Skip to main content

Advertisement

SpringerLink
Log in

Analysis of perioperative clinical features and complications after orthopaedic surgery in rheumatoid arthritis patients treated with tocilizumab in a real-world setting: results from the multicentre TOcilizumab in Perioperative Period (TOPP) study

  • Original Article
  • Published:
Modern Rheumatology

Abstract

Objective

To evaluate perioperative changes in rheumatoid arthritis (RA) patients treated with tocilizumab.

Methods

We collected RA cases with tocilizumab and orthopaedic surgery from 1999 to 2010. Incidences of postoperative infections, delayed wound healing, and RA symptom flare-ups were extracted from the data for comparison with patients without these postoperative events. We also evaluated the changes in C-reactive protein (CRP) and body temperature in patients without postoperative complications with normal CRP before surgery, i.e., patients without postoperative events in whom the tocilizumab level was maintained, for each duration to discontinuation before surgery.

Results

A total of 161 cases (n = 122) were collected. The patients had mean age of 56.9 years, and mean disease duration of 12.8 years at operation. Joint replacement surgery was performed in 89 cases. Three patients had postoperative infections (two superficial and one organ/space surgical-site infection), 20 had delayed wound healing, and 36 had RA symptom flare-ups. Delayed wound healing occurred most commonly in patients who underwent spinal surgery (P = 0.0061, versus patients without delayed wound healing). CRP levels were high when tocilizumab was restarted in patients with RA symptom flare-ups (P = 0.0010, versus patients without RA symptom flare-ups). Increased postoperative CRP was observed in patients without postoperative events when the duration from final tocilizumab infusion to surgery was long. The changes in body temperature showed a similar trend to CRP.

Conclusions

Although it has been demonstrated that infection rates in patients treated with tocilizumab are by no means high, incidence of delayed wound healing was significantly higher in cases with surgical interventions such as foot and spinal surgeries. Many patients treated with tocilizumab remained in a normal range of CRP even during the perioperative period. For prevention of perioperative complications, observation of postoperative conditions and surgical wounds, and subjective symptoms of patients are considered important.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Felson DT, Smolen JS, Wells G, Zhang B, van Tuyl LH, Funovits J, et al. American College of Rheumatology/European League against rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials. Ann Rheum Dis. 2011;70(3):404–13.

    Article  PubMed  Google Scholar 

  2. Yano K, Ikari K, Inoue E, Tokita A, Sakuma Y, Hiroshima R, et al. Effect of total knee arthroplasty on disease activity in patients with established rheumatoid arthritis: 3-year follow-up results of combined medical therapy and surgical intervention. Mod Rheumatol. 2010;20(5):452–7.

    Article  PubMed  Google Scholar 

  3. Momohara S, Tanaka S, Nakamura H, Mibe J, Iwamoto T, Ikari K, et al. Recent trends in orthopedic surgery performed in Japan for rheumatoid arthritis. Mod Rheumatol. 2011;21(4):337–42.

    Article  PubMed  Google Scholar 

  4. Yasui T, Nishino J, Kadono Y, Matsui T, Nakamura K, Tanaka S, et al. Impact of biologics on the prevalence of orthopedic surgery in the National Database of Rheumatic Diseases in Japan. Mod Rheumatol. 2010;20(3):233–7.

    Article  PubMed  Google Scholar 

  5. Doran MF, Crowson CS, Pond GR, O’Fallon WM, Gabriel SE. Frequency of infection in patients with rheumatoid arthritis compared with controls: a population-based study. Arthritis Rheum. 2002;46(9):2287–93.

    Article  PubMed  Google Scholar 

  6. Bernatsky S, Hudson M, Suissa S. Anti-rheumatic drug use and risk of serious infections in rheumatoid arthritis. Rheumatology (Oxford). 2007;46(7):1157–60.

    Article  CAS  Google Scholar 

  7. Bongartz T, Halligan CS, Osmon DR, Reinalda MS, Bamlet WR, Crowson CS, et al. Incidence and risk factors of prosthetic joint infection after total hip or knee replacement in patients with rheumatoid arthritis. Arthritis Rheum. 2008;59(12):1713–20.

    Article  PubMed  Google Scholar 

  8. den Broeder AA, Creemers MC, Fransen J, de Jong E, de Rooij DJ, Wymenga A, et al. 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. 2007;34(4):689–95.

    Google Scholar 

  9. Hirano Y, Kojima T, Kanayama Y, Shioura T, Hayashi M, Kida D, et al. Influences of anti-tumour necrosis factor agents on postoperative recovery in patients with rheumatoid arthritis. Clin Rheumatol. 2010;29:495–500.

    Article  PubMed  Google Scholar 

  10. Bibbo C, Goldberg JW. Infectious and healing complications after elective orthopaedic foot and ankle surgery during tumor necrosis factor-alpha inhibition therapy. Foot Ankle Int. 2004;25(5):331–5.

    PubMed  Google Scholar 

  11. Galloway JB, Hyrich KL, Mercer LK, Dixon WG, Ustianowski AP, Helbert M, et al. Risk of septic arthritis in patients with rheumatoid arthritis and the effect of anti-TNF therapy: results from the British Society for Rheumatology Biologics Register. Ann Rheum Dis. 2011;70(10):1810–4.

    Article  PubMed  CAS  Google Scholar 

  12. Giles JT, Bartlett SJ, Gelber AC, Nanda S, Fontaine K, Ruffing V, et al. Tumor necrosis factor inhibitor therapy and risk of serious postoperative orthopedic infection in rheumatoid arthritis. Arthritis Rheum. 2006;55(2):333–7.

    Article  PubMed  Google Scholar 

  13. Ruyssen-Witrand A, Gossec L, Salliot C, Luc M, Duclos M, Guignard S, et al. Complication rates of 127 surgical procedures performed in rheumatic patients receiving tumor necrosis factor alpha blockers. Clin Exp Rheumatol. 2007;25(3):430–6.

    PubMed  CAS  Google Scholar 

  14. Suzuki M, Nishida K, Soen S, Oda H, Inoue H, Kaneko A, et al. Risk of postoperative complications in rheumatoid arthritis relevant to treatment with biologic agents: a report from the Committee on Arthritis of the Japanese Orthopaedic Association. J Orthop Sci. 2011;16:778–84.

    Article  PubMed  Google Scholar 

  15. Nishimoto N, Miyasaka N, Yamamoto K, Kawai S, Takeuchi T, Azuma J. Long-term safety and efficacy of tocilizumab, an anti-IL-6 receptor monoclonal antibody, in monotherapy, in patients with rheumatoid arthritis (the STREAM study): evidence of safety and efficacy in a 5-year extension study. Ann Rheum Dis. 2009;68(10):1580–4.

    Article  PubMed  CAS  Google Scholar 

  16. Emery P, Keystone E, Tony HP, Cantagrel A, van Vollenhoven R, Sanchez A, et al. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial. Ann Rheum Dis. 2008;67(11):1516–23.

    Article  PubMed  CAS  Google Scholar 

  17. Jones G, Sebba A, Gu J, Lowenstein MB, Calvo A, Gomez-Reino JJ, et al. Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study. Ann Rheum Dis. 2010;69(1):88–96.

    Article  PubMed  CAS  Google Scholar 

  18. Smolen JS, Beaulieu A, Rubbert-Roth A, Ramos-Remus C, Rovensky J, Alecock E, et al. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial. Lancet. 2008;371(9617):987–97.

    Article  PubMed  CAS  Google Scholar 

  19. Genovese MC, McKay JD, Nasonov EL, Mysler EF, da Silva NA, Alecock E, et al. Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: the tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study. Arthritis Rheum. 2008;58(10):2968–80.

    Article  PubMed  CAS  Google Scholar 

  20. Hirao M, Hashimoto J, Tsuboi H, Nampei A, Nakahara H, Yoshio N, et al. Laboratory and febrile features after joint surgery in patients with rheumatoid arthritis treated with tocilizumab. Ann Rheum Dis. 2009;68(5):654–7.

    Article  PubMed  CAS  Google Scholar 

  21. Hiroshima R, Kawakami K, Iwamoto T, Tokita A, Yano K, Sakuma Y, et al. Analysis of C-reactive protein levels and febrile tendency after joint surgery in rheumatoid arthritis patients treated with a perioperative 4-week interruption of tocilizumab. Mod Rheumatol. 2011;21(1):109–11.

    Article  PubMed  Google Scholar 

  22. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31(3):315–24.

    Article  PubMed  CAS  Google Scholar 

  23. Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO 3rd, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League against Rheumatism collaborative initiative. Ann Rheum Dis. 2010;69(9):1580–8.

    Article  PubMed  Google Scholar 

  24. Koike R, Harigai M, Atsumi T, Amano K, Kawai S, Saito K, et al. Japan College of Rheumatology 2009 guidelines for the use of tocilizumab, a humanized anti-interleukin-6 receptor monoclonal antibody, in rheumatoid arthritis. Mod Rheumatol. 2009;19(4):351–7.

    Article  PubMed  CAS  Google Scholar 

  25. Mangram AJ, Horan TC, Pearson ML, Silver LC, Jarvis WR. Guideline for prevention of surgical site infection, 1999. Hospital Infection Control Practices Advisory Committee. Infect Control Hosp Epidemiol. 1999;20(4):250–278; quiz 279–280.

  26. Kawakami K, Ikari K, Kawamura K, Tsukahara S, Iwamoto T, Yano K, et al. 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 (Oxford). 2010;49(2):341–7.

    Article  CAS  Google Scholar 

  27. Momohara S, Kawakami K, Iwamoto T, Yano K, Sakuma Y, Hiroshima R, et al. Prosthetic joint infection after total hip or knee arthroplasty in rheumatoid arthritis patients treated with nonbiologic and biologic disease-modifying antirheumatic drugs. Mod Rheumatol. 2011;21(5):469–75.

    Article  PubMed  Google Scholar 

  28. Nagamine R, Chen W, Hara T, Kondo K, Sugioka Y. Immediate reduction of white blood cell count after tocilizumab administration was observed in some cases. Mod Rheumatol. 2009;19(3):348–50.

    Article  PubMed  Google Scholar 

  29. Gallucci RM, Simeonova PP, Matheson JM, Kommineni C, Guriel JL, Sugawara T, et al. Impaired cutaneous wound healing in interleukin-6-deficient and immunosuppressed mice. FASEB J. 2000;14(15):2525–31.

    Article  PubMed  CAS  Google Scholar 

  30. Lin ZQ, Kondo T, Ishida Y, Takayasu T, Mukaida N. Essential involvement of IL-6 in the skin wound-healing process as evidenced by delayed wound healing in IL-6-deficient mice. J Leukoc Biol. 2003;73(6):713–21.

    Article  PubMed  CAS  Google Scholar 

  31. Luckett-Chastain LR, Gallucci RM. Interleukin (IL)-6 modulates transforming growth factor-beta expression in skin and dermal fibroblasts from IL-6-deficient mice. Br J Dermatol. 2009;161(2):237–48.

    Article  PubMed  CAS  Google Scholar 

  32. Wortel CH, van Deventer SJ, Aarden LA, Lygidakis NJ, Buller HR, Hoek FJ, et al. Interleukin-6 mediates host defense responses induced by abdominal surgery. Surgery. 1993;114(3):564–70.

    PubMed  CAS  Google Scholar 

  33. Nishimoto N, Yoshizaki K, Tagoh H, Monden M, Kishimoto S, Hirano T, et al. Elevation of serum interleukin 6 prior to acute phase proteins on the inflammation by surgical operation. Clin Immunol Immunopathol. 1989;50(3):399–401.

    Article  PubMed  CAS  Google Scholar 

  34. Ohzato H, Yoshizaki K, Nishimoto N, Ogata A, Tagoh H, Monden M, et al. Interleukin-6 as a new indicator of inflammatory status: detection of serum levels of interleukin-6 and C-reactive protein after surgery. Surgery. 1992;111(2):201–9.

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors thank Dr. Masao Sato, Dr. Yuichiro Yabe, Dr. Katsumitsu Arai, Dr. Hajime Owaki, Dr. Sumito Kawamura, Dr. Hiroshi Sawano, Dr. Yasunori Shimaoka and Dr. Akihide Nampei for their support and comments on this article. This project was not financially supported by any foundation, and the doctors themselves played a leading role in this study.

Conflict of interest

S.M. has received speaking fees from Chugai Pharmaceutical Co. Ltd., Eisai Co. Ltd. and Mitsubishi Tanabe Pharma Corporation. J.H. has received speaking fees from Chugai Pharmaceutical Co. Ltd., Eisai Co. Ltd., Takeda Pharmaceutical Co. Ltd., Asahi Kasei Pharma Co. Ltd., Taisho Toyama Pharmaceutical Co. Ltd., Hisamitsu Pharmaceutical Co. Ltd., Eli Lilly Japan Co. Ltd. and Nakashima Medical Co. Ltd. A.K. has received speaking fees from Bristol–Myers Squibb, Chugai Pharmaceutical Co. Ltd., Eisai Co. Ltd., Mitsubishi Tanabe Pharma Corporation, Takeda Pharmaceutical Co. Ltd. and Pfizer Inc. H. Matsuno has received speaking fees from Chugai Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Corporation, Santen Pharmaceutical Co. Ltd. and Takeda Pharmaceutical Co. Ltd. T.N. has received speaking fees from Chugai Pharmaceutical Co. Ltd. K.K. has received speaking fees from Bristol-Myers Squibb, Chugai Pharmaceutical Co. Ltd., Eisai Co. Ltd., Mitsubishi Tanabe Pharma Corporation and Pfizer Inc. T.S. has received speaking fees from Abbott Japan Co. Ltd., Bristol-Myers Squibb, Chugai Pharmaceutical Co. Ltd., Eisai Co. Ltd., Pfizer Inc., Santen Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Corporation and Janssen Pharmaceutical K.K. Other authors declared no conflicts of interest.

Author information

Authors and Affiliations

  1. Department of Orthopaedic Surgery, Institute of Rheumatology, Tokyo Women’s Medical University, 10-22 Kawada, Shinjuku, Tokyo, 162-0054, Japan

    Shigeki Momohara

  2. Department of Rheumatology, National Hospital Organization Osaka Minami Medical Centre, Osaka, Japan

    Jun Hashimoto & Hideki Tsuboi

  3. Department of Rheumatology, National Hospital Organization Kyushu Medical Centre, Fukuoka, Japan

    Hisaaki Miyahara

  4. Department of Orthopaedic Surgery, Kohnan Kakogawa Hospital, Hyougo, Japan

    Natsuko Nakagawa

  5. Department of Orthopaedic Surgery, National Hospital Organization Nagoya Medical Centre, Nagoya, Aichi, Japan

    Atsushi Kaneko

  6. Department of Orthopaedic Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

    Naoki Kondo

  7. Matsuno Clinic for Rheumatic Diseases, Toyama, Japan

    Hiroaki Matsuno

  8. Department of Orthopaedic Surgery, Kansai Medical University Hirakata Hospital, Osaka, Japan

    Takahiko Wada

  9. Department of Orthopaedic Surgery, Kinki University School of Medicine, Osaka, Japan

    Tohgo Nonaka

  10. Department of Orthopaedic Surgery, Tokyo Women’s Medical University Medical Centre East, Tokyo, Japan

    Katsuaki Kanbe

  11. Department of Orthopaedic Surgery, Fukui Red Cross Hospital, Fukui, Japan

    Haruki Takagi

  12. Niigata Rheumatic Centre, Niigata, Japan

    Akira Murasawa

  13. Matsubara Mayflower Hospital, Hyougo, Japan

    Tsukasa Matsubara

  14. Department of Orthopaedic Surgery, Toho University School of Medicine, Tokyo, Japan

    Toru Suguro

Authors
  1. Shigeki Momohara
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jun Hashimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hideki Tsuboi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hisaaki Miyahara
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Natsuko Nakagawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Atsushi Kaneko
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Naoki Kondo
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hiroaki Matsuno
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Takahiko Wada
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Tohgo Nonaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Katsuaki Kanbe
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Haruki Takagi
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Akira Murasawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Tsukasa Matsubara
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Toru Suguro
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shigeki Momohara.

Additional information

All the listed authors approved and equally contributed to the final version of the manuscript.

About this article

Cite this article

Momohara, S., Hashimoto, J., Tsuboi, H. et al. Analysis of perioperative clinical features and complications after orthopaedic surgery in rheumatoid arthritis patients treated with tocilizumab in a real-world setting: results from the multicentre TOcilizumab in Perioperative Period (TOPP) study. Mod Rheumatol 23, 440–449 (2013). https://doi.org/10.1007/s10165-012-0683-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10165-012-0683-0

Keywords

Search

Navigation