الفهرس 
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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
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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
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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.