting psoriasis in order to be able to get on with life. Participants had different narrative trajectories and shifted between forms over time, with the nature of experience linked with the relative stability and severity of a person’s psoriasis and their beliefs about their ability to manage it. For 2), a randomised, double-blinded, placebo-controlled trial was conducted with 101 participants ≥ 18 years allocated to 100,000 International Units (IU) vitamin D3/month (n = 67) for 12 months (200,000 IU at baseline), or an identical placebo (n = 34). Psoriasis severity (Psoriasis Area and Severity Index [PASI]) and serum calcidiol concentrations were assessed at 3-monthly intervals. The primary outcome was the difference in PASI between treatment and placebo over time, assessed using a linear mixed model. Psoriasis severity did not differ between groups at any time (group F(1, 106) = 0.59, p = 0.44, group*time F(4, 370) = 0.52, p = 0.72). Yet these findings are inconclusive, as serum calcidiol significantly increased from baseline in both the treatment and the placebo group, and a mild improvement in PASI score from baseline also occurred in each group. A non-predetermined secondary analysis was performed by assessing the strength of the relationship between serum calcidiol concentration and PASI score across the whole sample, and this showed a significant inverse relationship between the two variables, in that elevation of serum calcidiol concentration by increments from 25 nmol/L to 125 nmol/L was associated with very mild decreases in PASI (estimated range of decrease 0 – 2.6; p = 0.002). Therefore, despite being unable to determine a benefit of vitamin D3 supplements for psoriasis, these findings support the notion of a potential benefit of increasing serum calcidiol concentrations across the psoriatic population. In conclusion, this thesis offers insight into ways in which people can experience psoriasis over time: as a temporary and fixable condition that must be overcome, as an overpowering force and source of significant suffering, and as a permanent condition that is reluctantly accepted. As the findings emphasise the negative influence of the difficulties around managing and treating psoriasis on the experience of psoriasis, they provide further support for the need for an effective, safe and convenient treatment. While the findings were inconclusive in regards to whether oral vitamin D3 can help people to manage their psoriasis, the significant association between psoriasis severity and systemic vitamin D concentration supports continued research into this potential

Plasma total antioxidant capacity and peroxidation biomarkers in psoriasis

Systemic biomarkers of oxidative stress can be relevant for assessment of psoriasis severity, for prediction of the outcome of therapy and of the development of comorbidities. In this review we aimed to evaluate the relationship between plasma total antioxidant capacity (TAC) and peroxidation biomarkers, as well as their association with dyslipidemia and systemic inflammation in psoriasis. The review of 59 case–control comparisons (from 41 studies) and 17 interventions (from 13 studies) suggests that peroxidation markers are more sensitive than TAC in the evaluation of oxidative stress in psoriasis. Although few studies investigated the effect of treatment on oxidative stress, it seems that biological drugs could be the better choice in the treatment of psoriasis. However, considering the limitations of TAC and plasma peroxidation markers, this review suggests that new methods should be developed in order to evaluate systemic oxidative stress in psoriasis

Multi-omics integration reveals molecular networks and regulators of psoriasis.

BackgroundPsoriasis is a complex multi-factorial disease, involving both genetic susceptibilities and environmental triggers. Genome-wide association studies (GWAS) and epigenome-wide association studies (EWAS) have been carried out to identify genetic and epigenetic variants that are associated with psoriasis. However, these loci cannot fully explain the disease pathogenesis.MethodsTo achieve a comprehensive mechanistic understanding of psoriasis, we conducted a systems biology study, integrating multi-omics datasets including GWAS, EWAS, tissue-specific transcriptome, expression quantitative trait loci (eQTLs), gene networks, and biological pathways to identify the key genes, processes, and networks that are genetically and epigenetically associated with psoriasis risk.ResultsThis integrative genomics study identified both well-characterized (e.g., the IL17 pathway in both GWAS and EWAS) and novel biological processes (e.g., the branched chain amino acid catabolism process in GWAS and the platelet and coagulation pathway in EWAS) involved in psoriasis. Finally, by utilizing tissue-specific gene regulatory networks, we unraveled the interactions among the psoriasis-associated genes and pathways in a tissue-specific manner and detected potential key regulatory genes in the psoriasis networks.ConclusionsThe integration and convergence of multi-omics signals provide deeper and comprehensive insights into the biological mechanisms associated with psoriasis susceptibility

Viewpoint on handling anti-TNF failure in psoriasis

An association among the occurrence of antidrug antibodies (ADAs), diminished trough serum drug levels (TSDLs) and non-response or loss of response has been described for several tumor necrosis factor alpha (TNF) blocking agents in a variety of diseases, including psoriasis. In a series of ten psoriasis patients with primary or secondary failure, or adverse reactions during anti-TNF therapy, we measured ADAs and TSDLs in patient serum using radioimmunoassay and ELISA, respectively. By proposing a treatment algorithm derived from research in this field, we show that measuring ADAs and TSDLs in psoriasis patients provides a more structured approach to clinical decision making for psoriasis patients who fail anti-TNF therapy

Evaluation of the cutaneous microbiome in psoriasis

Psoriasis, a highly prevalent disease of humans of unknown cause, is a chronic inflammatory disorder primarily involving skin, with distinctive clinical characteristics. With the newly developed tools that facilitate microbiome research, it now is possible to assess whether the cutaneous microbiome plays a role in the pathogenesis of this disorder. Preliminary data from our studies suggest that the cutaneous microbiome in psoriasis is complex and possibly different from normal. To deal with this complexity, we propose to examine the cutaneous microbiome in relation to psoriasis with explorations at several taxonomic and informatic levels. Our overall objective is to examine how changes in the normal cutaneous microbiome contributes to the pathogenesis of psoriasis. Since causality is complex and often difficult to prove, our overall hypothesis is that there are alterations in the cutaneous microbiome in areas of skin affected by psoriasis in comparison with the range observed in clinically unaffected areas, or in healthy persons. We also hypothesize that the characteristics of the microbiome may affect clinical responses to the immunomodulatory agents used to treat psoriasis. An alternative hypothesis is that effective treatment of psoriasis with systemic immunomodulatory agents will not substantially affect the disordered microbial ecosystem. Such observations would provide evidence for the roles of the microbiota in this disorder. Since an important consideration in microbiome research is the optimal level (e.g. phylum, genus, species, strain, gene) at which to examine a scientific question, and we are not yet certain what are the optimal levels for psoriasis, this also will be examined. Our studies of psoriasis should allow development of both approaches and tools that will have general utility for microbiome research. To test our hypothesis, we propose the following specific aims: 1. To understand the cutaneous microbiome species composition overlaying psoriatic lesions; 2. To investigate differences in metagenome content for psoriatic lesions compared to normal skin; 3. To identify differences in the transcriptional profiles of the microbiome and the host between normal skin and psoriatic lesions using high-throughput sequencing; and 4. To estimate the effects of systemic immunomodulatory therapy for psoriasis on microbiome composition. In total, these studies should help us understand the role of the microbiome in psoriasis pathogenesis

Nonadherence to psoriasis medication as an outcome of limited coping resources and conflicting goals: findings from a qualitative interview study with people with psoriasis

Background Medication nonadherence is known to limit the effectiveness of available therapies; however, little is known specifically about medication adherence in people with psoriasis. Medicines self‐management can feel onerous to those with dermatological conditions due to the nature of therapies prescribed and many individuals with psoriasis experience additional challenges such as physical and psychological comorbidities that place significant additional demands on individuals and may undermine adherence. Viewing nonadherence to medication as an outcome of limited personal coping resources and conflicting goals may help to explain medication nonadherence. Objectives To explore individuals’ perspectives of their psoriasis, medication and its management. Methods Twenty people with psoriasis were recruited from community samples in England and interviewed in‐depth about their perceptions of their psoriasis, medication, and adherence to medication and self‐management advice. Data were analysed using Framework Analysis. Results Participants reported that adhering to recommended treatment regimens conflicted with the management of the physical and psychological demands of living with psoriasis. Medication usage was viewed as a source of unresolved emotional distress and, for some, resulted in poor self‐reported adherence, which included medication overuse, underuse and rejection of prescribed therapies. Perceived lack of engagement by clinicians with participants’ self‐management difficulties was viewed as an additional source of stress and distress. Conclusions Adhering to medication in psoriasis can be an additional source of considerable emotional distress. We interpreted some episodes of nonadherence to psoriasis medication as rational attempts by individuals to minimize distress and to gain control over their life

Clinical and Genetic Risk Factors Associated with Psoriatic Arthritis among Patients with Psoriasis.

IntroductionPsoriatic arthritis (PsA) is a chronic, inflammatory arthritis that affects an estimated 30% of patients with psoriasis. PsA is underdiagnosed in primary care and dermatology clinics due to a variety of reasons, including failure of healthcare providers to ask about symptoms, overlap of symptoms and signs with other rheumatologic conditions, and lack of a specific diagnostic test. A delay in PsA diagnosis and treatment, even as short as 6 months, can lead to decreased quality of life, increased joint damage, and worse long-term physical function. In this study, we sought to identify the clinical and genetic factors that help discriminate patients with PsA from those with cutaneous psoriasis only.MethodsWe analyzed a cohort of 974 psoriasis patients at an academic medical center, of whom 175 had confirmed PsA, and performed univariate, multivariate, and predictive modeling to determine factors associated with PsA.ResultsThe univariate analysis revealed significant positive associations of PsA with age, nail involvement, scalp involvement, skin fold involvement, elbow/knee involvement, psoriasis severity, plaque subtype, erythrodermic subtype, hypertension, type 2 diabetes, and coronary artery disease, and a significant negative association of PsA with the human leukocyte antigen (HLA)-C*06:02 allele. In the multivariate analysis, nail involvement, type 2 diabetes, and pustular psoriasis remained significantly associated with PsA, while HLA-C*06:02 positivity remained protective. There was a trend towards an association of PsA with older age, younger age of psoriasis onset, and skin fold involvement, while there was protective trend for smoking. A predictive model including both clinical and genetic factors showed reasonable discriminative ability between psoriasis and PsA, with an area under the curve of 0.87 for a receiver operating characteristic curve.ConclusionThis study identified a number of clinical and genetic features that could help stratify patients who are at higher risk for having PsA and for whom rheumatology referral may be beneficial

Profile of tildrakizumab-asmn in the treatment of moderate-to-severe plaque psoriasis: evidence to date.

Plaque psoriasis is an immune-mediated skin disease that affects roughly 3% of adults in the United States. Advances over the past 20 years in understanding the immune-mediated pathophysiology of psoriasis have led to the development of targeted biologic therapies for this condition. Currently, biologic medications approved for the treatment of plaque psoriasis include tumor necrosis factor α inhibitors, interleukin (IL)-17 or IL-17 receptor inhibitors, IL-12/23 inhibitors, and IL-23 inhibitors. Tildrakizumab-asmn is a monoclonal antibody that targets the p19 subunit of IL-23 and is approved for use in adult patients with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. This article reviews the current pharmacologic, efficacy, and safety data on tildrakizumab-asmn

Psoriasis today: experiences of healthcare and impact on quality of life in a major UK cohort

Aim: To establish how people with psoriasis in the United Kingdom today experience living with their condition including diagnosis, treatment, healthcare provision and impact on daily life. Background: Psoriasis is a debilitating long-term inflammatory skin disease which can result in severe itching, discomfort and soreness, and may be associated with problems beyond the specific symptoms related to the skin. For many it is accompanied by difficult-to-manage treatment regimes, emotional distress and a negative impact on their quality of life and psychosocial functioning. To date there is little published information about the health experiences of people in the United Kingdom with psoriasis. Methods A postal self-administered questionnaire was completed by members of the Psoriasis Association and the responses analysed (n=1564). Findings The findings suggest some similarities to surveys in other nations, but specifically highlighted that patients feel under-informed and are dissatisfied with current treatment regimes. Responses provided an insight into aspects of the condition that treatments should be targeting. Specific areas of negative impact on psychosocial functioning were identified, including the lack of available support for those experiencing emotional distress. The research provides important information about how the care of patients with psoriasis can be improved, especially at primary care level. This includes: improved training in psoriasis knowledge and awareness at general practitioner level and greater use of dermatology specialist nurses in primary care settings; more effective and manageable treatment regimes that target visible areas and general well-being; greater support for emotional distress and psychosocial functioning.Peer reviewedFinal Accepted Versio