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• Are chronic glucocorticoids truly safe in older patients with rheumatoid arthritis?
  Giovanni Adami, Angelo Fassio, Maurizio Rossini, Davide Bertelle and Davide Gatti
  Published on: 7 September 2022
• The unbearable lightness of low-dose glucocorticoid therapy for rheumatoid arthritis
  Alessandro Giollo, Margherita Zen and Andrea Doria
  Published on: 23 July 2022

• Published on: 7 September 2022

  Are chronic glucocorticoids truly safe in older patients with rheumatoid arthritis?

  • Giovanni Adami, Rheumatologist Rheumatology Unit, Department of Medicine, University of Verona, Verona, Italy
  • Other Contributors:
    • Angelo Fassio, Rheumatologist
    • Maurizio Rossini, Rheumatologist
    • Davide Bertelle, Rheumatologist
    • Davide Gatti, Rheumatologist

  Dear Editor,
  We read with great interest the article by Boers and colleagues [1]. The GLORIA trial is one-of-a-kind study and certainly represents a milestone for rheumatoid arthritis (RA) treatment in seniors. The overall message conveyed by the investigators is that glucocorticoids (GCs) at a dose of 5 mg/day is somehow safe and effective (at least for 2-years) in older patients with RA. However, we have some concerns regarding the latter claim and several questions for the authors.
  First, mean time on study drug was 19 months and only 60% completed the study. The authors stated that “the high rates of events in both groups over the observation period make it unlikely that the risk estimate would be substantially different in a more complete data set”. We somehow disagree. Fracture risk in glucocorticoid induced osteoporosis (GIOP) strictly depends on the treatment duration [2]. In addition, fracture risk remains elevated even after 1 year from GCs withdrawal [3], with possible long-term effects that were not captured by the GLORIA trial.
  Second, “over 2 years, spine bone density decreased by about 1% in prednisolone, but increased by 3% in placebo patients”. We frankly think that this difference might be relevant to many patients. BMD increases (in similar magnitude of the placebo group of the GLORIA trial) have been associated with significantly lower incidence of fracture in both clinical trials and observational studies [4,5]. Remarkably, a 2% perce...

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  Dear Editor,
  We read with great interest the article by Boers and colleagues [1]. The GLORIA trial is one-of-a-kind study and certainly represents a milestone for rheumatoid arthritis (RA) treatment in seniors. The overall message conveyed by the investigators is that glucocorticoids (GCs) at a dose of 5 mg/day is somehow safe and effective (at least for 2-years) in older patients with RA. However, we have some concerns regarding the latter claim and several questions for the authors.
  First, mean time on study drug was 19 months and only 60% completed the study. The authors stated that “the high rates of events in both groups over the observation period make it unlikely that the risk estimate would be substantially different in a more complete data set”. We somehow disagree. Fracture risk in glucocorticoid induced osteoporosis (GIOP) strictly depends on the treatment duration [2]. In addition, fracture risk remains elevated even after 1 year from GCs withdrawal [3], with possible long-term effects that were not captured by the GLORIA trial.
  Second, “over 2 years, spine bone density decreased by about 1% in prednisolone, but increased by 3% in placebo patients”. We frankly think that this difference might be relevant to many patients. BMD increases (in similar magnitude of the placebo group of the GLORIA trial) have been associated with significantly lower incidence of fracture in both clinical trials and observational studies [4,5]. Remarkably, a 2% percent difference in BMD change at lumbar spine has been associated with 28% lower risk of vertebral fractures [5] which is, by coincidence, the same increase in risk seen in the GLORIA trial (RR 1.28) for vertebral fractures. Though, the study sample was not powered to assess such outcome.
  Third, we noted that the exclusion criteria mentioned: “Absolute contraindication to low-dose prednisolone, as determined by the treating physician, such as: […] osteoporosis. When these conditions are under control (e.g., with anti-osteoporosis drugs) these patients can enter”. We wonder if patients with osteoporosis at baseline (and not on anti-osteoporosis medications) were subsequently treated with an anti-osteoporosis drug. Such confounder might be relevant and, possibly, alter the results of the study. We also think that clarifications on baseline diagnosis of osteoporosis would be helpful. In other words, osteoporosis was reported in 25% of patients, baseline T-score <-2.5 in 11% and prevalent spine fracture in 32%, were these patients overlapping?
  Four, as regards infections, the authors claimed that “low-dose GC are not of special concern but should be viewed through the same lens as those of other DMARDs”. However, George et al found that GCs were associated with incremental risk of infection when associated with DMARDs [6]. Therefore, since it is highly plausible that a patient with RA will receive at least one DMARD as part of her treatment, one might argue that the trade off from treating chronically with GCs is questionable.
  Fifth, the authors claimed that confounding by indication is a peculiar feature of observational studies and should be attenuated by randomization. Nonetheless, they admit that “long-term treatment benefits were probably underestimated due to confounding”. We agree with the latter statement, but we ask ourselves if a similar consideration should be made also for the safety outcomes. Infection, as an example, are influenced by short-term course of steroids, which were permitted in the GLORIA trial. Would this confounding attenuate the differences in terms of infections?
  Finally, we agree with the authors that, in selected patients, the benefit and harm balance might be favorable. However, clinicians should fully recognize some of the GLORIA study limitations during the shared decision-making process and treat patients accordingly.

  References
  1 Boers M, Hartman L, Opris-Belinski D, et al. 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 2022;81:925–36. doi:10.1136/annrheumdis-2021-221957
  2 Adami G, Saag KG. Glucocorticoid-induced osteoporosis: 2019 concise clinical review. Osteoporos Int 2019;30:1145–56. doi:10.1007/s00198-019-04906-x
  3 De Vries F, Bracke M, Leufkens HGM, et al. Fracture risk with intermittent high-dose oral glucocorticoid therapy. Arthritis Rheum 2007;56:208–14. doi:10.1002/art.22294
  4 Adami G, Gavioli I, Rossini M, et al. Real-life short-term effectiveness of anti-osteoporotic treatments: a longitudinal cohort study. Therapeutic Advances in Musculoskeletal 2022;14:1759720X221105009. doi:10.1177/1759720X221105009
  5 Bouxsein ML, Eastell R, Lui L-Y, et al. Change in Bone Density and Reduction in Fracture Risk: A Meta-Regression of Published Trials. J Bone Miner Res 2019;34:632–42. doi:10.1002/jbmr.3641
  6 George MD, Baker JF, Winthrop K, et al. Risk for Serious Infection With Low-Dose Glucocorticoids in Patients With Rheumatoid Arthritis : A Cohort Study. Ann Intern Med 2020;173:870–8. doi:10.7326/M20-1594

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  Conflict of Interest:
  Giovanni Adami reports personal fees from Theramex, UCB, Lilly, Galapagos, Fresenius Kabi, Amgen. Davide Gatti has received advisory board honoraria, consultancy fees and/or speaker fees from Abiogen, Celgene, Eli-Lilly, Neopharmed-Gentili, Pfizer, UCB. Maurizio Rossini reports advisory board honoraria, consultancy fees and/or speaker fees from AbbVie, Abiogen, Amgen, BMS, Eli-Lilly, Galapagos, Theramex, UCB, outside the submitted work. Angelo Fassio reports personal fees from Abiogen, Novartis, Neopharmed.

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• Published on: 23 July 2022

  The unbearable lightness of low-dose glucocorticoid therapy for rheumatoid arthritis

  • Alessandro Giollo, Consultant in Rheumatology Rheumatology Unit, Department of Medicine, University of Padua, Italy
  • Other Contributors:
    • Margherita Zen, Researcher
    • Andrea Doria, Full Professor of Rheumatology

  Glucocorticoid (GC) therapy is still the mainstay in managing rheumatoid arthritis (RA). The benefits of low-dose GC therapy are well established after decades of clinical experience in RA. Yet, it is essential to appoint the danger of exposure to chronic GC therapy.
  For many patients with RA and other inflammatory rheumatic musculoskeletal diseases (RMD), starting prednisolone means taking glucocorticoids for several years or decades, often indefinitely.1 The long-term complications of GC therapy are rarely emphasised by most clinical trials that usually run for only 1 or 2 years. In this regard, the GLORIA trial2 has illuminated both the harms and benefits of 2-year low-dose (5 mg daily) prednisolone in 451 elderly patients (≥65 years) with moderately active established RA. Indeed, there was an 11% increase in patients with at least one adverse event (AE) of special interest (mainly mild to moderate infections) in the prednisolone arm, accounting for a 1.24 (95% CL 0.4) fold higher risk compared to placebo, just within two years of treatment.2
  The likelihood of major osteoporotic fractures in GC users increases with the dosage, but more importantly, with the cumulative dose and duration of GC therapy.3 Moreover, low-dose GC therapy (≤5 mg/day) did not seem to be associated with a reduction of bone mineral density (BMD) in patients with inflammatory RMD and current or prior exposure to GC.4 However, while GC therapy effectively alleviates inflammation, it has...

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  Glucocorticoid (GC) therapy is still the mainstay in managing rheumatoid arthritis (RA). The benefits of low-dose GC therapy are well established after decades of clinical experience in RA. Yet, it is essential to appoint the danger of exposure to chronic GC therapy.
  For many patients with RA and other inflammatory rheumatic musculoskeletal diseases (RMD), starting prednisolone means taking glucocorticoids for several years or decades, often indefinitely.1 The long-term complications of GC therapy are rarely emphasised by most clinical trials that usually run for only 1 or 2 years. In this regard, the GLORIA trial2 has illuminated both the harms and benefits of 2-year low-dose (5 mg daily) prednisolone in 451 elderly patients (≥65 years) with moderately active established RA. Indeed, there was an 11% increase in patients with at least one adverse event (AE) of special interest (mainly mild to moderate infections) in the prednisolone arm, accounting for a 1.24 (95% CL 0.4) fold higher risk compared to placebo, just within two years of treatment.2
  The likelihood of major osteoporotic fractures in GC users increases with the dosage, but more importantly, with the cumulative dose and duration of GC therapy.3 Moreover, low-dose GC therapy (≤5 mg/day) did not seem to be associated with a reduction of bone mineral density (BMD) in patients with inflammatory RMD and current or prior exposure to GC.4 However, while GC therapy effectively alleviates inflammation, it has a devastating effect on bone.5 Indeed, it is hard to estimate the risk of major osteoporotic fractures from glucocorticoid-induced osteoporosis (GIOP) using dual X-ray absorptiometry (DXA), as frailty fractures occur with normal or osteopenic BMD in many patients with GIOP. It is also worrisome that GIOP is often overlooked since only 13% of elderly patients with a diagnosis of osteoporosis received antiresorptive drugs despite initiating GC therapy.2 Moreover, minor complaints of ecchymosis, haematoma and skin atrophy are more common amongst long-dose GC users2 but highly relevant to their quality of life.
  In our cohort of 1366 RA patients actively treated with biological and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs), those older than 65 years represent almost 50% of the treated population. However, the risks of low-dose GC therapy in older RA patients taking b/tsDMARDs have received only a little attention. No randomised controlled trial has investigated the safety of low-dose GC in RA patients taking b/tsDMARDs. In the GLORIA trial, one of the few randomised controlled trials of low-dose GC therapy in RA, only 16% and 13% of patients took biologics at baseline in the prednisolone and placebo groups, respectively, and just ≃6% of participants per group initiated or switched to biological DMARDs during follow-up.2 Patients with RA included in the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis were at higher risk for nonserious infections if treated concomitantly with GC therapy (hazard ratio 1.25, 95% CI 1.19–1.32).6 One more extensive cohort study from the United States found similar higher risks for severe infection in patients receiving low-dose GC (≤5 mg daily) in addition to a b/tsDMARD (adjusted HR 1.26, 95% CI 1.20–1.33) or methotrexate without a b/tsDMARD (adjusted HR 1.32, 95% CI 1.26–1.37), compared to not using glucocorticoids.7
  In conclusion, there is a need for more data to determine the long-term (>2 years) balance between efficacy and harms of low-dose GC therapy for patients with RA.

  References
  1. Giollo A, Rossini M, Bettili F, et al. Permanent Discontinuation of Glucocorticoids in Polymyalgia Rheumatica Is Uncommon but May Be Enhanced by Amino Bisphosphonates. J Rheumatol 2019;46:318-322.
  2. Boers M, Hartman L, Opris-Belinski D for the GLORIA Trial consortium et al. Low dose, add-on prednisolone in patients with rheumatoid arthritis aged 65+: the pragmatic randomised, double-blind placebo-controlled GLORIA trial. Ann Rheum Dis 2022;81:925-936.
  3. Abtahi S, Driessen JHM, Burden AM, et al. Low-dose oral glucocorticoid therapy and risk of osteoporotic fractures in patients with rheumatoid arthritis: a cohort study using the Clinical Practice Research Datalink. Rheumatology (Oxford) 2022;61:1448-1458.
  4. Wiebe E, Huscher D, Schaumburg D, et al. Optimising both disease control and glucocorticoid dosing is essential for bone protection in patients with rheumatic disease. Ann Rheum Dis 2022 Jun 9:annrheumdis-2022-222339.
  5. Takahata M, Shimizu T, Yamada S, et al. Bone biopsy findings in patients receiving long-term bisphosphonate therapy for glucocorticoid-induced osteoporosis. J Bone Miner Metab 2022;40:613-622.
  6. Bechman K, Halai K, Yates M, et al. Nonserious Infections in Patients With Rheumatoid Arthritis: Results From the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis. Arthritis Rheumatol 2021;73:1800-1809.
  7. George MD, Baker JF, Winthrop K, et al. Risk for Serious Infection With Low-Dose Glucocorticoids in Patients With Rheumatoid Arthritis: A Cohort Study. Ann Intern Med 2020;173:870-878.

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  Conflict of Interest:
  None declared.

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