Alcohol use has been associated with reduced risk of RA in previous case–control studies ( 9 - 12 ). These findings have generated substantial public health interest and concern. However, as these case–control studies ascertained alcohol exposure retrospectively, there is the potential for recall bias and reverse causation bias. A recent prospective cohort study also found that moderate consumption of alcohol was associated with a reduced risk of RA, but was limited by a small number of cases (197 cases) and a short period of followup (from 2003 to 2009) ( 13 ). We studied the relationship between alcohol consumption and the risk of RA in 2 large prospective cohorts of women with information on alcoholic beverage consumption, as well as important potential confounders, such as cigarette smoking and reproductive factors, collected on an ongoing basis for up to 26 years. This approach permitted the use of long‐term exposure data and resulted in a more accurate estimate of exposure than in previous studies.

Rheumatoid arthritis (RA) is an autoimmune disease that causes a destructive, inflammatory arthritis and affects ∼1% of the adult population ( 1 , 2 ). The prevalence of RA is 3 times higher in women than in men ( 3 ). The cause of RA is unknown, but it is considered to be a multifactorial disease, resulting from the interaction of both genetic and environmental factors ( 1 ). Epidemiologic research has produced convincing data for strong environmental risk factors, including cigarette smoking ( 4 , 5 ), exogenous hormone use ( 6 ), and female reproductive factors ( 7 , 8 ).

To examine the effects of separate alcoholic beverages, we performed a secondary analysis in which we fitted a Cox proportional hazards model that included cumulative average consumption of beer, wine, or liquor, as well as the potential covariates listed above. We measured the frequency of consumption of each alcoholic beverage using ordinal variables (none, ≤1, 2–4, or ≥5 drinks/week). We also performed sensitivity analyses using the updated alcohol consumption values (again excluding the most recent FFQ), rather than the cumulative average measures, in time‐varying Cox proportional hazards models. Data analyses were performed using SAS 9.2 software (SAS Institute). P values (2‐sided) less than 0.05 were considered significant.

For each woman, the number of person‐years of followup was calculated from the date of return of the baseline questionnaire to the end of followup, which was defined as RA diagnosis, censorship due to reported psoriasis or rheumatic disease not confirmed as RA, censorship due to cancer, death, or end of the study, whichever came first. We used Cox proportional hazards models to assess associations after controlling for time‐varying covariates, including age, smoking status, body mass index, physical activity, parity and breastfeeding, menopause status, oral contraceptive use, total calorie intake, median census tract household income, and age at menarche. The multivariable‐adjusted hazard ratios (HRs), approximating the relative risk of associations between alcohol consumption and RA, were calculated, along with their 95% confidence intervals (95% CIs). Possible nonlinear associations were assessed using a restricted cubic spline method ( 21 ). The interaction terms between alcohol consumption (<5 gm/day versus ≥5 gm/day) and smoking (<20 pack‐years versus ≥20 pack‐years) were evaluated in the adjusted models using likelihood ratio tests. Analyses were repeated in both cohorts with stratification by RA serologic status (RF and/or anti‐CCP positive) to evaluate whether the association between alcohol consumption and RA differed by the RA patients' serologic status. Pooled HR estimates for the 2 cohorts were calculated using a random‐effects model, and heterogeneity was assessed using the DerSimonian and Laird method ( 22 ).

All analyses were conducted separately in the NHS and the NHSII. The primary analysis was to assess the influence of alcohol consumption on the incidence of RA. Descriptive statistics, such as frequency tables for categorical variables and minimum, maximum, mean, and standard deviation for continuous variables, were used to summarize the data as well as to detect outliers and missing values. Baseline age‐adjusted characteristics across categories of alcohol consumption were compared using Kruskal‐Wallis tests for continuous variables and chi‐square tests for categorical variables.

All information about potential confounders was self‐reported on the questionnaires that were mailed every 2 years since 1976 in the NHS and since 1989 in the NHSII and updated through followup. We selected covariates based on prior studies in NHS cohorts ( 5 , 7 ) for RA risk factors, or other studies showing an association between diet or lifestyle and alcohol intake. Cigarette smoking is a strong environmental risk factor for RA ( 5 ) and is highly correlated with alcohol intake. We adjusted for time‐varying pack‐years of smoking (number of years of smoking × number of packs of cigarettes smoked per day) in the analyses. Updated body mass index was computed for each 2‐year time interval by using the most recent weight (in kilograms) divided by the height (in meters squared). Recreational physical activity was measured biennially with a validated questionnaire asking about the average time spent engaged in 10 common activities. The information was summed and calculated as weekly energy expenditure in metabolic equivalent hours, weighting each activity by its intensity level ( 20 ). Reproductive covariates included parity and duration of breastfeeding (nulliparous, parous and not breastfeeding, parous and 1–12 months of breastfeeding, parous and >12 months of breastfeeding), oral contraceptive use, menopause status, and postmenopausal hormone use ( 7 ). Age at menarche was reported on the baseline questionnaire. The total intake of calories was measured through the FFQ. As a proxy of socioeconomic status, we included the 2000 US Census tract median income for the nurses' residences.

Identification of RA cases was a 2‐stage procedure. A connective tissue disease screening questionnaire was first mailed to those who had self‐reported having a physician's diagnosis of RA. Medical records of those who were positive at screening were requested and reviewed independently by 2 board‐certified rheumatologists (KHC and EWK) to confirm RA according to the American College of Rheumatology classification criteria ( 19 ). Women included in these analyses had definite, confirmed incident RA, documented serologic status (rheumatoid factor [RF] and/or anti–cyclic citrullinated peptide [anti‐CCP]), and dates of diagnosis and symptom onset from the medical records.

According to the Dietary Guidelines for Americans, drinking in moderation for women is typically defined as having up to 1 standard alcoholic drink per day (equal to 10–15 gm of pure alcohol). This definition refers to the amount consumed on any single day and is not intended to represent an average over several days ( 18 ). We therefore defined moderate alcohol consumption as <10 gm/day, on average, in the analysis. We coded alcohol consumption as an ordinal variable: none, 0.1–4.9 gm/day, 5.0–9.9 gm/day, or ≥10 gm/day.

We measured alcohol intake as the amount of alcohol consumed per day (in grams) and the number of drinks consumed per week on each FFQ. To minimize the inaccuracy of exposure information, we used cumulative average estimates of consumption, since they are more representative of regular alcohol exposure than a 1‐time measure ( 17 ). Cumulative average intake was calculated by averaging repeated measures of alcohol intake from baseline to 4–6 years before diagnosis in the RA cases. As it is possible that early symptoms of RA may cause a person to alter his or her behavior with regard to alcohol use, we excluded the most recent FFQ (lagged by 1 cycle) from the calculation of the cumulative average alcohol consumption in order to reduce the possibility of recall bias and reverse causation bias. For example, for RA incidence during the 1998–2000 time period, the cumulative average alcohol use was obtained by averaging the daily consumption reported from baseline to the 1994 FFQ (excluding the 1998 alcohol measure).

The reproducibility and validity of the assessment of alcohol intake were evaluated among 173 Boston‐area participants who completed a written 1‐week dietary record every 3 months for a year, during which time they weighed or measured all of their food and drinks. The correlation of alcohol intake on the questionnaire with alcohol intake on the dietary records was 0.9, by Spearman's correlation ( 16 ).

In the NHS, alcohol consumption was assessed with a semiquantitative food frequency questionnaire (FFQ), which included separate items for beer, wine, and liquor, in 1980, 1984, 1986, 1990, 1994, 1998, 2002, and 2006. In the NHSII, data on alcohol intake were collected by questionnaire in 1989 and by FFQ in 1991, 1995, 1999, 2003, and 2007. We specified standard portions as constituting a glass, bottle, or can of beer; a 4‐oz glass of wine; and a shot of liquor. For each beverage, participants were asked to estimate their average consumption over the previous year. The estimated alcohol content of each beverage was 13.2 gm per bottle or can of beer, 10.8 gm per glass of wine, and 15.1 gm per standard drink of liquor. Total alcohol intake was recorded as the sum of these 3 beverages.

We included in the present study participants in the NHS and NHSII cohorts who had data on alcohol consumption at baseline (1980 for the NHS and 1989 for the NHSII). We excluded prevalent cases of RA before 1982 in the NHS and before 1991 in the NHSII. We censored all participants who reported psoriasis, psoriatic arthritis, and connective tissue diseases in which the diagnosis was not subsequently confirmed as RA at a self‐reported date. Women lost to followup were censored at their last response to the questionnaires because incident cases could not be identified. Additionally, cancer or its treatments may alter the immune system, and the secondary symptoms (such as joint pain from paraneoplastic syndromes) may cause a person to change his or her behavior with regard to alcohol consumption. We therefore excluded participants with a history of cancer at baseline and censored incident cancer cases at the self‐reported date in the analysis. The final group included 82,469 women who were monitored from 1980 to 2008 in the NHS and 110,737 women who were monitored from 1989 to 2009 in the NHSII.

The Nurses' Health Study (NHS) was established in 1976 in the US and enrolled 121,701 female registered nurses ages 30–55 years. NHSII is a prospective cohort study that began in 1989, enrolling 116,430 female nurses ages 25–42 years. Based on self report, more than 90% of women in both cohorts are Caucasian, reflecting the ethnicity of women entering the nursing profession during the recruitment years. The rate of followup has been extremely high, with only 5.0% of person‐time lost to followup ( 14 ). In both cohorts, all women completed an initial questionnaire and have been contacted biennially to update exposures, lifestyle, health practices, and disease diagnoses. We routinely search the National Death Index every 2 years for those who do not respond to the attempts to contact them ( 15 ). All aspects of this study were approved by the Partners HealthCare Institutional Review Board.

Among individual alcoholic beverages, a significant association with the risk of RA was found for beer after controlling for the other 2 alcoholic beverages and the covariates listed above (Table 3 ). Compared with women who never drank beer, the pooled multivariable HR for 2–4 drinks/week was 0.69 (95% CI 0.50–0.95). In contrast, wine or liquor consumption of 2–4 drinks/week was associated with a nonsignificant reduced risk of RA, after controlling for the other 2 alcoholic beverages and potential confounding factors in both cohorts.

To examine the potential effect‐modification by smoking status, we included smoking × alcohol interactions in the adjusted models. No significant interactions were found between alcohol consumption and smoking status for all RA cases or for the seropositive or seronegative RA cases in both cohorts ( P > 0.05 for all comparisons).

In sensitivity analyses using the simple updated alcohol exposure values rather than the cumulative average alcohol consumption values, the association was attenuated, and no significant association was observed (pooled HR for 5.0–9.9 gm of alcohol per day was 0.98 [95% CI 0.77–1.24]). When we repeated the analysis including all the cancer cases, the results were highly consistent. Furthermore, we did not observe nonlinear relationships between alcohol consumption and the risk of all RA, seropositive RA, or seronegative RA. However, due to a limited number of incident RA cases, especially in the NHSII, there may not have been sufficient power to examine the effect of heavy alcohol intake on the risk of RA.

We also conducted separate analyses for seropositive and seronegative RA cases (Table 2 ). Among 580 incident RA cases in the NHS, 365 were seropositive and 215 were seronegative, and among 323 incident RA cases in the NHSII, 213 were seropositive and 110 were seronegative RA cases. For the seropositive RA cases, the pooled multivariable adjusted HR for alcohol use of 5.0–9.9 gm/day compared to no use was 0.69 (95% CI 0.50–0.95), while for seronegative RA cases, no significant associations were found.

The multivariable adjusted HRs of developing RA are shown in Table 2 , categorized according to the levels of alcohol intake. The pooled multivariable adjusted HR for alcohol use of 5.0–9.9 gm/day compared to no use was 0.78 (95% CI 0.61–1.00). We found a nonsignificant 25% decreased risk of developing RA for an alcohol intake of 5.0–9.9 gm/day in the NHS (HR 0.75 [95% CI 0.54–1.03], P = 0.077), but a significant inverse association for alcohol use of ≥10 gm/day in the NHSII (HR 0.48 [95% CI 0.29–0.82], P = 0.007).

The characteristics of the study participants at baseline (1980 in the NHS and 1989 in the NHSII) are shown in Table 1 , categorized according to the level of alcohol intake. Women with higher alcohol intake were more likely to be smokers and oral contraceptive users and to have higher income, lower BMI, and higher level of physical activities and were less likely to be parous and to have ever breastfed for >12 months. In the NHS, 44% of the participants were postmenopausal at baseline, while only 2.3% of the women in the NHSII were.

In this study, with alcohol exposure measured up to 4–6 years prior to RA onset, 580 incident cases of RA were diagnosed among 1.90 million person‐years from 1980 to 2008 in the NHS, and 323 incident RA cases were diagnosed among 1.78 million person‐years from 1989 to 2009 in the NHSII. The age‐adjusted incidence rates of RA were 28, 33, 23, and 34 per 100,000 person‐years in the NHS and 21, 18, 17, and 11 per 100,000 person‐years in the NHSII across increasing levels of alcohol consumption: none, 0.1–4.9 gm/day, 5.0–9.9 gm/day, or ≥10 gm/day, respectively.

DISCUSSION

In this large prospective cohort study, we observed a modest association between moderate alcohol intake and the risk of developing RA. Women who drank 5.0–9.9 gm/day of alcohol (equivalent to 3–5 standard drinks/week) had a 22% reduced risk of developing RA and a 31% reduced risk of developing seropositive RA as compared to women who did not drink any alcohol. Consistent with the primary analysis using total alcohol intake (in grams/day), intake of beer, but not wine or liquor, was associated with reduced risk of RA.

An indication that alcohol consumption may decrease the risk of developing RA and the risk of RA progression has come from several case–control studies (9, 12, 23). Consistent with findings of stronger associations between environmental factors and seropositive RA (5, 7), we found a significant association of moderate alcohol consumption with seropositive RA. Similarly, in a Danish study, individuals who consumed alcohol had an overall lower risk of developing anti–citrullinated protein antibody–positive RA compared to those who did not (9). A dose‐dependent effect was demonstrated in a subsequent analysis of 2 studies, the Epidemiologic Investigation of Rheumatoid Arthritis (EIRA) and the Danish Case–Control Study of Rheumatoid Arthritis (CACORA). Those with the highest consumption (≥5 drinks, or 80 gm of alcohol per week) had a decreased risk of RA on the order of 40–50% compared to those with low‐to‐no consumption (<0.5 gm of alcohol per week). However, case–control studies ascertain alcohol exposure retrospectively, which raises the potential of recall bias.

Early symptoms of RA and use of some medications, such as nonsteroidal antiinflammatory drugs or methotrexate, may cause a person to change his or her behavior with regard to alcohol use and in case–control studies may result in reverse causation bias. One published prospective study found no association between alcohol consumption and risk of RA (24), while a recent cohort study found that moderate consumption of alcohol was associated with a reduced risk of RA, but this study was also limited by its small number of incident cases examined (n = 197) and a short period of followup (13). Moreover, the investigators did not stratify by serologic status in the analysis and used only 2 alcohol assessments, which may have led to misclassification.

Using cumulative average intake to represent long‐term alcohol exposure over a time period as long as 26 years, our prospective analyses confirmed an inverse association between moderate alcohol consumption and the risk of developing RA. We used lagged analysis to eliminate the potential for recall bias and reverse causation bias. To our knowledge, this is the largest prospective study to date, including over 900 incident RA cases, evaluating RA risk in relation to alcohol consumption using repeated measures of alcohol consumption prior to the diagnosis of RA.

A mechanistic basis for a role of alcohol in the etiology of RA has not been well developed. Alcohol is thought to have effects on both the hormonal and immunologic systems, although current knowledge is incomplete and often conflicting. For example, in a study of healthy premenopausal women, alcohol use as low as ∼1 drink/day caused an increase in serum estradiol concentrations of 27–38% (25). Grimaldi and colleagues (26) demonstrated that estrogens play an important role in B cell maturation, selection, and activation, and potentially in the breakdown of immune tolerance.

From an immunologic perspective, several reports have suggested that alcohol intake influences systemic inflammation and inflammatory arthritis (27, 28). Alcohol has been shown to diminish the response to immunogens in animals as well as in humans and to significantly suppress the synthesis of proinflammatory cytokines and chemokines, such as tumor necrosis factor α (TNFα), interleukin‐6 (IL‐6), and IL‐8 both in vivo and in vitro in alveolar macrophages and human blood monocytes (29). Notably, addition of alcohol to the drinking water of mice was recently shown to reduce clinical signs of arthritis as well as joint destruction. The beneficial effects may be mediated by up‐regulation of testosterone production, which in turn, inhibits the activation of NF‐κB, leading to decreased cytokine/chemokine production and decreased chemotactic activity of leukocytes (27).

Using NHSII data, a previous study that included 473 women without RA found that women who consumed 1–2 drinks/drinking day had significantly lower levels of soluble TNF receptor type I (sTNFRI) and sTNFRII, as well as lower levels of C‐reactive protein and IL‐6 compared to nondrinkers (30). We recently found that the moderate alcohol consumption was associated with a reduction in plasma levels of biomarkers of inflammation, including sTNFRII and IL‐6, among women with pre‐RA, where blood was collected up to 12 years prior to the first symptoms of RA, suggesting an effect of alcohol during the asymptomatic phases (31). Therefore, moderate alcohol drinking may reduce inflammation in both the non‐RA population and the cases of preclinical RA. This suggests that alcohol consumption may prevent or delay the process of RA development.

We observed that moderate consumption of beer, but not wine or liquor, was associated with a decreased risk of RA. Similar, though not statistically significant, trends were also found for wine and liquor intake. This may be due to reduced statistical power in the stratified analyses. In sensitivity analyses using the updating alcohol consumption other than cumulative average measures, the association was attenuated. This suggests that the cumulative effect of long‐term moderate alcohol consumption, but not short‐term alcohol consumption, may reduce the risk of developing RA.

The strengths of this study include the large number of incident RA cases, the length of followup, and the detailed prospective and updated assessments of alcohol consumption across different age periods, affording the most comprehensive evaluation of the effect of alcohol consumption throughout a woman's adult life. We studied alcohol consumption and risk of RA in a lagged analysis by excluding the most recent alcohol measure. It is likely that immune changes and early symptoms of RA occur prior to the diagnosis of RA. Lagged analyses address the timing of alcohol exposure prior to the development of RA, reducing the potential for reverse causation bias.

Our study has some limitations. First, given our strict definition of RA, we may have excluded possible RA cases, introducing selection bias. Second, as an observational study, women were not randomly assigned to alcohol use. However, it is unlikely that such a long‐term randomized trial will ever be performed. Third, misclassification of alcohol exposures in this study may result from self reports on the FFQ. In our study, subjects were asked to relate alcohol intake to the previous year in general, which can reflect relatively long‐term consumption and can decrease the effect of short‐term variability. Moreover, we obtained repeated measurements of alcohol consumption during followup and used cumulative average estimates to reduce the within‐subject variation. Fourth, participants in the NHS and NHSII were from different generations of women with heterogeneous characteristics, although consistent results were found from the two cohorts. Finally, the study may have limited power to detect the effect of heavy drinking (such as >15 gm/day and >20 gm/day) and possible nonlinear relationships.

In summary, our study provides a comprehensive assessment of the relationship between alcohol intake and RA risk in terms of timing, quantity, and types of alcohol in 2 large prospective cohorts with detailed information on RA risk factors. We found a modest association between long‐term moderate alcohol consumption over multiple decades and a reduced risk of RA. Our findings have implications for RA prevention and could have large potential public health implications.