Guselkumab for Pityriasis Rubra Pilaris and Dysregulation of IL-23/IL-17 and NFkB Signaling: A Nonrandomized Trial.

Importance: There is no US Food and Drug Administration-approved treatment for pityriasis rubra pilaris (PRP), and it is common for patients to fail to experience improvement with several systemic options. Involvement of interleukin (IL) 23 suggests a potential therapeutic target. Objective: To determine whether guselkumab, an IL-23p19 inhibitor, provides clinical improvement for participants with PRP and better understand gene and protein dysregulation in PRP. Design, Setting, and Participants: This single-arm, investigator-initiated nonrandomized trial was conducted from October 2019 to August 2022 at a single-center academic university with participants from 8 states in the US. In total, 14 adults with moderate to severe PRP were enrolled; 12 completed the trial. Age-matched and sex-matched healthy controls provided skin and blood for proteomic and transcriptomic studies. The primary outcome was observed at 24 weeks, and additional follow-up occurred at 36 weeks. Intervention: Guselkumab is a fully human immunoglobulin G1 λ monoclonal antibody that selectively binds and inhibits the p19 subunit of IL-23. Subcutaneous injections were given at the US Food and Drug Administration-approved dosing schedule for psoriasis over a 24-week period. Main Outcomes and Measures: The primary outcome was the mean change in the Psoriasis Area Severity Index (PASI) score at week 24. Secondary outcomes included pruritus, Dermatology Life Quality Index score, clinical response at week 36, and association with transcriptomics and proteomics expression. Results: A per-protocol analysis was performed for the cohort of 4 female and 8 male patients who had a mean (SD) age of 56.5 (18.7) years. The mean improvement in PASI score, pruritus, and Dermatology Life Quality Index score was 61.8% (P < .001), 62.3% (P = .001), and 60.2% (P < .001), respectively. Nine participants (75%) achieved a 50% improvement in PASI. Among these clinical responders, at week 36, 8 of 9 achieved PASI75, and 6 of 9 achieved PASI90. No participants had pathogenic CARD14 gene variations. There was 1 serious adverse event that was not associated with the study drug. Proteomics and gene expression profiles identified dysregulation of a predominance of inflammatory pathways (such as T helper 17 and nuclear factor κ B) in participants with PRP who later responded well to treatment with guselkumab and stronger dysregulation of keratinocyte development pathways in individuals who did not respond to guselkumab. Conclusion and Relevance: The results of this nonrandomized trial suggest that guselkumab has efficacy in treating refractory moderate to severe adult PRP. Trial Registration: ClinicalTrials.gov Identifier: NCT03975153.

What can inherited immunodeficiencies reveal about pyoderma gangrenosum?

Pyoderma gangrenosum (PG) is a rare ulcerative neutrophilic dermatosis that is occasionally associated with primary immunodeficiency. Though contributions from dysregulation of the innate immune system, neutrophil dysfunction and genetic predisposition have been postulated, the precise pathogenesis of PG has not yet been elucidated. This article reviews reported cases of coexisting PG and primary immunodeficiency in order to gain insight into the complex pathophysiology of PG. Our findings suggest that variations in genes such as RAG1, ITGB2, IRF2BP2 and NFκB1 might play a role in genetically predisposing patients to develop PG. These studies support the feasibility of the role of somatic gene variation in the pathogenesis of PG which warrants further exploration to guide targeted therapeutics.

Malignant T Cell Activation by a Bacillus Species Isolated from Cutaneous T-Cell Lymphoma Lesions.

Cutaneous T-cell lymphoma (CTCL) is a life-debilitating malignancy of lymphocytes homing to the skin. Although CTCL is thought to arise from a combination of genetic, epigenetic, and environmental factors, specific triggers are unclear. The skin is colonized by a unique microbiota and is heavily influenced by its interactions. We hypothesized that adaptive immune responses to skin commensals lead to clonal T-cell proliferation and transformation in the appropriate genetic background. We therefore collected lesional and nonlesional skin microbiota from patients with CTCL to study T cell interactions using skin T cell explants and peripheral, skin-homing CD4+ T cells. By various methods, we identified Bacillus safensis in CTCL lesions, a rare human commensal in healthy skin, and showed that it can induce malignant T cell activation and cytokine secretion. Taken together, our data suggest microbial triggers in the skin microbiota of patients with CTCL as potential instigators of tumorigenesis.

Low-dose methotrexate in dermatology: the utility of serological monitoring in a real-world cohort.

When prescribing low-dose methotrexate, frequent serological testing is recommended in the dermatologic literature, although much of the supporting data is extrapolated from non-dermatologic conditions. We performed a retrospective cohort study to determine the cumulative incidence and timing of low-dose methotrexate-associated serological abnormalities over the first year of therapy, in a pragmatic cohort of patients with dermatologic compared to non-dermatologic diagnoses. Laboratory values recorded included white blood cell count, hemoglobin, platelet count, estimated glomerular filtration rate, alanine aminotransferase, and aspartate aminotransferase. Among 1376 patients, there were no cases of methotrexate-associated grade 4/very severe lab abnormality or fatality. Baseline risk factors associated with moderate-to-severe lab abnormalities included non-dermatologic diagnoses, low hemoglobin, low estimated glomerular filtration rate, and elevated transaminases. The incidence of moderate-to-severe lab abnormalities was 4.4% among all patients, 3.1% among patients with dermatologic diagnoses, and 2.3% among patients with normal baseline lab values. Lab abnormalities led to discontinuation of therapy in 0.8% of patients. Serious changes did not occur in the first two weeks of therapy. We conclude that the cumulative incidence of low-dose methotrexate-associated lab abnormality was lower in patients with dermatologic diagnoses or normal baseline testing and these factors may be used to adjust monitoring practices.

Patient Experience Surveys Reveal Gender-Biased Descriptions of Their Care Providers.

Patient experience surveys (PES) are collected by healthcare systems as a surrogate marker of quality and published unedited online for the purpose of transparency, but these surveys may reflect gender biases directed toward healthcare providers. This retrospective study evaluated PES at a single university hospital between July 2016 and June 2018. Surveys were stratified by overall provider rating and self-identified provider gender. Adjectives from free-text survey comments were extracted using natural language processing techniques and applied to a statistical machine learning model to identify descriptors predictive of provider gender. 109,994 surveys were collected, 17,395 contained free-text comments describing 687 unique providers. The mean overall rating between male (8.84, n = 8558) and female (8.80, n = 8837) providers did not differ (p = 0.149). However, highly-rated male providers were more often described for their agentic qualities using adjectives such as "informative," "forthright," "superior," and "utmost" (OR 1.48, p < 0.01)-whereas highly-rated female providers were more often described by their communal qualities through adjectives such as "empathetic," "sweet," "warm," "attentive," and "approachable" (OR 2.11, p < 0.0001). PES may contain gender stereotypes, raising questions about their impact on physicians and their validity as a quality metric which must be balanced with the need for unedited transparency. Future prospective studies are needed to further characterize this trend across geographically and racially diverse healthcare providers.

Shared Decision-making in Dermatology: A Scoping Review.

Importance: Shared decision-making (SDM) can improve the quality of care for patients. The extent to which this tool has been used and the evidence supporting its use in dermatology have not been systematically examined. Objective: To perform a scoping review of the literature regarding SDM in dermatology. Evidence Review: Searches of Ovid MEDLINE, PsycINFO, PsycARTICLES, Sciverse Scopus, and EBM Reviews were conduced on July 11, 2019, and March 6, 2020. There were no limits on date, type of article, language, or subject for the initial search. A total of 1673 titles and abstracts were screened by 2 independent reviewers in the Covidence mixed-methods platform. Forty-one full-text studies were assessed for eligibility. For inclusion, articles needed to include a dermatologic diagnosis as well as discussion of SDM or patient decision aids. Two independent reviewers screened 29 full-text articles for inclusion and extracted qualitative data using a set of 26 predefined codes. Qualitative coding was applied to excerpts to categorize the article, define and describe advantages and disadvantages of SDM, understand patient and physician requests for SDM, and discuss methods of implementation. Findings: Despite a small number of articles on SDM (n = 29) in dermatology, the selected literature provided consistent messages regarding the importance of SDM for dermatology and a number of strategies and tools for implementation. Medical dermatology was the most common subspecialty studied, with melanoma, psoriasis, and connective tissue diseases most examined. Only 5 publications introduced SDM tools specifically for dermatologic conditions; of these, only 2 tools were validated. Barriers to implementation that were cited included time and a lack of training for clinicians, although the literature also provided potential solutions to these issues. All articles emphasized the value of SDM for both patients and physicians. Conclusions and Relevance: The literature regarding SDM in dermatology consistently suggests that it is a useful tool for providing patient-centered care. Established tools have been proposed since 2012. More research is needed to implement better practices, especially in dermatologic subspecialties. However, there are substantial suggestions from the literature for strategies and tools with which to begin a shared decision-making practice.

Synergistic induction of IL-23 by TNFα, IL-17A, and EGF in keratinocytes.

IL-23 is an inflammatory cytokine that plays an essential role in Th17 immunity by enhancing Th17 cell proliferation and survival, and Th17 cytokine production. IL-23 has pathogenic roles in the development of Th17-mediated inflammatory diseases including psoriasis. Despite successful treatment of psoriasis by blocking IL-23, the regulation of IL-23 expression in psoriasis patients is largely unknown. Dendritic cells are generally considered to be the primary source of IL-23 in psoriasis. While high levels of IL-23 are found in psoriatic epidermis, IL-23 expression in psoriatic keratinoctyes remains a controversial issue. In this study, we demonstrated that IL-23 production is induced by a combination of TNFα and IL-17A in human keratinocytes. Additionally, this IL-23 induction by TNFα and IL-17A is further increased in psoriatic keratinocytes and is enhanced by EGFR signaling. Although IL-23 is also robustly induced by toll-like receptor agonists in dendritic cells and macrophages, IL-23 expression in these cell types is not regulated by TNFα, IL-17A, and EGFR signaling. Given that IL-23 is essential for maintaining Th17 activation, IL-23 induction by TNFα, IL-17A, and EGF in keratinocytes could play an important pathological role in psoriasis pathogenesis as well as the cutaneous rash associated with EGFR inhibition therapy.

Host-microbiota interactions in immune-mediated diseases.

Host-microbiota interactions are fundamental for the development of the immune system. Drastic changes in modern environments and lifestyles have led to an imbalance of this evolutionarily ancient process, coinciding with a steep rise in immune-mediated diseases such as autoimmune, allergic and chronic inflammatory disorders. There is an urgent need to better understand these diseases in the context of mucosal and skin microbiota. This Review discusses the mechanisms of how the microbiota contributes to the predisposition, initiation and perpetuation of immune-mediated diseases in the context of a genetically prone host. It is timely owing to the wealth of new studies that recently contributed to this field, ranging from metagenomic studies in humans and mechanistic studies of host-microorganism interactions in gnotobiotic models and in vitro systems, to molecular mechanisms with broader implications across immune-mediated diseases. We focus on the general principles, such as breaches in immune tolerance and barriers, leading to the promotion of immune-mediated diseases by gut, oral and skin microbiota. Lastly, the therapeutic avenues that either target the microbiota, the barrier surfaces or the host immune system to restore tolerance and homeostasis will be explored.