Treatment of severe psoriasis with infliximab

Psoriasis is a chronic, immune mediated inflammatory disease characterized by increased cell signalling via cytokines and chemokines on a background of up-regulated gene expression. There is substantial evidence that psoriasis should be regarded as more than a cutaneous disease; major psychological morbidity and increased mortality from cardiovascular disease and cancer are increasingly recognized. Improved understanding of the genetic and immunological mechanisms underpinning psoriasis has occurred concurrently with the development of targeted biological therapies including infliximab. These newer therapeutic approaches can be very effective but their long term safety profile is not yet fully determined

MicroRNA-146 and cell trauma down-regulate expression of the psoriasis-associated atypical chemokine receptor ACKR2

Chemokines are the principal regulators of leukocyte migration and are essential for initiation and maintenance of inflammation. Atypical chemokine receptor 2 (ACKR2) binds and scavenges proinflammatory CC-chemokines, regulates cutaneous T-cell positioning, and limits the spread of inflammation in vivo. Altered ACKR2 function has been implicated in several inflammatory disorders, including psoriasis, a common and debilitating T-cell–driven disorder characterized by thick erythematous skin plaques. ACKR2 expression is abnormal in psoriatic skin, with decreased expression correlating with recruitment of T-cells into the epidermis and increased inflammation. However, the molecular mechanisms that govern ACKR2 expression are not known. Here, we identified specific psoriasis-associated microRNAs (miRs) that bind ACKR2, inhibit its expression, and are active in primary cultures of human cutaneous cells. Using both in silico and in vitro approaches, we show that miR-146b and miR-10b directly bind the ACKR2 3′-UTR and reduce expression of ACKR2 transcripts and protein in keratinocytes and lymphatic endothelial cells, respectively. Moreover, we demonstrate that ACKR2 expression is further down-regulated upon cell trauma, an important trigger for the development of new plaques in many psoriasis patients (the Koebner phenomenon). We found that tensile cell stress leads to rapid ACKR2 down-regulation and concurrent miR-146b up-regulation. Together, we provide, for the first time, evidence for epigenetic regulation of an atypical chemokine receptor. We propose a mechanism by which cell trauma and miRs coordinately exacerbate inflammation via down-regulation of ACKR2 expression and provide a putative mechanistic explanation for the Koebner phenomenon in psoriasis

Risk of major cardiovascular events in patients with psoriasis receiving biologic therapies: a prospective cohort study.

BACKGROUND: The cardiovascular safety profile of biologic therapies used for psoriasis is unclear. OBJECTIVES: To compare the risk of major cardiovascular events (CVEs; acute coronary syndrome, unstable angina, myocardial infarction and stroke) in patients with chronic plaque psoriasis treated with adalimumab, etanercept or ustekinumab in a large prospective cohort. METHODS: Prospective cohort study examining the comparative risk of major CVEs was conducted using the British Association of Dermatologists Biologics and Immunomodulators Register. The main analysis compared adults with chronic plaque psoriasis receiving ustekinumab with tumour necrosis-α inhibitors (TNFi: etanercept and adalimumab), whilst the secondary analyses compared ustekinumab, etanercept or methotrexate against adalimumab. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using overlap weights by propensity score to balance baseline covariates among comparison groups. RESULTS: We included 5468 biologic-naïve patients subsequently exposed (951 ustekinumab; 1313 etanercept; and 3204 adalimumab) in the main analysis. The secondary analyses also included 2189 patients receiving methotrexate. The median (p25-p75) follow-up times for patients using ustekinumab, TNFi, adalimumab, etanercept and methotrexate were as follows: 2.01 (1.16-3.21), 1.93 (1.05-3.34), 1.94 (1.09-3.32), 1.92 (0.93-3.45) and 1.43 (0.84-2.53) years, respectively. Ustekinumab, TNFi, adalimumab, etanercept and methotrexate groups had 7, 29, 23, 6 and 9 patients experiencing major CVEs, respectively. No differences in the risk of major CVEs were observed between biologic therapies [adjusted HR for ustekinumab vs. TNFi: 0.96 (95% CI 0.41-2.22); ustekinumab vs. adalimumab: 0.81 (0.30-2.17); etanercept vs. adalimumab: 0.81 (0.28-2.30)] and methotrexate against adalimumab [1.05 (0.34-3.28)]. CONCLUSIONS: In this large prospective cohort study, we found no significant differences in the risk of major CVEs between three different biologic therapies and methotrexate. Additional studies, with longer term follow-up, are needed to investigate the potential effects of biologic therapies on incidence of major CVEs

A standardization approach to compare treatment safety and effectiveness outcomes between clinical trials and real‐world populations in psoriasis

Background: Patients recruited in randomized controlled trials (RCTs) for biologic therapies in psoriasis are not fully representative of the real‐world psoriasis population. Objectives: Firstly, to investigate whether patient characteristics are associated with being included in a psoriasis RCT. Secondly, to estimate the differences in the incidence of severe adverse events (SAEs) and the response rate between RCT and real‐world populations of patients on biologic therapies for psoriasis using a standardization method. Methods: Data from the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR) were appended to individual participant‐level data from two RCTs assessing ustekinumab in patients with psoriasis. Baseline variables were assessed for association of being in an RCT using a multivariable logistic regression model. Propensity score weights were derived to reweigh the registry population so that variables had the distribution of the trial population. We measured the C‐statistic of the model with trial status as the dependent variable, and the risk differences in the incidence rate of SAEs in the first year and Psoriasis Area and Severity Index (PASI) after 6 months in the BADBIR cohort before and after weighting. Results: In total 6790 registry and 2021 RCT participants were included. The multivariable logistic regression model had a C‐statistic of 0.82 [95% confidence interval (CI) 0.81–0.83]. The risk differences for the incidence rate of SAEs and the proportion of patients with PASI < 1.5 were 9.27 (95% CI −3.91–22.5) per 1000 person‐years and 0.95 (95% CI −1.98–4.15), respectively. Conclusions: Our results suggest that RCTs of biologic therapies in patients with psoriasis are not fully representative of the real‐world population, but this lack of external validity does not account for the efficacy–effectiveness gap

Optimizing atrio-ventricular delay in pacemakers using potentially implantable physiological biomarkers

Background Hemodynamically optimal atrioventricular (AV) delay can be derived by echocardiography or beat-by-beat blood pressure (BP) measurements, but analysis is labor intensive. Laser Doppler perfusion monitoring measures blood flow and can be incorporated into future implantable cardiac devices. We assess whether laser Doppler can be used instead of BP to optimize AV delay. Methods Fifty eight patients underwent 94 AV delay optimizations with biventricular or His-bundle pacing using laser Doppler and simultaneous noninvasive beat-by-beat BP. Optimal AV delay was defined using a curve of hemodynamic response to switching from AAI (reference state) to DDD (test state) at several AV delays (40–320 ms), with automatic quality control checking precision of the optimum. Five subsequent patients underwent an extended protocol to test the impact of greater numbers of alternations on optimization quality. Results 55/94 optimizations passed quality control resulting in an optimal AV delay on laser Doppler similar to that derived by BP (median absolute deviation 12 ms). An extended protocol with increasing number of replicates consistently improved quality and reduced disagreement between laser Doppler and BP optima. With only five replicates, no optimization passed quality control, and the median absolute deviation would be 29 ms. These improved progressively until at 50 replicates, all optimizations passed quality control and the median absolute deviation was only 13 ms. Conclusions Laser Doppler perfusion produces hemodynamic optima equivalent to BP. Quality control can be automatic. Adding more replicates, consistently improves quality. Future implantable devices could use such methods to dynamically and reliably optimize AV delays

The BSR-PsA:study protocol for the British Society for Rheumatology psoriatic arthritis register

Acknowledgements We acknowledge contribution of BSR-PsA study staff, under the supervision of KFK: Maureen Heddle, Barry Morris, Jonathan Lock and Jane Brady. We also acknowledge the support from the Centre for Healthcare Randomised Trials (CHaRT) at the University of Aberdeen, especially Mark Forrest and Brian Taylor, for database and IT support. We would like to thank Professor Iain McInnes from the University of Glasgow, and our International Advisory Committee (Professors Merete Hetland, Oliver Fitzgerald and Philip Mease), for their comments when developing the protocol and for advice in harmonising data collection with other international studies, and the staff at the British Society for Rheumatology, in particular Alan Roach, Ross Matthews, Chris Hiley and Debbie MacDonald. Finally, we are indebted to the staff at all participating NHS trusts (details of which are available from www.abdn.ac.uk/bsr-psa) and especially the NIHR Clinical Research Network research nurses for their assistance with participant recruitment and data collection. Funding The BSR-PsA is funded by the BSR as part of its rheumatology registers portfolio and, in turn, receives funding for this from pharmaceutical companies. At the time of publication, only Amgen (previously Celgene) have contributed to the funding of the BSR-PsA. Pharmaceutical companies providing funds to BSR do not participant in the conduct or oversight of the study. However, they do receive advance notice of publications on which they are able to comment. Companies contributing to the funding of the register can request anonymised data on clinically confirmed serious adverse events and some events of special interest (e.g. pregnancy) among participants prescribed the specific bDMARD or tsDMARD agents that they manufacture. Other than this information, they do not have access to any raw data. They may, however, request specific analyses to be performed, for which a pre-specific analysis plan is discussed, and additional funds are provided.Peer reviewedPublisher PD

Fine Mapping of the Psoriasis Susceptibility Locus PSORS1 Supports HLA-C as the Susceptibility Gene in the Han Chinese Population

PSORS1 (psoriasis susceptibility gene 1) is a major susceptibility locus for psoriasis. Several fine-mapping studies have highlighted a 300-kb candidate region of PSORS1 where multiple biologically plausible candidate genes were suggested. The most recent study has indicated HLA-Cw6 as the primary PSORS1 risk allele within the candidate region in a Caucasian population. In this study, a family-based association analysis of the PSORS1 locus was performed by analyzing 10 polymorphic microsatellite markers from the PSORS1 region as well as HLA-B, HLA-C and CDSN loci in 163 Chinese families of psoriasis. Five marker loci show strong evidence (P<10−3), and one marker locus shows weak evidence (P = 0.04) for association. The haplotype cluster analysis showed that all the risk haplotypes are Cw6 positive and share a 369-kb region of homologous marker alleles which carries all the risk alleles, including HLA-Cw6 and CDSN*TTC, identified in this study. The recombinant haplotype analysis of the HLA-Cw6 and CDSN*TTC alleles in 228 Chinese families showed that the HLA-Cw6−/CDSN*TTC+ recombinant haplotype is clearly not associated with risk for psoriasis (T∶NT = 29:57, p = 0.0025) in a Chinese population, suggesting that the CDSN*TTC allele itself does not confer risk without the presence of the HLA-Cw6 allele. The further exclusion analysis of the non-risk HLA-Cw6−/CDSN*TTC+ recombinant haplotypes with common recombination breakpoints has allowed us to refine the location of PSORS1 to a small candidate region. Finally, we performed a conditional linkage analysis and showed that the HLA-Cw6 is a major risk allele but does not explain the full linkage evidence of the PSORS1 locus in a Chinese population. By performing a series of family-based association analyses of haplotypes as well as an exclusion analysis of recombinant haplotypes, we were able to refine the PSORS1 gene to a small critical region where HLA-C is a strong candidate to be the PSORS1 susceptibility gene