New models for rheumatoid arthritis drugs

Dr Sandra Sacre

A new study, by Dr Sandra Sacre, Lecturer in Molecular Biology at BSMS found that fluoxetine (Prozac) and citalopram (Celexa) commonly used as antidepressants may provide drug development opportunities for rheumatoid arthritis.

The research performed at The Kennedy institute of Rheumatology studied the anti-inflammatory potential of these drugs, known as selective serotonin reuptake inhibitors (SSRIs). Both SSRIs exhibited anti-arthritic effects in models of rheumatoid arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease that causes inflammation in the lining of the joints. Typically, it first affects hand and foot joints and later the disease spreads to larger joints. Inflammation eventually erodes the cartilage between the joints causing pain, stiffness, joint deformity, and physical disability. According to the 2000 Global Disease Burden study by the World Health Organization (WHO), RA affects approximately 1% of the world population.

Dr Sacre, said: "We were interested in SSRIs because of their reported anti-inflammatory effects. Prior studies have shown that patients with depression who respond to treatment with SSRIs display a reduction in cytokine levels (signals that can induce inflammation), suggesting a connection between SSRIs and the immune system. Our studies observed reduced inflammation, reduced cartilage and bone erosion, and a preservation of the joint structure in a model of RA”.

Researchers also observed a decrease in cytokine production from cultures of human RA synovial joint tissues that were treated with SSRIs. Toll-like receptors (TLRs) are strong activators of immune cells leading to the production of cytokines that can induce inflammation. Fluoxetine was found to inhibit the activation of TLRs more effectively than citalopram.

"While the SSRIs effectively target TLRs and inflammation in RA models, they are not ideal candidates to progress into clinical trials," concluded Dr. Sacre. The levels of the SSRIs required to halt disease progression are higher than normally prescribed for standard treatment (depression in humans). "Our data suggests that effective inhibition of RA would require levels of the drugs higher than the safe therapeutic dosages." The authors suggest further study of the role of TLRs in chronic inflammation may uncover drugs that offer an effective treatment of RA in the future.

Full findings of this study are published in the March issue of Arthritis & Rheumatism, a journal of the American College of Rheumatology at www.rheumatology.org

Article: "Fluoxetine and Citalopram Exhibit Potent Antiinflammatory Activity in Human and Murine Models of Rheumatoid Arthritis and Inhibit Toll-like Receptors." Sandra Sacre, Mino Medghalchi, Bernard Gregory, Fionula Brennan, and Richard Williams. Arthritis & Rheumatism; Published Online: February 25, 2010 (DOI: 10.1002/art.23704); Print Issue Date: March 2010.