Methotrexate therapy is not associated with increased liver stiffness and significant liver fibrosis in rheumatoid arthritis patients: A cross-sectional controlled study with real-time two-dimensional shear wave elastography

Erre, Gian Luca; Cadoni, Maria Luisa; Meloni, Pierluigi; Castagna, Floriana; Mangoni, Arduino A.; Piga, Matteo; Passiu, Giuseppe; Carru, Ciriaco; Zinellu, Angelo; Vidili, Gianpaolo

doi:10.1016/j.ejim.2019.08.022

Cited by 15 publications

(23 citation statements)

References 29 publications

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“…We assessed the presence and severity of liver steatosis in 364 subjects (223 patients with RA and 141 controls) (see Table 1 ), of whom 273 (173 RA and 100 controls) were previously enrolled in a study aimed to evaluate liver fibrosis. 13 …”

Section: Resultsmentioning

confidence: 99%

“…Exclusion criteria were the following, as previously published: 13 history of hepatitis B and C virus infection; treatment with hepatotoxic drugs other than RA-specific drugs; alcohol abuse (i30 g/day in men and ⩾20 g/day in women); history or clinical suspicion of Wilson’s disease, α1-antitrypsin deficiency or genetic hemochromatosis; history or clinical suspicion of autoimmune liver disease; recent infection; cancer; and pregnancy. Patients with impaired fasting glucose (fasting glycaemia >106 mg/dl) or diabetes (diagnosed according to the patient’s history and treatment with insulin or oral hypoglycaemic agents) were also excluded from the study.…”

Section: Methodsmentioning

confidence: 99%

“…Given the lack of available reliable information about the prevalence and the determinants of moderate to severe steatosis in the RA population, a formal calculation of sample size adjusted for potential confounders was not done: however, considering the prevalence of age-adjusted moderate to severe steatosis in the general population of Western countries being 21% (as reported in the National Health and Nutrition Examination Survey, NHANES III) 16 and assuming a prevalence of moderate to severe steatosis of 34.5% (as estimated in a preliminary evaluation in 50 RA from a previous study) 13 we calculated that a sample size of 363 subjects (case: control = 1.5:1) would be needed to find a statistically significant difference ( p < 0.05) with a power of 80%.…”

Section: Methodsmentioning

confidence: 99%

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Prevalence and risk factors of moderate to severe hepatic steatosis in patients with rheumatoid arthritis: an ultrasonography cross-sectional case–control study

Erre

Castagna

Sauchella

et al. 2021

Therapeutic Advances in Musculoskeletal

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Background: The independent association between hepatic steatosis and rheumatoid arthritis is poorly defined. Methods: The presence of moderate to severe steatosis was assessed, using liver ultrasonography, in 364 consecutive non-diabetic subjects (223 patients with rheumatoid arthritis and 141 age- and sex-matched healthy controls). Adjusted multiple regression analysis was performed to explore the association between rheumatoid arthritis and moderate to severe steatosis in the overall sample and identify independent risk factors in the rheumatoid arthritis subgroup. Results: The prevalence of moderate to severe steatosis in the overall sample was 31.3%, with a significantly higher prevalence in patients with rheumatoid arthritis than healthy controls (38.7% versus 19.7%, p < 0.0001). After adjustment for sex, age, cholesterol, triglycerides, body mass index, waist, hypertension and smoke, rheumatoid arthritis remained significantly associated with moderate to severe steatosis [odds ratio (95% confidence interval) = 2.24 (1.31, 3.84); p = 0.003]. In the rheumatoid arthritis group, male sex, higher body mass index, higher triglycerides concentrations and higher cumulative dosage of methotrexate [odds ratio (95% confidence interval) = 1.11 (1.01, 1.23); p = 0.026] were significantly associated with moderate to severe steatosis, while systemic inflammation, disease activity, use of steroids and biologics were not. Conclusion: Rheumatoid arthritis is independently associated with moderate to severe steatosis, with male sex, higher body mass index and cumulative dose of methotrexate being predisposing factors. Further prospective studies are warranted to confirm our findings and to investigate the effect of steatosis on liver outcomes in the rheumatoid arthritis population.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Prevalence and risk factors of moderate to severe hepatic steatosis in patients with rheumatoid arthritis: an ultrasonography cross-sectional case–control study

Erre

Castagna

Sauchella

et al. 2021

Therapeutic Advances in Musculoskeletal

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“…Whilst it is possible that time may be the confounding factor here, cumulative dose is a surrogate marker for duration of treatment and indeed several studies directly examined duration of MTX treatment and found no significant association. 41,46,63 We believe that MTX-induced liver injury is not a distinct entity, but rather, that it is either under the umbrella of NAFLD or possibly a risk factor that can accelerate NAFLD/NASH in highly susceptible individuals. Evidence in support of this emerges from reports which have shown marked similarities in risk factors between those with presumed MTX-induced liver injury and NAFLD.…”

Section: Discussionmentioning

confidence: 96%

Is methotrexate hepatotoxicity associated with cumulative dose? A systematic review and meta‐analysis

Azzam

Jiyad

2021

Aust J Dermatology

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Background/objective: Methotrexate (MTX) is widely used in various medical specialties. However, hepatotoxicity is an ongoing concern and this is thought to be directly associated with cumulative dose. We sought to synthesise the published literature to evaluate the association between methotrexate hepatotoxicity and cumulative dose.Methods: A systematic review of Medline (PubMed) EMBASE, CINAHL and The Cochrane Library was performed. Full texts of articles were examined, and excluded articles were recorded with reasons for exclusion. A meta-analysis of correlation coefficients was performed using Fisher's z-transformation and a random effects model. Cochran's Q-test and the I 2 statistic were calculated to assess heterogeneity.Results: A total of 35 studies met inclusion criteria.Measures of hepatotoxicity were highly varied and included liver biopsy, elastography, FibroTest, biochemical tests and scoring systems (Fib-4, APRI, AST:ALT). Some studies analysed for the association with MTX cumulative dose using more than one modality. Overall, 38 analyses found no significant association between MTX cumulative dose and hepatoxicity vs eight that identified a significant association. The pooled correlation coefficient from five studies which utilised elastography was 0.18 (95% CI, À0.09 to 0.42), with significant heterogeneity between studies (P < 0.0001), I 2 = 92%).Conclusions: Our synthesis of a large volume of studies in this review found no significant association between MTX cumulative dose and hepatotoxicity, both in terms of vote counting and with regard to the meta-analysis of correlation coefficients from studies that utilised elastography. This challenges the long-held belief that liver injury is a direct result of drug accumulation.

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“…The results were measured in kilopascals. The distinguishing point of liver fibrosis was established at 7.1 kPa and 13 kPa for liver cirrhosis which corresponds with METAVIR F2 and F4 degrees in vast majority of analyzed studies [8,[10][11][12][13][14]. In case of acquiring fewer than 10 or lesser than 60% valid shots or the variability of measurements was higher than 30% of the median value of liver stiffness the result was counted as unreliable (equivocal result).…”

Section: Data Collection and Participantsmentioning

confidence: 99%

Usefulness of noninvasive diagnostic procedures for assessment of methotrexate hepatotoxicity in patients with rheumatoid arthritis

et al. 2021

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Methotrexate (MTX) is recommended as a first-line treatment for rheumatoid arthritis (RA). There are no strict guidelines regarding monitoring for liver damage in RA patients. This study aimed to evaluate noninvasive diagnostic procedures in assessing liver fibrosis in RA patients. Ninety-six RA patients were recruited for this study. The procollagen III N-terminal peptide (PIIINP) serum level was measured in all patients. The Enhanced Liver Fibrosis score (ELF-1) was calculated for 82 patients. Transient elastography (TE) was performed in 91 patients, those examined were divided into two groups: a study and control group, comprising patients with and without risk factors for liver fibrosis, respectively. The TE result correlated only with the body mass index—BMI (p < 0.05); there was no correlation with the cumulative MTX dose (p = 0.33). The TE result was significantly higher in those with risk factors for liver fibrosis than in those without risk factors (TE result > = 7.1 kPa 28/42 vs 13/41, HR = 2.103, Mann–Whitney U test, approximately 0.02). There was a positive correlation between the PIIINP level and body weight (p = 0.028), cumulative MTX dose (p = 0.007), RA activity (p = 0.028) and diabetes mellitus (DM) (p = 0.001). There was a positive correlation between the ELF-1 score and age (p < 0.001), cumulative MTX dose (p = 0.007) and RA activity (p < 0.001). The PIIINP level and ELF-1 score are not organ specific, and readings may vary depending on RA activity. TE is organ specific and can be performed by a skilled ultrasonographer might be useful to assess actual liver condition.

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Methotrexate therapy is not associated with increased liver stiffness and significant liver fibrosis in rheumatoid arthritis patients: A cross-sectional controlled study with real-time two-dimensional shear wave elastography

Cited by 15 publications

References 29 publications

Prevalence and risk factors of moderate to severe hepatic steatosis in patients with rheumatoid arthritis: an ultrasonography cross-sectional case–control study

Prevalence and risk factors of moderate to severe hepatic steatosis in patients with rheumatoid arthritis: an ultrasonography cross-sectional case–control study

Is methotrexate hepatotoxicity associated with cumulative dose? A systematic review and meta‐analysis

Usefulness of noninvasive diagnostic procedures for assessment of methotrexate hepatotoxicity in patients with rheumatoid arthritis

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