Abstract
Background
The epidemiologic association between alcohol and rosacea is unclear and inconsistent based on prior cross-sectional or case-control studies.
Objective
We conducted a cohort study to determine the association between alcohol intake and the risk of incident rosacea.
Methods
A total of 82,737 women were included from the Nurses’ Health Study II (1991–2005). Information on alcohol intake was collected every four years during follow-up. Information on history of clinician-diagnosed rosacea and year of diagnosis was collected in 2005.
Results
Over 14 years of follow-up, we identified 4,945 incident cases of rosacea. Compared with never drinkers, increased alcohol intake was associated with a significantly elevated risk of incident rosacea (P for trend<0.0001). The multivariable-adjusted HRs (95% CIs) were 1.12 (95% CI 1.05–1.20) for alcohol intake of 1–4 g/day, and 1.53 (1.26–1.84) for ≥30 g/day. The associations remained consistent across categories of smoking status. Further examination of types of alcoholic beverage consumed revealed that white wine (P for trend <0.0001) and liquor intake (P for trend =0.0006) were significantly associated with higher risk of rosacea.
Limitations
This was an epidemiologic study without examination into etiologic mechanisms.
Conclusions
Alcohol intake was significantly associated with an increased risk of incident rosacea in women.
Keywords: cohort studies, rosacea, alcohol intake, epidemiology, smoking, dose-response relationship
INTRODUCTION
Rosacea is a chronic inflammatory skin disorder which affects approximately 16 million people in the United States.1–3 Dysfunction in the innate and adaptive immune response, dysregulation of the vascular and nervous systems, and their interplay with the inflammatory response have been implicated in the development of rosacea.1–4
Alcohol impairs the vasomotor center of the brain, inducing peripheral vasodilatation, and is known to have a profound effect on the immune system.5,6 It has been suggested that resultant cutaneous vasodilatation and pro-inflammatory effects may contribute to the hallmark redness and flushing, exacerbating rosacea.5,7–10
The epidemiologic association between alcohol and rosacea is unclear and inconsistent based on prior studies.11–14 Several case-control studies or case series did not find significant associations between alcohol and rosacea.11–13 Recently, though, one large case-control study reported an elevated risk of rosacea by increasing alcohol intake.14 No prospective studies have investigated the association between alcohol intake and the risk of incident rosacea.
In the present study, we investigated the association between alcohol intake and the risk of incident rosacea in a total of 82,737 women from the Nurses’ Health Study II (NHS II).
SUBJECTS AND METHODS
Study population
Details of NHS II, a women’s cohort, have been described previously.15,16 Information on alcohol use was collected in 1991, 1995, 1999, and 2003. Women in NHS II were asked how often, on average, they had consumed regular beer, light beer (12 oz.), red wine, white wine (4 oz.), or liquor (1 standard drink) during the past year. Intake of each beverage was ascertained in 9 categories (number of drinks): none or <1/month, 1–3/month, 1/week, 2–4/week, 5–6/week, 1/day, 2–3/day, 4–5/day, and ≥6/day. Total alcohol intake was calculated as the sum of the alcohol intake from beer, wine, and liquor, as detailed previously17. In 2005, nurses were asked whether they ever had clinician-diagnosed rosacea, and if so, their diagnosis year in time intervals (before 1991, 1991–1994, 1995–1998, 1999–2002, or 2003–2005). Among women who responded to the 2005 questionnaire (n=97,476), we excluded rosacea cases that occurred before 1991 or with missing diagnosis year (n=1,158), and women with missing total alcohol intake information (n=13,581). A total of 82,737 women remained in the analysis.
Statistical analysis
We calculated person-years from the return date of the 1991 questionnaire to the date of diagnosis of rosacea or the end of follow-up (June 2005), whichever came first.
We conducted Cox proportional hazards analysis stratified by age and 2-year intervals to estimate age- and multivariate-adjusted (See eMethod 1 for collection of covariates) hazard ratios (HR) and 95% confidence intervals (CI) for the risk of incident rosacea associated with total alcohol intake and each individual alcoholic beverage. Information on the exposure was updated in 4-year questionnaire cycles, whenever available. Trend tests for total alcohol intake and each individual alcoholic beverage were carried out using continuous measures of these variables by assigning the median to each category. Adjusted Cox proportional hazards models was fitted using a restricted cubic spline regression analysis to examine the shape of the dose-response relations between alcohol intake and risk of incident rosacea.18
We examined the association between alcohol intake and risk of rosacea stratified by smoking status19. To address the concern of reverse-causation bias, a 4-year lag analysis was conducted by excluding rosacea cases documented within the first four years of each updated assessment of alcohol intake.
All statistical analyses were conducted using SAS, version 9.4 (SAS Institute, Inc., Cary, North Carolina). All statistical tests were 2-tailed, and the significance level was set at P < 0.05.
RESULTS
Table 1 shows the characteristics of the women in 1991 by total alcohol intake; 42.3% of the women never had alcohol intake, 38.8% had alcohol intake of 1–4 g/day and 1.1% had alcohol intake of more than 30 g/day. Women with high alcohol intake were more likely to smoke and use oral contraceptives.
Table 1.
Age-standardized characteristics of study participants by total alcohol intake in 1991: the Nurses’ Health Study IIa
| Characteristics | None (n=35,037) |
1–4 g/day (n=32,095) |
5–9 g/day (n=8,267) |
10–14 g/day (n=4,227) |
15–29 g/day (n=2,233) |
30+ g/day (n=878) |
|---|---|---|---|---|---|---|
| Ageb, years, Mean (SD) | 36.3(4.6) | 36.0(4.6) | 36.0(4.7) | 36.5(4.7) | 37.0(4.6) | 37.6(4.3) |
| Body mass index, kg/m2, Mean(SD) | 25.3(5.8) | 24.2(5.0) | 23.3(4.0) | 23.2(4.0) | 23.3(3.9) | 23.6(4.3) |
| Physical activity, metabolic equivalent hours/week, Mean(SD) | 18.3(24.9) | 21.5(26.6) | 24.1(30.3) | 25.1(29.5) | 24.6(28.4) | 22.6(28.2) |
| Postmenopausal hormone use, % | 4.1 | 3.4 | 2.7 | 2.8 | 3.0 | 3.2 |
| Caucasian, % | 91.7 | 94.8 | 95.7 | 95.3 | 94.9 | 95.0 |
| Oral contraceptive use, % | 81.4 | 86.2 | 88.4 | 89.2 | 89.0 | 88.2 |
| UV flux, 5th quintile, % | 18.7 | 16.8 | 18.7 | 20.0 | 21.9 | 22.8 |
| Current smoking, % | 8.5 | 11.8 | 14.3 | 18.9 | 22.8 | 36.5 |
| Past smoking, % | 16.2 | 24.4 | 31.2 | 32.5 | 35.3 | 31.8 |
Abbreviation: SD, standard deviation.
Values are standardized to the age distribution of the study population.
Values are not age-adjusted.
During 1,120,050 person-years of follow-up, we identified 4,945 incident cases of rosacea. Compared with never drinkers, increased alcohol intake was associated with an elevated risk of incident rosacea (P-trend<0.0001). The multivariable-adjusted HRs (95% CIs) were 1.12 (95% CI 1.05–1.20) for alcohol intake of 1–4 g/day, 1.19 (1.08–1.31) for 5–9 g/day, 1.28 (1.14–1.44) for 10–14 g/day, 1.37 (1.20–1.56) for 15–29 g/day, and 1.53 (1.26–1.84) for ≥30 g/day (Table 2). Results of the spline regression suggested that the dose-response relationship between alcohol intake and risk of incident rosacea were primarily linear (Figure 1). For individual alcoholic beverage types, we found that increased intake of white wine or liquor was associated with significantly increased risk of rosacea (P-trend<0.0001 for white wine and P-trend = 0.0006 for liquor) (Table 3). For other individual alcoholic beverages, we did not observe statistically significant associations with the risk of rosacea. Sensitivity analysis fitting five alcoholic beverage types into one model to test for independent associations showed similar findings, with significant associations for white wine and liquor (data not shown).
Table 2.
Hazard ratios for risk of incident rosacea according to total alcohol intake in the Nurses’ Health Study II (1991–2005)
| No. of Case |
No. of Person-Years |
Age-Adjusted
|
Multivariate-Adjusteda
|
|||
|---|---|---|---|---|---|---|
| HR | 95% CI | HR | 95% CI | |||
| None | 1,820 | 459,976 | 1.00 | Referent | 1.00 | Referent |
| 1–4 g/day | 1,797 | 413,341 | 1.10 | 1.03–1.18 | 1.12 | 1.05–1.20 |
| 5–9 g/day | 588 | 121,319 | 1.15 | 1.05–1.27 | 1.19 | 1.08–1.31 |
| 10–14 g/day | 358 | 67,807 | 1.23 | 1.09–1.37 | 1.28 | 1.14–1.44 |
| 15–29 g/day | 264 | 40,989 | 1.31 | 1.15–1.49 | 1.37 | 1.20–1.56 |
| 30+ g/day | 118 | 16,618 | 1.43 | 1.19–1.72 | 1.53 | 1.26–1.84 |
| Ptrend | <0.0001 | <0.0001 | ||||
Abbreviations: CI, confidence interval; HR, hazard ratio.
Adjusted for age (continuous variable), race, body mass index (kg/m2; continuous variable), postmenopausal hormone use (premenopause, never, current or past users), smoking status (Never smokers, past smokers 1–4, past smokers 5–14, past smokers 15–24, past smokers ≥25, current smokers 1–4, current smokers 5–14, current smokers 15–24, current smokers ≥25 cigarettes/day), and physical activity level (metabolic equivalent hours/week in quintiles)
Figure 1*. Dose-response hazard ratio (with 95% confidence interval) of incident rosacea by alcohol intake.
*Model was adjusted for age (continuous variable), race, body mass index (kg/m2; continuous variable), postmenopausal hormone use (premenopause, never, current or past users), smoking status (Never smokers, past smokers 1–4, past smokers 5–14, past smokers 15–24, past smokers ≥25, current smokers 1–4, current smokers 5–14, current smokers 15–24, current smokers ≥25 cigarettes/day), and physical activity level (metabolic equivalent hours/week in quintiles)
Table 3.
Hazard ratios for risk of incident rosacea with consumption of individual alcoholic beverages in the Nurses’ Health Study II (1991–2005)
| No. of Case |
No. of Person-Years |
Age-Adjusted
|
Multivariate-Adjusteda
|
|||
|---|---|---|---|---|---|---|
| HR | 95% CI | HR | 95% CI | |||
| Beer (drinks) | ||||||
| Never | 3,863 | 899,281 | 1.00 | Referent | 1.00 | Referent |
| 1–3 per month | 605 | 121,681 | 1.16 | 1.07–1.27 | 1.17 | 1.07–1.27 |
| 1 per week | 270 | 53,844 | 1.18 | 1.05–1.34 | 1.20 | 1.06–1.35 |
| 2–4 per week | 139 | 31,332 | 1.05 | 0.89–1.24 | 1.07 | 0.90–1.27 |
| ≥5 per week | 68 | 13,913 | 1.15 | 0.90–1.46 | 1.21 | 0.95–1.54 |
| Ptrend | 0.14 | 0.05 | ||||
| Light beer (drinks) | ||||||
| Never | 3,797 | 850,693 | 1.00 | Referent | 1.00 | Referent |
| 1–3 per month | 615 | 141,018 | 1.03 | 0.95–1.12 | 1.03 | 0.95–1.13 |
| 1 per week | 264 | 60,412 | 1.06 | 0.93–1.20 | 1.06 | 0.94–1.20 |
| 2–4 per week | 168 | 43,859 | 0.93 | 0.80–1.09 | 0.95 | 0.81–1.11 |
| ≥5 per week | 101 | 24,068 | 0.98 | 0.80–1.19 | 1.04 | 0.85–1.27 |
| ptrend | 0.17 | 0.43 | ||||
| Red wine (drinks) | ||||||
| Never | 3371 | 827,555 | 1.00 | Referent | 1.00 | Referent |
| 1–3 per month | 787 | 162,948 | 1.09 | 1.01–1.18 | 1.09 | 1.01–1.18 |
| 1 per week | 366 | 61,403 | 1.24 | 1.11–1.38 | 1.24 | 1.11–1.38 |
| 2–4 per week | 287 | 46,819 | 1.18 | 1.04–1.33 | 1.19 | 1.05–1.34 |
| ≥5 per week | 134 | 21,327 | 1.13 | 0.95–1.34 | 1.15 | 0.96–1.37 |
| ptrend | 0.08 | 0.07 | ||||
| White wine (drinks) | ||||||
| Never | 2,667 | 659,921 | 1.00 | Referent | 1.00 | Referent |
| 1–3 per month | 1,216 | 264,471 | 1.14 | 1.06–1.22 | 1.14 | 1.07–1.22 |
| 1 per week | 470 | 92,602 | 1.20 | 1.09–1.33 | 1.21 | 1.10–1.34 |
| 2–4 per week | 360 | 68,324 | 1.21 | 1.08–1.35 | 1.23 | 1.10–1.38 |
| ≥5 per week | 232 | 34,733 | 1.45 | 1.27–1.66 | 1.49 | 1.30–1.70 |
| ptrend | <0.0001 | <0.0001 | ||||
| Liquor (drinks) | ||||||
| Never | 3,752 | 880,122 | 1.00 | Referent | 1.00 | Referent |
| 1–3 per month | 710 | 149,251 | 1.08 | 1.00–1.17 | 1.08 | 1.00–1.17 |
| 1 per week | 244 | 47,124 | 1.14 | 1.00–1.29 | 1.15 | 1.01–1.31 |
| 2–4 per week | 151 | 28,358 | 1.17 | 0.99–1.37 | 1.19 | 1.01–1.40 |
| ≥5 per week | 88 | 15,196 | 1.23 | 0.99–1.51 | 1.28 | 1.04–1.59 |
| ptrend | 0.0024 | 0.0006 | ||||
Abbreviations: CI, confidence interval; HR, hazard ratio.
Adjusted for age (continuous variable), race, body mass index (kg/m2; continuous variable), postmenopausal hormone use (premenopause, never, current or past users), smoking status (Never smokers, past smokers 1–4, past smokers 5–14, past smokers 15–24, past smokers ≥25, current smokers 1–4, current smokers 5–14, current smokers 15–24, current smokers ≥25 cigarettes/day), and physical activity level (metabolic equivalent hours/week in quintiles).
Stratified analyses by smoking status showed generally consistent associations between alcohol intake and risk of rosacea in never, past and current smokers (Table 4). We did not find effect modification by smoking status on the association between alcohol intake and risk of rosacea (P-interaction=0.61).
Table 4.
Stratified analysis by smoking status of the association between total daily alcoholic intake and risk of incident rosacea in the Nurses’ Health Study II (1991–2005)
| No. of Case |
No. of Person-Years |
Age-Adjusted
|
Multivariate-Adjusteda
|
|||
|---|---|---|---|---|---|---|
| HR | 95% CI | HR | 95% CI | |||
| Never smokers | ||||||
| None | 1,347 | 343,645 | 1.00 | Referent | 1.00 | Referent |
| 1–4 g/day | 1,190 | 265,426 | 1.14 | 1.06–1.23 | 1.15 | 1.07–1.25 |
| 5–9 g/day | 325 | 67,896 | 1.13 | 1.00–1.27 | 1.16 | 1.03–1.31 |
| 10–14 g/day | 187 | 34,333 | 1.24 | 1.07–1.45 | 1.29 | 1.10–1.50 |
| 15+ g/day | 163 | 24,191 | 1.31 | 1.11–1.54 | 1.34 | 1.14–1.58 |
| ptrend | <0.0001 | <0.0001 | ||||
| Past smokers | ||||||
| None | 376 | 78,958 | 1.00 | Referent | 1.00 | Referent |
| 1–4 g/day | 493 | 104,339 | 1.01 | 0.88–1.16 | 1.04 | 0.90–1.19 |
| 5–9 g/day | 214 | 39,024 | 1.12 | 0.95–1.33 | 1.17 | 0.99–1.39 |
| 10–14 g/day | 134 | 23,345 | 1.13 | 0.93–1.38 | 1.20 | 0.98–1.47 |
| 15+ g/day | 177 | 21,750 | 1.41 | 1.18–1.69 | 1.49 | 1.24–1.79 |
| Ptrend | <0.0001 | <0.0001 | ||||
| Current smokers | ||||||
| None | 92 | 36,119 | 1.00 | Referent | 1.00 | Referent |
| 1–4 g/day | 110 | 42,158 | 1.04 | 0.79–1.37 | 1.04 | 0.79–1.38 |
| 5–9 g/day | 48 | 14,055 | 1.32 | 0.93–1.88 | 1.32 | 0.92–1.88 |
| 10–14 g/day | 36 | 9,921 | 1.38 | 0.93–2.03 | 1.38 | 0.94–2.05 |
| 15+ g/day | 42 | 11,466 | 1.31 | 0.9101.89 | 1.29 | 0.89–1.87 |
| Ptrend | 0.04 | 0.07 | ||||
Abbreviations: CI, confidence interval; HR, hazard ratio.
Adjusted for age (continuous variable), race, body mass index (kg/m2; continuous variable), postmenopausal hormone use (premenopause, never, current or past users), physical activity level (metabolic equivalent hours/week in quintiles), and number of cigarettes per day in past and current smokers.
The 4-year Lag analysis did not materially change the results (data not shown). Secondary analysis which examined updated cumulative average intake of total alcohol did not change the results appreciably (eTable 1). Analyses using updated cumulative average intake of individual alcoholic beverages did not alter the findings from that primary analysis either (data not shown). Sensitivity analysis additionally adjusted for oral contraceptive use, cumulative ultraviolet (UV) flux, and personal history of major chronic diseases, or sensitivity analysis excluding non-Caucasians also yielded similar results to the primary analyses (data not shown).
DISCUSSION
We found that alcohol intake is associated with increased risk of rosacea in a dose-dependent manner. Of individual types of alcoholic beverage, increased consumption of white wine or liquor was significantly associated with an elevated risk of rosacea. The associations were independent of major confounders and remained robust in our sensitivity analyses.
Several cross-sectional and case-control studies have examined the associations between alcohol intake and rosacea with inconsistent results.11–14 The findings of a recent large case-control study (60,042 cases and 60,042 controls) based on the General Practice Research Database (UK) reported a 51% increased risk of rosacea among participants who consumed ≥25 units alcohol/week (OR=1.51, 95%CI:1.41–1.63), compared with nondrinkers.14 The effect estimate was similar to our finding for alcohol intake of ≥30g/day (OR=1.53, 95%CI:1.26–1.84), although the UK study did not specify the definition for units of alcohol intake.14
A variety of mechanisms may be involved, including alcohol-induced vasodilation and subsequent temperature elevation.5 Specifically, alcohol intake may induce catecholamine release,20,21 ultimately leading to bradykinin-induced facial vasodilation.22 Alcohol intake has been shown to increase production of inflammatory cytokines.7,8 Further, alcohol can induce cell cycle activators, which may contribute to epidermal hyperproliferation in rosacea.7,23
Traditionally, red wine has been posited as a rosacea trigger and a survey by the National Rosacea Society (n>700 rosacea patients) found that red wine was the top food trigger of rosacea, followed by white wine (https://www.rosacea.org/rr/2004/winter/article_3.php). The extent of flushing after red wine intake is often asked in clinics for rosacea diagnosis. In contrast, our study found that among the individual types of alcoholic beverages, only white wine and liquor were significantly associated with the incident risk of rosacea. It is therefore likely that developing rosacea and the phenomenon of flushing with red wine intake leading to rosacea exacerbation are distinct. It is worth noting that white wine and liquor are the only two types of alcoholic beverages with higher concentrations of alcohol, and they do not contain anti-inflammatory components (such as flavonoids) of red wine.24 However, red wine was shown to contain more histamine and other inflammatory factors (such as resveratrol) which may contribute to flushing among rosacea patients.25,26 Further investigations are warranted to elucidate the mechanisms underlying the differential associations for individual alcoholic beverages.
Our study has several strengths. Our assessment of alcohol intake was updated every four years, and major covariates were updated biennially in the prospective follow-up, thus avoiding misclassification and permitting a detailed examination of the influence of alcohol on rosacea. The large number of women and long-term follow-up facilitated the documentation of a sufficient number of incident cases of rosacea for robust associations.
We acknowledge some limitations. First, information on lifetime diagnosis of rosacea was self-reported in 2005 and no validation study was conducted. The retrospective data collection of rosacea may have led to recall bias. However, because the women are health professionals, a high validity of the self-report is expected. For example, our prior validation study indicated a very high validity of psoriasis self-report, with >90% self-reported cases confirmed.27 Any misclassification of rosacea may tend to be non-differential according to alcohol intake. We considered the possibility that the association between alcohol intake and incident rosacea may reflect alcohol intake among affected, symptomatic subjects who had not yet received a physician-defined diagnosis. However, the 4-year lag analyses excluding rosacea cases that occurred within the first four years of each updated assessment of alcohol intake did not demonstrate a material change in the associations, which helped address the concern on reverse causation bias. Second, there may be etiologic heterogeneity underlying different types of rosacea,1,28 but we did not have information on rosacea subtypes. Third, an epidemiologic study cannot rule out the possibility of residual confounding due to unmeasured or imperfectly measured confounders.
In summary, based on a large, well-established cohort of women, we found that alcohol intake is associated with an increased risk of rosacea. The associations were particularly significant for elevated intake of white wine and liquor. Our study may have implications for rosacea etiology and the clinical approach to rosacea.
Supplementary Material
Capsule Summary.
The association between alcohol intake and rosacea is unclear.
Alcohol intake, particularly white wine and liquor, may be associated with an increased risk of incident rosacea in women.
The findings may assist in understanding the etiology of rosacea and in managing affected patients.
Acknowledgments
We would like to thank the participants and staff of the Nurses’ Health Study II, for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, and WY. The authors assume full responsibility for analyses and interpretation of these data. The authors have no competing interests or financial relationships to disclose.
Funding: This work was supported by Department of Dermatology, Warren Alpert Medical School of Brown University and Nurses’ Health Study II grant (UM1 CA176726). Wen-Qing Li was supported by the Research Grant of National Rosacea Society and the Research Career Development Award of Dermatology Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Abbreviations
- CI
confidence interval
- HR
hazard ratio
- NHS II
Nurses’ Health Study II
- UV
ultraviolet
Footnotes
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Institutional Review Board (IRB) Approval: This study was approved by the Institutional Review Board of Brigham and Women’s Hospital. The participants’ completion and return of the self-administered questionnaires were considered as informed consent.
Clinical Trial Registration: not applicable
Author contributions: Suyun Li: Statistical analysis; analysis and interpretation of data; drafting of the manuscript; Eunyoung Cho: Analysis and interpretation of data; critical revision of the manuscript for important intellectual content; Aaron Drucker: Analysis and interpretation of data; critical revision of the manuscript for important intellectual content; Abrar A Qureshi: Study concept and design; acquisition of data; critical revision of the manuscript for important intellectual content; funding support; study supervision; Wen-Qing Li: Study concept and design; statistical analysis; analysis and interpretation of data; critical revision of the manuscript for important intellectual content, study supervision
Potential conflicts of interest: Dr. Drucker has received honoraria from Astellas Canada (speaker) and serves as the investigator (with no financial compensation) of Sanofi and Regeneron. The other authors declare no conflicts of interest.
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