Understanding Methotrexate And Alcohol Interaction

Quantifying the hepatotoxic risk of alcohol consumption in patients with rheumatoid arthritis taking methotrexate

Methotrexate (MTX) is an anti-metabolic agent drug with functions as an immunosuppressant of rheumatic arthritis. Liderle Company discovered the medicine in 1950 and it was until 1988 that the medicine was approved for administration to patients with rheumatoid arthritis in the United States. Since then, the MTX drug has been utilized to provide medication against cases of rheumatoid arthritis. Studies have identified that methotrexate medicine is effective and is well tolerated in the body of the patients. However, like most medicines, there are some common side effects of the medication such as potential hepatotoxicity to the patients. Patients prescribed to take methotrexate drug are often required to reduce and avoid alcohol consumption when under medication. This is aimed at reducing the reaction of the alcohol with the medicine resulting in the resistance of the body to the medication. The effectiveness of the medication is reliant of the positive response of the medicine by the body.

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Since the production of methotrexate medication, the drug is available in pharmacies in different dosages such as 2.5. 5. 7.5, 10 and 15 mg tablets and can be utilized for purposes like intramuscular, intravenous, and intrathecal purposes. However, although studies have extensively reviewed the relationship between methotrexate (MTX) and hepatotoxicity, there is insufficient evidence that clearly quantifies the potential effect of alcohol on the functioning of the MTX medicine. This has resulted in some studies recommending that regular consumption of alcohol should not occur when under medication due to the absence of data to quantify the amount of alcohol consumed that is considered safe for rheumatoid arthritis patients under the medication.

Studies in the consumption of alcohol during medication with some focusing on the histopathological changes in serial liver biopsies have been developed. However, they have still failed to conclusively demonstrate the association between increased alcohol consumption and hepatotoxicity or liver damage. Many patients, especially those accustomed to drinking prefer to drink modestly and since there is little evidence on the exact image of alcohol consumption on the medication, it becomes difficult to either restrict the consumption of alcohol or permit the patients to drink. This study quantifies the hepatotoxicity of alcohol consumption in patients with rheumatoid arthritis taking methotrexate.

In a study on the effect of both methotrexate and alcohol on liver tissue liver biopsy,(Roenigk ,1971; Malatjalian 1996) express that the effect is determined by measuring the values of serum liver enzymes through conducting liver function test (LFTs) which include a number of enzymes and substances: Alanine transaminase (ALT) enzyme, Aspartate aminotransferase (AST) enzyme, Alkaline phosphatase (ALP) enzyme, Gamma-Glutamyltransferase (GGT) enzyme, Albumin, and Bilirubin.

The hepatotoxicity of methotrexate was well studied mainly for the long use of this drug for treating rheumatoid arthritis. However, combining another hepatotoxic agent such as alcohol during treatment period diminished the clarity of the toxicity levels and made the researcher focus on the relation between alcohol consumption and increasing the incidence of hepatotoxicity in rheumatoid arthritis patient receiving methotrexate as a treatment for this disease. The enzymes which are produced by the liver are important in determining the effect of any hepatotoxic agent on the liver and by measuring the value of these enzymes through a blood test allows for the determination of the toxicity of these agents on the liver tissue and any elevation in the level of an enzyme may be a sign of damage or inflammation. (Morris 2016).

Testing the liver is reliant on some enzymes which are responsible for determining the toxicity of methotrexate on the body. Alanine Aminotransferase (ALT) enzyme act as a converter of the amino acid called alanine which is a part of proteins to pyruvate and it plays an important role as an intermediate in cellular energy production. While the aspartate aminotransferase (AST) enzyme main action is related in amino acid metabolism by catalysing the reversible transfer of the α-amino group between aspartate and glutamate (Kirsch, 1984). This enzyme is found in the liver, brain, pancreas, heart, kidneys, lungs, and skeletal muscles and any damage in the tissue of these organs will lead to increase the level of this enzyme in blood (Burke 2016; Humphreys, 2017). Increasing in AST enzyme level is indicative of tissue (liver, brain, heart, skeletal muscles) injury rather than only for liver injury while the increase in ALT enzyme value is an indication of the liver problem because this enzyme is found mainly in the liver cell. The examination of tests of these enzymes can provide insights on the level of damage of substances like alcohol and methotrexate on the body tissues, especially the liver.

The ALT/AST ratio is crucial in determining the level of injury on the liver. In this case, the quantification of the ration can be categorized as acute (high ALT value), or chronic (high AST value) and the type of the disease affecting the liver (Anon 2009). Studies generally argue that the AST/ALT ratio value of less than one is an indication of a fatty liver disease of non-alcoholic type. Additionally, AST/ALT ratio value equal to one signifies acute viral hepatitis or liver toxicity due to drug whereas a ratio value of higher than one indicates liver cirrhosis (Anon 2009). This framework can be used to quantify hepatotoxicity associated with alcohol consumption in patients with rheumatoid arthritis.

Methods:

The general study design was categorized into three different and interrelated themes.

Patients and setting: A total of 44,586 patients with rheumatoid arthritis who are registered in the database of the clinical practice research data link (CPRD) and who received methotrexate as a treatment for their condition between 1987 and February 2016 were included in this study. The number was then decreased to 11839 patients (8,401 female, mean age 61 years) after excluding the rest due to several factors affecting the study (not on methotrexate during the study, less than 6 times per year, and on-alcohol status recorded in the CPRD ) (Humphreys et al , 2017)

Exposure and outcome: The primary outcome was transaminases referring to the elevation in liver enzymes levels three times above the upper normal limit. (Humphreys et al, 2017). Only Patients who their ALT enzyme and AST enzyme were measured at least 6 times for the last 12 months were included in the analysis and only if they had to indicate compliance with regular blood monitoring and avoid introducing surveillance bias, (Humphreys et al , 2017)

At the beginning of the study Alcohol consumption was registered as yes/no, and then it was identified by units of alcohol consumed per week. (Humphreys et al, 2017). Alcohol unit which was used to determine the amount of alcohol consumed was 10mL equal to 8 g of pure alcohol (Humphreys et al, 2017). The earliest value of alcohol consumption for the patient recorded was the data following the first methotrexate prescription for the participant. (Humphreys et al, 2017).

From the available data alcohol consumption (yes/no) which registered at the beginning of the study, the non-drinking patients were recorded as drinking zero alcohol units to increase the power of the study (Humphreys et al, 2017). For the patients who stopped taking their medication on their own choice or by doctor recommendation, they were included in the study only for the time in which they used their medication. Thus, transaminases occurring while the patient was not receiving their drug were excluded. (Humphreys et al, 2017). Furthermore, Patients were censored at the time of the first episode of transaminases, death or after 29th February 2016.

The main advantage of this method is the focused approach in selection of participants with quality information by narrowing down the sample size to collect information from the informative participant. The adoption of carefully planned time-frame of observation helps to substantiate the information collected over a period of time. This aid in acquiring conclusive and comprehensive information on the subject and the findings of the study will provide for detailed analysis and quantification of hepatotoxic risk in arthritis patients consuming alcohol while under methotrexate medication.

Statistical analysis: All patient with transaminitis in rate for 1000 person-years were calculated first, then calculated in drinkers versus non-drinkers and finally by dividing alcohol units into categories of increasing consumption (0/1–7 (mild), 8–14 (moderate), 15–21 (moderate-high) and >21 (high) (Humphreys et al , 2017), and the study analysis conducted by running the Cox proportional hazard models to detect the association between alcohol Consumption and time to the first episode of transaminitis, age, and gender variables were adjusted. (Humphreys et al, 2017)

Different models were constructed to determine the crude rate. Identification of the transaminitis risk factor between the drinker and non-drinker was conducted. First, the four alcohol unit categories consumers were then studied and finally treating alcohol units consumed as a continuous variable (Humphreys et al, 2017). Posterior probability graphs were drawn to assess the probability of the hazard ratio (HR) exceeding a clinically significant increase, set a priori at a 50% increase in rates of transaminitis, in each of the four categories of alcohol consumption compared with nonalcohol consumption. All analyses were carried out for both primary and secondary definitions of transaminitis.

Statistical analysis based on the Cox proportional hazard model is quite common in medical studies and has been a reliable tool for analyzing data and developing findings which clearly substantiate the study. In fact, the model can be used to provide treatment estimates on the survival following adjustment of one or more variables in the study. This means that the adoption of the cox model in the statistical analysis enhances the validity and reliability of the study findings. However, it must be noted that due to the volume of the participants and the duration for collecting data from individual patients may require detailed analysis in order to capture all the information relevant to the study.

The study espouses key weaknesses in data collection and analysis. First, monitoring transaminitis may not fully capture all the liver damage occurring in patients with methotrexate on a weekly basis creating inconsistencies in the available results. This is even difficult for patients who additionally consume alcohol while on medication since it may be difficult to accurately quantify how the body is affected. There are instances where patients develop hepatotoxicity from other conditions other that initiated by the combination of methotrexate medication and alcohol consumption.

Additionally, the study did not address the effect of obesity factor and the presence of other diseases associated with rheumatoid arthritis such as diabetes as well as race and ethnicity factors. Rheumatoid arthritis is a medical condition that stems from a number of different factors and limiting the study to alcoholism and methotrexate medication leaves out other medical complications that can cause arthritis and can be further aggravated by alcoholism. Failure to measure these factors can result in a bias in the study results some of which, bearing in mind that alcoholism and vital information are self-reported may be actually a mixture of alcoholism, methotrexate medicine and one or more additional factor like obesity.

Results and discussion

A total of 44 586 patients with RA were identified, of whom 11 839 were included in the study, 8401 (71%) were female mean age (SD) was (61). Results showed that the crude rate of transaminitis per 1000 person-years was 10.08 in patients who reported no alcohol consumption, 10.25 In consumers of 1 to 7 units of alcohol per week (age/gender-adjusted hazard ratio [HR], 1.03; 95% CI, 0.82, 1.28), and 9.94 in consumers of 7 to 14 units of alcohol per week (age/gender adjusted HR, 1.01; 95% CI, 0.73, 1.40), differences that were not statistically significant.

A potential risk for liver damage was seen in patients consuming 15 to 21 units per week (age/gender adjusted HR, 1.35; 95% CI, 0.85, 2.14), and a significant risk was seen in patients consuming over 21 units per week (age/gender adjusted HR, 1.85; 95% CI, 1.17, 2.93). No increase in the risk of transaminitis in patients who consume 14 units of alcohol per week while taking methotrexate. This may provide useful information that drinking alcohol within nationally recommended levels in the UK is safe, in terms of risk of transaminitis, for patients commencing MTX therapy for RA.

From the study, crucial insights can be drawn. To begin with, the study generally identified that the increase in consumption of alcohol among patients with Ra taking MTX medication increases the risk of transaminitis. This can be attributed to the combination of the damage of alcohol on the body tissues and the side effects accompanying the MTX medication which may further hamper the health of the patient not to mention the ability of alcohol to increase the body’s insensitivity to medication. Interestingly, the study established that patients on MTX who take less than 14 units of alcohol a week reported significantly minimal differences with those who are on MTX medication but do not drink alcohol.

The findings from the study identified uncertainties about the acceptable levels of alcohol consumption while taking MTX medication, that different rheumatologist and clinical professionals may have divergent views and advice on MTX medication. The effect of This further decrease of the results from the study since there is a possibility that different pieces of advice and prescriptions from clinicians and rheumatologists may significantly contribute to the variations in the progress of the patients taking MTX medications. By and large, there are a number of limitations identified from this study. One limitation of this approach is that the outcome definition requires three sequential raised values. If a clinician sees a clinically meaningful rise in LFTs, they would be inclined to stop the MTX therapy following which the transaminases may return to normal and thus not fulfill the outcome definition of three sequential abnormal results. Therefore, the authority and role of medical practitioners in the therapeutic process can significantly impact the response of the patients in the recovery. Clinicians have significant authority and can influence the patients to either consume or refrain from consuming alcohol in the course of their medication. Different medical conditions like availability of Methotrexate dosage can also impact the response of the patients. Nonetheless, it is soothing that both examinations give similar poise in the safety of modest alcohol consumption.

There are a number of other limitations within the study. The setting within primary care database implies the study’s reliance on existing general practitioner (GP) codes to identify cases of RA. Though the study endeavored to validate algorithms, it is conceivable that some misclassification remains. The possible misclassifications further raise questions on the results presented in the study. Furthermore, given that the study design constrained the RA population to MTX users, misclassification is likely to be less than that for an unselected RA cohort. Alcohol use was self-reported and thus is also prone to misclassification. The self-reporting of the alcohol use may also be subject to fabrications since patients may likely present under-estimated figures on their consumption of alcohol which significantly impacts the study findings leading to underestimation of the study results. This presents a typically different picture than the magnitude of the real situation.

In conclusion, quantifying the hepatotoxic risk of alcohol consumption in patients with rheumatoid arthritis taking methotrexate is prudent in managing rheumatoid arthritis through understanding factors that could inhibit effective therapy. This study has thus attempted to provide a detailed picture and statistics on the level of alcohol consumption and its impact on the medication.

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References

  • (Anon., 2009) Alcohol consumption during low-dose weekly methotrexate therapy, the pharmaceutical journal, retrieved from https://www.pharmaceutical-journal.com/learning/learning-article/alcohol-consumption-during-low-dose-weekly-methotrexate-therapy/10962945.article?firstPass=false
  • Roenigk HH Jr , Bergfeld WF , St Jacques R , et al (1971); Hepatotoxicity of methotrexate in the treatment of psoriasis. Arch Dermatol; 103: 250–6 , et al (jr & al, 1971)
  • Malatjalian DA, (1996): report of 104 patients from Nova Scotia, with analysis of risks from obesity, diabetes and alcohol consumption during long term follow-up. Can J Gastroenterol1996; 10:369–75.
  • Morris, (5th July, 2016) Popular Causes of Elevated Liver Enzymes, Active beat. Retrieved from https://www.activebeat.com/your-health/10-causes-of-elevated-liver-enzymes/
  • Kirsch JF, (1984)Mechanism of action of aspartate aminotransferase proposed on the basis of its spatial structure Author links open overlay panel Jack Gregor ,Eichele§Geoffrey C.Ford∥ Michael G. Vincent https://www.healthline.com/health/ast
  • Burke D, (2016) Aspartate Aminotransferase (AST) Test, Health line, Retrieved from https://www.healthline.com/health/ast
  • Humphreys J, Warner A, Costello R, Lunt M, Verstappen S, & Dixo W. (2017)Quantifying the hepatotoxic risk of alcohol consumption in patients with rheumatoid arthritis taking methotrexate, Clinical and epidemiological report,74 1509-1514

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