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Three Ways to Improve Prednisone in RA

June 13 2015 6:00 AM ET via RheumReports RheumReports

I love prednisone. There I said it. Dr. Tony Russell please don’t hurt me. I love prednisone because it makes the world a better place - patients feel better, I feel better, and my secretary feels better. I hate prednisone. I hate prednisone because the side effects can be devastating, patients get cataracts, diabetes, fractures and the worst of all … weight gain!

Steroids have been in use for more than 60 years. They far exceed other drugs in terms of the numbers of patients treated, the variety of applications, and the pharmacologic experience in humans. They are still the most important and most frequently employed class of immunosuppressive drugs in rheumatology with a steady rise in therapeutic use in the recent years. They are used to treat about 60% of RA patients and about 1.2% of the US population is regularly taking a glucocorticoid. They are a cornerstone in RA therapy. You can’t argue the facts.

On a cellular level, glucocorticoids inhibit leukocyte traffic and the access of leukocytes to sites of inflammation. They interfere with the functions of leukocytes, fibroblasts, and endothelial cells. They also suppress the production and actions of humoral factors involved the inflammatory process.

In RA, steroids have been shown to reduce the signs and symptoms and retard radiographic progression of the disease (Kirwin et al, NEJM 1995). 

The sensible approach to the use of steroids in RA is to use them responsibly.  Deliver them directly to the site of inflammation (i.e. injections), use as much as necessary and as little as possible, and evaluate co-morbidities. 

In recent years, alternatives approaches and delivery methods of steroids have been studied. One such approach has been the development of Selective Glucocorticoid Receptor Agonists (SEGRA) also known as Dissociated Agonist of Glucocorticoid Receptors (DAGR). Here’s the science behind this - Glucocoriticoids work by 2 mechanisms of action called transrepression and transactivation. Currently it is thought that transactivation result in side effects whereas transrepression mediates the beneficial effects of glucocorticoids. SEGRA and DAGR are designed to preferentially use transrepression.

In an early study 45 patients with RA were randomized to DAGR 1 mg, 5 mg, 10 mg, or 15 mg, OD vs Prednisone 5 mg and 10 mg OD  or PBO. The DAGR was as effective as prednisone in terms of DAS-28 scores at week 8. In terms of side effects there may be a trend in improved glucose metabolism with DAGR although the numbers were small and the time period was short. Stay tuned.

Another way of improving the benefit-risk of steroids is to encapsulate them inside liposomes made of polyethylene glycol (PEG). The trick is the liposomes are given intravenously and accumulate in the site of inflammation. Macrophages phagocytose the liposomal vesicles and carry them to the site of inflammation. The vesicles also accumulate where the pH is low and inflammation is a site of lower pH. Finally, these liposomes can also leak through the permeable vessels at the site of inflammation. This has been employed in animal models and there is ongoing research in this area. 

Finally, chronotherapy with modified or delayed release prednisone therapy. Over the years we have learned that our immune system is very active at night. When we sleep we don’t need ATP for our muscles so we use our energy to focus on ATP in the brain and in the immune system. The immune system is very active at night so is our autoimmune reactivity. This is driven by a molecule called IL-6 which drives many immune processes as we know. IL-6 is upregulated at night and therefore may be a reason why patients have such AM stiffness. IL-6 levels start to rise at 2 AM and progressively increase through the night. The idea its to give a delayed release prednisone that is given at 10 pm and is released 4 hours later.  Studies (Ann Rheum Dis) have been published showing rapid and relevant improvements in RA signs and symptoms.


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About the Author

Dr. Andy Thompson
Dr. Andy Thompson

Dr. Andy Thompson is an Associate Professor at Western University and founder of Rheuminfo.com, Rheumtalks.com, and RheumReports.com.

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