Critique 084: Moderate drinking lowers risk of developing rheumatoid arthritis in women — 17 July 2012

Di Giuseppe D, Alfredsson L, Bottai M, Askling J, Wolk A.  Long term alcohol intake and risk of rheumatoid arthritis in women: a population based cohort study.  BMJ 2012;345:e4230 doi: 10.1136/bmj.e4230 (Published 10 July 2012)

Authors’ Abstract

Objective To analyse the association between alcohol intake and incidence of rheumatoid arthritis in women.

Design Prospective cohort study with repeated measurements.

Setting The Swedish Mammography Cohort, a population based cohort from central Sweden.

Participants 34,141 women born between 1914 and 1948, followed up from 1 January 2003 to 31 December 2009.

Main outcome measures Newly diagnosed cases of rheumatoid arthritis identified by linkage with two Swedish national registers. Data on alcohol consumption were collected in 1987 and 1997.

Results During the follow-up period (226,032 person years), 197 incident cases of rheumatoid arthritis were identified. There was a statistically significant 37% decrease in risk of rheumatoid arthritis among women who drank >4 glasses of alcohol (1 glass = 15 g of ethanol) per week compared with women who drank <1 glass per week or who never drank alcohol (relative risk 0.63 (95% confidence interval 0.42 to 0.96), P=0.04). Drinking of all types of alcohol (beer, wine, and liquor) was non-significantly inversely associated with the risk of rheumatoid arthritis.  Analysis of long term alcohol consumption showed that women who reported drinking >3 glasses of alcohol per week in both 1987 and 1997 had a 52% decreased risk of rheumatoid arthritis compared with those who never drank (relative risk 0.48 (0.24 to 0.98)).

Conclusion Moderate consumption of alcohol is associated with reduced risk of rheumatoid arthritis.

Forum Comments

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic, destructive, debilitating arthritis that affects ~1% of the adult population.¹  A number of case-control studies have shown that moderate drinking is associated with lower occurrence and severity of RA.^2,3   However, few prospective cohort studies have an adequate number of cases to test the association of alcohol consumption with the development of RA. 

This prospective study is based on a large cohort of women in Sweden, of which 197 had a diagnosis of RA made during follow up.  The study suggests that drinkers of all types of alcohol have a lower risk of developing RA than do never drinkers. 

Mechanism of alcohol’s effects:  Forum members agree with the authors that down regulation of the immune response and a decrease in pro-inflammatory cytokines is the probable mechanism of alcohol’s effect on the risk of RA.  An especially important previous study, based on 174 incident RA cases in the Nurses’ Health Study, included measurements obtained from stored blood collected 1–16 years prior to RA symptoms (preclinical RA).⁴  The results of that study showed that among subjects who subsequently developed RA, those who reported daily alcohol consumption had lower levels of several key markers of inflammation than did non-drinkers.  Their findings support the conclusions of the present study of a lower risk of developing RA for moderate drinkers, in comparison with non-drinkers.

Alcohol and inflammation:  As stated by a Forum reviewer: “This paper brings a further contribution to a basic concept recently emerging from biomedical literature.  Apparently, ethanol produces an anti-inflammatory effect.  It is known that ethanol produces electrophiles.  These are unquestionably toxic at high doses, but at low doses activate the defense system.

“The excess of inflammation produces different pathologies such as autoimmunity, sepsis, cancer, and metabolic disorders.⁵  We know that inflammation operates through the formation of oxidants (electrophiles) and is controlled by reductants (nucleophiles).  Activating the electrophile response element is the physiological mechanism that dampens inflammatory signals and increases antioxidant defense.”  He concludes: “I am convinced that the molecular mechanism of hormesis is the key factor for understanding why ethanol produces the series of protective effects we have been observing for many years.  The leitmotif is the control of the excess of inflammation (i.e., reaction to injury).”

Alcohol content of a standard “drink”:  States another Forum reviewer:  “This is an excellent study with a suitable cohort of moderate drinking Swedish women, a convincing validation of the effects of long term intake of alcohol on the risk of RA.  We note the rather high alcohol content of the defined “drink,” 15 grams of alcohol, in the present analysis. (The intake of 4 drinks would amount to almost 8 British “drinks” of 8 grams of alcohol.)  It is remarkable that the study was done in Sweden, a country with a long history of prohibition and strict alcohol control, where even today alcohol may only be bought in special stores.  The Swedish medical community has for many years nurtured strong bias against claims of health benefits of alcohol – a fact that in my opinion augments the credibility of the results of this study.”

Added another Forum reviewer: “At least 4 drinks of 15 grams each per week would correspond to the equivalent of almost 10 g of alcohol per day, that is the average amount of alcohol previously reported to be associated with the maximal beneficial effect of alcohol against all-cause mortality.⁶  In that meta-analysis the beneficial effect of alcohol disappeared in women at lower amounts than in men (18 vs 38 grams/day).  Attention should therefore be made to the fact that the Swedish cohort was only composed of women.”

Need for further studies on this topic:  It must be pointed out that the number of subjects with RA, even in this very large database, was quite small.  Thus, it will be important that further large-scale studies report on the association between alcohol and the development of RA.  Based on data currently available, however, there is considerable evidence that alcohol consumption may lower the risk and severity of RA, probably through an anti-inflammatory effect.

References

1.  Alamanos Y, Drosos AA.  Epidemiology of adult rheumatoid arthritis.  Autoimmun Rev 2005;4:130–136.

2.  Kallberg H, Jacobsen S, Bengtsson C, Pedersen M, Padyukov L, Garred P, et al.  Alcohol consumption is associated with decreased risk of rheumatoid arthritis: results from two Scandinavian case-control studies. Ann Rheum Dis 2009;68:222–227.

3.  Nissen MJ, Gabay C, Scherer A, Finckh A, for the Swiss Clinical Quality Management Project in Rheumatoid Arthritis. The effect of alcohol on radiographic progression in rheumatoid arthritis.  Arthritis Rheum 2010;62:1265–1272.

4.  Lu B, Solomon DH, Costenbader KH, Keenan BT, Chibnik LB, Karlson EW.    Alcohol consumption and markers of inflammation in women with preclinical rheumatoid arthritis.  Arthritis Rheum 2010;62:3554-9. doi: 10.1002/art.27739.

5.  Medzhitov R.  Origin and physiological roles of inflammation.  Nature 2008;454:428-435.

6.  Di Castelnuovo A, Costanzo S, Bagnardi V, Donati MB, Iacoviello L, de Gaetano G.  Alcohol dosing and total mortality in men and women: an updated meta-analysis of 34 prospective studies.  Arch Intern Med 2006;166:2437-2445.

Forum Summary

A follow-up study of more than 34,000 women in Sweden has shown that moderate drinkers, in comparison with abstainers, were at significantly lower risk of developing rheumatoid arthritis (RA), an often serious and disabling type of arthritis.  RA is known to relate to inflammation, and it is postulated that this is blocked to some degree by the consumption of alcohol.  In this study, women who consumed at least 4 drinks per week (with a drink being defined as containing 15 grams of alcohol) had 37% lower risk of developing RA than subjects reporting never drinking or consuming less than 1 drink/week. 

This large study is important as few prospective studies are of adequate size to have sufficient cases of RA to evaluate factors related to its development.  The study supports previous research showing a lower risk of developing RA, or milder severity of the disease, among moderate drinkers than among abstainers. 

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Comments in this critique by the International Scientific Forum on Alcohol Research were provided by the following members:

 Fulvio Ursini, MD, Dept. of Biological Chemistry, University of Padova, Padova, Italy

Erik Skovenborg, MD, Scandinavian Medical Alcohol Board, Practitioner, Aarhus, Denmark

Yuqing Zhang, MD, DSc, Epidemiology, Boston University School of Medicine, Boston, MA, USA

Harvey Finkel, MD, Hematology/Oncology, Boston University Medical Center, Boston, MA, USA

Arne Svilaas, MD, PhD, general practice and lipidology, Oslo University Hospital, Oslo, Norway

R. Curtis Ellison, MD, Section of Preventive Medicine & Epidemiology, Boston University School of Medicine, Boston, MA, USA

Creina Stockley, MSc, MBA, Clinical Pharmacology, Health and Regulatory Information Manager, Australian Wine Research Institute, Glen Osmond, South Australia, Australia 

David Van Velden, MD, Dept. of Pathology, Stellenbosch University, Stellenbosch, South Africa

Giovanni de Gaetano, MD, PhD, Research Laboratories, Catholic University, Campobasso, Italy