Calculating the hepatotoxic risk of alcohol consumption in rheumatoid arthritis patients taking Methotrexate

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Calculating the hepatotoxic risk of alcohol consumption in rheumatoid arthritis patients taking Methotrexate
Key Take-Away: 

Weekly alcohol consumption of <14 units per week was not associated with an increased risk of transaminitis.

Methotrexate (MTX) is a conventional disease modifying anti-rheumatic drug (cDMARDs) considered as a first-line therapy for rheumatoid arthritis (RA).


Methotrexate (MTX) is a conventional disease modifying anti-rheumatic drug (cDMARDs) considered as a first-line therapy for rheumatoid arthritis (RA). It is a useful and well-tolerated drug, but its hepatotoxicity has always been a concern for its use. The recent studies have revealed that clinicians and doctors discourage the use of alcohol in patients consuming MTX as it may exert additional harmful effects on liver. Clinical evidence has established an association between hepatotoxicity and MTX use, but there is a lack of evidence regarding the use of alcohol and its effects on the liver in RA patients prescribed with MTX.

The American College of Rheumatology (ACR) guidelines, issued in 1994, support abstinence from alcohol with only occasional exceptions. On the contrary, a recent guideline from the British Society for Rheumatology, written in 2008, have proposed that patients taking MTX should limit their alcohol intake to ‘well within the UK national recommendations,' without further specification. Certainly, the ACR guidance clarifies that daily alcohol consumption should be avoided as there is no evidence about the quantity of alcohol that can safely be consumed with MTX.

Previous studies relied on histopathological changes in liver biopsies and determined that patients should either abstain from alcohol altogether or avoid MTX. If alcohol is consumed alongside MTX modestly, patients anecdotally describe feeling anxious or ill at ease. There are no pieces of evidence regarding harmful effects of increased alcohol consumption along with MTX.

Rationale behind the research

  • There is lack of data regarding the use of alcohol in conjunction with MTX in RA patients.
  • This study has been conducted to calculate the amount of alcohol that can exert harmful effects in RA patients taking MTX.


To calculate the risk of alcohol consumption on hepatotoxicity in a group of RA patients prescribed with MTX.




  • Study outcome measures
  • The study measured crude rates of transaminitis, defined as alanine transaminase (ALT) or aspartate aminotransferase (AST) levels of three times the upper limit of normal (ULN) or higher, (according to local laboratory standards) per 1000 person-years, categorized by weekly alcohol consumption in units (0/1–7 (mild)/8–14 (moderate)/15–21 (moderate-high) and >21 (high)).
  • Time Points:  Baseline and after 1 week


Study outcomes:

  • Elevated weekly alcohol consumption was linked with increased risk of transaminitis, adjusted HR (95% CI) per unit consumed 1.01 (1.00 to 1.02)
  • Alcohol consumption between 15 and 21 units was associated with a possible increased risk of hepatotoxicity (Fig 1)
  • Alcohol consumption for more than 21 units per week increased the rates of transaminitis, adjusted HR (95% CI) 1.85 (1.17 to 2.93). (Fig 1)

Fig1: Association between weekly alcohol consumption and occurrence of transaminitis



This study determined that increased levels of alcohol consumption increases the risk of transaminitis in patients with RA taking MTX. The risk in patients consuming ≤14 units of alcohol per week was comparable to those who do not drink alcohol. This is the first study that explained the quantity-based risk of different levels of alcohol consumption in a large group of patients taking long-term MTX.

There is a lack of studies providing a quantitative measure of the risk of alcohol consumption and hepatotoxicity in MTX users. Moreover, previous literature is available from 1970s and 1980s, and the patients included were of psoriasis and not of RA. The studies were retrospective with small sample size and also suffered from a lot of abnormalities pre-existent to MTX therapy. The criteria used for the study was based on liver biopsies which are not used in the present study as they are associated with high rates of mortality and morbidity. The previous studies made an emphasis on rates of liver enzyme abnormalities and found no significant association between current alcohol use and abnormal LFTs. They used standard linear regression as opposed to Cox models, which would not consider the fact that once a person has had an elevated AST, they are more likely to have that blood test repeated. This could lead to counting elevated AST measure more than once, when in fact they are part of the same clinical incidence. This study used a Cox regression analysis along with a secondary transaminitis definition of three consecutive LFTs above the ULN.

Overall, it can be concluded that drinking alcohol within nationally recommended levels in the UK is safe, regarding the risk of transaminitis for patients commencing MTX therapy for RA. However, this study refers only to RA patients and thus cannot be automatically generalized to other populations. It was suggested that some acceptable alcohol levels could be included in clinical guidelines and patient information leaflets may well improve informed decision-making, clinical outcomes, reduce decision conflict and improve overall quality of life.

Humphreys JH et al. Annals of the Rheumatic Diseases.23 March 2017.
Exploratory, Methotrexate, Rheumatoid arthritis, Joints, DMARDs, Safety, Hepatotoxicity
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