Glucocorticoid Use in Rheumatoid Arthritis Management Focus of Ongoing Debate

Sixty-six years after the discovery of glucocorticoids by Philip S. Hench, Edward Kendall and Tadeus Reichstein, the debate over the use of these powerful drugs in rheumatoid arthritis (RA) continues in the rheumatology community.

“Few issues in rheumatology evoke the ire of rheumatologists as much as discussions around who should or should not get glucocorticoids,” says Kenneth G. Saag, MD, MSc, Jane Knight Lowe Professor of Medicine, Division of Clinical Immunology and Rheumatology, and director of the Center for Education and Research on Therapeutics (CERTs), Center for Outcomes Effectiveness and Education (COERE), and Center of Research Translation (CORT) in Gout and Hyperuricemia at the University of Alabama at Birmingham. The current debate revolves around questions of whether glucocorticoids should be used as bridge therapy, in long-term low dosages, in low-dose timed-release formulas—or not at all. “This continues to be a contentious topic,” says Dr. Saag.

Why is the question of steroid use still so divisive? We talked recently with those on both sides of the debate and explored the reasons for ongoing diversity of opinion. Clearly, there is not much dissension about use of high-dose steroids in RA. “Although they’re necessary in many serious disorders, we generally do not advocate for chronic high-dose steroid use,” says Dr. Saag. But a number of factors in the past 20 years have reinvigorated the debate for what might constitute safe and effective use of chronic low-dose steroids.

Dr. Saag

Professor Anthony Russell, MD, Division of Rheumatology, Department of Medicine, University of Alberta, Edmonton, Canada, is not a proponent of giving steroids to patients with RA [see “Why Oral Corticosteroids Should Not Be Used in Patients with Rheumatoid Arthritis,” The Rheumatologist (April 2013)]. The debate in favor of steroids, he says, was revived by studies showing that low-dose prednisolone retarded X-ray changes in the joint.^1,2,3

Slowing progression of structural damage “is the classic definition of what a DMARD [disease-modifying antirheumatic drug] is,” notes Dr. Saag.

Dr. Russell

Dr. Russell maintains that these studies are responsible for what he calls the “increased fashion” for use of steroids. However, he believes that the time for including steroids in the RA treatment armamentarium has passed. “Yes, they work, but why bother?” he says. “We’ve got good drugs, and we don’t need steroids any more,” he asserts.

Maarten Boers, MD, PhD, MSc, professor of clinical epidemiology and a rheumatologist at VU University Medical Center and the Reade Clinic, Amsterdam, The Netherlands, is a vocal member of the “pro” glucocorticoid camp and has spent his time “trying to get the message across that we should listen to what the data [are] telling us, and that we should give glucocorticoids back their rightful place in the treatment of rheumatoid arthritis.”

Off to an Overzealous Start?

“The first 50 years of data on glucocorticoids are really poor,” says Dr. Boers. “Although glucocorticoids were among the very first drugs to be tested in clinical trials—high-quality studies designed by Sir Bradford Hill—these were not followed by larger studies to adequately determine the balance of benefit and harm at the optimal dose.” Reports of dramatic clinical responses were enough to justify wide prescription of the drugs (and to earn the discoverers the Nobel Prize for Medicine in 1950).

Dr. Boers

Unfortunately, says Theodore (Ted) P. Pincus, MD, clinical professor, Rush University Medical Center, Chicago, “Many doctors felt that if a little is good, a lot must be better. More importantly, in the 1950s–1970s, steroids were given as monotherapy, rather than the current practice of including methotrexate and/or other DMARDs or biologics in RA, cyclophosphamide or mycophenolate in SLE.” When prednisone was the sole antiinflammatory drug, “It seemed that one needed to give much higher doses,” he explains. Very quickly, though, the adverse effects of these higher doses became clear. “If you give patients more than 5 mg a day for several months, the adrenal glands shut down,” says Dr. Pincus, and the side effects—weight gain, diabetes, hypertension, etc.—begin to accumulate. Dr. Pincus has written about the historical uses of steroids, and notes that by the late 1950s steroids were being used mostly on a short-term basis as “bridge therapy,” or for life-threatening extra-articular disease.⁴

Dr. Pincus

Prof. Maurizio Cutolo, MD, president of the European League Against Rheumatism (EULAR) and director, Research Laboratories, Academic Division of Clinical Rheumatology and Postgraduate School on Rheumatology in the Department of Internal Medicine at the University of Genoa, Italy, a coauthor with Dr. Pincus on the historical retrospective about glucocorticoids,⁴ notes that much of the disagreement about use of steroids emanates from these earlier patterns. Given at the wrong dosages, steroids inhibit endogenous production of glucocorticoids, producing dependency on higher and higher dosages, and the cascade of dangerous side effects leading to hypertension, osteoporosis, glaucoma and the like.

Dr. Boers adds that these side effects were not dismissed by the drugs’ discoverers. Having read Dr. Hench’s Nobel acceptance speech, Dr. Boers says that Hench was “already aware of the dangers of inappropriately high doses and that physicians should not be treating patients with very high doses for prolonged periods of time.”

Low Doses Best?

Even among those who advocate low-dose steroid therapy, agreement on the best treatment regimen is hard to come by. For example, what amount is a safe and effective low dose: 7.5 mg, 5 mg—or the 3 mg that Dr. Pincus prescribes for his patients and for which he has documented significant differences vs. placebo in a withdrawal clinical trial?5 Dr. Pincus notes that many rheumatologists believe he does not prescribe enough for his patients. “It is possible that higher doses such as 5, 7.⁵ or 10 mg might have greater efficacy and effectiveness, but there appears little doubt that doses of 3 mg are effective,” says Dr. Pincus. “These findings are, of course, confounded in part by most of these patients having taken methotrexate or another DMARD. But that’s the point. No patient with a chronic rheumatic disease should be treated with prednisone only, which almost never controls chronic inflammation optimally, while practices suggesting high-dose prednisone were developed when prednisone was the only agent used as monotherapy.”

If given in lower dosages, especially with attention to the body’s circadian cycles, glucocorticoids function as hormone replacement for adrenal insufficiency. ‘You don’t expect any damage because you give the right dosage at the right time; it’s like giving insulin in diabetes.’

—Dr. Cutolo

Dr. Pincus says he has not treated patients for more than a week with more than 10 mg or more than a month with more than 5 mg in 25 years. He reports no increase in hypertension, diabetes or cataracts in RA patients treated with prednisone over long periods, including more than 100 patients treated over more than eight years. No significant differences were seen in efficacy in patients treated with <5 vs. 5 or more mg/day.⁶ He also reports substantially better status after 2000, compared to the 1980s, according to joint counts, radiographs, laboratory tests and patient questionnaire responses in patients who took never took more than 5 mg.⁷

Dr. Boers is careful to counsel his patients regarding possible side effects from taking glucocorticoids. For example, he advises them to resist the feelings of abnormal hunger, which may accompany the first few weeks of therapy, and to eat normal amounts to avoid weight gain. Before an injection of the drugs, he warns them about the effects of restlessness and a boost of energy. “If you explain things, people are very accepting,” he says.

Timing Is All

Dr. Cutolo has conducted many studies on the use of nighttime-release prednisone to combat the morning stiffness that is characteristic in RA, and which is a consequence of the circadian night reactivation of the immune/inflammatory process. If given in lower dosages, especially with attention to the body’s circadian cycles, says Dr. Cutolo, glucocorticoids function as hormone replacement for adrenal insufficiency. “You don’t expect any damage because you give the right dosage at the right time; it’s like giving insulin in diabetes,” he says.

Dr. Cutolo

The theory behind this approach is that the clinical efficacy of late-night (as opposed to upon-awakening) prednisone should prevent patients’ symptoms of morning stiffness. In fact, as already seen in such physiological conditions as polymyalgia rheumatica, the gradual rise of cortisol in the very early morning hours downregulates ongoing immune reactivity. The stiffness and resulting functional disability that RA patients experience upon awakening is consistent, he says, with the reduced physiological adrenal cortisol production during the night in realized chronic inflammatory conditions, which becomes insufficient to inhibit the ongoing immune/inflammatory reaction.

Several trials, including CAPRA-1 and -2, conceived by Dr. Buttgereit from Germany, have investigated a modified-release (MR) form of prednisone that patients take at bedtime and that then delivers the steroid around 2 a.m., and these studies have also established the MR prednisone as safe and not harmful to the HPA axis. It has been suggested that this type of chronotherapy could be applied to other agents, such as methotrexate.^8,9,10

Dr. Saag thinks this approach may work for certain patients, but the questions are still somewhat unsettled. “It makes some pathophysiologic sense to better mimic the circadian patterns of glucocorticoids with a product that can be released at night,” he says. “It’s good to have this choice to provide a tailored therapy for individuals; the question is really, ‘Who should get this more expensive therapy?’”

Dr. Cutolo concludes, “For sure, the approach of chronotherapy is applicable at best for the medium- to long-term, low-dose glucocorticoid treatments in chronic inflammatory diseases, like polymyalgia rheumatica and, of course, rheumatoid arthritis.”

Setting a Dangerous Precedent?

Dr. Russell remains unconvinced that steroids should still have a role in RA management. He was on the EULAR committee that published recommendations on management of systemic glucocorticoids seven years ago.¹¹ “I was the only one who was antisteroids on that committee,” he reports. He was able to persuade fellow committee members, however, to insert language about obtaining informed consent whenever patients were prescribed glucocorticoids. That informed consent should include discussing with patients the potential adverse effects of glucocorticoid therapy, from cardiovascular to gastrointestinal to ophthalmologic to psychological effects. He wonders, though, how many patients are thoroughly apprised of the possible consequences of the therapy before the treatment begins.

What about the use of glucocorticoids as bridging therapy, to bring symptoms under control while methotrexate or biologics take hold? “I don’t believe that 5 mg a day for three months is going to cause any serious problems for a particular patient,” he says. But this practice, he believes, will cause serious problems “to the management of RA patients in general.” The reason for this belief, Dr. Russell explains, is that family and internal medicine colleagues will continue to assume, because rheumatologists have prescribed glucocorticoids, that the practice is acceptable. He has observed that patients then arrive at his office after having seen their family doctors who kept them on steroids for a year, “with terrible erosive disease” and no complementary DMARD therapy.

“This is an addictive drug,” says Dr. Russell. “If I refuse to give it to patients after bridging therapy, they may try to go back to their family doctor to obtain a prescription.” The answer to this dilemma, he says, is to reach out to physician colleagues in the community, and to increase one’s own availability for referrals so patients can be treated appropriately and early in the course of their disease.

Awaiting Resolution

Dr. Saag admits that there is a paucity of well-conducted clinical trials that would establish the best practices for use of steroids in RA. EULAR has addressed the question, and Dr. Saag reports that the ACR is on target to release recommendations regarding use of low-dose glucocorticoids in 2015.¹¹

Dr. Boers, who was recently funded by the EU Commission in the Horizon 2020 program to conduct a large pragmatic trial on low-dose prednisolone in elderly RA patients, thinks addressing the topic is an important first step for the ACR. He contends that there is now ample evidence of the benefits of the therapy and growing evidence that inflammation itself is causing some of the side effects traditionally attributed to glucocorticoids. Example: An Amsterdam study showed over half of patients with early RA had impaired glucose tolerance or even undiagnosed type 2 diabetes before initiating therapy with glucocorticoids. “As expected, some of these patients progressed to overt diabetes upon exposure to a week of high-dose (30 or 60 mg/d) prednisolone. However, a similar number actually normalized their glycemic profile, so that on average glucose tolerance was unchanged after one week of treatment.”

Similarly, active RA itself induces an atherogenic blood lipid profile and bone loss, effects traditionally ascribed to glucocorticoids. He concludes, “I think the tragedy is that people are being stopped too early because of guidelines saying ‘use as briefly as possible and at the lowest possible dose,’ and that their disease is not going into remission.”

Gretchen Henkel is a medical journalist based in California.