|Year : 2018 | Volume
| Issue : 4 | Page : 246-251
Assessment of hepatic fibrosis in patients with rheumatoid arthritis on long-term methotrexate therapy using transient elastography
Abhishek Kumar1, Vivek Vasdev2, Manish Manrai3, Aprajita Bhayana2, Arun Hegde2, MN Arjun2, Kunal Kishore2
1 Department of Rheumatology, Command Hospital (Eastern Command), Kolkata, West Bengal, India
2 Department of Rheumatology, Army Hospital Research and Referral, Delhi, India
3 Department of Gastroenterology, Army Hospital Research and Referral, Delhi, India
|Date of Web Publication||18-Nov-2018|
Dr. Vivek Vasdev
Department of Rheumatology, Army Hospital Research and Referral, Delhi -110 010
Source of Support: None, Conflict of Interest: None
Background: Methotrexate (MTX) is has been associated with hepatotoxicity including hepatic fibrosis; however, the incidence of severe hepatic fibrosis or cirrhosis with MTX use has remained a controversial issue. The gold standard test for detecting liver fibrosis has been a liver biopsy, which is an invasive procedure with potentially serious complications. The transient elastography (TE) is a noninvasive method of assessing hepatic fibrosis. The primary objective of this study was to assess the prevalence of hepatic fibrosis associated with long-term MTX therapy in patients with RA and the secondary objective was to assess the correlation of cumulative MTX dose with hepatic fibrosis as assessed by TE using Fibroscan.
Methods: In this cross-sectional study patients with RA who had been on MTX treatment for >5 years were included. Hepatic fibrosis was determined by measuring the hepatic stiffness by TE method (by FibroScan) in kilopascal (kPa) in study patients. The hepatic stiffness of the patient group was compared with that of healthy controls.
Results: A total of 160 patients and 63 healthy controls were included in the study. The mean age of the patients was 51±10.9 years and there were 139 female and 21 male patients.The median duration of MTX use was 317.5 weeks (range 260, 1302 years). Median MTX cumulative dose was 4225 mg (range 2340, 18,200 mg). Mean hepatic stiffness was 4.8 kPa (SD 1.35) in the patient group and 4.7 kPa (SD 1.07) in the control group (P = 0.550). Cumulative dose or duration of MTX treatment did not correlate with hepatic fibrosis.
Conclusions: Severe hepatic fibrosis or cirrhosis as detected by the TE using Fibroscan was uncommon with high cumulative dose of MTX when administered in the low-dose weekly schedule. The cumulative dose of MTX did not correlate with hepatic fibrosis as assessed by FibroScan.
Keywords: FibroScan, hepatic fibrosis, liver fibrosis, methotrexate, transient elastography
|How to cite this article:|
Kumar A, Vasdev V, Manrai M, Bhayana A, Hegde A, Arjun M N, Kishore K. Assessment of hepatic fibrosis in patients with rheumatoid arthritis on long-term methotrexate therapy using transient elastography. Indian J Rheumatol 2018;13:246-51
|How to cite this URL:|
Kumar A, Vasdev V, Manrai M, Bhayana A, Hegde A, Arjun M N, Kishore K. Assessment of hepatic fibrosis in patients with rheumatoid arthritis on long-term methotrexate therapy using transient elastography. Indian J Rheumatol [serial online] 2018 [cited 2019 Dec 15];13:246-51. Available from: http://www.indianjrheumatol.com/text.asp?2018/13/4/246/244574
| Introduction|| |
Methotrexate (MTX) has been the pivot of disease-modifying anti-rheumatic drugs (DMARDs) for the treatment of many rheumatic conditions, including rheumatoid arthritis (RA) over the decades. Hepatic fibrosis has been one of the most important and serious side effect associated with long-term MTX treatment. Any level of hepatic dysfunction can pose a challenge to the treating rheumatologist by limiting the choice of DMARDs which can be used. Early diagnosis of hepatic fibrosis is of utmost clinical importance. Management guidelines in the past have recommended a serial liver biopsy to monitor this potential adverse effect., Although liver biopsy remains the “gold standard” technique for the detection of hepatic fibrosis, it is not devoid of procedure-related serious complications and other limitations. In addition, liver biopsy being an invasive procedure is not a suitable screening test for the detection of hepatic fibrosis in a large population. Off late, transient elastography (TE) has been found to be a reliable, noninvasive method for the detection of hepatic fibrosis without any side effects and has been used to assess hepatic fibrosis in many conditions such as hepatitis C virus (HCV) infection., Over a period of time, it has now become a validated method for the assessment of liver fibrosis., The primary objective of this study was to assess the prevalence of hepatic fibrosis associated with long-term MTX therapy in patients with RA and the secondary objective was to assess the correlation of cumulative MTX dose with hepatic fibrosis as assessed by TE.
| Methods|| |
This was a cross-sectional study conducted from March 2016 to May 2016 at the Department of Rheumatology of our institute.
All patients with >18 years of age, being followed up in our department, fulfilling the 2010 ACR/EULAR criteria for RA, and receiving uninterrupted weekly oral or injectable MTX for 5 years (60 months from the day of initiation) or more were included in this study.
Patients with evidence of chronic liver disease, current or previous hepatitis B virus (HBV), HCV, or human immunodeficiency virus (HIV) infection, alcohol intake more than 10 g per day, metabolic syndrome (as per the International Diabetes Federation Consensus criteria for Asian-Indian population; independent cause for high FibroScan score), and history of nonalcoholic fatty liver disease (NAFLD) were excluded from the study. Patients receiving leflunomide or other drugs contributing to hepatic fibrosis were also excluded from the study.
For every patient, MTX cumulative dose and duration of treatment were recorded. Biochemical parameters were measured using Siemens RxL Max auto-analyzer. Liver function assessment was done by the measurement of biochemical tests (including serum aspartate transaminase [AST], alanine transaminase [ALT], alkaline phosphatase [ALP], total protein, albumin, and total bilirubin levels), prothrombin time (PT), and international normalized ratio (INR). Ultrasonography (USG) was done to assess the liver echogenicity and features of portal hypertension. A complete blood count of the patient was performed by Siemens ADVIA 2120i auto-analyzer.
Transient elastography was done using FibroScan (Echosens, Paris, France), by the method as mentioned by the manufacturer, and liver stiffness (FibroScan score) was expressed in kilopascal (kPa). Only patients with 10 validated measurements and interquartile range (IQR) <30% of median liver stiffness were included. The cutoff values for various stages of fibrosis by TE were adopted as proposed in the Tsochatzis et al. meta-analysis: 6 kPa for the presence of fibrosis, 7.2 kPa for significant fibrosis, 9.6 kPa for severe fibrosis, and 14.5 kPa for liver cirrhosis. Considering the risk associated with liver biopsy, the cutoff value for liver biopsy was kept at 9.6 kPa.
Healthy controls were selected from the general population. Controls were matched to patients by their age, gender, and body mass index (BMI). All the controls were screened by the same hepatologist. Individuals with a previous history of any liver disease or icteric illness, history of blood transfusion, and any other risk for the chronic liver disease were not considered for inclusion as a control. USG abdomen was done for all the controls to rule out any liver or spleen abnormality or any other features to suggest chronic liver disease.
Kurtosis was used for testing the distribution of numerical variables. For the comparison of normally distributed quantitative variables, parametric (t-test) tests were used, and nonparametric (Mann–Whitney) tests were used for nonnormally distributed variables. Chi-square test was used to compare the categorical variables. Spearman's rank correlation coefficient was used to assess the correlation between variables with nonnormal distribution. Pearson's correlation coefficient was used to assess the correlation between normally distributed quantitative variables. Linear regression analysis was used to assess the effect of BMI, MTX cumulative dose, or duration toward the FibroScan score.
The protocol of this study was approved by the institutional ethics committee. Written informed consent was obtained from all the participants.
| Results|| |
A total of 166 patients with RA who were on MTX treatment for >5 years our department were screened. Six patients were later excluded due to the presence of various exclusion criteria (3 NAFLD, 2 HBV infection, and 1 HCV infection) and 160 patients were included in the study. There were 139 female and 21 male patients (female:male ratio of 6.6:1).
The demographic profile and main results of the study and control populations are summarized in [Table 1].
|Table 1: Demographic profile and results of the study population and control population|
Click here to view
Control group composed of 63 healthy individuals among which 52 were female and 11 were male. There was no statistically significant difference in the demographic profiles of the study and control population [Table 1].
Median duration of MTX use was 317.5 weeks (range 260, 1302; IQR 191). Median MTX cumulative dose was 4225 mg (range 2340, 18,200 mg; IQR 2795).
Liver function tests
Mean hepatic stiffness among the patient group was 4.8 kPa (minimum 2.0 kPa, maximum 9.0 kPa, SD 1.35). Mean AST, ALT, and albumin levels were 28.1 IU/L (SD 9.41), 33 IU/L (SD 15.3), and 3.87 g/dl (SD 0.4), respectively. Eleven patients (6.87%) had transient episodes of elevated transaminases (less than twice the upper limit of normal value) recorded in their medical records which reduced to the normal range in subsequent follow-ups. None of the patients underwent liver biopsy. Mean FibroScan score in the patient and control groups was 4.8 kPa (SD 1.35; range 2, 9) and 4.7 kPa (SD 1.07; range 2.9, 7.4), respectively. There were few outliers in the patient group; however, there was no statistical difference between the two groups [P = 0.55, 95% confidence interval − 0.54, 0.49; [Figure 1]. There was no correlation found between the cumulative dose of MTX and the FibroScan score of the study patients [R = 0.016, P = 0.843; [Figure 2]a. Similarly, no correlation between the duration of MTX treatment and FibroScan was found (R = 0.02, P = 0.785).
|Figure 1: Distribution of Fiborscan scores among cases and controls. Cases had few outliers and with kurtosis of 1.07; however, it was considered as normally distributed in the study group for the purpose of statistical analysis|
Click here to view
|Figure 2: Scatterplot of the cumulative dose of methotrexate (mg) and FibroScan score (kPa) in the study group (a) and in a subgroup of patients with FibroScan score ≥6 (b)|
Click here to view
A subgroup of 26 (16.2%, 23 females and 3 males) patients in the study group and eight controls (12.7%, 5 females and 3 males, P = 0.586) were found to have FibroScan scores in the range to which defined the presence of liver fibrosis (≥6 kPa). Main characteristics of these are described in [Table 2]. The patients in this subgroup were exposed to a wide range of cumulative dose of MTX (median 4418 mg; range 2340, 18,200 mg) in a wide range of duration of treatment (median 269 weeks, minimum 266 weeks, and maximum 1198 weeks). Twelve of these 26 patients had FibroScan score >7.1 kPa to signify significant liver fibrosis. Regression analysis was done to assess any relation of the FibroScan score of these patients, with the cumulative dose of MTX received (R = 0.178, P =0.246). However, there was no correlation found between the cumulative MTX dose and FibroScan score [Figure 2]b. The FibroScan scores and cumulative MTX dose in this subgroup were compared to other patients in the study group (FibroScan score <6) and there was no statistical difference found for cumulative MTX dose (P = 0.427) despite a statistically significant different FibroScan scores (P < 0.000).
|Table 2: Comparative study of the characteristics of patients with FibroScan scores (≥6) with others in the study group|
Click here to view
| Discussion|| |
Hepatic fibrosis has been considered to be a major safety concern for long-term MTX-based therapy. However, in the present study, no significant difference has been found in the FibroScan scores of RA patients exposed to a wide range of cumulative dose MTX in low-dose weekly pulse schedule and healthy controls. The cumulative dose of MTX also did not correlate with the FibroScan score.
In 1983, Hoffmeister reported his 15-year experience on safety and efficacy of low-dose pulse MTX therapy in 78 RA patients. A total of 67 liver biopsy samples were obtained from 34 patients with MTX exposure duration ranging from 3 to 15 years. Only 17 biopsy samples were found to have abnormal histology, and none of the samples revealed necrosis or cirrhosis. None of the patients who showed increased hepatic fibrosis in biopsy had a normal biopsy before the commencement of MTX therapy. Moreover, the histological abnormalities described in patients with RA on MTX therapy were also found in MTX-naïve RA patients. Thus, this was one of the first studies to report that hepatic fibrosis is not a serious concern with low-dose pulse MTX therapy and serial liver biopsy is not mandatory. In one meta-analysis which included 32 studies (13,177 patients) till April 2014, and 28 of which included RA patients, MTX use was not found to be associated with increased risk of liver failure, cirrhosis, or death. Similarly, in a number of studies on liver biopsy in a wide range of cumulative dose of MTX from 1125 to 7000 mg, none of the studies reported significant hepatic fibrosis or cirrhosis of the liver.,,,,,,
Thus, the findings of this study corroborate with other studies in the literature where liver fibrosis has been assessed by liver biopsy. There are not many studies published so far on use of TE for the assessment of hepatic fibrosis in patients with RA. In the present study, 12 (7.5%) patients were found to have significant hepatic fibrosis (FibroScan score >0.1). In a similar study by Barbero-Villares et al. of 64 patients on long-term MTX therapy with heterogeneous diseases (including 17 RA patients), only 7.5% of the patients were detected to have significant liver fibrosis with the mean cumulative dose of MTX of 1805 mg. In another study by Laharie et al., 518 patients on MTX therapy were assessed using FibroScan and results were compared with MTX-naïve patients. This study included 149 patients with RA (102 females), and a median cumulative dose of MTX was1950 mg (range 780, 3750 mg). They had a mean FibroScan score of 4.3 kPa which did not correlate with cumulative dose or duration of MTX treatment. Thus, the incidence of severe hepatic fibrosis or cirrhosis as measured by TE in these studies has been uncommon, and there was no correlation between the cumulative dose of MTX and hepatic fibrosis. In our study also, the incidence of severe fibrosis has been found to be low, and none of the patients meets the cutoff value for cirrhosis at wide range of cumulative dose of MTX (2340, 18,200 mg) and cumulative dose of MTX has not correlated with FibroScan score (R = 0.016, P = 0.843).
Thus, based on the findings of this study and various other aforementioned studies it appears that significant hepatic fibrosis or cirrhosis of the liver is not a major concern in long-term MTX treatment in low-dose weekly pulse schedule. Many of the serious adverse effects of MTX have been attributed to it in the older studies when daily dosing schedule or higher doses of MTX up to 3 mg/kg per week was used., In the studies published later which have included patients with RA treated with a low dose weekly pulse of MTX, significant or life-threatening hepatic fibrosis associated with long-term MTX use has rarely been reported. This low incidence of severe fibrosis can be explained by several factors. The histological changes found in MTX-treated patients are not specific and have also been found in other hepatic diseases or patients with RA before treatment with MTX., In animal studies, it has been reported that rats given daily doses of MTX developed hepatic fibrosis while animals exposed to weekly doses of MTX did not develop fibrosis at all., Folic acid supplementation has been found to reduce the incidence of elevation in transaminases. Weekly use of a lower dose of MTX may produce a lesser degree of liver injury with adequate time for the liver to recuperate from the injury.
The detection of significant liver fibrosis or cirrhosis is of paramount importance as not only it significantly limits the treatment options available at affordable cost, but it also marks the stage where the patient should be monitored for development of portal hypertension and hepatocellular carcinoma. Liver biopsy represents the gold standard investigation for the assessment of liver pathology, but it is also inherent with many limitations of sampling error, risk of mortality, and interpersonal variation in interpretation.,,,, So far, no validated cutoff values of TE have been established for different stages of fibrosis; however, it has been found to be of significant use in ruling in cirrhosis of the liver with a positive predictive value of 96% than ruling out cirrhosis (negative predictive value 74%). The incidence of severe hepatic fibrosis or cirrhosis as assessed by TE in this study, as well as previous studies, is consistent with observations in various studies which included liver biopsy as evidence of hepatic fibrosis. Thus, it may be inferred that TE can be a novel and useful tool for the assessment of hepatic fibrosis.
The present study has some major limitations. Firstly, none of the patients in the study underwent a liver biopsy. Histological changes in the liver and its correlation with FibroScan score could have consolidated our findings. Secondly, there is a significant association of metabolic syndrome with RA. Since the present study has excluded the patients with metabolic syndrome, the inference of our study may not be extrapolated to patients with RA and coexisting metabolic syndrome.
In conclusion we found that severe hepatic fibrosis or cirrhosis as detected by TE using Fibroscan was uncommon with long-term and high cumulative dose of MTX when administered in the low-dose weekly schedule. The cumulative dose of MTX did not correlate with hepatic fibrosis as assessed by FibroScan. TE can be a valuable tool for assessment of hepatic fibrosis in patients on long-term MTX therapy.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Kremer JM, Alarcón GS, Lightfoot RW Jr., Willkens RF, Furst DE, Williams HJ, et al.
Methotrexate for rheumatoid arthritis. Suggested guidelines for monitoring liver toxicity. American College of Rheumatology. Arthritis Rheum 1994;37:316-28.
Saag KG, Teng GG, Patkar NM, Anuntiyo J, Finney C, Curtis JR, et al.
American college of rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum 2008;59:762-84.
Bedossa P, Dargère D, Paradis V. Sampling variability of liver fibrosis in chronic hepatitis C. Hepatology 2003;38:1449-57.
Castéra L, Vergniol J, Foucher J, Le Bail B, Chanteloup E, Haaser M, et al.
Prospective comparison of transient elastography, fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C. Gastroenterology 2005;128:343-50.
Mendoza J, Gómez-Domínguez E, Moreno-Otero R. Transient elastography (Fibroscan), a new non-invasive method to evaluate hepatic fibrosis. Med Clin (Barc) 2006;126:220-2.
European Association for the Study of the Liver. EASL clinical practice guidelines: Management of hepatitis C virus infection. J Hepatol 2011;55:245-64.
European Association for the Study of the Liver. EASL clinical practice guidelines: Management of chronic hepatitis B virus infection. J Hepatol 2012;57:167-85.
Roulot D, Czernichow S, Le Clésiau H, Costes JL, Vergnaud AC, Beaugrand M, et al.
Liver stiffness values in apparently healthy subjects: Influence of gender and metabolic syndrome. J Hepatol 2008;48:606-13.
Tsochatzis EA, Gurusamy KS, Ntaoula S, Cholongitas E, Davidson BR, Burroughs AK, et al.
Elastography for the diagnosis of severity of fibrosis in chronic liver disease: A meta-analysis of diagnostic accuracy. J Hepatol 2011;54:650-9.
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.
Hoffmeister RT. Methotrexate therapy in rheumatoid arthritis: 15 years experience. Am J Med 1983;75:69-73.
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.
Kremer JM, Tolman K, Samowitz W. Long-term prospective sequential liver biopsies in patients with rheumatoid arthritis on weekly oral methotrexate. Arthritis Rheum 1990;33 Suppl 9:40.
Brick JE, Moreland LW, Al-Kawas F, Chang WW, Layne RD, DiBartolomeo AG, et al.
Prospective analysis of liver biopsies before and after methotrexate therapy in rheumatoid patients. Semin Arthritis Rheum 1989;19:31-44.
Rau R, Karger T, Herborn G, Frenzel H. Liver biopsy findings in patients with rheumatoid arthritis undergoing longterm treatment with methotrexate. J Rheumatol 1989;16:489-93.
Shergy WJ, Polisson RP, Caldwell DS, Rice JR, Pisetsky DS, Allen NB, et al.
Methotrexate-associated hepatotoxicity: Retrospective analysis of 210 patients with rheumatoid arthritis. Am J Med 1988;85:771-4.
Willkens RF, Leonard PA, Clegg DO, Tolman KG, Ward JR, Marks CR, et al
. Liver histology in patients receiving low dose pulse methotrexate for the treatment of rheumatoid arthritis. Ann Rheum Dis 1990;49:591-3.
Sterling G. Methotrexate Hepatotoxicity. Rheum Dis Clin North Am 1997;23:883-915.
Barbero-Villares A, Mendoza J, Trapero-Marugan M, Gonzalez-Alvaro I, Daudén E, Gisbert JP, et al.
Evaluation of liver fibrosis by transient elastography in methotrexate treated patients. Med Clin (Barc) 2011;137:637-9.
Laharie D, Seneschal J, Schaeverbeke T, Doutre MS, Longy-Boursier M, Pellegrin JL, et al.
Assessment of liver fibrosis with transient elastography and fibroTest in patients treated with methotrexate for chronic inflammatory diseases: A case-control study. J Hepatol 2010;53:1035-40.
Wilke WS, Biro JA, Segal AM. Methotrexate in the treatment of arthritis and connective tissue diseases. Cleve Clin J Med 1987;54:327-38.
Black RL, O'brien WM, Vanscott EJ, Auerbach R, Eisen AZ, Bunim JJ, et al.
methotrexate therapy in psoriatic arthritis; double-blind study on 21 patients. JAMA 1964;189:743-7.
Kevat S, Ahern M, Hall P. Hepatotoxicity of methotrexate in rheumatic diseases. Med Toxicol Adverse Drug Exp 1988;3:197-208.
Weinblatt ME, Tesser JR, Gilliam JH 3rd
. The liver in rheumatic diseases. Semin Arthritis Rheum 1982;11:399-405.
Hall PD, Jenner MA, Ahern MJ. Hepatotoxicity in a rat model caused by orally administered methotrexate. Hepatology 1991;14:906-10.
Kaplan MM. Methotrexate hepatotoxicity and the premature reporting of Mark Twain's death: Both greatly exaggerated. Hepatology 1990;12:784-6.
van Ede AE, Laan RF, Rood MJ, Huizinga TW, van de Laar MA, van Denderen CJ, et al.
Effect of folic or folinic acid supplementation on the toxicity and efficacy of methotrexate in rheumatoid arthritis: A forty-eight week, multicenter, randomized, double-blind, placebo-controlled study. Arthritis Rheum 2001;44:1515-24.
Chalmers RJ, Kirby B, Smith A, Burrows P, Little R, Horan M, et al.
Replacement of routine liver biopsy by procollagen III aminopeptide for monitoring patients with psoriasis receiving long-term methotrexate: A multicentre audit and health economic analysis. Br J Dermatol 2005;152:444-50.
Campbell MS, Reddy KR. Review article: The evolving role of liver biopsy. Aliment Pharmacol Ther 2004;20:249-59.
Regev A, Berho M, Jeffers LJ, Milikowski C, Molina EG, Pyrsopoulos NT, et al.
Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection. Am J Gastroenterol 2002;97:2614-8.
Brunetti E, Silini E, Pistorio A, Cavallero A, Marangio A, Bruno R, et al.
Coarse vs. Fine needle aspiration biopsy for the assessment of diffuse liver disease from hepatitis C virus-related chronic hepatitis. J Hepatol 2004;40:501-6.
Rousselet MC, Michalak S, Dupré F, Croué A, Bedossa P, Saint-André JP, et al.
Sources of variability in histological scoring of chronic viral hepatitis. Hepatology 2005;41:257-64.
Ganne-Carrié N, Ziol M, de Ledinghen V, Douvin C, Marcellin P, Castera L, et al.
Accuracy of liver stiffness measurement for the diagnosis of cirrhosis in patients with chronic liver diseases. Hepatology 2006;44:1511-7.
Zhang J, Fu L, Shi J, Chen X, Li Y, Ma B, et al.
The risk of metabolic syndrome in patients with rheumatoid arthritis: A meta-analysis of observational studies. PLoS One 2013;8:e78151.
[Figure 1], [Figure 2]
[Table 1], [Table 2]