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Efficacy and Safety of Etanercept in Elderly Patients with Rheumatoid Arthritis: A Post-Hoc Analysis of Randomized Controlled Trials

  • Christopher J. EdwardsEmail author
  • Katherine Roshak
  • Jack F. Bukowski
  • Ronald Pedersen
  • Mazhar Thakur
  • Cecilia Borlenghi
  • Cinzia Curiale
  • Heather Jones
  • Lisa Marshall
Original Research Article
  • 24 Downloads

Abstract

Background

Elderly individuals are disproportionately affected by rheumatoid arthritis (RA), but few studies have addressed the efficacy and safety of treatments in this population.

Objective

Our objective was to assess the efficacy and safety of etanercept in elderly patients (aged ≥ 65 years) with RA.

Methods

The efficacy analysis was a post hoc analysis of data from the open-label period of three phase IV clinical trials of etanercept for RA. Least squares (LS) change from baseline (cfb) in 28-joint Disease Activity Score (DAS28), Health Assessment Questionnaire Disability Index (HAQ-DI), and modified Total Sharp Scores (mTSS) were analyzed by age (< 65 vs. ≥ 65 years) for each study. The safety analyses were of data pooled from the double-blind, placebo-controlled periods of 19 phase I–IV randomized studies of etanercept in patients with RA. The percentage occurrence of adverse events (AEs) in placebo- and etanercept-treated patients was analyzed by age (< 65 vs. ≥ 65 years).

Results

There were no significant differences in LS mean cfb in DAS28 or mTSS between the two age groups. LS mean cfb in HAQ-DI scores was consistently lower in elderly than in non-elderly patients, although significant differences were not observed in all trials. Overall, AE occurrence was higher in elderly than non-elderly patients, regardless of treatment. In etanercept-treated patients, there were small yet statistically significant increases in the occurrence of congestive heart failure, serious infections, and non-melanoma skin cancers in elderly versus non-elderly patients. For most AEs, occurrence did not significantly differ between elderly and non-elderly patients.

Conclusion

Overall, there were no substantial differences in the efficacy or safety of etanercept between elderly and non-elderly patients with RA.

Notes

Compliance with Ethical Standards

Funding

This study was funded by Pfizer. Medical writing support was provided by Lorna Forse, PhD, of Engage Scientific Solutions and was funded by Pfizer.

Conflict of Interest

Professor Edwards has received honoraria for advisory boards and speakers’ bureau and research support from AbbVie, BMS, Biogen, Celgene, Fresenius, Janssen, Lilly, Mundipharma, Pfizer, MSD, Novartis, Roche, Samsung, Sanofi, and UCB. Ms. Roshak was an employee of Pfizer at the time of data generation and manuscript initiation. Dr. Thakur is an employee of RegSafe Consulting Limited and was contracted by Pfizer in connection with the development of the manuscript. Mr. Pedersen, Dr. Borlenghi, and Dr. Curiale are employees of and own stock in Pfizer. Dr. Bukowski, Ms. Jones, and Dr. Marshall were employees of Pfizer at the time of data generation and manuscript development and own stock in Pfizer.

Ethical Approval

As a non-interventional study, ethical approval was not required for this analysis. This article does not contain any studies with human participants or animals performed by any of the authors.

Data Sharing

Upon request, and subject to certain criteria, conditions, and exceptions (see https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information), Pfizer will provide access to individual de-identified participant data from Pfizer-sponsored global interventional clinical studies conducted for medicines, vaccines, and medical devices (1) for indications that have been approved in the USA and/or EU or (2) in programs that have been terminated (i.e., development for all indications has been discontinued). Pfizer will also consider requests for the protocol, data dictionary, and statistical analysis plan. Data may be requested from Pfizer trials 24 months after study completion. The de-identified participant data will be made available to researchers whose proposals meet the research criteria and other conditions, and for which an exception does not apply, via a secure portal. To gain access, data requestors must enter into a data access agreement with Pfizer.

Supplementary material

40266_2019_691_MOESM1_ESM.pdf (386 kb)
Supplementary material 1 (PDF 386 kb)

References

  1. 1.
    Uhlig T, Moe RH, Kvien TK. The burden of disease in rheumatoid arthritis. Pharmacoeconomics. 2014;32:841–51.CrossRefGoogle Scholar
  2. 2.
    Scott DL, Wolfe F, Huizinga TW. Rheumatoid arthritis. Lancet. 2010;376:1094–108.CrossRefGoogle Scholar
  3. 3.
    Alamanos Y, Voulgari PV, Drosos AA. Incidence and prevalence of rheumatoid arthritis, based on the 1987 American College of Rheumatology criteria: a systematic review. Semin Arthritis Rheum. 2006;36:182–8.CrossRefGoogle Scholar
  4. 4.
    Soubrier M, Tatar Z, Couderc M, Mathieu S, Dubost JJ. Rheumatoid arthritis in the elderly in the era of tight control. Drugs Aging. 2013;30:863–9.CrossRefGoogle Scholar
  5. 5.
    Papadopoulos IA, Katsimbri P, Alamanos Y, Voulgari PV, Drosos AA. Early rheumatoid arthritis patients: relationship of age. Rheumatol Int. 2003;23:70–4.CrossRefGoogle Scholar
  6. 6.
    Cross M, Smith E, Hoy D, Carmona L, Wolfe F, Vos T, et al. The global burden of rheumatoid arthritis: estimates from the global burden of disease 2010 study. Ann Rheum Dis. 2014;73:1316–22.CrossRefGoogle Scholar
  7. 7.
    World Health Organization. Proposed working definition of an older person in Africa for the MDS Project. 2002. http://www.who.int/healthinfo/survey/ageingdefnolder/en/. Accessed 04 Sept 2018.
  8. 8.
    Konrat C, Boutron I, Trinquart L, Auleley GR, Ricordeau P, Ravaud P. Underrepresentation of elderly people in randomised controlled trials. The example of trials of 4 widely prescribed drugs. PLoS One. 2012;7:e33559.CrossRefGoogle Scholar
  9. 9.
    Ogasawara M, Tamura N, Onuma S, Kusaoi M, Sekiya F, Matsudaira R, et al. Observational cross-sectional study revealing less aggressive treatment in Japanese elderly than nonelderly patients with rheumatoid arthritis. J Clin Rheumatol. 2010;16:370–4.CrossRefGoogle Scholar
  10. 10.
    Ng B, Chu A, Khan MM. A retrospective cohort study: 10-year trend of disease-modifying antirheumatic drugs and biological agents use in patients with rheumatoid arthritis at Veteran Affairs Medical Centers. BMJ Open. 2013;3:e002468.CrossRefGoogle Scholar
  11. 11.
    Mueller RB, Kaegi T, Finckh A, Haile SR, Schulze-Koops H, von Kempis J. Is radiographic progression of late-onset rheumatoid arthritis different from young-onset rheumatoid arthritis? Results from the Swiss prospective observational cohort. Rheumatology (Oxford). 2014;53:671–7.CrossRefGoogle Scholar
  12. 12.
    Innala L, Berglin E, Möller B, Ljung L, Smedby T, Södergren A, et al. Age at onset determines severity and choice of treatment in early rheumatoid arthritis: a prospective study. Arthritis Res Ther. 2014;16:R94.CrossRefGoogle Scholar
  13. 13.
    Lahaye C, Tatar Z, Dubost JJ, Soubrier M. Overview of biologic treatments in the elderly. Jt Bone Spine. 2015;82:154–60.CrossRefGoogle Scholar
  14. 14.
    Fraenkel L, Rabidou N, Dhar R. Are rheumatologists’ treatment decisions influenced by patients’ age? Rheumatology (Oxford). 2006;45:1555–7.CrossRefGoogle Scholar
  15. 15.
    Kievit W, van Hulst L, van Riel P, Fraenkel L. Factors that influence rheumatologists’ decisions to escalate care in rheumatoid arthritis: results from a choice-based conjoint analysis. Arthritis Care Res (Hoboken). 2010;62:842–7.CrossRefGoogle Scholar
  16. 16.
    United Nations. Ageing. 2017. http://www.un.org/en/sections/issues-depth/ageing/index.html. Accessed 18 Dec 2018.
  17. 17.
    van Onna M, Boonen A. The challenging interplay between rheumatoid arthritis, ageing and comorbidities. BMC Musculoskelet Disord. 2016;17:184.CrossRefGoogle Scholar
  18. 18.
    Pavelka K, Akkoç N, Al-Maini M, Zerbini CAF, Karateev DE, Nasonov EL, et al. Maintenance of remission with combination etanercept-DMARD therapy versus DMARDs alone in active rheumatoid arthritis: results of an international treat-to-target study conducted in regions with limited biologic access. Rheumatol Int. 2017;37:1469–79.CrossRefGoogle Scholar
  19. 19.
    Smolen JS, Nash P, Durez P, Hall S, Ilivanova E, Irazoque-Palazuelos F, et al. Maintenance, reduction, or withdrawal of etanercept after treatment with etanercept and methotrexate in patients with moderate rheumatoid arthritis (PRESERVE): a randomised controlled trial. Lancet. 2013;381:918–29.CrossRefGoogle Scholar
  20. 20.
    Emery P, Hammoudeh M, FitzGerald O, Combe B, Martin-Mola E, Buch MH, et al. Sustained remission with etanercept tapering in early rheumatoid arthritis. N Engl J Med. 2014;371:1781–92.CrossRefGoogle Scholar
  21. 21.
    Ward MM, Guthrie LC, Alba MI. Clinically important changes in individual and composite measures of rheumatoid arthritis activity. Ann Rheum Dis. 2015;74:1691–6.CrossRefGoogle Scholar
  22. 22.
    European Medicines Agency. Enbrel procedural steps taken and scientific information after the authorisation. 2017. https://www.ema.europa.eu/en/documents/procedural-steps-after/enbrel-epar-procedural-steps-taken-scientific-information-after-authorisation_en.pdf. Accessed 12 July 2018.
  23. 23.
    European Medicines Agency. Enbrel Summary of Product Characteristics. 2018. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000262/WC500027361.pdf. Accessed 12 July 2018.
  24. 24.
    CIOMS Working Group III. Guidelines for preparing core clinical-safety information on drugs. Geneva: CIOMS; 1995.Google Scholar
  25. 25.
    Orbai AM, Bingham CO 3rd. Patient reported outcomes in rheumatoid arthritis clinical trials. Curr Rheumatol Rep. 2015;17:28.CrossRefGoogle Scholar
  26. 26.
    Bathon JM, Fleischmann RM, Van der Heijde D, Tesser JR, Peloso PM, Chon Y, et al. Safety and efficacy of etanercept treatment in elderly subjects with rheumatoid arthritis. J Rheumatol. 2006;33:234–43.Google Scholar
  27. 27.
    Genevay S, Finckh A, Ciurea A, Chamot AM, Kyburz D, Gabay C. Tolerance and effectiveness of anti-tumor necrosis factor alpha therapies in elderly patients with rheumatoid arthritis: a population-based cohort study. Arthritis Rheum. 2007;57:679–85.CrossRefGoogle Scholar
  28. 28.
    Filippini M, Bazzani C, Favalli EG, Marchesoni A, Atzeni F, Sarzi-Puttini P, et al. Efficacy and safety of anti-tumour necrosis factor in elderly patients with rheumatoid arthritis: an observational study. Clin Rev Allergy Immunol. 2010;38:90–6.CrossRefGoogle Scholar
  29. 29.
    Radovits BJ, Kievit W, Fransen J, van de Laar MA, Jansen TL, van Riel PL, et al. Influence of age on the outcome of antitumour necrosis factor alpha therapy in rheumatoid arthritis. Ann Rheum Dis. 2009;68:1470–3.CrossRefGoogle Scholar
  30. 30.
    Köller MD, Aletaha D, Funovits J, Pangan A, Baker D, Smolen JS. Response of elderly patients with rheumatoid arthritis to methotrexate or TNF inhibitors compared with younger patients. Rheumatology (Oxford). 2009;48:1575–80.CrossRefGoogle Scholar
  31. 31.
    Krishnan E, Sokka T, Häkkinen A, Hubert H, Hannonen P. Normative values for the Health Assessment Questionnaire disability index: benchmarking disability in the general population. Arthritis Rheum. 2004;50:953–60.CrossRefGoogle Scholar
  32. 32.
    Boots AM, Maier AB, Stinissen P, Masson P, Lories RJ, De Keyser F. The influence of ageing on the development and management of rheumatoid arthritis. Nat Rev Rheumatol. 2013;9:604–13.CrossRefGoogle Scholar
  33. 33.
    Humphreys J, Hyrich K, Symmons D. What is the impact of biologic therapies on common co-morbidities in patients with rheumatoid arthritis? Arthritis Res Ther. 2016;18:282.CrossRefGoogle Scholar
  34. 34.
    Roubille C, Richer V, Starnino T, McCourt C, McFarlane A, Fleming P, et al. The effects of tumour necrosis factor inhibitors, methotrexate, non-steroidal anti-inflammatory drugs and corticosteroids on cardiovascular events in rheumatoid arthritis, psoriasis and psoriatic arthritis: a systematic review and meta-analysis. Ann Rheum Dis. 2015;74:480–9.CrossRefGoogle Scholar
  35. 35.
    Judge A, Garriga C, Arden NK, Lovestone S, Prieto-Alhambra D, Cooper C, et al. Protective effect of antirheumatic drugs on dementia in rheumatoid arthritis patients. Alzheimers Dement (NY). 2017;3:612–21.Google Scholar
  36. 36.
    Rich MW. Epidemiology, pathophysiology, and etiology of congestive heart failure in older adults. J Am Geriatr Soc. 1997;45:968–74.CrossRefGoogle Scholar
  37. 37.
    Crossley KB, Peterson PK. Infections in the elderly. Clin Infect Dis. 1996;22:209–15.CrossRefGoogle Scholar
  38. 38.
    Garcovich S, Colloca G, Sollena P, Andrea B, Balducci L, Cho WC, et al. Skin cancer epidemics in the elderly as an emerging issue in geriatric oncology. Aging Dis. 2017;8:643–61.CrossRefGoogle Scholar
  39. 39.
    Brahma DK, Wahlang JB, Marak MD, Ch Sangma M. Adverse drug reactions in the elderly. J Pharmacol Pharmacother. 2013;4:91–4.CrossRefGoogle Scholar
  40. 40.
    Zhang J, Xie F, Yun H, Chen L, Muntner P, Levitan EB, et al. Comparative effects of biologics on cardiovascular risk among older patients with rheumatoid arthritis. Ann Rheum Dis. 2016;75:1813–8.CrossRefGoogle Scholar
  41. 41.
    Lurati A, Marrazza M, Angela K, Scarpellini M. Safety of etanercept in elderly subjects with rheumatoid arthritis. Biologics. 2010;4:1–4.Google Scholar
  42. 42.
    Galloway JB, Hyrich KL, Mercer LK, Dixon WG, Fu B, Ustianowski AP, et al. Anti-TNF therapy is associated with an increased risk of serious infections in patients with rheumatoid arthritis especially in the first 6 months of treatment: updated results from the British Society for Rheumatology Biologics Register with special emphasis on risks in the elderly. Rheumatology (Oxford). 2011;50:124–31.CrossRefGoogle Scholar
  43. 43.
    Schneeweiss S, Setoguchi S, Weinblatt ME, Katz JN, Avorn J, Sax PE, et al. Anti-tumor necrosis factor alpha therapy and the risk of serious bacterial infections in elderly patients with rheumatoid arthritis. Arthritis Rheum. 2007;56:1754–64.CrossRefGoogle Scholar
  44. 44.
    Kawashima H, Kagami SI, Kashiwakuma D, Takahashi K, Yokota M, Furuta S, et al. Long-term use of biologic agents does not increase the risk of serious infections in elderly patients with rheumatoid arthritis. Rheumatol Int. 2017;37:369–76.CrossRefGoogle Scholar
  45. 45.
    Busquets N, Tomero E, Descalzo MÁ, Ponce A, Ortiz-Santamaria V, Surís X, et al. Age at treatment predicts reason for discontinuation of TNF antagonists: data from the BIOBADASER 2.0 registry. Rheumatology (Oxford). 2011;50:1999–2004.CrossRefGoogle Scholar
  46. 46.
    Cho SK, Sung YK, Kim D, Won S, Choi CB, Kim TH, et al. Drug retention and safety of TNF inhibitors in elderly patients with rheumatoid arthritis. BMC Musculoskelet Disord. 2016;17:333.CrossRefGoogle Scholar
  47. 47.
    Murota A, Kaneko Y, Yamaoka K, Takeuchi T. Safety of biologic agents in elderly patients with rheumatoid arthritis. J Rheumatol. 2016;43:1984–8.CrossRefGoogle Scholar
  48. 48.
    Denson AC, Mahipal A. Participation of the elderly population in clinical trials: barriers and solutions. Cancer Control. 2014;21:209–14.CrossRefGoogle Scholar
  49. 49.
    Bourgeois FT, Olson KL, Tse T, Ioannidis JP, Mandl KD. Prevalence and characteristics of interventional trials conducted exclusively in elderly persons: a cross-sectional analysis of registered clinical trials. PLoS One. 2016;11:e0155948.CrossRefGoogle Scholar
  50. 50.
    Martin WJ, Shim M, Paulus HE, Chaudhari S, Feng J, Elashoff D, et al. Older age at rheumatoid arthritis onset and comorbidities correlate with less Health Assessment Questionnaire-Disability Index and Clinical Disease Activity Index response to etanercept in the RADIUS 2 registry. J Clin Rheumatol. 2014;20:301–5.Google Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Christopher J. Edwards
    • 1
    Email author
  • Katherine Roshak
    • 2
  • Jack F. Bukowski
    • 2
  • Ronald Pedersen
    • 2
  • Mazhar Thakur
    • 3
  • Cecilia Borlenghi
    • 4
  • Cinzia Curiale
    • 5
  • Heather Jones
    • 2
  • Lisa Marshall
    • 2
  1. 1.NIHR Clinical Research FacilityUniversity Hospital SouthamptonSouthamptonUK
  2. 2.PfizerCollegevilleUSA
  3. 3.RegSafe Consulting LtdWokinghamUK
  4. 4.Pfizer ArgentinaBuenos AiresArgentina
  5. 5.Pfizer ItalyRomeItaly

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