Etiology Of Psoriasis Research Articles

Updated Perspectives on Keratinocytes and Psoriasis: Keratinocytes are More Than Innocent Bystanders.

Psoriasis is a complex disease triggered by genetic, immunologic, and environmental stimuli. Many genes have been linked to psoriasis, like the psoriasis susceptibility genes, some of which are critical in keratinocyte biology and epidermal barrier function. Still, the exact pathogenesis of psoriasis is unknown. In the disease, the balance between the proliferative and differentiative processes of keratinocytes becomes altered. Multiple studies have highlighted the role of dysregulated immune cells in provoking the inflammatory responses seen in psoriasis. In addition to immune cells, accumulating evidence shows that keratinocytes are involved in psoriasis pathogenesis, as discussed in this review. Although certain immune cell-derived factors stimulate keratinocyte hyperproliferation, activated keratinocytes can also produce anti-microbial peptides, cytokines, and chemokines that can promote their proliferation, as well as recruit immune cells to help initiate and reinforce inflammatory feedback loops. Psoriatic keratinocytes also show intrinsic differences from normal keratinocytes even after removal from the in vivo inflammatory environment; thus, psoriatic keratinocytes have been found to exhibit abnormal calcium metabolism and possible epigenetic changes that contribute to psoriasis. The Koebner phenomenon, in which injury promotes the development of psoriatic lesions, also provides evidence for keratinocytes’ contributions to disease pathogenesis. Furthermore, transgenic mouse studies have confirmed the importance of keratinocytes in the etiology of psoriasis. Finally, in addition to immune cells and keratinocytes, data in the literature support roles for other cell types, tissues, and systems in psoriasis development. These other contributors are all potential targets for therapies, suggesting the importance of a holistic approach when treating psoriasis.

Psoriasis between Autoimmunity and Oxidative Stress: Changes Induced by Different Therapeutic Approaches.

Psoriasis is defined as chronic, immune-mediated disease. Regardless of the development of new therapeutic approaches, the precise etiology of psoriasis remains unknown and speculative. The aim of this review was to systematize the results of previous research on the role of oxidative stress and aberrant immune response in the pathogenesis of psoriasis, as well as the impact of certain therapeutic modalities on the oxidative status in patients with psoriasis. Complex immune pathways of both the innate and adaptive immune systems appear to be major pathomechanisms in the development of psoriasis. Oxidative stress represents another important contributor to the pathophysiology of disease, and the redox imbalance in psoriasis has been reported in skin cells and, systemically, in plasma and blood cells, and more recently, also in saliva. Current immune model of psoriasis begins with activation of immune system in susceptible person by some environmental factor and loss of immune tolerance to psoriasis autoantigens. Increased production of IL-17 appears to be the most prominent role in psoriasis pathogenesis, while IL-23 is recognized as master regulator in psoriasis having a specific role in cross bridging the production of IL-17 by innate and acquired immunity. Other proinflammatory cytokines, including IFN-γ, TNF-α, IL-1β, IL-6, IL-22, IL-26, IL-29, or IL-36, have also been reported to play important roles in the development of psoriasis. Oxidative stress can promote inflammation through several signaling pathways. The most noticeable and most powerful antioxidative effects exert various biologics compared to more convenient therapeutic modalities, such as methotrexate or phototherapy. The complex interaction of redox, immune, and inflammatory signaling pathways should be focused on further researches tackling the pathophysiology of psoriasis, while antioxidative supplementation could be the solution in some refractory cases of the disease.

The Brain-Skin Axis in Psoriasis-Psychological, Psychiatric, Hormonal, and Dermatological Aspects.

Psoriasis is a chronic inflammatory skin disease with systemic manifestation, in which psychological factors play an important role. The etiology of psoriasis is complex and multifactorial, including genetic background and environmental factors such as emotional or physical stress. Psychological stress may also play a role in exacerbation of psoriasis, by dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, sympathetic–adrenal–medullary axis, peripheral nervous system, and immune system. Skin cells also express various neuropeptides and hormones in response to stress, including the fully functional analog of the HPA axis. The deterioration of psoriatic lesions is accompanied by increased production of inflammatory mediators, which could contribute to the imbalance of neurotransmitters and the development of symptoms of depression and anxiety. Therefore, deregulation of the crosstalk between endocrine, paracrine, and autocrine stress signaling pathways contributes to clinical manifestations of psoriasis, which requires multidisciplinary approaches.

Analysis of selected genetic variants in psoriasis susceptibility and response to treatment.

Aetiology of psoriasis is complex with risk factors involving both environmental triggers and genetic background. Although the best characterized genetic risk factor for psoriasis is HLA-C*06 allele, a number of other variants were associated with the disease. In the current paper we have conducted a confirmation study for SNPs located in 9 gene regions in a case-control analysis of 507 psoriatic patients and 396 controls from the Polish population. Subsequently the impact of genetic variants on response to topical and NB-UVB therapy (reduction in the Psoriasis Area and Severity Index) was analysed. Significant differences in genotype and/or allelic frequency were observed for the following SNPs: rs33980500 (TRAF3IP2), rs582757 (TNFAIP3I), rs12188300 (IL12B), rs28998802 (NOS2), and rs2233278 (TNIP1). None of the genetic factors was associated with treatment outcome. Although the genetic variants have an impact on the disease risk, they are unlikely to be useful in personalization of topical therapy.

Deciphering the mechanism of Fang-Ji-Di-Huang-Decoction in ameliorating psoriasis-like skin inflammation via the inhibition of IL-23/Th17 cell axis

Ethnopharmacological relevanceIn the theory of traditional Chinese medicine (TCM), the etiology of psoriasis is assigned to damp-heat internal depression, blood poisoning, Yin deficiency and loss of nourishment. Fang-Ji-Di-Huang-Decoction (FJDH), a well-known Chinese traditional formula, is recorded in Synopsis of the Golden Chamber (in the Eastern Han Dynasty). This decoction is composed of dried roots of Rehmannia glutinosa (Gaertn.) DC., dried roots of Stephania tetrandra S. Moore, roots of Saposhnikovia divaricata (Turcz.) Schischk., dried twigs of Cinnamomum cassia (L.) J. Presl and dry roots and rhizomes of Glycyrrhiza uralensis Fisch. FJDH has the function of clearing heat, removing dampness, and nourishing blood. Therefore, in modern medical theory, FJDH can regulate the infiltration of inflammatory cells and the secretion of inflammatory cytokines in the process of psoriasis. Aim of the studyThis study evaluated whether FJDH treated psoriasis and its specific mechanism for the efficacy in mice. At the same time, it clarified s what important role of the copperware played s in the curative effect of FJDH. Methods and materialsWe used imiquimod (IMQ) to induce psoriasis-like skin inflammation in mice. Mice were treated with imiquimod for one week, and FJDH was given by intragastric administration one week in advance. Record the weight change and psoriasis Area and Severity Index (PASI) score of the mouse during the whole process to assess the severity of psoriasis were recored mouse. Hematoxylin-eosin staining was used to evaluate skin tissue structure change. Immunohistochemistry was performed to observe the expressions of Ki67 and proliferating cell nuclear antigen (PCNA) in skin tissue. In order to further explore the mechanism of FJDH in the treatment of psoriasis, we used network pharmacology to predict the therapeutic target. TCMSP and Uniprot were used to collect compounds and genes of FJDH. Genecards was used for obtaining genes of psoriasis. String was used to analyze the relationship between genes. Metascape was used for gene enrichment and pathway prediction. Using molecular biological detection methods, we verified whether FJDH could regulate Interleukin 17 signaling pathway and T helper cell 17 (Th17) cell differentiation. Flow cytometry was used to detect Th17 cell differentiation in mouse spleen. Quantitative Real-time PCR was used to detect mRNA expression of IL-17 signaling pathway-related inflammatory factors in mouse skin tissues. UPLC-Triple TOF-MS/MS and Phenol-Sulphate colorimetry were used to explore the main components of FJDH, and further elaborate the mechanism of FJDH in the treatment of psoriasis. ResultsFJDH with copper was found to improve psoriasis-related pathological symptoms in a dose-dependent manner, possibly by inhibiting IL-23/Th17 cell axis and reducing inflammatory cytokines such as IL-17A, IL-17F, IL-22 and TNF-α. Furthermore, R. glutinosa polysaccharide in FJDH was the main substance that exerted the drug effect and it work by forming a complex with copper. Experimental data proved that Rehmannia glutinosa polysaccharide and copper complex had the same pharmacological activity and therapeutic effect as FJDH. ConclusionsFJDH may attenulated imiquimod-induced psoriasis-like skin inflammation in mice by inhibiting IL-23/Th17 cell axis. The material basis for the therapeutic effect may be the formation of complexes between the polysaccharides of R. glutinosa and copper in FJDH to produce the effect. These findings suggest that FJDH can be used as an effective Chinese medicine to treat psoriasis.

Curcumin alleviates imiquimod-induced psoriasis in progranulin-knockout mice

Recent advances have revealed that progranulin (PGRN) is related to the aetiology of psoriasis. Moreover, curcumin, a compound derived from turmeric, has been proposed as a potential therapeutic approach in psoriasis-like dermatitis, but it is still unclear whether curcumin affects the development of psoriasis-like skin lesions under PGRN-deficient conditions. Therefore, in this study, we developed a mouse model of psoriatic skin lesions using topical application of imiquimod (IMQ) in both wild type and PGRN-knockout mice to test this possibility. We observed that PGRN deficiency not only increased proinflammatory cytokine IL-17A levels and aggravated psoriasis-like damaged appearance and epidermal thickening but also directly mediated changes in keratinocyte proliferation (Krt 14, cyclinD1 and c-Myc) and differentiation (Krt 10 and Filaggrin) associated gene expression following IMQ challenge, compared to those in the control group. Furthermore, curcumin treatment (50 mg/kg and 200 mg/kg, intragastrically) for 21 consecutive days suppressed the IMQ exposure-induced increase in PGRN expression. Importantly, curcumin treatment significantly alleviated the PGRN deficiency-induced exacerbation of psoriatic appearance, histological features and keratinocyte proliferation after IMQ exposure. In summary, these results demonstrate the direct regulation of PGRN in keratinocyte proliferation and differentiation in psoriatic lesions and demonstrate the protective effect of curcumin on PGRN deficiency-induced psoriatic skin lesion exacerbation.

Tumor necrosis factor-α gene promoter −308 and −238 polymorphisms and its serum level in psoriasis

BackgroundPsoriasis is a chronic, immune-mediated, inflammatory skin disease affecting genetically predisposed individuals and requiring long-term treatment. The etiology of psoriasis is not fully understood. This article aimed to determine association between genetic polymorphisms in tumor necrosis factor-α (TNF -α) promoter −308 (rs1800629) and −238 (rs 361,525) and its serum level in psoriasis patients. MethodsThe study was conducted on 70 patients with psoriasis and 70 age and sex-matched, healthy individuals. All patients were subjected to history taking and complete medical examination. The polymorphisms of TNF -α promoter gene −308 (rs1800629) and −238 (rs 361,525) were detected by real time PCR and Serum levels of TNF -α were measured by ELISA technique. ResultsAG polymorphism and A allele of TNF-α −238 G/A (rs 361,525) were significantly more in patients than controls, whereas AG polymorphism and A allele of TNF-α −308 G/A (rs1800629) were significantly more in controls than patients. There were significant high levels of TNF-α in serum of patients in comparison to controls. ConclusionsThe AG polymorphism and A allele of TNF-α −238G/A (rs 361,525) may act as a risk factor for occurrence of psoriasis, whereas AG polymorphism and A allele of TNF-α −308G/A (rs1800629) may have protective role. There is pivotal role of TNF-α as a pro-inflammatory mediator in pathogenesis of psoriasis.

Abnormal\ufeff composition of microbiota in the gut and skin of imiquimod-treated mice

Psoriasis is a chronic, inflammatory skin disease. Although the precise etiology of psoriasis remains unclear, gut–microbiota axis might play a role in the pathogenesis of the disease. Here we investigated whether the composition of microbiota in the intestine and skin is altered in the imiquimod (IMQ)-treated mouse model of psoriasis. Topical application of IMQ to back skin caused significant changes in the composition of microbiota in the intestine and skin of IMQ-treated mice compared to control mice. The LEfSe algorithm identified the species Staphylococcus lentus as potential skin microbial marker for IMQ group. Furthermore, there were correlations for several microbes between the intestine and skin, suggesting a role of skin–gut–microbiota in IMQ-treated mice. Levels of succinic acid and lactic acid in feces from IMQ-treated mice were significantly higher than control mice. Moreover, the predictive functional analysis of the microbiota in the intestine and skin showed that IMQ caused alterations in several KEGG pathways. In conclusion, the current data indicated that topical application with IMQ to skin alters the composition of the microbiota in the gut and skin of host. It is likely that skin–gut microbiota axis plays a role in pathogenesis of psoriasis.

Frequency, Distribution and Genotyping of Malassezia Species in Patients with Psoriasis vulgaris

Abstract Background: Malassezia species are reported to play a role in the etiology of Psoriasis vulgaris. Objective: The aim of this study was to determine the presence, frequency, distribution, and genotyping of skin colonization of Malassezia species in Psoriasis vulgaris and to compare with healthy individuals and to investigate its relationship with the severity of the disease. Methods: Skin samples were taken from scalp, arm, body, and leg of 34 psoriasis patients (lesional/non-lesional skin) and 30 healthy volunteers. Overall, 392 skin scraping samples were taken for the isolation of Malassezia species, which were incubated on the modified-Dixon agar. Conventional culture methods were used for Malassezia species identification. In isolates, genotyping was carried out by PCR-RFLP method. Results: In the samples from psoriatic lesions, most frequently isolated Malassezia species were M.globosa and M.furfur. Similarly, the most frequently isolated species in healthy volunteers was M. globosa; followed by M.restricta and M.sympodialis. The M.furfur isolation rate in psoriatic scalp and leg lesions of the patients was significantly higher than in healthy volunteers. There was no relationship between the severity of the disease and the isolated species. Conclusion: It was found that there was a difference between patients with psoriasis and healthy controls regarding presence and frequency of Malassezia species. Therefore, our study results support the view that Malessezia species may be associated with the etiopathogenesis of psoriasis. In addition, we surmise that the treatment applications for the regulation of skin microbiota of psoriasis patients will contribute positively to the treatment of psoriasis.

Evaluation of Serum Level of Netrin 1 in Patients with Psoriasis vulgaris

The etiology of psoriasis stays indistinct, in spite of the fact that there is proof for hereditary inclination. The part of the resistant framework in psoriasis causation is likewise a significant subject of examination. The point of the current investigation was to assess serum levels of netrin 1 protein in patients with psoriasis and it's relationship with sickness seriousness Patient and strategies: A cross area case control study was led on ninety subjects ordered into two gatherings: Patient gathering: Sixty patients grumbling of psoriasis vulgaris. Control gathering: Thirty clear solid age and sex coordinated with individual . Psoriasis seriousness was assessed by PASI score. All read subjects were tried for Serum level of nertin 1 by compound connected immunosorbent measure (ELISA). Results: There was high critical negative relationship between's Netrin1 level and degree additionally there was huge negative connection between's Netrin1and Disease term while there was no huge connection between's Netrin 1 and age and sex Conclusion: There is a job of Nerrin1 in the pathogenesis of psoriasis.Netrin1 can be utilized as pointer of sickness degree and infection length.

The correlation TNF-α gene promoter region -238G, -308G, -857, and -1031 polymorphism with psoriasis vulgaris

Background: Psoriasis vulgaris is a recurrent chronic skin disorder signed by hyperproliferation and epidermal inflammation. One of the etiology of psoriasis is genetic factors related to genetic polymorphism as disease susceptibility markers. This study was aimed to analyze the correlation of TNF-α gene promoter region polymorphism with psoriasis vulgaris. Methods: An analytical observational study with cross-sectional design to identify correlation TNF-region promoter polymorphisms with psoriasis vulgaris. This study included 45 psoriasis vulgaris patients and 45 non-psoriasis vulgaris patients from April to October 2016 at Immuno-dermatology Polyclinic of Dermatology and Venereology/Haji Adam Malik Hospital, Medan. We isolated DNA from the blood sample then ran into the PCR process with specific primers. PCR results were examined by electrophoresis with 2% agarose. Chi-Square test was used to test the hypothesis of a relationship between the TNF-α promoter region and psoriasis vulgaris at a significance of P <0.05. Result: Analysis by Chi-Square test found a significant correlation of polymorphism in TNF-α gene promoter region with psoriasis vulgaris in -308G (p=0,001) and 1031 (p=0,002) loci.Conclusion: TNF-α gene promoter region polymorphism TNF-α gene -1031 was more frequent in the case group, -308G was commonly found in the control group. Both of them were significantly correlated with psoriasis vulgaris.

Study on serum copper, zinc and selenium trace element levels in Psoriasis

Introduction: Psoriasis is one of the skin disorder, mainly characterized by scaly papules and plaques. The etiology of psoriasis is multifactorial and still not properly understood. In our study, we tried to elucidate the relation between psoriasis and trace elemens namely Zinc, Copper and Selenium. Materials and Methods: This study enrolled 50 psoriasis patients with 37 males and 13 females, with 10- 80 years age. The patients were randomly selected from the outpatient clinic of Dermatology, Venereology and Leprosy Department, Narayana medical college and hospital. The age, sex matched 50 healthy volunteers included as controls in this study. Levels of serum Copper (Cu), Zinc(Zn), and Selenium(Se) analysed using Atomic absorption Spectrophotometery. Results: In our study, the mean Serum Zinc, Selenium and Copper levels were 61.968015.96824, 64.206017.44780 and 56.41208.51976 respectively, lower than the controls which was stastically significant (P Conclusion: In psoriasis, serum Cu, Zn and Se levels were observed to be low, needs to manage therapeutically by oral supplementation. More studies are required to carryout to standardize the diagnostic levels of Cu, Zn and Se and their role in psoriasis pathogenseis. Keywords: Psoriasis, Zinc, Copper, Selenium P Value 0667 0266.

ACT1 Is Required for Murine IL-23–Induced Psoriasiform Inflammation Potentially Independent of E3 Ligase Activity

Psoriasis is a debilitating skin disease characterized by epidermal thickening, abnormal keratinocyte differentiation, and proinflammatory immune cell infiltrate into the affected skin. IL-17A plays a critical role in the etiology of psoriasis. ACT1, an intracellular adaptor protein and a putative ubiquitin E3 ligase, is essential for signal transduction downstream of the IL-17A receptor. Thus, IL-17A signaling in general, and ACT1 specifically, represent attractive targets for the treatment of psoriasis. We generated Act1 knockout and Act1 L286G knockin (ligase domain) mice to investigate the potential therapeutic effects of targeting ACT1 and its U-box domain, respectively. Act1 knockout, but not Act1 L286G knockin, mice were resistant to increases in CXCL1 plasma levels induced by subcutaneous injection of recombinant IL-17A. Moreover, in a mouse model of psoriasiform dermatitis induced by intradermal IL-23 injection, Act1 knockout, but not Act1 L286G knockin, was protective against increases in ear thickness, keratinocyte hyperproliferation, expression of genes for antimicrobial peptides and chemokines, and infiltration of monocytes and macrophages. Our studies highlight the critical contribution of ACT1 to proinflammatory skin changes mediated by the IL-23/IL-17 signaling axis and illustrate the need for further insight into ACT1 E3 ligase activity.

ROLE OF PATHYAPATHYA IN THE MANAGEMENT OF EKA KUSHTHA (PSORIASIS)

Ayurveda is not merely a medical science. It is a complete life science. In Ayurveda all skin diseases are described under the Kushtha, which are further divided into Maha Kushtha and Kshudra Kushtha. Eka Kushtha is one of the Kshudra Kushtha described in different Ayurvedic classics. It is Vata-Kaphaj disorder. Ekakushtha has signs and symptoms i.e., Aswedanam (absence of sweating), Mahavastu (big size lesions) and Matsyasha kalopamam (scaling) which can be compared with Psoriasis. The exact etiology of Psoriasis is not known but many precipitating factors like genetic, dietary, immunological and psychological has been found. It is spreading fast because of unsuitable lifestyle changes such as dietary pattern, busy schedule and stress. The aim is to find out safe and effective treatment for psoriasis. Ayurveda plays an important role. There are three basic principles to treat any disease in Ayurveda i.e., Shodhana, Shamana and Nidana Parivarjana. Nidana Parivarjana is considered as the first line of treatment in most of the diseases. In Ayurveda diet plays a major role in the prevention and management of the disease. Sometimes Pathya and Apathya are the complete treatment of any diseases. So the main aim of this article is to focus on etiological factors of Ekakushtha and its management by various dietary regimens described in different Ayurvedic texts.

Potential Role of Cytosolic RNA Sensor MDA5 as an Inhibitor for Keratinocyte Differentiation in the Pathogenesis of Psoriasis.

BackgroundPsoriasis is a chronic inflammatory skin disease. The etiology of psoriasis is not fully understood, but the genetic background is considered to be the most important factor. To date, many psoriasis-related genes have been discovered, but the role of many important genes has not been well understood.ObjectiveThe purpose of this study is to uncover possible roles of MDA5 in psoriasis.MethodsExpression of MDA5 was investigated using immunohistochemistry. Then, MDA5 was overexpressed in keratinocytes using a recombinant adenovirus.ResultsAs a result of immunohistochemical staining, the expression of MDA5 was significantly increased in the epidermis of psoriasis compared to normal skin. Similarly, the expression of MDA5 was increased in imiquimod-induced psoriasiform dermatitis model. In cultured keratinocytes, toll-like receptor 3 agonist poly(I:C) induced expression of MDA5 at both mRNA and protein levels. When MDA5 was overexpressed using a recombinant adenovirus, poly(I:C)-induced cytokine expression was significantly increased. Finally, MDA5 overexpression significantly inhibited calcium-induced differentiation of keratinocytes.ConclusionThese results suggest that MDA5 increases in psoriasis and negatively regulates keratinocyte differentiation.

Role of Oxidative Stress in various stages of Psoriasis

Background: Psoriasis is a chronic inflammatory, immune mediated, provocative and challenging skin condition. It is a non-contagious but debilitating disease and a leading cause of socioeconomic burden on the health system.
 Objective: To evaluate the role of antioxidant levels, lipid peroxidation status and lipid profile in the etiology and degree of severity of psoriatic illness among psoriasis patients presenting in Dermatology department.
 Study Design: This study was carried out as a retrospective case control study.
 Place and duration of Study: It was carried out by the Department of Biochemistry, Basic Medical Sciences Institute (BMSI) in collaboration with Departmnt of Biochemistry, Khyber Medical College, Peshawar and Department of Skin and Venereal disease, Jinnah Post Graduate Medical Centre (JPMC) Karachi.
 Material and Methods: One hundred and twenty cases (n=130) of already diagnosed psoriasis patients were randommely and fifty healthy matched controls (n=50) of the same age and gender were included from the general population for comparison. Lipid profile including serum total cholesterol, TG, HDL-c and LDL-c levels were measured by enzyme colorimetric analysis on Micro Lab 300 (Merck & Germany). Antioxidant status SOD and lipid peroxidation status MDA were measured by ELISA technique. Statistical analysis was performed using SPSS software Version 16. In this analysis, a “p” value of less than 0.05 was considered to be significant.
 Results: The study showed significantly elevated levels of MDA, serum TG, total cholesterol and LDL-c levels in psoriatic patients in comparison with controls, whereas SOD levels and HDL-c levels were found to be significantly lower in psoriatic patients as compared to normal healthy matched controls.
 Conclusion: The findings of this study support the hypothesis that an imbalance in oxidant-antioxidant system may play a role in the etiology of psoriasis and the degree of severity of its presentation. The study also concluded that dyslipidemia was an observed risk factor for the development of cardiovascular diseases in psoriatic patients..

Systemic treatment of psoriasis: from methotrexate to biologics

Psoriasis is one of the most frequent chronic inflammatory skin diseases and it has been of interest to many scientists for ages. The review presents data on all systemic treatment options, that are to date officially registered in Russian Federation for moderate-to-severe psoriasis. Aspects of the mechanism of action, efficacy and tolerability of both basic drugs (methotrexate, cyclosporine, acitretin) and biologics (infliximab, adalimumab, etanercept, certolizumab pegol, ustekinumab, guselkumab, secukinumab, ixekizumab, netakimab) and small molecules (tofacitinib, apremilast) are considered in detail. Special emphasis is placed on the important nuances of biological therapy: immunogenicity, drugs' survival and switch due to lack of efficacy. Invention of biologics signified a new era of moderate-to-severe psoriasis treatment. It became possible to achieve complete clinical remission more safely, which significantly improved the quality of life of patients. However, due to the unknown etiology of psoriasis, there is still no universal remedy that would allow to cure every patient, this fact makes scientists from all over the world keep conducting numerous clinical trials to find even more effective and safe therapeutic options.

Guidelines for the Diagnosis and Treatment of Psoriasis in China: 2019 Concise Edition#

Abstract Psoriasis is an immune-mediated chronic, recurrent, systemic inflammatory disease induced by the combination of hereditary and environmental factors. The etiology of psoriasis involves hereditary, immune, environmental, and other factors, and its pathogenesis is considered to involve excessive proliferation of keratinocytes or inflammatory activation of synovial cells and chondrocytes within joints; these processes are caused by an immune response that is mainly mediated by T lymphocytes and various other immune cells. Psoriasis is an incurable disease, and the goal of treatment is to control the progression of disease and maintain long-term efficacy. Treatment protocols should be based on the patients’ conditions. Patients with mild psoriasis can be mainly treated with topical agents, and those with moderate to severe psoriasis can be treated with systemic medications. Targeted biological agents can be appropriately chosen for cases of psoriasis that are resistant to traditional systemic treatment. New drugs and treatments for psoriasis continue to evolve and emerge, and our updated guidelines are designed to deliver new achievements from China and to physicians worldwide and to keep pace with global progress on psoriasis research. Compared with the previous two editions, part of contents have been modified and revised in the present guidelines; this will further facilitate standardization and increase the efficiency of the diagnosis and treatment of psoriasis in China, and improve patients’ quality of life.

Multi-omics study in monozygotic twins confirm the contribution of de novo mutation to psoriasis

BackgroundGenome-wide association studies have identified over 120 risk loci for psoriasis. However, most of the variations are located in non-coding region with high frequency and small effect size. Pathogenetic variants are rarely reported except HLA-C*0602 with the odds ratio being approximately 4.0 in Chinese population. Although rare variations still account for a small proportion of phenotypic variances in complex diseases, their effect on phenotypes is large. Recently, more and more studies focus on the low-frequency functional variants and have achieved a certain amount of success. MethodWhole genome sequencing and sanger sequencing was performed on 8 MZ twin pairs discordant for psoriasis to scan and verified the de novo mutations (DNMs). Additionally, 665 individuals with about 20 years' medical history versus 2054 healthy controls and two published large population studies which had about 8 years’ medical history (including 10,727 cases versus 10,582 controls) were applied to validate the enrichment of rare damaging mutations in two DNMs genes. Besides, to verify the pathogenicity of candidate DNM in C3, RNA-sequencing for CD4+, CD8+ T cells of twins and lesion, non-lesion skin of psoriasis patients were carried out. Meanwhile, the enzyme-linked immunosorbent assay kit was used to detect the level of C3, C3b in the supernatant of peripheral blood. ResultA total of 27 DNMs between co-twins were identified. We found six of eight twins carry HLA-C∗0602 allele which have large effects on psoriasis. And it is interesting that a missense mutation in SPRED1 and a splice region mutation in C3 are found in the psoriasis individuals in the other two MZ twin pairs without carrying HLA-C*0602 allele. In the replication stage, we found 2 loss-of-function (LOF) variants of C3 only in 665 cases with about 20 years' medical history and gene-wise analysis in 665 cases and 2054 controls showed that the rare missense mutations in C3 were enriched in cases (OR = 1.91, P = 0.0028). We further scanned the LOF mutations of C3 in two published studies (about 8 years’ medical history), and found one LOF mutation in the case without carrying HLA-C*0602. In the individual with DNM in C3, RNA sequencing showed the expression level of C3 in skin was significant higher than healthy samples in public database (TPM fold change = 1.40, P = 0.000181) and ELISA showed protein C3 in peripheral blood was higher (~2.2-fold difference) than the other samples of twins without DNM in C3. ConclusionTo the best of our knowledge, this is the first report that DNM in C3 is the likely pathological mutations, and it provided a better understanding of the genetic etiology of psoriasis and additional treatments for this disease.

118 Altered intestinal barrier in psoriasis is associated with disease severity, gastrointestinal symptoms and presence of bacteria metabolites in the blood

Growing body of evidence suggests a functional interplay between gut microbiome, intestinal barrier and immune system. That so-called “gut-skin axis” has been considered as a key factor in the etiology of psoriasis. The aim of this study was to compare psoriasis severity, intensity of self-reported gastrointestinal symptoms and concentration of gut microbiota-derived metabolites (trimethylamine N-oxide; TMAO and indoxyl sulfate) between psoriatic patients with and without altered intestinal barrier. One hundred twenty consecutive patients with chronic plaque psoriasis were enrolled. To examine gut barrier integrity we investigated serum concentrations of claudin-3, a modulator of intestinal tight junctions and intestinal fatty acid-binding protein, a marker of enterocyte damage. Gastrointestinal symptoms were evaluated with a validated questionnaire – Gastrointestinal Symptom Rating Scale (GSRS). Concentration of TMAO and indoxyl sulfate was measured through high performance liquid chromatography. Patients with altered gut barrier showed significantly higher score in GSRS (3.09 vs 1.23; p<0.05), especially in “indigestion” section. Moreover, patients with psoriasis and disrupted intestinal barrier demonstrated higher disease activity (PASI: 18.9±1.9 vs 10.1±2.5, p<0.05). The inflammatory parameters and markers of bacterial translocation were significantly higher in a subgroup of patients with damaged gut integrity (TMAO: 375.7±51.9 vs 119.4±27.5 ng/mL; indoxyl sulfate: 1016.4±85.3 vs 654.2±69.1 ng/mL). Our results support the hypothesis that alterations of the intestinal barrier may play an essential role in the pathogenesis of psoriasis. Further study should focus on developing therapies that enhance intestinal barrier function.