Drugs & Aging

, Volume 23, Issue 11, pp 855–860 | Cite as

Anti-Tumour Necrosis Factor-α Therapy for Rheumatoid and Other Inflammatory Arthropathies

Update on Safety in Older Patients
  • Paul Ornetti
  • Hélène Chevillotte
  • Amal Zerrak
  • Jean Francis Maillefert
Leading Article


Anti-tumour necrosis factor (TNF)-α represents a major advance in the treatment of rheumatoid arthritis (RA), ankylosing spondylitis and psoriatic arthritis. It is usually well tolerated, but a potential increase in the incidence of some infections in patients taking anti-TNFα agents has been reported.

Compared with younger people, elderly patients have more co-morbidities and are likely to be taking more medications. Moreover, the aging process induces an increase in the rate of infections. Nevertheless, in recent studies analysing the databases of etanercept trials, the normalised incidence of adverse events, serious adverse events, medically important infections and deaths was not increased in patients aged ≥65 years. However, these trials included patients who might have been healthier than elderly RA patients in the general population and therefore not truly representative. Conflicting results have been reported in several ‘real-life’ observational studies.

Taken together, the available data are reassuring for carefully selected populations, at least for etanercept, but it is not possible to claim that anti-TNFα agents do, or do not, pose a particular risk for the general population of older patients. Additional studies aiming at determining the safety and benefit-risk ratio of anti-TNFα agents in elderly patients are needed. In addition, since the benefit-risk ratio of anti-TNFα agents might be different in patients aged 65, 75 or >80 years, when possible, subgroup analysis might also be useful.


  1. 1.
    Harriman G, Harper LK, Schaible TF. Summary of clinical trials in rheumatoid arthritis using infliximab, an anti-TNFα treatment. Ann Rheum Dis 1999; 58Suppl. I: 161–4Google Scholar
  2. 2.
    Hochberg MC, Tracy JK, Flores RH. “Stepping-up” from methotrexate: a systematic review of randomised placebo controlled trials in patients with rheumatoid arthritis with an incomplete response to methotrexate. Ann Rheum Dis 2001; 60Suppl. 3: iii51–4PubMedGoogle Scholar
  3. 3.
    Lipsky PE, van der Heijde DM, St Clair EW, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. N Engl J Med 2000; 343: 1594–602PubMedCrossRefGoogle Scholar
  4. 4.
    Brandt J, Sieper J, Braun J. Infliximab in the treatment of active and severe ankylosing spondylitis. Clin Exp Rheumatol 2002; 20Suppl. 28: S106–10PubMedGoogle Scholar
  5. 5.
    Braun J, Brandt J, Listing J, et al. Long-term efficacy and safety of infliximab in the treatment of ankylosing spondylitis: an open, observational, extension study of a three-month, randomized, placebo-controlled trial. Arthritis Rheum 2003; 48(8): 2224–33PubMedCrossRefGoogle Scholar
  6. 6.
    Schnarr S, Kuipers JG, Zeidler H. Anti-tumour necrosis factor (TNF)-α therapy in undifferentiated spondyloarthropathy. Clin Exp Rheumatol 2002; 20Suppl. 28: S126–9PubMedGoogle Scholar
  7. 7.
    Temekonidis TI, Alamanos Y, Nikas SN, et al. Infliximab therapy in patients with ankylosing spondylitis: an open label 12 month study. Ann Rheum Dis 2003; 62: 1218–20PubMedCrossRefGoogle Scholar
  8. 8.
    Moreland LW, Schiff MH, Baumgartner SW, et al. Etanercept therapy in rheumatoid arthritis: a randomized, controlled trial. Ann Intern Med 1999; 130: 478–86PubMedGoogle Scholar
  9. 9.
    Bathon JM, Martin RW, Fleischmann RM, et al. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med 2000; 343: 1586–93PubMedCrossRefGoogle Scholar
  10. 10.
    Weinblatt ME, Kremer JM, Bankhurst AD, et al. A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med 1999; 340: 253–9PubMedCrossRefGoogle Scholar
  11. 11.
    Klareskog L, van der Heijde D, de Jager JP, et al. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomized trial. Lancet 2004; 363: 675–81PubMedCrossRefGoogle Scholar
  12. 12.
    Smolen JS, van der Heijde D, St Clair EW, et al. Predictors of joint damage in patients with early rheumatoid arthritis treated with high-dose methotrexate with or without concomitant infliximab: results from the ASPIRE trial. Arthritis Rheum 2006; 54: 702–10PubMedCrossRefGoogle Scholar
  13. 13.
    Breedveld FC, Weisman MH, Kavanaugh AF, et al. The PREMIER study: a multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis Rheum 2006; 54: 26–37PubMedCrossRefGoogle Scholar
  14. 14.
    Keystone EC, Kavanaugh AF, Sharp JT, et al. Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial. Arthritis Rheum 2004; 50: 1400–11PubMedCrossRefGoogle Scholar
  15. 15.
    Davis Jr JC, van der Heijde D, Braun J, et al. Recombinant human tumor necrosis factor receptor (etanercept) for treating ankylosing spondylitis: a randomized, controlled trial. Arthritis Rheum 2003; 48: 3230–6PubMedCrossRefGoogle Scholar
  16. 16.
    Mease PJ, Kivitz AJ, Burch FX, et al. Etanercept treatment of psoriatic arthritis: safety, efficacy, and effect on disease progression. Arthritis Rheum 2004; 50: 2264–72PubMedCrossRefGoogle Scholar
  17. 17.
    Mease PJ, Gladman DD, Ritchlin CT, et al. Adalimumab for the treatment of patients with moderately to severely active psoriatic arthritis: results of a double-blind, randomized, placebo-controlled trial. Arthritis Rheum 2005; 52: 3279–89PubMedCrossRefGoogle Scholar
  18. 18.
    Ellerin T, Weinblatt ME. Infections and anti-tumor necrosis α therapy. Arthritis Rheum 2003; 48: 3013–22PubMedCrossRefGoogle Scholar
  19. 19.
    Cunnane G, Doran M, Bresnihan B. Infections and biological therapy in rheumatoid arthritis. Best Pract Res Clin Rheumatol 2003; 17: 345–63PubMedCrossRefGoogle Scholar
  20. 20.
    Bongartz T, Sutton AJ, Sweeting MJ, et al. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA 2006; 295: 2275–85PubMedCrossRefGoogle Scholar
  21. 21.
    Day R. Adverse reactions to TNF-alpha inhibitors in rheumatoid arthritis. Lancet 2002; 359: 540–1PubMedCrossRefGoogle Scholar
  22. 22.
    Weisman MH. What are the risks of biologic therapy in rheumatoid arthritis? An update on safety. J Rheumatol 2002; 29Suppl. 65: 33–8Google Scholar
  23. 23.
    Gomez-Reino JJ, Carmona L, Valverde VR, et al. Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors may predispose to significant increase in tuberculosis risk: a multicentre-active surveillance report. Arthritis Rheum 2003; 48: 2122–7PubMedCrossRefGoogle Scholar
  24. 24.
    Salmon D, GTI, AFSSAPS. Groupe Tuberculose et Infliximab. Agence Française de Sécurité Sanitaire de Produits de Santé. Recommendations about the prevention and management of tuberculosis in patients taking infliximab. Joint Bone Spine 2002; 69: 170–2PubMedCrossRefGoogle Scholar
  25. 25.
    Harney S, O’Shea FD, Fitzgerald O. Peptostreptococcal pericarditis complicating anti-tumour necrosis factor alpha treatment in rheumatoid arthritis. Ann Rheum Dis 2002; 6: 653–4CrossRefGoogle Scholar
  26. 26.
    Kroesen S, Widmer AF, Tyndall A, et al. Serious bacterial infections in patients with rheumatoid arthritis under anti-TNF-alpha therapy. Rheumatology 2003; 42: 617–21PubMedCrossRefGoogle Scholar
  27. 27.
    Matzkies FG, Manger B, Schmitt-Haendle M, et al. Severe septicaemia in a patient with polychondritis and Sweet’s syndrome after initiation of treatment with infliximab. Ann Rheum Dis 2003; 62: 81–2PubMedCrossRefGoogle Scholar
  28. 28.
    Listing J, Strangfeld A, Kary S, et al. Infections in patients with rheumatoid arthritis treated with biologic agents. Arthritis Rheum 2005; 52: 3403–12PubMedCrossRefGoogle Scholar
  29. 29.
    American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines: guidelines for the management of rheumatoid arthritis. 2002 update. Arthritis Rheum 2002; 46: 328–46Google Scholar
  30. 30.
    Ledingham J, Deighton C, on behalf of the BSR Standards, Guidelines and Audit Working Group, et al. Update of the BSR guidelines for prescribing TNFα blockers in adults with rheumatoid arthritis. Rheumatology 2005; 44: 157–63PubMedCrossRefGoogle Scholar
  31. 31.
    Gabriel SE, Crowson CS, O’Fallon WM. The epidemiology of rheumatoid arthritis in Rochester, Minnesota, 1955–1985. Arthritis Rheum 1999; 42: 415–20PubMedCrossRefGoogle Scholar
  32. 32.
    Harrison MJ, Kim CA, Silverberg M, et al. Does age bias the aggressive treatment of elderly patients with rheumatoid arthritis? J Rheumatol 2005; 32: 1243–8PubMedGoogle Scholar
  33. 33.
    Doran MF, Crowson CS, Pond GR, et al. Predictors of infection in rheumatoid arthritis. Arthritis Rheum 2002; 46: 2294–300PubMedCrossRefGoogle Scholar
  34. 34.
    Fleischmann RM, Baumgartner SW, Tindall EA, et al. Response to etanercept (Enbrel) in elderly patients with rheumatoid arthritis: a retrospective analysis of clinical trial results. J Rheumatol 2003; 30: 691–6PubMedGoogle Scholar
  35. 35.
    Fleischmann RM, Baumgartner SW, Weisman M, et al. Long-term safety of etanercept in elderly subjects with rheumatic diseases. Ann Rheum Dis 2006; 65: 379–84PubMedCrossRefGoogle Scholar
  36. 36.
    Bathon JM, Fleischmann RM, van der Heijde D, et al. Safety and efficacy of etanercept treatment in elderly subjects with rheumatoid arthritis. J Rheumatol 2006; 33: 234–43PubMedGoogle Scholar
  37. 37.
    Sokka T, Pincus T. Eligibility of patients in routine care for major clinical trials of anti-tumor necrosis factor a agents in rheumatoid arthritis. Arthritis Rheum 2003; 48: 313–8PubMedCrossRefGoogle Scholar
  38. 38.
    Furst DE. Observational cohort studies and well controlled clinical trials: we need them both! J Rheumatol 2004; 31: 1476–7PubMedGoogle Scholar
  39. 39.
    Genevay S, Finckh A, Genta MS, et al. Efficacy and tolerance of TNF inhibitors in elderly patients with rheumatoid arthritis: a population based study [abstract no. SAT 0068]. Ann Rheum Dis 2005; 64Suppl. III: 430Google Scholar
  40. 40.
    Salliot C, Gossec L, Ruyssen-Witrand A, et al. The risk of serious infections is higher in daily practice than in clinical trials for rheumatic patients receiving TNF blockers: a systematic retrospective study of 770 patients [abstract no. 858]. Arthritis Rheum 2005; 52 Suppl.: S340Google Scholar
  41. 41.
    Legrand JL, Solau-Gervais E, Vieillard MH, et al. Anti-TNF alpha chez le sujet âgé: profil des patients et tolérance [abstract no. Lu.33]. Rev Rhum 2005; 72: 974CrossRefGoogle Scholar
  42. 42.
    Chevillotte-Maillard E, Ornetti P, Mistrih R, et al. Survival and safety of treatment with infliximab in the elderly population. Rheumatology 2005; 44: 695–6PubMedCrossRefGoogle Scholar
  43. 43.
    Maillard H, Ornetti P, Grimault L, et al. Severe pyogenic infections in patients taking infliximab: a regional cohort study. Joint Bone Spine 2005; 72: 330–4PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2006

Authors and Affiliations

  • Paul Ornetti
    • 1
    • 2
  • Hélène Chevillotte
    • 1
  • Amal Zerrak
    • 1
  • Jean Francis Maillefert
    • 1
    • 2
  1. 1.Department of RheumatologyDijon University HospitalDijonFrance
  2. 2.University of BurgundyDijonFrance

Personalised recommendations