Background Guidelines suggest glucocorticoids (GC) should be used as bridge therapy in rheumatoid arthritis (RA), but many patients are treated chronically with low doses. The effects of withdrawal in such patients has not been studied extensively.
Objectives To study disease activity score (DAS28), disease flares and signs of adrenal insufficiency after withdrawal of blinded trial medication (prednisolone 5 mg/day or placebo for 2 years).
Methods The 2-year, double-blind GLORIA trial evaluated the long-term benefits and harms of low dose GC added to standard care (see main GLORIA trial abstract). Senior RA patients (≥ 65 years) were randomly assigned to prednisolone 5 mg/day or placebo.
After the final trial visit study medication was linearly tapered to zero in 3 months by adding a stop day every two weeks, and patients were reassessed. Those who successfully completed the trial and did not receive open-label GC during the 4 weeks after the final trial visit were included in this follow-up study.
The primary outcome was change in DAS28 at follow-up compared to the final trial visit. Secondary outcomes included the occurrence of disease flares (DAS28 increase > 0.6 or open-label GC between week 4 and 12 of the taper phase) and signs of adrenal insufficiency, assessed by 9 items selected from the 57-symptom list from the MDHAQ questionnaire (1) and hypotension (systolic RR < 90 or diastolic RR < 60). In a subset of patients from 3 Dutch centres, cortisol and ACTH were measured in spot serum samples during the follow-up visit.
Analysis of covariance assessed the change in DAS28. Linear regression and chi-square test were used for the remaining outcomes.
Results 278 participants completed the GLORIA study, 21 received GC within 4 weeks after the end of the trial, 58 had missing data, leaving 199 patients eligible for this study.
34 patients received open label GC after 4 weeks and were excluded for the primary analysis. In the remaining 165 patients (80 prednisolone, 85 placebo), mean (SD) DAS28 was higher on placebo: 3.14 (1.04) vs 2.92 (1.13) prednisolone at the final trial visit. After tapering, disease activity increased significantly (p=0.02) in the prednisolone group to 3.18 (1.20) but was stable in placebo (3.14). The difference in the increase of DAS28 between the groups was 0.21 (95%CI –0.05;0.47; p=0.11).
For signs of adrenal insufficiency, 33 out of 165 had missing data, leaving 60 in the prednisolone group and 72 in placebo (Table 1). Mean (SD) number of signs for prednisolone was 1.1 (1.1) versus 0.9 (1.3) for placebo at final trial visit and 0.8 (1.2) versus 0.8 (1.0) at follow-up. Difference in the change of the number of signs was –0.1 (95%CI –0.4;0.3; p=0.66).
No differences were seen in ACTH or cortisol levels: mean (SD) ACTH was 5.8 (4.1) in 23 prednisolone patients, and 5.1 (3.7) in 24 placebo patients; cortisol 296 (113) v 310 (166), cortisol/ACTH 67 (40) v 77 (54). Two prednisolone and one placebo patient had cortisol levels below 80. None developed clinical hypoadrenalism during further follow-up.
199 patients qualified for the disease flares sample, 99 prednisolone and 100 placebo; 44 patients flared on prednisolone tapering vs 31 on placebo, relative risk 1.43 (95%CI 0.99; 2.07; p=0.07).
Conclusion Tapering prednisolone moderately increases disease activity to placebo levels (mean still at low disease activity levels) and numerically increases the risk of flare without any evidence of adrenal insufficiency. This suggests that withdrawal of low dose prednisolone is feasible after 2 years of administration.
References DeWalt DA et al. Clin Exp Rheumatol. 2004;22:453-61.
Acknowledgements The GLORIA trial is registered at clinicaltrials.gov under NCT02585258.
The GLORIA project is funded by the European Union’s Horizon 2020 research and innovation programme under the topic ‘’Personalizing Health and Care’’, grant agreement No 634886.
Disclosure of Interests Abdullah Almayali: None declared, Maarten Boers Consultant of: Novartis, Linda Hartman: None declared, Daniela Opris-Belinski Consultant of: Abbvie, Pfizer, MSD, Novartis, Eli Lilly, Ewo Pharma, UCB, Reinhard Bos: None declared, Marc R Kok: None declared, José Antonio P. da Silva: None declared, Eduard N. Griep: None declared, Ruth Klaasen: None declared, Cornelia Allaart: None declared, Paul Baudoin: None declared, Hennie Raterman Consultant of: AbbVie, Amgen, Celgene, Roche, Sandoz, Sanofi Genzyme and UCB, Zoltán Szekanecz: None declared, Frank Buttgereit Consultant of: Abbvie, AstraZeneca, Gruenenthal, Horizon Therapeutics, Mundipharma, Pfizer, Roche, Pavol MASARYK: None declared, WIllem Lems Consultant of: Pfizer, Galapagos, Lilly, Amgen, UCB., Maurizio Cutolo: None declared, Marieke ter Wee: None declared
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