A. David Burden

Differential Drug Survival of Biologic Therapies for the Treatment of Psoriasis: A Prospective Observational Cohort Study from the British Association of Dermatologists Biologic Interventions Register (BADBIR).

Drug survival reflects a drugs effectiveness, safety, and tolerability. We assessed the drug survival of biologics used to treat psoriasis in a prospective national pharmacovigilance cohort (British Association of Dermatologists Biologic Interventions Register (BADBIR)). The survival rates of the first course of biologics for 3,523 biologic-naive patients with chronic plaque psoriasis were compared using survival analysis techniques and predictors of discontinuation analyzed using a multivariate Cox proportional hazards model. Data for patients on adalimumab (n=1,879), etanercept (n=1,098), infliximab (n=96), and ustekinumab (n=450) were available. The overall survival rate in the first year was 77%, falling to 53% in the third year. Multivariate analysis showed that female gender (hazard ratio (HR) 1.22; 95% confidence interval (CI): 1.09-1.37), being a current smoker (HR 1.19; 95% CI: 1.03-1.38), and a higher baseline dermatology life quality index (HR 1.01; 95% CI: 1.00-1.02) were predictors of discontinuation. Presence of psoriatic arthritis (HR 0.82; 95% CI: 0.71-0.96) was a predictor for drug survival. As compared with adalimumab, patients on etanercept (HR 1.63; 95% CI: 1.45-1.84) or infliximab (HR 1.56; 95% CI: 1.16-2.09) were more likely to discontinue therapy, whereas patients on ustekinumab were more likely to persist (HR 0.48; 95% CI: 0.37-0.62). After accounting for relevant covariates, ustekinumab had the highest first-course drug survival. The results of this study will aid clinical decision making when choosing biologic therapy for psoriasis patients.

Meta-Analysis Confirms the LCE3C_LCE3B Deletion as a Risk Factor for Psoriasis in Several Ethnic Groups and Finds Interaction with HLA-Cw6

A multicenter meta-analysis including data from 9,389 psoriasis patients and 9,477 control subjects was performed to investigate the contribution of the deletion of genes LCE3C and LCE3B, involved in skin barrier defense, to psoriasis susceptibility in different populations. The study confirms that the deletion of LCE3C and LCE3B is a common genetic factor for susceptibility to psoriasis in the European populations (OR(Overall) = 1.21 (1.15-1.27)), and for the first time directly demonstrates the deletions association with psoriasis in the Chinese (OR = 1.27 (1.16-1.34)) and Mongolian (OR = 2.08 (1.44-2.99)) populations. The analysis of the HLA-Cw6 locus showed significant differences in the epistatic interaction with the LCE3C and LCE3B deletion in at least some European populations, indicating epistatic effects between these two major genetic contributors to psoriasis. The study highlights the value of examining genetic risk factors in multiple populations to identify genetic interactions, and indicates the need of further studies to understand the interaction of the skin barrier and the immune system in susceptibility to psoriasis.

Psoriasis and Other Complex Trait Dermatoses: From Loci to Functional Pathways

Driven by advances in molecular genetic technologies and statistical analysis methodologies, there have been huge strides taken in dissecting the complex genetic basis of many inflammatory dermatoses. One example is psoriasis where application of classical linkage analysis and genome wide association investigation has identified genetic loci of major and minor effect. Although most loci independently have modest genetic effect, they identify important biological pathways potentially relevant to disease pathogenesis and therapeutic intervention. In the case of psoriasis these appear to involve the epidermal barrier, NF-κB mechanisms and Th17 adaptive immune responses. The advent of next generation sequencing methods will permit a more detailed and complete map of disease genetic architecture, a key step in developing personalised medicine strategies in the clinical management of the complex inflammatory dermatoses.

AP1S3 Mutations Are Associated with Pustular Psoriasis and Impaired Toll-like Receptor 3 Trafficking

Adaptor protein complex 1 (AP-1) is an evolutionary conserved heterotetramer that promotes vesicular trafficking between the trans-Golgi network and the endosomes. The knockout of most murine AP-1 complex subunits is embryonically lethal, so the identification of human disease-associated alleles has the unique potential to deliver insights into gene function. Here, we report two founder mutations (c.11T>G [p.Phe4Cys] and c.97C>T [p.Arg33Trp]) in AP1S3, the gene encoding AP-1 complex subunit σ1C, in 15 unrelated individuals with a severe autoinflammatory skin disorder known as pustular psoriasis. Because the variants are predicted to destabilize the 3D structure of the AP-1 complex, we generated AP1S3-knockdown cell lines to investigate the consequences of AP-1 deficiency in skin keratinocytes. We found that AP1S3 silencing disrupted the endosomal translocation of the innate pattern-recognition receptor TLR-3 (Toll-like receptor 3) and resulted in a marked inhibition of downstream signaling. These findings identify pustular psoriasis as an autoinflammatory phenotype caused by defects in vesicular trafficking and demonstrate a requirement of AP-1 for Toll-like receptor homeostasis.

IL36RN mutations define a severe autoinflammatory phenotype of generalized pustular psoriasis

Safia Hussain, BSc, Dorottya M Berki, BSc, Siew-Eng Choon, MRCP, A David Burden, MD, FRCP, Michael H Allen, PhD, Juan I Arostegui, MD, PhD, Antonio Chaves, MD, Michael Duckworth, Alan D Irvine, MD, Maja Mockenhaupt, MD, PhD, Alexander A Navarini, MD, PhD, Marieke MB Seyger, MD, PhD, Pere Soler-Palacin, MD, PhD, Christa Prins, MD, Laurence Valeyrie-Allanore, MD, M Asuncion Vicente, MD, Richard C Trembath, FMedSci, Catherine H Smith, MD, FRCP, Jonathan N Barker, MD, FRCP,* Francesca Capon, PhD,*

Quantitative Evaluation of Biologic Therapy Options for Psoriasis: A Systematic Review and Network Meta-Analysis

Multiple biologic treatments are licensed for psoriasis. The lack of head-to-head randomized controlled trials makes choosing between them difficult for patients, clinicians, and guideline developers. To establish their relative efficacy and tolerability, we searched MEDLINE, PubMed, Embase, and Cochrane for randomized controlled trials of licensed biologic treatments for skin psoriasis. We performed a network meta-analysis to identify direct and indirect evidence comparing biologics with one another, methotrexate, or placebo. We combined this with hierarchical cluster analysis to consider multiple outcomes related to efficacy and tolerability in combination for each treatment. Study quality, heterogeneity, and inconsistency were evaluated. Direct comparisons from 41 randomized controlled trials (20,561 participants) were included. All included biologics were efficacious compared with placebo or methotrexate at 3–4 months. Overall, cluster analysis showed adalimumab, secukinumab, and ustekinumab were comparable in terms of high efficacy and tolerability. Ixekizumab and infliximab were differentiated by very high efficacy but poorer tolerability. The lack of longer term controlled data limited our analysis to short-term outcomes. Trial performance may not equate to real-world performance, and so results need to be considered alongside real-world, long-term safety and effectiveness data. These data suggest that it is possible to discriminate between biologics to inform clinical practice and decision making (PROSPERO 2015:CRD42015017538).

Activating CARD14 mutations are associated with generalized pustular psoriasis but rarely account for familial recurrence in psoriasis vulgaris

Caspase recruitment family member 14 (CARD14, also known as CARMA2), is a scaffold protein that mediates NF-κB signal transduction in skin keratinocytes. Gain-of-function CARD14 mutations have been documented in familial forms of psoriasis vulgaris (PV) and pityriasis rubra pilaris (PRP). More recent investigations have also implicated CARD14 in the pathogenesis of pustular psoriasis. Follow-up studies, however, have been limited, so that it is not clear to what extent CARD14 alleles account for the above conditions. Here, we sought to address this question by carrying out a systematic CARD14 analysis in an extended patient cohort (n=416). We observed no disease alleles in subjects with familial PV (n=159), erythrodermic psoriasis (n=23), acral pustular psoriasis (n=100), or sporadic PRP (n=29). Conversely, our analysis of 105 individuals with generalized pustular psoriasis (GPP) identified a low-frequency variant (p.Asp176His) that causes constitutive CARD14 oligomerization and shows a significant association with GPP in Asian populations (P=8.4×10(-5); odds ratio=6.4). These data indicate that the analysis of CARD14 mutations could help stratify pustular psoriasis cohorts but would be mostly uninformative in the context of psoriasis and sporadic PRP.

AP1S3 Mutations Cause Skin Autoinflammation by Disrupting Keratinocyte Autophagy and Up-Regulating IL-36 Production

Prominent skin involvement is a defining characteristic of autoinflammatory disorders caused by abnormal IL-1 signaling. However, the pathways and cell types that drive cutaneous autoinflammatory features remain poorly understood. We sought to address this issue by investigating the pathogenesis of pustular psoriasis, a model of autoinflammatory disorders with predominant cutaneous manifestations. We specifically characterized the impact of mutations affecting AP1S3, a disease gene previously identified by our group and validated here in a newly ascertained patient resource. We first showed that AP1S3 expression is distinctively elevated in keratinocytes. Because AP1S3 encodes a protein implicated in autophagosome formation, we next investigated the effects of gene silencing on this pathway. We found that AP1S3 knockout disrupts keratinocyte autophagy, causing abnormal accumulation of p62, an adaptor protein mediating NF-κB activation. We showed that as a consequence, AP1S3-deficient cells up-regulate IL-1 signaling and overexpress IL-36α, a cytokine that is emerging as an important mediator of skin inflammation. These abnormal immune profiles were recapitulated by pharmacological inhibition of autophagy and verified in patient keratinocytes, where they were reversed by IL-36 blockade. These findings show that keratinocytes play a key role in skin autoinflammation and identify autophagy modulation of IL-36 signaling as a therapeutic target.

IgA class anticardiolipin antibodies in cutaneous leukocytoclastic vasculitis

BACKGROUND Autoantibodies may be detected in the serum of some patients with cutaneous leukocytoclastic vasculitis. We have previously reported the presence of IgA anticardiolipin antibodies (ACAs) in one patient with leukocytoclastic vasculitis associated with IgA nephropathy. OBJECTIVE Our purpose was to determine the prevalence of IgA ACAs in unselected groups of patients with cutaneous vasculitis, IgA nephropathy, and Henoch-Schönlein purpura. METHODS Thirty patients (10 each with cutaneous vasculitis, IgA nephropathy, and Henoch-Schönlein purpura) and 31 healthy control subjects were studied. ACA titers were measured by a standardized enzyme-linked immunosorbent assay. RESULTS ACAs restricted to the IgA isotype were present in 6 of 10 patients with cutaneous leukocytoclastic vasculitis. IgA ACA levels were significantly higher in these patients than in the control subjects. The presence of IgA ACAs did not correlate with disease severity or involvement of other organs and persisted after resolution of the vasculitis in most patients. In five of the six patients with IgA ACAs, drugs were implicated in the pathogenesis of the vasculitis. By contrast, ACAs were present in only a minority of children with Henoch-Schönlein purpura and adults with IgA nephropathy and were not restricted to the IgA isotype. CONCLUSION We have demonstrated a clear association between IgA ACAs and cutaneous leukocytoclastic vasculitis. The absence of IgA ACAs in Henoch-Schönlein purpura argues against their being an epiphenomenon in vasculitis.

IgA anticardiolipin antibodies associated with Henoch-Schönlein purpura

Henoch-Schönlein purpura is associated with the deposition of immune complexes containing IgA. The nature of the antigen in these immune complexes is uncertain but in some reported cases has included autoantigens such as IgA rheumatoid factor and IgA antineutrophil cytoplasmic antibody. We report the finding of an IgA class anticardiolipin antibody in a 51-year-old patient with Henoch-Schönlein purpura. A potential role for IgA autoantibodies in Henoch-Schönlein purpura needs to be further explored.