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.

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.

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.

Evaluation of Ixekizumab Treatment for Patients With Pityriasis Rubra Pilaris: A Single-Arm Trial.

Importance: Pityriasis rubra pilaris is a rare and disabling cutaneous disease that is frequently recalcitrant to conventional therapies and appears to involve interleukin (IL)-17 overexpression. Objective: To investigate the clinical response and safety of ixekizumab in treating pityriasis rubra pilaris. Design, Setting, and Participants: Single-arm, investigator-initiated trial conducted in adult patients with moderate to severe pityriasis rubra pilaris at a single-center academic university from June 2018 to January 2020. A total of 41 patients were screened, 12 were enrolled, and 11 completed the full duration of therapy. A referred, consecutive sample was used during participant selection. The treatment period and primary outcome occurred over 24 weeks with additional patient follow-up through 36 weeks. Intervention: Subcutaneous administration of ixekizumab, a humanized IgG4 antibody that binds IL-17A, at the US Food and Drug Administration-approved dosing schedule for treatment of psoriasis for 24 weeks. Main Outcomes and Measures: The primary outcome was the mean change in Psoriasis Area and Severity Index at 24 weeks. Secondary outcomes included change in affected body surface area, quality of life, induction of sustained remission, and association of improvement with CARD14 genetic variations and cutaneous cytokine expression. Results: A total of 12 white patients (mean [SD] age, 49.8 [15.1] years; 8 male [67%]) were enrolled between June 2018 and April 2019, with 11 completing the full course of intervention. The mean (SEM) improvements in Psoriasis Area and Severity Index, affected body surface area, and Dermatology Life Quality Index were 15.2 (2.1) (P < .0001), 29.8% (9.3%) (P = .009), and 9.5 (2.5) (P = .004), respectively. The 4 participants with the most improvement in Psoriasis Area and Severity Index at week 24 stayed in remission at week 36 (defined as lack of increase in Psoriasis Area and Severity Index from week 24 through week 36), off therapy. Relative dermal IL-17A expression decreased by a 1.9 log-fold change. No participants had known pathogenic CARD14 variations. There were no serious adverse events. Conclusions and Relevance: In this single-armed trial, ixekizumab was associated with reduced clinical signs and symptoms of pityriasis rubra pilaris in a subset of patients, including those in whom other systemic therapies have failed. Trial Registration: ClinicalTrials.gov Identifier: NCT03485976.

A Diet-Sensitive Commensal Lactobacillus Strain Mediates TLR7-Dependent Systemic Autoimmunity.

Western lifestyle is linked to autoimmune and metabolic diseases, driven by changes in diet and gut microbiota composition. Using Toll-like receptor 7 (TLR7)-dependent mouse models of systemic lupus erythematosus (SLE), we dissect dietary effects on the gut microbiota and find that Lactobacillus reuteri can drive autoimmunity but is ameliorated by dietary resistant starch (RS). Culture of internal organs and 16S rDNA sequencing revealed TLR7-dependent translocation of L. reuteri in mice and fecal enrichment of Lactobacillus in a subset of SLE patients. L. reuteri colonization worsened autoimmune manifestations under specific-pathogen-free and gnotobiotic conditions, notably increasing plasmacytoid dendritic cells (pDCs) and interferon signaling. However, RS suppressed the abundance and translocation of L. reuteri via short-chain fatty acids, which inhibited its growth. Additionally, RS decreased pDCs, interferon pathways, organ involvement, and mortality. Thus, RS exerts beneficial effects in lupus-prone hosts through suppressing a pathobiont that promotes interferon pathways implicated in the pathogenesis of human autoimmunity.

Commensal orthologs of the human autoantigen Ro60 as triggers of autoimmunity in lupus.

The earliest autoantibodies in lupus are directed against the RNA binding autoantigen Ro60, but the triggers against this evolutionarily conserved antigen remain elusive. We identified Ro60 orthologs in a subset of human skin, oral, and gut commensal bacterial species and confirmed the presence of these orthologs in patients with lupus and healthy controls. Thus, we hypothesized that commensal Ro60 orthologs may trigger autoimmunity via cross-reactivity in genetically susceptible individuals. Sera from human anti-Ro60-positive lupus patients immunoprecipitated commensal Ro60 ribonucleoproteins. Human Ro60 autoantigen-specific CD4 memory T cell clones from lupus patients were activated by skin and mucosal Ro60-containing bacteria, supporting T cell cross-reactivity in humans. Further, germ-free mice spontaneously initiated anti-human Ro60 T and B cell responses and developed glomerular immune complex deposits after monocolonization with a Ro60 ortholog-containing gut commensal, linking anti-Ro60 commensal responses in vivo with the production of human Ro60 autoantibodies and signs of autoimmunity. Together, these data support that colonization with autoantigen ortholog-producing commensal species may initiate and sustain chronic autoimmunity in genetically predisposed individuals. The concept of commensal ortholog cross-reactivity may apply more broadly to autoimmune diseases and lead to novel treatment approaches aimed at defined commensal species.