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 Table of Contents  
EDITORIAL
Year : 2018  |  Volume : 13  |  Issue : 4  |  Page : 220-221

Methotrexate and the liver: Think beyond the drug!


1 Department of Pharmacology College of Medical Technology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
2 Department of Clinical Immunology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India

Date of Web Publication18-Nov-2018

Correspondence Address:
Dr. Pallavi Patro
Guest Faculty, Department of Pharmacology, College of Medical Technology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Type IV/62, Rae Bareily Road, Lucknow - 226 014, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/injr.injr_146_18

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How to cite this article:
Patro P, Agarwal V. Methotrexate and the liver: Think beyond the drug!. Indian J Rheumatol 2018;13:220-1

How to cite this URL:
Patro P, Agarwal V. Methotrexate and the liver: Think beyond the drug!. Indian J Rheumatol [serial online] 2018 [cited 2018 Dec 15];13:220-1. Available from: http://www.indianjrheumatol.com/text.asp?2018/13/4/220/245574



Methotrexate is one of the most commonly used disease-modifying antirheumatic drugs (DMARDs) for patients with inflammatory arthritis, including rheumatoid arthritis (RA). Hematological and hepatic toxicity remain key considerations for clinicians while monitoring patients on methotrexate therapy.[1] In this context, the recent article in the journal discussing the utility of Fibroscan® in detecting liver fibrosis in patients with RA is relevant.[2] The authors have compared the extent of liver stiffness using the ultrasonographic technique of transient elastography (commonly referred to as Fibroscan®) in 160 patients with RA on weekly methotrexate with 63 clinically healthy controls. In this study, despite the use of methotrexate for a median of 6 years, with a median cumulative dose of 4.2 g, the authors could not identify a significant difference in liver stiffness between the patient and control population.[3] The large sample size, long duration of methotrexate use, significant cumulative dose of methotrexate used, and the lack of such previous literature in an Indian context are major strengths of the study. However, the lack of testing of the healthy control group for chronic viral hepatitis serologies and liver function tests (albeit all of them underwent clinical evaluation and ultrasonography of abdomen), as well as the absence of concomitant liver biopsies for histopathologic correlation, are potential limiters toward the exact understanding of the study results.

Transient elastography or Fibroscan® has emerged as a promising, noninvasive modality in recent years to assess the extent of liver fibrosis, whose use was initially described in patients with chronic viral hepatitis, and later in nonalcoholic fatty liver disease, and is now considered a viable substitute for liver biopsy to quantify the extent of liver fibrosis.[3] In patients with RA, many of the drugs used, including methotrexate, sulfasalazine, leflunomide and nonsteroidal anti-inflammatory drugs (NSAIDs), can cause hepatic injury, and require monitoring for the same with periodic transaminases and serum albumin levels, Should such tests show persistent abnormalities, it is prudent to withdraw the potential culprit drugs in an attempt to reduce the ongoing liver injury, and subsequent liver fibrosis.[1]

The recommendations for the monitoring of liver toxicity in patients on methotrexate vary depending on the practice setting. In the dermatology literature, where methotrexate is commonly used in psoriasis, for those patients at risk of liver toxicity or those having received at least 1.5 g of methotrexate, recommendations suggest the use of noninvasive serological test for Type II Procollagen amino-terminal peptide, which if elevated twice over a period of 3–6 months, may need further specialist consultation, including consideration for a liver biopsy. Similarly, although the literature on the same is more sparse, Fibroscan® may be done one a year in such a patient population.[4] Conversely, in the rheumatology literature, the concerns of hepatic fibrosis with methotrexate appear to be less evident, with major society guidelines such as the British Society of Rheumatology guidelines on DMARD use recommending only routine serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and serum albumin testing, for patients on methotrexate, and modulation of methotrexate dosing in such individuals with abnormal transaminases or serum albumin, without recommending routine liver biopsies or other quantitative noninvasive assessment of liver fibrosis such as Fibroscan® in such individuals.[1] The basis for such recommendations is formed by two classic papers published more than two decades earlier, which followed up patients with RA receiving methotrexate over 8 years with serial liver biopsies, and could demonstrate only mild, clinically insignificant liver fibrosis and steatosis in such individuals, with an accurate reflection of significant liver injury by monitoring serum AST, ALT, and albumin.[1],[5],[6] The potential contributory role of other known factors for liver injury and fibrosis in patients undergoing methotrexate therapy needs adequate consideration. Patients with features of nonalcoholic fatty liver disease, often a consequence of metabolic syndrome and increased insulin resistance, may be at greater risk of significant liver fibrosis with methotrexate.[7] The role of other hepatotoxic drugs, including DMARDs such as leflunomide [8] and NSAIDs,[9] which are often co-prescribed with methotrexate in patients with RA, in portending a greater risk of hepatic fibrosis also merits consideration. However, the overall risk of chronic liver toxicity in patients receiving methotrexate remains low. A systematic review of liver abnormalities in patients with psoriasis on methotrexate, which was limited by significant heterogeneity in the presented data as well as the lack of adequate information on other risk factors for liver fibrosis like alcohol use and diabetes, revealed that while the risk or cirrhosis was slightly but significantly increased with methotrexate, the overall risk of any degree of fibrosis with methotrexate was not significantly higher.[10] Another systematic review analyzed liver injury in patients with inflammatory rheumatic diseases receiving methotrexate, including 32 studies, and could not identify an increased risk of hepatocellular failure, cirrhosis or death in those receiving methotrexate, despite an overall increase in either major or minor elevations in transaminases in such patients.[11]

To conclude, while being a cornerstone DMARD in the management of RA, the overall risk of liver toxicity resulting in clinically significant fibrosis or cirrhosis remains low. While managing such patients on long-term methotrexate, routine monitoring of liver function tests is mandatory, with ensuing dose adjustment or stoppage of therapy should these become abnormal. The concomitant role of other medications such as leflunomide and NSAIDs in causing liver injury should always be a consideration in such patients. Avoidance of alcohol, as well as actively seeking and addressing components of metabolic syndrome that may exist in such patients, is also critical factors that help minimize liver toxicity due to methotrexate use.



 
  References Top

1.
Ledingham J, Gullick N, Irving K, Gorodkin R, Aris M, Burke J, et al. BSR and BHPR guideline for the prescription and monitoring of non-biologic disease-modifying anti-rheumatic drugs. Rheumatology (Oxford) 2017;56:865-8.  Back to cited text no. 1
    
2.
Kumar A, Vasdev V, Manrai M, Bhayana A, Hegde A, Arjun MN, et al. Assessment of hepatic fibrosis in patients with rheumatoid arthritis on long-term methotrexate therapy using transient elastography. Indian J Rheumatol 2018;13:246-51.  Back to cited text no. 2
  [Full text]  
3.
Wilder J, Patel K. The clinical utility of FibroScan(®) as a noninvasive diagnostic test for liver disease. Med Devices (Auckl) 2014;7:107-14.  Back to cited text no. 3
    
4.
Paul C, Gallini A, Maza A, Montaudié H, Sbidian E, Aractingi S, et al. Evidence-based recommendations on conventional systemic treatments in psoriasis: Systematic review and expert opinion of a panel of dermatologists. J Eur Acad Dermatol Venereol 2011;25 Suppl 2:2-11.  Back to cited text no. 4
    
5.
Kremer JM, Lee RG, Tolman KG. Liver histology in rheumatoid arthritis patients receiving long-term methotrexate therapy. A prospective study with baseline and sequential biopsy samples. Arthritis Rheum 1989;32:121-7.  Back to cited text no. 5
    
6.
Kremer JM, Kaye GI, Kaye NW, Ishak KG, Axiotis CA. Light and electron microscopic analysis of sequential liver biopsy samples from rheumatoid arthritis patients receiving long-term methotrexate therapy. Followup over long treatment intervals and correlation with clinical and laboratory variables. Arthritis Rheum 1995;38:1194-203.  Back to cited text no. 6
    
7.
Shetty A, Cho W, Alazawi W, Syn WK. Methotrexate hepatotoxicity and the impact of nonalcoholic fatty liver disease. Am J Med Sci 2017;354:172-81.  Back to cited text no. 7
    
8.
Lee SW, Park HJ, Kim BK, Han KH, Lee SK, Kim SU, et al. Leflunomide increases the risk of silent liver fibrosis in patients with rheumatoid arthritis receiving methotrexate. Arthritis Res Ther 2012;14:R232.  Back to cited text no. 8
    
9.
Park JS, Park MC, Park YB, Lee SK, Lee SW. Concurrent use of methotrexate and celecoxib increases risk of silent liver fibrosis in rheumatoid arthritis patients with subclinical reduced kidney function. Clin Rheumatol 2014;33:1415-23.  Back to cited text no. 9
    
10.
Maybury CM, Jabbar-Lopez ZK, Wong T, Dhillon AP, Barker JN, Smith CH. Methotrexate and liver fibrosis in people with psoriasis: A systematic review of observational studies. Br J Dermatol 2014;171:17-29.  Back to cited text no. 10
    
11.
Conway R, Low C, Coughlan RJ, O'Donnell MJ, Carey JJ. Risk of liver injury among methotrexate users: A meta-analysis of randomised controlled trials. Semin Arthritis Rheum 2015;45:156-62.  Back to cited text no. 11
    




 

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