The AMPK Modulator Metformin as a Novel Adjunct to Conventional Therapy in Rheumatoid Arthritis Patients
The AMPK Modulator Metformin as a Novel Adjunct to Conventional Therapy in Rheumatoid Arthritis Patients
Metformin, a traditional antidiabetic medication, exerts glucose lowering effects by
 activating AMP-activated protein kinase (AMPK), a critical enzyme involved in the lipid and
 glucose metabolism. In addition to the antidiabetic effect, metformin has been shown to
 inhibit Lipopolysaccharide-Induced Inflammation (LPS)-induced inflammation by suppress NF-κB
 production, which is also regulated by AMPK. These regulatory effects of AMPK on the
 inflammation, immune and fibroblast-like synovial cells have prompted the investigation on
 the effects of metformin on rheumatoid arthritis.
Rheumatoid arthritis (RA) is a chronic, multisystem inflammatory disorder of unknown
 etiology. It is characterized by polyarthritis and systemic inflammation. The inflammation in
 the hyperplastic synovium can destruct the structure of affected joints. Although the exact
 molecular mechanism underlying the pathogenesis of RA remains unknown, it is suggested that T
 helper cell (Th) 17 plays a central role. Interleukin (IL)-17, mostly secreted by Th17, has
 synergistic effects with tumor necrosis factor- (TNF-α), IL-1β and IL-6 in cases of RA.
 Metformin, a traditional antidiabetic medication, exerts glucose lowering effects by
 activating AMP-activated protein kinase (AMPK), a critical enzyme involved in the lipid and
 glucose metabolism. In addition to the antidiabetic effect, metformin has been shown to
 inhibit Lipopolysaccharide-Induced Inflammation (LPS)-induced inflammation by suppress NF-κB
 production, which is also regulated by AMPK . In addition, metformin activated AMPK may
 inhibit mammalian target of rapamycin (mTOR), which then regulate the differentiation of T
 cells in vitro and in vivo. In particular, AMPK has been reported to be associated with the
 inhibition of TH17 cells through suppressing the phosphorylation of mTOR and its downstream
 signal transducers, suggesting the therapeutic potential of AMPK agonists. Besides the
 imbalance between Th17 cells and Treg cells is responsible for the chronic inflammation in
 RA, synovium hyperplasia also plays a central role in the joint destruction. It has been
 reported that rapamycin, an inhibitor of mTOR, is able to significantly reduce fibroblastlike
 synovial cell invasion in RA via suppressing mTOR signaling pathway. These regulatory effects
 of AMPK on the inflammation, immune and fibroblast-like synovial cells have prompted the
 investigation on the effects of metformin on rheumatoid arthritis.
Inclusion Criteria:

 -  Patients with active rheumatoid arthritis based on DAS28 score. Patients received the
 standard therapy (i.e. one or more conventional DMARDs) for at least three months.

 Exclusion Criteria:

 -  Known hypersensitivity to metformin.

 -  Patients who have a prior diagnosis with diabetes mellitus.

 -  Patients receive metformin for any other indications.

 -  Patients with congestive heart failure.

 -  Patients with a history of myocardial infarction.

 -  Patients with severe anemia.

 -  Patients with active infections or other inflammatory diseases.

 -  Patients receiving biological therapy.

 -  Pregnancy or lactation.

 -  Patients with impaired liver functions.

 -  Patients with impaired kidney functions (serum creatinine concentrations ≥1.5 and ≥1.4
 mg/dL in males and females respectively).

 -  Patients with malignancies.