Elevation of serum hepatic aminotransferases during treatment of rheumatoid arthritis with low-dose methotrexate: Risk factors and response to folic acid

Suzuki, Ryoma

doi:10.1080/03009749950155454

Cited by 42 publications

(5 citation statements)

References 7 publications

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“…Increased serum activities of these enzymes are extensively used as indicators of anti-inflammatory, therapy-induced hepatic lesion in rheumatic arthritis [40,41]. In the present study, elevated ALT and ALP activities were found in the serum of AIA control group when compared with the normal group.…”

Section: Resultssupporting

confidence: 59%

Anti-Inflammatory Activity and Mechanism of a Lipid Extract from Hard-Shelled Mussel (Mytilus Coruscus) on Chronic Arthritis in Rats

Li¹,

Fu²,

Zheng³

et al. 2014

Marine Drugs

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The present study was designed to investigate the anti-inflammatory activity and mechanism of a lipid extract from hard-shelled mussel (Mytilus coruscus) on adjuvant-induced (AIA) and collagen-induced arthritis (CIA) in rats. AIA and CIA rats that received hard-shelled mussel lipid extract (HMLE group) at a dose of 100 mg/kg demonstrated significantly lower paw swelling and arthritic index, but higher body weight gain than those which received olive oil (control group). Similar results were found in arthritic rats that received New Zealand green-lipped mussel lipid extract (GMLE) at the same dosage. The levels of leukotriene B4 (LTB4), prostaglandin E2 (PGE2), thromboxane B2 (TXB2) in the serum, and interleukin-1β (IL-1β), IL-6, interferon-γ (INF-γ), tumor necrosis factor-α (TNF-α) in the ankle joint synovial fluids of HMLE group rats were significantly lower than those of control group. However, the levels of IL-4 and IL-10 in HMLE group rats were significantly higher than those in the control group. Decreased mRNA expressions of matrix metalloproteinase 1 (MMP1) and MMP13, but increased tissue inhibitor of metalloproteinase 1 (TIMP1) were observed in the knee joint synovium tissues of HMLE group rats when compared with the control group. No hepatotoxicity was observed in both HMLE and GMLE group rats. The present results indicated that HMLE had a similarly strong anti-inflammatory activity as GMLE. Such a strong efficacy could result from the suppression of inflammatory mediators (LTB4, PGE2, TXB2), pro-inflammatory cytokines (IL-1β, IL-6, INF-γ, TNF-α) and MMPs (MMP1, MMP13), and the promotion of anti-inflammatory cytokines (IL-4, IL-10) and TIMPs (TIMP1) productions.

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Section: Resultssupporting

confidence: 59%

Anti-Inflammatory Activity and Mechanism of a Lipid Extract from Hard-Shelled Mussel (Mytilus Coruscus) on Chronic Arthritis in Rats

Li¹,

Fu²,

Zheng³

et al. 2014

Marine Drugs

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“…As for RA patients, Kent et al identified obesity and hyperlipidemia as risk factors for the permanent discontinuation of MTX because of AST elevations [ 39 ]. Other studies showed that elevations of hepatic aminotransferases were more likely to occur in MTX users with obesity and hyperlipidemia [ 40 , 41 ]. In the present study, we identified obesity, type 2 diabetes, hyperlipidemia, and hyperuricemia as possible risk factors for persistent transaminitis during low-dose MTX treatment for RA.…”

Section: Discussionmentioning

confidence: 99%

Non-alcoholic steatohepatitis-like pattern in liver biopsy of rheumatoid arthritis patients with persistent transaminitis during low-dose methotrexate treatment

Mori

Arima²,

Ito

et al. 2018

PLoS ONE

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ObjectiveThe mechanism of liver injury with low-dose methotrexate (MTX) is incompletely understood. This study was designed to evaluate the association between non-alcoholic fatty liver disease (NAFLD) and liver injury during MTX treatment for rheumatoid arthritis (RA).MethodsBetween October 2014 and May 2015, we enrolled all MTX users for RA and monitored participant serum hepatic transaminase levels for 1 year. All patients had normal transaminase levels before the first MTX prescription. Using diagnostic criteria for non-alcoholic steatohepatitis (NASH), we performed histological analyses for patients presenting persistent transaminitis, defined as elevations of hepatic transaminases in four of six determinations during the follow-up period. Possible risk factors for persistent transaminitis were also examined.ResultsWe followed 846 RA patients with a mean cumulative MTX dose of 2.48 g and identified 51 patients presenting persistent transaminitis. According to multivariate logistic regression analysis, obesity (odds ratio [OR] 3.23, p < 0.001), type 2 diabetes (OR 3.52, p = 0.001), hypercholesterolemia (OR 2.56, p = 0.004), and hyperuricemia (OR 3.52, p = 0.019), which are recognized as risk factors for NAFLD, were independently associated with a risk of persistent transaminitis. Among patients with persistent transaminitis, 42 showed fatty liver at ultrasonography. These patients had no evidence of alcoholic fatty liver, chronic viral hepatitis, autoimmune liver diseases, or hereditary liver diseases. Biopsy specimens were obtained from 32 patients, and we found that a NASH-like pattern was the most prevalent histological abnormality. There was no significant impact of MTX dose and duration on the histological severity.ConclusionRisk factors and histological findings are similar between NAFLD/NASH and liver injury during low-dose MTX treatment for RA, which suggests a strong association between both entities. NAFLD/NASH may be an underlying condition causing persistent transaminitis in MTX-treated RA patients. The results of this study illustrate the need for monitoring liver injury in RA patients with NAFLD risk factors during MTX treatment.

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“…4 ). Liver injury, represented by a transient or prolonged increase in AST and ALT levels is one of the adverse effects of MTX [ 21 ] and is reportedly observed in approximately 50% of patients who received it [ 22 ]. Because TCR is mainly eliminated from the body via metabolism by hepatic CYP3A, the increase in AST and ALT levels after MTX administration may explain the decreased clearance of TCR.…”

Section: Discussionmentioning

confidence: 99%

Elevation of tacrolimus concentration after administration of methotrexate for treatment of graft-versus-host disease in pediatric patients received allogeneic hematopoietic stem cell transplantation

Inoue,

Yamamoto,

Miyata

et al. 2023

J Pharm Health Care Sci

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Background Methotrexate (MTX) is used to treat graft-versus-host disease (GVHD) following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Recently, a case was encountered in which the blood concentration of tacrolimus (TCR) at steady state increased after intravenous MTX administration for GVHD treatment (therapeutic IV-MTX administration). Therefore, this study aimed to investigate the effect of therapeutic IV-MTX administration on the pharmacokinetics of TCR. Methods This single-center, retrospective, observational study included patients who underwent allo-HSCT and received therapeutic IV-MTX administration during immunosuppressive therapy with continuous intravenous infusion (CIV) of TCR from April 2004 to December 2021. Here, each therapeutic IV-MTX administration was defined as a case and independently subjected to subsequent analyses. The blood concentration of TCR at steady state (Css), ratio of Css to daily TCR dose (C/D), and clinical laboratory data were compared before and after therapeutic IV-MTX administration. In addition, dose changes in the TCR after therapeutic IV-MTX administration were evaluated. Results Ten patients (23 cases) were included in this study. The C/D value significantly increased after therapeutic IV-MTX administration (median: 697 vs. 771 (ng/mL)/(mg/kg), 1.16-fold increase, P < 0.05), indicating a reduction in the apparent clearance of TCR. Along with the increase in C/D, significant increases were observed in aspartate transaminase level (median: 51.0 vs. 92.9 U/L, P < 0.01) and alanine aminotransferase level (median: 74.5 vs. 99.4 U/L, P < 0.01) indicating that liver injury after therapeutic IV-MTX administration contributes to the observed C/D increase. In addition, the daily dose of TCR was reduced in 11 cases (47.8%) after therapeutic IV-MTX administration, and the relative frequency of dose reduction tended to be higher than that of dose increase (median: 37.5% vs. 0.0%, P = 0.0519, permuted Brunner-Munzel test). The magnitude of dose reduction was 18.8% (7.4–50.0%) in the 11 cases with dose reduction. Conclusions Therapeutic IV-MTX administration cause a significant increase in C/D, which requires TCR dose reduction. Careful therapeutic drug monitoring of TCR is needed after therapeutic IV-MTX administration in patients receiving immunosuppressive therapy with TCR after allo-HSCT.

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Elevation of serum hepatic aminotransferases during treatment of rheumatoid arthritis with low-dose methotrexate: Risk factors and response to folic acid

Cited by 42 publications

References 7 publications

Anti-Inflammatory Activity and Mechanism of a Lipid Extract from Hard-Shelled Mussel (Mytilus Coruscus) on Chronic Arthritis in Rats

Anti-Inflammatory Activity and Mechanism of a Lipid Extract from Hard-Shelled Mussel (Mytilus Coruscus) on Chronic Arthritis in Rats

Non-alcoholic steatohepatitis-like pattern in liver biopsy of rheumatoid arthritis patients with persistent transaminitis during low-dose methotrexate treatment

Elevation of tacrolimus concentration after administration of methotrexate for treatment of graft-versus-host disease in pediatric patients received allogeneic hematopoietic stem cell transplantation

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