Presentation presentations health medicine pptx

Presentation

1. Psoriasis ( Key features) Psoriasis is a chronic, immune-mediated disorder that results from a polygenic predisposition combined with environmental triggers, e.g. trauma, infections or medications The underlying pathophysiology involves T cells and their interactions with dendritic cells and cells involved in innate immunity, including keratinocytes Identification of susceptibility genes has pointed to a major role for both the innate and the adaptive immune systems Sharply demarcated, scaly, erythematous plaques characterize the most common form of psoriasis; occasionally, sterile pustules are seen The most common sites of involvement are the scalp, elbows and knees, followed by the nails, hands, feet and trunk (including the intergluteal fold) Typical histologic findings include acanthosis with elongated rete ridges, hypogranulosis , hyper- and parakeratosis, dilated blood vessels and a perivascular infiltrate of lymphocytes with neutrophils singly or within aggregates in the epidermis Psoriatic arthritis is the major associated systemic manifestation and the most common presentation is asymmetric oligoarthritis of the small joints of the hands and feet; other comorbidities include cardiovascular disease in patients with moderate to severe disease Phototherapy, methotrexate, cyclosporine and “biologic” therapies that target key immune effector cells and cytokines lead to significant clinical improvement

2. INTRODUCTION Psoriasis is an immune-mediated polygenic skin disorder. Various environmental triggering factors, e.g. trauma, infections or medications, may elicit disease in predisposed individuals1. The characteristic lesion is a sharply demarcated erythematous plaque with micaceous scale, and the plaques may be localized or widespread in distribution. Histologically, hyperkeratosis, parakeratosis, acanthosis of the epidermis, tortuous and dilated vessels, and an inflammatory infiltrate composed primarily of lymphocytes are observed . Psoriasis is a systemic disease process in which up to 20–30% of the patients have or will develop psoriatic arthritis. In addition, in patients with moderate to severe psoriasis, there is an increased relative risk for metabolic syndrome and atherosclerotic cardiovascular disease. Psoriasis also has a significant impact on patients’ quality of life2, and in surveys, patients feel that the current treatments, although often effective, do not provide a satisfactory long-term solution.

3. HISTORY Hippocrates and his school (460–377 BC) provided meticulous descriptions of many skin disorders. In their classification, dry scaly eruptions were grouped together under the heading “ lopoi ”. This group probably included psoriasis and leprosy. Between 129 and 99 BC, the word “ psora ” (meaning a desquamative condition) was first used by Galen to describe a skin disorder characterized by a scaliness of the eyelids, corners of the eyes, and scrotum. The condition was pruritic and excoriations were present. Although called psoriasis, this affliction was probably a type of eczema. It was not until the nineteenth century that psoriasis was recognized as an entity distinct from leprosy. Although Robert Willan (1809) was the first to give an accurate description of psoriasis, it would be another 30 years before Hebra (in 1841) definitively separated the clinical features of psoriasis from those of leprosy. In 1879, Heinrich Koebner described the development of psoriatic plaques at sites of skin injury. He designated this phenomenon as “artificial production of the psoriatic lesion”.

4. EPIDEMIOLOGY AND GENETICS In most reviews, the prevalence of psoriasis is said to be 2% of the world’s population. However, in the US and Canada, prevalences as high as 4.6% and 4.7% have been reported, respectively. This contrasts with frequencies in Africans, African-Americans, Norwegian Lapps, and Asians of between 0.4% and 0.7%2. Brandrup and Green reported that two-thirds of affected individuals were suffering from mild psoriasis, while one-third had more severe involvement. In one large group of patients with psoriasis ( n = 1728), 79% had nail changes. Psoriatic arthritis has been found to affect 5–30% of patients with cutaneous psoriasis in different series. Psoriasis can first appear at any age, from infancy to the eighth decade of life. Two peaks in age of onset have been reported: one at 20–30 years of age and a second peak at 50–60 years. In approximately 75% of patients, the onset is before the age of 40 years5–7, and in 35–50%, it is before the age of 20 years. Although the age of onset is earlier in women than in men, the natural history is similar – chronic with intermittent remissions. In one epidemiologic study, 39% of the patients stated they had experienced remissions of 1–54 years. In Europe, the overall prevalence rate for juvenile psoriasis was found to be ~0.7%8,9, with an increase from 0.37–0.55% in those 0 to 9 years of age to 1.01–1.37% in those 10-19 years of age8–10. Plaque psoriasis is the most frequent form of the disease in children, followed by guttate psoriasis.

5. Genetic Factors Depending upon the series, a positive family history has been reported by 35% to 90% of patients with psoriasis. Based on a large survey-based study in Germany, if both parents had psoriasis, the risk of their child developing psoriasis was 41%, whereas if only one parent were affected, the risk was 14%; the risk was 6% if just one sibling had psoriasis. Analysis of concordance rates among monozygotic and dizygotic twins is another method for examining the influence of genetic factors on a disease. Farber and Nall13 reviewed the published data from twin pair studies in psoriasis. Of 141 monozygotic twin pairs, 82 were concordant for psoriasis and 59 were discordant; of 155 dizygotic twin pairs, only 31 were concordant and 124 were discordant for psoriasis. Thus, there is a two- to threefold increased risk of psoriasis in monozygotic twins as compared to dizygotic twins, implying that genetic factors are important. The distribution of the lesions, the severity, and the age of onset were similar in the monozygotic twin pairs, whereas these features differed in the dizygotic twin pairs. This observation suggested that genetic factors also play a role in the clinical course of psoriasis.

6. HLA studies Histocompatibility antigens (HLA) are surface antigens on human cells, and the corresponding chromosomal region is called the major histocompatibility complex (MHC). It is situated on the short arm (p) of chromosome 6. Psoriasis is associated with HLA-Cw6, with the presence of HLA-Cw6 conferring a relative risk of 13 for developing psoriasis in the Caucasian population and 25 in the Japanese. HLA-Cw6 is strongly linked to the age of onset of psoriasis. In one series, HLA-Cw6 was expressed in 90% of the patients with early-onset psoriasis, in 50% of those with late-onset psoriasis, and only in 7% of a control population. A specific MHC class II antigen (DRB1*0701/2) also appeared to be associated with early-onset psoriasis, and the psoriasis-associated HLA alleles were often in an extended haplotype: Cw6-B57-DRB1*0701-DQA1*0201-DQB1*0303. Individuals carrying this haplotype were found to have a 26-fold increased risk of developing early-onset psoriasis. As a result, some clinicians have designated patients with early-onset psoriasis, a positive family history of psoriasis, and expression of HLA-Cw6 as having type I psoriasis and those with late-onset disease, no family history, and a lack of expression of HLA-Cw6 as having type II psoriasis 15. Other HLA alleles may be associated with different psoriasis variants and related conditions. For example, the HLA-B27 allele is a marker for sacroiliitis -associated psoriasis and reactive arthritis

7. Genome-wide association studies Classic genome-wide linkage analysis has identified at least nine psoriasis susceptibility regions (PSORS1–9) in different chromosomal locations16. By far the most important genetic region is PSORS1 (on chromosome 6p), which is estimated to account for up to 50% of psoriasis risk. PSORS1 contains genes such as HLA-C (with the HLA-Cw6 risk allele; see above) and corneodesmosin ( CDSN ). Due to high linkage disequilibrium in PSORS1 (i.e. genes within this region are inherited as a block), it has been challenging to determine which gene(s) within PSORS1 contribute to psoriasis pathogenesis. Use of genome-wide association studies (GWAS) has recently provided new insights into the genetic basis of psoriasis. In GWAS, hundreds of thousands of s ingle n ucleotide p olymorphisms (SNPs) across the entire human genome are examined in thousands of patients. Genes that have been associated with psoriasis through utilization of this and other methods are summarized in Table1 . Several conclusions regarding the genetic factors in psoriasis can be drawn from recent GWAS18,19. First, most of the genes that have been implicated have immune-related functions, underscoring the importance of the innate and adaptive immune systems in the pathogenesis of psoriasis; in contrast, relatively few genes that encode skin-specific proteins have been associated with psoriasis. Second, thus far surprisingly few interactions among the genetic variants have been identified (with the exception of HLA-Cw6 and ERAP-1; ). Third, associated genes encode proteins with roles in particular immunologic and signaling pathways, especially those involving tumor necrosis factor (TNF), NF- κB , interferons (IFN) and interleukin (IL)-23/Th17 cells (see Immunopathogenesis ). Lastly, the ERAP1 gene encoding an aminopeptidase involved in MHC class I antigen processing is only associated with psoriasis risk in individuals carrying the HLA-Cw6 risk allele, providing evidence for the role of an MHC-restricted antigen and its presentation through HLA-C in the pathogenesis of psoriasis.

8. Table 1 Genetic loci linked to psoriasis. Gene/Locus Chromosomal location Odds ratio for psoriasis Comments Other disease associations PSORS1 6p 6.4 Contains HLA-Cw6 ( putative immune function; major candidate gene) and CDSN None PSORS2 17q – Putative role in immune synapse formation None IL12B 5q 1.4 T-cell differentiation Crohn’s disease IL23R 1p 2.0 T-cell differentiation Crohn’s disease , unkylosing spondylitis , psoriatic arthritis ZNF313 ( RNF114 ) 20q 1.25 Ubiquitin pathway None CDKAL1 6p 1.26 Unknown Crohn’s disease, type 2 diabetes mellitus PTPN22 18p 1.3 T-cell signalling Juvenile idiopathic arthritis, systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, mellitus , autoimmune thyroid disease

9. Table 1 Genetic loci linked to psoriasis (continues). Gene/Locus Chromosomal location Odds ratio for psoriasis Comments Other diseaseassociations IL4/IL13 5q 1.27 T-cell differentiation Crohn’s disease (distinct variant) cytokine gene cluster LCE3B/3C/3D 1q 1.31 Epidermal differentiation IL23A 12q 1.68 IL-23/Th17 axis ERAP1 5q 1.27 MHC class I antigen processing Ankylosing spondylitis TNFAIP3 6q 1.28 NF- κ B pathway Rheumatoid arthritis TNIP1 5q 1.72 NF- κ B pathway TRAF3IP2 6q 1.36 NF- κB pathway/ IL-23/Th17 i Psoriatic arthritis NFKBIA 14q 1.19 NF- κ B pathway In addition, polymorphisms in other genes, e.g. interferon induced with helicase C domain 1 ( IFIH1 ), have been associated with a decreased risk of developing psoriasis. CDKAL1, cyclin -dependent kinase 5 regulatory protein subunit 1-like 1; CDSN, corneodesmosin ; ERAP1, endoplasmic reticulum aminopeptidase 1; IL, interleukin; LCE, late cornified envelope; MHC, major histocompatibility complex; NFKBIA, nuclear factor of κ light chain gene enhancer in B cells inhibitor α ; PTPN22, protein tyrosine phosphatase non-receptor type 22; TNFAIP3, tumor necrosis factor- α- induced protein 3; TNIP1, TNFAIP-interacting protein 1; TRAF3IP2, TNF receptor-associated protein 3 interacting protein 2; ZNF313, zinc finger protein 313.

10. PATHOGENESIS Because it primarily affects the interfollicular epidermis, psoriasis was long regarded as an epidermal disease in which the biochemical or cellular defect resided within the keratinocyte. Accordingly, prior to the early 1980s, a number of biochemical mediators, enzymes and pathways involved in epidermal function were incriminated as being abnormal in psoriasis, including cyclic AMP, eicosanoids, protein kinase C, phospholipase C, polyamines and transforming growth factor (TGF)-α. Although associated immunologic abnormalities were reported in the late 1970s, a major paradigm shift occurred when T-cell suppressive agents such as cyclosporine were found to result in significant improvement of psoriasis. For the past two decades, psoriasis has been regarded as a T-cell-driven disease. The role of lymphocyte subsets as well as cytokines involved in chemotaxis, homing and activation of inflammatory cells has been extensively investigated, culminating in the development of novel therapeutic approaches. Although some regard psoriasis as an autoimmune disease, to date no true autoantigen has been definitively identified.

11. Immunopathogenesis of psoriasis. The occurrence of triggering environmental factors in genetically predisposed individuals, carrying susceptibility alleles of psoriasis-associated genes, results in disease development. During the initiation phase, stressed keratinocytes can release self DNA and RNA, which form complexes with the cathelicidin LL37 that then induce interferon- α ( IFN- α) production by plasmacytoid dendritic cells ( pDCs ; recruited into the skin via fibroblast-released chemerin ), thereby activating dermal DCs ( dDCs ). Keratinocyte-derived interleukin-1 β ( IL-1 β), IL-6 and tumor necrosis factor- α ( TNF- α) also contribute to the activation of dDCs . Activated dDCs then migrate to the skin-draining lymph nodes to present an as-yet-unknown antigen (either of self or of microbial origin) to naive T cells and (via secretion of different types of cytokines by DCs) promote their differentiation into T helper 1 (Th1), Th17 and Th22 cells. Th1 cells (expressing cutaneous lymphocyte antigen [CLA], CXC-chemokine receptor 3 [CXCR3] and CC-chemokine receptor 4 [CCR4]), Th17 cells (expressing CLA, CCR4 and CCR6) and Th22 cells (expressing CCR4 and CCR10) migrate via lymphatic and blood vessels into psoriatic dermis, attracted by the keratinocyte-derived chemokines CCL20, CXCL9–11 and CCL17; this ultimately leads to the formation of a psoriatic plaque. Th1 cells release IFN- γ and TNF- α, which amplify the inflammatory cascade, acting on keratinocytes and dDCs . Th17 cells secrete IL-17A and IL-17F (and also IFN- γ and IL-22), which stimulate keratinocyte proliferation and the release of β- defensin 1/2, S100A7/8/9 and the neutrophil-recruiting chemokines CXCL1, CXCL3, CXCL5 and CXCL8. Neutrophils (N) infiltrate the stratum corneum and produce reactive oxygen species (ROS) and α- defensin with antimicrobial activity, as well as CXCL8, IL-6 and CCL20. Th22 cells secrete IL-22, which induces further release of keratinocyte-derived T cell-recruiting chemokines. Moreover, inflammatory DCs ( iDCs ) produce IL-23, nitric oxide (NO) radicals and TNF- α, while natural killer T (NKT) cells release TNF- α and IFN- γ. Keratinocytes also release vascular endothelial growth factor (VEGF), basic fibroblast growth factor ( bFGF ), and angiopoietin ( Ang ), thereby promoting neoangiogenesis . Macrophage (M)-derived chemokine CCL19 promotes clustering of Th cells expressing chemokine receptor CCR7 with DC in the proximity of blood vessels, with further T-cell activation. At the dermal–epidermal junction, memory CD8+ cytotoxic T cells (Tc1) expressing very-late antigen-1 (VLA-1) bind to collagen IV, allowing entry into the epidermis and contributing to disease pathogenesis by releasing both Th1 and Th17 cytokines. Cross-talk between keratinocytes, producing TNF- α, IL-1 β and transforming growth factor- β ( TGF- β), and fibroblasts, which in turn release keratinocyte growth factor (KGF), epidermal growth factor (EGF) and TGF- β, and possibly Th22 cells releasing FGFs, contribute to tissue reorganization and deposition of extracellular matrix (e.g. collagen, proteoglycans). LC, Langerhans cell. .

12. Triggering Factors External triggering factors Triggering factors, both external (directly interacting with the skin) and systemic, can elicit psoriasis in genetically predisposed individuals. The Koebner phenomenon, i.e. the elicitation of psoriatic lesions by injury to the skin, is observed in approximately 25% of patients with psoriasis. A particular patient may be “Koebner-negative” at one point in time and later become “Koebner-positive”. The Koebner phenomenon suggests that psoriasis is a systemic disease that can be triggered locally in the skin. Psoriatic lesions can also be induced by other forms of cutaneous injury, e.g. sunburn, morbilliform drug eruption, viral exanthem . The lag time between the trauma and the appearance of skin lesions is usually 2–6 weeks

13. Endocrine factors Psychogenic stress Hypocalcemia has been reported to be a triggering factor for generalized pustular psoriasis. Although active vitamin D3 analogues improve psoriasis, abnormal vitamin D3 levels have not been shown to induce psoriasis. Pregnancy may alter disease activity, e.g. 50% of the patients in one series reported improvement. However, pregnant women may develop pustular psoriasis, also referred to as impetigo herpetiformis (see below), sometimes in association with hypocalcemia. Psychogenic stress is a well-established systemic triggering factor in psoriasis50. It has been associated with initial presentations of the disease as well as flares of pre-existing psoriasis. In a prospective study, cognitive and behavioral patterns of worrying and scratching were both independently related to an increase in disease severity and pruritus 4 weeks later