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OP0263 FAVORABLE BALANCE OF BENEFIT AND HARM OF LONG-TERM, LOW-DOSE PREDNISOLONE ADDED TO STANDARD TREATMENT IN RHEUMATOID ARTHRITIS PATIENTS AGED 65+: THE PRAGMATIC, MULTICENTER, PLACEBO- CONTROLLED GLORIA TRIAL

2022; BMJ; Volume: 81; Issue: Suppl 1 Linguagem: Inglês

10.1136/annrheumdis-2022-eular.698

1468-2060

Maarten Boers, L. Hartman, Daniela Opriş-Belinski, R. Bos, Marc R. Kok, J. A. P. da Silva, E. N. Griep, R. Klaasen, C. Allaart, P. Baudoin, H. Raterman, Z. Szekanecz, F. Buttgereit, P. Masaryk, T. Klausch, S. Paolino, A. M. Schilder, W. Lems, M. Cutolo,

Biosimilars and Bioanalytical Methods

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 (Table 1). Table 1. 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 (Figure 1), and was lower on prednisolone (adjusted mean difference in DAS28 over 2 years: 0.37, 95%CL 0.23, p<0.0001). The contrast in early (3-month) response was larger in 331 patients adherent to protocol on stable treatment: mean difference in DAS28 0.62 (95%CL 0.44), more responders on prednisolone (Figure 1). Significant time-treatment interaction in secondary analyses suggested a decrease in contrast after the first year, most likely caused by significantly more changes in DMARD treatment on placebo. Joint damage progression over 2 years was significantly lower on prednisolone: mean 0.6 (SD 1.9) v 1.8 (6.4) score points on placebo, difference 1.2 (95%CL 0.2, p=0.02). 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 (Table 1). During the study 1 vs 2 patients died, and 3 vs 0 died within 5 months of discontinuation. Per 100 patient-years, AE totaled 278 in prednisolone vs 206 in placebo patients, and the difference was most marked for infections (Table 1); these were mostly mild or moderately severe. Other GC-specific AESI were rare without relevant differences. 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