2017 Research Trainee Symposium: Project Summaries and Posters
Title: “Understanding Quality of Life across the Spectrum of Psoriasis”
Psoriasis affects more than 7.4 million Americans and touches all aspects of a patient’s life—physical, emotional, social, and financial. Patients with psoriasis have higher rates of depression, anxiety, sleep problems, and a worse quality of life. We are looking at the frequency and severity of itch, pain, and sleeping problems in psoriasis and how these symptoms affect other areas of their lives. At our academic medical center, patients complete health assessments at each doctor’s visit. By assessing itchiness, pain, sleeping problems, and quality of life, we can get a clearer picture of how common and important these symptoms are to people with psoriasis (>5,000 patient visits in 2016 at our medical center). We will also use focus groups to explore the reasons for itchiness, pain, and sleeping problems by interviewing patients and family members. Our research can lead to better treatments and fewer or less severe psoriasis symptoms. Our ultimate goal is to improve the quality of life of patients with psoriasis.
Ofir Elalouf, M.D.
Title: “Mortality in psoriasis and psoriatic arthritis”
Psoriasis is a chronic inflammatory skin disease, affecting around 2-3% of the world’s population. Psoriatic arthritis (PsA) is an inflammatory arthritis that affects about 30% of people with psoriasis, and can lead to significant joint damage and disability. Recently, there is a growing understanding psoriatic disease is not solely skin or joint disease, but part of a broader systemic inflammatory process that influences many aspects of global health. Increasing amount of data have accumulated regarding the relation between psoriasis and PsA and increased risk of other comorbidities such as ischemic heart disease, stroke, depression, metabolic syndrome and more. A recent systematic review covering around 90 studies showed that heart disease, stroke and peripheral vascular disease were found to be more prevalent in psoriatic patients, although since cardiovascular risk factors were more common as well, and causality cannot be determined. Although the information about cardiovascular risk in PsA is limited compared to psoriasis, several studies demonstrated similar trend. Mortality is also reported to be increased in psoriasis and PsA patients, but the data are sparse and conflicting, another important factor is the treatment of psoriasis and PsA in the last decades that has changed dramatically with the advent of biologic agents. One of the aims of this study is to examine the influence of persistent disease and inflammation on mortality and to find out whether the biologic treatments reduce the mortality rate compared with classic DMARDs. Objectives: 1. To determine the overall mortality rates in psoriasis and PsA during the last decade compared to the previous decades. 2. To determine cause specific mortality rates. 3. To identify predictors for mortality as well as cause specific mortality. 4. To examine the effect of new biologic treatments on mortality in PsA. Patients and methods: Our PsA registry consists of around 1500 patients that are documented since 1978 (The largest registry in the world). The psoriasis cohort follows around 700 patients for around 8 years. Patients with psoriasis and PsA are followed according to the same standard protocol which includes demographics, clinical features, laboratory assessments, detailed therapeutic information and mortality data. PsA patients are seen at 6-12 month intervals. Psoriasis patients are seen at 12 month intervals. Patients with PsA undergo radiologic evaluation at 2 year intervals. All data are kept in a web-based database. Comparisons will be performed between psoriasis and PsA each to the general population of Ontario, and between psoriasis and PsA. To determine whether this cohort of PsA patients had an excessive number of deaths as compared with the general population of Ontario, Canada, standardized mortality ratios (SMRs) will be computed. Mortality data for the general population of Ontario stratified by 5-year age bands, sex, and calendar year (from 1978 to 2016), will be used to calculate the reference rates. Overall SMRs will be calculated, and SMRs by male and female sex will be calculated separately, through the use of Poisson regression models for the number of observed deaths, with the logarithm of the expected number of deaths as an offset in the models. This study will provide further information on mortality risk and cause in PsA and psoriasis and the effect of biologic therapies on mortality risk.
Clinton Enos, M.D.
Title: “Investigating the possible impact of psoriasis on the eye”
The past decade has brought many advancements in our understanding of the systemic nature of psoriasis; however, the impact of psoriasis on the eye is not fully understood. In another systemic, inflammatory disease, diabetes, diabetic retinopathy not only threatens vision but also is a predictor of all-cause mortality and cardiovascular events. With the use of cutting-edge imaging modalities early microvascular and neurodegenerative changes in the eye are now detectable, improving the routine care of these patients. We are investigating the presence of subclinical eye disease in those with severe psoriasis in a cross-sectional pilot study. Eye exams from thirty patients with psoriasis and thirty healthy, age and gender-matched controls will be compared and evaluated for subclinical microvascular and neurodegenerative changes using Optos ultra-widefield fluorescein angiography, optical coherence tomography, and slit lamp exams. We hypothesize that differences will exist between patients with psoriasis and controls, demonstrating subclinical peripheral vascular eye disease.
Laurent Gorvel, Ph.D.
Title: “CD5+ skin Dendritic cells are associated with the development of Psoriasis”
Dendritic cells (DCs) are important in regulating both immunity and tolerance. Hence, we hypothesized that alterations in skin DC subsets may contribute to the pathogenesis of psoriasis, an autoimmune disease characterized by autoreactive T cells. We undertook a comprehensive immune-phenotyping approach by analyzing the expression of 400 immune-related proteins in human skin DCs. We found that both Langerhans cells in the epidermis, and CD1a(dim) DCs, in the dermis, contained a novel population of CD5-expressing inflammatory DCs. While present in low amounts in healthy skin, we found that CD5+ DCs dominates psoriatic plaques. We found that the CD5+ DCs were specialized in driving IL-22 and IFN-γ-helper T cell responses, as well as effector CD8+ T cells, a hallmark of psoriasis pathogenesis. Moreover, we identified a unique CD34 CD123+CD117(dim)CD45RA+ cord blood and dermal skin layer progenitor that was an immediate precursor to the CD1c+CD11c+CD5+ DCs. Moreover, TNF family cytokines including TNF-α and LTα/β, which are abundant in psoriatic skin, enhanced the generation of the CD5+ DCs from bone marrow progenitors. Overall, our discovery of the CD5-expressing DC subtype suggests that strategies to regulate their composition or function in the skin will represent an innovative approach for the treatment of immune-mediated disorders in the skin.
Jason Hawkes, M.D.
Title: “Defining the Molecular Profiles of Guttate and New-Onset Psoriasis”
Psoriasis is a heterogeneous, inflammatory skin disease characterized by systemic inflammation and several distinct clinical subtypes. Despite tremendous advances in the treatment of psoriasis, significant research gaps still exist. These knowledge gaps include a limited understanding of the etiology of less common clinical subtypes, the lack of molecular and/or genetic biomarkers for early disease detection, and an incomplete understanding of the immune mechanisms driving psoriasis-associated comorbidities. Guttate psoriasis is an acute, eruptive form of psoriasis characterized by small erythematous, scaly papules and plaques. This variant is clinically mild and typically does not progress to chronic disease. However, the etiology of guttate psoriasis is poorly characterized, including the molecular mechanisms responsible for its self-limited disease course and relatively small skin lesions. Studying acute or early forms of psoriasis may provide insights into the initiating inflammatory events driving the development of chronic disease. We recently reported that IL-17 signaling was higher in clinically “mild” versus “severe” psoriasis phenotypes and appears to be fundamental to the development of chronic psoriasis plaques. Additionally, we observed a subsequent decrease in IL-17 signaling and negative immune regulators (e.g. CTLA-4, CD69) in long-standing skin lesions. We hypothesize that the immune cell populations and inflammatory signaling profiles associated with new-onset (< 6 months of disease) and guttate psoriasis tissues will be distinctly different than the molecular profile of chronic plaque psoriasis. We predict that the one of the distinguishing features of newonset disease will be significantly higher levels of IL-17 signaling and negative regulators of the immune response, including increased numbers of regulatory T (Treg) cells. This study will characterize the molecular phenotype of new-onset and guttate psoriasis, enabling us to elucidate the immune events that define early stage psoriasis. We anticipate that this study will improve our understanding of the initiating events in early psoriasis, lead to the identification of novel biomarkers of new-onset disease, and guide treatment strategies for these disease subtypes. We believe that this work will, ultimately, build the foundation for long-term funding aimed at evaluating whether early, aggressive, targeted therapies may alter the natural history of psoriasis by inducing complete disease remission.
Ernest Lee, Ph.D.
Title: “NETs generate immune complexes to amplify TLR9-based inflammation in psoriasis”
The molecular pathogenesis of psoriasis is characterized in part by immune dysregulation driven by recognition of self-DNA by Toll-like receptor-9 (TLR9). In one mechanism of aberrant immune activation, the overexpressed endogenous cationic antimicrobial peptide (AMP) LL37 organizes self-DNA into immunogenic complexes that potently hyperactivate TLR9 in plasmacytoid dendritic cells (pDCs). Recent work has demonstrated that cationic molecules that organize DNA into lattices with inter-DNA spacings commensurate with the steric size of TLR9 can amplify inflammation, while complexes poorly matched to TLR9 cannot. However, at present, it is unclear how and why nucleosomal DNA activates TLR9 in psoriasis. Here, we combine synchrotron X-ray scattering, computer simulations, and mathematical modeling with measurements of pDC interferon production to illuminate how nucleosome core particles (NCPs) in neutrophil extracellular traps (NETs) and NCPs released during necrotic cell death amplify TLR9-mediated inflammation. Interestingly, in the presence of common NETs components, NCPs self-assemble into liquid-crystalline columnar nanostructures that exhibit altered DNA wrapping states. Computer simulations and x-ray measurements suggest that the superhelical pitch of DNA within the NCP column relaxes into a value that is well-matched with the steric size of TLR9, allowing for optimal interdigitation with multiple TLR9 simultaneously like threads on a cylindrical screw, leading to multivalent electrostatic interactions that amplify binding and TLR9 activation. Our results elucidate the structural mechanism for TLR9 activation by NCPs and may more generally explain why nucleosomes released from different modes of cell death can induce immune activation through a shared pathway.
Megan Noe, M.D., M.P.H.
Infection is a cause of significant morbidity and mortality in patients with psoriasis. Unfortunately, baseline rates of infection, which may be altered due disease-associated immune defects, impaired epidermal barrier function, other co-morbid diseases and behaviors, including under-vaccination, and use of immune suppressive treatments, are generally poorly defined. Based on our prior work, infection is estimated to be the second leading cause of excess mortality in patients with moderate to severe psoriasis, after cardiovascular disease. Respiratory infections are of special importance as they are relatively common causes of morbidity and mortality, and immunization strategies against viral and bacterial causes of pneumonia in psoriasis patients are not well understood. The purpose of this study is to determine the risk of hospitalization for pneumonia in adults with psoriasis, and identify risk factors for hospitalization. Finally, we will determine the rate of influenza and pneumonia vaccination and identify predictors of vaccination, because vaccination represents a modifiable risk factor to prevent serious morbidity and mortality. The investigation of these aims will improve the care of psoriasis patients by identifying patients at highest risk for serious pneumonia while identifying opportunities for prevention.
Tina Porter, M.D.
Title: “Addressing the Under-Treatment of Patients with Psoriasis: Results from patient surveys”
Despite the availability of highly efficacious treatments for psoriasis, many patients are untreated or undertreated. Our research strives to better characterize the treatment barriers in psoriasis care from the patient’s perspective using the Health Belief Model (HBM) framework. Sixty-two subjects with psoriasis completed a 36-question survey. An approximately equal number of subjects reported mild, moderate, and severe pre-treatment psoriasis. Skin symptoms and embarrassment about skin appearance were the most important factors influencing patients’ decisions to seek treatment. Subjects with severe disease were happier than those with mild or moderate disease on several dimensions. We found that happy severe patients more commonly reported improvement in disease (60% vs. 9%, p<0.05), feeling informed about treatment options (100% vs 67%, p<0.05), and feeling their medications were safe (87% vs. 42%, p=0.01). Preliminary results from this study suggest that external sources, such as family support or advertisements, are less impactful on health engagement for psoriasis. Patients on systemic therapy may receive more education about psoriasis and available treatments, resulting in greater levels of treatment satisfaction. Further investigation into the prescribing patterns for systemic medications by primary care providers and the development of interventions to improve patient access to systemic treatments is warranted.
Sahil Sekhon, M.D.
Title: “Immunogenetic profiling of Goeckerman Therapy in the Treatment of Psoriasis Vulgaris”
Goeckerman therapy, which combines UV-B phototherapy and topical application of crude coal tar, is a highly efficacious and rapid-acting therapy for the treatment of psoriasis. Studies show that it has a 100% PASI-75 response rate. However, this treatment regimen, one of the oldest treatments available, happens to also be one of our least understood. It is currently thought that the mechanism by which crude coal tar has its action is through the Aryl Hydrocarbon receptor (AhR), with some hypothesizing that the active component, out of the roughly 10,000 components in crude coal tar, is the aryl hydrocarbon carbazole. However, the specific immunologic pathways that crude coal tar and the Goeckerman regimen affect have not been elucidated. This study aims to evaluate the effect of Goeckerman therapy by characterizing individual skin cell populations over time at the protein and RNA level using Cytometry by Time-Of-Flight (CyTOF) to separately analyze distinct skin cell populations including CD4+ T-cells, CD8+ T-Cells, regulatory T-cells, and myeloid dendritic cells as well as measure production of proteins and cytokines such as IL-17, TNF-α, IFN-γ, and IL-2 in parallel from each individual cell population. Ultimately our goal is to find new drug targets to improve psoriasis treatment.
Cory Simpson, M.D., Ph.D.
Title: “Role of autophagy in psoriasis pathogenesis”
Autophagy is a degradative pathway that allows cells to recycle damaged organelles or degrade normal organelles and nuclei during terminal differentiation. Interestingly, autophagy was recently genetically linked to psoriasis. Our studies aim to understand the mechanisms governing autophagy in normal keratinocytes with the goal of uncovering pathways that could restore differentiation in psoriatic epidermis. Autophagy receptors confer specificity to autophagic degradation by recognizing only certain organelles and sequestering them into autophagosomes, which fuse with lysosomes and degrade the organelles. We hypothesize that keratinocytes up-regulate specific autophagy receptors to degrade nuclei and organelles within the granular layers to initiate cornification. We have addressed this question in vitro by combining confocal microscopy with a live three-dimensional human skin model that replicates epidermal cornification. Using this system, we identified two autophagy receptors, NBR1 and NIX, that are expressed only in the outermost epidermal layers. Imaging of stratified keratinocytes expressing fluorophore-labeled NBR1 and NIX revealed robust localization to autophagosomes and organelle fragments. These data lead us to propose a model in which epidermal autophagy receptor expression is temporally and spatially regulated to precisely initiate organelle and nuclear degradation only in the granular layers and failure of this mechanism may underlie defective cornification in psoriasis.
Kanika Sood, M.D.
Increasing evidence suggests that PI3k/Akt/mTOR signaling pathway plays a central role in the regulation cell proliferation survival and differentiation. In both psoriasis and psoriatic arthritis (PsA) the key pathological outcomes- 1) Psoriasis plaque and 2) Pannus (hyper-proliferative synovial tissue) are because of uncontrolled proliferation of keratinocyte (KC) and synovial cells (FLS). We have observed that pmTOR is up-regulated in psoriatic plaques and IL-17 and IL-22 are the two critical pro-inflammatory cytokines that regulate the proliferation and survival of KC and FLS through the mTOR signaling cascade. Based on these preliminary results, here we will test our hypothesis that the mTOR signaling proteins has a regulatory role on the proliferation and survival of keratinocyte (KC), joint synovial cells (FLS), endothelial cells (EC) and T cell activation-the effector cells which build psoriasis plaques and lay the pannus in the joints.
Marilyn Wan, MBChB, M.P.H.
Title: “Psoriasis and risk of diabetes: A prospective population-based cohort study"
Multiple studies indicate that psoriasis is associated with an increased risk of diabetes. However, data from population based, prospective studies evaluating the impact of objectively measured disease severity on this risk are lacking. Therefore, we conducted a population-based cohort study nested within The Health Improvement Network, a United Kingdom electronic medical records database. Eligible patients between the ages of 25-65 with (n=8124) and without (n=76599) psoriasis were randomly selected for inclusion, matched on practice, visit date, and age strata. We prospectively surveyed general practitioners (GPs; response rate=95.5%) to confirm the diagnosis of psoriasis and assess disease severity. Among those with psoriasis, there were 280 (3.44%) incident cases of diabetes and 1867 (2.44%) incident cases of diabetes in those without psoriasis. After adjusting for age, sex and body mass index, the hazard ratios (95%CI) for developing incident diabetes were 1.21 (1.01-1.44), 1.01 (0.81-1.26), and 1.64 (1.23-2.18) in the ≤2% Body Surface Area (BSA)), 3-10% BSA, and >10% BSA groups compared to those without psoriasis, respectively (p=0.004 for trend). The results demonstrate that BSA affected by psoriasis is an independent prognostic factor for future diabetes. The excess risk of diabetes attributable to psoriasis is most clinically significant in patients with 10% or greater BSA affected with patients in this category experiencing approximately 6 additional new cases of diabetes per 1000 patients per year, compared to those without psoriasis. Worldwide, we estimate an additional 125,650 new diagnoses of type 2 diabetes mellitus per year in patients with psoriasis as compared to those without, of which, approximately 25,000 have psoriasis affecting 10% or greater of their body surface area.
Yan Zhou, M.D., Ph.D.
The transient receptor potential ion channel receptors TRPV1 and TRPA1 are known to mediate pain from heat and capsaicin (V1) and other noxious chemicals (A1), and may also play roles in mediating pruritus. Their roles in dermal inflammation, however, are unclear, and we hypothesized that they may regulate dermal inflammation or barrier function in conditions such as psoriasis in which pruritus is common. Herein, we assessed transepidermal water loss (TEWL) using quantitative instrumentation, epidermal hyperplasia (by H&E staining), and the dermal inflammatory infiltrate (by Giemsa and immunohistochemical staining) in wild type and TRPV1 and TRPA1 knockout (KO) mice following daily application of topical Imiquimod (IMQ) cream for 5 days (a standard protocol for inducing psoriasiform inflammation). Strikingly, TEWL scores were significantly decreased in TRPV1/TRPA1 KO mice by 50.07% and 54.36%, compared with WT mice, suggesting a reduction in IMQ-mediated barrier defects. Furthermore, epidermal hyperplasia was decreased in both TRPV1/A1 KO mice by 31.13% and 26.33%, respectively. Additionally, the area of epidermal Munro (neutrophilic) microabscesses was decreased in TRPV1/A1 KO mice by 27.32% and 68.32% compared with WT mice, suggesting that neutrophil recruitment was impacted in the KO mice. Lastly, mast cells as well as CD31+ blood vascular cells, CD45+ leukocytes, and CD3 T cells were all reduced in the lesional skin of TRPV1/TRPA1 KO mice, suggesting that dermal inflammation is reduced in these KO mice. In summary, key markers for psoriatic inflammation, including dermal inflammation and epidermal hyperplasia, are reduced in TRPV1 and TRPA1 KO mice, suggesting a novel role for these sensory receptors in psoriasiform inflammation and new avenues for therapeutic intervention.