Background: Methotrexate is an anchor drug in the treatment of Rheumatoid arthritis. But it can cause liver toxicity on long term treatment. Liver enzymes are conventionally monitored to detect the liver toxicity. Transient elastography (TE) is a novel tool to detect the fibrosis of the liver.

Aim:  To find out the utility of Transient elastography of liver in patients with Rheumatoid arthritis on methotrexate

Materials and Methods: 50 patients with Rheumatoid arthritis (RA) on methotrexate for more than 2 years were subjected to Transient elastography evaluation. The resistance or stiffness offered by the liver was measured in kilopascals. According to the stiffness of the liver, the amount of fibrosis was graded from F0 to F4 using colour codes. Stiffness of < 6 kilopascals (kpa) is graded under F0; 6-7.2 kpa = grade F1; 7.3 -8.1 KPA = grade F2; 8.2 – 8.8 kpa = grade F2-F3; 8.9 – 10.5 kpa = grade F3; 10.6 – 11.8 kpa = grade F3-F4; > 11.8 kpa = grade F4. Serum Alanine transaminase (ALT) was measured in all patients.

Results: 50 patients with RA on methotrexate for more than 2 years were enrolled. The duration of treatment with methotrexate ranged from 2- 6.5 years. The stiffness of liver ranged from 2.7 to 8.6kpa. Grade 0 fibrosis (F0) = 40 patients; Grade 1 fibrosis (F1) = 7 patients; Grade 2 fibrosis (F2) = 2 patients; Grade 2-3 fibrosis (F2-F3) = 1; No patients were in grade 3 fibrosis or more.10 patients had elevated ALT above upper limit of normal (40 U/L).  No patients had elevated serum ALT of more than two times of normal. Nine patients with normal ALT had evidence for fibrosis in TE. One patient in F2 grade and one patient in F2-F3 grade had normal ALT.  

Conclusion: Transient elastography of liver is more useful than liver enzymes in monitoring the liver toxicity in RA patients on long term methotrexate.  

Keywords: methotrexate, liver toxicity, alanine transaminase, Transient elastography.

1. Ankoor Shaw, E. William St. Clair. Rheumatoid Arthritis. Harrison’s principles of internal medicine, 19^th edition volume II, page 2136.
2. Richard Conway and John J Carey. Risk of liver disease in methotrexate treated patients. World J Hepatol. 2017 Sep 18; 9(26): 1092-1100.
3. Lewis JH. The art and science of diagnosing and managing drug induced liver injury in 2015 and beyond. Clin Gastroenterol Hepatol. 2015 Nov; 13(12):2173-89.
4. Senior JR. New biomarkers for drug induced liver injury: are they really better? What do they diagnose? Liver international: official journal of the International Association for the study of the liver. 2014;34(3):325-327.
5. Harriet S Cheng, Marius Rademaker. Monitoring methotrexate induced liver fibrosis in patients with psoriasis: utility of transient elastography. Psoriasis (Auckl) 2018; 8: 21-29
6. Van Ede AE, Laan RF, Rood MJ et al. Effect of folic or folinic acid supplementation on the toxicity and efficacy of methotrexate in Rheumatoid arthritis: a forty eight week, multicentre randomized, double blind placebo controlled study. Arthritis Rheum. 2001; 44: 1515-1524.
7. Chan ES, Montestinos MC et al. Adenosine A(2A) receptors play a role in the pathogenesis of hepatic cirrhosis. Br J Pharmacol. 2006;148(8):1144-1155.
8. Mueller M, Kratzer W et al. Percutaneous ultrasonographically guided liver punctures: an analysis of 1961 patients over a period of ten years. BMC Gastroenterol. 2012;12:173.
9. Maharaj B, Maharaj RJ et al. Sampling variability and its influence on the diagnostic yield of percutaneous needle biopsy of the liver. Lancet. 1986;1(8480): 523-525.
10. Rademaker M, Gupta M et al. The Australasian Psoriasis Collaboration view on methotrexate for psoriasis in the Australasian setting. Australas J Dermatol. 2017;58(3):166-170.
11. Visser K, van der heijde DM. Risk and management of liver toxicity during methotrexate treatment in rheumatoid and psoriatic arthritis: a systematic review of the literature. Clin Exp Rheumatol. 2009;27:1017-1025.
12. Robinson JK,Baughman RD et al. Methotrexate hepatotoxicity in psoriasis. Considerationof liver biopsies at regular intervals. Arch Dermatol. 1980;116(4): 413-415.
13. Boffa MJ, Chalmers RJ et al. Sequential liver biopsies during long term methotrexate treatment for psoriasis. A reappraisal. Br J Dermatol. 1995;133(5): 774-778.
14. Malatjalian DA, ross JB et al. Methotrexate hepatotoxicity in psoriasis: 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(6):369-375.
15. Rosenberg P, Urvitz H et al. Psoriasis patients with diabetes type 2 are at high risk of developing liver fibrosis during methotrexate treatment. J Hepatol. 2007;46(6):1111-1118.
16. Talwalker JA, Kurtz DM et al. Ultrasound based Transient Elastography for the detection of hepatic fibrosis: systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2007;5(10): 1214-1220.
17. Salliot C, van der Heijde D. Long term safety of methotrexate monotherapy in patients with rheumatoid arthritis. A systematic literature review. Ann Rheum Dis. 2009;68: 1100-1104.
18. Curtis JR, Beukelman T et al. Elevated liver enzyme tests among patients with rheumatoid arthritis or psoriatic arthritis treated with methotrexate and/or lefluno-mide. Ann Rheum Dis.2010;69:43-47
19. Dirven L, Klarenbeek NB et al. Risk of alanine transferase (ALT) elevation in patients with rheumatoid arthritis treated with methotrexate in a DAS steered strategy. Clin Rheumatol.2013;32:585-590.

Dr Poppy Rejoice

Assistant Professor, Dept of Medical Gastroenterology, Kanyakumari Govt. Medical College, Asaripallam, India