الفهرس | Only 14 pages are availabe for public view |
Abstract Rheumatoid Arthritis (RA) is a chronic, inflammatory autoimmune disorder with clinical manifestations not limited only to joint damage but also a wide range of systemic manifestations. Joint destruction, disability, reduced productivity and the ability to perform the activities of daily living, reduced quality of life (QOL), and high mortality rates are hallmarks of inappropriately managed RA. Pathogenesis of RA is complex and involves activation of residential synoviocytes and macrophages as well as influx of many inflammatory cells under the influence of various cytokines and inflammatory mediators shifting the hemostasis towards inflammation. Current guidelines recommendation is to achieve clinical remission or at least low disease activity in these patients within six months of the diagnosis to prevent joint destruction and disease progression. Despite sticking to the guidelines recommended therapies, many patients have many unmet needs across many disease areas suggesting the need for additional therapeutic options for RA management. De-novo drug synthesis is a challenging process and is associated with many difficulties such as long time, high cost, and high failure rates. Drug repositioning is a promising approach which includes using existing drugs in management of other conditions. Metformin, the first-line agent in the management of type II diabetes, has several advantages such as: a low cost, high safety, and favorable metabolic actions. Metformin was consistently reported in the animal studies and in clinical trials conducted in non-RA patients to have antiinflammatory and immunomodulatory effects. The aim of this prospective, randomized, placebo-controlled study was to assess clinical outcomes in terms of efficacy and safety of metformin use in patients with active RA in adjunction to conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs). The study protocol was revised, approved by Research Ethics Committee of Experimental and Clinical Studies of Faculty of Pharmacy, Ain Shams University and patients were required to sign a written informed consent prior to participation. Summary P a g e 69 The study was conducted at Rheumatology and Immunology Unit of Internal Medicine Department at Al- Zahraa Universty Hospital located at Cairo during the period between October 2018 and March 2020. Patients were included if they were adult (older than 18 years), diagnosed with RA according to American College of Rheumatology/ European league Against Rheumatism (ACR/EULAR) 2010 criteria with moderate to high disease activity identified as disease activity score-28 based on C-reactive protein (CRP) levels (DAS-28-CRP) >3.2, receiving stable regimen of one or more csDMARDs for at least three months prior to inclusion. Exclusion criteria were; a known hypersensitivity to metformin, prior diagnosis with diabetes mellitus, receiving metformin for any other indications, receiving biologic DMARDs therapy, impaired liver functions (liver transaminases level ≥ three times upper normal limits), impaired kidney functions (estimated glomerular filtration rate (eGFR) <30 ml/min), pregnancy and lactation, as well as the presence of any of the following comorbidities including congestive heart failure, history of myocardial infarction, severe anemia, active infections, other inflammatory diseases, and malignancies. Sixty six RA patients were recruited and simply randomized into either: Metformin group: 33 RA patients who received 850 mg twice daily added to their stable baseline anti-rheumatic medications, followed-up for the next six months. Control group: 33 RA patients who received placebo twice daily added to their stable baseline anti-rheumatic medications, followed-up for the next six months. All patients were subjected to evaluation of baseline demographic and clinical characteristics. The following parameters were assessed to evaluate efficacy and safety of metformin use during the study duration: Level of serum C-reactive protein (CRP): assessed at baseline, three, and six months. Disease activity score of 28 joints based on serum C-reactive protein levels: assessed at baseline, three, and six months. Level of serum adiponectin: assessed at baseline and six months. Patients‟ QOL: assessed at baseline, three, and six months. Occurrence and incidence of adverse or side effects (if any). Summary P a g e 70 The current study has shown that Non-significant differences between the study groups regarding their demographic data and clinical characteristics at baseline. A significant reduction of serum CRP levels of the metformin group compared to the control group after six months. A significant reduction of DAS-28-CRP of the metformin group compared to the control group after six months. A significant reduction of serum adiponectin levels of the metformin group compared to a significant increase in serum adiponectin levels of the control group after six months. A significant improvement of QOL of the metformin group compared to the control group after three and six months. Safety and tolerability of metformin use in adjunction to csDMARDs where the most commonly reported adverse effects were gastrointestinal (GI) disturbances including nausea, abdominal pain, flatulence, and diarrhea which were mild to moderate in severity. |