Rituximab and Omalizumab Combination Therapy for Bullous Pemphigoid.

This research letter reports on a case series of 10 patients with bullous pemphigoid treated with rituximab combined with omalizumab.

Development of a Skin-Directed Scoring System for Stevens-Johnson Syndrome and Epidermal Necrolysis: A Delphi Consensus Exercise.

Importance: Scoring systems for Stevens-Johnson syndrome and epidermal necrolysis (EN) only estimate patient prognosis and are weighted toward comorbidities and systemic features; morphologic terminology for EN lesions is inconsistent. Objectives: To establish consensus among expert dermatologists on EN terminology, morphologic progression, and most-affected sites, and to build a framework for developing a skin-directed scoring system for EN. Evidence Review: A Delphi consensus using the RAND/UCLA appropriateness criteria was initiated with a core group from the Society of Dermatology Hospitalists to establish agreement on the optimal design for an EN cutaneous scoring instrument, terminology, morphologic traits, and sites of involvement. Findings: In round 1, the 54 participating dermatology hospitalists reached consensus on all 49 statements (30 appropriate, 3 inappropriate, 16 uncertain). In round 2, they agreed on another 15 statements (8 appropriate, 7 uncertain). There was consistent agreement on the need for a skin-specific instrument; on the most-often affected skin sites (head and neck, chest, upper back, ocular mucosa, oral mucosa); and that blanching erythema, dusky erythema, targetoid erythema, vesicles/bullae, desquamation, and erosions comprise the morphologic traits of EN and can be consistently differentiated. Conclusions and Relevance: This consensus exercise confirmed the need for an EN skin-directed scoring system, nomenclature, and differentiation of specific morphologic traits, and identified the sites most affected. It also established a baseline consensus for a standardized EN instrument with consistent terminology.

A review of topical probiotic therapy for atopic dermatitis.

Atopic dermatitis (AD) is a common, chronic skin disorder that is associated with dysbiosis of the skin microbiome along with an impaired skin barrier and abnormal immune signalling. Particularly, AD has been associated with increased abundance of Staphylococcus aureus and decreased overall bacterial diversity. Topical probiotic formulations are garnering further interest in the treatment of AD and may be derived from commensal bacteria found on healthy epithelium or from exogenous bacteria. Strains chosen for clinical trials have often demonstrated antimicrobial actions to S. aureus in vitro. Multiple randomized clinical trials with topical probiotics have resulted in significant improvements in clinical severity, decreased abundance of S. aureus in treated lesional skin and increased bacterial diversity. Side-effects from available studies have been minimal apart from one patient who developed a furuncle in the treatment area. Topical probiotics have been shown to be safe and potentially efficacious in AD; however, further research including larger, longer-term clinical trials need to be performed before topical probiotics should be recommended to patients.

Cell-Specific and Variant-Linked Alterations in Expression of ERAP1, ERAP2, and LNPEP Aminopeptidases in Psoriasis.

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-ß1 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.

Biogeographic and disease-specific alterations in epidermal lipid composition and single-cell analysis of acral keratinocytes.

The epidermis is the outermost layer of skin. Here, we used targeted lipid profiling to characterize the biogeographic alterations of human epidermal lipids across 12 anatomically distinct body sites, and we used single-cell RNA-Seq to compare keratinocyte gene expression at acral and nonacral sites. We demonstrate that acral skin has low expression of EOS acyl-ceramides and the genes involved in their synthesis, as well as low expression of genes involved in filaggrin and keratin citrullination (PADI1 and PADI3) and corneodesmosome degradation, changes that are consistent with increased corneocyte retention. Several overarching principles governing epidermal lipid expression were also noted. For example, there was a strong negative correlation between the expression of 18-carbon and 22-carbon sphingoid base ceramides. Disease-specific alterations in epidermal lipid gene expression and their corresponding alterations to the epidermal lipidome were characterized. Lipid biomarkers with diagnostic utility for inflammatory and precancerous conditions were identified, and a 2-analyte diagnostic model of psoriasis was constructed using a step-forward algorithm. Finally, gene coexpression analysis revealed a strong connection between lipid and immune gene expression. This work highlights (a) mechanisms by which the epidermis is uniquely adapted for the specific environmental insults encountered at different body surfaces and (b) how inflammation-associated alterations in gene expression affect the epidermal lipidome.

Proprotein convertase subtilisin/kexin type 9 is a psoriasis-susceptibility locus that is negatively related to IL36G.

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.

Real-world utilization of Delphi consensus diagnostic criteria for suspected pyoderma gangrenosum.

We found that the systematic use of Delphi consensus diagnostic criteria resulted in substantial changes in management patterns in cases of suspected pyoderma gangrenosum (PG), including a reduction in systemic corticosteroid use, and significantly improved clinical outcomes. This improvement may have resulted from a combination of reduced misdiagnosis, optimized management and reduced iatrogenic harm. Increased utilization of validated diagnostic criteria for PG could optimize provider heuristics, increase diagnostic accuracy, and optimize management and clinical outcomes.

Complexities of care: Common components of models of care in geriatrics.

As people age, they are more likely to have an increasing number of medical diagnoses and medications, as well as healthcare providers who care for those conditions. Health professionals caring for older adults understand that medical issues are not the sole factors in the phenomenon of this "care complexity." Socioeconomic, cognitive, functional, and organizational factors play a significant role. Care complexity also affects family caregivers, providers, and healthcare systems and therefore society at large. The American Geriatrics Society (AGS) created a work group to review care to identify the most common components of existing healthcare models that address care complexity in older adults. This article, a product of that work group, defines care complexity in older adults, reviews healthcare models and those most common components within them and identifies potential gaps that require attention to reduce the burden of care complexity in older adults.

Evaluation of a Case Series of Patients With Generalized Pustular Psoriasis in the United States.

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.

Evaluation of a Case Series of Patients With Palmoplantar Pustulosis in the United States.

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.

Case report: Mounded and refractory keratoses (MARK), a novel presentation of pemphigus vulgaris.

Pemphigus vulgaris (PV) is a rare immunobullous disease. Although it classically presents as generalized flaccid blisters affecting the skin and mucosae, atypical cases of PV can be diagnostically challenging. Herein, we report an underrecognized non-blistering manifestation of pemphigus vulgaris, which we call mounded and refractory keratoses (MARK). MARK presents as exuberant scaling plaques on the scalp, often in the skin of color. When MARK features are present, pemphigus vulgaris is prone to misdiagnosis, clinically and histopathologically, leading to delays in appropriate treatment. Specifically, biopsies from these patients may resemble acantholytic dyskeratosis, resulting in initial misdiagnosis. Thus, recognizing this presentation may aid physicians in diagnosing and monitoring the recurrence of pemphigus vulgaris.