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

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 4

IL-17 signaling during initial NM exposure is involved in predisposing participants to an exaggerated response upon subsequent NM exposure.

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IL-17 signaling during initial NM exposure is involved in predisposing p...
(A) PCA of samples taken 72hrs P-E (n = 28). Green and orange arrows show where Mild (n = 14) and Severe (n = 14) participants fall within the total group. The 95% CI ellipses for 72hrs P-E Mild and Severe are shown. (B) Dot plots of DEGs increased (log2FC > 1) in 72hrs P-E Severe relative to Mild participants that enrich the IL-17 signaling pathway. Significance was determined by Wald test followed by Benjamini-Hochberg correction for multiple comparisons; *Padj < 0.05, **Padj < 0.01, ***Padj < 0.001, ****Padj < 0.0001. (C) Venn diagram of NM injury DEPs (NPX > 1) in Mild (n = 12) and Severe (n = 12) groups at 72hrs P-E relative to baseline (n = 24). Dot plots show mean NPX; data are shown as mean ± SEM, with error bars of DEPs uniquely increased in 72hrs P-E Severe relative to baseline. Significance was determined by linear mixed-effects modeling followed by Benjamini-Hochberg correction for multiple comparisons; *Padj < 0.05, **Padj < 0.01, ****Padj < 0.0001. (D) Pie charts show the percent composition of significantly enriched KEGG pathways using NM injury DEP lists as input from comparisons between 72hrs P-E Severe and Mild relative to baseline. Significant enrichment was determined by a 2-sided hypergeometric test, and P values were corrected using Bonferroni step down. **pV < 0.01. (E) Dot plots of severity score (scores 0–3) means; data are shown as mean ± SEM, with error bars in H&E sections taken 72hrs P-I and grouped by response severity. Unpaired t tests were used to determine statistical significance; *P < 0.05. (F) Dot plot of arm redness differences between exposed and unexposed sites taken after first NM exposure. Two-way ANOVA followed by Tukey’s multiple-comparison test were used to determine statistical significance; *Padj < 0.05.