Objective To evaluate the impact of tumour necrosis factor α (TNFα) blockers on the presence of liver fibrosis in patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA) treated with methotrexate (MTX).
Methods Participants were consecutive patients with RA and PsA who had undergone MTX treatment for at least 1 year ± TNF blockade for over 6 months. Liver fibrosis was assessed using non-invasive transient elastography (FibroScan). Regression models were used to compare FibroScan values of patients with RA and patients with PsA receiving TNFα blockers with those who were not.
Results FibroScan assessments were performed on 51 patients with RA and 43 patients with PsA. Compared to patients with RA, those with PsA were predominantly young men, received lower cumulative dosages of MTX and exhibited a higher incidence of liver steatosis and hyperlipidaemia. An abnormal result was observed in 7.1% of the anti-TNFα-naïve and in 13% of the anti-TNFα-treated patients in the RA group and in 30% of the anti-TNFα-naïve and 4.3% of the anti-TNFα-treated patients in the PsA group (OR=0.11, 95% CI 0.02 to 0.98). Results of the PsA group were robust when adjusted for baseline characteristics.
Conclusion The results suggest a protective effect of TNFα inhibitors against the development of liver fibrosis in patients with PsA.
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Longstanding treatment with methotrexate (MTX) in patients with rheumatoid arthritis (RA) or psoriatic arthritis (PsA) is associated with increased liver toxicity. Institutional guidelines for monitoring of MTX-associated hepatotoxicity are effective in most countries and include periodic determination of aminotransferase serum levels or liver biopsy.1 However, the role of liver biopsy has been questioned,2 3 and it has been proposed that the detection of abnormal serum levels of the N-terminal peptide of type III procollagen might identify patients at risk, thereby reducing the number of biopsies in patients who are psoriatic by 45%.4 Recently, transient elastography (FibroScan; Echosens, Paris, France)was accepted as an alternative method to quantify liver tissue stiffness.5 This method has been widely used and validated in patients with viral hepatitis where the results correlate histologically with hepatic fibrosis.6 7
Anti-tumour necrosis factor α (anti-TNFα) treatment for concomitant rheumatic disorders in patients with chronic hepatitis C8 and non-alcoholic steatohepatitis (NASH)9 showed a favourable outcome of liver disease. We hypothesised that MTX-related liver toxicity could also benefit from anti-TNFα treatment and therefore performed a prospective observational study to assess liver fibrosis using FibroScan in a population consisting of patients with PsA and RA on long-term treatment with MTX who had been given additional TNFα blockade.
Patients and methods
We included patients with RA and patients with PsA with a valid baseline FibroScan (see supplementary methods 1 for detailed information) who had been consecutively recruited from the outpatient clinic of the Department of Rheumatology and Immunology at Bern University Hospital, Bern, Switzerland (see supplementary methods 2 for the patient flow).
All patients had been receiving MTX treatment for at least 1 year with or without anti-TNF blockade for over 6 months. RA and PsA diagnoses were based on established classification criteria.10 11 Demographic information was obtained through direct questioning (age, sex, body mass index (BMI), diabetes mellitus, alcohol consumption, MTX application, folic acid supplementation) or using retrospective chart reviews (disease duration, MTX cumulative dose, hyperlipidaemia, steatosis, hepatitis). Measurements of liver enzyme levels during MTX exposure were screened for any elevations (over twice the upper limit of aspartate aminotransferase (ASAT) or alanine aminotransferase (ALAT) levels).
Patient characteristics stratified by disease (RA and PsA) and TNFα treatment were compared using the Kruskal–Wallis rank test for continuous variables and Fisher's exact test for categorical variables. To describe the association of anti-TNFα treatments with abnormal FibroScan measurements in terms of odds ratios, we fitted logistic regression models with FibroScan assessments as the outcome variables. To assess whether the association with anti-TNFα treatment differed between patients with RA and patients with PsA we included in the regression models an appropriately constructed effect modification term and reported its p value, allowing us to determine the statistical likelihood that effect modification was present. In sensitivity analyses we included additional baseline characteristics in the logistic regression models to adjust for BMI, age, gender, alcohol intake, diabetes mellitus, disease duration, cumulative MTX dose and cumulative folic acid dose and tested for the interaction between each of these factors with MTX and anti-TNFα treatments. All p values are two sided and analyses were performed in Stata V.10 (Stata Corporation, College Station, Texas, USA).
Patients' baseline characteristics
Table 1 demonstrates the differences in demographics, disease-related and treatment-related factors, comorbidities and FibroScan findings between 51 patients with RA and 43 patients with PsA (all with oligoarticular or polyarticular disease courses) either treated with MTX alone or with a combination of MTX and a TNFα blocker. Compared to patients with RA, those with PsA were younger and consisted of more men. Patients with PsA had received a lower cumulative dose of MTX with a trend to shorter disease duration compared to their RA counterparts. There was no difference between patient groups with regard to weekly MTX dose, route of MTX administration, dose of folic acid supplementation, or comedication with non-steroidal anti-inflammatory drugs or prednisone. At the time of the FibroScan exam all patients were at least in partial remission.
When comparing the incidence of comorbidities between patients with PsA and patients with RA we found no differences in BMI, current or past alcohol consumption, or concomitant diabetes mellitus. More patients in the PsA group had hyperlipidaemia and sonographically detected liver steatosis (seven patients with PsA vs no patients with RA and seven patients with PsA vs one patient with RA, respectively).
FibroScan measurements and association with anti-TNFα treatment
When analysing only patients with a valid FibroScan exam, we found abnormal results in 9.8% of patients with RA and 16.3% of patients with PsA. An abnormal result was observed in 2 of 28 anti-TNFα-naïve (7.1%) and in 3 of 23 anti-TNFα-treated (13%) patients in the RA group, but in 6 of 20 anti-TNFα-naïve (30%) and in only 1 of 23 anti-TNFα-treated (4.3%) patients with PsA. When stratified by anti-TNFα treatment, these findings resulted in a crude OR of 1.95 with a 95% CI of 0.30 to 12.8 for the RA group and a crude OR of 0.11 with a 95% CI of 0.02 to 0.98 for the PsA group (p=0.05 for interaction; table 2). These findings were confirmed by the higher absolute mean FibroScan value in the anti-TNFα-naïve PsA group (8.1 kPa) compared to the other groups (FibroScan values between 4.9 and 5.5 kPa, p value for trend 0.06; figure 1). Our results were robust to adjustment for BMI, age, gender, alcohol intake, diabetes mellitus, disease duration, cumulative MTX dose and folic acid dose, with adjusted ORs ranging from 0.02 to 0.13 in the PsA group. When adjusting for all variables, we obtained an OR of 0.03 (95% CI 0.02 to 1.11). Adjustments in the RA group resulted in a slightly more heterogenous picture. Whereas adjustment for BMI, age, gender, alcohol intake and diabetes mellitus did not change the OR, adjustment for disease duration, cumulative MTX dose and folic acid dose yielded an adjusted OR of 1.14. However, adjusting for all variables still showed an OR of 1.73 (95% CI 0.16 to 18.2) (table 2).
This observational study is the first to show that treatment with TNFα blockers may exert a protective effect against liver fibrosis in patients with PsA treated with MTX. This finding was robust to the adjustment for potentially confounding factors. Patients with RA had lower FibroScan values than patients with PsA in the MTX alone group, despite a higher cumulative dosage of MTX. These low FibroScan values may have masked a potential antifibrotic effect of TNF inhibition in the cohort of patients with RA. The discrepancy between the PsA and RA MTX alone groups supports earlier notions that disease-associated factors, either pathogenesis linked or comorbidity linked, play an important role in liver fibrosis.
While this is the first study that has used a mixed cohort of patients with RA and patients with PsA to report benefits of anti-TNFα treatment for liver fibrosis, it has its limitations. The number of patients was low and the duration of anti-TNFα treatment compared to MTX treatment was short. In addition, some of the data collection (eg, disease duration, cumulative MTX dose, comorbidities) had to be performed retrospectively, as we included patients with longstanding disease. However, we tried to minimise the impact of this potential bias by blinding the chart reviewer to the FibroScan outcome.
Our results are in good agreement with the favourable hepatological outcomes previously described in patients with chronic hepatitis C7 or NASH8 following anti-TNFα treatment for concomitant rheumatic disorders. These human data, as well as recent results obtained from an experimental model of NASH in rats,12 underline the pathogenic role of TNFα in acute and chronic liver disorders. There is an abundance of indirect evidence that TNFα might be involved in the pathogenesis of liver fibrosis in systemic rheumatic diseases caused either by the inflammatory rheumatic processes themselves or by concomitant comorbidities. For instance, TNFα plays a key role inducing fibrogenic growth factors such as transforming growth factor β (TGFβ)13 and connective tissue growth factor (CTGF)14 in fibrotic liver diseases. Additionally, liver fibrosis is thought to be the result of chronic portal inflammation in non-alcoholic fatty liver disease15 that is often linked to obesity16 and dyslipidaemia,17 comorbidities that along with diabetes mellitus define the metabolic syndrome that is often associated with psoriasis.18 Moreover, patients with MTX-treated psoriasis and risk factors for liver disease, particularly type 2 diabetes or obesity, are at higher risk of developing severe liver fibrosis compared to those without such risk factors, even when lower cumulative MTX doses are given.19 Accordingly, in our study we found a higher prevalence of liver steatosis and dyslipidaemia at baseline in the PsA group compared to the RA group.
We cannot discern whether the higher frequency of liver pathology in patients with PsA is due to associated hepatotoxic comorbidities such as liver steatosis rather than to liver disease caused by the chronic immunologically mediated inflammatory process itself. Irrespective of the cause of liver inflammation, however, the results of this study provide the first evidence that anti-TNFα treatment is likely to protect against the evolution of liver fibrosis in patients with PsA. To validate the findings of our study, prospective studies with repeated FibroScans in patients with PsA before and after starting MTX and/or anti-TNFα treatment will be needed.
Competing interests None.
Ethics approval The local research committee deemed the study as a quality improvement activity and waived the requirement for institutional review board approval.
Provenance and peer review Not commissioned; externally peer reviewed.
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