Tree-Based Machine Learning to Identify Predictors of Psoriasis Incidence at the Neighborhood Level: A Populational Study from Quebec, Canada.

BACKGROUND: Psoriasis is a major global health burden affecting ~ 60 million people worldwide. Existing studies on psoriasis focused on individual-level health behaviors (e.g. diet, alcohol consumption, smoking, exercise) and characteristics as drivers of psoriasis risk. However, it is increasingly recognized that health behavior arises in the context of larger social, cultural, economic and environmental determinants of health. We aimed to identify the top risk factors that significantly impact the incidence of psoriasis at the neighborhood level using populational data from the province of Quebec (Canada) and advanced tree-based machine learning (ML) techniques. METHODS: Adult psoriasis patients were identified using International Classification of Disease (ICD)-9/10 codes from Quebec (Canada) populational databases for years 1997-2015. Data on environmental and socioeconomic factors 1 year prior to psoriasis onset were obtained from the Canadian Urban Environment Health Consortium (CANUE) and Statistics Canada (StatCan) and were input as predictors into the gradient boosting ML. Model performance was evaluated using the area under the curve (AUC). Parsimonious models and partial dependence plots were determined to assess directionality of the relationship. RESULTS: The incidence of psoriasis varied geographically from 1.6 to 325.6/100,000 person-years in Quebec. The parsimonious model (top 9 predictors) had an AUC of 0.77 to predict high psoriasis incidence. Amongst top predictors, ultraviolet (UV) radiation, maximum daily temperature, proportion of females, soil moisture, urbanization, and distance to expressways had a negative association with psoriasis incidence. Nighttime light brightness had a positive association, whereas social and material deprivation indices suggested a higher psoriasis incidence in the middle socioeconomic class neighborhoods. CONCLUSION: This is the first study to highlight highly variable psoriasis incidence rates on a jurisdictional level and suggests that living environment, notably climate, vegetation, urbanization and neighborhood socioeconomic characteristics may have an association with psoriasis incidence.

National trends in incidence and geographic distribution of melanoma and keratinocyte carcinoma in the Russian Federation.

Keratinocyte Carcinomas (KC), including basal cell and cutaneous squamous cell carcinomas, are the most common skin cancers in Fitzpatrick phototype I-III individuals, while melanoma is one of the deadliest skin cancer types. The incidence of both melanoma and KC is increasing in Russia. KCs' incidence increases from north-to-south across the Russian Federation. In contrast, while melanoma's incidence increases from north-to-south in the eastern part of the country, in the west of Russia a reverse latitude gradient trend is noted, where northern more affluent regions of Russia display higher rates of melanoma than the southern jurisdictions. Furthermore, our detailed analysis of incidence by jurisdiction highlights that affluent northern capital cities have higher rates of melanoma than the surrounding regions. The observed melanoma incidence trends in the western portion of Russia are similar to the findings in the western Europe and opposite of the findings in Canada.

Burden and geographic distribution of oral cavity and oropharyngeal cancers in the Russian Federation.

Background: The global incidence of lip and oral cavity cancers (OCCs) and oropharyngeal cancers (OPCs) is steadily increasing. While tobacco and alcohol consumption are established risk factors, a considerable proportion of these cancers has become attributed to human papilloma virus (HPV) infection. We aimed to describe the occurrence and identify potential risk factors of OCCs and OPCs across the Russian Federation during 2007-2018. Methods: We conducted an ecological analysis using publicly accessible data from the P.A. Herzen Moscow Oncology Research Institute. Incidence and mortality rates by jurisdiction were mapped for geospatial analysis. We pre-defined 11 potential contributing risk factors and used univariable and multivariable Poisson regression model with backwards stepwise variable selection to identify associated factors with OCC and OPC. Results: A total of 190,585 individuals were diagnosed with OCCs and OPCs in Russia between 2007-2018. Non-uniform geographic distribution of cancer cases was noted where the Far Eastern Federal District had the highest rate of OCC and the Central Federal District of OPCs. Districts with high weekly alcohol consumption had significantly higher incidence and mortality rates in both sexes. Districts with high rates of daily smoking had higher incidence of OCC among females, and those with low smoking trends had lower mortality rates for OCCs and OPCs. Conclusion: We detail the burden of OCCs and OPCs across Russia, with the aim of elucidating modifiable risk factors and proposing evidence-based prevention strategies. Tobacco/alcohol sales control measures and smoking/drinking cessation programs should continue to be prioritized as public health measures, especially for females.

The Role of Sex and Gender in Dermatology - From Pathogenesis to Clinical Implications.

BACKGROUND: Sex and gender have increasingly been recognized as significant risk factors for many diseases, including dermatological conditions. Historically, sex and gender have often been grouped together as a single risk factor in the scientific literature. However, both may have a distinct impact on disease incidence, prevalence, clinical presentation, severity, therapeutic response, and associated psychological distress. OBJECTIVES AND PROJECT DESCRIPTION: The mechanisms that underlie differences in skin diseases between males, females, men, and women remain largely unknown. The specific objectives of this review paper are:To highlight the biological differences between males and females (sex), as well as the sociocultural differences between men and women (gender) and how they impact the integumentary system.To perform a literature review to identify important sex- and gender-related epidemiological and clinical differences for various skin conditions belonging to a range of disease categories and to discuss possible biological and sociocultural factors that could explain the observed differences.To discuss dermatological skin conditions and gender-affirming treatments within the transgender community, a population of individuals who have a gender identity which is different than the gender identity they were assigned at birth. FUTURE IMPACT: With the rising number of individuals that identify as non-binary or transgender within our increasingly diverse communities, it is imperative to recognize gender identity, gender, and sex as distinct entities. By doing so, clinicians will be able to better risk-stratify their patients and select treatments that are most aligned with their values. To our knowledge, very few studies have separated sex and gender as two distinct risk factors within the dermatology literature. Our article also has the potential to help guide future prevention strategies that are patient-tailored rather than using a universal approach.

Skin disorders and interstitial lung disease: Part II-The spectrum of cutaneous diseases with lung disease association.

Part 2 of this 2-part CME introduces dermatologists to noninfectious inflammatory skin diseases associated with pulmonary involvement. In many cases, dermatologists may be the first physicians recognizing respiratory complications associated with these diagnoses. Because pulmonary involvement is often the leading cause of morbidity and mortality, dermatologists should be comfortable screening and monitoring for lung disease in high-risk patients, recognizing cutaneous stigmata of lung disease in these patients and referring to pulmonary specialists, when appropriate, for prompt treatment initiation. Some treatments used for skin disease may not be appropriate in the context of lung disease and hence, choosing a holistic approach is important. Interstitial lung disease and pulmonary hypertension are the most common pulmonary complications and a significant cause of mortality in autoimmune connective tissue diseases, especially systemic sclerosis, dermatomyositis, and mixed connective tissue disease. Pulmonary complications, notably interstitial lung disease, are also common and life-threatening in sarcoidosis and vasculitis, while they are variable in neutrophilic and autoimmune blistering diseases.

Risk factors and communities disproportionately affected by cervical cancer in the Russian Federation: A national population-based study.

Background: Cervical cancer is one of the leading causes of cancer in women of childbearing age worldwide. A substantial fraction of cervical cancer is associated with Human Papilloma Virus (HPV) infection and is preventable through vaccination and screening. The aim of the study is to describe geographic and epidemiologic trends in incidence and mortality of cervical cancer in Russia during 2007-2018. Methods: Publicly accessible data from the P.A. Herzen Moscow Oncology Research Institute and the Ministry of Health of Russian Federation for 2007-2018 was used for this study. Cervical cancer incidence and mortality rates were analyzed using descriptive statistics and results were mapped to determine the geographic distribution. Potential contributing risk factors in the population were studied using univariate and multivariate Poisson regression analyses. Findings: A total of 187,013 patients were diagnosed with cervical cancer in Russia between 2007 and 2018. The average age-standardized incidence (ASIR) and mortality rates (ASMR) were 15.70/100,000 and 5.76/100,000 females, respectively, with a 27% increase in the incidence observed between 2007 and 2018. The highest ASIR was observed in the Far Eastern Federal District and the lowest in the Central Federal District. Multivariate model for cervical cancer ASIR showed that daily smoking (p = 0·0003) and syphilis (p = 0.003) were significantly associated with cervical cancer incidence. Interpretation: The incidence of cervical cancer in Russia is rising at a significant pace. This trend can in part be attributed to a lack of nationwide cervical cancer screening . The presented results are valuable for informing public health policy on HPV vaccinations, smoking prevention and cervical cancer screening as urgent interventions are needed to combat a troubling trend. Funding: This work was supported by the Cancer Research Society (CRS)-Canadian Institutes for Health Research (CIHR) Partnership Grant #25343 to Dr. Litvinov. Canadian Dermatology Foundation research grant to Dr. Litvinov, and by the Fonds de la recherche du Québec - Santé to Dr. Sasseville (#22648) and to Dr. Litvinov (#34753 and #36769). This research was further supported by the CIHR Catalyst Grant #428712 to Dr. Litvinov.

Omalizumab for the Treatment of Bullous Pemphigoid: A Systematic Review of Efficacy and Safety.

Bullous pemphigoid (BP) is an autoimmune blistering skin disease. Current treatment strategies are limited by their efficacy and/or side effect profile and the need for safer and effective alternatives is undeniable. We aimed to conduct a systematic review focusing on the efficacy and safety of omalizumab in BP patients. Embase, PubMed, Cochrane, and clinicaltrials.gov were searched for English and French articles published from inception to July 1, 2021, using search terms "omalizumab" OR "Xolair" OR "IGE025" OR "olizumab" AND "bullous pemphigoid." Screening and data extraction was performed by two raters independently. The primary outcome was complete response (CR), and secondary outcomes were partial response (PR), flare-ups, adverse events/vital status. In total, 22 articles were included, with a total of 56 patients. All patients had a refractory BP with mean disease duration of 13.5 ± 20.2 months (Standard Deviation (SD)) and failed 3.1 ± 1.6 therapies and many remained corticosteroids dependent. Overall, 87.5% of patients responded to treatment (55.4% CR and 32.1% PR), 7.1% discontinued the protocol and only 5.4% were non responders. A third of patients were able to discontinue all other therapies and most others were able to discontinue or taper systemic corticosteroids to <10 mg daily. Flare-ups occurred in 57.7% of patients upon discontinuation of omalizumab and/or steroid tapering, most patients recaptured response thereafter. Omalizumab was well tolerated by most patients. Omalizumab appears to be a promising treatment for BP with a good response rate and safety profile. However, several limitations were identified in current literature, and highlight the need for randomized controlled trials of omalizumab in BP.

Novel role of long non-coding RNAs in autoimmune cutaneous disease.

Systemic autoimmune rheumatic diseases (SARDs) are a heterogeneous group of chronic multisystem inflammatory disorders that are thought to have a complex pathophysiology, which is not yet fully understood. Recently, the role of non-coding RNAs, including long non-coding RNA (lncRNA), has been of particular interest in the pathogenesis of SARDs. We aimed to summarize the potential roles of lncRNA in SARDs affecting the skin including, systemic sclerosis (SSc), dermatomyositis (DM) and cutaneous lupus erythematosus (CLE). We conducted a narrative review summarizing original articles published until July 19, 2021, regarding lncRNA associated with SSc, DM, and CLE. Several lncRNAs were hypothesized to play an important role in disease pathogenesis of SSc, DM and CLE. In SSc, Negative Regulator of IFN Response (NRIR) was thought to modulate Interferon (IFN) response in monocytes, anti-sense gene to X-inactivation specific transcript (TSIX) to regulate increased collagen stability, HOX transcript antisense RNA (HOTAIR) to increase numbers of myofibroblasts, OTUD6B-Anti-Sense RNA 1 to decrease fibroblast apoptosis, ncRNA00201 to regulate pathways in SSc pathogenesis and carcinogenesis, H19X potentiating TGF-ß-driven extracellular matrix production, and finally PSMB8-AS1 potentiates IFN response. In DM, linc-DGCR6-1 expression was hypothesized to target the USP18 protein, a type 1 IFN-inducible protein that is considered a key regulator of IFN signaling. Additionally, AL136018.1 is suggested to regulate the expression Cathepsin G, which increases the permeability of vascular endothelial cells and the chemotaxis of inflammatory cells in peripheral blood and muscle tissue in DM. Lastly, lnc-MIPOL1-6 and lnc-DDX47-3 in discoid CLE were thought to be associated with the expression of chemokines, which are significant in Th1 mediated disease. In this review, we summarize the key lncRNAs that may drive pathogenesis of these connective tissue diseases and could potentially serve as therapeutic targets in the future.

Prominent Role of Type 2 Immunity in Skin Diseases: Beyond Atopic Dermatitis.

Type 2 immunity, illustrated by T helper 2 lymphocytes (Th2) and downstream cytokines (IL-4, IL-13, IL-31) as well as group 2 innate lymphoid cells (ILC2), is important in host defense and wound healing.1 The hallmark of type 2 inflammation is eosinophilia and/or high IgE counts and is best recognized in atopic diathesis. Persistent eosinophilia, such as seen in hypereosinophilic syndromes, leads to fibrosis and hence therapeutic Type 2 inhibition in fibrotic diseases is of high interest. Furthermore, as demonstrated in cutaneous T cell lymphoma, advanced disease is characterized by Th1 to Th2 switch allowing cancer progression and immunosuppression. Development of targeted monoclonal antibodies against IL-4Rα (eg, dupilumab) led to a paradigm shift for the treatment of atopic dermatitis (AD) and stimulated research to better understand the role of Type 2 inflammation in other skin conditions. In this review, we summarize up to date knowledge on the role of Type 2 inflammation in skin diseases other than AD and highlight whether the use of Type 2 targeted therapies has been documented or is being investigated in clinical trials. This manuscript reviews the role of Type 2 inflammation in dermatitis, neurodermatitis, IgE-mediated dermatoses (eg, bullous pemphigoid, chronic spontaneous urticaria), sclerodermoid conditions and skin neoplasms.

Non-Melanoma Skin Cancer Distribution in the Russian Federation.

BACKGROUND: Non-melanoma skin cancer (NMSC) incidence has been increasing steadily around the world. The aim of the study is to describe geographic trends in incidence and mortality of NMSC in Russia between 2007 and 2017 and compare findings to other European countries. METHODS: We used geospatial analysis to map the incident cases and descriptive statistical analysis to analyze trends. Additionally, we assessed the relationship between ethnicity, geographic latitude/longitude, and NMSC incidence/mortality rates. We retrospectively analyzed the data from the Moscow Oncology Research Institute, Ministry of Health of the Russian Federation, for 2007-2017. Routine methods of descriptive epidemiology were used to study incidence and mortality rates by age groups, years, and jurisdictions (i.e., Federal Districts and Federal Subjects). RESULTS: In total, 733,723 patients were diagnosed with NMSC in Russia over the period 2007-2017, of whom 63% were women. The overall age-standardized incidence and mortality rates were 29.64/100,000 and 0.70/100,000, respectively. There was a consistent increase in age-standardized incidence rates over the study period, with a decreasing mortality rate. Geographic mapping revealed north-to-south and east-to-west gradients for NMSC. CONCLUSIONS: This study demonstrated longitudinal trends for NMSC incidence in Russia documenting that skin phototype, latitude/longitude, climate zones, and cultural practices remain dominant risk factors defining the epidemiology of NMSC. Moreover, this work identified several regions in the country (i.e., Republic of Adygea, Samara, Krasnodar Krai, etc.), where patient education/sun awareness campaigns will be useful to help reduce the risk of this malignancy.

Inhibition of IL-13: A New Pathway for Atopic Dermatitis [Formula: see text].

Dupilumab, a monoclonal antibody against the common receptor of interleukin (IL)-4 and IL-13, was the first biologic therapy approved in Canada for treatment of moderate-to-severe atopic dermatitis (AD). While it is considered safe and effective, dupilumab is not universally effective and 8%-38% of patients develop conjunctivitis, while some patients develop head and neck dermatitis. Thus, new therapeutic options are warranted. While both IL-4 and IL-13 play important roles in the pathogenesis of AD, it has been recently demonstrated that IL-13 is the primary upregulated cytokine in AD skin biopsy samples. A placebo-controlled phase 2b clinical trial evaluating the efficacy and safety of lebrikizumab, an IL-13 inhibitor, in AD demonstrated that, at 16 weeks, Eczema Area and Severity Index (EASI) 75 and Investigator's Global Assessment (IGA) 0/1 were achieved by 60.6% and 44.6% of patients taking lebrikizumab at its highest dose (vs 24.3% and 15.3% of patients taking placebo, respectively). Moreover, treatment with lebrikizumab was associated with rapid improvement of pruritus and low rates of conjunctivitis (1.4%-3.8%). Another IL-13 monoclonal antibody, tralokinumab, was evaluated for safety and efficacy in moderate-to-severe AD. By week 12, among adults receiving 300 mg tralokinumab, 42.5% achieved EASI-75 and 26.7% achieved IGA 0/1 score (vs 15.5% and 11.8% in the placebo group, respectively). Both lebrikizumab and tralokinumab demonstrated acceptable safety profiles in AD (and non-AD) trials with adverse events often being comparable between treatment and control groups. Thus, IL-13 inhibitors may provide a safe and effective treatment alternative for patients with moderate-to-severe AD.

Malignancy in psoriatic disease: Results from prospective longitudinal cohorts.

OBJECTIVES: To estimate the prevalence and incidence of malignancy and its types in psoriatic arthritis (PsA) and psoriasis without arthritis (PsC) patients, in comparison to the general population, and to identify the predictive factors for developing cancer in psoriatic disease (PsD). METHODS: PsA patients followed prospectively since 1978 and PsC patients followed since 2006 at 6-to-12 month intervals according to a standard protocol were included. Malignancies were recorded prospectively and linkages with Cancer Care Ontario and the Death Registry were carried out to confirm the presence and type of malignancy up to December 2016. Standardized incidence ratios (SIR) were calculated for overall cancers and by age and sex. Cox regression analysis was conducted to identify risk factors associated with the development of malignancy after the diagnosis of PsD. RESULTS: 2051 patients (PsD) were included of whom 228 (11%) developed cancer. 168 patients developed cancer after first clinic visit and are included in this report. Overall SIR for malignancy was 0.83 (0.68, 1.00), SIR for females was 1.06 (0.80, 1.37), and for males was 0.67 (0.50, 0.88). The most common malignancies were skin, breast, and hematological. Skin cancer was the only specific cancer that had a higher incidence than the general population with SIR = 3.37 (1.84, 5.66). There was insufficient evidence to suggest an increased risk of malignancy associated with biologics use. CONCLUSIONS: In this long-term prospective follow-up of patients with PsA and PsC the overall malignancy risk was not found to be higher than the general population, while skin cancer increased.

Toward Understanding of Environmental Risk Factors in Systemic Sclerosis [Formula: see text].

IMPORTANCE: Systemic sclerosis (SSc) is a severe, chronic, and incurable autoimmune fibrotic skin disease with significant extracutaneous involvement. Low concordance rate in twin studies and unequal geographic distribution of SSc argues for importance of environment in disease initiation and progression. OBJECTIVE: In this manuscript we provide a summary of all investigated potential external risk factors for SSc. DATA SOURCES: A literature search in PubMed and EMBASE database was performed for studies published until January 1, 2020 by 2 reviewers (EN and LO) independently. FINDINGS: Occupational and/or environmental exposures to silica and organic solvents are associated with increased incidence and severity of SSc. Exposure to epoxy resins, asbestos, and particulate air pollution favors increased risk of SSc, but data are based on limited number of observational studies. There is insufficient evidence to conclude an association between SSc development and other occupational (eg, welding fumes) or personal exposures (eg, smoking, vitamin D deficiency). Association of SSc with silicone breast implants has been disproven. Infectious pathogens (eg, Helicobacter pylori and angiotropic viruses) and dysbiosis seem to play a role in SSc development and severity, but their role remains to be clarified. CONCLUSIONS AND RELEVANCE: It may be prudent to counsel our patients with SSc (or those at risk of SSc) to avoid occupations with exposure to silica, organic solvents, asbestos and epoxy resins; restraint from smoking, using cocaine or drugs with pro-fibrotic potential. While the association between low vitamin D and SSc remains to be confirmed, we believe that SSc patients should be encouraged to maintain healthy vitamin D levels as benefits outweigh the risks.

Cutaneous Immune-Related Adverse Events (irAEs) to Immune Checkpoint Inhibitors: A Dermatology Perspective on Management [Formula: see text].

Immune checkpoint inhibitors have proven to be efficacious for a broad spectrum of solid organ malignancies. These monoclonal antibodies lead to cytotoxic T-cell activation and subsequent elimination of cancer cells. However, they can also lead to immune intolerance and immune-related adverse event (irAEs) that are new and specific to these therapies. Cutaneous irAEs are the most common, arising in up to 34% of patients on PD-1 inhibitors and 43% to 45% on CTLA-4 inhibitors. The most common skin manifestations include maculopapular eruption, pruritus, and vitiligo-like lesions. A grading system has been proposed, which guides management of cutaneous manifestations based on the percent body surface area (BSA) involved. Cutaneous irAEs may prompt clinicians to reduce drug doses, add systemic steroids to the regiment, and/or discontinue lifesaving immunotherapy. Thus, the goal is for early identification and concurrent management to minimize treatment interruptions. We emphasize here that the severity of the reaction should not be graded based on BSA involvement alone, but rather on the nature of the primary cutaneous pathology. For instance, maculopapular eruptions rarely affect <30% BSA and can often be managed conservatively with skin-directed therapies, while Stevens-Johnson syndrome (SJS) affecting even 5% BSA should be managed aggressively and the immunotherapy should be discontinued at once. There is limited literature available on the management of the cutaneous irAEs and most studies present anecdotal evidence. We review the management strategies and provide recommendations for psoriatic, immunobullous, maculopapular, lichenoid, acantholytic eruptions, vitiligo, alopecias, vasculitides, SJS/toxic epidermal necrolysis, and other related skin toxicities.

Geographic Variations in Cutaneous Melanoma Distribution in the Russian Federation.

BACKGROUND: Cutaneous melanoma (CM) incidence has been increasing around the world. The goal of this study is to describe geographic trends in incidence and mortality of CM in Russia between 2001 and 2017. METHODS: To achieve this we used geo-informatic technique (mapping) and descriptive statistical analysis. Additionally, we studied the associations between ethnicity, geographic latitude/longitude, and CM incidence/mortality rates. We retrospectively analyzed the data from the Moscow Oncology Research Institute, Ministry of Health of the Russian Federation, for the period of the study. Routine methods of descriptive epidemiology were used to study incidence and mortality rates by age groups, years, and jurisdictions (i.e., Federal Districts and Federal Subjects of Russia). RESULTS: In total, 141,597 patients were diagnosed with melanoma in Russia over the period 2001-2017, of whom 62% were women. The overall age-standardized incidence and mortality rates were 4.27/100,000 and 1.62/100,000, respectively. Geographic mapping revealed north-to-south and east-to-west gradients. As the study was fully descriptive, retrospective, and based on official statistical reports, detailed characteristics of clinical forms, anatomic sites, Breslow depth, and treatments could not be analyzed. CONCLUSIONS: This study outlined the burden of melanoma in the Russian Federation, and the trends were similar to those observed in countries with similar latitudes and skin phenotype. The importance of the skin color gradient and recreational/cultural practices were some of the most important risk factors highlighted in this study for the development of melanoma in Russia.