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ERAP1, ERAP2, and LNPEP are aminopeptidases implicated in autoimmune pathophysiology. In this study, we show that ERAP2 is upregulated and ERAP1 is downregulated in patients with psoriasis who are homozygous for autoimmune-linked variants of ERAP. We also demonstrate that aminopeptidase expression is not uniform in the skin. Specifically, the intracellular antigen-processing aminopeptidases ERAP1 and ERAP2 are strongly expressed in basal and early spinous layer keratinocytes, whereas granular layer keratinocytes expressed predominantly LNPEP, an aminopeptidase specialized in the processing of extracellular antigens for presentation to T cells. In psoriasis, basal keratinocytes also expressed the T-cell- and monocyte-attracting chemokine, CCL2, and the T-cell-supporting cytokine, IL-15. In contrast, TGF-β1 was the major cytokine expressed by healthy control basal keratinocytes. SFRP2-high dermal fibroblasts were also noted to have an ERAP2-high expression phenotype and elevated HLA-C. In psoriasis, the SFRP2-high fibroblast subpopulation also expressed elevated CXCL14. From these results, we postulate that (i) an increased ERAP2/ERAP1 ratio results in altered antigen processing, a potential mechanism by which ERAP risk alleles predispose individuals to autoimmunity; (ii) ERAP2-high expressing cells display a unique major histocompatibility complex-bound peptidome generated from intracellular antigens; and (iii) the granular layer peptidome is skewed toward extracellular antigens., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Proprotein convertase subtilisin/kexin type-9 (PCSK9) is a posttranslational regulator of the LDL receptor (LDLR). Recent studies have proposed a role for PCSK9 in regulating immune responses. Using RNA-Seq-based variant discovery, we identified a possible psoriasis-susceptibility locus at 1p32.3, located within PCSK9 (rs662145 C > T). This finding was verified in independently acquired genomic and RNA-Seq data sets. Single-cell RNA-Seq (scRNA-Seq) identified keratinocytes as the primary source of PCSK9 in human skin. PCSK9 expression, however, was not uniform across keratinocyte subpopulations. scRNA-Seq and IHC demonstrated an epidermal gradient of PCSK9, with expression being highest in basal and early spinous layer keratinocytes and lowest in granular layer keratinocytes. IL36G expression followed the opposite pattern, with expression highest in granular layer keratinocytes. PCSK9 siRNA knockdown experiments confirmed this inverse relationship between PCSK9 and IL36G expression. Other immune genes were also linked to PCSK9 expression, including IL27RA, IL1RL1, ISG20, and STX3. In both cultured keratinocytes and nonlesional human skin, homozygosity for PCSK9 SNP rs662145 C > T was associated with lower PCSK9 expression and higher IL36G expression, when compared with heterozygous skin or cell lines. Together, these results support PCSK9 as a psoriasis-susceptibility locus and establish a putative link between PCSK9 and inflammatory cytokine expression.

Importance: Generalized pustular psoriasis (GPP) is a chronic, orphan disease with limited epidemiological data., Objective: To describe the clinical characteristics, treatments, longitudinal disease course, and disease-specific health care utilization among patients with GPP across the United States., Design, Setting, and Participants: A retrospective longitudinal case series involving 95 adults who met the European Rare and Severe Psoriasis Expert Network consensus definition for GPP and were treated at 20 US academic dermatology practices between January 1, 2007, and December 31, 2018., Main Outcomes and Measures: The primary outcome is to describe the patient characteristics, associated medical comorbidities, treatment patterns complications, and GPP-specific health care utilization., Results: Sixty-seven of 95 patients (70.5%) were women (mean age, 50.3 years [SD, 16.1 years]). In the initial encounter, 35 patients (36.8%) were hospitalized and 64 (67.4%) were treated with systemic therapies. In total, more than 20 different systemic therapies were tried. During the follow-up period, 19 patients (35.8%) reported hospitalizations at a median rate of 0.5 hospitalizations per year (IQR, 0.4-1.6). Women had a decreased risk of an emergency department or hospital encounter (odds ratio, 0.19; 95% CI, 0.04-0.83)., Conclusions and Relevance: Generalized pustular psoriasis is a rare, chronic disease without standard treatment and is associated with continued health care utilization over time.

Importance: Palmoplantar pustulosis (PPP) is a is a chronic, orphan disease with limited epidemiological data., Objective: To describe the clinical characteristics, treatments, longitudinal disease course, and health care utilization in adults with PPP across the US., Design, Setting, and Participants: This retrospective, longitudinal case series from 20 academic dermatology practices in the US included a consecutive sample of 197 adults who met the European Rare and Severe Psoriasis Expert Network consensus definition for PPP between January 1, 2007, and December 31, 2018. Data analysis was performed June 2020 to December 2020., Main Outcomes and Measures: The primary outcome was to describe the patient characteristics, associated medical comorbidities, treatment patterns, complications, and PPP-specific health care utilization., Results: Of 197 patients, 145 (73.6%) were female, and the mean (SD) age at presentation was 53.0 (12.6) years, with a mean (SD) follow-up time of 22.1 (28.0) months. On initial presentation, 95 (48.2%) patients reported skin pain, and 39 (19.8%) reported difficulty using hands and/or feet. Seventy patients (35.5%) were treated with systemic treatments, and use of more than 20 different systemic therapies was reported. In patients with at least 6 months of follow-up (n = 128), a median (IQR) of 3.7 (4-10) dermatology visits per year were reported; 24 (18.8%) patients had 5 or more visits during the study period., Conclusions and Relevance: In this case series, PPP was associated with persistent symptoms, continued health care utilization, and a lack of consensus regarding effective treatments, emphasizing the unmet medical need in this population. Additional research is necessary to understand treatment response in these patients.

Psoriasis (PsO) and psoriatic arthritis (PsA) are chronic immune-mediated inflammatory diseases of multifactorial etiology. In addition to genetic and environmental factors, evidence supports involvement of a dysregulated human microbiome in the pathogenesis of psoriatic disease. In particular, alterations in the composition of the microbiome, termed dysbiosis, can result in downstream proinflammatory effects in the gut, skin, and joints. Both the cutaneous and intestinal microbial populations are implicated in the pathogenesis of psoriatic disease, although exact mechanisms are unclear. Herein, we review the relationship between the human microbiome and psoriatic disease. Further insight into the functions of the microbiome may allow for greater understanding of inflammatory disease processes and identification of additional therapeutic targets., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Pyoderma gangrenosum is an inflammatory, neutrophil-mediated disorder that is difficult to treat. Tumor necrosis factor and other inflammatory mediators are among the most promising therapeutic targets. We present a case of a 60-year-old woman with recalcitrant pyoderma gangrenosum treated with adalimumab, who paradoxically developed psoriasis. Secukinumab, an interleukin-17 inhibitor, was added to her regimen, resulting in successful treatment of her psoriasis. Secukinumab was later replaced by methotrexate, resulting in remission of both pyoderma gangrenosum and maintenance of a psoriasis-free state. We conclude that paradoxically induced psoriatic lesions can resolve with adjunct therapy despite continuation of anti-tumor necrosis factor agents. J Drugs Dermatol. 2020;19(2)199-201. doi:10.36849/JDD.2020.4662

The present paradigm of psoriasis pathogenesis revolves around the IL-23/IL-17A axis. Dual-secreting Th17 T cells presumably are the predominant sources of the psoriasis phenotype-driving cytokines, IL-17A and IL-22. We thus conducted a meta-analysis of independently acquired RNA-seq psoriasis datasets to explore the relationship between the expression of IL17A and IL22 . This analysis failed to support the existence of dual secreting IL-17A/IL-22 Th17 cells as a major source of these cytokines. However, variable relationships amongst the expression of psoriasis susceptibility genes and of IL17A, IL22 , and IL23A were identified. Additionally, to shed light on gene expression relationships in psoriasis, we applied a machine learning nonlinear dimensionality reduction strategy (t-SNE) to display the entire psoriasis transcriptome as a 2-dimensonal image. This analysis revealed a variety of gene clusters, relevant to psoriasis pathophysiology but failed to support a relationship between IL17A and IL22 . These results support existing theories on alternative sources of IL-17A and IL-22 in psoriasis such as a Th22 cells and non-T cell populations.

Proprotein convertase subtilisin/kexin type-9 (PCSK9) is a posttranslational regulator of the LDL receptor (LDLR). Recent studies have proposed a role for PCSK9 in regulating immune responses. Using RNA-Seq-based variant discovery, we identified a possible psoriasis-susceptibility locus at 1p32.3, located within PCSK9 (rs662145 C > T). This finding was verified in independently acquired genomic and RNA-Seq data sets. Single-cell RNA-Seq (scRNA-Seq) identified keratinocytes as the primary source of PCSK9 in human skin. PCSK9 expression, however, was not uniform across keratinocyte subpopulations. scRNA-Seq and IHC demonstrated an epidermal gradient of PCSK9, with expression being highest in basal and early spinous layer keratinocytes and lowest in granular layer keratinocytes. IL36G expression followed the opposite pattern, with expression highest in granular layer keratinocytes. PCSK9 siRNA knockdown experiments confirmed this inverse relationship between PCSK9 and IL36G expression. Other immune genes were also linked to PCSK9 expression, including IL27RA, IL1RL1, ISG20, and STX3. In both cultured keratinocytes and nonlesional human skin, homozygosity for PCSK9 SNP rs662145 C > T was associated with lower PCSK9 expression and higher IL36G expression, when compared with heterozygous skin or cell lines. Together, these results support PCSK9 as a psoriasis-susceptibility locus and establish a putative link between PCSK9 and inflammatory cytokine expression.

Psoriatic arthritis (PsA) is a large volume of our clinical practice and its management can be challenging. Traditional DMARDs have been used over last six decades and observational studies have substantiated an effective use of many of these drugs. However, in last two decades use of anti-TNF agents has brought a new dimension in treatment of PsA and in many other autoimmune diseases. Regulatory role of the Th17 cells and its cytokines in the pathogenesis of PsA has successfully paved the foundations of anti-IL antibody based therapies in PsA. Newer therapies targeting the IL-23/IL-17 cytokines and its signaling proteins are now in development and bringing new promises for management of PsA. Herein, we provide an overview of the landscape of drug therapies, including IL-17, IL-12/23, IL-23 inhibitors, and janus kinase (JAK) inhibitors, as well as those in development, such as RORγt inhibitors, anti-NGF agents, mTOR inhibitors and T cell ion-channel blockers. • Psoriatic arthritis (PsA) is associated with heterogeneous musculoskeletal involvement and dermatological manifestations. • csDMARDs have only a modest benefit in PsA • Biologics such as anti-tumor necrosis factor (TNF) agents are highly effective for all clinical domains involved in PsA. • Promising new therapies in trials for PsA are anti-IL-23 and its several signaling proteins • mTOR, NGF, RORgt and potassium ion channel inhibitors are in development stage for novel therapies of PsA • PsA patients need a "Total Care Program", that is treatment of all comorbidities; and exemplary care of the skin and joint. [ABSTRACT FROM AUTHOR]