Effect of Silymarin in Rheumatoid Arthritis Patients Treated With Methotrexate

Phase 4

Not yet recruiting

• Conditions: Rheumatoid Arthritis (RA)
• Interventions: Drug: MTX S.C or IM and Silymarin 140 mg tab; Drug: MTX S.C or IM

• Registration Number: NCT06724952
• Lead Sponsor: Tanta University

Brief Summary

The goal of this clinical trial is to evaluate the anti-rheumatic activity and the role of silymarin in attenuating methotrexate toxicity in patients with rheumatoid arthritis.

Methodology:

This is a randomized, double blind placebo controlled parallel study that will be conducted on 44 patients with active rheumatoid arthritis.

Group1 (placebo group; n=22) which will receive IM or SC Methotrexate plus placebo tablet once daily for 3 months.

Group2 (Silymarin group; n=22) which will receive IM or SC Methotrexate plus Silymarin tablets 140 mg once daily for 3 months.

Duration: 3 months

Monitoring:

Participants will be followed up by weekly telephone calls and monthly direct meeting at scheduled visits to assess their adherence and to report any drug related adverse effects.

In summary, this clinical trial is designed to determine if Silymarin is a safe and effective treatment for Rheumatoid Arthritis Patients Treated with Methotrexate by comparing its effects to a placebo and closely monitoring participants throughout the study.

Detailed Description

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.

Study Timeline

• Study First Submitted: 2024-10-06
• Status Verified: 2024-12
• Study First Submitted QC: 2024-12-06
• Last Update Submitted: 2024-12-06
• Study First Posted: 2024-12-09
• Last Update Posted: 2024-12-09
• Study Start: 2024-12-10
• Primary Completion: 2025-03-10
• Study Completion: 2025-04-10

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 44

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
MTX S.C or IM _ Silymarin tab	MTX S.C or IM and Silymarin 140 mg tab	IM or S.C MTX plus Silymarin 140 mg Tab once daily
MTX S.C or IM _ Placebo tablet	MTX S.C or IM	IM or S.C MTX plus Placebo Tablet once daily

Primary Outcome Measures

Name	Time	Method
Calculation of DAS-28-CRP score for measure disease activity.	From enrollment to the end of treatment at 3 months	This is a score for measure of disease activity in Rheumatoid Arthritis; Less than 2.6 mean RA is in remission, 2.6 to 3.2 mean low level of disease activity, More than 3.2 mean active disease that may require change in medication, More than 5.1 mean very active disease that requires careful monitoring and adjustment to medication

Secondary Outcome Measures

Name	Time	Method
Measurement of serum Nuclear factor kappa-B p65 (NF-κ B p65) & Lipoprotein lipase (LPL).	From enrollment to the end of treatment at 3 months	Before and 3 months after the intervention, 5 ml of venous blood will be withdrawn by antecubital venipuncture from each participant between 8:30 and 10:30 am. Blood samples will be transferred into a plain test tube and centrifuged at 3000 rpm for 10 min. the separated serum will be used for determination of: serum Nuclear factor kappa-B p65 (NF-κ B p65) \& Lipoprotein lipase (LPL).; serum Nuclear factor kappa-B p65 (NF-κ B p65): one of the main inflammatory pathways in the Autoimmune Disease (AD) Rheumatoid Arthritis (RA), which exhibits high levels of inflammatory cytokines such as IL-1, TNFa and IL-6.; Lipoprotein lipase: Overexpression of liver X receptor α (LXRα) and several key lipogenic enzymes regulated by LXRα, including lipoprotein lipase (LPL) were observed in adjuvant-induced arthritis.

Trial Locations

Locations (1)

Outpatient Clinic of Internal Medicine, Rheumatology and Immunology Department, Mansoura University Hospital, Mansoura, 35511; 🇪🇬 Mansoura, Egypt