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Randomized Controlled Trial
. 2022 Jul;81(7):925-936.
doi: 10.1136/annrheumdis-2021-221957. Epub 2022 May 31.

Low dose, add-on prednisolone in patients with rheumatoid arthritis aged 65+: the pragmatic randomised, double-blind placebo-controlled GLORIA trial

Maarten Boers  1   2 , Linda Hartman  3   2 , Daniela Opris-Belinski  4 , Reinhard Bos  5 , Marc R Kok  6 , Jose Ap Da Silva  7 , Eduard N Griep  8 , Ruth Klaasen  9 , Cornelia F Allaart  10 , Paul Baudoin  11 , Hennie G Raterman  12 , Zoltan Szekanecz  13 , Frank Buttgereit  14 , Pavol Masaryk  15 , L Thomas Klausch  3 , Sabrina Paolino  16 , Annemarie M Schilder  5 , Willem F Lems  2 , Maurizio Cutolo  16 ; GLORIA Trial consortium
Collaborators, Affiliations
Randomized Controlled Trial

Low dose, add-on prednisolone in patients with rheumatoid arthritis aged 65+: the pragmatic randomised, double-blind placebo-controlled GLORIA trial

Maarten Boers et al. Ann Rheum Dis. 2022 Jul.

Abstract

Background: Low-dose glucocorticoid (GC) therapy is widely used in rheumatoid arthritis (RA) but the balance of benefit and harm is still unclear.

Methods: The GLORIA (Glucocorticoid LOw-dose in RheumatoId Arthritis) pragmatic double-blind randomised trial compared 2 years of prednisolone, 5 mg/day, to placebo in patients aged 65+ with active RA. We allowed all cotreatments except long-term open label GC and minimised exclusion criteria, tailored to seniors. Benefit outcomes included disease activity (disease activity score; DAS28, coprimary) and joint damage (Sharp/van der Heijde, secondary). The other coprimary outcome was harm, expressed as the proportion of patients with ≥1 adverse event (AE) of special interest. Such events comprised serious events, GC-specific events and those causing study discontinuation. Longitudinal models analysed the data, with one-sided testing and 95% confidence limits (95% CL).

Results: We randomised 451 patients with established RA and mean 2.1 comorbidities, age 72, disease duration 11 years and DAS28 4.5. 79% were on disease-modifying treatment, including 14% on biologics. 63% prednisolone versus 61% placebo patients completed the trial. Discontinuations were for AE (both, 14%), active disease (3 vs 4%) and for other (including covid pandemic-related disease) reasons (19 vs 21%); mean time in study was 19 months. Disease activity was 0.37 points lower on prednisolone (95% CL 0.23, p<0.0001); joint damage progression was 1.7 points lower (95% CL 0.7, p=0.003). 60% versus 49% of patients experienced the harm outcome, adjusted relative risk 1.24 (95% CL 1.04, p=0.02), with the largest contrast in (mostly non-severe) infections. Other GC-specific events were rare.

Conclusion: Add-on low-dose prednisolone has beneficial long-term effects in senior patients with established RA, with a trade-off of 24% increase in patients with mostly non-severe AE; this suggests a favourable balance of benefit and harm.

Trial registration number: NCT02585258.

Keywords: arthritis, rheumatoid; glucocorticoids; osteoporosis; therapeutics.

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Conflict of interest statement

Competing interests: Maarten Boers: Novartis. Linda Hartman: none. Daniela Opris-Belinski: Abbvie, Pfizer, MSD, Novartis, Eli Lilly, Ewo Pharma, UCB. Reinhard Bos: none. Marc R. Kok: none. José A.P. da Silva: none. Eduard N. Griep: none. Ruth Klaasen: none. Cornelia F. Allaart: none. Paul Baudoin: none. Hennie G. Raterman: AbbVie, Amgen, Celgene, Roche, Sandoz, Sanofi Genzyme, UCB. Zoltan Szekanecz: none. Frank Buttgereit: Abbvie, AstraZeneca, Gruenenthal, Horizon Therapeutics, Mundipharma, Pfizer, Roche. Pavol Masaryk: none. L. Thomas Klausch: none. Sabrina Paolino: none. Annemarie M. Schilder: Eli Lilly, Novartis, Genzyme. Willem F. Lems: Pfizer, Galapagos, Lilly, Amgen, UCB. Maurizio Cutolo: none.

Figures

Figure 1
Figure 1
Description of analysis populations and patient disposition. For the early response analysis, extra criteria were applied as listed. ITT, intention to treat; PP, per protocol.
Figure 2
Figure 2
Better response in disease activity on prednisolone compared with placebo. Left: long-term change in disease activity estimated in primary model, model with time-treatment interactions, and as observed (unadjusted), with numbers of patients with available data. Right: short-term response at 3 months in the per-protocol population, according to EULAR and ACR criteria, and for minimal disease activity state (DAS28 <2.60) and Boolean remission. The time–treatment interaction terms for 3, 18 and 24 months were statistically significant. The grey area depicts the one-sided 95% confidence bound for the difference between groups at each time point. Error bars depict one half of the two-sided 95% CI for the group means. ACR, American College of Rheumatology; DAS28, Disease Activity Score 28 joints; EULAR, European League Against Rheumatism.
Figure 3
Figure 3
Patients with multiple adverse events (AE) have a major impact on the total number of events in both treatment groups. Infection events in top panels, all AE in bottom panels. Left panels show the distribution of patients by number of events/patient. This shows most patients experience no or only a few events. Right panels plot bivariate cumulative distributions of patients by AE. The numbers next to the series indicate the maximum number of events of the population at that point. The right panels show the impact of multiple events: for example, in the top right panel, 75% of patients (with 0 or 1 infection) contribute only 25% of all infections. Another example, in the bottom right panel, read in reverse, 50% of patients (with 2 respectively 3 or more events) contribute almost 90% of all AE. To facilitate interpretation, grey vertical bars indicate 10% on the vertical scale.
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