Efficacy of Vitamin E in Methotrexate-Induced Hepatotoxicity in Rheumatoid Arthritis: An Open-Label Case-Control Study

Vaidya, Binit; Bhochhibhoya, Manisha; Nakarmi, Shweta

doi:https://doi.org/10.1155/2020/5723485

International Journal of Rheumatology

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Abstract Introduction Materials and Methods Results Discussion Conclusion Data Availability Disclosure Conflicts of Interest Acknowledgments References Copyright Related Articles

Clinical Study | Open Access

Volume 2020 | Article ID 5723485 | https://doi.org/10.1155/2020/5723485

Efficacy of Vitamin E in Methotrexate-Induced Hepatotoxicity in Rheumatoid Arthritis: An Open-Label Case-Control Study

Binit Vaidya,¹Manisha Bhochhibhoya,¹and Shweta Nakarmi¹

Academic Editor: Bruce M. Rothschild

Received31 Mar 2020

Accepted15 Apr 2020

Published01 May 2020

Abstract

Objective. To examine the efficacy of vitamin E in methotrexate- (MTX-) induced transaminitis in patients with rheumatoid arthritis (RA). Methods. A case-control study was conducted at a tertiary rheumatology center for 12 months. Patients with RA on MTX and deranged aminotransferases were included. Patients with previous liver diseases, baseline transaminitis before methotrexate initiation, alcohol intake, muscle diseases, under hepatotoxic drugs, and times the upper normal limit were excluded. The patients were divided into treatment (vitamin E 400 mg bid for 3 months) and control groups (no vitamin E) using a random number table. The dose of MTX was unaltered. Follow-up was done after 3 and 6 months. Independent -test was done to compare means of two groups. Paired -test was done to compare differences in mean. Results. Among 230 patients, 86.5% were female with a mean BMI of kg/m². In the treatment group, SGPT and SGOT at baseline were and IU/L, respectively; at 3-month follow-up and IU/L, respectively; and at 6-month follow-up and IU/L, respectively. In the control group, SGPT and SGOT at baseline were and IU/L, respectively, and at 3-month follow-up and IU/L, respectively. Significant decrease in the level of aminotransferases was seen in the treatment group ( value < 0.001) and not in the control group ( values 0.161 and 0.728, respectively). The change in levels of SGPT and SGOT from baseline to 3 months of follow-up was statistically significant in between two study groups ( values 0.007 and <0.001, respectively). From the control group, 29 patients were crossed over to vitamin E for the next 3 months. SGPT and SGOT decreased from to and to IU/L, respectively ( values 0.031 and 0.017, respectively). Conclusion. Vitamin E significantly attenuates MTX-induced transaminitis.

1. Introduction

Methotrexate (MTX) is a folate antagonist which inhibits dihydrofolate reductase (DHFR) [1]. It is considered a sheet anchor drug in the management of rheumatoid arthritis (RA) [2]. Low-dose MTX in weekly regime has been used as either monotherapy or in combination with other disease-modifying drugs for the past 3 decades [3]. It has transformed the management of RA by altering the course of disease, improving the patient’s quality of life, and decreasing disease-related morbidity [4, 5]. However, it is associated with numerous side effects, common ones being gastrointestinal adverse effects, hepatotoxicity, stomatitis, alopecia, and hematological abnormalities [6, 7]. Liver abnormalities ranging from asymptomatic transaminase elevations to fibrosis and fatal hepatic necrosis can be associated with MTX [8]. Elevated transaminase is one of the most common adverse reactions seen with the use of low-dose MTX with a cumulative incidence of 48.9% and elevation above twice the upper limit of normal (UNL) in 16.8% leading to either discontinuation or dose reduction [9, 10]. With proper monitoring and treatment regimes, the incidence has decreased in current years to 22%, with less than 1% developing transaminitis more than twice the UNL [9].

Concurrent use of folic acid at the dose of 1 mg per day is recommended to reduce MTX toxicity, including hepatotoxicity. In case of transaminitis, monitoring of serum aminotransferases is done on a monthly basis with ongoing MTX treatment and withdrawal of MTX is recommended if the serum aminotransferase level is more than three times the UNL [11] or persistently above twice the UNL for more than 1 month [12].

The usage of natural compounds or drugs, nontoxic cytoprotective agents like ursodeoxycholic acid, β-carotene, etc. as adjuvants may play a significant role in decreasing the incidence of side effects of MTX [13, 14]. Among various adjuvant agents, vitamin E or alpha-tocopherol has reconstructing and antioxidant effects [15]. Pretreatment with vitamin E had shown protective effects in the intestinal tissue of MTX-treated rats [16]. Also, it was effective in the prevention of hepatotoxicity induced by MTX in the animal model [17]. But limited studies have been done showing the effectiveness of vitamin E supplementation in the treatment of hepatotoxicity induced by MTX in humans.

Thus, this study is aimed at observing the efficacy of vitamin E in MTX-induced hepatotoxicity in RA patients.

2. Materials and Methods

2.1. Patient Selection

This was a prospective, randomized, open-labeled, case-control study on the patients with RA conducted at the National Center for Rheumatic Diseases (NCRD), Kathmandu, Nepal, for 6 months. The ethical clearance for the study was obtained from the Nepal Health Research Center (NHRC), Nepal. Patients aged ≥18 years presenting to the rheumatology outpatient department and diagnosed as having RA according to 2010 American College of Rheumatology (ACR)/European League against Rheumatism (EULAR) classification criteria for RA [18] under MTX treatment and deranged aminotransferases between 1 and 3 times the UNL were selected. Patients with previous liver diseases including nonalcoholic fatty liver disease, deranged transaminases of unknown cause at baseline, and muscle diseases; patients under hepatotoxic drugs; alcoholics; and patients with times the UNL were excluded. Informed written consent was taken from the candidates who met the criteria.

2.2. Randomization

Convenient sampling technique was used where patients with rheumatoid arthritis visiting the rheumatology clinic at NCRD were recruited. Randomization was done with the help of a random number table generated online. Each patient was then assigned to either treatment or control group. Both physician and patient were aware of the treatment received.

2.3. Treatment Protocol

The treatment protocol for the treatment group is as follows: oral MTX (7.5-20 mg) weekly (continuation of patient’s ongoing dose) and folic acid (1 mg daily) with vitamin E 400 mg twice a day along with advice on reduced fat and carbohydrate diet and aerobic exercises for at least 30 minutes a day for at least 5 days a week for 3 months. Vitamin E was given at a dose of 800 mg daily (in divided doses) as it was the most commonly used regime for nonalcoholic steatohepatitis [19, 20] with acceptable drug safety. If the level of transaminases remained high (more than 1-fold and less than 3-fold) at 3-month follow-up, the dose of methotrexate was reduced. If the level increased to more than 3-fold, then methotrexate was discontinued.

The treatment protocol for the control group is as follows: oral MTX (7.5-20 mg)/week (continuation of patient’s ongoing dose) and folic acid (1 mg daily) along with advice on reduced fat and carbohydrate diet and aerobic exercises for at least 30 minutes a day for at least 5 days a week for 3 months. If the level of transaminases remained high (more than 1-fold and less than 3-fold) at 3-month follow-up, vitamin E was added in the abovementioned protocol (crossover group) and patients were followed up after 3 months.

2.4. Follow-Up Protocol

A dedicated research officer recorded the sociodemographic and clinical profiles at baseline and follow-ups (3 months and 6 months) in a predesigned excel sheet. C-reactive protein (CRP, mg/L; turbidimetry), erythrocyte sedimentation rate (ESR, mm/h; Westergren’s method), complete blood count, kidney function test, and liver function tests (SGPT and SGOT) were done at baseline and subsequent follow-ups. SGPT and SGOT were measured using the International Federation of Clinical Chemistry (IFCC) recommendations without pyridoxal phosphate activation method [21] and expressed in IU/L. The normal reference ranges of SGPT and SGOT are 5-42 IU/L and 5-37 IU/L, respectively.

2.5. Quality Control Measures

Similar dietary and lifestyle advice was given to patients of both the groups. The patients in the treatment group were also asked to fill a drug diary on a daily basis and submit empty foils of vitamin E capsule on follow-up to ensure good compliance of the drug. All blood samples for transaminases were tested in the same laboratory with a fully automatic biochemistry analyzer (Erba Lachema XL 200, Czech Republic).

2.6. Statistical Analysis

Statistical analysis was done using SPSS 21 (IBM Corporation, USA). Simple descriptive statistics were used to describe baseline parameters. Mean, standard deviation, frequency, and percentages were used where applicable. Paired -test was used to assess the difference in means of each group at baseline and follow-ups. Independent -test was done to compare means between two groups. The value of <0.05 was considered significant.

3. Results

A total of 230 patients were enrolled in the study. Among them, 86.5% were female, majority being housewives (69.5%). The mean age of the participants was years with a mean BMI of kg/m². The most frequent (47.0%) dose of MTX where transaminitis occurred was 20 mg per week. Other sociodemographic and clinical profiles are shown in Table 1.

In the treatment group, vitamin E was administered in 106 patients. At baseline, the mean SGPT and SGOT levels were and IU/L, respectively. There was a statistically significant decrease in the levels of SGPT and SGOT to and IU/L, respectively ( value < 0.001) at 3 months. (Table 2). The change in mean SGPT from baseline to 3-month follow-up in treatment and control groups was and IU/L, respectively, and the change in mean SGOT in treatment and control groups was and.

, respectively. The change in levels of SGPT and SGOT from baseline to 3-month follow-up was statistically significant in between two study groups ( value 0.007 and <0.001, respectively) (Table 3). At 6-month follow-up, the SGPT and SGOT levels were and , respectively.

In the control group, one hundred and twenty-four (124) patients were maintained on the same dose of MTX and were followed up at 3 months after dietary and exercise advice. The mean SGPT and SGOT levels at baseline were and IU/L, respectively, and at 3-month follow-up were and , respectively. The decline was not statistically significant for SGPT and SGOT at 3-month follow-up ( value 0.161 and 0.728, respectively) (Table 2).

3.1. Crossover Group

In a subsequent follow-up, 29 patients from the control group were switched to the treatment group as the serum transaminase level increased from baseline. The SGPT and SGOT levels increased from 63.9 to 97.6 and 43.7 to 69.3 IU/L, respectively. After vitamin E supplementation at a dose mentioned for the treatment group, the level of serum SGPT and SGOT decreased significantly at follow-up 3 months later (Table 4).

3.2. Side Effect Profile

Mild nausea was observed in 2 patients which subsided on its own without any active intervention. Only 1 patient complained of abdominal discomfort, for which pantoprazole 40 mg once daily was added for few days with positive response.

4. Discussion

The discovery of methotrexate has enabled the control of many immune-mediated inflammatory diseases like RA, which were once considered to have no treatment options [22, 23]. However, it comes with a significant toxicity profile, the most important being hepatotoxicity when used at a high-dose or low-dose continuous therapy [6, 7, 10]. With more understanding of the mechanism of methotrexate action, weekly therapy and the use of folate supplementation have significantly reduced the rates of such reported toxicities [11, 24].

The exact mechanism for methotrexate-induced liver injury is not known. Various experimental studies have postulated local folate depletion causing intracellular accumulation of adenosine and oxidative injury with increased susceptibility to reactive oxygen species as possible mechanisms. Histological studies have shown various stages of methotrexate hepatotoxicity [25, 26] progressing from steatosis to cell hypertrophy, fibrosis, and cirrhosis [8]. A study showed an increased oxidative injury as measured by markers of lipid peroxidation in rabbits treated with methotrexate. The same study also demonstrated a beneficial effect of coadministration of vitamin E in the prevention of methotrexate-induced oxidative injury [27]. This increase in oxidative stress induced by methotrexate, as measured by malondialdehyde (MDA) levels, nitrite and nitrate levels, and the activities of antioxidants like superoxide dismutase (SOD), catalase (CAT), and total antioxidant status (TAS), was also shown to be beneficial in inducing apoptosis in psoriatic patients [28]. We believe that the use of vitamin E, which has shown a beneficial effect in nonalcoholic steatohepatitis, at an early stage of transaminase elevation (which probably would reflect the stage of steatosis), can ameliorate methotrexate-induced liver injury.

Based on these theories, a few animal studies have tested various compounds with antioxidant properties in the prevention of methotrexate-induced liver injury. Animal studies have shown beneficial effects of β-carotene, melatonin, and metformin in methotrexate-induced hepatotoxicity [14]. In this study, we tried to examine the effect of vitamin E (α-tocopherol) in patients with elevated transaminase levels after methotrexate administration at a low dose for varying intervals because of its proven potent antioxidant effects. α-Tocopherol functions as a peroxyl radical scavenger thus having an important function of maintaining the integrity of long-chain polyunsaturated fatty acids in the membranes of cells and maintaining their bioactivity [29].

Our results showed that the improvement in transaminase levels was statistically significant in those treated with vitamin E without modifying the dose of methotrexate as compared to those who were just advised diet and weight control. Even though the baseline liver enzymes were higher in the treatment group, use of vitamin E reduced them to significantly lower levels than the control group. We went a little further to explore the effectiveness in a subgroup of patients in a control group whose transaminase level deteriorated on follow-up. An improved transaminase level in this subgroup of patients further strengthened our hypothesis. Patients with elevation more than three times the upper limit were excluded due to ethical reasons, but we believe that coadministration of vitamin E might help them to maintain their dose so that the clinical benefit is not lost.

5. Limitations of the Study

The study was not placebo-controlled, and both the patients and investigators were not blinded to the treatment groups. Also, the crossover was not preplanned for all patients in the control group. The histological findings cannot be interpreted with the current methodology to prove our hypothesis.

6. Conclusion

This study showed that vitamin E coadministration is promising in attenuating the hepatotoxic effects of methotrexate and thus helps to maintain the effective dose in patients. However, more extensive studies in humans with a large sample size and longer intervention period need to be conducted for a better understanding of vitamin E in RA patients under long-term MTX therapy.

Data Availability

The data used to support the findings of this study are available from the corresponding author upon request.

Disclosure

The abstract of this manuscript was presented as a poster in Indian Rheumatology Association Conference (IRACON) 2019.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Acknowledgments

The authors would like to acknowledge Ms. Rakshya Joshi, research officer at NCRD, for her help during data collection, and Dr. Jayanti Rai, consultant rheumatologist at NCRD, for her support during patient care.

References

M. Cutolo, A. Sulli, C. Pizzorni, B. Seriolo, and R. H. Straub, “Anti-inflammatory mechanisms of methotrexate in rheumatoid arthritis,” Annals of the Rheumatic Diseases, vol. 60, no. 8, pp. 729–735, 2001.
View at: Publisher Site | Google Scholar
T. Pincus, Y. Yazici, T. Sokka, D. Aletaha, and J. S. Smolen, “Methotrexate as the “anchor drug” for the treatment of early rheumatoid arthritis,” Clinical and Experimental Rheumatology, vol. 21, 5 Supplement 31, pp. S179–S185, 2003.
View at: Google Scholar
M. E. Weinblatt, “Methotrexate in rheumatoid arthritis: a quarter century of development,” Transactions of the American Clinical and Climatological Association, vol. 124, pp. 16–25, 2013.
View at: Google Scholar
G. S. Hazlewood, C. Barnabe, G. Tomlinson, D. Marshall, D. Devoe, and C. Bombardier, “Methotrexate monotherapy and methotrexate combination therapy with traditional and biologic disease modifying antirheumatic drugs for rheumatoid arthritis: abridged Cochrane systematic review and network meta-analysis,” BMJ, vol. 353, article i1777, 2016.
View at: Publisher Site | Google Scholar
M. C. Wasko, A. Dasgupta, H. Hubert, J. F. Fries, and M. M. Ward, “Propensity-adjusted association of methotrexate with overall survival in rheumatoid arthritis,” Arthritis and Rheumatism, vol. 65, no. 2, pp. 334–342, 2013.
View at: Publisher Site | Google Scholar
S. T. Gilani, D. A. Khan, F. A. Khan, and M. Ahmed, “Adverse effects of low dose methotrexate in rheumatoid arthritis patients,” Journal of the College of Physicians and Surgeons–Pakistan, vol. 22, no. 2, pp. 101–104, 2012.
View at: Google Scholar
S. M. Attar, “Adverse effects of low dose methotrexate in rheumatoid arthritis patients. A hospital-based study,” Saudi Medical Journal, vol. 31, no. 8, pp. 909–915, 2010.
View at: Google Scholar
K. Visser and D. M. van der Heijde, “Risk and management of liver toxicity during methotrexate treatment in rheumatoid and psoriatic arthritis: a systematic review of the literature,” Clinical and Experimental Rheumatology, vol. 27, no. 6, pp. 1017–1025, 2009.
View at: Google Scholar
R. Conway and J. J. Carey, “Risk of liver disease in methotrexate treated patients,” World Journal of Hepatology, vol. 9, no. 26, pp. 1092–1100, 2017.
View at: Publisher Site | Google Scholar
S. Cohen, G. W. Cannon, M. Schiff et al., “Two-year, blinded, randomized, controlled trial of treatment of active rheumatoid arthritis with leflunomide compared with methotrexate. Utilization of Leflunomide in the Treatment of Rheumatoid Arthritis Trial Investigator Group,” Arthritis and Rheumatism, vol. 44, no. 9, pp. 1984–1992, 2001.
View at: Publisher Site | Google Scholar
“LiverTox: Clinical and Research Information on Drug-Induced Liver Injury,” https://www.ncbi.nlm.nih.gov/books/NBK548219/.
View at: Google Scholar
K. W. Jones and S. R. Patel, “A family physician’s guide to monitoring methotrexate,” American Family Physician, vol. 62, no. 7, pp. 1607–12, 1614, 2000, 14.
View at: Google Scholar
M. Bordbar, N. Shakibazad, M. Fattahi, S. Haghpanah, and N. Honar, “Effect of ursodeoxycholic acid and vitamin E in the prevention of liver injury from methotrexate in pediatric leukemia,” The Turkish Journal of Gastroenterology, vol. 29, no. 2, pp. 203–209, 2018.
View at: Publisher Site | Google Scholar
N. Vardi, H. Parlakpinar, A. Cetin, A. Erdogan, and I. Cetin Ozturk, “Protective effect of beta-carotene on methotrexate-induced oxidative liver damage,” Toxicologic Pathology, vol. 38, no. 4, pp. 592–597, 2010.
View at: Publisher Site | Google Scholar
“LiverTox: Clinical and Research Information on Drug-Induced Liver Injury,” https://www.ncbi.nlm.nih.gov/books/NBK548283/.
View at: Google Scholar
B. Burcu, M. Kanter, Z. N. Orhon, O. Yarali, and R. Karabacak, “Protective effects of vitamin E on methotrexate-induced jejunal mucosal damage in rats,” Analytical and Quantitative Cytopathology and Histopathology, vol. 38, no. 2, pp. 87–94, 2016.
View at: Google Scholar
R. Pradhan, S. Koirala, N. Adhikari et al., “Protection against methotrexate induced hepato-renal toxicity in rats by zinc and its combination with vitamin C and vitamin E,” Medical Safety & Global Health, vol. 5, no. 2, 2016.
View at: Publisher Site | Google Scholar
D. Aletaha, T. Neogi, A. J. Silman et al., “2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative,” Annals of the Rheumatic Diseases, vol. 69, no. 9, pp. 1580–1588, 2010.
View at: Publisher Site | Google Scholar
J. E. Lavine, J. B. Schwimmer, M. van Natta et al., “Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial,” Journal of the American Medical Association, vol. 305, no. 16, pp. 1659–1668, 2011.
View at: Publisher Site | Google Scholar
A. J. Sanyal, N. Chalasani, K. V. Kowdley et al., “Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis,” The New England Journal of Medicine, vol. 362, no. 18, pp. 1675–1685, 2010.
View at: Publisher Site | Google Scholar
H. U. Bergmeyer, G. N. Bowes Jr., M. Hørder, and D. W. Moss, “Provisional recommendations on IFCC methods for the measurement of catalytic concentrations of enzymes Part 2. IFCC method for aspartate aminotransferase,” Clinica Chimica Acta, vol. 70, no. 2, pp. F19–F42, 1976.
View at: Publisher Site | Google Scholar
D. M. Nathan, J. H. Iser, and P. R. Gibson, “A single center experience of methotrexate in the treatment of Crohn’s disease and ulcerative colitis: a case for subcutaneous administration,” Journal of Gastroenterology and Hepatology, vol. 23, no. 6, pp. 954–958, 2008.
View at: Publisher Site | Google Scholar
O. Yelamos and L. Puig, “Systemic methotrexate for the treatment of psoriasis,” Expert Review of Clinical Immunology, vol. 11, no. 5, pp. 553–563, 2015.
View at: Publisher Site | Google Scholar
Z. Ortiz, B. Shea, M. E. Suarez-Almazor, D. Moher, G. A. Wells, and P. Tugwell, “The efficacy of folic acid and folinic acid in reducing methotrexate gastrointestinal toxicity in rheumatoid arthritis. A metaanalysis of randomized controlled trials,” The Journal of Rheumatology, vol. 25, no. 1, pp. 36–43, 1998.
View at: Google Scholar
J. S. Kim, K. E. Lowe, and B. Shane, “Regulation of folate and one-carbon metabolism in mammalian cells. IV. Role of folylpoly-gamma-glutamate synthetase in methotrexate metabolism and cytotoxicity,” The Journal of Biological Chemistry, vol. 268, no. 29, pp. 21680–21685, 1993.
View at: Google Scholar
H. Tabassum, S. Parvez, S. T. Pasha, B. D. Banerjee, and S. Raisuddin, “Protective effect of lipoic acid against methotrexate-induced oxidative stress in liver mitochondria,” Food and Chemical Toxicology, vol. 48, no. 7, pp. 1973–1979, 2010.
View at: Publisher Site | Google Scholar
M. Taghizadieh, F. Afshari, N. Shokri, and B. Hajipour, “Protective role of vitamin E on methotrexate induced renal injury in rabbits,” Galen Medical Journal, vol. 3, no. 3, p. 94, 2014.
View at: Google Scholar
T. Elango, H. Dayalan, P. Gnanaraj, H. Malligarjunan, and S. Subramanian, “Impact of methotrexate on oxidative stress and apoptosis markers in psoriatic patients,” Clinical and Experimental Medicine, vol. 14, no. 4, pp. 431–437, 2014.
View at: Publisher Site | Google Scholar
M. G. Traber and J. Atkinson, “Vitamin E, antioxidant and nothing more,” Free Radical Biology & Medicine, vol. 43, no. 1, pp. 4–15, 2007.
View at: Publisher Site | Google Scholar

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Copyright © 2020 Binit Vaidya et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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