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.

Metformin directly targets the H3K27me3 demethylase KDM6A/UTX

“…These findings support the notion that since transporters involved in uptake and extrusion of metformin were designed by nature for endogenous substrates, the metabolic effects of metformin might involve substrate competition phenomena with metabolites or nutrients (Glossmann & Reider, 2013). Metformin and related biguanides are known to bind endogenous metals such as Zn 2+ , Cu 2+ , Fe 3+ that independently inhibit pro‐inflammatory proteases (Glossmann & Reider, 2013; Lockwood, 2010; Logie et al., 2012; Sweeney et al., 2003; Thorne & Lockwood, 1991). Accordingly, our systematic chemoinformatics approach confirmed that metallopeptidases and proteins with transition metal ion‐binding properties were significantly overrepresented among the predicted targets for metformin.…”

Mechanism of action and effect of immune-modulating agents in the treatment of psoriasis

“…agonist showed a significant reduction in the level of serum CRP compared to patients with psoriasis who did not receive treatment. Metformin, a biguanide family member, is antiinflammatory and immunosuppressive in various experimental mouse models of autoimmune diseases [28]. Metformin may have a specific interaction with mechanisms involved in CRP synthesis or secretion dampening related to chronic inflammation [29].…”

Nutrition: a key environmental dietary factor in clinical severity and cardio-metabolic risk in psoriatic male patients evaluated by 7-day food-frequency questionnaire

“…To date, a careful evaluation of dietary intake using the 7-day food records, considered the “gold standard” of self-administered food frequency questionnaires [ 16 , 17 ], has not been yet provided, and no studies evaluating separately the dietary intake in males and females with psoriasis are available. Moreover, the large majority of studies have included patients in treatment with anti-psoriatic agents, such as biologics, systemic corticosteroids or methotrexate, which may have interfered with anthropometric measures and blood glucose and lipid profile [ 18 ]. Finally, in the setting of the inflammation-related insulin resistance, the association between psoriasis and other cardio-metabolic risk indices, such as the Visceral Adiposity Index (VAI), a gender-specific indicator of adipose distribution and dysfunction [ 19 ], and the Fatty Liver Index (FLI), as an accurate predictor of HS [ 20 ] has not yet evaluated.…”