Background: Low-dose glucocorticoid (GC) therapy is widely used in RA but the true balance of benefit and harm is still unknown.
Objectives: We studied the effects of prednisolone (5 mg/day, 2 years) in RA patients aged 65+, requiring adjustment of antirheumatic therapy (DAS28≥2.60).
Methods: Pragmatic double-blind placebo-controlled randomized trial; all co-treatments and changes therein were allowed during the trial except long-term open label GC; Ca/D supplementation was advised in all patients. Minimal exclusion criteria were tailored to seniors.
Harm outcome: the number of patients with ≥1 serious adverse event (SAE), or ≥1 ‘other adverse event of special interest’ (other AESI). Other AESI comprised any AE (except worsening of RA) causing study discontinuation, and GC-specific events (
Adverse events of special interest (AESI).*
prednisolone (n=224) | placebo (n=225) | |||
---|---|---|---|---|
Events by protocol-defined category | SAE | other AESI | SAE | other AESI |
Infection | 26 | 124 | 16 | 91 |
Urinary tract | 4 | 49 | 4 | 29 |
Pneumonia | 2 | 17 | 2 | 13 |
Other | 20 | 58 | 10 | 49 |
Cardiovascular | 8 | 2 | 6 | 0 |
Symptomatic fracture | 2 | 11 | 4 | 6 |
New onset | ||||
Hypertension | 1 | 4 | 0 | 7 |
Diabetes mellitus | 0 | 2 | 0 | 1 |
Cataract | 0 | 7 | 2 | 6 |
Glaucoma | 0 | 1 | 0 | 3 |
Other † | 43 | 43 | 35 | 26 |
Total | 80 | 194 | 63 | 140 |
*AESI: Comprises serious adverse events (SAE) and other AESI, defined by protocol.
†‘Other’ other AESI: non-serious AE outside of the above predefined categories, but associated with premature discontinuation.
Benefit outcomes: improvement in disease activity (DAS28) and joint damage progression (Sharp/van der Heijde).
Longitudinal mixed models analyzed the data. Given prior knowledge we report one-sided 95% confidence limit (95%CL) and statistical tests, performed only for the main outcomes.
Results: We randomized 451 RA patients in 7 EU countries, 449 received the intervention; of these 63% prednisolone vs 61% placebo patients completed 2 years of follow up. Discontinuations were similar in both groups: for AE (14%) and active disease (4%); the remainder mostly for ‘trial fatigue’ and covid-related access issues (20%). Mean time on study drug was 19 (SD 8) months.
70% of patients were female, mean age was 72 (max 88) years, RA duration 11 years; 67% were RF+, 56% ACPA+, 96% had joint damage on radiographs: mean score 20, median 8. Mean DAS28 was 4.5. Most patients (79%) were on current DMARD treatment, including 14% on biologics; 47% had previously used GC, 14% changed DMARD therapy at baseline. Patients had mean 2.1 active comorbidities, and used median 7 drugs.
Benefit: Disease activity rapidly declined to stabilize after 1 year (
Harm: 60% prednisolone vs 49% placebo patients experienced the harm outcome: adjusted RR 1.24, 95%CL 1.04, p=0.02; number needed to harm 9.5 (
Conclusion: Add-on low dose prednisolone has beneficial long-term effects on disease activity and damage progression in senior RA patients on standard treatment. The tradeoff is a 24% increase in patients with mostly mild to moderate AE, suggesting a favorable balance of benefit and harm.
Acknowledgements: Trial registration: NCT02585258 (clinicaltrials.gov).
The trial is part of a larger project funded by the European Union’s Horizon 2020 research and innovation program under grant agreement No. 634886.
Apart from the listed authors and centers, the GLORIA Trial Consortium comprises:
L.M. Middelink, Middelinc BV The Netherlands, Operational Lead;
V. Dekker, Amsterdam UMC, Vrije Universiteit, Financial Lead;
Partners:
Trial operations: N. van den Bulk, CR2O BV, The Netherlands;
Study Medication (Development, Manufacturing & Supply): R.M.A. Pinto,
Bluepharma – Indústria Farmacêutica, S.A., Portugal;
Data management: L. Doerwald, Linical Netherlands BV, The Netherlands; S. Manger, Department of Epidemiology & Data Science, Amsterdam UMC, Vrije Universiteit, The Netherlands.
Adherence monitoring: J. Redol, BeyonDevices LDA, Portugal;
Safety monitoring: K. Prinsen, Clinfidence BV, The Netherlands;
Patient partner: M. Scholte-Voshaar, Stichting Tools (Tools2Use), The Netherlands.
Investigators (other recruiting centers):
T.L.T.A. Jansen, VieCuri – location Venlo, The Netherlands;
C. Codreanu, Clinical Center for Rheumatic Diseases, Bucarest, Rumania;
R.M.Zandhuis-Mooij, MSc, Gelre Ziekenhuis, Apeldoorn, The Netherlands;
E. Molenaar, Groene Hart Ziekenhuis, Gouda, The Netherlands;
J.M. van Laar, UMC Utrecht, The Netherlands;
Y.P.M. Ruiterman, Haga Ziekenhuis, Den Haag, The Netherlands;
A.E.R.C.H. Boonen, MUMC, Maastricht, The Netherlands;
M. Micaelo, Instituto Português de Reumatologia, Lisboa, Portugal;
J. Costa, Hospital de Ponte Lima, Portugal;
M. Sieburg, Rheumatologische Facharztpraxis Magdeburg, Germany;
J.P.L. Spoorenberg, UMC Groningen, The Netherlands;
U. Prothmann, Knappschaftsklinikum Saar GbmH, Puettlingen, Germany;
M.J. Saavedra, Hospital de Santa Maria, Lisboa, Portugal;
I. Silva, Hospital de Egas Moniz, Lisboa, Portugal;
M.T. Nurmohamed, Reade, Amsterdam, The Netherlands;
J.W.G. Jacobs, UMC Utrecht, The Netherlands; and
S.W. Tas, Amsterdam UMC, University of Amsterdam, The Netherlands.
Scientific Advisory Committee:
J.W.J. Bijlsma, UMC Utrecht, The Netherlands;
R. Christensen, The Parker Institute, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark;
Y.M. Smulders, Amsterdam UMC, VU University, The Netherlands; and
S.H. Ralston, University of Edinburgh, Edinburgh, UK.
Radiographic assessment:
D.M.F.M. van der Heijde (Imaging Rheumatology BV, the Netherlands)
coordinated the reading of the hand and foot x-rays.
A.F. Marsman and W.F. Lems scored the spine X-rays.
Patient panel:
C. Rusthoven and M. Bakkers, The Netherlands
E. Frazão Mateus, and G. Mendes, Portugal
C. Elling-Audersch and D. Borucki, Germany
A. Cardone, Italy
P. Corduta and O. Constantinescu, Romania
P. Richards, United Kingdom
G. Aanerud, Norway
Disclosure of Interests: 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, Pfizer, MSD, Novartis, Eli Lilly, Ewo Pharma, UCB, Zoltán Szekanecz: None declared, Frank Buttgereit Consultant of: Abbvie, AstraZeneca, Gruenenthal, Horizon Therapeutics, Mundipharma, Pfizer, Roche, Pavol MASARYK: None declared, Thomas Klausch: None declared, Sabrina Paolino: None declared, Annemarie M. Schilder Consultant of: Eli Lilly, Novartis, Genzyme, WIllem Lems Consultant of: Pfizer, Galapagos, Lilly, Amgen, UCB., Maurizio Cutolo: None declared