Medicines Q&As
Q&A 241.3
Can patients drink alcohol whilst taking long-term low-dose
methotrexate?
Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals
Before using this Q&A, read the disclaimer at www.ukmi.nhs.uk/activities/medicinesQAs/default.asp
Date prepared: March 2013
Summary
 Patients may drink alcohol whilst taking long-term low weekly doses of methotrexate (25mg or
less), but they should limit their intake.
 Evidence suggests that consumption of alcohol increases the risk of methotrexate-induced liver
toxicity. The risk of liver fibrosis or cirrhosis is 2.5 to 5 times greater in patients who drink more
than 12.5 units of alcohol per week. However there are insufficient data to establish what
amount of alcohol patients can safely consume without causing damage.
 Methotrexate is usually unsuitable for patients suspected of alcohol abuse or with a history of
liver disease, especially if caused by alcohol. It should not be given to patients with significantly
impaired liver function.
 National guidelines recommend that patients taking low-dose weekly methotrexate (by any
route of administration) should ensure their consumption of alcohol is well within maximum
national limits (two to three units a day for women and three to four units a day for men).
Patients with psoriasis or psoriatic arthritis should not drink more than six units of alcohol per
week because they may have a higher risk for liver toxicity than those with other inflammatory
conditions; some may be advised not to drink any alcohol at all.
Background
Long-term use of methotrexate in low weekly doses up to 25mg can cause liver fibrosis and cirrhosis [1].
The risk of significant liver damage is three times greater in patients with psoriatic disease than in those
with rheumatoid arthritis [2,3]. Case reports and prospective studies published in the 1960s and 1970s
suggest that patients with psoriasis who drink alcohol whilst taking methotrexate are more likely to
develop liver damage [1,4,5]. This led to the recommendation that they should avoid alcohol [1]. More
recent research indicates that the incidence of fibrosis and cirrhosis with low-dose methotrexate is much
lower than previously estimated [6], but confirms that risk of liver toxicity is increased by a number of
factors including previous or current alcohol use, regardless of the disease being treated [3,7,8].
This Medicines Q&A reviews the evidence that alcohol increases risk of methotrexate-induced liver
toxicity, and summarises current recommendations on safe levels of alcohol consumption by patients
taking low-dose weekly methotrexate.
Answer
What is the evidence that alcohol increases risk of methotrexate-induced liver toxicity?
An increased risk of liver toxicity with long-term low-dose methotrexate and concurrent alcohol intake
was confirmed by a meta-analysis published in 1991 [9]. Fifteen studies involving 636 patients with
psoriasis, psoriatic arthritis or rheumatoid arthritis taking a mean weekly dose of 11.3mg (maximum
30mg) methotrexate, for a mean duration of 210.5 weeks, were included. All patients had undergone a
liver biopsy before and/or after starting methotrexate and results were classified according to the
Roenigk scale. Those without baseline biopsies were considered to have histological progression if their
biopsy showed grade II or greater changes. In patients whose alcohol consumption could be determined,
73 were described as heavy drinkers (100g or 12.5 units or more weekly) and 420 as light drinkers (less
than 100g or 12.5 units weekly). Heavy drinkers were more likely to have advanced changes on liver
biopsy (grade IIIb severe fibrosis or IV cirrhosis) than light drinkers (17.8% [95% CI 9.8 to 28.5] vs. 4.5%
Q&A 241.3 Can patients drink alcohol whilst taking long-term low-dose methotrexate?
From the NHS Evidence website www.evidence.nhs.uk
[2.8 to 7.2], respectively; p=0.0003), and to show histological progression (73.3% [44.9 to 92.2] vs.
26.3% [21.1 to 32.2], respectively; p=0.0003). These differences were similar regardless of whether
patients had psoriatic or rheumatoid disease. Despite some limitations (questionable accuracy of alcohol
consumption histories, small number of heavy drinkers [leading to wide confidence intervals], lack of an
untreated control group, absence of data on hepatitis infection status and folic acid use, and potential for
overestimating risk of toxicity in patients without baseline biopsies), the authors concluded that risk of
fibrosis or cirrhosis is 2.5 to 5 times greater in patients who drink more than 12.5 units of alcohol per
week.
Several studies investigating the effect of current alcohol consumption on risk of low-dose methotrexateinduced liver toxicity have been published since the meta-analysis [10-15]. However data are insufficient
to clarify the alcohol dose-risk relationship and suffer important limitations:

In a case-control study, alcohol consumption was not associated with liver toxicity in 24 patients with
rheumatoid arthritis who developed liver cirrhosis (grade IV biopsy result or clinical symptoms of liver
failure) whilst taking low-dose methotrexate for at least five years [10]. However detailed alcohol
consumption histories were not available and no explanation was provided of how alcohol intake was
categorised.

Occasional alcohol use did not increase risk of biopsy grade progression or severe hepatotoxicity in
a retrospective cross sectional study [11]. Baseline and annual biopsy data from 104 patients with
psoriasis taking 5 to 25mg methotrexate weekly for between one and 11 years were analysed. All
patients had been advised to avoid alcohol but 24 men and 13 women admitted occasionally drinking
no more than two units of alcohol three times a week. No baseline biopsy showed evidence of
alcoholic hepatitis. Risk of biopsy grade progression was not influenced by alcohol use (odds ratio
0.96 [95% CI 0.38 to 2.46]; p=0.93). Overall 21 patients developed severe fibrosis and three
developed cirrhosis, an incidence of severe hepatotoxicity of 23.1%, but this was also not associated
with alcohol use (OR 2.23 [0.81 to 6.10]; p=0.12).

A retrospective sub-group analysis of a randomised controlled trial, conducted to explore whether
alcohol consumption was associated with a persistent increase in transaminase levels in 43 patients
with psoriasis started on 15mg methotrexate weekly, failed to show a link between alcohol
consumption and liver toxicity [12]. However transaminase levels do not correlate with histological
damage in patients with psoriasis, and fibrosis and cirrhosis can occur in those with normal liver
enzymes [1,2,16]. Also no patients received folic acid and no information was provided on how
alcohol consumption histories were obtained.

Alcohol use was not associated with liver toxicity (as measured by transaminase levels) in a cross
sectional study of 619 patients with rheumatoid or psoriatic arthritis taking oral methotrexate doses of
between 1.25mg and 30mg weekly [13]. 168 randomly selected patients were posted a questionnaire
and asked to recall their alcohol consumption in the previous year. Amongst 133 responders, there
was no significant difference in amount of alcohol consumed between those with psoriatic and
rheumatoid disease (mean 6.6 vs. 5.15 units per week). No data were provided on incidence of
raised transaminase levels in this subgroup but, in the study cohort overall, significantly more
patients with psoriatic arthritis had raised transaminase levels than patients with rheumatoid disease
(14.5% vs. 7.5%).

Liver biopsy data from 71 patients in Sweden taking low-dose methotrexate for psoriasis showed that
risk of severe fibrosis was dependent on at least one risk factor (high alcohol consumption, diabetes,
viral hepatitis, or being overweight) but alcohol alone did not significantly increase risk [14]. Patients
were grouped into over-consumers (n=9; drinking more than 30g alcohol daily; approximately four
units) and those who were not (n=62). All nine over-consumers developed fibrosis compared with 41
(66%) patients who were not over-consumers; severe fibrosis was seen in two and 11 patients,
respectively (p=0.599). However the group who did not over-consume alcohol could have included
women exceeding daily UK limits for safe alcohol use and this limits applicability of the data to UK
settings.

Alcohol consumption did not influence alanine transaminase (ALT) levels in 139 patients with
rheumatoid arthritis taking methotrexate (doses not reported) [15]. All had been counselled at the
start of treatment to restrict alcohol intake to seven units or less per week. In response to an
Q&A 241.3 Can patients drink alcohol whilst taking long-term low-dose methotrexate?
From the NHS Evidence website www.evidence.nhs.uk
anonymised postal questionnaire (validated for community surveys), 14 patients recalled exceeding
this limit over the previous two years, with only four reported consuming more than 21 units of
alcohol per week. Alcohol use was not predictive of changes in ALT from baseline or highest level
reported.
Most recently in 2011, a meta-analysis of three studies involving 291 patients with psoriasis who were
taking methotrexate and had undergone liver biopsies (including two studies described above [11,14])
concluded that alcohol consumption was not associated with a greater risk of developing liver fibrosis
(OR 1.74 [0.87 to 3.47]; p=0.12; I2=0%) [16]. However, the authors note the small number of patients
involved and variable criteria used to define alcoholism, so advise caution when interpreting these data.
What advice should patients be given on safe consumption of alcohol?
Evidence indicates that alcohol consumption increases the risk of severe liver toxicity with low-dose
methotrexate. However it is not clear what amount of alcohol patients can safely drink without causing
damage [2,8,17]. Methotrexate is usually unsuitable for patients suspected of alcohol abuse or with a
history of liver disease, especially if caused by alcohol [18,19]. It should not be given to patients with
significantly impaired liver function [20,21]. The manufacturers of methotrexate advise that patients
should avoid concurrent use of alcohol [20,21]. National guidelines for use of methotrexate in the
management of psoriasis and rheumatoid arthritis are more pragmatic, acknowledging that occasional
consumption of alcohol may be safe yet reflecting the greater risk sometimes seen in patients with
psoriasis [18,19]. Numerous reasons why patients with psoriasis appear to be at greater risk have been
suggested. They include a predisposition to liver toxicity caused by psoriasis itself [3], or a higher
prevalence of additional risk factors for liver toxicity (dyslipidaemia, obesity and diabetes mellitus) [2] or a
tendency to greater alcohol consumption in patients with psoriasis compared to those with rheumatoid
disease [8]. Other suggestions are that patients with rheumatoid arthritis take lower doses of
methotrexate [1], a strong emphasis is placed on alcohol avoidance, monitoring and concomitant use of
folic acid, and other anti-inflammatories known to suppress liver fibrinogenesis are co-prescribed [3].
However, the finding may be coincidental or because early studies did not control for other risk factors for
liver toxicity [1].
Advice from national guidelines on alcohol consumption by patients taking low-dose methotrexate is as
follows:

Psoriasis or psoriatic arthritis
The British Association of Dermatologists (BAD) advises that patients with psoriasis taking low-dose
methotrexate (by any route of administration) should limit their alcohol intake to four to six units a
week [18,19]. However, some patients may be advised to completely avoid alcohol [22]. There is no
guidance available for patients with psoriatic arthritis. Since this condition is considered to be more
like psoriasis than rheumatoid arthritis [3] it seems advisable to follow BAD guidelines.

Rheumatoid arthritis
The British Society for Rheumatology suggests that patients with rheumatoid arthritis receiving lowdose methotrexate (by any route) should stay well within national limits for alcohol use [18] (two to
three units a day for women and three to four units a day for men [23]). The British Society for
Paediatric and Adolescent Rheumatology advises that patients should not drink alcohol while taking
methotrexate. However, as long as the patient is legally old enough to drink alcohol, an occasional
glass of wine or beer is unlikely to be harmful. Excessive regular alcohol and binge drinking should
be avoided [24].

Other inflammatory conditions
The National Patient Safety Agency recommends that people with inflammatory conditions taking
weekly oral methotrexate doses of 25mg or less should ensure their consumption of alcohol is well
within maximum recommended limits [22].
Q&A 241.3 Can patients drink alcohol whilst taking long-term low-dose methotrexate?
From the NHS Evidence website www.evidence.nhs.uk
Limitations
The available data are limited by the difficulty in obtaining accurate details of alcohol consumption from
patients and by controlling for other risk factors for liver toxicity. There are no published studies
investigating the effect of alcohol use on low-dose methotrexate-induced liver toxicity in patients with
conditions other than psoriasis, psoriatic arthritis or rheumatoid arthritis.
References
1. West SG. Methotrexate hepatotoxicity. Rheum Dis Clin North Am 1997; 23: 883-915.
2. Taylor WJ, Korendowych E, Nash P, Helliwell PS, Choy E, et al. Drug use and toxicity in
psoriatic disease: Focus on methotrexate. J Rheum 2008; 35: 1454-7.
3. Lindsay K and Gough A. Psoriatic arthritis, methotrexate and the liver – are rheumatologists
putting their patients at risk? Rheumatol 2008; 47: 939-41.
4. Baxter K (ed), Stockley’s Drug Interactions. [online] London: Pharmaceutical Press. Accessed
via www.medicinescomplete.com on 11/02/2013.
5. Zachariae H. Alcohol interactions with drugs and its effect on the treatment of skin diseases. Clin
Dermatol 1999; 17: 443-5.
6. Zachariae H. Have methotrexate-induced liver fibrosis and cirrhosis become rare? Dermatol
2005; 211: 307-8.
7. Schnabel A and Gross WL. Low-dose methotrexate in rheumatic diseases – efficacy, side
effects, and risk factors for side effects. Semin Arth Rheum 1994; 23: 310-27.
8. Bangert CA and Costner MI. Methotrexate in dermatology. Dermatol Ther 2007; 20: 216-28.
9. Whiting-O’Keefe QE, Fye KH and Sack KD. Methotrexate and histologic hepatic abnormalities: A
meta-analysis. Am J Med 1991; 90: 711-6.
10. Walker AM, Funch D, Dreyer NA, Tolman KG, Kremer JM, et al. Determinants of serious liver
disease among patients receiving low-dose methotrexate for rheumatoid arthritis. Arth Rheum
1993; 36: 329-35.
11. Malatjalian DA, Ross JB, Williams CN, Colwell SJ, and Eastwood BJ. Methotrexate
hepatotoxicity in psoriatics: Report of 104 patients from Nova Scotia, with analysis of risks from
obesity, diabetes and alcohol consumption during long term follow-up. Can J Gastroenterol
1996; 10: 369-75.
12. Heydendael VMR, Spuls PI, Bossuyt PMM, Bos JD, and de Rie MA. Analysis of risk factors in
psoriatic patients with methotrexate-induced increases in transaminase levels. Arch Dermatol
2004; 140: 1289-90.
13. Tilling L, Townsend S and David J. Methotrexate and hepatic toxicity in rheumatoid arthritis and
psoriatic arthritis. Clin Drug Invest 2006; 26: 55-62.
14. Rosenberg P, Urwitz H, Johannesson A, Ros A-M, Lindholm J, Kinnman N, and Hultcrantz R.
Psoriasis patients with diabetes type 2 are at high risk of developing liver fibrosis during
methotrexate treatment. J Hepatol 2007; 46: 1111-8.
15. Rajakulendran S, Gadsby K, and Deighton C. Rheumatoid arthritis, alcohol, leflunomide and
methotrexate. Can changes to the BSR guidelines for leflunomide and methotrexate on alcohol
consumption be justified? Musculoskelet Care 2008; 6: 233-46.
16. Montaudie H, Sbidian E, Paul C, Maza A, Gallini A et al. Methotrexate in psoriasis: a systematic
review of treatment modalities, incidence, risk factors and monitoring of liver toxicity. J Eur Acad
Dermatol Vener 2011; 25 (Suppl 2): 12-18.
17. Rau R and Herborn G. Benefit and risk of methotrexate treatment in rheumatoid arthritis. Clin
Exp Rheum 2004; 22 (Suppl 35): S83-94.
18. Chakravarty K, McDonald H, Pullar T, Taggart A, Chalmers R, et al on behalf of the British
Society for Rheumatology, British Health Professionals in Rheumatology Standards, Guidelines
and Audit Working Group in consultation with the British Association of Dermatologists.
BSR/BHPR guideline for disease-modifying anti-rheumatic drug (DMARD) therapy in
consultation with the British Association of Dermatologists. Rheum 2008; 1-16.
19. The British Association of Dermatologists. Clinical guidelines: Psoriasis – general management.
2008. Accessed via www.bad.org.uk/site/769/Default.aspx and
www.bad.org.uk/site/1121/Default.aspx on 12/02/2013.
20. Summary of product characteristics – methotrexate 2.5mg tablets. Hospira UK Ltd. Accessed via
www.medicines.org.uk on 12/02/2013.
21. Summary or product characteristics and Patient information leaflet – Maxtrex tablets 2.5mg.
Pharmacia Ltd. Accessed via www.medicines.org.uk on 11/02/2013.
Q&A 241.3 Can patients drink alcohol whilst taking long-term low-dose methotrexate?
From the NHS Evidence website www.evidence.nhs.uk
22. National Patient Safety Agency. Oral methotrexate pre-treatment patient information leaflet.
Accessed via www.npsa.nhs.uk on 12/02/2013.
23. DrinkAware. How much alcohol is too much? Accessed via www.drinkaware.co.uk/check-thefacts/what-is-alcohol/daily-guidelines on 13/02/2013.
24. The British Society for Paediatric and Adolescent Rheumatology. Methotrexate patient
information leaflet. March 2011. Accessed via www.bspar.org
.uk/DocStore/FileLibrary/PDFs/BSPAR%20guidance%20for%20methotrexate%20(information%
20for%20parents%20and%20carers)%202012.pdf on 12/02/2013.
QualityAssurance
Prepared by
Joanne McEntee, North West Medicines Information Centre, 70 Pembroke Place, Liverpool, L69 3GF.
Contact
nwmedinfo@nhs.net
Date Prepared
March 2013.
Checked by
Justine Howard, Lindsay Banks and Christine Proudlove. North West Medicines Information Centre,
Pharmacy Practice Unit, 70 Pembroke Place, Liverpool, L69 3GF.
Date of check
March 2013.
Search strategy
 Embase 1974 to date [exp *METHOTREXATE] AND ([exp ALCOHOL] or [exp ALCOHOLIC
BEVERAGE] OR [ALCOHOL CONSUMPTION]); [Limit to: Human]; limited to 2011 onwards.
 Medline 1950 to date [exp *METHOTREXATE] AND ([exp ALCOHOLIC BEVERAGE] OR
[ALCOHOL DRINKING] OR [ALCOHOLISM] OR [ALCOHOLIC INTOXICATION] OR
[ETHANOL]); [Limit to: Humans]; limited to 2011 onwards.
 Cochrane Library [methotrexate] AND [alcohol].
 www.bad.org.uk
 www.rheumatology.org.uk
 www.npsa.nhs.uk
 www.bspar.org.uk
 www.evidence.nhs.uk
 In-house database/ resources.
Q&A 241.3 Can patients drink alcohol whilst taking long-term low-dose methotrexate?
From the NHS Evidence website www.evidence.nhs.uk