A marriage of two “Methusalem” drugs for the treatment of psoriasis?

Abstract

In this article we present arguments that the “antidiabetic” drug metformin could be useful as an add-on therapy to methotrexate for the treatment of psoriasis and, perhaps, for rheumatoid arthritis as well. Biochemical data suggest that both drugs may share a common cellular target, the AMP-activated protein kinase (AMPK). This enzyme is a master regulator of metabolism and controls a number of downstream targets, e.g., important for cellular growth or function in many tissues including T-lymphocytes. Clinical observations as well as experimental results argue for anti-inflammatory, antineoplastic and antiproliferative activities of metformin and a case-control study suggests that the drug reduces the risk for psoriasis.

Patients with psoriasis have higher risk of metabolic syndrome, type 2 diabetes and cardiovascular mortality. Metformin has proven efficacy in the treatment of prediabetes and leads to a pronounced and sustained weight loss in overweight individuals. We expect that addition of metformin to methotrexate can lead to positive effects with respect to the PASI score, reduction of the weekly methotrexate dose and of elevated cardiovascular risk factors in patients with metabolic syndrome and psoriasis. For reasons explained later we suggest that only male, overweight patients are to be included in a pilot trial. On the other side of the coin are concerns that the gastrointestinal side effects of metformin are intolerable for patients under low dose, intermittent methotrexate therapy. Metformin has another side effect, namely interference with vitamin B₁₂ and folate metabolism, leading to elevated homocysteine serum levels. As patients must receive folate supplementation and will be controlled with respect to their B₁₂ status increased hematological toxicity is unlikely to result.

Keywords: :

• psoriasis
• metformin
• methotrexate
• AMP-activated protein kinase
• anti-inflammatory

Disclosure of Potential Conflicts of Interest

Both authors have received an honorarium by Pfizer for their contributions at a Symposium in Vienna on occasion of the 50th anniversary of methotrexate. No other conflicts of interest exist with respect to the above work.

Acknowledgments

The authors would like to thank numerous colleagues who supplied us with additional information including papers in press or reprints. Prof. Alan Dronsfield informed us on the real facts behind the “Magic Cure” with flumamime. Librarians of the University of Innsbruck were helpful providing us with long forgotten, not easily obtainable literature. Paula Olbrich and Johannes Werner supported us in organizing the literature, design of figures and more. We are very grateful for their help.

Notes

† If abdominal discomfort is a problem and since dermatology is interested in transdermal delivery or local therapy, the reader is referred to www.freepatentsonline.com/y2012/0283332.html.