Risk of Cutaneous T Cell Lymphoma with Psoriasis Biologic Therapies.

BACKGROUND: The risk of developing cutaneous T cell lymphoma (CTCL) in patients using psoriasis biologics has not been well characterized. The goals of this review were to investigate the incidence of CTCL in patients with psoriasis receiving biologic therapy in clinical trials and psoriasis registries, and to review cases of CTCL and biologic use reported in scientific publications. METHODS: The US National Library of Medicine clinical trials database (clinicaltrials.gov) was queried to identify phase 3 and 4 clinical trials of the 12 biologic agents currently FDA approved for psoriatic disease. The incidence of CTCL in these trials was examined and summarized. To examine the incidence of CTCL in psoriasis registries, a Medline search was conducted. Finally, we performed a systematic review of CTCL cases reported in the literature. RESULTS: Only two cases of CTCL were reported in 35,801 subjects with psoriasis receiving a biologic agent in the active arm of 108 psoriasis phase 3 clinical trials. One of these CTCL cases was determined by the investigator to be CTCL misdiagnosed as psoriasis prior to randomization. No cases of CTCL were reported in 5440 subjects with psoriasis in 34 phase 4 clinical trials. Only one case of CTCL was identified in 34,111 registry subjects. In the literature, tumor necrosis factor (TNF) inhibitors had the highest number of reported cases of CTCL (34 cases), followed by interleukin (IL)-17 inhibitors (7 cases), and IL-12/23 inhibitors (6 cases). No cases of CTCL were found to be reported with IL-23 inhibitors. CONCLUSION: Our findings indicate that the development of CTCL is rare in the setting of psoriasis biologic use. Of the limited number of cases of CTCL found, most were in the setting of TNF inhibitor use and no cases of CTCL were reported in the setting of IL-23 inhibitor use.

Mendelian Randomization Studies in Atopic Dermatitis: A Systematic Review.

Prior studies have found associations between atopic dermatitis (AD) and comorbidities, including depression, obesity, asthma, and allergic rhinitis. Although observational studies often cannot establish robust causality between potential risk factors and AD, Mendelian randomization minimizes confounding when exploring causality by relying on random allelic assortment at birth. In this study, we systematically reviewed 30 Mendelian randomization studies in AD. Body mass index, gut microbial flora, the IL-18 signaling pathway, and gastroesophageal reflux disease were among the causal factors for AD, whereas AD was causal for several medical conditions, including heart failure, rheumatoid arthritis, and conjunctivitis. These insights may improve preventive counseling in AD.

Management of Plaque Psoriasis in Adults: Clinical Utility of Tapinarof Cream.

Topical medications represent the most commonly used drugs in the treatment of psoriasis. However, topical steroids are mainly limited to short-term or intermittent use, and traditional non-steroidal topicals such as vitamin D analogues, topical calcineurin inhibitors, and topical retinoids are limited by low efficacy and poor local skin tolerability. Tapinarof (GSK2894512, DMVT-505) is a novel, topical aryl hydrocarbon receptor (AHR) agonist, which was recently approved by the FDA for the treatment of plaque psoriasis in adults. Tapinarof acts to improve psoriasis through diminished IL-17A production by CD4+ T cells, increased barrier gene expression in keratinocytes, and reduced production of reactive oxygen species. Both short-term and long-term efficacy and safety have been evaluated in two Phase II and two Phase III (PSOARING 1 and 2) clinical trials in addition to a long-term extension study (PSOARING 3). Overall, the drug has shown beneficial effects in achieving clear skin in adults with moderate-to-severe psoriasis, good local tolerability, and also a long duration of effect even after discontinuation of the drug. Therefore, this therapy provides a new, highly effective and safe non-steroidal option to add to our psoriasis treatment toolbox for both initial clearance and long-term maintenance of disease.

Association Between Poor Sleep and Myocardial Infarction in Patients with Psoriasis: Findings from a Cross-Sectional Study with the National Psoriasis Foundation.

BACKGROUND: Poor sleep quality occurs in patients with psoriasis at rates nearly twice that of the general population. Chronic sleep impairment is an independent risk factor for the development of cardiovascular disease. Here, we examine the association between sleep quantity and history of myocardial infarction in patients with psoriasis. METHODS: This observational, cross-sectional study utilized data from the 2020 National Psoriasis Foundation Annual Survey. Effect estimates were obtained using a multivariate logistic regression model, which controlled for prespecified covariates. RESULTS: Based on data from 1405 individuals with psoriasis, our analysis demonstrated a significant association between sleep quantity and history of myocardial infarction: odds ratio (OR) 0.67 [95% confidence interval (CI) 0.49-0.92], p = 0.012. The association was not significantly influenced by psoriasis severity (OR 1.01, [95% CI 0.99-1.03], p = 0.38), comorbid psoriatic arthritis (OR 1.06, [95% CI 0.48-2.38], p = 0.88), sleep apnea, or other traditional risk factors for myocardial infarction. CONCLUSION: Our analyses indicate an association between sleep quantity and history of myocardial infarction in patients with psoriasis. For each hour increase in average nightly sleep, patients with psoriasis have a 33% decrease in the odds of having a history of myocardial infarction. The chief limitation of this study is its cross-sectional design limiting ascertainment of causality.

Development of SkinTracker, an integrated dermatology mobile app and web portal enabling remote clinical research studies.

Introduction: In-person dermatology clinical research studies often face recruitment and participation challenges due to travel-, time-, and cost-associated barriers. Studies incorporating virtual/asynchronous formats can potentially enhance research subject participation and satisfaction, but few mobile health tools are available to enable remote study conduct. We developed SkinTracker, a patient-facing mobile app and researcher-facing web platform, that enables longitudinal collection of skin photos, patient reported outcomes, and biometric health and environmental data. Methods: Eight design thinking sessions including dermatologists, clinical research staff, software engineers, and graphic designers were held to create the components of SkinTracker. Following iterative prototyping, SkinTracker was piloted across six adult and four pediatric subjects with atopic dermatitis (AD) of varying severity levels to test and provide feedback on SkinTracker for six months. Results: The SkinTracker app enables collection of informed consent for study participation, baseline medical history, standardized skin photographs, patient-reported outcomes (e.g., Patient Oriented Eczema Measure (POEM), Pruritus Numerical Rating Scale (NRS), Dermatology Life Quality Index (DLQI)), medication use, adverse events, voice diary to document qualitative experiences, chat function for communication with research team, environmental and biometric data such as exercise and sleep metrics through integration with an Apple Watch. The researcher web portal allows for management and visualization of subject enrollment, skin photographs for examination and severity scoring, survey completion, and other patient modules. The pilot study requested that subjects complete surveys and photographs on a weekly to monthly basis via the SkinTracker app. Afterwards, participants rated their experience in a 7-item user experience survey covering app function, design, and desire for participation in future studies using SkinTracker. Almost all subjects agreed or strongly agreed that SkinTracker enabled more convenient participation in skin research studies compared to an in-person format. Discussion: To our knowledge, SkinTracker is one of the first integrated app- and web-based platforms allowing collection and management of data commonly obtained in clinical research studies. SkinTracker enables detailed, frequent capture of data that may better reflect the fluctuating course of conditions such as AD, and can be modularly customized for different skin conditions to improve dermatologic research participation and patient access.

Novel Insights From Basic Science in Psoriatic Disease at the GRAPPA 2022 Annual Meeting.

Recent basic science advances in psoriatic disease (PsD) were presented and discussed at the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) 2022 annual meeting. Topics included clinical applications of biomarkers, what the future of biomarkers for PsD may hold, the challenges of developing biomarker research to the point of clinical utility, advances in total-body positron emission tomography/computed tomography imaging, and emerging concepts from single-cell studies in PsD.

Sociodemographic and clinical characteristics associated with multiple biologic failure in psoriasis: A 2015-2022 prospective cohort analysis of the CorEvitas psoriasis registry.

BACKGROUND: Psoriasis patients with poor therapeutic response to multiple biologic agents are not well-characterized. OBJECTIVE: To describe the characteristics associated with development of multiple biologic failure (MBF) versus good clinical response (GR) to the first biologic. METHODS: This prospective cohort analysis evaluated patients in the multicenter CorEvitas Psoriasis Registry who initiated their first biologic between 2015 and 2020 and were followed for ≥24 months. Multivariable logistic regression identified sociodemographic, clinical, and patient-reported outcomes that differed between MBF (discontinued ≥2 biologics of different classes, each used for ≥90 days, due to inadequate efficacy) and GR (continued use of first biologic for ≥2 years) patients. RESULTS: One thousand thirty-nine patients were analyzed (490 GR [47.2%], 65 MBF [6.3%]). Female sex, shorter psoriasis duration, earlier year of biologic initiation, prior nonbiologic systemic therapy use, history of hyperlipidemia, and Medicaid insurance were significantly associated with MBF, though the latter 2 variables exhibited wider confidence intervals, indicating a lower level of support. The first-to-second biologic sequence most observed with MBF was Tumor necrosis factor-α inhibitor to IL-17 inhibitor use. LIMITATIONS: Biologic adherence between visits was not evaluated. CONCLUSION: Approximately 6% of psoriasis patients met MBF criteria. The results identify characteristics associated with MBF that may distinguish patients warranting more frequent follow-up.

Clinical Utility of Deucravacitinib for the Management of Moderate to Severe Plaque Psoriasis.

Introduction: Psoriasis is a chronic, immune-mediated skin condition with significant detriments to physical/mental health. While systemic therapies are available for the treatment of moderate-to-severe psoriasis, patients can experience therapeutic failure, loss of efficacy, or medical contraindications that require other therapeutic options. Objective: With the recent approval of deucravacitinib, a first-in-class TYK2 small molecule inhibitor administered orally for psoriasis patients, we reviewed data from randomized controlled trials (RCTs) to synthesize its clinical utility. To our knowledge, this is the first systematic review and meta-analysis of deucravacitinib comparing its clinical efficacy to placebo in psoriasis. Methods: A literature search was conducted in PubMed (MEDLINE), Embase, and the Cochrane Central Register of Controlled Trials to identify RCTs studying deucravacitinib in human patients with moderate-to-severe psoriasis. Results: One placebo-controlled Phase II RCT and two placebo-controlled/active-comparator Phase III RCTs were included for review. Patients (N=1953) treated with deucravacitinib 6 mg daily showed marked improvement in disease severity (Psoriasis Area and Severity Index (PASI), static Physician Global Assessment (sPGA) and quality-of-life outcomes compared to patients administered comparator (apremilast) and placebo. Clinical improvement given deucravacitinib was noted for scalp psoriasis but not fingernail psoriasis. Meta-analysis (deucravacitinib, n=888; placebo, n=466) comparing rates of clearance (sPGA 0/1) demonstrated superior efficacy of deucravacitinib compared to placebo (odds ratio, 12.87; 95% confidence interval, 8.97-18.48; χ2=4.08, I2=51%). Deucravacitinib was well-tolerated, with similar rate of occurrence and type of adverse events reported among patients treated with placebo or apremilast at Week 12-16. No cardiovascular events, serious infections, or lab abnormalities were noted. Conclusion: Deucravacitinib possesses good efficacy, with no report of safety concerns associated with prior JAK inhibitors used for psoriasis. Meta-analysis demonstrated deucravacitinib's superiority compared to placebo, indicating its promising clinical utility. Further studies are needed to observe long-term safety and efficacy, and to compare deucravacitinib to existing treatments.

Living with Psoriasis Vulgaris and Multi-Treatment Failure: A Patient and Dermatologist Perspective.

Psoriasis vulgaris is a systemic, chronic inflammatory disease affecting 2-3% of the population. Recent advances in the understanding of the pathophysiology of psoriatic disease have facilitated the development of novel therapeutic options with improved safety and efficacy. This article is coauthored by a patient with a lifelong history of psoriasis who experienced multiple treatment failures. He details his diagnosis and treatment experiences, as well as the physical, mental, and social ramifications of his skin condition. He then goes on to elaborate how evolutions in the treatment of psoriatic disease have impacted his life. This case is then discussed from the perspective of a dermatologist specializing in inflammatory skin disorders. We highlight the clinical features of psoriasis, its medical and psychosocial comorbidities, and the current landscape of psoriatic disease treatments.

Mendelian Randomization Studies in Psoriasis and Psoriatic Arthritis: A Systematic Review.

Psoriasis (PSO) and psoriatic arthritis (PSA) are inflammatory diseases with complex genetic and environmental contributions. Although studies have identified environmental and clinical associations with PSO/PSA, causality is difficult to establish. Mendelian randomization (MR) employs the random assortment of genetic alleles at birth to evaluate the causal impact of exposures. We systematically reviewed 27 MR studies in PSO/PSA examining health behaviors, comorbidities, and biomarkers. Exposures, including smoking, obesity, cardiovascular disease, and Crohn's disease, were causal for PSO and PSA, whereas PSO was causally associated with several comorbidities. These findings provide insights that can guide preventive counseling and precision medicine.

Apremilast in Palmoplantar Psoriasis and Palmoplantar Pustulosis: A Systematic Review and Meta-analysis.

BACKGROUND: This review's goals were to investigate apremilast's efficacy versus placebo in palmoplantar psoriasis (PP) and palmoplantar pustulosis (PPP), and apremilast's efficacy versus methotrexate in PP. METHODS: A literature search was conducted in PubMed, clinicaltrials.gov, and Embase in July 2022. Publications investigating subjects with PP or PPP, treated with apremilast, which reported palmoplantar-specific outcomes were used. Exclusion criteria included cases of drug-induced PP/PPP, case studies, non-English texts, omission of palmoplantar-specific outcomes, and incomplete publications. Studies were assessed for risk of bias using Cochrane Review Manager application and CASP checklist. Primary endpoints were a 50% improvement of the Palmoplantar Psoriasis/Pustulosis Area and Severity Index (PPPASI 50) and improvement of the Palmoplantar Physician Global Assessment (PPPGA) to 0 or 1 in patients with baseline PPPGA ≥ 3. RESULTS: Seventeen original studies including five placebo-controlled randomized clinical trials (RCTs), one phase II clinical trial, two randomized methotrexate comparative trials, six cohort studies, and three case series were analyzed, totaling 1117 participants. Meta-analysis of four placebo-controlled RCTs investigating PP found apremilast treatment to be superior to placebo in achieving a PPPGA of 0/1 (baseline PPPGA of ≥ 3) after 16 weeks of treatment (n = 244; OR = 2.69 [1.39-5.22]). Apremilast was superior to placebo in achieving PPPASI 50 at week 16 in the only placebo-controlled RCT of PPP (78.3 vs. 40.9%) [P = 0.0003]. Apremilast was comparable to methotrexate in achieving PPPASI 50 at week 16 in PP (59.5 vs. 64.3%; n = 84; [P = 0.65]). Non-randomized studies generally showed marked improvement in PPPASI, PPPGA, and DLQI scores following apremilast treatment. DISCUSSION: Apremilast treatment in PP and PPP resulted in significant improvement in objective, palmoplantar-specific clinical parameters versus placebo, and comparable efficacy with methotrexate in PP. Limitations in interpreting these results include variations in palmoplantar-specific metrics used and risk of bias of included studies.

Ethnoracial representation in hidradenitis suppurativa clinical trials.

BACKGROUND: Hidradenitis suppurativa (HS) is an inflammatory skin disorder characterized by recurring painful and suppurating lesions, with the disease disproportionately affecting black populations in the United States. Ethnoracial representation in clinical trials is vital to ensuring results are generalizable. The purpose of this study is to examine whether ethnic or racial disparities exist in HS clinical trials. METHODS: The US National Library of Medicine clinical trials database (clinicaltrials.gov) was queried to identify HS clinical trials. Trials that did not present ethnic or racial data on either the website or publication were not considered. RESULTS: A total of 57 HS trials were identified. Of these, 23 trials, containing 2530 patients, included racial or ethnic data (Table 1). White patients made up 76.1% (1435/1886) of the study population, followed by Blacks or African Americans (13.7% (238/1732)), Hispanics or Latinos (7.2% (20/279), Asians (2.6% (26/1016)), American Indians or Alaska Natives (1.3% (14/1051)), and Native Hawaiians or Other Pacific Islanders (0.4% (4/926)). DISCUSSION: Our results establish a significant lack of minority ethnoracial representation in HS clinical trials. Since HS prevalence is highest among Blacks or African Americans, it is imperative that future clinical trials are conducted with a larger proportion of this population. Furthermore, clinical trials that did not report racial or ethnic information were conducted in countries with predominantly White populations, which likely skewed the results of this study and caused underreporting of these patients.

Duration of Diabetes as a Risk Factor for Retinal Microvasculature Alterations Detected with Optical Coherence Tomography Angiography in Patients without Clinical Retinopathy.

In this study, we examined the impact of diabetes mellitus (DM) disease duration on optical coherence tomography angiography (OCTA) parameters in diabetic patients without diabetic retinopathy (DR). A total of 1118 eyes from 1118 DM patients without DR were divided into three groups by DM duration: 0−5 years (short cohort; n = 571), 6−10 years (medium cohort; n = 306), and >10 years (long cohort; n = 241). Ultra-widefield fundus photography and nine OCTA parameters derived from the superficial retinal capillary plexus were analyzed. Perfusion density (PD) and vessel length density (VD) were significantly decreased within the 1 mm patch in patient OCTAs from the medium cohort compared to the short cohort. Conversely, PD and VD were significantly decreased within the 6 mm patch and inner ring among the long cohort compared to the short and medium cohorts. These findings remained consistent after controlled analysis. Patients in the medium cohort had the largest FAZ area, while patients in the long cohort had the smallest FAZ area, with a statistically significant difference between the two groups. Superficial PD and VD significantly decreased among the medium and long cohorts compared to the short cohort, confirming that subclinical, progressive macular vasculature change is associated with longer DM duration. However, while FAZ area significantly increased in the medium cohort, the long cohort exhibited decreased FAZ area, suggesting the latter may possess protective factors that decrease overall risk of DR development.

Biologic insights from single-cell studies of psoriasis and psoriatic arthritis.

INTRODUCTION: Psoriasis (PSO) and psoriatic arthritis (PSA) represent a large burden of global inflammatory disease, but sustained treatment response and early diagnosis remain challenging. Both conditions arise from complex immune cell dysregulation. Single-cell techniques, including single-cell RNA sequencing (scRNA-seq), have revolutionized our understanding of pathogenesis by illuminating heterogeneous cell populations and their interactions. AREAS COVERED: We discuss the transcriptional profiles and cellular interactions unique to PSO/PSA affecting T cells, myeloid cells, keratinocytes, innate lymphoid cells, and stromal cells. We also review advances, limitations, and future challenges associated with single-cell studies. EXPERT OPINION: Following analyses of 22 single-cell studies, several themes emerged. A small subpopulation of cells can have a large impact on disease pathogenesis. Multiple cell types identified via scRNA-seq play supporting roles in PSO pathogenesis, contrary to the traditional paradigm focusing on IL-23/IL-17 signaling among dendritic cells and T cells. Immune cell states are dynamic, with psoriatic subpopulations aberrantly re-activating and differentiating into inflammatory phenotypes depending on surrounding signaling cues. Comparison of circulating immune cells with resident skin/joint cells has uncovered specific T cell clonotypes associated with the disease. Finally, machine learning models demonstrate great promise in identifying biomarkers to diagnose clinically ambiguous rashes and PSA at earlier stages.

In the Mind of the Ophthalmology Residency Applicant: Deciding Where to Apply, Interview, and Rank.

Objective This article characterizes the resources used by ophthalmology residency applicants when deciding where to apply, interview, and rank. Design Cross-sectional, online survey. Participants All applicants to the University of California-San Francisco ophthalmology residency program during the 2019 to 2020 and 2020 to 2021 application cycles. Methods A secure, anonymous, 19-item post-match questionnaire was distributed to participants inquiring about demographic information, match outcomes, and resources used to learn and make decisions about residency programs. Results were analyzed using qualitative and quantitative methods. Main Outcome Measures Qualitative ranking of resources used to decide where to apply, interview, and rank. Results One hundred thirty-six of 870 solicited applicants responded to the questionnaire, for a response rate of 15.6%. Digital platforms were ranked as more important resources than people (i.e., faculty, career advisors, residents, and program directors) when applicants were deciding where to apply and interview. Digital platforms became far less important when applicants were formulating their rank lists, at which time the program's academic reputation, perceived happiness of residents and faculty, interview experience, and geographic location were more important. When learning about residency programs, 100% of respondents engaged with program Web sites, and the majority engaged with program emails ( n =88 [85.4%]), Doximity ( n =82 [79.6%]), Reddit ( n =64 [62.1%]), Instagram ( n =59 [57.3%]), the FREIDA residency program database ( n =55 [53.4%]), and YouTube ( n =53 [51.5%]). All 13 digital platforms included in the survey were utilized by at least 25% of respondents, largely passively (i.e., reading rather than producing content). Respondents indicated that the most important topics to include on program Web sites were the number of residents accepted per year, current resident profiles, and resident alumni job/fellowship placement. Conclusion Applicants engage heavily with digital media in deciding where to apply and interview but rely heavily on their personal experiences with the program in deciding where to rank. Ophthalmology programs may facilitate recruitment of applicants by optimizing their digital media platforms.

Clinical Characteristics of 18 Patients with Psoriasis and Multiple Myeloma Identified Through Digital Health Crowdsourcing.

Psoriasis is a skin condition that affects over 100 million people worldwide, while multiple myeloma (MM) accounts for 10% of all hematologic malignancies in the US. There has been limited research on the intersection of psoriasis and MM, and clinicians often face difficult decisions in treating patients diagnosed with both conditions. For instance, the management of psoriasis with systemic immunotherapies in MM patients can be challenging because of concern about immunosuppression and possible worsening of MM. Online crowdsourcing platforms have recently become innovative tools that can actively empower patients in scientific research by enabling the contribution of health data. One such platform, HealthTree®, helps MM patients find optimal myeloma treatments and has registered > 6000 patients, many of whom have uploaded medical records and genetic profiles. By taking advantage of patient health data available on HealthTree, researchers can gain a greater understanding of the clinical characteristics and treatment responses of patients diagnosed with psoriasis and MM. In this case series, we first report a psoriasis and MM patient treated with the IL-17 inhibitor ixekizumab who demonstrated a temporary, 2-month improvement in MM biomarkers (M-protein, kappa, and kappa:lambda ratio). We then report on the clinical characteristics of 18 patients with verified profiles on HealthTree indicating concurrent psoriasis and MM conditions. We surveyed gender, age, psoriasis type, psoriasis treatment history, myeloma type, myeloma genetic features, and myeloma association with bone damage, hypercalcemia, or osteopenia. Four patients were treated with systemic immunomodulators for psoriasis, with responses suggesting that these therapies did not worsen MM progression. Our results validate crowdsourcing as a way to assess patient demographics and treatment responses for use in dermatology research. We examine the demographics of patients diagnosed with psoriasis and MM and investigate the use of systemic immunomodulators for treatment of psoriasis in MM patients.

Gli is activated and promotes epithelial-mesenchymal transition in human esophageal adenocarcinoma.

Esophageal adenocarcinoma (EAC) accounts for the most esophageal cancer cases in the US, and is notoriously aggressive. This study examines the role of Sonic Hedgehog (SHh)/Gli signaling in the regulation of epithelial-mesenchymal transition (EMT), a process tied to invasion and metastasis, in EAC. Gli/EMT protein expression levels were examined by western blot in paired EAC patient tissues (n = 24) and cell lines (OE19, OE33). Functional analyses were performed (siRNA, treatment with Gli-inhibitor, AKT-inhibitor, and N-Shh recombinant proteins) to investigate SHh/Gli signaling and EMT, cell cycle, and prognostic markers in EAC cell lines. MTS, luciferase reporter, qRT-PCR, western blot, wound healing, and transwell assays were executed to analyze pathway activity, cell migration, and invasion. Aberrant Gli1/2 expression was found in EAC patient tissues, and was significantly associated with increased EMT and AKT pathway activity. Stimulation of SHh/Gli resulted in EMT signaling, including expression of E-cadherin, N-cadherin, Vimentin, ß-catenin, Snail, and Slug, as well as cell cycle progression at mRNA and protein levels in EAC cell lines. Gli inhibition via small molecule administration and siRNA significantly reduced EMT, decreasing cell mobility and invasion. Both Gli and AKT inhibition rescued E-cadherin expression and suppressed AKT phosphorylation. This study provides evidence for a strong association between aberrant Gli1/2 expression and AKT/EMT markers in EAC; activated SHh/Gli signaling may be a critical component in promoting cell survival, metastases, and resistance to chemotherapy, and represents a promising avenue to target tumor proliferation and mobility.