Why Oral Corticosteroids Should Not be Used in Patients with Rheumatoid Arthritis

There are two main reasons for arguing against the use of oral steroids in patients with rheumatoid arthritis (RA):

1. The risk of developing long-term side effects for relatively little long-term gain.
2. They are commonly used by nonrheumatologists inappropriately and in excessive dosage; however, the marked short-term symptomatic benefit may delay referral for better long-term treatment.

Why Are Corticosteroids Used?

Recent studies initially by Kirwan and subsequently by several other groups have shown that when initiated alongside disease modifying antirheumatic drug (DMARD) therapy, steroids are associated with a decrease in radiologic progression.^1-4 In one longer study, the difference at four years, while statistically significant, was hardly clinically important—a mere four Sharp score units.² Nevertheless, a DMARD effect exists. In the most recent study, patients with less than one year of RA were treated with a tight control strategy using methotrexate along with 10 mg of prednisone daily (“low dose”).³ At the study completion at the end of two years, there was no observed difference in median Sharp scores, but the percentage of patients with new erosions was statistically different; 78% of those on prednisone and methotrexate were still erosion free compared to 67% on methotrexate alone. The clinical benefit (calculated by DAS28) that was very obvious in the first months of the trial had largely disappeared by the end of the first year of treatment. This is a recurrent theme of studies that use prednisone to treat RA and, despite the radiologic difference observed at two years, Kirwan noted that the clinical effect “did not persist into the second year.”

Thus, the rationale for persistent long-term clinical benefit does not seem to hold up when formally tested in a controlled trial rather than using what Dr. Ted Pincus has coined “eminence-based” medicine.

There are no longer-term data beyond four years to say whether the mean four units of Sharp score difference at four years will increase over the next 30 years or remain unchanged. Data from the Better Anti-Rheumatic Farmacotherapy (BARFOT) study observed no change in Sharp scores between Years 1 and 4.²

Why Corticosteroids Shouldn’t Be Used

In contrast, we have clear-cut long-term toxicity data to balance against this minor radiologic difference. In 1983, Scott published a 20-year follow-up of RA patients who were receiving steroids along with DMARDs such as gold.⁵ Many of the patients had become disabled and several had died, with some of deaths thought to be steroid related. In ground-breaking studies, Pincus emphasized the increased mortalities associated with RA and likened it to triple-vessel coronary artery disease or lymphoma.⁶ He also showed that the mortality rate was increased in those patients receiving steroids versus those who were not (but this is less often emphasized). A study of patients with early RA followed over 15 years found that 39% of those patients who died had been on steroids compared to just 3% of those who were alive.⁷

A common counter-argument to this thesis is that more severe patients are treated with steroids chronically, thus the increased mortality seen is more a reflection of RA severity. The evidence, however, suggests otherwise: some investigators have found that it is a characteristic of the physician rather than the patient that determines the use of steroids.⁸ Some time ago, the ARAMIS database showed steroids to be associated with increased mortality, whereas azathioprine, at that time reserved for more severe patients, was not.⁹ In our own study, patients who were initially matched for severity were either treated with low-dose steroids or none at all.¹⁰ Those patients on steroids showed a significantly worse outcome at the five-year follow-up.

The side effects of steroids can be broken down to specifics. Osteoporotic fractures are the best understood. They can occur remarkably quickly, within three months of initiating steroids, but the likelihood of fracture can be reduced with antiresorptive therapy.¹¹ However, I wonder what percentage of patients with RA on steroids are actually receiving effective antiresorptive therapy. Hospitalization rates for pneumonia increase with steroid use and, in those patients receiving anti–tumor necrosis factor agents, concomitant steroids may be more important risk factors for infection than the biologic drug itself.^12,13 The rate of Herpes zoster infection is increased with the use of steroids, as is tuberculosis.^14,15 A recent study confirmed the prior impression that steroid use in rheumatoid patients is associated with serious lower gastrointestinal events and death.¹⁶

The good news is that in North America, physicians recognize the hazards of long-term steroid use and patients are more frequently started on limited, short-term therapy. Over a brief period, many, if not most, patients are tapered off steroids.¹⁷ Indeed, it is a measure of biologic therapy’s success that this can be achieved.

In continental Europe, the DMARD evidence favoring steroids seems to have persuaded doctors to use this drug routinely. Yet, it was interesting to observe that in Bakker’s study, about one-third of those patients who were solicited to participate in the study declined to do so.³ Eighty percent of these patients stated that they would not participate because they did not want to take steroids.

In my opinion, the most troublesome “side effect” of steroids is that, if rheumatologists are seen to regularly prescribe oral steroids (compared to joint injections), this may provide cover for the primary care physician (PCP) to do the same without recognizing the importance of concomitant DMARD therapy. Unfortunately, even among some rheumatologists, the importance of concomitant DMARD therapy is not always recognized.¹⁸

As my colleagues and I once observed, “the decision to institute steroid therapy emanates in part from a simple desire to rapidly alleviate patients’ symptoms.”¹⁹ This “quick fix” can prove misleading to both patient and doctor regarding the need for longer-term DMARD control of the RA. The published guidelines of the ACR recommend DMARD therapy if active disease is present.²⁰ A patient whose PCP recently prescribed steroids for early RA—permitted in the guidelines—could have their disease activity inappropriately masked so they are not started on DMARDs—or even worse, not referred to a rheumatologist until damage is done.

In summary, we are using a drug with impressive long-term toxicity and without demonstrable symptomatic benefit after one year of use even at 10 mg per day. All of this for a demonstrated benefit of four Sharp score units at four years!

I am reminded of a quote from Lewis Carroll’s Through the Looking Glass: “I didn’t say it was good for you,” the king replied. “I said that there was nothing like it.”

Dr. Russell is professor of medicine at the University of Alberta in Edmonton.

References

1. Kirwan JR, and the arthritis and rheumatism council low dose glucocorticoid study group. The effect of glucocorticoids on joint destruction in. N Engl J Med. 1995;333:142-146.
2. Hafstrom I, Albertsson,K, Boonen A, van derHeijde D, Landewe R, Svenson B, for the BARFOT study group. Remission achieved after 2 years treatment with low-dose prednisolone in addition to disease-modifying anti-rheumatic drugs in early rheumatoid arthritis is associated with reduced joint destruction after 4 years: An open 2 year continuation study. Ann Rhem Dis. 2009;68:508-513.
3. Bakker MF, Jacobs JWG, Websing PMJ, et al. Low-dose prednisone inclusion and methotrxate based tight control strategy for early rheumatoid arthritis. Ann Int Med. 2012:156:329-339.
4. Van-Everdingen AA, Jacobs JWG, van Reesema DRS, Bijlsma WJ. Low-dose prednisone therapy for patients with early active rheumatoid arthritis: Clinical efficacy, disease modifying properties and side effects: A randomized double-blind placebo-controlled clinical trial. Ann Int Med. 2002;136:1-12.
5. Scott DL, Coulton BL, Chapman JH, Bacon PA, Popert AJ. The long-term effects of treating rheumatoid arthritis. J R Coll Physicians Lond. 1983;17:79-85.
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18. Lacaille D, Anis AH, Guh DP, Esdaile JM. Gaps in care for rheumatoid arthritis: A population study. Arth Care Res. 2005;53:241-248.
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20. Singh JA, Furst DE, Bharat A, et al. 2012 Update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken). 2012;64:625-639.