Regulatory T Cells in Skin Facilitate Epithelial Stem Cell Differentiation.

The maintenance of tissue homeostasis is critically dependent on the function of tissue-resident immune cells and the differentiation capacity of tissue-resident stem cells (SCs). How immune cells influence the function of SCs is largely unknown. Regulatory T cells (Tregs) in skin preferentially localize to hair follicles (HFs), which house a major subset of skin SCs (HFSCs). Here, we mechanistically dissect the role of Tregs in HF and HFSC biology. Lineage-specific cell depletion revealed that Tregs promote HF regeneration by augmenting HFSC proliferation and differentiation. Transcriptional and phenotypic profiling of Tregs and HFSCs revealed that skin-resident Tregs preferentially express high levels of the Notch ligand family member, Jagged 1 (Jag1). Expression of Jag1 on Tregs facilitated HFSC function and efficient HF regeneration. Taken together, our work demonstrates that Tregs in skin play a major role in HF biology by promoting the function of HFSCs.

Vaccination recommendations for adults receiving biologics and oral therapies for psoriasis and psoriatic arthritis: Delphi consensus from the medical board of the National Psoriasis Foundation.

BACKGROUND: For psoriatic patients who need to receive nonlive or live vaccines, evidence-based recommendations are needed regarding whether to pause or continue systemic therapies for psoriasis and/or psoriatic arthritis. OBJECTIVE: To evaluate literature regarding vaccine efficacy and safety and to generate consensus-based recommendations for adults receiving systemic therapies for psoriasis and/or psoriatic arthritis receiving nonlive or live vaccines. METHODS: Using a modified Delphi process, 22 consensus statements were developed by the National Psoriasis Foundation Medical Board and COVID-19 Task Force, and infectious disease experts. RESULTS: Key recommendations include continuing most oral and biologic therapies without modification for patients receiving nonlive vaccines; consider interruption of methotrexate for nonlive vaccines. For patients receiving live vaccines, discontinue most oral and biologic medications before and after administration of live vaccine. Specific recommendations include discontinuing most biologic therapies, except for abatacept, for 2-3 half-lives before live vaccine administration and deferring next dose 2-4 weeks after live vaccination. LIMITATIONS: Studies regarding infection rates after vaccination are lacking. CONCLUSION: Interruption of antipsoriatic oral and biologic therapies is generally not necessary for patients receiving nonlive vaccines. Temporary interruption of oral and biologic therapies before and after administration of live vaccines is recommended in most cases.

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.

Layilin Anchors Regulatory T Cells in Skin.

Regulatory T cells (Tregs) reside in nonlymphoid tissues where they carry out unique functions. The molecular mechanisms responsible for Treg accumulation and maintenance in these tissues are relatively unknown. Using an unbiased discovery approach, we identified LAYN (layilin), a C-type lectin-like receptor, to be preferentially and highly expressed on a subset of activated Tregs in healthy and diseased human skin. Expression of layilin on Tregs was induced by TCR-mediated activation in the presence of IL-2 or TGF-ß. Mice with a conditional deletion of layilin in Tregs had reduced accumulation of these cells in tumors. However, these animals somewhat paradoxically had enhanced immune regulation in the tumor microenvironment, resulting in increased tumor growth. Mechanistically, layilin expression on Tregs had a minimal effect on their activation and suppressive capacity in vitro. However, expression of this molecule resulted in a cumulative anchoring effect on Treg dynamic motility in vivo. Taken together, our results suggest a model whereby layilin facilitates Treg adhesion in skin and, in doing so, limits their suppressive capacity. These findings uncover a unique mechanism whereby reduced Treg motility acts to limit immune regulation in nonlymphoid organs and may help guide strategies to exploit this phenomenon for therapeutic benefit.

Single-cell RNA sequencing of psoriatic skin identifies pathogenic Tc17 cell subsets and reveals distinctions between CD8+ T cells in autoimmunity and cancer.

BACKGROUND: Psoriasis is an inflammatory, IL-17-driven skin disease in which autoantigen-induced CD8+ T cells have been identified as pathogenic drivers. OBJECTIVE: Our study focused on comprehensively characterizing the phenotypic variation of CD8+ T cells in psoriatic lesions. METHODS: We used single-cell RNA sequencing to compare CD8+ T-cell transcriptomic heterogeneity between psoriatic and healthy skin. RESULTS: We identified 11 transcriptionally diverse CD8+ T-cell subsets in psoriatic and healthy skin. Among several inflammatory subsets enriched in psoriatic skin, we observed 2 Tc17 cell subsets that were metabolically divergent, were developmentally related, and expressed CXCL13, which we found to be a biomarker of psoriasis severity and which achieved comparable or greater accuracy than IL17A in a support vector machine classifier of psoriasis and healthy transcriptomes. Despite high coinhibitory receptor expression in the Tc17 cell clusters, a comparison of these cells with melanoma-infiltrating CD8+ T cells revealed upregulated cytokine, cytolytic, and metabolic transcriptional activity in the psoriatic cells that differed from an exhaustion program. CONCLUSION: Using high-resolution single-cell profiling in tissue, we have uncovered the diverse landscape of CD8+ T cells in psoriatic and healthy skin, including 2 nonexhausted Tc17 cell subsets associated with disease severity.

Review of Apremilast Combination Therapies in the Treatment of Moderate to Severe Psoriasis.

Psoriasis is a chronic inflammatory skin condition resulting from the dysregulation of cytokines. Apremilast, an oral phosphodiesterase-4 inhibitor is approved by the Federal Drug Administration (FDA) for the treatment of moderate to severe plaque psoriasis in patients who are eligible for phototherapy or systemic therapy. The drug increases cyclic adenosine monophosphate, cAMP, modulating the expression of pro-inflammatory cytokines. This review aims to explore and categorize current literature describing the efficacy and safety profile of the addition of apremilast to existing therapies including topicals, phototherapy, and systemic agents for the treatment of psoriasis. One database was used for the literature search. Seventeen studies with 617 patients met inclusion criteria and were included. Fifteen studies demonstrated beneficial results with excellent safety and efficacy of apremilast combination therapy (CT). Apremilast has been shown to improve the quality of life and reduce symptom severity in moderate to severe psoriasis. The drug’s simple dosing schedule with mild side effect profile makes it a practical option for patients as combination therapy. J Drugs Dermatol. 2021;20(8):837-843. doi:10.36849/JDD.5845.

Innovations in translational research in dermatology: minimally invasive methods for biosample acquisition.

Translational research has improved patient care over the last decade. In dermatology, this research often requires human tissue for laboratory analysis. The skin biopsy remains the gold standard for tissue acquisition, but the procedure comes with a small risk of bleeding and infection. It also causes scarring and anxiety in certain populations. These risks and concerns may affect participation rates in translational studies, which can require multiple biopsies. Minimally invasive procedures may mitigate these risks and concerns. We queried the PubMed database for all minimally invasive technologies studied as of May 2021. Of the 53 articles reviewed, we identified 13 unique, minimally invasive methods for tissue biosample acquisition. Herein, we describe each sampling method, biosample type analyzed, disease target, molecular application, procedure, quantity of obtained biosample, purpose, and required equipment. We organize this information into a comprehensive chart. We then synthesize this information into another table that compares the pros and cons of each intervention. We found that tape stripping, suction blistering, hair plucking, microbiopsy, and microneedle patching provide a variety of useful biosample types for laboratory analysis. In translational research, these technologies have the potential to replace more invasive methods like the punch biopsy, likely improving participation in studies.

Off-label uses of TNF-a inhibitors and IL-12/23 inhibitors in dermatology.

TNF-a inhibitors, which include adalimumab, infliximab, etanercept, certolizumab, and golimumab, and IL-12/23 inhibitor, ustekinumab, have been widely used as a U.S. Food and Drug Administration (FDA) approved for the treatment of psoriasis. Outside of psoriasis, high levels of TNF-a had also been found in several skin diseases including hidradenitis suppurativa. IL-12 and IL-23 play important role in the pathogenesis of SLE, alopecia areata, and vitiligo. This paper reviews the off-label uses of TNF-a inhibitors and IL-12/23 inhibitors in skin disorders.

Aiming for Cure and Preventive Initiatives in Psoriatic Disease: Building Synergy at NPF, GRAPPA, and PPACMAN.

PURPOSE OF REVIEW: To provide a general overview of the organizations dedicated to advance clinical and translational research in the field of psoriatic disease and to describe the current and future opportunities for team science approaches to overcome unmet needs in the field. Descriptions of initiatives from the NPF, PPACMAN, and GRAPPA are summarized. RECENT FINDINGS: Program projects have recently identified areas of knowledge gaps in diagnosis, treatment, and prevention of psoriasis and psoriatic arthritis (PsA). NPF's Psoriasis Prevention Initiative aims to identify interventions that can prevent the onset and relapse of psoriatic disease or related comorbidities. The Psorcast Study is a joint venture between PPACMAN and Sage Bionetworks based on patient-generated smartphone measurements of psoriatic disease. Similarly, GRAPPA is involved in a number of projects related to axial PsA, enthesitis prevalence, and biomarker discoveries. As important initiatives bring new targets for diagnosis and therapeutics in psoriatic disease, supra-endeavors such as the NIH-Accelerating Medicines Partnership (AMP) and the European Innovative Medicines Initiative (IMI) are promising public-private partnerships that can significantly catapult the field forward.

Candidate long-range regulatory sites acting on the IL17 pathway genes TRAF3IP2 and IL17RA are associated with psoriasis.

BACKGROUND: Drug-mediated disruption of IL17A, IL17F and IL17RA proteins is effective in psoriasis. However, disruption of the IL17 pathway by functional mutations has so far only been shown to affect risk in IL23R and TRAF3IP2. It is unclear whether this is due to rarity of disruptive mutations. OBJECTIVE: (a) To delineate the prevalence of mutations in key IL17 pathway genes and (b) to identify candidate regulatory sites acting on IL23R, IL17A, IL17RA and TRAF3IP2 from a distance. METHODS: Extraction of mutation frequencies from ExAc data, evolutionary sequence alignment; mapping of long-range interacting (LRI) enhancers; and genetic association testing in a novel psoriasis cohort. RESULTS: The prevalence of disruptive mutations in genes such as IL17RA is sufficient to have been detectable by existing data sets. Therefore, lack of their association with psoriasis indicates that genetic risk primarily resides in variants acting from a distance. We identify two LRI enhancer sites, regulating IL17RA and TRAF3IP2, respectively. The TRAF3IP2 regulator localizes to the TRAF3IP2 antisense promoter, suggesting feedback regulation. Both LRI sites are associated with psoriasis in a novel Scottish psoriasis cohort and the TRAF3IP2-LRI at rs71562294 replicates in the WTCCC cohort. CONCLUSION: Genetic risk for psoriasis may be encoded at LRI sites regulating IL17 pathway genes from a distance.

A cross-sectional study of the distribution of psoriasis subtypes in different ethno-racial groups.

Skin of colored patients with psoriasis are more likely to remain undiagnosed and experience a greater impact on quality of life than their white counterparts. A better understanding of the ethno-racial differences in the presentation of psoriasis can help address these disparities. To compare the prevalence of psoriatic subtypes (plaque, guttate, pustular, erythrodermic, palmoplantar, and inverse) and lesion locations in Caucasian, Asian, and Hispanic/Latino patients, we analyzed cross-sectional, patient-reported, physician-reviewed survey data from 882 adult and 16 pediatric psoriasis patients seen at the University of California, San Francisco Department of Dermatology between 2006 and 2016. Multivariate logistic regression was used to compare the prevalence of psoriasis subtypes and lesional distributions amongst the ethno-racial groups. Asians and Hispanics/Latinos had higher odds of having pustular psoriasis compared to Caucasians (OR=4.36 [95%CI: 1.24-17.62], P=0.026; and OR=5.94 [95%CI: 1.03-31.03], P=0.036, respectively). Asians also had a higher frequency of erythrodermic psoriasis (OR=5.56 [95%CI: 1.41-27.17], P=0.018), but a lower frequency of inverse psoriasis compared to Caucasians (OR=0.26 [95%CI: 0.06-0.80], P=0.036). These differences may relate to genetic or environmental factors or access to care. Clinician awareness of ethno-racial differences in psoriasis subtype and lesion location can facilitate earlier diagnosis and therapeutic intervention.

Influence of diet on the gut microbiome and implications for human health.

Recent studies have suggested that the intestinal microbiome plays an important role in modulating risk of several chronic diseases, including inflammatory bowel disease, obesity, type 2 diabetes, cardiovascular disease, and cancer. At the same time, it is now understood that diet plays a significant role in shaping the microbiome, with experiments showing that dietary alterations can induce large, temporary microbial shifts within 24 h. Given this association, there may be significant therapeutic utility in altering microbial composition through diet. This review systematically evaluates current data regarding the effects of several common dietary components on intestinal microbiota. We show that consumption of particular types of food produces predictable shifts in existing host bacterial genera. Furthermore, the identity of these bacteria affects host immune and metabolic parameters, with broad implications for human health. Familiarity with these associations will be of tremendous use to the practitioner as well as the patient.

Tumor necrosis factor-α inhibitor-induced psoriasis: Systematic review of clinical features, histopathological findings, and management experience.

BACKGROUND: Tumor necrosis factor-α (TNF-α) inhibitors have been reported to induce new-onset psoriasis. OBJECTIVE: To better define the demographic, clinical features, and treatment approach of TNF-α inhibitor-induced psoriasis. METHODS: Systematic review of published cases of TNF-α inhibitor-induced psoriasis. RESULTS: We identified 88 articles with 216 cases of new-onset TNF-α inhibitor-induced psoriasis. The mean age at psoriasis onset was 38.5 years. The most common underlying diseases were Crohn disease (40.7%) and rheumatoid arthritis (37.0%). Patients underwent TNF-α therapy for an average of 14.0 months before psoriasis onset with 69.9% of patients experiencing onset within the first year. The majority of patients received skin-directed therapy, though patients who discontinued TNF therapy had the greatest resolution of symptoms (47.7%) compared with those who switched to a different TNF agent (36.7%) or continued therapy (32.9%). LIMITATIONS: Retrospective review that relies on case reports and series. CONCLUSION: While TNF-α inhibitor cessation may result in resolution of induced psoriasis, lesions may persist. Decisions regarding treatment should be weighed against the treatability of TNF-α inhibitor-induced psoriasis, the severity of the background rheumatologic or gastrointestinal disease, and possible loss of efficacy with cessation followed by retreatment. Skin-directed therapy is a reasonable initial strategy except in severe cases.