Background/Purpose: 1) To analyze the impact of rheumatoid arthritis (RA) in the liver function, 2) To evaluate the impact of obesity and the effect of methotrexate (MTX) and leflunomide (LFN) in the liver alterations.

Methods: Human data: cross-sectional study carried out in 300 RA patients (200 non-obese and 100 obese), 100 obese non-RA and 100 healthy donors (HDs). Clinical and laboratory parameters were analyzed. In vitro model: Hep G2 cells were treated with IgG-ACPAs isolated from RA patients.  Mouse model: Collagen induced arthritis (CIA) was developed in obese and lean mice. 55 C57Bl/6 mice (4-5 weeks) were used. Forty mice were fed with high fat diet (60%) until reaching 30g (obese) (OB). CIA-OB mice were treated with LFN (10 mg/kg daily) or MTX (3mg/kg three times/week) for 15 days. Liver samples were collected. The expression of genes related to fibrogenesis (TGF-b1, COL1A1, a-SMA, TIMP1, MMMP-9, MMP-12), lipid metabolism (PLIN, MCAD, CD36, PPARg, DGAT, LPL), insulin signal (AKT, IRS-1, IRS-2 and GLUT-2), endoplasmic reticulum and oxidative stress (AOX and CHOP) and inflammation (TNF-a, IL-6, MCP-1, CD11c, F4/80) was analyzed.

Results: Within the normal range, the percentage of RA patients with altered levels of hepatic enzymes and albumin was significantly increased. Moreover, these levels were associated with autoimmunity and inflammatory markers. The in vitro treatment of HepG2 cells with IgG-ACPAs induced the expression of inflammatory and oxidative stress markers and altered the expression of genes involved in lipid and glucose metabolisms.  

On the other hand, RA non-OB patients treated with MTX or LFN did not show any differences in the hepatic subclinical alteration associated with RA. As expected OB non-RA subjects had altered levels of hepatic enzymes. Of note, RA OB patients taking MTX had significant increased levels of hepatic enzymes compared to RA non-OB and OB non-RA patients, suggesting the deleterious effect of MTX in those patients with obesity.

The induction of arthritis in both lean and obese mice elevated inflammatory, endoplasmic reticulum, oxidative stress and fibrogenesis related genes compared to non-disease mice. Supporting the data observed in the human study, treatment of CIA-OB mice with MTX significantly increased the hepatic alteration observed in OB mice. In contrast, LFN reduced genes involved in fibrogenesis, inflammation, endoplasmic reticulum and oxidative stress, suggesting an improvement of the liver function.

Conclusion:

1. RA patients display a subclinical alteration of the hepatic enzymes associated with inflammation and autoimmunity, suggesting that RA might be associated with liver abnormalities induced at least partially by the effect of ACPAs.
2. In mice, the generation of arthritis induced inflammation, fibrosis, endoplasmic reticulum and oxidative stress and an alteration in glucose and lipid metabolisms in the liver.
3. Methotrexate could affect the hepatic function as long as there is a subclinical pre-existent alteration of the liver such as obesity.

Funded by ISCIII (PI17/01316) co-funded with FEDER and Roche Pharma.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/liver-dysfunction-associated-with-rheumatoid-arthritis-impact-of-obesity-and-effects-of-dmards-in-hepatic-alterations/