expert roundtables

In a Perfect World, Could Targeted Therapy Eliminate the Use of Corticosteroids in Rheumatoid Arthritis?

by Leonard H. Calabrese, DO; Jeffrey R. Curtis, MD, MS, MPH; and Jonathan Kay, MD

Overview

Corticosteroids are highly effective in the treatment of rheumatoid arthritis (RA) and can rapidly decrease disease activity. The elimination of these agents due to their side-effect profiles remains an important, but very challenging, goal.

Q: Could highly selective therapeutics revolutionize the future, leading to the steroid-free treatment of RA?

Jonathan Kay, MD

Professor of Medicine and Population and Quantitative Health Sciences
Timothy S. and Elaine L. Peterson Chair in Rheumatology
Director of Clinical Research, Rheumatology
University of Massachusetts Medical School
Worcester, MA

“Any targeted therapy used to take the place of corticosteroids should have a very rapid onset of action and be very effective in controlling disease activity in most patients.”

Jonathan Kay, MD

Corticosteroids are used to treat RA because they usually are very effective and have a rapid and reliable onset of action. They are used to induce remission and also as a bridging therapy. When initiating methotrexate to treat a patient with RA with active synovitis, corticosteroid therapy for the first several weeks will provide the patient with both symptomatic relief and reduction of synovial inflammation while waiting for methotrexate to exert its therapeutic effect. Corticosteroids also reduce the rate of progression of structural damage.

The downside of corticosteroids is the high likelihood of developing adverse effects—many of which can be quite consequential—including osteoporosis, avascular necrosis of bone, diabetes, cataracts, glaucoma, and hypertension. Compared with nonusers, patients taking corticosteroids also have higher rates of cardiovascular events.

So, how might one avoid the use of corticosteroids in RA? To do so with a targeted therapy, you would want an agent that has a very rapid onset of action and is very effective in controlling disease activity in most patients. An ideal such drug would provide persistent control of disease activity. Presently, Janus kinase (JAK) inhibitors seem best suited to fill that role, despite their potential adverse effects (eg, thromboembolic events). JAK inhibitors have a rapid onset of action, but perhaps not as fast as that experienced with corticosteroids.

Jeffrey R. Curtis, MD, MS, MPH

Marguerite Jones Harbert-Gene V. Ball, MD Professor of Medicine
Co-Director, UAB Pharmacoepidemiology and Pharmacoeconomics Research (PEER) Unit
Division of Clinical Immunology and Rheumatology
University of Alabama at Birmingham
Birmingham, AL

“Even in the world that we are living in today, I think that some of our existing therapies would actually permit us to taper steroids, with no meaningful loss of response.” 

Jeffrey R. Curtis, MD, MS, MPH

Even in the world that we are living in today, I think that some of our existing therapies would actually permit us to taper steroids, with no meaningful loss of response. For instance, a randomized trial assessing the steroid-sparing ability of the interleukin 6 inhibitor tocilizumab (NCT02573012) compared corticosteroid tapering with continuation in patients receiving tocilizumab with a background of chronic corticosteroid use (ie, prednisone 5 mg/day). Those who remained on corticosteroids had marginally better disease control (Disease Activity Score 28 [DAS28]-erythrocyte sedimentation rate [ESR]) compared with the taper group. The trial was double-blinded, and the change in the DAS28-ESR was only approximately 0.5 units between arms. Approximately two-thirds of the patients who tapered experienced treatment success. No tapered patients discontinued due to lack of flare control, and the taper schedule was safe regarding adrenal insufficiency. So, I think the major takeaway point is that we it may be possible to discontinue corticosteroids and that roughly two-thirds of patients will do quite well.

It is important to set expectations when you start corticosteroids so that patients understand that you would like them to be off of steroids within 3 to 6 months. In practice, physicians probably do not attempt to taper as often as we should. Data suggest that, among patients on biologics, surprisingly few are able to stop corticosteroids. This may reflect more of a volitional problem on the part of the rheumatologists in many cases, rather than a true unwillingness or inability to stop or taper corticosteroids. Also, patient selection for tapering is predicated on the observation that the patient has been doing well. And, in the setting of long-term steroid use, I am going to want more than just 1 visit to confirm that they are doing well before we begin tapering the steroids. Finally, it takes commitment, and patients want to know that they have access to you and that you have a plan in place if the taper goes awry.

Leonard H. Calabrese, DO

Professor of Medicine
RJ Fasenmyer Chair of Clinical Immunology
Director, RJ Fasenmyer Center for Clinical Immunology
Vice Chair, Department of Rheumatic and Immunologic Diseases
Cleveland Clinic Foundation
Cleveland, OH

“It takes some work and a lot of collaboration to taper patients off of corticosteroids.”

Leonard H. Calabrese, DO

We use corticosteroids generally, whatever the disease-modifying drug, when disease activity and symptoms are persistent. That is the scenario in which patients get stuck on them. I do think that we are currently more aware of the risk of long-term steroid use. And we are currently more prepared to go without them or to limit exposure to them because our RA treatments are so much more effective and they begin to work a lot quicker than the treatments of previous generations. But the fact remains that steroids work, and they work quickly, and often people rely on them.

The notable part for me is that, while it appears plausible to taper steroids, it is a very difficult thing to do, and patients are not eager to do it. Many individuals with RA are on corticosteroids, and at least half of the patients in almost any of the clinical trials of biologic therapies are on some form of low-dose steroids. Additionally, in studies of the type mentioned by Dr Curtis, I am not certain that the withdrawal symptoms from steroids are really adequately reflected in the DAS score when long-term users taper off even low doses of corticosteroids. If you do it too quickly, then patients feel poorly and they are reluctant to continue tapering. It takes some work and a lot of collaboration to do this. In patients who have been on steroids for 5 years, for instance, it is unlikely that you would be successful in discontinuing the steroids completely in a short span of time. It just does not happen this way. So, I agree that we should be committed to reducing steroid exposure, but I also think that we should go about this in way that makes sense, recognizing some of the challenges.

References

Burmester GR, Buttgereit F, Bernasconi C, et al. A randomized controlled 24-week trial evaluating the safety and efficacy of blinded tapering versus continuation of long-term prednisone (5 mg/day) in patients with rheumatoid arthritis who achieved low disease activity or remission on tocilizumab [abstract L18]. Arthritis Rheumatol. 2018;70(suppl 10). https://acrabstracts.org/abstract/a-randomized-controlled-24-week-trial-evaluating-the-safety-and-efficacy-of-blinded-tapering-versus-continuation-of-long-term-prednisone-5-mg-day-in-patients-with-rheumatoid-arthritis-who-achieved-l/. Accessed January 3, 2020.

ClinicalTrials.gov. Study to compare the efficacy of tocilizumab with or without glucocorticoid discontinuation in rheumatoid arthritis participants. https://clinicaltrials.gov/ct2/show/NCT02573012. Accessed January 14, 2020.

Fleischmann R, Selmi C, González-Gay MA, et al. Glucocorticoid dose is progressively reduced in patients with RA receiving sarilumab: results from the open-label EXTEND study [abstract 1379]. Arthritis Rheumatol. 2019;71(suppl 10). https://acrabstracts.org/abstract/glucocorticoid-dose-is-progressively-reduced-in-patients-with-ra-receiving-sarilumab-results-from-the-open-label-extend-study/. Accessed January 3, 2020.

Kirwan JR, Bijlsma JW, Boers M, Shea BJ. Effects of glucocorticoids on radiological progression in rheumatoid arthritis. Cochrane Databaase Syst Rev. 2007;(1):CD006356.

Spivey CA, Griffith J, Kaplan C, Postlethwaite A, Ganguli A, Wang J. A retrospective analysis of corticosteroid utilization before initiation of biologic DMARDs among patients with rheumatoid arthritis in the United States. Rheumatol Ther. 2018;5(1):255-270. 

Verhoeven MM, de Hair MJ, Tekstra J, et al. Initiating tocilizumab, with or without methotrexate, compared with starting methotrexate with prednisone within step-up treatment strategies in early rheumatoid arthritis: an indirect comparison of effectiveness and safety of the U-Act-Early and CAMERA-II treat-to-target trials. Ann Rheum Dis. 2019 ;78(10):1333-1338.

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