Elsevier

The Lancet

Volume 396, Issue 10246, 25–31 July 2020, Pages 267-276
The Lancet

Articles
Continuing versus tapering glucocorticoids after achievement of low disease activity or remission in rheumatoid arthritis (SEMIRA): a double-blind, multicentre, randomised controlled trial

https://doi.org/10.1016/S0140-6736(20)30636-XGet rights and content

Summary

Background

Patients with inflammatory diseases, such as rheumatoid arthritis, often receive glucocorticoids, but long-term use can produce adverse effects. Evidence from randomised controlled trials to guide tapering of oral glucocorticoids is scarce. We investigated a scheme for tapering oral glucocorticoids compared with continuing low-dose oral glucocorticoids in patients with rheumatoid arthritis.

Methods

The Steroid EliMination In Rheumatoid Arthritis (SEMIRA) trial was a double-blind, multicentre, two parallel-arm, randomised controlled trial done at 39 centres from six countries (France, Germany, Italy, Russia, Serbia, and Tunisia). Adult patients with rheumatoid arthritis receiving tocilizumab and glucocorticoids 5–15 mg per day for 24 weeks or more were eligible for inclusion if they had received prednisone 5 mg per day for 4 weeks or more and had stable low disease activaity, confirmed by a Disease Activity Score for 28 joints–erythrocyte sedimentation rate (DAS28-ESR) of 3·2 or less 4–6 weeks before and on the day of randomisation. Patients were randomly assigned 1:1 to either continue masked prednisone 5 mg per day for 24 weeks or to taper masked prednisone reaching 0 mg per day at week 16. All patients received tocilizumab (162 mg subcutaneously every week or 8 mg/kg intravenously every 4 weeks) with or without csDMARDs maintained at stable doses during the entire 24-week study. The primary outcome was the difference in mean DAS28-ESR change from baseline to week 24, with a difference of more than 0·6 defined as clinically relevant between the continued-prednisone group and the tapered-prednisone group. The trial is registered with ClinicalTrials.gov, NCT02573012.

Findings

Between Oct 21, 2015, and June 9, 2017, 421 patients were screened and 259 (200 [77%] women and 59 [23%] men) were recruited onto the trial. In all 128 patients assigned to the continued-prednisone regimen, disease activity control was superior to that in all 131 patients assigned to the tapered-prednisone regimen; the estimated mean change in DAS28-ESR from baseline to week 24 was 0·54 (95% CI 0·35–0·73) with tapered prednisone and −0·08 (–0·27 to 0·12) with continued prednisone (difference 0·61 [0·35–0·88]; p<0·0001), favouring continuing prednisone 5 mg per day for 24 weeks. Treatment was regarded as successful (defined as low disease activity at week 24, plus absence of rheumatoid arthritis flare for 24 weeks and no confirmed adrenal insufficiency) in 99 (77%) patients in the continued-prednisone group versus 85 (65%) patients in the tapered-prednisone group (relative risk 0·83; 95% CI 0·71–0·97). Serious adverse events occurred in seven (5%) patients in the tapered-prednisone group and four (3%) patients in the continued-prednisone group; no patients had symptomatic adrenal insufficiency.

Interpretation

In patients who achieved low disease activity with tocilizumab and at least 24 weeks of glucocorticoid treatment, continuing glucocorticoids at 5 mg per day for 24 weeks provided safe and better disease control than tapering glucocorticoids, although two-thirds of patients were able to safely taper their glucocorticoid dose.

Funding

F Hoffmann-La Roche.

Introduction

Glucocorticoids are widely used to treat inflammatory diseases; prevalence of glucocorticoid use is estimated to be 0·9–1·2% in high-income countries,1, 2 and is higher in people older than 50 years.2 Long-term glucocorticoid use is associated with adverse events, including osteoporosis, cataracts, cardiovascular complications, and infections.3, 4 Tapering glucocorticoid doses is generally recommended to avoid or reduce the risk for adverse events.5, 6 Rheumatoid arthritis management guidelines advise restricting glucocorticoids to low doses for the shortest possible time.5, 7 Despite these recommendations, approximately two-thirds of patients with rheumatoid arthritis receive glucocorticoids in clinical practice, often for more than 6 months,8, 9 and the spontaneous glucocorticoid discontinuation rate has been reported at 35%.10 Hesitancy to implement glucocorticoid tapering might be associated with the dose reduction process. Tapering must be done carefully to avoid disease flare, adrenal insufficiency, and glucocorticoid withdrawal syndrome, which can result in a severe or life-threatening condition.6, 11 Evidence-based oral glucocorticoid tapering strategies that aim to maintain disease control and avoid adrenal insufficiency have not been developed for rheumatoid arthritis11, 12 or other diseases.

Research in context

Evidence before this study

Tapering of low-dose glucocorticoids is a common clinical issue across many disciplines. We searched the PubMed database from its inception to Oct 30, 2019, using the terms (“rheumatoid arthritis“ AND [“prednisone” OR “glucocorticoid” OR “corticosteroid”] AND [“taper” OR “withdrawal” OR “step-down”]). We reviewed the results and identified 12 clinical trial articles that included glucocorticoid tapering. Two trials included an appropriate control for the effect of glucocorticoid tapering in stable disease activity conditions. Only one of these trials was a blinded study; this single-centre randomised, placebo-controlled withdrawal trial of 31 patients with established rheumatoid arthritis receiving long-term treatment, including conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), suggested that continued low-dose (1–4 mg per day) prednisone leads to fewer patient-reported poor efficacy events than tapering (1 mg every 4 weeks) prednisone in a usual clinical care setting. Another single-centre open-label study in 58 patients with established rheumatoid arthritis receiving long-term prednisone with or without csDMARDs showed that receiving the continued prednisone regimen led to better clinical outcomes and no apparent negative effect on bone mineral density compared with randomisation to prednisone tapering. There were no reports from double-blind, randomised, placebo-controlled trials investigating a specific low-dose prednisone tapering schedule compared with continuing low-dose prednisone in patients receiving biological therapy who achieved rheumatoid arthritis disease control.

Added value of this study

This is the first large randomised, placebo-controlled, multicentre trial to investigate tapering of low-dose prednisone in patients with rheumatoid arthritis who achieved stable disease control with glucocorticoids and csDMARDs. Patients who achieved low disease activity with tocilizumab with or without csDMARDs and at least 6 months of prednisone-equivalent glucocorticoids 5–15 mg per day who continued prednisone 5 mg per day had superior disease activity control compared with those who tapered prednisone from 5 mg per day to 0 mg per day. Treatment success (defined as disease control, no flare, and no adrenal insufficiency necessitating replacement therapy) was achieved by 77% of patients in the continued-prednisone group and 65% of those who received the tapered regimen. More adverse events were observed in the tapering group than the continuing group over 24 weeks. There were no reports of clinically manifest adrenal insufficiency or deaths.

Implications of all the available evidence

The safe and effective use of glucocorticoids reported in this study might influence future treatment guideline updates on the optimal timing of low-dose glucocorticoid withdrawal in patients with rheumatoid arthritis and low disease activity receiving effective biological therapy. The 65% treatment success rate with prednisone tapering has the potential to inform shared decision making. Although no adrenal insufficiency was observed with the tapering scheme, information about monitoring and prophylaxis should be provided to physicians and patients. Our findings offer a potential framework for investigations into glucocorticoid tapering and discontinuation in other therapeutic areas in which there may be uncertainty regarding the risks and benefits of glucocorticoid withdrawal.

The Steroid EliMination In Rheumatoid Arthritis (SEMIRA) trial was the first to apply a rigorous, randomised, double-blind design to investigate a scheme for tapering oral glucocorticoids compared with continuing low-dose oral glucocorticoids developed in collaboration with endocrinologists. Patients with rheumatoid arthritis with low disease activity following treatment with tocilizumab, an anti-IL-6 receptor α antibody, and 5 mg per day of prednisone were enrolled.

Section snippets

Study design and participants

SEMIRA was a multicentre, two parallel-arm, double-blind, placebo-controlled, randomised withdrawal study done between Oct 21, 2015, and Feb 20, 2018, at 39 centres across six countries (France [5], Germany [20], Italy [3], Russia [5], Serbia [5], and Tunisia [1]). Participant inclusion criteria were age of 18 years or older, bodyweight of less than 150 kg, and rheumatoid arthritis diagnosed at least 6 months before enrolment according to the revised 1987 American College of Rheumatology

Results

Between Oct 21, 2015, and June 9, 2017, 421 patients were screened and 259 were enrolled into the trial (200 [77%] women and 59 [23%] men). After screening, 68 tocilizumab-experienced patients who were receiving tocilizumab and 5 mg per day prednisone-equivalent glucocorticoids were randomly assigned to one of the two treatment groups within 6 weeks of screening. After screening, 246 patients with active rheumatoid arthritis who were tocilizumab-naive entered the 24-week tocilizumab lead-in

Discussion

SEMIRA is the first clinical trial to evaluate a double-blind, oral glucocorticoid dose-tapering regimen with stable biological background therapy in rheumatoid arthritis. It was designed to compare disease activity changes between patients receiving tocilizumab who were given 5 mg per day glucocorticoids over the 24-week period with those who received a tapered glucocorticoid regimen. Standardised glucocorticoid-tapering strategies are not established for patients with rheumatoid arthritis

Data sharing

Qualified researchers can request access to de-identified study data on publication through the clinical study data request platform (http://www.clinicalstudydatarequest.com). Further details on F Hoffmann-La Roche criteria for eligible studies are available at https://clinicalstudydatarequest.com/Study-Sponsors/Study-Sponsors-Roche.aspx. For further details on F Hoffmann-La Roche Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents,

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    Authors contributed equally to this work

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