Effect of Silymarin in Rheumatoid Arthritis Patients Treated With Methotrexate

Rheumatoid arthritis (RA) is an autoimmune disorder in which immune systems mistakenly attacks the host body systems. Its clinical features are often characterized as chronic synovial non-infectious inflammation, cartilage, and bone destruction (1). Currently, no effective drugs can be used to cure RA in the clinic. For the treatment of RA, recommended medications include disease-modifying anti-rheumatic drugs (DMARDs) and biologic agents, which intend to achieve the remission of symptoms, but these medications also confer severe side effects when they exert therapeutic efficiency (2). Due to drug resistance and side effects, a big proportion of RA patients do not effectively respond to the treatment and urgently need new drugs or therapeutic strategies.

Approximate 60% of RA patients are overweight and suffering from metabolic disorders (3). Clinical features of lipid paradox often occur in active RA patients, leading to high risk of developing cardiovascular morbidity and mortality (4-6). In addition, the deregulated lipid metabolism is yet present in the early stage of RA and/or pre-RA (7). In recent years, lipid-lowering therapy with statins is demonstrated to be effective in RA treatment (8,9) and in the prevention of the dyslipidemia development in RA patients (10). In short, we can confirm that lipid metabolism must be implicated in the pathogenesis of RA, which conserves the drug-target capacity for therapeutic discovery against RA in the clinic, especially for overweight patients with dyslipidemia (10).

Silymarin, a major flavonoid from milk thistle (silymarin), has been used to treat many liver disorders, such as nonalcoholic steatohepatitis (NASH), cirrhosis, and liver cancer, based on its anti-oxidant, anti-inflammation, anti-fibro genetic and lipid-lowering pharmacological activities (11).

Overexpression of liver X receptor α (LXRα) and several key lipogenic enzymes regulated by LXRα, including lipoprotein lipase (LPL), cholesterol 7α and 27α hydroxylase (CYP7A, CYP27A), adipocyte fatty acid-binding protein (aP2/FABP4) and fatty acid translocase (CD36/FAT), were observed in AIA rats, which mostly accounted for dyslipidemia during arthritis development. Metabolomics, docking technology, and biochemical results indicated that antiarthritis effects of silymarin related to suppressing the up-regulated LXRα and abnormal lipid metabolism. Notably, activation of LXRα could potentiate cell inflammatory process induced by LPS (Lipopolysaccharide) through the regulation of NF-κB pathway, however, suppression of LXRα agonism by siRNA or silymarin reduced the nuclear translocation of NF-κB as well as the induction of downstream cytokines, indicating LXRα agonism is the important factor for the arthritis development and could be a potential target (12). Considering the priority of silymarin in drug-safety, and the potential in improving lipid metabolism, therefore our effort attempted to explore the therapeutic potential of silymarin against RA with dyslipidemia, effect of silymarin on lipid profile and lipoprotein lipase and decipher associated molecular mechanisms accordingly.

Methotrexate has remained the "anchor drug" for most patients since the late 1980s (13). However, despite its long-term and widespread use for RA, methotrexate induce liver and nephrotoxicity, In study done by Adel A Hagag et al, on 80 children with newly diagnosed Acute Lymphoblastic Leukemia (ALL) received Silymarin 420 mg/day in 3 divided doses for one week after each MTX dose indicate that Silymarin improved some hepatic and renal functions in children with ALL who received MTX-based chemotherapy protocols (14).

In the present study, we evaluate the lipid profile and the major lipid metabolic enzymes in rheumatoid arthritis patients treated with methotrexate, and further explore the effects of silymarin in ameliorating both arthritis, dyslipidemia, the underlying mechanism of silymarin against RA through the regulation of lipoprotein lipase / lipid metabolism as well as effect of silymarin on methotrexate liver and renal toxicity.

• Inclusion criteria:

• Patients with active rheumatoid arthritis (not in remission) according to 28 joints disease activity score (DAS-28) >2.6.
• Age range between 18 and 60 years old.
• Both sexes.
• Sex ratio, age, disease activity, and disease duration matched patients.
• Patients receive methotrexate plus traditional therapy
• Exclusion criteria:

• Patients with renal or hepatic diseases (chronic liver disease, liver cirrhosis, alcoholic hepatitis, or chronic alcoholism).
• Patients receiving biological DMARDs.
• Patients with hypersensitivity to study medications.
• Patients using antioxidants except silymarin.
• Pregnant and lactating females.