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

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Boers, Maarten, Hartman, Linda, Opris-Belinski, Daniela, Bos, Reinhard, Kok, Marc R, Da Silva, Jose AP, Griep, Eduard N, Klaasen, Ruth, Allaart, Cornelia F, Baudoin, Paul, Raterman, Hennie G, Szekanecz, Zoltan, Buttgereit, Frank, Masaryk, Pavol, Klausch, L Thomas, Paolino, Sabrina, Schilder, Annemarie M, Lems, Willem F, Cutolo, Maurizio, Middelink, LM, Dekker, V, van den Bulk, N, Pinto, RMA, Doerwald, L, Manger, S, Redol, J, Prinsen, K, Scholte-Voshaar, M, Jansen, TLTA, Codreanu, C, Molenaar, E, van Laar, JM, Ruiterman, YPM, Boonen, AERCH, Boonen, AERCH, Micaelo, M, Costa, J, Sieburg, M, Spoorenberg, JPL, Prothmann, U, Saavedra, MJ, Silva, I, Nurmohamed, MT, Jacobs, JWG, Tas, SW, Bijlsma, JWJ, Christensen, R, Smulders, YM, Ralston, SH, van der Heijde, DMFM, Marsman, AF, Lems, WF, Rusthoven, C, Bakkers, M, Frazão Mateus, E, Mendes, G, Elling-Audersch, C, Borucki, D, Celano, A, Corduta, P, Constantinescu, O, Richards, P, Aanerud, GJ·2022·Annals of the Rheumatic Diseases
DOI 10.1136/annrheumdis-2021-221957PMC PMC9209692
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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.

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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 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.CC BY-NC · PubMed Central
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 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.CC BY-NC · PubMed Central
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.
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.CC BY-NC · PubMed Central

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Metadata

Authors
Boers, M., Hartman, L., Opris-Belinski, D., Bos, R., Kok, M. R., Da Silva, J. A., Griep, E. N., Klaasen, R., Allaart, C. F., Baudoin, P., Raterman, H. G., Szekanecz, Z., Buttgereit, F., Masaryk, P., Klausch, L. T., Paolino, S., Schilder, A. M., Lems, W. F., Cutolo, M., Middelink, L., Dekker, V, van den Bulk, N., Pinto, R., Doerwald, L., Manger, S., Redol, J., Prinsen, K., Scholte-Voshaar, M., Jansen, T., Codreanu, C., Molenaar, E., van Laar, J., Ruiterman, Y., Boonen, A., Boonen, A., Micaelo, M., Costa, J., Sieburg, M., Spoorenberg, J., Prothmann, U., Saavedra, M., Silva, I., Nurmohamed, M., Jacobs, J., Tas, S., Bijlsma, J., Christensen, R., Smulders, Y., Ralston, S., van der Heijde, D., Marsman, A., Lems, W., Rusthoven, C., Bakkers, M., Frazão Mateus, E., Mendes, G., Elling-Audersch, C., Borucki, D., Celano, A., Corduta, P., Constantinescu, O., Richards, P., & Aanerud, G.
Affiliations
  • Amsterdam University Medical Centers (NL)
  • Medisch Centrum Leeuwarden (NL)
  • Maasstad Ziekenhuis (NL)
  • Antonius Ziekenhuis (NL)
  • Meander Medisch Centrum (NL)
  • Leiden University Medical Center (NL)
  • Noordwest Ziekenhuisgroep (NL)
  • Charité – Universitätsmedizin Berlin (DE)
  • National Institute of Rheumatic Diseases (SK)
  • University of Genoa (IT)
Corresponding author
Boers, Maarten
ORCID
Venue
Annals of the Rheumatic Diseases
Publisher
Elsevier BV
Published
2022-07
Volume
81
Issue
7
Pages
925-936
ISSN
0003-4967 (ISSN-L)
DOI
10.1136/annrheumdis-2021-221957
PMC
PMC9209692
OpenAlex
W4282930667
Cited by
169
References
0
Citations by year
2026: 29 · 2025: 33 · 2024: 48 · 2023: 43 · 2022: 15
FWCI
25.30
Type
journal article
Language
en
Open access
Licence
Locations
  • Annals of the Rheumatic Diseases (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Leiden Repository (Leiden University) (submittedVersion, cc-by)
  • Data Archiving and Networked Services (DANS) (submittedVersion, cc-by)
  • University of Debrecen Electronic Archive (University of Debrecen) (submittedVersion, other-oa)
  • CINECA IRIS Institutial Research Information System (University of Genoa) (submittedVersion, other-oa)
  • Amsterdam UMC (VU Amsterdam) - Institutional Repository (submittedVersion, other-oa)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
Funders
European Commission (Horizon 2020: 634886)
Topics
  • Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
  • Health Sciences › Medicine › Hematology › Autoimmune and Inflammatory Disorders Research
  • Health Sciences › Medicine › Rheumatology › Osteoarthritis Treatment and Mechanisms
Keywords
rheumatoid arthritis, prednisolone, low-dose glucocorticoids, older adults, disease activity, joint destruction, adverse events, infection, adjunctive therapy, benefit-harm balance, disease-modifying antirheumatic drugs, biologics, comorbidities, COVID-19 pandemic, trial discontinuation
MeSH terms
Aged, Arthritis, Rheumatoid, Double-Blind Method, Drug Therapy, Combination, Glucocorticoids, Humans, Methotrexate, Prednisolone, Treatment Outcome, Antirheumatic Agents

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Boers, M., Hartman, L., Opris-Belinski, D., Bos, R., Kok, M. R., Da Silva, J. A., Griep, E. N., Klaasen, R., Allaart, C. F., Baudoin, P., Raterman, H. G., Szekanecz, Z., Buttgereit, F., Masaryk, P., Klausch, L. T., Paolino, S., Schilder, A. M., Lems, W. F., Cutolo, M., . . . Aanerud, G. (2022). Low dose, add-on prednisolone in patients with rheumatoid arthritis aged 65+: the pragmatic randomised, double-blind placebo-controlled GLORIA trial. Annals of the Rheumatic Diseases. https://doi.org/10.1136/annrheumdis-2021-221957