Faculty Bibliography

Whereas the cellular and molecular features of human inflammatory skin diseases are well characterized, their tissue context and systemic impact remain poorly understood. We thus profiled human psoriasis (PsO) as a prototypic immune-mediated condition with a high predilection for extracutaneous involvement. Spatial transcriptomics (ST) analyses of 25 healthy, active lesion, and clinically uninvolved skin biopsies and integration with public single-cell transcriptomics data revealed marked differences in immune microniches between healthy and inflamed skin. Tissue-scale cartography further identified core disease features across all active lesions, including the emergence of an inflamed suprabasal epidermal state and the presence of B lymphocytes in lesional skin. Both lesional and distal nonlesional samples were stratified by skin disease severity and not by the presence of systemic disease. This segregation was driven by macrophage-, fibroblast-, and lymphatic-enriched spatial regions with gene signatures associated with metabolic dysfunction. Together, these findings suggest that mild and severe forms of PsO have distinct molecular features and that severe PsO may profoundly alter the cellular and metabolic composition of distal unaffected skin sites. In addition, our study provides a valuable resource for the research community to study spatial gene organization of healthy and inflamed human skin.

OBJECTIVES/OBJECTIVE:Autoantibody seroconversion has been extensively studied in the context of COVID-19 infection but data regarding post-vaccination autoantibody production is lacking. Here we aimed to determine the incidence of common autoantibody formation following mRNA COVID-19 vaccines in patients with inflammatory arthritis (IA) and in healthy controls. METHODS:Autoantibody seroconversion was measured by serum ELISA in a longitudinal cohort of IA participants and healthy controls before and after COVID-19 mRNA-based immunization. RESULTS:Overall, there was a significantly lower incidence of ANA seroconversion in participants who did not contract COVID-19 prior to vaccination compared with those who been previously infected (7.4% vs 24.1%, p= 0.014). Incidence of de novo anti-cyclic citrullinated protein (CCP) seroconversion in all participants was low at 4.9%. Autoantibody levels were typically of low titer, transient, and not associated with increase in IA flares. CONCLUSIONS:In both health and inflammatory arthritis, the risk of autoantibody seroconversion is lower following mRNA-based immunization than following natural SARS-CoV-2 infection. Importantly, seroconversion does not correlate with self-reported IA disease flare risk, further supporting the encouragement of mRNA-based COVID-19 immunization in the IA population.

INTRODUCTION:Psoriatic arthritis (PsA) is a complex, immune-mediated disease associated with skin psoriasis that, if left untreated, can lead to joint destruction. Up to 30% of patients with psoriasis progress to PsA. In most cases, psoriasis precedes synovio-entheseal inflammation by an average of 5-7 years, providing a unique opportunity for early and potentially preventive intervention in a susceptible and identifiable population. Guselkumab is an effective IL-23p19 inhibitor Food and Drug Administration (FDA-approved for treatment of moderate-to-severe psoriasis and PsA. The Preventing Arthritis in a Multicentre Psoriasis At-Risk cohort (PAMPA) study aims to evaluate the efficacy of guselkumab in preventing PsA and decreasing musculoskeletal power Doppler ultrasound (PDUS) abnormalities in a population of patients with psoriasis who are at-increased risk for PsA progression. METHODS AND ANALYSIS:The PAMPA study is a multicentre, randomised, double-blind, placebo-controlled, interventional, preventive trial comparing PDUS involvement and conversion to PsA in patients with psoriasis at-increased risk for progression treated with guselkumab compared with non-biological standard of care. The study includes a screening period, a double-blind treatment period (24 weeks) and an open-label follow-up period (72 weeks). At baseline, 200 subjects will be randomised (1:1) to receive either guselkumab 100 mg (arm 1) or placebo switching to guselkumab 100 mg starting at week 24 (arm 2). Arm 3 will follow 150 at-risk psoriasis patients who decline biological therapy and randomisation. Changes from baseline in the PDUS score at week 24 and the difference in proportion of patients transitioning to PsA at 96 weeks will be examined as the coprimary endpoints. ETHICS AND DISSEMINATION:Ethics approval for this study was granted by the coordinating centre's (NYU School of Medicine) Institutional Review Board (IRB). Each participating site received approval through their own IRBs. The findings will be shared in peer-reviewed articles and scientific conference presentations. TRIAL REGISTRATION NUMBER:NCT05004727.

Background/Purpose: The skin is recognized as a window into the immunopathogenic mechanisms driving the vast phenotypic spectrum of psoriatic disease.
Method(s): To better decipher the cellular landscape of both healthy and psoriatic skin, we employed spatial transcriptomics (ST), a ground-breaking technology that precisely maps gene expression from histologically-intact tissue sections (Fig. 1A).
Result(s): Findings gleaned from computationally integrating our 23 matched lesional and non-lesional psoriatic and 7 healthy control samples with publicly-available single-cell ribonucleic acid (RNA) sequencing datasets established the ability of ST to recapitulate the tissue architecture of both healthy and inflamed skin (Fig. 1B) and highlighted topographic shifts in the immune cell milieu, from a predominantly perifollicular distribution in steady-state skin to the papillary and upper reticular dermis in psoriatic lesional skin. We also incidentally discovered that ST's ability to ascertain gene expression patterns from intact tissue rendered it particularly conducive to studying the transcriptome of lipid-laden cells such as dermal adipose tissue and sebaceous glands (Fig. 1C), whose expression profiles are typically lost in the process of tissue handling and dissociation for bulk and single-cell RNA seq. Unbiased clustering of pooled healthy and psoriatic samples identified two epidermal clusters and one dermal cluster that were differentially expanded in psoriatic lesional skin (p values <=0.05) (Fig. 1D); pathway analysis of these clusters revealed enrichment of known psoriatic inflammatory pathways (Fig. 1E). Unsupervised classification of skin-limited psoriasis and psoriatic arthritis samples revealed stratification by cutaneous disease severity or Psoriasis Area and Severity Index (PASI) score and not by presence or absence of concomitant systemic/synovial disease (Fig. 1F). Remarkably, this PASI-dependent segregation was also evident in distal, non-lesional samples and was driven by the dermal macrophage and fibroblast cluster and the lymphatic endothelium (Fig. 2A). Inquiry into the mechanistic drivers of this observed stratification yielded enrichment of pathways associated with key T cell and innate immune cell activation, B cells, and metabolic dysfunction (Fig. 2B). Finally, tissue scale computational cartography of gene expression revealed differences in regional enrichment of specific cell types across phenotypic groups, most notably upward extension of fibroblasts to the upper dermis in both lesional and non-lesional samples from mild psoriasis and restriction to the lower dermis in the moderate-to-severe psoriasis samples (Fig. 2C), suggesting that disease severity stratification may be driven by emergent cellular ecosystems in the upper dermis. Fig. 1. (A) Schematic of spatial transcriptomics study workflow. Four mm skin punch biopsies were obtained from healthy volunteers (n=3) and lesional and non-lesional skin from patients with psoriatic disease (n=11). Ten micron-thick sections were then placed on capture areas on the ST microarray slide, each containing molecularly barcoded, spatially encoded spots with a diameter of 50 microns and a center-to-center distance of 100 microns. (B) Side-by-side comparison of a hematoxylin-eosin (H&E) stained section of representative healthy, lesional, and non-lesional skin samples and the corresponding ST plots showed concordance of unbiased gene expression-based clustering with histologic tissue architecture. (C) Pathway analysis of the adipose cluster in healthy skin (cluster 2) confirmed upregulation of lipid-associated processes. Inset: Spots corresponding to the adipose cluster highlighted in yellow. (D) Wilcoxon rank sum test (results displayed as box plots) yielded statistically significant expansion of three clusters in lesional skin compared to both non-lesional and healthy skin-inflamed suprabasal epidermis (cluster 4), epidermis 2 (cluster 7), and inflamed dermis (cluster 10). HC=healthy control, L=lesional psoriatic skin, NL=non-lesional psoriatic skin. (E) Pathways enriched in clusters 4, 7, and 10. (F) Principal component analysis (PCA) plots demonstrating segregation of samples by severity of cutaneous disease in both lesional and non-lesional samples along the first principal component (right) that was not seen in the samples categorized according to presence or absence of arthritis (left). PsA=psoriatic arthritis, PsO=skin-limited psoriasis. Fig. 2. (A) PCA of lesional and non-lesional samples colored by disease severity in spatial clusters 1 (left) and 12 (right) revealed more discrete clustering. (B) Pathways significantly enriched in clusters 1 (left) and 12 (right) showed enrichment of pathways associated with key T cell and innate immune cell activation, B cells, and metabolic dysfunction (highlighted in red). (C) SpaceFold one dimension projection of cell distribution from an independently-generated single-cell RNA seq data set on aggregated ST lesional and non-lesional samples from mild (PASI-low) and moderate-severe (PASI-high) samples. Y-axis represents tissue position, starting with the lower dermis marked as position 0 to suprabasal epidermis marked as position 1. Dashed line represents epidermal-dermal junction, discerned by cell types in the basal epidermal layer (melanocytes and Langerhans cells). Fibroblast signatures (red arrows) were largely relegated to the lower dermis in the PASI-high group, but extended to the upper dermis in the PASI-low group. This striking difference in fibroblast localization was also noted in non-lesional PASI-high vs. PASI-low groups. In addition to fibroblasts, lymphatic, endothelial, myeloid, and T cells signatures (black arrows) were also observed in the upper dermis of lesional PASI-low samples, but were much lower in the dermis of PASI-low non-lesional and all samples in the PASI-high group. Interfollicular epidermis (IFE), hair follicle and infundibulum (HF/IFN), n= number of individual biopsies.
Conclusion(s): Thus, we have been able to successfully leverage ST integrated with independently-generated single-cell RNA seq data to spatially define the emergent cellular ecosystems of healthy and matched psoriatic lesional and non-lesional skin and in so doing, demonstrated the value of ST in unearthing the genetic groundwork at both the site of inflammation and in distal, clinically-uninvolved skin

Dermatomyositis (DM) and alopecia areata (AA) are two diseases characterized by aberrant interferon (IFN) signaling. While patchy alopecia of the scalp is a known feature of DM, alopecia universalis, which involves hair loss over the entire body, has rarely been reported in conjunction with DM. Herein, we report the case of a 30-year-old female with dermatomyositis who developed refractory cutaneous disease and alopecia universalis that were successfully treated with tofacitinib. This could suggest that concomitant severe alopecia and refractory cutaneous dermatomyositis may reflect a strong baseline interferon gene signature that may predict responsiveness to JAK inhibitors.

At the 2021 Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) annual meeting, a summary of the research conducted by the recipients of the 2020 GRAPPA Research Awards was presented by the awardees. The summary of the 4 presentations is provided here.

Immune checkpoint inhibitors (ICIs) are a class of medications targeting mostly the PD-1/PD-L1 and CTLA-4 immune pathways in the treatment of many cancers. Despite the encouraging success of ICIs, they are associated with immune-related adverse events as well as exacerbation of underlying autoimmune conditions. The treatment of these conditions often involves discontinuation of ICI in addition to the utilization of immunomodulatory agents. In this report, we discuss a case in which a patient with metastatic renal cell carcinoma experienced exacerbation of underlying paraneoplastic dermatomyositis after treatment with ICI. He was successfully continued on ICI with the use of intravenous immunoglobulin. The patient experienced adequate control of his myositis but also experienced deepening of his antitumor response.