Written by: Osman Bhatty MD, Padmini Parameswaran MD, Christon Grant MD, Mohamed Tageldin, MD, Michael Lucke, MD. Allegheny Health Network Division of Rheumatology

Based on: Burmester GR et al. Continuing versus tapering glucocorticoids after achievement of low disease activity or remission in rheumatoid arthritis (SEMIRA): a double-blind, multicentre, randomised controlled trial. Lancet. 2020 Jul 25;396(10246):267-276.

Overview:

Glucocorticoids have long been a bittersweet player in the treatment of patients with rheumatoid arthritis (RA) pumping up the crowd with much needed symptom relief while simultaneously getting their share of boos with long term adverse side effects. In spite of widespread teaching that these medications should be in the game for the shortest amount of time and with the lowest dose possible, two-thirds of patients in clinical practice receive glucocorticoids for longer than 6 months! Possible reasons for the lack tapering may include inducing disease flares, adrenal insufficiency and withdrawal symptoms. A lack of evidence-based tapering strategies may also be adding to the hesitancy. In fact, a search of PubMed looking for double-blind, placebo-controlled trials pertaining to glucocorticoid tapering in rheumatoid arthritis yields only one result underscoring our dire need for further studies. The Steroid EliMination in Rheumatoid Arthritis (SEMIRA) trial is the first trial of its kind to investigate a scheme with tapering low dose steroids versus continuation in patients with RA and low disease activity. This multicenter, double blind, placebo-controlled, randomized study was done across 39 centers across 6 countries. Patients had a diagnosis of RA maintained on tocilizumab and a stable 5 mg prednisone dose for 4 weeks prior to randomization while having low disease activity using DAS28-ESR (<3.2). 246 patients were randomized to one of two groups; one in which 5 mg of prednisone was continued daily or a second in which they underwent a 1 mg taper every 4 weeks until tapering off by week 16. After 24 weeks the primary endpoint, change in DAS28-ESR from baseline, was lower in the continued prednisone group (-0.08 [-0.27-0.12]) compared to the tapered group (0.54 [0.35-0.73]. Of particular interest was the secondary endpoint which showed that 65% of patients in the tapered group became prednisone free without disease flare, adrenal insufficiency and remained in low disease activity. 77% of patients in the continued prednisone group were able to reach this endpoint as well.

Implications for Patients, Providers, & Researchers

Current implications: Talk about coming up in the clutch! Despite a mean disease duration of 9 years and a history of prior biologic use in one-third of patients, many were able to successfully discontinue steroid therapy by the end of the trial. In fact, when compared to the group continuing steroids, 8 patients would need to undergo steroid taper before one patient experienced a flare or loss of low disease activity. With this number needed to harm patients and providers should continue to view steroid taper as a natural next step in rheumatoid arthritis management. Also of note is that patients who flared were usually on prednisone 1 mg or 0 mg daily therefore even a failed attempt can be viewed as an opportunity to reduce their daily steroid maintenance dose by more than 50%. Swoosh!

Future implications: Providers should be reassured by the fact that no cases of adrenal insufficiency occurred in the prednisone withdrawal group. Given the high success rate, eventual withdrawal of steroid therapy can be viewed as a standard of care in all patients with rheumatoid arthritis. With the abundance of therapies available, patients who fail withdrawal should be offered therapy modification with the aim of one day attaining steroid-free remission.

Will SEMIRA win in its First Round Match-up?

We believe SEMIRA has the higher odds of winning its tough first round against the harms of short-term steroid study for numerous reasons. Firstly, our opponent’s study is a self-controlled case series from only one health care system that makes it more vulnerable to bias. SEMIRA on the other hand is the first of its kind and a good one at that – a double-blind, multicenter, randomized controlled trial across 6 countries to look at a glucocorticoid tapering regimen in stable RA patients with stable biologic therapy. Moreover, SEMIRA shows that an incredible two thirds of stable RA patients were able to be safely tapered off steroids. That’s a statistic that will be sure to bring the crowd to its feet! Additionally, a significant limitation in the harms of short terms steroid study is the lack of accounting for possible confounding factors, and the study relies on prescription data of Medrol dose packs, which is hardly the most commonly used modality for achieving RA disease control. Finally, the study did not have any patients with rheumatologic illnesses and therefore the applicability to patients with RA is questionable.

Could SEMIRA Win it All?

Is SEMIRA the Cinderella story at this year’s tournament? We think it’s very possible that SEMIRA can win the tournament and bring it all home! Let’s review the facts – SEMIRA is groundbreaking as the first randomized control trial evaluating prednisone taper in seven decades! Rheumatologists everywhere can unclutch their pearls now that we know adrenal insufficiency is not as big of a problem as once feared. Rheumatologists can also pop their collars and show off their kicks as improvising tapers can become a thing of the past with SEMIRA providing an evidence-based protocol. We’d say the outlook for SEMIRA is pretty good in the first and second rounds alone based on the very practical implications of the study – these are results that will be referred to on a daily basis! Finally, it may not bring the flashiness of the SLE and ANCA trials but we’d choose the solid and consistent performance of a trial like SEMIRA whose implications will be referred to daily rather than the pizzazz of trials dealing with diseases far less common.

Reference(s)

1. Burmester GR, Buttgereit F, Bernasconi C, Álvaro-Gracia JM, Castro N, Dougados M, Gabay C, van Laar JM, Nebesky JM, Pethoe-Schramm A, Salvarani C, Donath MY, John MR; SEMIRA collaborators. Continuing versus tapering glucocorticoids after achievement of low disease activity or remission in rheumatoid arthritis (SEMIRA): a double-blind, multicentre, randomised controlled trial. Lancet. 2020 Jul 25;396(10246):267-276. doi: 10.1016/S0140-6736(20)30636-X. PMID: 32711802.
2. Haraoui B, Jovaisas A, Bensen WG, et al Use of corticosteroids in patients with rheumatoid arthritis treated with infliximab: treatment implications based on a real-world Canadian population. RMD Open 2015;1:doi: 10.1136/rmdopen-2015-000078

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