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 6

Clinical vignette and proposed mechanism of NM injury and VitD intervention.

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Clinical vignette and proposed mechanism of NM injury and VitD intervent...
(A) Exaggerated inflammatory response to topical NM therapy in a patient with Stage IA CTCL before (left) and 5 days after (right) a single dose of 100,000 IU oral VitD and twice daily topical clobetasol 0.05% ointment. (B) Theoretical, simplified mechanisms of NM injury and VitD intervention in Mild (right) and Severe responders (left). Initial keratinocyte damage leads to the release of proinflammatory mediators that recruit and activate immune cells. Macrophage activation stimulates iNOS and NF-κB signaling and secretion of inflammatory factors, such as CXCL8 and CSF1 (63–65). VitD mediates acute inflammation by suppressing CXCL5, CXCL6, and CXCL8 expression (Supplemental Table 6). We identified CCL20, CCL2, and CXCL8 as exaggerated response markers. CCL20 binds CCR6 to stimulate IL-17 signaling and attract lymphocytes and myeloid DCs (37). These APCs travel to secondary lymphoid tissues and activate T cells. CXCL8 is a neutrophilic chemokine known to induce neutrophil extracellular trap (NET) formation at high concentrations (39, 66, 67). pDCs, which do not normally respond to self-antigens, may become activated by NETs due to the colocalization of self-DNA with pDC activating factors (68–70). Activated pDCs secrete type-1 IFN at the local injury site, contributing to acute inflammation and priming mature neutrophils to favor NET fate (71). Activated pDCs in secondary lymphoid organs selectively induce Th1 and Th17 differentiation and activate B cells (68, 70, 72). The resulting antibody production exacerbates tissue injury and may induce NETs, creating a vicious inflammatory cycle (66). NETs have also been shown to mediate activation of both CD4+ and memory T cells by direct contact, lowering their activation threshold to specific antigens and suboptimal stimuli (69). IL-17 signaling further activates neutrophils, macrophages, and keratinocytes and perpetuates vicious inflammatory cycles potentially responsible for increased response severity. VitD suppresses these vicious cycles by suppressing CXCL8, CCL20, and CCL2 upregulation.