Alcohol intake in rheumatic disease: good or bad?

N. Sofat and A. Keat

Northwick Park and St Marks' Hospital, Watford Road, Harrow, Middlesex HA1 3UJ, UK


    Introduction
 Top
 Introduction
 References
 
Alcohol is a major cause of morbidity and mortality. In 1983 the World Health Organization (WHO) declared alcohol-related problems to be among the world's major health concerns [1]. Recent developments in basic science and clinical research have led to an improved understanding of the mechanisms of the effects of alcohol on musculoskeletal diseases. These vary from the site of action of the cytokine–hormone axis on the development of osteoporosis to the variety of epidemiological studies of alcohol in diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and seronegative arthropathies.

Alcohol might be beneficial in rheumatic disease. There are examples of reduced alcohol-related deaths in RA and SLE [26]. However, acute and chronic alcohol intake is known to result in myopathies, which may lead to falls and consequent fractures [717]. There is a body of data emerging about the link between vertebral osteoporotic fractures and alcohol, particularly in men [7]. Alcohol has also been implicated in the increased death rate from violence and accident-related deaths in ankylosing spondylitis [18]. This review will discuss recent data obtained regarding alcohol intake in the above conditions.

Alcohol can have harmful effects on the musculoskeletal system. It is associated with osteoporosis and an increased incidence of fractures [79]. The strongest link is seen in spinal osteoporosis, where alcoholic men are most at risk. In one study, 38% of mobile chronic alcoholics demonstrated radiological evidence of spinal and/or forearm bone loss [8]. Riggs et al. found the risk of spinal osteoporosis with vertebral fracture was significantly greater among men who drank alcoholic beverages (relative risk=2.4) than those who did not [7]. The risk increased by a factor of 1.007 for each ounce year of cumulative exposure. In this study, a multiple logistic model was used to show a multiplied risk in drinkers who also smoked. An Australian study also found that drinkers had diminished bone formation rates [8]. However, factors such as gonadal status, body mass and physical activity may also alter osteoblast function in these patients.

In women, there are conflicting data, particularly regarding ethanol use and spinal osteoporosis. In the European Vertebral Osteoporosis Study, alcohol consumption appeared to reduce the risk of vertebral fractures in women who consumed alcohol more than five days a week [10, 11]. Others have found reduced bone formation rates in women with established alcoholic liver disease [8]. The conflicting results may be attributed to varying doses of alcohol intake in the two studies. However, the risk factors of late menarche, early menopause, a low dairy product consumption, low physical activity and family history of hip fracture do appear to be stronger predictors of vertebral fracture in women [12].

The mechanism by which ethanol promotes bone loss in both men and women is not fully understood. Some work has proposed that ethanol promotes osteoporosis through the alteration of production and resorption pathways of bone remodelling. Osteoblasts derive from the mesenchymal lineage marrow stroma and osteoclasts from the haemopoietic lineage [19]. Ethanol inhibits proliferation of human osteoblasts [20]. In one study, ethanol increased bone resorption in rat trabecular bone [21], suggesting that the osteoclastic phase is also affected by ethanol.

The development of osteoclasts from their progenitors is dependent on stromal–osteoblastic cells, which are a major source of cytokines that are critical in osteoclastogenesis. In vitro studies using human osteoblasts show that cytokine mediators include interleukin (IL)-1{alpha} (IL-1{alpha}), tumour necrosis factor {alpha} (TNF-{alpha}), IL-6 and IL-11 [22]. In humans, sex steroids [19, 23] regulate IL-6 production by stromal-osteoblastic cells, including the response of bone marrow cells to this cytokine and IL-11. The production of IL-6 by cultured bone marrow stromal and osteoblastic cell lines is inhibited by oestrogens [19]. Others have not found a regulatory effect of 17ß-oestradiol in osteoblast cell preparations stimulated with IL-1b and TNF-{alpha} [24]. The inhibitory effect of oestrogen on IL-6 production is mediated by inhibition of IL-6 gene transcription through an oestrogen receptor-mediated effect on the transcriptional activity of an identified promoter sequence [25].

Inhibition of sex steroids, such as is seen in the low serum free testosterone concentration in male drinkers [9], may affect osteoclast activity [19, 23]. Androgens have already been shown to have an effect on IL-6 transcription, which is similar to oestrogen receptor-mediated effects, by acting through androgen-specific receptors [26]. Furthermore, in a study using IL-6 knockout mice, Dai et al. [27] found that mice that produced IL-6 and were fed ethanol for 4 months had reduced bone mineral density and cancellous bone formation compared with IL-6 knockouts, which had no change in these parameters with ethanol. Ethanol may therefore achieve its effect by inducing bone loss through IL-6 mediation. They proposed that this process may occur by IL-6 inducing increased receptor activation of NF{kappa}B ligand messenger RNA expression in IL-6 mice, promoting granulocyte–macrophage colony-forming units and osteoclastogenesis.

Studies in mice with oophorectomies show that osteoclast formation increases in response to IL-6 or the combination of the soluble IL-6 receptor and IL-11 in bone marrow cultures [28]. These findings suggest that osteoclast precursors have an enhanced response to IL-6 and IL-11 in oestrogen-deficient states, which correlates with clinical scenarios. Furthermore, in mice that have undergone orchidectomy, there is increased replication of granulocyte–macrophage colony-forming units with increased formation of osteoclasts [29]. These effects are prevented by testosterone or IL-6-neutralizing antibody [26]. It follows that the bone loss occurring through loss of gonadal function in both sexes may be mediated in both sexes through mechanisms involving IL-6.

The results from the studies described above show that there is clearly a complex interaction between ethanol use, sex hormones, cytokines and the osteoblastic and osteoclastic processes that contribute to osteoporosis in susceptible individuals.

Excessive alcohol intake can lead to myopathies, which could lead to increased susceptibility to falls, possibly resulting in osteoporotic fractures, as described above. However, alcohol-induced myopathies themselves can exist in acute and chronic forms. They are underdiagnosed and undertreated [30]. Three main types have been identified. Type 1 is subclinical and is only detected by elevated serum muscle enzyme levels [31]. Type 2 is an acute form with variable severity. There is often gross elevation of serum creatine kinase with varying degrees of myoglobinuria, consistent with rhabdomyolysis. Patients complain of muscle pain and often demonstrate weakness [32]. Type 3 is the commonest form, taking weeks or months to develop. Symptoms of weakness are more common than those of pain. Muscle biopsy shows predominant atrophy of type II fibres [33] on a background of diffuse muscle atrophy.

Shoulder and pelvic girdle muscles are most often affected. The serum creatine kinase concentrations are only mildly elevated and rhabdomyolysis does not occur. Abstinence from alcohol usually results in improvement.

More rarely, an eosinophilic myositis associated with alcohol has been described by a few authors [13, 14]. Eosinophilic infiltration was confirmed on muscle biopsy of these patients. The presentation varied from subacute symmetrical proximal weakness to local inflammatory swelling, often in the lower limbs.

In acute muscle injuries such as are seen in rhabdomyolysis, alcohol accounts for at least 20% of cases [32]. Ethanol triggers muscle necrosis, resulting in derangement of oxidative or glycolytic energy production and ATP depletion.

Animal and human studies have shown that chronic alcohol use results in negative nitrogen balance resulting from net catabolism of skeletal muscle proteins [15]. A prolonged imbalance of protein metabolism leads to the erosion of lean body mass and the proximal myopathy seen in alcoholics [16, 17].

Although alcohol affects all muscle groups to some extent, the fast-twitch type-II fibres appear to be particularly vulnerable [16, 17]. The rate of protein synthesis in skeletal muscle has been examined by stimulating alcohol intoxication, showing that the rate of protein synthesis was reduced in humans [15]. Chronic alcohol feeding in rats has also demonstrated a reduction in protein synthesis in skeletal muscle [34]. In the same study, chronic alcohol consumption was found to produce a relatively rapid and large decline in the amount of total RNA in rat skeletal muscle.

Fewer studies in humans have aimed to analyse the behaviour of muscle fibres in alcoholics. Estruch and colleagues studied 30 chronic alcoholics in a 5 year study [35]. They found that the mean muscle strength of abstaining alcoholics increased but was weaker than that of controls, suggesting that although some recovery can occur, an element of irreversibility from necrotic muscle fibres also exists.

Most studies in RA have shown a reduced incidence of alcohol-related deaths [24]. The mechanism of this effect is not well understood: it has been proposed that alcohol directly protects from RA or that subjects reduce their alcohol intake after developing RA. In the first theory, some have proposed that rheumatoid patients use alcohol to diminish joint pain [36]. The second theory seems more likely, as patients are usually warned to reduce alcohol intake with non-steroidal anti-inflammatory drugs (NSAIDs) and second-line drugs. Similarly, in two large studies of patients with SLE, there was an inverse association between alcohol consumption and SLE [5, 6]. Possible explanations of the findings of these two studies may be from post-diagnosis changes in ethanol intake, or patients taking advice from medical staff about reducing their intake. The cardioprotective effects of moderate alcohol intake are already recognized [18]. Whether alcohol exerts a cardioprotective effect in SLE remains unclear, although it is an issue worth exploring.

In other rheumatic diseases, such as ankylosing spondylitis, alcohol has also been shown to have a detrimental effect. In a study of 71 subjects with the disease, their lifespan was 6–8 yr shorter than that of the population as a whole [37]. There was a surplus of deaths from accidents and violence. Alcohol was found to be a factor in most of these deaths.

Alcohol also requires consideration in some of the treatments used for rheumatic diseases. Most guidelines recommend abstention from alcohol with the use of certain disease-modifying therapy. The most notable example is methotrexate. The risk of serious adverse hepatotoxicity is increased with concomitant alcohol intake [38]. The link of adverse reactions with other disease-modifying drugs is less well recognized, but certainly any of the commonly used drugs which can cause deranged liver function, e.g. sulphasalazine and azathioprine, should be used with great caution in patients with known alcoholic liver disease. In these cases, knowledge of baseline liver function tests is a necessity if alcohol abuse is suspected. In difficult cases a liver biopsy may be necessary to decide on the merits of commencing disease-modifying drugs. The use of NSAIDs in patients with known high alcohol intake is also undesirable, especially in the presence of peptic ulcer disease, as the presence of these two factors would potentially increase the risk of gastrointestinal bleeding.

In this review we have looked at the beneficial and detrimental effects of alcohol on rheumatic disease based on recent clinical studies and basic science information. Future studies are clearly required to expand on recent findings. In the field of alcohol and bone density, future studies are needed to elucidate the effect of different alcohol doses on bone mineral density. Further basic research will help define the mechanisms of the effects of cytokines and growth factors on both sexes in bone remodelling at the cellular level. Finding the answers to these questions will help to determine the degree of risk for the wide range of alcohol use seen in society. In addition, levels of alcohol consumption compatible with bone health need to be determined. The epidemiological studies performed so far show reduced associations of alcohol use in RA and SLE, with a strong association between alcohol, mortality and ankylosing spondylitis. The causes of these links will require further studies to improve our understanding of the mechanisms involved. As a result of such increased understanding, we may in the future be further able to apply our increased knowledge of these processes to improve patient care.


    Notes
 
Correspondence to: A. Keat. Back


    References
 Top
 Introduction
 References
 

  1. Jernigan DH, Monteiro M, Room R, Saxena S. Towards a global alcohol policy: alcohol, public health and the role of WHO. Bull World Health Org2000;78:491–9.[ISI][Medline]
  2. Myllykangas-Luosujarvi R, Aho K, Kautiainen H, Hakala M. Reduced incidence of alcohol related deaths in subjects with rheumatoid arthritis. Ann Rheum Dis2000;59:75–6.[Abstract/Free Full Text]
  3. Voigt LF, Koepsell TD, Nelson JL, Dugowson CE, Daling JR. Smoking, obesity, alcohol consumption and the risk of rheumatoid arthritis. Epidemiology1994;5:525–32.[ISI][Medline]
  4. Aho K, Heloivaara M. Alcohol, androgens and arthritis. Ann Rheum Dis1993;52:897.[ISI][Medline]
  5. Nagata C, Fujita S, Iwata H et al. Systemic lupus erythematosis: A case-control epidemiologic study in Japan. Int J Dermatol1995;34:333–7.[ISI][Medline]
  6. Hardy CJ, Palmer BP, Muir KR, Sutton AJ, Powell RJ. Smoking history, alcohol consumption and SLE: A case-control study. Ann Rheum Dis1998;57:451–5.[Abstract/Free Full Text]
  7. Seeman E, Melton J, O'Fallon M, Riggs BL. Risk factors for spinal osteoporosis in men. Am J Med1983;75:977–83.[ISI][Medline]
  8. Diamond T, Stiel D, Lurier M, Wilkinson M, Posen S. Ethanol reduces bone formation and may cause osteoporosis. Am J Med1989;86:282–8.[ISI][Medline]
  9. Spencer H, Rubio N, Rubio E, Indreika M, Seitan A. Chronic alcoholism: frequently overlooked cause of osteoporosis in men. Am J Med1986;80:393–7.[ISI][Medline]
  10. O'Neill TW, Silman AJ, Diaz MN, Cooper C, Kanis J, Felsenberg D. European Vertebral Osteoporosis Study Group. Influence of hormonal and reproductive factors on risk of vertebral deformity in European women. Osteoporosis Int1997;7:72–8.[ISI][Medline]
  11. Diaz MN, O'Neill TW, Silman AJ. European Vertebral Osteoporosis Study Group. The influence of alcohol consumption in the risk of vertebral deformity. Osteoporosis Int1997;7:65–71.[ISI][Medline]
  12. Lunt M, Felsenberg D, Reeve J et al. Bone density variation and its effects on risk of vertebral deformity in men and women in studies in thirteen European centers: the EVOS Study. J Bone Miner Res1997;12:1883–94.[ISI][Medline]
  13. Walsh JC, Conomy AB. The effect of ethyl alcohol on striated muscle: Some clinical and pathological observations. Aust NZ J Med1997;7:485–90.
  14. Kamm MA, Dennett X, Byrne E. Relapsing eosinophilic myositis. A cause of pseudothrombophlebitis in an alcoholic. J Rheumatol1987;14:831–4.[ISI][Medline]
  15. Preedy VR, Peters TJ, Patel VB, Miell JP. Chronic alcoholic myopathy: transcription and translational alterations. FASEB J1994;8:1146–51.[Abstract/Free Full Text]
  16. Martin F, Ward K, Slavin G, Levi J, Peters TJ. Alcoholic skeletal myopathy, a clinical and pathological study. Q J Med1985;55:233–51.[Medline]
  17. Trounce L, Byrne X, Dennett X, Santamaria J, Doery J, Pappard R. Chronic alcohol proximal wasting: physiological, morphological and biochemical studies in skeletal muscle. Aust NZ J Med1987;17:413–9.[ISI][Medline]
  18. Figuerdo VM. The effects of alcohol on the heart—detrimental or beneficial? Postgrad Med1997;101:165.
  19. Girasole G, Jilka RL, Passeri G et al. 17ß-Estradiol inhibits interleukin-6 production by bone marrow-derived stromal cells and osteoblasts in vitro: a potential mechanism for the antiosteoporotic effect of estrogens. J Clin Invest1992;89:883–91.[ISI][Medline]
  20. Friday KE, Howard GA. Ethanol inhibits human bone cell proliferation and function in vitro. Metabolism1991;40:562–5.[ISI][Medline]
  21. Baran DT, Teitelbaum SL, Bergfeld MA, Parker G, Cruvant EM, Avioli LV. Effect of alcohol ingestion on bone and mineral metabolism in rats. Am J Physiol1980;238:E507–10.[Abstract/Free Full Text]
  22. Manolagas SC. Role of cytokines in bone resorption. Bone1995;17(Suppl.):635–75.
  23. Manolagas SC, Jilka RL. Bone marrow, cytokines and bone remodelling. Emerging insights into the pathophysiology of osteoporosis. N Engl J Med1995;332:305–11.[Free Full Text]
  24. Chaudary LR, Spelsberg TC, Riggs BL. Production of various cytokines by normal human osteoblast-like cells in response to interleukin-1b and tumor necrosis factor-a: lack of regulation by 17ß oestradiol. Endocrinology1992;130:2528–34.[Abstract]
  25. Pottratz S, Bellido T, Mocharla H, Crabb D, Manolagas SC. 17B-estradiol inhibits expression of human interleukin-6 promoter-reporter constructs by a receptor-dependent mechanism. J Clin Invest1994;93:944–50.[ISI][Medline]
  26. Bellido T, Girasole G, Jilka RL, Crabb D, Manolagas SC. Demonstration of androgen receptors in bone marrow stromal cells and their role in the regulation of transcription from the human interleukin-6 gene promoter [abstract]. J Bone Miner Res1993;(Suppl. 1):S131.
  27. Dai J, Lin D, Zhang J et al. Chronic alcohol ingestion induces osteoclastogenesis and bone loss through IL-6 in mice. J Clin Invest2000;106:887–95.[Abstract/Free Full Text]
  28. Jilka RL, Girasole G, Passeri G, Munshi M, Howe N, Manolagas SC. Estrogen deficiency induces sensitivity of the osteoclastic process to IL-6 [abstract]. J Bone Miner Res1994;9(Suppl. 1):S143.
  29. Girasole G, Passeri G, Knutson S, Manolagas SC, Jilka RL. Upregulation of osteoclastogenic potential of the marrow is induced by orchidectomy and is reversed by testosterone replacement in the mouse. [abstract]. J Bone Miner Res1992;7(Suppl.):S96.
  30. Urbano-Marquez A, Estruch R, Navarro-Lopez F. The effects of alcoholism on skeletal and cardiac muscle. N Engl J Med1989;320:409–15.[Abstract]
  31. Perkoff GT. Alcoholic myopathy. Annu Rev Med1971;22:125–32.[ISI][Medline]
  32. Haller RG, Knochel JP. Skeletal muscle disease in alcoholism. Med Clin N Am1984;68:91–103.[ISI][Medline]
  33. Charness ME, Simon RP, Greenberg DA. Ethanol and the nervous system. N Engl J Med1989;321:442–54.[ISI][Medline]
  34. Preedy VR, Peters VJ. Changes in protein, RNA, DNA and rates of protein synthesis in muscle-containing tissues in the mature rat in response to ethanol feeding: a comparative study of heart, small intestine and gastrocnemius muscle. Alcohol Alcohol1990;25:489–98.[ISI][Medline]
  35. Estruch R, Sacanella E, Fernandez-Sola J, Nicolas JM, Rubin E, Urbano-Marquez A. Natural history of alcoholic myopathy: A 5-year study. Alcohol Clin Exp Res1998;22:2023–8.[ISI][Medline]
  36. Bradlow A, Mowat AG. Alcohol consumption in arthritis patients: Clinical and laboratory studies. Ann Rheum Dis1985;44:163–8.[Abstract]
  37. Myllykangas-Luosujarvi R, Aho K, Lehtinen K, Kautiainen H, Hakala M. Increased incidence of alcohol-related deaths from accidents and violence in subjects with ankylosing spondylitis. Br J Rheumatol1998;37:688–90.[ISI][Medline]
  38. West SG. Methotrexate hepatotoxicity. Rheum Dis Clin N Am1997;23:883–915.[ISI][Medline]
Submitted 15 January 2001; Accepted 7 August 2001





This Article
Full Text (PDF)
Alert me when this article is cited
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Disclaimer
Request Permissions
Google Scholar
Articles by Sofat, N.
Articles by Keat, A.
PubMed
PubMed Citation
Articles by Sofat, N.
Articles by Keat, A.
Related Collections
Other Rheumatology