Clinical trial NCT06724952: Effect of Silymarin in Rheumatoid Arthritis Patients Treated With Methotrexate
Official title: Clinical Study Evaluating Anti Rheumatic Activity and The Role of Silymarin in Attenuating Methotrexate Toxicity in Patients With Rheumatoid Arthritis
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE4
Conditions: Rheumatoid Arthritis (RA)
Keywords: Rheumatoid Arthritis
Silymarin
Methotrexate
Lead sponsor: Tanta University
Sponsor class: OTHER
First posted: 2024-12-09
Enrollment: 44
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: * 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.

Primary outcomes:
measure: Calculation of DAS-28-CRP score for measure disease activity.
timeFrame: From enrollment to the end of treatment at 3 months
Secondary outcomes:
measure: Measurement of serum Nuclear factor kappa-B p65 (NF-κ B p65) & Lipoprotein lipase (LPL).
timeFrame: From enrollment to the end of treatment at 3 months
Other outcomes:
Locations:
city: Mansoura
country: Egypt
facility: Outpatient Clinic of Internal Medicine, Rheumatology and Immunology Department, Mansoura University Hospital, Mansoura, 35511
Study officials:
References:
citation: Hagag AA, Elgamsy MA, El-Asy HM, Mabrouk MM. Protective Role of Silymarin on Hepatic and Renal Toxicity Induced by MTX Based Chemotherapy in Children with Acute Lymphoblastic Leukemia. Mediterr J Hematol Infect Dis. 2016 Sep 1;8(1):e2016043. doi: 10.4084/MJHID.2016.043. eCollection 2016.
citation: Weinblatt ME, Coblyn JS, Fox DA, Fraser PA, Holdsworth DE, Glass DN, Trentham DE. Efficacy of low-dose methotrexate in rheumatoid arthritis. N Engl J Med. 1985 Mar 28;312(13):818-22. doi: 10.1056/NEJM198503283121303.
citation: Xie Y, Feng SL, Mai CT, Zheng YF, Wang H, Liu ZQ, Zhou H, Liu L. Suppression of up-regulated LXRalpha by silybin ameliorates experimental rheumatoid arthritis and abnormal lipid metabolism. Phytomedicine. 2021 Jan;80:153339. doi: 10.1016/j.phymed.2020.153339. Epub 2020 Sep 19.
citation: Karimi G, Vahabzadeh M, Lari P, Rashedinia M, Moshiri M. "Silymarin", a promising pharmacological agent for treatment of diseases. Iran J Basic Med Sci. 2011 Jul;14(4):308-17.
citation: Nurmohamed MT, Dijkmans BA. Dyslipidaemia, statins and rheumatoid arthritis. Ann Rheum Dis. 2009 Apr;68(4):453-5. doi: 10.1136/ard.2008.104497. No abstract available.
citation: Soulaidopoulos S, Nikiphorou E, Dimitroulas T, Kitas GD. The Role of Statins in Disease Modification and Cardiovascular Risk in Rheumatoid Arthritis. Front Med (Lausanne). 2018 Feb 8;5:24. doi: 10.3389/fmed.2018.00024. eCollection 2018.
citation: Das S, Mohanty M, Padhan P. Outcome of rheumatoid arthritis following adjunct statin therapy. Indian J Pharmacol. 2015 Nov-Dec;47(6):605-9. doi: 10.4103/0253-7613.169585.
citation: Kerekes G, Nurmohamed MT, Gonzalez-Gay MA, Seres I, Paragh G, Kardos Z, Barath Z, Tamasi L, Soltesz P, Szekanecz Z. Rheumatoid arthritis and metabolic syndrome. Nat Rev Rheumatol. 2014 Nov;10(11):691-6. doi: 10.1038/nrrheum.2014.121. Epub 2014 Aug 5.
citation: Giles JT, Allison M, Blumenthal RS, Post W, Gelber AC, Petri M, Tracy R, Szklo M, Bathon JM. Abdominal adiposity in rheumatoid arthritis: association with cardiometabolic risk factors and disease characteristics. Arthritis Rheum. 2010 Nov;62(11):3173-82. doi: 10.1002/art.27629.
citation: Erum U, Ahsan T, Khowaja D. Lipid abnormalities in patients with Rheumatoid Arthritis. Pak J Med Sci. 2017 Jan-Feb;33(1):227-230. doi: 10.12669/pjms.331.11699.
citation: Amezaga Urruela M, Suarez-Almazor ME. Lipid paradox in rheumatoid arthritis: changes with rheumatoid arthritis therapies. Curr Rheumatol Rep. 2012 Oct;14(5):428-37. doi: 10.1007/s11926-012-0269-z.
citation: Roubenoff R, Roubenoff RA, Cannon JG, Kehayias JJ, Zhuang H, Dawson-Hughes B, Dinarello CA, Rosenberg IH. Rheumatoid cachexia: cytokine-driven hypermetabolism accompanying reduced body cell mass in chronic inflammation. J Clin Invest. 1994 Jun;93(6):2379-86. doi: 10.1172/JCI117244.
citation: Guo Q, Wang Y, Xu D, Nossent J, Pavlos NJ, Xu J. Rheumatoid arthritis: pathological mechanisms and modern pharmacologic therapies. Bone Res. 2018 Apr 27;6:15. doi: 10.1038/s41413-018-0016-9. eCollection 2018.
citation: McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med. 2011 Dec 8;365(23):2205-19. doi: 10.1056/NEJMra1004965. No abstract available.