Rheumatology International

, Volume 32, Issue 1, pp 5–13 | Cite as

Should anti-TNF therapy be discontinued in rheumatoid arthritis patients undergoing elective orthopaedic surgery? A systematic review of the evidence

  • Leslie GohEmail author
  • Teresa Jewell
  • Catherine Laversuch
  • Ash Samanta
Review Article


Anti-tumour necrosis factor (TNF) therapies have revolutionized the management of rheumatoid arthritis (RA). A high proportion of RA patients are now established users of anti-TNF agents. Unfortunately, many RA patients with longstanding disease still require elective orthopaedic procedures. Published studies on the influence of TNF antagonist on infection rates in RA patients undergoing surgery are conflicting. However, national registries of RA patients on anti-TNF reported an increased risk of infection. The risk of anti-TNF-related infection is highest at the start of treatment with frequent involvement of the skin and subcutaneous tissue. Infection at these sites could negatively influence the healing of surgical wound. Current guidelines suggest that treatment with biologics should be discontinued prior to surgery. Patients with established disease are more likely to flare compared to those with early disease on stopping treatment. Consequently, TNF blockers need to be reinstated promptly after surgery to avoid the risk of RA flare.


Rheumatoid arthritis Anti-TNF Infections Orthopaedic surgery 



The authors are grateful to the librarians at Musgrove Park Hospital for their assistance in retrieving articles for this project.


  1. 1.
    Finckh A, Choi HK, Wolfe F (2006) Progression of radiographic damage joint damage in different eras: trends towards milder disease in rheumatoid arthritis are attributable to improved treatment. Ann Rheum Dis 65:1192–1197PubMedCrossRefGoogle Scholar
  2. 2.
    Massardo L, Gabriel SE, Crowson CS, O’ Fallon WM, Matteson EL (2002) A population based assessment of the use of orthopedic surgery in patients with rheumatoid arthritis. J Rheumatol 29:52–56PubMedGoogle Scholar
  3. 3.
    Da Silva E, Doran MF, Crowson CS, O’Fallon WM, Matteson EL (2003) Declining use of orthopaedic surgery in patients with rheumatoid arthritis? Results of a long-term, population-based assessment. Arthritis Rheum 49:216–220PubMedCrossRefGoogle Scholar
  4. 4.
    Fries JF, Williams CA, Morfeld D, Singh G, Sibley J (1996) Reduction in long-term disability in patients with rheumatoid arthritis by disease-modifying antirheumatic drug-based treatment strategies. Arthritis Rheum 39:616–622PubMedCrossRefGoogle Scholar
  5. 5.
    Louie G, Ward MM (2010) Changes in the rates of joint surgery among patients with rheumatoid arthritis in California, 1983–2007. Ann Rheum Dis 69:868–871PubMedCrossRefGoogle Scholar
  6. 6.
    Beutler BA (1999) The role of tumour necrosis factor in health and disease. J Rheumatol Suppl 57:16–21PubMedGoogle Scholar
  7. 7.
    Khalil AA, Hall JC, Aziz FA, Price P (2006) Tumour necrosis factor: implications for surgical patients. ANZ J Surg 76:1010–1016PubMedCrossRefGoogle Scholar
  8. 8.
    Bottner F, Wegner A, Winkelmann W, Becker K, Erren M, Gotze C (2007) Interleukin-6, procalcitonin and TNF-alpha: markers of peri-prosthetic infection following total joint replacement. J Bone Joint Surg Br 89:94–99PubMedCrossRefGoogle Scholar
  9. 9.
    Mooney DP, O’Reilly M, Garmelli RL (1990) Tumor necrosis factor and wound healing. Ann Sur 211:124–129CrossRefGoogle Scholar
  10. 10.
    Busti AJ, Hooper JS, Amaya CJ, Kazi S (2005) Effects of perioperative anti-inflammatory immunomodulating therapy on surgical wound healing. Pharmacotherapy 25:1566–1591PubMedCrossRefGoogle Scholar
  11. 11.
    Pieringer H, Stuby U, Biesenbach G (2008) The place of Methotrexate perioperatively in elective orthopaedic surgeries in patients with rheumatoid arthritis. Clin Rheumatol 27:1217–1220PubMedCrossRefGoogle Scholar
  12. 12.
    Loza E, Martinez-Lopez JA, Carmona L (2009) A systematic review on the optimum management of the use of methotrexate in rheumatoid arthritis patients in the perioperative period to minimize perioperative morbidity and maintain disease control. Clin Exp Rheumatol 27:856–862PubMedGoogle Scholar
  13. 13.
    Edwards CJ, Cooper C, Fisher D, Field M, van Staa TP, Arden NK (2007) The importance of the disease process and disease-modifying anti rheumatic drug treatment in the development of septic arthritis in patients with rheumatoid arthritis. Arthritis Rheum 57:1151–1157PubMedCrossRefGoogle Scholar
  14. 14.
    Doran MF, Crowson CS, Pond GR, O’Fallon WM, Gabriel SE (2002) Frequency of infection in patients with rheumatoid arthritis compared with controls: a population-based study. Arthritis Rheum 46:2287–2293PubMedCrossRefGoogle Scholar
  15. 15.
    Schrama JC, Espehaug B, Hallan G, Engesaeter LB, Furnes O, Havelin LI et al (2010) Risk of revision for infection in primary total hip and knee arthroplasty in patients with rheumatoid arthritis compared with osteoarthritis: a prospective, population-based study on 108, 786 hip and knee joint arthroplasties from the Norwegian arthroplasty register. Arthritis Care Res 62(4):473–479CrossRefGoogle Scholar
  16. 16.
    Bongartz T, Halligan CS, Osmon DR, Reinalda MS, Bamlet WR, Crowson CS (2008) Incidence and risk factors of prosthetic joint infection after total hip or knee replacement in patients with rheumatoid arthritis. Arthritis Rheum 59(12):1713–1720PubMedCrossRefGoogle Scholar
  17. 17.
    Jamsen E, Huhtala H, Puolakka T, Moilanen T (2009) Risk factors for infection after knee arthroplasty. A register-based analysis of 43, 149 cases. J Bone Joint Surg Am 91:38–47PubMedCrossRefGoogle Scholar
  18. 18.
    Bengtson S, Knutson K (1991) The infected knee arthroplasty. A 6-year follow-up of 357 cases. Acta Orthop Scand 62:301–311PubMedCrossRefGoogle Scholar
  19. 19.
    Robertsson O, Knutson K, Lewold S, Lidgren L (2001) The Swedish knee arthroplasty register 1975–1997: an update with special emphasis on 41, 223 knees operated on in 1988–1997. Acta Orthop Scand 72:503–513PubMedCrossRefGoogle Scholar
  20. 20.
    Wilson MG, Kelley K, Thornhill TS (1990) Infection as a complication of total knee-replacement arthroplasty. Risk factors and treatment in sixty-seven cases. J Bone Joint Surg Am 72:878–883PubMedGoogle Scholar
  21. 21.
    Wymenga AB, van Horn JR, Theeuwes A, Muytjens HL, Slooff TJ (1992) Perioperative factors associated with septic arthritis after arthroplasty. Prospective multicentre study of 362 knee and 2651 hip operations. Acta Orthop Scand 63:665–671PubMedGoogle Scholar
  22. 22.
    Berbari EF, Hanssen AD, Duffy MC, Steckelberg JM, IIstrup DM, Harmsen WS et al (1998) Risk factors for prosthetic joint infection: case-control study. Clin Infect Dis 27:1247–1254PubMedCrossRefGoogle Scholar
  23. 23.
    Talwalkar SC, Grennan DM, Gray J, Johnson P, Hayton MJ (2005) Tumour necrosis factor alpha antagonists and early postoperative complications in patients with inflammatory joint disease undergoing elective orthopaedic surgery. Ann Rheum Dis 64:650–651PubMedCrossRefGoogle Scholar
  24. 24.
    Wendling D, Balblanc JC, Brousse A, Lohse A, Lehuede G, Garbuio P et al (2005) Surgery in patients receiving anti-tumour necrosis factor alpha treatment in rheumatoid arthritis: an observational study on 50 surgical procedures. Ann Rheum Dis 64:1378–1379PubMedCrossRefGoogle Scholar
  25. 25.
    den Broeder AA, Creemers MC, Fransen J, de Jong E, de Rooij DJ, Wymenga A et al (2007) Risk factors for surgical site infections and other complications in elective surgery in patients with rheumatoid arthritis with special attention for anti-tumor necrosis factor: a large retrospective study. J Rheumatol 34(4):689–695Google Scholar
  26. 26.
    Bibbo C, Goldberg JW (2004) Infectious and healing complications after elective orthopaedic foot and ankle surgery during tumor necrosis factor-alpha inhibition therapy. Foot Ankle Int 25:331–335PubMedGoogle Scholar
  27. 27.
    Hirano Y, Kojima T, Kanayama Y, Shioura T, Hayashi M, Kida D et al (2010) Influences of anti-tumour necrosis factor agents on postoperative recovery in patients with rheumatoid arthritis. Clin Rheumatol 29:495–500PubMedCrossRefGoogle Scholar
  28. 28.
    Kawakami K, Ikari K, Kawamura K, Tsukahara S, Iwamoto T, Yano K et al (2010) Complications and features after joint surgery in rheumatoid arthritis patients treated with tumour necrosis factor-alpha blockers: perioperative interruption of tumour necrosis factor alpha blockers decreases complications? Rheumatology 49:341–347PubMedCrossRefGoogle Scholar
  29. 29.
    Gilson M, Gossec L, Mariette X, Gherissi D, Guyot MH, Berthelot JM et al (2010) Risk factors for total joint arthroplasty infection in patients receiving tumor necrosis factor alpha-blockers: a case-control study. Arthritis Res Ther 12:R145PubMedCrossRefGoogle Scholar
  30. 30.
    Giles JT, Bartlett SJ, Gelber AC, Nanda S, Fontaine K, Ruffing V et al (2006) Tumor necrosis factor inhibitor therapy and risk of serious postoperative orthopedic infection in rheumatoid arthritis. Arthritis Rheum 55:333–337PubMedCrossRefGoogle Scholar
  31. 31.
    Ruyssen-Witrand A, Gossec L, Salliot C, Luc M, Duclos M, Guignard S et al (2007) Complication rates of 127 surgical procedures performed in rheumatic patients receiving tumour necrosis factor alpha blockers. Clin Exp Rheumatol 25:430–436PubMedGoogle Scholar
  32. 32.
    Saleem B, Keen H, Goeb V, Parmar R, Nizam S, Hensor EM et al (2010) Patients with RA in remission on TNF blockers: when and in whom can TNF blocker therapy be stopped? Ann Rheum Dis 69:1636–1642PubMedCrossRefGoogle Scholar
  33. 33.
    Quinn MA, Conaghan PG, O’Connor PJ, Karim Z, Greenstein A, Brown A et al (2005) Very early treatment with Infliximab in addition to Methotrexate in early, poor-prognosis rheumatoid arthritis reduces magnetic resonance imaging evidence of synovitis and damage, with sustained benefit after Infliximab withdrawal: results from a twelve–month randomized, double-blind, placebo-controlled trial. Arthritis Rheum 52:27–35PubMedCrossRefGoogle Scholar
  34. 34.
    Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, van Zeben D, Kerstens PJ, Hazes JM et al (2005) Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeST study): a randomised, controlled trial. Arthritis Rheum 52:3381–3390PubMedCrossRefGoogle Scholar
  35. 35.
    Brown AK, Quinn MA, Karim Z, Conaghan PG, Peterfy CG, Hensor E et al (2006) Presence of significant synovitis in rheumatoid arthritis patients with disease-modifying antirheumatic drug-induced clinical remission: evidence from an imaging study may explain structural progression. Arthritis Rheum 54:3761–3773PubMedCrossRefGoogle Scholar
  36. 36.
    Brocq O, Millasseau E, Albert C, Grisot C, Flory P, Roux CH et al (2009) Effect of discontinuing TNF alpha antagonist therapy in patients with remission of rheumatoid arthritis. Joint Bone Spine 76:350–355PubMedCrossRefGoogle Scholar
  37. 37.
    Tanaka Y, Takeuchi T, Mimori T, Saito K, Nawata M, Kameda H et al (2010) Discontinuation of Infliximab after attaining low disease activity in patients with rheumatoid arthritis: RRR (remission induction by Remicade in RA) study. Ann Rheum Dis 69:1286–1291PubMedCrossRefGoogle Scholar
  38. 38.
    Saag KG, Teng GG, Patkar NM, Anuntiyo J, Finney C, Curtis JR et al (2008) American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum 59:762–784PubMedCrossRefGoogle Scholar
  39. 39.
    Ding T, Ledingham J, Luqmani R, Westlake S, Hyrich K, Lunt M et al (2010) BSR and BHPR rheumatoid arthritis guidelines on safety of anti-TNF therapies. Rheumatology 49:2217–2219PubMedCrossRefGoogle Scholar
  40. 40.
    Pham T, Claudepierre P, Deprez X, Fautrel B, Goupille P, Hilliquin P et al. (2005) Anti TNF alpha therapy and safety monitoring. Clinical tool guide elaborated by the Club Rhumatismes et Inflammation (CRI), section of the French Society of Rheumatology (Societe Francaise de Rhumatologie, SFR). Joint Bone Spine 72 (Suppl 1):S1–S58Google Scholar
  41. 41.
    Inanc N, Direskeneli H (2006) Serious infections under treatment with TNF-alpha antagonists compared to traditional DMARDS in patients with rheumatoid arthritis. Rheumatol Int 27:67–71PubMedCrossRefGoogle Scholar
  42. 42.
    Askling J, Fored CM, Brandt I, Baecklund E, Bertilsson L, Feltelius N et al (2007) Time-dependent increase in risk of hospitalisation with infection among Swedish RA patients treated TNF antagonists. Ann Rheum Dis 66:1339–1344PubMedCrossRefGoogle Scholar
  43. 43.
    Carmona L, Descalzo MA, Perez-pampin E, Ruiz-Montesinos D, Erra A, Cobo T et al (2007) All-cause and cause-specific mortality in rheumatoid arthritis are not greater than expected when treated with tumour necrosis factor antagonists. Ann Rheum Dis 66:880–885PubMedCrossRefGoogle Scholar
  44. 44.
    Favalli EG, Desiati F, Atzeni F, Sarzi-Puttini P, Caporali R, Pallavicini FB et al (2009) Serious infections during anti-TNFalpha treatment in rheumatoid arthritis patients. Autoimmun Rev 8:266–273PubMedCrossRefGoogle Scholar
  45. 45.
    Galloway JB, Hyrich KL, Mercer LK, Dixon WG, Fu B, Ustianowski AP et al (2011) 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 50:124–131PubMedCrossRefGoogle Scholar
  46. 46.
    Keystone EC, Kavanaugh AF, Sharp JT, Tannenbaum H, Hua Y, Teoh LS et al (2004) 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 50:1400–1411PubMedCrossRefGoogle Scholar
  47. 47.
    Rajakulendran S, Gadsby K, Allen D, O’Reilly S, Deighton C (2006) Neutropenia while receiving anti-tumour necrosis factor treatment for rheumatoid arthritis. Ann Rheum Dis 65:1678–1679PubMedCrossRefGoogle Scholar
  48. 48.
    Hastings R, Ding T, Butt S, Gadsby K, Zhang W, Moots RJ et al (2010) Neutropenia in patients receiving anti-tumor necrosis factor therapy. Arthritis Care Res (Hoboken) 62:764–769CrossRefGoogle Scholar
  49. 49.
    Royal College of Nursing (2009) Assessing, managing and monitoring biologic therapies for inflammatory arthritis. Guidance for rheumatology practitioners. Royal College of Nursing, LondonGoogle Scholar
  50. 50.
    Dixon WG, Symmons DP, Lunt M, Watson KD, Hyrich KL (2007) Serious infection following anti-tumor necrosis factor alpha therapy in patients with rheumatoid arthritis: lessons from interpreting data from observational studies. Arthritis Rheum 56:2896–2904PubMedCrossRefGoogle Scholar
  51. 51.
    Curtis JR, Patkar N, Xie A, Martin C, Allison JJ, Saag M et al (2007) Risk of serious bacterial infections among rheumatoid arthritis patients exposed to tumor necrosis factor alpha antagonists. Arthritis Rheum 56:1125–1133PubMedCrossRefGoogle Scholar
  52. 52.
    Ledingham J, Deighton C (2005) Update on the British society for rheumatology guidelines for prescribing TNF alpha blockers in adults with rheumatoid arthritis (update of previous guidelines of April 2001). Rheumatology 44:157–163PubMedCrossRefGoogle Scholar
  53. 53.
    Kay LJ, Griffiths ID (2006) UK consultant rheumatologists’ access to biological agents and views on the BSR biologic register. Rheumatology 45:1376–1379PubMedCrossRefGoogle Scholar
  54. 54.
    Moreland LW, Cohen SB, Baumgartner SW, Tindall EA, Bulpitt K, Martin R et al (2001) Long-term safety and efficacy of etanercept in patients with rheumatoid arthritis. J Rheumatol 28:1238–1244PubMedGoogle Scholar
  55. 55.
    Genovese MC, Bathon JM, Fleischmann RM, Moreland LW, Martin RW, Whitmore JB et al (2005) Longterm safety, efficacy, and radiographic outcome with etanercept treatment in patients with early rheumatoid arthritis. J Rheumatol 32:1232–1242PubMedGoogle Scholar
  56. 56.
    Breedveld FC, Weisman MH, Kavanaugh AF, Cohen SB, Pavelka K, van Vollenhoven R et al (2006) The PREMIER study: a multicentre, 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 54:26–37PubMedCrossRefGoogle Scholar
  57. 57.
    Gardner GC, Weisman MH (1990) Pyarthrosis in patients with rheumatoid arthritis: a report of 13 cases and a review of the literature from the past 40 years. Am J Med 88:503–511PubMedCrossRefGoogle Scholar
  58. 58.
    Dubost JJ, Fis I, Denis P, Lopitaux R, Soubrier M, Ristori JM et al (1993) Polyarticular septic arthritis. Medicine (Baltimore) 72:296–310Google Scholar
  59. 59.
    Blackburn WD Jr, Dunn TL, Alarcon GS (1986) Infection versus disease activity in rheumatoid arthritis: eight years’ experience. South Med J 79:1238–1241PubMedCrossRefGoogle Scholar
  60. 60.
    Favero M, Schiavon F, Riato L, Carraro V, Punzi L (2008) Rheumatoid arthritis is the major risk factor for septic arthritis in rheumatological settings. Autoimmun Rev 8:59–61PubMedCrossRefGoogle Scholar
  61. 61.
    Doran MF, Crowson CS, Pond GR, O’Fallon WM, Gabriel SE (2002) Predictors of infection in rheumatoid arthritis. Arthritis Rheum 46:2294–2300PubMedCrossRefGoogle Scholar
  62. 62.
    Colombel JF, Loftus EV, Tremaine WJ, Pemberton JH, Wolff BG, Young-Fadok T et al (2004) Early postoperative complications are not increased in patients with Crohn’s disease treated perioperatively with Infliximab or immunosuppressive therapy. Am J Gastroenterol 99: 878–883Google Scholar
  63. 63.
    Marchal L, D’Haens G, Van Assche G, Vermeire S, Noman M, Ferrante M et al (2004) The risk of post-operative complications associated with Infliximab therapy for Crohn’s disease: a controlled cohort study. Aliment Pharmacol Ther 19:749–754PubMedCrossRefGoogle Scholar
  64. 64.
    Topstad DR, Panaccione R, Heine JA, Johnson DR, MacLean AR, Buie WD (2003) Combined seton placement, Infliximab infusion, and maintenance immunosuppressive improve healing rate in fistulizing anorectal Crohn’s disease: a singer centre experience. Dis Colon Rectum 46:577–583PubMedCrossRefGoogle Scholar
  65. 65.
    Nasir BS, Dozois EJ, Cima RR, Pemberton JH, Wolff BG, Sandborn WJ et al (2010) Perioperative anti-tumor necrosis factor therapy does not increase the rate of early postoperative complications in Crohn’s disease. J Gastrointest Surg 14:1859–1865Google Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Leslie Goh
    • 1
    Email author
  • Teresa Jewell
    • 1
  • Catherine Laversuch
    • 1
  • Ash Samanta
    • 2
  1. 1.Department of RheumatologyMusgrove Park HospitalTaunton, SomersetUK
  2. 2.Department of RheumatologyUniversity Hospitals of Leicester NHS Trust, Leicester Royal InfirmaryLeicesterUK

Personalised recommendations