Friday, 20 Sep 2019

You are here

Alcohol and Methotrexate - What Do You Advise?

What are your rules on methotrexate and alcohol use? How about casual, social or occasional alcohol use? If one alcoholic beverage is ok, what about 2, 3 or six while taking MTX? Many rheumatologists have crafted alcohol and methotrexate policies to protect patients and reduce the risk associated with coadministration of these potential hepatotoxins.

I’ve questioned many rheumatologists, on multiple continents, on their “policy” and instructions to patients regarding MTX and alcohol. The responses are unified only by their certainty and bravado. Yet the instructions are varied, ranging from the temperance-driven “lips that touch liquor shall never touch methotrexate” to “only 4 drinks per year (and not on the same day)” to “just not on the same day” and “no worry as long as you’re not an alcoholic…you’re not right”? Nevertheless, the warning of alcohol avoidance is highly prevalent but unfortunately comes with no evidence to support the dictum.

What has perplexed me is that most of my colleagues in the US have abolitionist rules against alcohol, but not so for my colleagues in France, Great Britain and Canada. Do they know something I don’t? Is beer, wine and Scotch safer or more temperately used in these regions? Certainly there is no evidence that MTX is better tolerated in the USA or more hazardous outside of the US. Thiry years of practicing, observing and research has lead me to relax my own views. The evidence is compiled below.

The cardiovascular benefits of alcohol (and red wine) have been long recognized. Also, research in the last five years has shown that alcohol is anti-inflammatory and in animal and humans has been shown to decrease the risk of rheumatoid arthritis or lessen the disease activity (Citation source http://buff.ly/1OQqhw9). Lu and colleagues from the Brigham and Women's Hospital BRASS registry studied 662 RA patients with questionnaires on smoking and alcohol consumption (Citation source http://buff.ly/1O2NAS6). With four years of follow-up, smoking was associated with more activity especially in seropositive patients. Alcohol consumption of 5.1-10.0 g/day was associated with a significant decrease of MHAQ (p = 0.02) especially in HLA-SE-positive RA than HLA-SE-negative RA. In an earlier abstract on the same issue, the BRASS registry showed 38% of patients used more alcohol than ACR recommended (> 2 drinks/month; mean use was 8 drinks/month) and that there was no difference between drinkers and abstainers in elevated LFTs or adjusted ALT, AST levels and finally, alcohol drinkers had less pain and better HAQ scores.

Formal guidelines on this common issue are not easily identified. Many point to the original paper from Kremer, Alarcon, et al on the recommended guidelines for MTX use. Yet few can recall the particulars. (Citation source http://buff.ly/1kDuk2g)

To refresh your memory, this paper was written in an era when we were still defining the extent of hepatotoxicity and the potential need for liver biopsies in patients receiving chronic, oral, low-dose MTX. What was known then was that patients with MTX-related clinically serious liver disease (CSLD) or cirrhosis were mostly observed in psoriatic patients (more so than RA) and in those with significant pre-existing liver disease (especially alcoholic liver disease). Mild to moderate elevations of hepatic enzymes were a common nuisance for which monitoring guidelines were proposed. But such transaminitis was not tied to rare or social alcohol use. Some of the relevant quotes from the authors of this paper, that may influence your views, include:

  • A pretreatment liver biopsy should be considered only for patients with a history of prior excessive alcohol consumption, persistently abnormal baseline AST values, or chronic hepatitis B or C infection
  • Patients beginning treatment with MTX must agree to abstain from alcohol consumption. Exceptions to this may be made on occasion, but regular alcohol consumption must not occur since there are no data about the quantity of alcohol that can be safely consumed with MTX, and we therefore believe a very conservative approach is appropriate.
  • Patients should be counseled about the possible risk factors for clinically serious liver disease, including alcohol consumption, cumulative dose, and age, as well as the projected frequency of liver disease based on the current literature.

The package insert (PI) for methotrexate (Rheumatrex) also lacks specificity on this issue. There are clear contraindications to MTX use with significant pre-existing liver disease. But alcohol use is only a problem with a history of alcohol excess. Note that the PI fails to provide any evidence that casual or intermittent alcohol use is linked to a greater risk of hepatoxicity when taking MTX. Under the “contraindications” section it says:

  • Patients with psoriasis or rheumatoid arthritis with alcoholism, alcoholic liver disease or other chronic liver disease should not receive methotrexate.
  • In studies in psoriatic patients, hepatotoxicity appeared to be a function of total cumulative dose and appeared to be enhanced by alcoholism, obesity, diabetes and advanced age. An accurate incidence rate has not been determined; the rate of progression and reversibility of lesions is not known. Special caution is indicated in the presence of preexisting liver damage or impaired hepatic function.
  • The potential for increased hepatotoxicity when methotrexate is administered with other hepatotoxic agents has not been evaluated. However, hepatotoxicity has been reported in such cases. Therefore, patients receiving concomitant therapy with methotrexate and other potential hepatotoxins (e.g., azathioprine, retinoids, sulfasalazine) should be closely monitored for possible increased risk of hepatotoxicity.

The “Patient Instructions” section of the product label differs by being more explicit about alcohol and says:

  • Do not take MTX if you drink alcohol or have liver problems from alcohol abuse or if you have chronic liver disease.
  • Do not drink alcohol. Alcohol drinks, including beer and wine, may increase some of the side effects with methotrexate (RHEUMATREX®), including the chance of liver damage.

There have been several surveys showing that the majority of (RA) patients are made aware of some risks associated with alcohol consumption while on MTX – some being told alcohol should be limited and others told it should be avoided.

The British Society of Rheumatology has guidelines for DMARD use (published in Rheumatology 2008) stating that “any patient suspected of alcohol abuse is usually unsuitable for methotrexate therapy”. Dermatologists may allow patients, receiving methotrexate, to continue taking small amounts of alcohol (4–6 units/week). Rheumatologists should advise the patients receiving methotrexate to limit their alcohol intake well within national recommendations (defined as within 4–8 units/ week). (Citation source: http://buff.ly/1kxPBKZ)

At the same time the BSR guidelines were published, a survey of 200 UK patients on MTX also showed that nearly 70% of patients recalled receiving alcohol advice from their physician. While 39% did not drink alcohol prior to taking methotrexate patients, 64.3% of methotrexate treated patients continued to drink alcohol while on the DMARD. Despite the use alcohol while on MTX (or leflunomide), no patterns emerged to suggest that alcohol consumptions influenced ALT levels. (Citation source: http://buff.ly/1SBPbxn)

Thus, the current BSR guidelines advise that patients should limit their alcohol use to fall within the UK national recommendations which is no more than two to three units of alcohol a day for women and three to four units for men, with at least two or three alcohol-free days each week (1 unit = 8g of alcohol).

The European League Against Rheumatism has advised avoiding methotrexate in patients with a history of alcohol abuse, but does not specify any restrictions to alcohol consumption in patients receiving methotrexate.

The American College of Rheumatology has published guidelines on the monitoring of DMARDs and there makes mention that alcohol should be avoided on methotrexate. The current ACR website information on MTX states “Methotrexate should not be taken if kidney or liver function is not normal. Alcohol significantly increases the risk for liver damage while taking methotrexate, so alcohol should be avoided while on this medication”.

Some patients may ignore strict advice on limiting or avoiding alcohol, or seek to avoid drugs that might curtail their alcohol intake, which in turn might deny them access to efficacious drugs (1). A balanced management approach needs to be tailored to each patient.

Price and colleagues reviewed MTX and alcohol in 2010 and made the following recommendations (Citation source http://buff.ly/1QLfgvI ):

  1. Starting methotrexate mandates a good history asking about any previous or existing liver problems;
  2. For patients starting methotrexate – they should be told that the evidence about alcohol use is limited. In the absence of preexisting liver disease, patients should be informed there is a 3% chance of severe liver disease if they drink more than 100g of alcohol per week (approximately 10-12 glasses/wk); also that taking no alcohol is the safest option;
  3. All patients should receive regular liver function test monitoring while on methotrexate; and
  4. Use the lowest dose of methotrexate to control disease activity.

I concur with these recommendations and use them in daily practice, but these also too only define the extremes of when not to consume alcohol. It’s a no-brainer to prohibit alcohol, MTX, leflunomide and a wide array of other hepatotoxins in patients with known liver disease, CSLD or cirrhosis. Whats hard and debateable are the draconian vs liberal practices on casual alcohol use if taking MTX. So, for what its worth:

My Policies on Methotrexate & Alcohol (based on data, observations and what Ive actually told patients)

  • No alcohol is allowed if you have psoriasis, psoriatic arthritis or clinically inactive hepatitis C or hepatitis B (I probably would not be using MTX in the latter 2 examples);
  • RA patients: rare or social alcohol use is permitted as long as alcohol is not consumed every day of the week – meaning “alcohol should not be a part of your daily routine while you are on MTX”;
  • All patients are reminded that no alcohol is always safer than some alcohol (I believe the same can be said for milk shakes) and that there may be alternative medications wherein alcohol use is not in question.
Disclosures: 
The author has no conflicts of interest to disclose related to this subject

Rheumatologists' Comments

Dr Cush: In the absence of great evidence and realizing that much of the early evidence for serious hepatotoxicity was in psoriasis patients in Scandanavia (ie heavy drinkers) I have 2 pieces of advice for my my patients on MTX: 1) Do not take the MTX with alcohol (no good reason for that one- mainly aesthetic) 2) Do not drink more than I do (3-4 glasses red wine/week) Arthur Weinstein
Art...sage advice as always. I've often heard this rule about drinking no more alcohol than you doctor does (including you, Ted Pincus has said and written the same). Of course, this only opens up the question just how much do you drink doctor? As I prefer to avoid do as I do lessons, I like that you a) have a rule you can live by and b) have limits to what you think is a safe amount. I only wish some of our larger databases and registries would tackle this issue. Without data we are left with "the best I can do with what little I've got". Thanks!!
Jack, I like your common sense approach at the end of this piece. Would just like to make a few comments: -No one has ever studied how much alcohol is safe in a large population of RA pts taking MTX. No one ever will. There is likely to be a huge bell shaped curve depending on both MTX and alcohol dehydrogenase enzyme levels in individuals. That is, some pts can get away with a lot of EtOH, and some will be nailed to the wall. -Nyfors described a 26% incidence of cirrhosis of the liver in Scandanavian psoriatics on MTX. Nyfors associated alcohol intake with the Cirrhotic event. This was published in the Arch of Derm in 1973. I can get you the exact reference if you want. (It may have been Acta Dermatologica Scandanavia) Anyway, when we wrote the guidelines they were based upon serial annual liver biopsies in patients who were forbidden to drink any EtOH. Over a period of 11 yrs, the histology and EM of the livers improved on MTX! And, Yes, we didn't have a control group, but those results were not expected.
So the answer to how much is too much is "It depends". I allow 2-3 drinks per week and monitor LFTs. (The contribution of the guidelines paper was to document that LFTs are indeed associated with hepatic histologic changes in any given year (although there were frequent bumps in LFTs the dose of MTX was always adjusted when this happened). These recs were very different from the Roenigk (derm) papers which indicated that there was no correlation with transaminase levels [and they obtained labs on the day of the biopsy and never in between! Joel

More Like This

Checkpoint Inhibitors: Who Gets Myocarditis?

The usual risk factors for myocarditis may not apply to who gets it while on immune checkpoint inhibiting cancer drugs, an FDA adverse event database suggested.

NSAIDs Mediate Cardiovascular Risk in OA

NSAIDs have been linked to an increased risk of cardiovascular disease, but does this also hold for osteoarthritis (OA) patients.

Tofacitinib Gets a New Boxed Warning for Blood Clots and Death with Higher Doses

The U.S. Food and Drug Administration has approved new warnings about an increased risk of blood clots and of death with the 10 mg twice daily dose of tofacitinib (Xeljanz, Xeljanz XR), which is used in patients with ulcerative colitis. 

EHR-Related Adverse Events Usually Involve Medications

Concerns about the unintended risks inherent in electronic health records (EHR) by analysis of EHR–related harms identified from large database of malpractice suits and claims; they found that EHR related adverse events exist, and may be associated with an severe harms and uncommonly, death.

Methotrexate Use Not Linked to Interstitial Lung Disease in RA

People with rheumatoid arthritis have a significant risk of developing interstitial lung disease (RA-ILD), yet there is often a question as to whether methotrexate (MTX) exposure can cause or worsen ILD.  A controlled cohort study suggests that MTX use is not associated with an increased risk of RA-ILD and instead, there is evidence suggesting MTX use may delay the onset of ILD.