Tripterygium glycosides (TGs) are widely used in the treatment of rheumatoid arthritis (RA); however, their long-term application is frequently limited by hepatotoxicity. In this study, we observed that TGs significantly increased the incidence of hypoalbuminemia in RA patients, notably in the absence of concurrent liver enzyme abnormalities.

A retrospective analysis was conducted in 146 RA patients treated with TGs, 62 with methotrexate (MTX), and 54 with combination therapy (TGs + MTX). Serum albumin levels were measured before and after treatment. Logistic regression was employed to identify risk factors associated with post-treatment hypoalbuminemia. In parallel, a preclinical study was conducted in collageninduced arthritis (CIA) rats treated with TGs to assess portal vein pathological morphology of the liver and the intestine, lipopolysaccharide (LPS), intestinal tight junction proteins, and ferroptosis markers.

Baseline serum albumin levels were comparable among the three groups. Following treatment, the TGs and TGs + MTX groups exhibited significant reductions in mean serum albumin levels, whereas the MTX group showed stable levels. Consequently, the incidence of hypoalbuminemia increased significantly in the TGs group (from 3.4% to 26.0%, ) and the TGs + MTX group (from 0% to 18.5%, ), but not in the MTX group (from 1.6% to 4.8%, ). Multivariable logistic regression identified advanced age as an independent risk factor for the development of hypoalbuminemia. Preliminary experimental data from TGs-treated collagen-induced arthritis (CIA) rats revealed elevated portal vein lipopolysaccharide (LPS) levels, decreased intestinal tight junction protein expression (ZO-1 and Occludin), and increased markers of ferroptosis (ASCL-4), without evidence of hepatocellular necrosis.

Treatment with TGs, either alone or in combination with MTX, is associated with the development of hypoalbuminemia in RA patients, particularly in those of advanced age. These findings suggest that TGs-induced hypoalbuminemia may represent a distinct subtype of hepatotoxicity, potentially mediated by gut barrier dysfunction and ferroptosis, warranting closer monitoring in vulnerable populations.