Editor’s note: The ACR recently released a call for possible partners for a new RA guideline development effort beginning this year. The new guidelines would include DMARDs, steroids, and biologics, including newer oral agents. Look for more information on these efforts in the May issue of The Rheumatologist.
Enthusiasm for the new often results in overlooking the continuing, or even developing, advantages of the familiar. Thus, in our enthusiasm to embrace new treatment options, we may fail to notice that existing therapies, used in appropriate ways, offer more than we first thought.
The pharmaceutical industry is locked into a commercial system that demands the development and promotion of new agents to maintain patent rights and continuing income generation, and has no interest in the intelligent use of existing agents. Rheumatologists, on the other hand, are looking for the best treatment options independently of commercial considerations. Remember the story of methotrexate? In the 1950s, it was used in anticancer therapy and in patients with severe psoriasis. It was noticed that, in some patients, their psoriatic arthritis improved, and in a landmark paper from the Royal National Hospital for Rheumatic Diseases in Bath, Kersley reported the first series of 10 patients successfully treated for psoriatic arthritis.1 It was not long before methotrexate was taken up for rheumatoid arthritis (RA) as well, and in a series of substantial and important randomized controlled trials, led principally from North America, the rheumatology community established its clear success as a disease-modifying agent.
Historical Look at Glucocorticoids
Finding the best way to use glucocorticoids in the treatment of RA is another example of clinical persistence in the face of commercial neglect. In their seminal report announcing the therapeutic use of glucocorticoids for the first time, Hench, Kendall, Slocumb, and Polley recalled that it was 1929 when Hench first noted the beneficial effects of pregnancy and jaundice on RA.2 It was this observation that started the hunt for an underlying agent, but it was not until 1948 that a sufficient amount was available to test it in a patient with RA. The symptomatic benefit was astounding.2,3
The efficacy of glucocorticoids in treating inflammation was established early, but enthusiastic overtreatment also led to some early serious adverse effects and the pharmaceutical industry turned to the development of nonsteroidal antiinflammatory drugs. While glucocorticoids are widely used, particularly in the U.S., their use was, paradoxically, widely condemned.4
The first suggestion that glucocorticoids, in addition to suppressing inflammation, might be able to halt the underlying progression of destructive erosions in RA was in a study published in 1959, but my own interest in this area was stimulated by Dr. John Decker, one of the fathers of rheumatology in the U.S., who encouraged me to try to clarify the role of glucocorticoid therapy in RA.5 We set up the first of several studies carried out by authors from different countries that proved conclusively that glucocorticoids are the strongest disease-modifying agent and can substantially hold back the destructive process of RA.6 So why are they not recommended by the ACR in their guidelines for the treatment of newly diagnosed disease? Because glucocorticoids, “were not within the purview” of the recommendations or of a recent update, even though it was recognized that “these may be important components of RA treatment.”7 How could this be? What reason might there be for omitting consideration of a treatment shown so clearly to be beneficial?
Recent Evidence
In a recent evidence based–medicine project at our medical school, 260 undergraduate students halfway through their course took on the task of finding the best evidence for treating newly diagnosed RA, and comparing this to published guidelines. In one afternoon, and with only access to the Internet, each other, and a few facilitating teachers in support, they concluded that all newly diagnosed patients should be offered the opportunity to take glucocorticoids, a recommendation also promulgated by the UK National Institute for Health and Clinical Excellence. The students were astonished that the ACR guidelines omitted this treatment, and asked if ACR guidelines for other diseases are likely to be equally deficient.
Some will be overly concerned with the possibility of adverse effects. Such concerns do not sit well with current widespread use, but neither are they supported by the literature. Recent systematic reviews have not found evidence of serious consequences of short- or medium-term treatment with relatively low doses of glucocorticoids. Indeed, in many randomized controlled trials, the frequency of adverse effects is lower than in the comparator arm, perhaps because glucocorticoids protect against the adverse effects of other treatments used at the same time such as methotrexate.
Some clinicians might consider an emphasis on “tight control” treatment strategies would be a more worthy effort, even though these have not yet been shown to be cost effective. However, adding glucocorticoids to a tight control strategy undoubtedly improves outcome even further. In an editorial commenting on the paper that reports this finding, I suggested that combination therapy including glucocorticoids is the new gold standard for early treatment in RA—a position I continue to advocate here.8
Dr. Kirwan is professor of rheumatic diseases at the University of Bristol and consultant rheumatologist at the University Hospitals Bristol NHS Foundation Trust, both in the U.K.
References
- Kersley GD. Amethopterin (methotrexate) in connective tissue disease-psoriasis and polyarthritis. Ann Rheum Dis. 1968;27:64-66.
- Hench PS, Kendall EC, Slocumb CH, Polley HF. Effects of a hormone of the adrenal cortex (17-hydroxy-11 dehydrocorticosterone: compound E) and of pituitary adrenocorticotrophic hormone on rheumatoid arthritis: Preliminary report. Proc Staff Meet Mayo Clin. 1949;24:181-197.
- Hench PS, Kendall EC, Slocumb CH, et al. Effects of cortisone acetate and pituitary ACTH on rheumatoid arthritis, rheumatic fever and certain other conditions. Arch Intern Med. 1950;85:545-666.
- Pincus T, Marcum SB, Callahan LF. Long-term drug therapy for rheumatoid arthritis in seven rheumatology private practices: II. Second line drugs and prednisone. J Rheumatol. 1992;19:1885-1894.
- Kirwan JR. The origins, results and consequences of the 1995 Arthritis Research Campaign Low-dose Glucocorticoid Study. Clin Exp Rheum. 2011; 29(Suppl. 68):S52-S58.
- Kirwan JR, Bijlsma JWJ, Boers M, Shea BJ. Effects of glucocorticoids on radiological progression in rheumatoid arthritis. Cochrane Database of Systematic Reviews, 2007;1:CD006356.
- 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.
- Kirwan JR. Combination therapy including glucocorticoids: The new gold standard for early treatment in rheumatoid arthritis? Ann Intern Med. 2012;156:390-391.