Corticosteroid Use In Rheumatoid Arthritis
Corticosteroids have a complicated role in treating RA. How are researchers working to find the balance between the benefits and risks?
In 1929, Dr. Philip Hench of the Mayo Clinic in Rochester, Minn., began noticing that patients with RA saw improvement in symptoms when their bodies were under other physiological stress – such as jaundice, pregnancy, surgery or infection.
Those observations led, nearly 20 years later, to the isolation and first use of what would be called cortisone.
Cortisone – the original corticosteroid – was considered a miracle drug at the time because of the dramatic and quick effect it had on rheumatoid arthritis. Newer treatments for the disease have come along, but corticosteroids – also commonly referred to as glucocorticoids – remain a powerful, if somewhat flawed, weapon in the anti-inflammatory arsenal, and there’s emerging evidence they do more than just provide symptomatic relief.
In fact, a recent study from the Netherlands, published in March 2012 in the Annals of Internal Medicine, found that adding the corticosteroid prednisone to a methotrexate regimen early in the disease process had numerous positive effects versus using methotrexate alone, including less joint damage, less physical disability and reduced disease activity.
“The correct use of [corticosteroids] will help to protect the joints from future damage and will mean that some patients will not need to go on to other treatments, such as biological agents, which are more dangerous and much more expensive,” says John R. Kirwan, MD, of the University of Bristol Academic Rheumatology Unit, Bristol, United Kingdom.
Dr. Kirwan recently authored a commentary, also in the March 2012 Annals of Internal Medicine, suggesting that therapy with corticosteroids – specifically, prednisone – in conjunction with another disease-modifying antirheumatic drug, or DMARD, should be considered the “gold standard” for early treatment of RA. And yet, Dr. Kirwan admits some doctors avoid use of corticosteroids for RA, primarily because of concern about side effects.
The Ups and Downs of Corticosteroids
Without a doubt, prednisone and other drugs in the class do come with a substantial number of possible side effects – most of which are dose-related.
“Some of the side effects include weight gain, thinning of the skin, which can lead to increased bruising, says Stanley Cohen, MD, past president of the American College of Rheumatology ( ACR) and a practicing rheumatologist in Dallas. “There’s acceleration of bone loss with higher risk of fracture, increases in blood sugar and in every clinical trial, the group of patients on prednisone always had a greater risk of infection.”
To address bone loss, the ACR recommends base-line bone density measurements on patients using prednisone six months or longer, with additional monitoring and possible use of calcium and vitamin D supplements and/or prescription agents which help maintain bone density.
Elena M. Massarotti, MD, a rheumatologist at the Brigham and Women’s Hospital, Boston, Mass., and an associate professor at Harvard University, calls the use of prednisone and other corticosteroids “the classic double-edged sword.”
“There’s some evidence prednisone in low doses may improve the radiographic features of rheumatoid arthritis,” Dr. Massarotti says. But, because of the high potential for side effects, as far as she’s concerned, the ideal duration of prednisone treatment would be “zero days.
"The general teaching in the management of patients with rheumatoid arthritis has been to minimize corticosteroid use and preferably to eliminate it altogether,” Dr. Massarotti says. "Basically you want as low a dose as possible of corticosteroids and for as short a duration as possible.”
Dr. Massarotti says prednisone’s primary utility in rheumatoid arthritis is as a “bridge” drug – one which can provide relief for a short time while other, safer drugs are taking effect – or one which can be used if a patient experiences a flare. “So they might need a short course of corticosteroids to quiet symptoms down,” she says.
Corticosteroids reduce inflammation because they are chemically similar to the body’s natural anti-inflammatory substance, cortisol, which is produced by the adrenal glands. In RA, the inflammatory response within the joints is greatly exaggerated – such that the body’s natural supply of cortisol is insufficient to relieve symptoms.
Aside from side effects, one of the dangers of using glucocorticoids is sudden withdrawal. As the body gets used to what it senses is extra “cortisol” on board, it slows down production of the real thing. Gradually lowering the dose of the corticosteroid gives the adrenal glands time to step-up natural production, thus preventing such withdrawal symptoms as severe weakness and fatigue.
While some RA patients may be leery of corticosteroids, others embrace them – and no wonder, says Dr. Cohen. “They make the patient feel tremendously better.”
Building a Better Corticosteroid
Given that, efforts are underway to develop a better and safer corticosteroid – and with some recent success. Horizon Pharma just received Food and Drug Administration approval for a delayed-release form of prednisone, Rayos. This preparation, dosed before bedtime, releases its prednisone into the system at a time during the night when the adrenal glands are at their lowest activity. The result for patients is an improvement in early morning sitffness, one of the hallmarks of RA.
“People with RA know that symptoms are usually much worse in the mornings,” says Dr. Kirwan. “This delayed release formulation has been shown to get better control of morning stiffness compared to taking corticosteroids in the morning.” In June 2012, Dr. Kirwan co-authored a review of time-released prednisone for Therapeutic Advances In Musculoskeletal Disease.
Dr. Kirwan says researchers are looking for other ways to mitigate side effects of corticosteroids without sacrificing therapeutic effects. “One option is to find a new type of substance, called a SEGRA, or selective glucocorticoid receptor agonist, which only affects the inflammation action, not the metabolic one.”
Another involves creating what might be called ‘smart’ corticosteroid injections. “The [corticosteroid] is attached to liposomes (basically a protective enclosure) which naturally home in on places where inflammation is happening,” he says.
“If you can develop a safe steroid, that would be phenomenal,” Dr. Cohen says.
Because flawed as these drugs may be, clinicians and patients agree, they work.