Measuring niacin-associated skin toxicity (NASTy) stigmata along with symptoms to aid development of niacin mimetics

Richard L Dunbar,Harsh Goel,Sony Tuteja,Wen-Liang Song,Grace Nathanson,Zeeshan Babar,Dusanka Lalic,Joel M Gelfand,Daniel J Rader,Gary L Grove

doi:10.1194/jlr.d071696

Abstract

Though cardioprotective, niacin monotherapy is limited by unpleasant cutaneous symptoms mimicking dermatitis: niacin-associated skin toxicity (NASTy). Niacin is prototypical of several emerging drugs suffering off-target rubefacient properties whereby agonizing the GPR109A receptor on cutaneous immune cells provokes vasodilation, prompting skin plethora and rubor, as well as dolor, tumor, and calor, and systemically, heat loss, frigor, chills, and rigors. Typically, NASTy effects are described by subjective patient-reported perception, at best semi-quantitative and bias-prone. Conversely, objective, quantitative, and unbiased methods measuring NASTy stigmata would facilitate research to abolish them, motivating development of several objective methods. In early drug development, such methods might better predict clinical tolerability in larger clinical trials. Measuring cutaneous stigmata may also aid investigations of vasospastic, ischemic, and inflammatory skin conditions. We present methods to measure NASTy physical stigmata to facilitate research into novel niacin mimetics/analogs, detailing characteristics of each technique following niacin, and how NASTy stigmata relate to symptom perception. We gave niacin orally and measured rubor by colorimetry and white-light spectroscopy, plethora by laser Doppler flowmetry, and calor/frigor by thermometry. Surprisingly, each stigma's abruptness predicted symptom perception, whereas peak intensity did not. These methods are adaptable to study other rubefacient drugs or dermatologic and vascular disorders.

Highlights

Niacin lowers LDL-cholesterol and triglycerides, raises HDL-cholesterol [1,2,3,4], and 1 g thrice daily reduces morbidity from coronary heart disease (CHD) and mortality [5,6,7]
We present methods to measure niacin-associated skin toxicity (NASTy) physical stigmata to facilitate research into novel niacin mimetics/analogs, detailing characteristics of each technique following niacin, and how NASTy stigmata relate to symptom perception
To measure NASTy physical stigmata, we focused on three signs that lend themselves to high-frequency measurement: 1) rubor; 2) plethora; and 3) calor

Summary

Introduction

Niacin lowers LDL-cholesterol and triglycerides, raises HDL-cholesterol [1,2,3,4], and 1 g thrice daily reduces morbidity from coronary heart disease (CHD) and mortality [5,6,7]. Cutaneous vasodilation causes the most visible manifestations, plethora and rubor. These may not be the most irritating symptoms. Some symptoms correspond to cutaneous physical stigmata and lend themselves to objective measurement: plethora (hyperemia, i.e., increased blood flow), rubor (gross redness of the skin), calor (warmth), and tumor (edema). Massive heat loss presages an important systemic physical change to a vital sign: frigor praeter naturam, body temperature colder than normal ( frigor). This cutaneous symptom complex is simplistically referred to as “flushing” (i.e., superficial rubor alone), but is more aptly named niacin-associated skin toxicity (NASTy) [8]. NASTy effects are the main reason patients stop taking niacin, >25% within months [1, 9,10,11]

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Discussion

Conclusion