Hedström AK, Hillert J, Olsson T, Alfredsson L. Alcohol as a modifiable lifestyle factor affecting multiple sclerosis risk. JAMA Neurology 2014; doi:10.1001/jamaneurol.2013.5858; published online January 6, 2014.
IMPORTANCE Alcohol consumption may be a modifiable lifestyle factor that affects the risk of developing multiple sclerosis (MS). Results of previous studies have been inconsistent.
OBJECTIVE To investigate the possible association of alcohol consumption with the risk of developing MS and to relate the influence of alcohol to the effect of smoking.
DESIGN, SETTING, AND PARTICIPANTS This report is based on 2 case-control studies: Epidemiological Investigation of Multiple Sclerosis (EIMS) included 745 cases and 1761 controls recruited from April 2005 to June 2011, and Genes and Environment in Multiple Sclerosis (GEMS) recruited 5874 cases and 5246 controls between November 2009 and November 2011. All cases fulfilled the McDonald criteria. Both EIMS and GEMS are population-based studies of the Swedish population aged 16 to 70 years. In EIMS, incident cases of MS were recruited via 40 study centers, including all university hospitals in Sweden. In GEMS, prevalent cases were identified from the Swedish national MS registry. In both studies, controls were randomly selected from the national population register, matched by age, sex, and residential area at the time of disease onset.
MAIN OUTCOME AND MEASURE Multiple sclerosis status.
RESULTS There was a dose-dependent inverse association between alcohol consumption and risk of developing MS that was statistically significant in both sexes. In EIMS, women who reported high alcohol consumption had an odds ratio (OR) of 0.6 (95% CI, 0.4-1.0) of developing MS compared with nondrinking women, whereas men with high alcohol consumption had an OR of 0.5 (95% CI, 0.2-1.0) compared with nondrinking men. The OR for the comparison in GEMS was 0.7 (95% CI, 0.6-0.9) for women and 0.7 (95% CI, 0.2-0.9) for men. In both studies, the detrimental effect of smoking was more pronounced among nondrinkers.
CONCLUSIONS AND RELEVANCE Alcohol consumption exhibits a dose-dependent inverse association with MS. Furthermore, alcohol consumption is associated with attenuation of the effect of smoking. Our findings may have relevance for clinical practice because they give no support for advising patients with MS to completely refrain from alcohol.
Multiple sclerosis (MS) is a serious, chronic neurological disease, for which no cure is currently available. It is generally considered to be an autoimmune disease; other such diseases (e.g., lupus erythematosus, rheumatoid arthritis) have shown a relation with alcohol consumption. Thus, the authors reviewed data from two large Swedish studies on MS to determine if there was an association with reported alcohol consumption. Key results showed that in both of the case-control analyses, there was a dose-response inverse relation between alcohol consumption and the risk of developing MS. In comparison with subjects reporting no alcohol intake in the 5- or 10-year period during which the diagnosis of MS was first made, subjects in the highest alcohol consumption group (> 112 g/week, about 9 drinks per week for women; >168 g/week, about 14 drinks per week for men) had 30% to 50% lower risk of developing MS. A variety of potential confounders were included in the analysis, including smoking, education, and SES.
Specific comments by Forum members on the paper: Reviewer Ellison stated: “The strengths of this paper include the large number of cases and, especially, the consistency of results within both groups of subjects. Also, there was a clear dose-response effect noted. It appears that alcohol consumption may attenuate the increase in risk associated with smoking; while the authors state that the interaction for this relation was significant in only one group, there were almost identical ORs in both studies. In the discussion, the authors did a good job of dealing with potential biases that could have affected their results. They also present a good discussion of potential mechanisms by which alcohol could affect immunity and lead to a lower risk of auto-immune diseases.”
Reviewer Waterhouse stated that “The effect seems very strong, and the authors’ comments regarding other auto-immune diseases suggest other interesting avenues of investigation. The observed dose dependency is striking, but because of a limited number of heavy drinkers, the authors could not determine the upper limit of alcohol consumption that may have a beneficial effect on MS. MS is not a common enough disease that these results would lead to general recommendations for people to consume alcohol to prevent the disease; however, it might be important to determine if, for people who already have MS, moderate drinking would affect progression of the disease.”
Forum member Skovenborg agreed with Waterhouse that this was a very well-done study. He added: “The prevalence of multiple sclerosis depends on who you are and where you live. In my region of the world, Scandinavia, the prevalence is around 150 – 163 per 100,000 inhabitants. The most comprehensive review of MS prevalence to date confirmed a statistically significant positive association between MS prevalence and latitude globally. Exceptions to the gradient in the Italian region and northern Scandinavia are likely a result of genetic and behavioural-cultural variations. The persistence of a positive gradient in Europe after adjustment for HLA-DRB1 allele frequencies strongly supports a role for environmental factors which vary with latitude, the most prominent candidates being ultraviolet radiation (UVR)/vitamin D. (Simpson S Jr, Blizzard L, Otahal P, Van der Mei I, Taylor B. Latitude is significantly associated with the prevalence of multiple sclerosis: a meta-analysis. J Neurol Neurosurg Psychiatry 2011;82:1132-41). The association of latitude, vitamin D and alcohol is not obvious.”
Skovenborg continued: “The updated distribution of MS in Europe, showing many exceptions to the previously described north-south gradient, requires more explanation than simply a prevalence-latitude relationship. Prevalence data imply that racial and ethnic differences are important in influencing the worldwide distribution of MS and that its geography must be interpreted in terms of the probable discontinuous distribution of genetic susceptibility alleles, which can however be modified by environment (Rosati G. The prevalence of multiple sclerosis in the world: an update. Neurol Sci 2001;22:117-139). The environmental and genetic determinants of geographic gradients are by no means mutually exclusive, however, and the connection with alcohol intake is not obvious.”
Reviewer Van Velden stated: “Our group has done research at Stellenbosch University on MS, and our results support the findings of this paper. In our study, among 114 patients diagnosed with MS, their disability status was measured using the Expanded Disability Status Scale (EDSS – Kurtzke 1983). We found that the effect of alcohol intake on disability status formed a J-shaped curve, similar to the effect found in cardiovascular disease. The optimal protection for alcohol intake against disability in our study was 1-2 units of alcohol per week.”
Because of several concerns, Forum member de Gaetano believed that the authors may have overstated their results: “The authors could not determine if subjects classified as ‘non-drinkers’ included former drinkers; also, while the estimates of effect were similar between the two studies, in the smaller study only that of the highest alcohol group reached statistical significance. Further, the authors failed to discuss possible anti-inflammatory effects of wine polyphenols, in addition to alcohol.”
Reviewer Thelle stated: “We are still facing the inherent problems with case-control studies in regard to how the controls are selected (and select themselves), even if the authors have done a good job arguing against biases and taken care of confounders. The observed effects, however, are weak and one would like to see more studies on the same issue from other populations, also those with lower MS risk.” Reviewer Ellison points out: “The relative rarity of MS makes it difficult to have an adequate number of cases in a prospective study for definitive results, so we are usually forced to base our opinions on case-control studies. Also, while the statistical significance values of the results are not large, the estimated effects (generally about 30% lower risk of MS among drinkers of moderate or higher amounts of alcohol in comparison with non-drinkers) are rather impressive.”
Mechanisms by which alcohol could reduce the risk of MS: Reviewer Finkel thought this was a well-done study, but wanted to know how secure our assumptions are that MS is an autoimmune disease, and how alcohol may prevent such diseases. Reviewer Estruch commented: “Multiple sclerosis is an autoimmune disease that affects the brain and the spinal cord in which the nerve damage is due to inflammation, demyelization and axonal damage. Since alcoholic beverages exert an anti-inflammatory effect, it seems very logical that moderate drinking could help to prevent the development of the disease and its relapses. In addition, since polyphenols exert a strong anti-inflammatory effect, it seems logical that wine showed a higher protective effect than other alcoholic beverages. I think that the authors should include in the discussion the potential anti-inflammatory effect of the polyphenols in wine. Ethanol by itself has an anti-inflammatory effect but, due to its polyphenolic content, that of red wine is greater (Chiva-Blanch et al, Differential effects of polyphenols and alcohol of red wine on the expression of adhesion molecules and inflammatory cytokines related to atherosclerosis: a randomized clinical trial. Am J Clin Nutr 2012; 95:326-334).”
Forum member Ursini wrote: “This paper, the comments from several members of the Forum, and the pertinent previous studies quoted, nicely illustrate the most welcome convergence between epidemiology and basic science in identifying an anti-inflammatory effect of ethanol and (even more) of wine. Considering inflammation a ‘reaction to injury,’ it is easily understandable that too much reaction produces a pathological outcome. While the reaction to an injury (or a stress in general) is activated by NFkB in a more electrophilic (oxidant) environment, the counteracting (switching off) reaction is supported by nucleophilic system expressed under the control of Keap1/Nrf2. Notably, the latter is activated by oxidants (hormetic effect) or oxidized antioxidants (para-hormetic effect). Within this (simplified) scenario there is room for accounting the series of effects of ethanol and wine and the nice convergence of epidemiological and basic biomedicine evidence.”
Alcohol, uric acid levels, and MS; Beverage-specific effects: Forum member Skovenborg raised another question regarding the etiology of MS: “Several studies indicate that patients with multiple sclerosis have low serum levels of the endogenous antioxidant uric acid (UA), although it has not been established whether UA is primarily deficient or secondarily reduced due to its peroxynitrite scavenging activity. Sotgui et al measured serum urate levels in 124 MS patients and 124 age- and sex-matched controls with other neurological diseases (Sotgiu S, Pugliatti M, Sanna A, Sotgiu A, Fois ML, Arru G, Rosati G. Serum uric acid and multiple sclerosis. Neurol Sci 2002;23:183-188). Those investigators also compared UA levels when MS patients were stratified according to disease activity (by means of clinical examination and MRI), duration, disability, and course. MS patients had significantly lower serum urate levels than controls (p= 0.001). However, UA levels did not significantly correlate with disease activity, duration, disability or course. The results favour the view that reduced UA in MS is a primary, constitutive loss of protection against oxidative agents.”
Forum member Zhang also has studied alcohol intake and uric acid levels. He stated: “In terms of the effects of the consumption of different alcoholic beverages on levels of serum uric acid, the findings seem to be conflicting, at least findings from studies in the USA. Some investigators reported that moderate wine drinking was not associated with high levels of UA. For example, Choi et al (Choi HK, et al. Beer, liquor, and wine consumption and serum uric acid level: the Third National Health and Nutrition Examination Survey. Arthritis Rheum 2004;51:1023–1029) described the associations of different alcoholic beverages with UA. They concluded that both beer and liquor (spirits) intake were associated with increases in UA, while moderate intake of wine was not.
“Also, results from the Coronary Artery Risk Development in Young Adults (CARDIA) cohort showed that an association between higher UA concentrations and greater beer intake was consistent and pronounced among women, but also present in men. An association between greater spirits intake and higher UA concentrations was only seen for men at the year 20 evaluation. Wine intake was not associated with UA in either sex (Gaffo et al. Serum urate and its relationship with alcoholic beverage intake in men and women: findings from the Coronary Artery Risk Development in Young Adults (CARDIA) cohort. Ann Rheum Dis 2010;69:1965-1970). I personally believe that consumption of any type of alcoholic beverage would increase levels of UA and be associated with an increased risk of gout attacks. However, to assess whether an effect of alcohol on the risk of MS was mediated by UA, one would have to perform a mediation analysis to assess the direct and indirect effects of alcohol. It seems beyond the scope of the current manuscript to verify whether the effect of alcohol on the risk of MS is partly mediated by UA, especially to speculate which type of alcoholic beverage has stronger effect on UA or on MS.”
A new member of the Forum, Professor Mladen Boban, has studied the association of uric acid and the antioxidant effects of wine and alcohol. A review by Boban and Modun (Boban M, Modun D. Uric acid and antioxidant effects of wine. Croat Med J 2010;51:16-22; doi: 10.3325/cmj.2010.51.16) concludes: “Acute plasma urate increase after wine consumption is not likely to cause detrimental effects to human health associated with chronic hyperuricemia. Quite the opposite if wine is consumed with meals; the timed elevation of plasma uric acid may significantly contribute to the wine’s protective effects against postprandial oxidative stress.”
In response to the present paper, Reviewer Boban stated: “I have several concerns about this paper. In their efforts to explain possible mechanisms by which alcohol affects risk of MS, surprisingly the authors did not mention a possible role of uric acid (UA). There are numerous observations and experimental data indicating a protective role of UA in different neurodegenerative diseases, including MS. On the other side it is well established that alcohol intake may result in elevated plasma UA levels. Indeed, intake of a moderate amount of wine (in contrast to spirits) is associated with moderate and transient elevation in plasma UA. That phenomenon accounts for approximately 60% of the increase in plasma antioxidant capacity that is observed after wine intake. The increase in plasma UA following wine intake roughly overlaps with the rise of postprandial oxidative stress markers. I personally believe that this phenomenon is largely included in beneficial effects of wine when taken with a meal. I do not know if this argument can be related to the pathophysiology of MS. In my opinion it deserves to be mentioned as one possible mechanism. Moreover, the idea of an association of wine and UA is in line with the results of this study that indicate that wine might have greater effects than other alcoholic beverages; this possible difference was not commented on by the authors. Although extensive questionnaires were used to collect information from the participants in the study, there are no data on drinking pattern, which could also have an impact on the results of the paper. Other than this, I find the article well written and discussed (especially the bias issue).”
Previous research has shown that alcohol consumption may be associated with a reduced risk of rheumatoid arthritis, lupus erythematosus, and other autoimmune diseases. There have also been reports that alcohol may lower the risk of multiple sclerosis (MS). The authors of the present paper have used data from two large Swedish case-control studies of MS to evaluate the relation of alcohol consumption to MS. Key results showed that in both of the case-control analyses, there was a dose-response inverse relation between alcohol consumption and the risk of developing MS. In comparison with subjects reporting no alcohol intake in the 5- or 10-year period during which the diagnosis of MS was first made, subjects in the highest alcohol consumption group (> 112 g/week, about 9 drinks per week for women; >168 g/week, about 14 drinks per week for men) had 30% to 50% lower risk of developing MS. A variety of potential confounders were included in the analysis, including smoking, education, and SES.
Forum members who reviewed this paper all thought that it reflected a well-done analysis. The main concerns were that, as are most studies of uncommon diseases, these were case-control comparisons (which may be associated with recall bias, reverse causation, and other potential confounding variables), and that the investigators could not determine if the “non-drinkers,” their referent group, were lifetime abstainers or former drinkers. Also, while earlier research has shown that the polyphenols in wine may provide protection beyond that of alcohol in combating inflammation, there were no data on beverage-specific results.
In general, however, Forum members welcomed this contribution to our knowledge on the subject, and thought that the authors did a good job in discussing the strengths and weaknesses of their study. There was a brief discussion of potential mechanisms by which alcoholic beverages could lower the risk of MS, but no discussion of the potential added effects related to polyphenolic substances. Forum members also thought that serum uric acid (which may increase with alcohol consumption) could play a role in an autoimmune disease, but this was not discussed by the authors.
Based on previous research and the results of this paper, it is probable that moderate alcohol intake, especially of wine, may lower the risk of developing MS, a neurological disease for which no cure is currently available. While MS is too uncommon a condition to use these findings to recommend alcohol consumption for the prevention of the disease, it would be useful if future research could help determine if, for subjects who already have MS, moderate drinking may affect the progression of their disease.
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Comments on this critique by the International Scientific Forum on Alcohol Research were provided by the following members of the Forum:
Mladen Boban, MD, PhD, Professor and Head of the Department of Pharmacology, University of Split School of Medicine, Croatia
Giovanni de Gaetano, MD, PhD, Department of Epidemiology and Prevention, IRCCS Istituto Neurologico Mediterraneo NEUROMED, Pozzilli, Italy
R. Curtis Ellison, MD, Section of Preventive Medicine & Epidemiology, Boston University School of Medicine, Boston, MA, USA
Ramon Estruch, MD, PhD, Department of Medicine, University of Barcelona, Spain
Harvey Finkel, MD, Hematology/Oncology, Boston University Medical Center, Boston, MA, USA
Dominique Lanzmann-Petithory,MD, PhD, Nutrition/Cardiology, Praticien Hospitalier Hôpital Emile Roux, Paris, France
Ulrich Keil, MD, PhD, Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany
Erik Skovenborg, MD, Scandinavian Medical Alcohol Board, Practitioner, Aarhus, Denmark
Creina Stockley, PhD, MBA, Clinical Pharmacology, Health and Regulatory Information Manager, Australian Wine Research Institute, Glen Osmond, South Australia, Australia
Arne Svilaas, MD, PhD, general practice and lipidology, Oslo University Hospital, Oslo, Norway
Pierre-Louis Teissedre, PhD, Faculty of Oenology – ISVV, University Victor Segalen Bordeaux 2, Bordeaux, France
Dag S. Thelle, MD, PhD, Senior Professor of Cardiovascular Epidemiology and Prevention, University of Gothenburg, Sweden; Senior Professor of Quantitative Medicine at the University of Oslo, Norway
Fulvio Ursini, MD, Dept. of Biological Chemistry, University of Padova, Padova, Italy
David Van Velden, MD, Dept. of Pathology, Stellenbosch University, Stellenbosch, South Africa
Andrew L. Waterhouse, PhD, Marvin Sands Professor, Department of Viticulture and Enology, University of California, Davis; Davis, CA, USA
Yuqing Zhang, MD, DSc, Epidemiology, Boston University School of Medicine, Boston, MA, USA