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

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.

Experimental Therapeutics for Challenging Clinical Care of a Patient with an Extremely Rare Homozygous APOC2 Mutation.

BACKGROUND: Among many causes of hypertriglyceridemia (HTG), familial chylomicronemia syndrome (FCS) is a rare monogenic disorder that manifests as severe HTG and acute pancreatitis. Among the known causal genes for FCS, mutations in APOC2 only account for <2% of cases. Medical nutrition therapy is critical for FCS because usual triglyceride- (TG-) lowering medications are ineffective. Therapeutic plasma exchange (TPE) with fresh frozen plasma (FFP) is an option to urgently reduce TG and pancreatitis episodes. Several novel biologics are under development to treat HTG and may provide therapeutic options for FCS in the future. OBJECTIVE: We present the challenging care of a 43-year-old man with FCS with apoC-II deficiency and the results of two types of TPE and of investigational TG-lowering biologic therapies. RESULTS: The patient's lipid profile was consistent with FCS. A novel homozygous variant was identified in APOC2, and its pathogenicity was confirmed. Even on a fat-restricted diet, his care was tremendously complicated with unremitting bouts of pancreatitis. TPE with FFP replacement lowered TG >90% post-sessions and appeared to reduce pancreatitis episodes. Experimental ANGPTL3 and APOC3 inhibitors each lowered TG by >50%. CONCLUSIONS: Our case demonstrates the importance of delineating and defining the underlying etiology of a rare disorder to optimize therapy and to minimize unfavorable outcomes.