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

BackgroundLow-dose glucocorticoid (GC) therapy is widely used in RA but the true balance of benefit and harm is still unknown.ObjectivesWe studied the effects of prednisolone (5 mg/day, 2 years) in RA patients aged 65+, requiring adjustment of antirheumatic therapy (DAS28≥2.60).MethodsPragmatic 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 categorySAEother AESISAEother AESI Infection261241691 Urinary tract449429 Pneumonia217213 Other20581049 Cardiovascular8260 Symptomatic fracture21146 New onset Hypertension1407 Diabetes mellitus0201 Cataract0726 Glaucoma0103 Other†43433526Total8019463140*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.ResultsWe 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.ConclusionAdd-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.AcknowledgementsTrial 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; andS.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; andS.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 NetherlandsE. Frazão Mateus, and G. Mendes, PortugalC. Elling-Audersch and D. Borucki, GermanyA. Cardone, ItalyP. Corduta and O. Constantinescu, RomaniaP. Richards, United KingdomG. Aanerud, NorwayDisclosure of InterestsMaarten 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