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Vitamin D3 and deconvoluting a rash
Madison K. Ernst, … , Kevin D. Cooper, Kurt Q. Lu
Madison K. Ernst, … , Kevin D. Cooper, Kurt Q. Lu
Published January 24, 2023
Citation Information: JCI Insight. 2023;8(2):e163789. https://doi.org/10.1172/jci.insight.163789.
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Clinical Medicine Clinical trials Dermatology

Vitamin D3 and deconvoluting a rash

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Abstract

BACKGROUND Adverse drug reactions are unpredictable immunologic events presenting frequent challenges to clinical management. Systemically administered cholecalciferol (vitamin D3) has immunomodulatory properties. In this randomized, double-blinded, placebo-controlled interventional trial of healthy human adults, we investigated the clinical and molecular immunomodulatory effects of a single high dose of oral vitamin D3 on an experimentally induced chemical rash.METHODS Skin inflammation was induced with topical nitrogen mustard (NM) in 28 participants. Participant-specific inflammatory responses to NM alone were characterized using clinical measures, serum studies, and skin tissue analysis over the next week. All participants underwent repeat NM exposure to the opposite arm and then received placebo or 200,000 IU cholecalciferol intervention. The complete rash reaction was followed by multi-omic analysis, clinical measures, and serum studies over 6 weeks.RESULTS Cholecalciferol mitigated acute inflammation in all participants and achieved 6 weeks of durable responses. Integrative analysis of skin and blood identified an unexpected divergence in response severity to NM, corroborated by systemic neutrophilia and significant histopathologic and clinical differences. Multi-omic and pathway analyses revealed a 3-biomarker signature (CCL20, CCL2, CXCL8) unique to exaggerated responders that is suppressed by cholecalciferol and implicates IL-17 signaling involvement.CONCLUSION High-dose systemic cholecalciferol may be an effective treatment for severe reactions to topical chemotherapy. Our findings have broad implications for cholecalciferol as an antiinflammatory intervention against the development of exaggerated immune responses.TRIAL REGISTRATION clinicaltrials.gov (NCT02968446).FUNDING NIH and National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS; grants U01AR064144, U01AR071168, P30 AR075049, U54 AR079795, and P30 AR039750 (CWRU)).

Authors

Madison K. Ernst, Spencer T. Evans, Jose-Marc Techner, Robert M. Rothbaum, Luisa F. Christensen, Ummiye Venus Onay, Dauren Biyashev, Michael M. Demczuk, Cuong V. Nguyen, Kord S. Honda, Thomas S. McCormick, Lam C. Tsoi, Johann E. Gudjonsson, Kevin D. Cooper, Kurt Q. Lu

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Figure 3

Repeat NM exposure reveals an intervention-independent divergent inflammatory response.

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Repeat NM exposure reveals an intervention-independent divergent inflamm...
(A) Principal component analysis (PCA) of RNA-Seq data from all samples (n = 110) colored by time of biopsy collection with corresponding 95% CI ellipses shown. Arrows denote 2 distinct clusters within the 72hrs P-I samples (n = 28) whose 95% CI ellipses are shown in the subsequent PCA. (B) Heatmap of percent transformed cell type enrichment scores for 72hrs P-I RNA-Seq counts. Column dendrogram denotes unsupervised clustering of samples, and corresponding group membership of samples is shown below. (C) Representative H&E staining of 72hrs P-I Mild (n = 14) and Severe (n = 14) responders. Examples of spongiosis, degree of interface change, and inflammation are denoted by the triangle, arrowhead, and arrow, respectively. Scale bar: 100 μm. (D) Dot plots of severity scores for degree of spongiosis, interface change, and inflammation observed on H&E sections taken 72hrs P-I. Data are shown as mean ± SEM. Unpaired t tests were used to determine statistical significance. **P < 0.01, ****P < 0.0001. (E) Representative gross images of Mild and Severe participants’ arms 72hrs P-I. Dashed circles denote NM exposure site. (F) Dot plot of arm redness differences between exposed and unexposed sites taken after second NM exposure. Two-way ANOVA followed by Tukey’s multiple-comparison test were used to determine statistical significance ***Padj < 0.001, ****Padj < 0.0001. mv, mitral valve; ly, lymphocytic; Tcm, central memory T cell; Tem, effector memory T cell; pDC, plasmacytoid DCs.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

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