Komorbidität bei Psoriasis vulgaris

Psoriasis is a systemic chronic inflammatory disease associated with comorbidity. Many epidemiological studies have shown that psoriasis is associated with psoriatic arthritis as well as cardiovascular and metabolic diseases. Furthermore, obesity and psychological diseases such as depression and anxiety disorders are linked with psoriasis and play a central role in its management. The association of psoriasis and its comorbidity can be partly explained by genetic and pathophysiological mechanisms. Approximately 40 psoriasis susceptibility loci have been described with the majority linked to the innate and adaptive immune system. In some associated diseases, such as psoriatic arthritis, an overlap of their genetic susceptibility exists. Pathophysiologically the “psoriatic march” is a model that describes the development of metabolic and cardiovascular diseases due to the presence of underlying systemic inflammation. Dermatologists are the gatekeepers to treatment for patients with psoriasis. The early detection and the management of comorbidity is part of their responsibility. Concepts for the management of psoriasis and tools to screen for psoriatic comorbidity have been developed in order to support dermatologists in daily practice.     

GENETICS OF PSORIASIS AND PSORIATIC ARTHRITIS

It is well established that psoriasis and psoriatic arthritis (PsA) have a strong genetic component. Recent advances in genetics have confirmed previous associations and new loci have been discovered. However, these loci do not fully account for the high heritability of psoriasis and PsA and therefore many genetic as well as environmental factors remain to be identified. This paper reviews the current status of genetic studies in psoriasis and PsA.     

The quest for psoriasis susceptibility genes in the postgenome-wide association studies era: charting the road ahead

The International Psoriasis Council, a global nonprofit organization dedicated to advancing psoriasis research and treatment, organized its inaugural genetics workshop in Montreal, on 12 October 2011. The presentations included a summary of the remarkable progress achieved through the implementation of genome-wide association studies, which have highlighted key pathogenic pathways for psoriasis. Ongoing meta-analyses are identifying further susceptibility genes, bringing the number of known loci close to 40. The functional characterization of low-risk alleles is proving problematic, but next-generation sequencing approaches are expected to identify rare deleterious variants, which will be easier to investigate. Elucidating the genetic architecture of psoriasis will have major implications in terms of understanding disease mechanisms and predicting response to treatment.     

Genetics of common chronic inflammatory skin diseases : An update on atopic dermatitis and psoriasis

Atopic dermatitis and psoriasis are two common chronic inflammatory skin diseases. Both are multifactorial disorders caused by an interaction between genetic and environmental factors. Epidemiological studies estimated a high heritability of up to 80% for both diseases, indicating a major role of genetic susceptibility factors in disease development and progression. However, in contrast to monogenic disorders, complex diseases are not caused by single gene mutations, but are the result of a complicated network of numerous susceptibility loci, many of which exert additive or synergistic effects, but have only a small role when considered in isolation. Knowledge on the genetic architecture of atopic dermatitis and psoriasis is still incomplete, but major advances have been made in the past years, in particular through genome-wide association approaches.     

Genome-wide studies of psoriasis susceptibility loci: a review

Psoriasis is a chronic inflammatory dermatosis affecting approximately 0.3-5% world-wide. Since 1997, nine genome-wide scans have been published in the search for predisposing genes to psoriasis and psoriatic arthritis. These genome-wide scans have provided results that both confirm earlier work, but which also suggest novel regions of interest on the genome. This article reviews the results of these genome-wide scans, in particular two novel regions on chromosomes 3p and 15p, and compares the study types and designs. The results in these two regions were compared in the different studies providing no further suggestive evidence, and we suggest that these results may be false-positives, population-specific susceptibility loci or due to the stratification used in the study design. We suggest stratifying the data into epidemiological subgroups in order to make the genome-wide scans more sensitive to loci specific to these subgroups. This approach could provide a much more powerful technique to study the genetics of a complex disease such as psoriasis.     

Loss-of-function variants of the filaggrin gene are not major susceptibility factors for psoriasis vulgaris or psoriatic arthritis in German patients

Psoriasis vulgaris and atopic dermatitis share a number of features such as chronic cutaneous inflammation and disturbed epidermal barrier function. Genome-wide scans have revealed a conspicuous overlap of susceptibility loci for both diseases involving chromosomal regions 1q21, 3q21, 17q25, and 20p12. Recently, two loss-of-function variants in the gene encoding filaggrin at 1q21 were shown to be strongly associated with atopic dermatitis. In view of a possible genetic overlap of the two skin diseases, we investigated 375 patients suffering from psoriasis vulgaris, 375 patients with psoriatic arthritis, and 376 control probands. Moreover we directly studied expression of filaggrin in 10 patients suffering from psoriasis vulgaris. Our immunohistochemical analysis revealed a checkered pattern with alternating positive broadened or almost absent filaggrin expression. However, no association was found for the two variants of filaggrin (FLG). We conclude that despite a markedly altered filaggrin expression in psoriatic skin, loss-of-function variants of the FLG gene are neither associated with psoriasis vulgaris nor with psoriatic arthritis. The abnormal staining might reflect the altered epidermal differentiation. Our findings imply that the genetic background underlying the epidermal barrier defect in psoriasis is distinct from that found in atopic dermatitis.     

Current understanding of human genetics and genetic analysis of psoriasis

During the past 5 years, genome-wide association studies (GWAS), primarily based on single nucleotide polymorphism markers, have identified many loci as potential psoriasis susceptibility regions. These studies appeared to provide strong evidence because the susceptibility genes are involved in the interleukin-23/T-helper 17 axis of psoriasis immunopathogenesis and/or skin barrier functions. However, the "identified" genes only explained a small proportion of psoriasis heritability, although it is known to be comparatively higher than that of other common diseases. GWAS are based on the hypothesis that disease-causing variants are high frequency variants within populations. However, this hypothesis is problematic because deleterious variants such as those predisposing to specific diseases will generally not be maintained by selection pressure throughout human evolution. This issue also affects psoriasis studies. Here, we review the current paradigm shift in human genetic analyses and its implications for detection of psoriasis-causing variants based on linkage analysis and GWAS, except the well-known psoriasis susceptibility locus HLA-C.     

Genetic susceptibility to vitiligo: Recent progress from genome-wide association studies

Generalized vitiligo (GV) is a complicated disease in which patchy depigmentation results from the autoimmune loss of melanocytes from affected regions. It may follow a pattern of polygenetic or multifactorial inheritance. Previously, a number of genetic susceptibility factors have been identified through linkage and candidate gene studies, such as HLA, PTPN22, NALP1, and XBP1. Recently, a series of genome-wide association studies have been carried out in different populations to further explore the susceptibility variants for GV. More than 30 robust susceptibility loci have been identified and confirmed. Most of these associated genes encode components of biological pathways reaching from the immune cell to the melanocytes. In this review, we summarize the advances of vitiligo epidemiology and genetics, and highlight recent findings from genome-wide association studies, emphasizing susceptibility loci and comparing the susceptibility loci between Chinese people and Caucasians. These genetic studies may help in providing an insight into the pathogenesis of this disease and initiating the feasibility of genetic diagnosis and personalized treatment for patients with GV in the future.     

内质网氨基肽酶1在银屑病发病中的作用

银屑病是一种慢性炎症性皮肤病，其发病机制尚不清楚，可能涉及遗传、环境及自身免疫等多方面因素。近年来，随着全基因组关联研究的进展，众多银屑病易感位点陆续被发现，内质网氨基肽酶1基因便是其中之一。几乎所有种族人群的研究均表明，内质网氨基肽酶1区域的许多单核苷酸多肽性与银屑病相关，且与HLA—c之间可能存在交互作用。内质网氨基肽酶1参与人白细胞抗原I类分子翻译后的加工，并与多种细胞膜表面受体的分裂有关。内质网氨基肽酶1还参与免疫调节，尤其与cD8T细胞的活化有关，与其他炎性细胞和细胞因子共同作用，诱发或维持银屑病的皮损。     

New biologics for psoriasis and psoriatic arthritis

The prevalence of psoriasis is estimated to be 2.2% in the United States, and 6–39% of patients with psoriasis also develop psoriatic arthritis. New advances have been made in developing treatment options. A new human tumor necrosis factor (TNF)-α antibody, golimumab, has been shown to significantly improve symptoms of psoriatic arthritis. In addition, clinical trials of certolizumab pegol, a PEGylated Fab' fragment of an anti-TNF-α monoclonal antibody, show promising results for treating rheumatoid arthritis and suggest that it may be applicable for treating psoriasis and psoriatic arthritis in the future. New biologic therapies also include antibodies to interleukin-12 and interleukin-23. Phase II studies suggest that ustekinumab is effective in alleviating symptoms of psoriasis and psoriatic arthritis. However, longer studies with radiographic evaluation will be required before their impact on joint destruction can be assessed.     

CARD15 mutations in patients with plaque-type psoriasis and psoriatic arthritis: lack of association

Psoriasis has a strong genetic component in the development of the disease as indicated by familial occurrence and a high concordance rate among monozygotic twins. In genome-wide scans for psoriasis several susceptibility loci have been detected, but the disease-causing genes have not yet been identified. A recent scan, performed on psoriatic arthritis (PsA), which occurs in about 15% of the psoriasis patients showed a significant locus on chromosome 16 in a region that was already described by genome scan for psoriasis. CARD15, a major susceptibility gene for Crohn’s disease (CD) on chromosome 16q, is an interesting candidate gene for psoriasis, because there is a documented clinical association of CD with psoriasis, and recently the association of CARD15 mutations with PsA was reported in Newfoundland population. We investigated the association of this variant with PsA and the overall psoriasis genotype in 59 independent patients with PsA in comparison with 361 age and sex-matched controls. In addition, a second cohort of 89 independent North American PsA patients was included. The diagnosis of psoriasis was made by a dermatologist based on standard clinical criteria. In these patients, PsA was defined as an inflammatory joint disease, negative rheumatoid factor, and lack of another causative condition for arthritis. Using case-control analysis, the G908R mutation was weakly associated with psoriasis and PsA, but due to the low frequency of this mutation statistical significance was not reached. All other variants including leu1007fsinsC and R702W did not show any association with psoriasis or PsA. In conclusion, a disease-causing role for CARD15 mutations could not be confirmed in German or American subjects with PsA.     

An investigation of rheumatoid arthritis loci in patients with early‐onset psoriasis validates association of the REL gene

Background Phenotypically diverse autoimmune conditions share common genetic susceptibility loci and underlying molecular pathways. Objectives By systematically searching for single nucleotide polymorphisms (SNPs) associated with another autoimmune disease, rheumatoid arthritis (RA), we aimed to elucidate novel genetic markers of psoriasis. Methods We investigated 18 SNPs, previously confirmed as being associated with RA, in a U.K. cohort of 623 patients with early‐onset psoriasis (presenting before age 40 years), comparing them with 2662 control subjects. Results Our findings confirm the association of early‐onset psoriasis with REL (rs13031237, P = 0·0027). The minor allele of REL had opposing effects upon susceptibility to disease in patients with psoriasis and RA. Conclusion Similar exploration of additional autoimmune loci and fine mapping of such regions may provide further insight into the genetics and molecular pathophysiology of psoriasis.     

Long-term study of infliximab in Japanese patients with plaque psoriasis, psoriatic arthritis, pustular psoriasis and psoriatic erythroderma

The efficacy and safety of infliximab in patients with plaque psoriasis, psoriatic arthritis, pustular psoriasis (excluding localized type) and psoriatic erythroderma were assessed in clinical practice. Without washout of the existing treatment of psoriasis, treatment was switched to infliximab, which was given at a dose of 5 mg/kg at weeks 0, 2 and 6 and then every 8 weeks up to week 46. The primary end-points were 75% improvement in Psoriasis Area and Severity Index score (PASI 75 response rate) for plaque psoriasis, 20% improvement in American College of Rheumatology criteria (ACR 20 response rate) for psoriatic arthritis, and global improvement in pustular psoriasis and psoriatic erythroderma. The PASI 75 response rate in plaque psoriasis was 72.2% at week 10 and 53.6% at week 50. The ACR 20 response rate in psoriatic arthritis was 66.7% at week 14 and 80.0% at week 46. The response defined as global improvement in pustular psoriasis was between 66.7% and 100.0% during the 2–50-week period. The response defined as global improvement in psoriatic erythroderma was between 75.0% and 100.0% during the week-2–50 period. There were 14 discontinued patients. The most frequently reported reason for discontinuation was the development of adverse events. However, there were no serious respiratory diseases, infections or infusion reactions. In patients with plaque psoriasis, psoriatic arthritis, pustular psoriasis and psoriatic erythroderma, infliximab was well tolerated, regardless of prior treatment, and also showed superior efficacy over a period of approximately 1 year.     

Lack of association between angiotensin I‐converting enzyme insertion/deletion polymorphism and psoriasis or psoriatic arthritis in Spain

Data on the potential influence of the angiotensin‐converting enzyme (ACE) insertion/ deletion (I/D) genotype on psoriasis are contradictory. Our aim was to investigate the relationship between the ACE gene I/D polymorphism and psoriasis/psoriatic arthritis. To investigate this, a genetic association study was conducted among 268 unrelated patients with psoriasis and 272 controls. The distribution of DD, ID, and II genotypes did not significantly differ between psoriatic patients and controls (DD: 39.6% vs. 34.2%; ID: 46.3% vs. 53.3%; II: 14.1% vs. 12.5%). In conclusion, the ACE polymorphism is not likely to be associated with either psoriasis or psoriatic arthritis in this study.     

Psoriasis and uveitis: a literature review

Psoriasis is a systemic, chronic, immunologically mediated disease, with significant genetic and environmental influences. It affects from 1 to 3% of the world population. Recently, the relation between psoriasis and different comorbidities, particularly metabolic syndrome, has become extremely relevant. Uveitis is characterized by a process of intraocular inflammation resulting from various causes. Considering psoriasis and uveitis as immune-mediated diseases, this study aims to evaluate the possible association of psoriasis and/or psoriatic arthritis with uveitis and its subtypes. Few studies have evaluated the association of uveitis and psoriasis without joint involvement. It seems that psoriasis without arthropathy is not a risk factor for the development of uveitis. Uveitis tends to develop more frequently in patients with arthropathy or pustular psoriasis than in patients with other forms of psoriasis. Ophthalmic examination should be performed periodically in patients with psoriasis and uveitis. If ophthalmopathy is diagnosed, the patient should receive adequate treatment with anti-inflammatory drugs or immunomodulators to prevent vision loss.     

Association of skin barrier genes within the PSORS4 locus is enriched in Singaporean Chinese with early-onset psoriasis

Psoriasis (OMIM#177900) is a common polygenic skin disorder affecting approximately 2% of the northern European population and 0.1% of the Han Chinese. Psoriasis patients suffer from chronic skin inflammation, manifested by erythematous scaly lesions. PSORS1-PSORS9 have been confirmed as psoriasis susceptibility loci in independent genetic studies on predominantly Caucasian populations, with psoriasis susceptibility loci (PSORS1, PSORS9) and additional loci at 9q33-34 and 2p22.3-11.2 reported in Han Chinese patients. In this study, we show the association of PSORS4 with psoriasis in Singaporean Chinese. Dense genotyping of single-nucleotide polymorphism-tagging candidate genes within the epidermal differentiation complex revealed significant association in the proximity of the involucrin gene (IVL); the strongest association was seen in early-onset psoriasis patients (P=0.0014). A follow-up genome-wide association screen localized the psoriasis susceptibility region to approximately 360 kb along chromosome 1 in the vicinity of IVL, small proline-rich region (SPRR) and proline-rich region 9 (PRR9) genes. The study of interactions between the causative variant(s) in this locus will provide insights into a possible role for epidermal barrier formation in the pathogenesis of psoriasis.     

Lack of evidence for genetic association to RUNX1 binding site at PSORS2 in different German psoriasis cohorts

A DNA variant, rs734232, altering a RUNX1 binding site was recently reported as susceptibility allele at PSORS2 (17q25) in cohorts of psoriasis patients from the US. A testing of this variant in psoriasis patients from Germany did not confirm this association in 300 trios nor in two case-control studies with 281 patients with psoriasis vulgaris and 375 patients with psoriatic arthritis, respectively. These results fail to support rs734232 as a psoriasis susceptibility factor in German psoriasis patients.     

Risk factors and predictors of psoriatic arthritis in patients with psoriasis

Given the potential consequences of joint damage for patients with psoriatic arthritis, we believe that the optimization of screening methods and the investigation of arthritis in patients with psoriasis are a medical priority. It is very useful to identify predictors of arthritis in patients with psoriasis. In fact, there is a consensus among doctors that the large gap between the diagnosis of psoriasis and that of psoriatic arthritis should be narrowed. In order to better manage patients with psoriasis, the authors review and discuss recent publications on the evidence of current predictors of arthritis in patients with psoriasis.     

Arthritis as an important determinant for psoriatic patients to develop severe vascular events in Taiwan: a nation‐wide study

Background Psoriasis is an important systemic inflammatory disease that often leads to severe vascular diseases. This study was launched to determine if joint involvement affects incidence of vascular comorbidities in psoriatic patients. In addition, potential vasculo‐protective effects of methotrexate in psoriatic patients were also evaluated. Method A population‐based retrospective cohort study was conducted using the Taiwanese National Health Insurance database spanning from 1996 to 2006. Accordingly, 7648 and 284 psoriatic patients without or with arthritis, respectively, were identified. To ensure the temporal relationship between different events, those with date of first diagnosis psoriasis during the year of 1996 were excluded from subsequent analyses. In addition, those with diagnosis of cerebrovascular or cardiovascular diseases prior to onset of psoriasis were also excluded from relevant subsequent analyses. Result Taking psoriatic patients without arthritis as the referent group, the hazard ratio for incident cerebrovascular disease was 1.82 (95% CI = 1.17–2.82) for psoriatic patient with arthritis. In addition, psoriatic patients without arthritis who had methotrexate treatment showed reduced risks for incident cerebrovascular disease as compared with those with no arthritis and had received no methotrexate/retinoid treatment. Similar analyses were performed on cardiovascular diseases, and equivalent results were obtained. Conclusion Our study indicated that arthritis is a potential determinant for psoriatic patients in terms of incident vascular comorbidities. In addition, methotrexate treatment may be associated with reduced risks for development of severe vascular diseases in psoriatic patients without arthritis. Further studies should focus on the clinical complications associated with psoriatic patients with or without arthritis.