Marcus Schmitt-Egenolf

Genomewide Scan in German Families Reveals Evidence for a Novel Psoriasis-Susceptibility Locus on Chromosome 19p13

Psoriasis is a common chronic inflammatory skin disease with a strong genetic component. Few psoriasis-susceptibility loci have been reported, and only two have been confirmed in independent data sets. This article reports results of a genomewide scan that was performed, using 370 microsatellite markers, for psoriasis-susceptibility loci in 32 German extended families, comprising 162 affected and 195 unaffected individuals. Nonparametric linkage analysis of all families provided strong evidence for a novel psoriasis-susceptibility locus on chromosome 19p (Zlr=3.50; P=.0002). Parametric analysis revealed a heterogeneity LOD score of 4.06, corresponding to a genomewide significance level of.037, under the assumption of a recessive model with high disease-allele frequency and 66% as the proportion of linked families. This study confirms linkage of psoriasis to the HLA region on chromosome 6p and suggests additional regions on chromosomes 8q and 21q for further investigations.

Association between interleukin-1 receptor antagonist (IL-1ra) gene polymorphism and early and late-onset psoriasis

Association between interleukin-1 receptor antagonist (IL-1ra) gene polymorphism and early and late-onset psoriasis

The higher proportion of men with psoriasis treated with biologics may be explained by more severe disease in men.

Objectives Moderate to severe psoriasis, once regarded as merely a skin disease, is today seen as an inflammatory systemic disease. The sex ratio of the prevalence of psoriasis is balanced. In recent years several reports have documented that men receive more systemic or UV treatment than women, and different hypotheses were made. In PsoReg, the national registry for systemic treatment of psoriasis in Sweden, we have, like other European registries, observed a predominance of men (59%), especially of men treated with biologics (63%). Biologics are a relatively new group of very effective but high-priced drugs. The objective of this study was to analyse if women are discriminated by not having the same access to the high-priced biologics. Design Population based cohort study using data from a nationwide quality register of psoriasis patients. Population 2294 patients with moderate to severe psoriasis receiving systemic treatment from a specialist in dermatology. Main Outcome Measures Time to initiation of biologic treatment. A multiple Cox proportional hazard’s regression was performed, with time to initiating a biologic treatment as the outcome in order to assess the independent role of the patient’s sex in initiating such therapy. The psoriasis severity was defined as a time-varying variable. Results Men had more severe psoriasis than women according to the Psoriasis Area and Severity Index (PASI), regardless of age at enrolment, and throughout the study period. The analysis in the multiple Cox regression show that age, psoriasis severity and psoriasis arthropathy were relevant factors for initiating biologic therapy, whereas sex is not. Conclusions Although as many women as men are believed to suffer from psoriasis, men seem to be more severely affected by psoriasis. The asymmetry in allocation of biologic therapy thereby probably reflects the differing disease activity between the sexes, and is not a discrimination against women per se.

Analysis of three outcome measures in moderate to severe psoriasis : a registry-based study of 2450 patients

Summary Background  As moderate to severe psoriasis is a systemic disease with large effects on health‐related quality of life, generic measures that include overall health, not only skin involvement, are necessary. Knowledge about the relationship between the generic preference‐based EuroQol 5D (EQ‐5D) and dermatology‐specific measures in psoriasis is limited.

PsoReg - The Swedish Registry for Systemic Psoriasis Treatment The Registry's Design and Objectives

With the introduction of new systemic drugs for the management of psoriasis, we felt an obligation in Sweden to establish a trusted tool to monitor their use. We formed PsoReg to create a solid, long-term database in order to analyze safety and effectiveness of different systemic psoriasis treatment regimens. PsoReg will provide information to help clinicians individualize therapy on a rational basis through evaluation of effectiveness and adverse effects in specific patient subgroups. Designed and managed by specialized health care professionals, PsoReg will enroll all psoriasis patients on systemic treatment to allow a fair comparison of old versus new-generation psoriasis treatments. PsoReg will even create benchmark data for quality assurance of the medical service. A web-based design allows real-time pharmacovigilance and enables the registry to assist clinicians in their day-to-day management of psoriasis patients. In this way PsoReg can become an integrated part of tomorrow’s dermatology.

Psoriasis Therapy in Real Life: The Need for Registries

The introduction of new therapeutic options for the management of psoriasis is a challenge for the dermatology community, and new tools are needed to face this challenge. This article argues for the establishment of profession-based registries to collect solid, long-term data on the safety and effectiveness of different psoriasis treatment regimens. Managed by health care professionals, registries will be most successful if they enroll patients based on indications for treatment rather than on drugs given. This protects the evaluation process from commercial influences and allows a fair comparison of old- versus new-generation psoriasis treatments. In contrast to the patients in a registry who receive care in the natural clinical setting, subjects in randomized clinical trials (RCTs) are selected according to study criteria and may therefore not reflect the experience of patients in clinical practice. It is possible that particular risks and opportunities in the real patient population may therefore go undetected in RCTs.

Association scan of the novel psoriasis susceptibility region on chromosome 19: evidence for both susceptible and protective loci.

Abstract:  To follow up the novel psoriasis susceptibility region on chromosome 19 (PSORS6), we performed an association scan for psoriasis vulgaris using 45 evenly spaced DNA microsatellite markers. For this study, a new independent sample of 210 nuclear psoriasis families (trio design) from Northern Germany was recruited. We used the family based association test (FBAT) for an association scan over the chromosome 19 region encompassing 50.8 cM. We obtained a positive association for the markers D19S922 (allele 5, P = 0.008) and D19S916 (allele 13, P = 0.016), which correspond to the peak of the region identified in a previously performed scan. We identified two novel regions by a single marker, each showing negative association at D19S917 on 19p13.1 (allele 8, P = 0.0034) and at D19S425 (allele 9, P = 0.0005), compatible with the hypothesis of protective loci. These two novel regions were explored in more detail using novel microsatellite markers at an average distance of 100 kb. A separate analysis distinguishing between familial (n = 137) and sporadic (n = 73) psoriasis families showed that the familial trios contribute strongly in the region around D19S425 (P = 0.004), while the comparably small subset of 73 sporadic trios has a stronger effect at the locus around D19S917 (P = 0.026). These studies confirm the existence of a psoriasis susceptibility locus on chromosome 19 and give first evidence for the existence of both susceptible and protective loci in this region. Analysis of a dense marker set from these refined regions will eventually allow identification of the underlying susceptibility alleles.

Switch to Biological Agent in Psoriasis Significantly Improved Clinical and Patient-Reported Outcomes in Real-World Practice

Background: Although clinical studies have shown efficacy of biological agents in moderate to severe psoriasis, observational studies of real-world effectiveness are rare. Objective: To analyse the psoriasis area and severity index (PASI) and quality of life by the EQ-5D questionnaire and dermatology quality of life index (DLQI) in psoriasis patients who switched from conventional systemic treatment to biological agents in clinical practice. Furthermore, to analyse patient groups with the highest benefit of biological agents. Methods: Longitudinal, observational study based on the Swedish National Registry for Systemic Treatment of Pso-riasis, PsoReg. Outcomes of biological-naïve patients who switched to a biological agent (n = 267) were analysed before switch and at the first follow-up. Results: Patients significantly improved in EQ-5D, DLQI and PASI (p < 0.001). Patients with DLQI ≥10 and/or PASI ≥10 had the greatest benefits from biological agents in terms of EQ-5D. Conclusions: Patients with moderate to severe psoriasis benefit from biological agents in clinical practice; the patients with the highest benefits were those with high pretreatment PASI and DLQI scores.

Challenges for Synthesising Data in a Network of Registries for Systemic Psoriasis Therapies

Background: Large disease registries are the preferred method to assess long-term treatment safety. If psoriasis registries collaborate in a network, their power to assess safety is increased. Objective: To identify heterogeneity in psoriasis registries and methodological challenges for synthesising the data they provide. Methods: We surveyed the registries in PSONET and identified and addressed the challenges to collaborative analysis for the network in several round table meetings. Results: Eight out of 10 registries had a prospective comparator cohort with similar disease characteristics but not on biologics. Registries differed in the coding and validation or follow-up of adverse events and in the way they sampled their population. Fifteen challenges to registries collaborating were identified in the areas of operational governance, structural conduct, bias and analysis. Conclusions: Participation in PSONET, a network of psoriasis registries, helps identify and solve common issues, enhancing the individual registries, and provides larger sets of more powerful safety data in a diverse population. Challenges to interpreting data collectively include heterogeneity in sampling, variable penetration of biologics and compatibility of different datasets.

EDAR mutation in autosomal dominant hypohidrotic ectodermal dysplasia in two Swedish families

BackgroundHypohidrotic ectodermal dysplasia (HED) is a genetic disorder characterized by defective development of teeth, hair, nails and eccrine sweat glands. Both autosomal dominant and autosomal recessive forms of HED have previously been linked to mutations in the ectodysplasin 1 anhidrotic receptor (EDAR) protein that plays an important role during embryogenesis.MethodsThe coding DNA sequence of the EDAR gene was analyzed in two large Swedish three-generational families with autosomal dominant HED.ResultsA non-sense C to T mutation in exon 12 was identified in both families. This disease-specific mutation changes an arginine amino acid in position 358 of the EDAR protein into a stop codon (p.Arg358X), thereby truncating the protein. In addition to the causative mutation two polymorphisms, not associated with the HED disorder, were also found in the EDAR gene.ConclusionThe finding of the p.Arg358X mutation in the Swedish families is the first corroboration of a previously described observation in an American family. Thus, our study strengthens the role of this particular mutation in the aetiology of autosomal dominant HED and confirms the importance of EDAR for the development of HED.