Oral nicotinamide reduces transepidermal water loss: a randomized controlled trial

Dear Editor, Transepidermal water loss (TEWL) is a measure of barrier function which correlates with stratum corneum disruption1 and clinical severity in atopic dermatitis.2 Emollients may increase or decrease TEWL,3 but may not fully restore barrier function. Nicotinamide (an amide form of vitamin B3) has central roles in energy metabolism and DNA repair.4 We recently found that nicotinamide reduced new nonmelanoma skin cancers and actinic keratoses in patients at high risk.5 Nicotinamide also increases biosynthesis of stratum corneum lipids such as ceramides.6 Aquaporin‐3, which encodes water‐permeable channels, is associated with increased TEWL and is upregulated in atopic dermatitis.7 Nicotinamide attenuates aquaporin‐3 upregulation in vitro8 and topical nicotinamide may reduce TEWL.6 In 20 healthy participants 5% nicotinamide cream was associated with increased stratum corneum thickness and decreased TEWL compared with vehicle after 28 days.9 The effect of oral nicotinamide on TEWL in humans is unknown. We measured TEWL 3‐monthly for 12 months in participants at one study site within the ONTRAC (Oral Nicotinamide To Reduce Actinic Cancer) randomized trial5 to evaluate the effect of oral nicotinamide on TEWL. Eligible adults with two or more nonmelanoma skin cancers in the past 5 years were recruited to the phase 3 double‐blind ONTRAC study (Australian New Zealand Clinical Trials Registry number ACTRN12612000625875), conducted at two sites in Sydney, Australia. Participants at the Royal Prince Alfred Hospital site (n = 292) also took part in the TEWL study; the skin cancer data have been reported previously.5 Exclusion criteria included immunosuppression, pregnancy/breastfeeding, significant hepatic or renal impairment, recent oral retinoid use, actinic keratosis field treatments or nicotinamide supplements in the past 4 weeks. The study was approved by the relevant human ethics committees and conducted in accordance with Declaration of Helsinki principles. All participants provided written informed consent. Participants were enrolled (A.C.C., D.L.D.) and randomized 1 : 1 (NHMRC Clinical Trials Centre) to receive nicotinamide 500 mg twice daily or placebo for 12 months, with stratification by 5‐year nonmelanoma skin cancer history (< 6; ≥ 6), sex and study site. Identically coated tablets [nicotinamide 500 mg (Insolar™) or placebo] were manufactured and supplied by Blackmores Ltd (Warriewood, NSW, Australia). Two averaged TEWL measurements were taken 3‐monthly for 12 months, with a VapoMeter (Delfin Technologies Ltd, Kuopio, Finland)10 at three body sites (midline forehead, left volar forearm and left medial lower leg) by a single investigator blinded to allocation. Compliance was measured by tablet counts at each visit. Participants were asked to avoid make‐up, sunscreens or moisturizers on TEWL measurement days, and were rested for at least 5 min before each measurement. The primary endpoint of ONTRAC, upon which the sample size was based, was new skin cancers to 12 months.5 TEWL was a secondary endpoint. Analyses were by intention‐to‐treat and pre‐specified in a statistical analysis plan. The 3‐monthly post‐baseline TEWL data were analysed using a mixed model for repeated measures that included treatment group, centre, baseline value, time point, and a time‐by‐treatment group interaction as covariates. The right‐skewed distribution of the TEWL data was rectified by applying a loge transformation (with results back‐transformed for reporting). From July 2012 to June 2013, 292 participants at the Royal Prince Alfred Hospital were randomized to receive placebo (n = 147) or nicotinamide (n = 145; Fig. S1). Median compliance was 96% and 94%, respectively, and the groups were clinically similar (Table 1). Mean ambient temperature and mean relative humidity during TEWL measurements were 22·6 °C (SD 1·2) and 53·2% (SD 8·7), respectively. Baseline characteristics BCCs, basal cell carcinomas; NMSCs, nonmelanoma skin cancers; NSAID, nonsteroidal anti‐inflammatory drug; SCCs, squamous cell carcinomas. Baseline characteristics BCCs, basal cell carcinomas; NMSCs, nonmelanoma skin cancers; NSAID, nonsteroidal anti‐inflammatory drug; SCCs, squamous cell carcinomas. TEWL was increased in winter and reduced by nicotinamide. Baseline TEWL measurements were higher on the forehead (mean, 23 g m−2 h−1) compared with the limbs (baseline forearm and lower leg TEWL 9·8 and 9·7 g m−2 h−1, respectively). In participants taking placebo, there was a 15% relative increase in TEWL on the forehead in winter (June–August) compared with summer (December–February; P < 0·0001). Seasonal differences in limb TEWL were not significant. TEWL on the face and limbs tended to be lower with nicotinamide (Fig. 1). Transepidermal water loss (TEWL) was reduced with nicotinamide (n = 145) compared with placebo (n = 146 of 147 with post‐baseline data) at the forehead (a) and limbs (b). For the forehead, the estimated reduction in mean TEWL with nicotinamide compared with placebo was 5% at 3 months (P = 0·13), 5% at 6 months (P = 0·13), 6% at 9 months (P = 0·033) and 6% at 12 months (P = 0·039). For the limbs (forearm + lower leg measures combined), the estimated reduction in mean TEWL with nicotinamide was 2% at 3 months (P = 0·53), 4% at 6 months (P = 0·30), 1% at 9 months (P = 0·72) and 8% at 12 months (P = 0·04). Figure 1 shows TEWL at each 3‐month visit (mean and 95% confidence intervals). For the forehead, the estimated reduction in mean TEWL with nicotinamide compared with placebo was 5% at 3 months [95% confidence interval (CI) –1% to 10%; P = 0·13], 5% at 6 months (95% CI −1% to 10%; P = 0·13), 6% at 9 months (95% CI 1–12%; P = 0·033) and 6% at 12 months (95% CI 0–12%; P = 0·039). The estimated reduction in mean limb TEWL (arm + leg) with nicotinamide was 2% at 3 months (95% CI −5% to 9%; P = 0·53), 4% at 6 months (95% CI −4% to 11%; P = 0·30), 1% at 9 months (95% CI −6% to 9%; P = 0·72) and 8% at 12 months (95% CI 0–14%; P = 0·04). None of the between‐group differences in TEWL for the forearm and lower leg alone reached significance. There was no statistical evidence that the effect of nicotinamide on TEWL was modified by age. We found higher baseline TEWL at the forehead compared with the limbs. TEWL corresponds to the number of corneocyte layers, with approximately nine layers on the forehead, compared with ~ 16 on the forearm and ~ 18 on the lower leg.11 Other site factors that might influence TEWL include variations in lipid species and concentration,12 greater facial hair follicle density13 and sweating. TEWL was increased in winter on the forehead but not the limbs. This may reflect greater sensitivity of the face, with its higher baseline TEWL and lower number of corneocyte layers, to changes in ambient humidity. Oral nicotinamide consistently reduced TEWL by ~ 6–7% compared with placebo on the face and limbs in our largely elderly cohort, with a suggestion of improvement as early as the first 3‐month visit. There were no differences in adverse events between the groups.5 Whereas niacin (nicotinic acid) causes flushing, headache and syncope, nicotinamide has an established safety profile and lacks these vasodilatory side‐effects.14 Oral nicotinamide reduced TEWL by a magnitude equivalent to approximately half of the TEWL variation observed between the extremes of summer and winter. Nicotinamide is safe, accessible and inexpensive, and may benefit conditions associated with impaired barrier function. We are most grateful to our study volunteers for their generous participation in this project. We thank Blackmores Ltd (Warriewood, NSW, Australia) for supply of the placebo and nicotinamide tablets, and clinical trials pharmacists Katherine Snowden, Tuong‐Vi Phan and Romana Cecchele for coordinating tablet distribution. Thanks also to Mr David Espinoza for assistance with participant randomization, and Mr Tamati Paki for database setup and maintenance. Funding sources: This study was funded by National Health and Medical Research Council Project Grant 1026977; A.C.C. was supported by an Australian Postgraduate Award and a University of Sydney Postgraduate Scholarship in Dermatology. Conflicts of interest: none declared. Figure S1. Study flow diagram.