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Infectious risk associated to orthopaedic surgery for rheumatoid arthritis patients treated by anti-TNFalpha
G Model BONSOI-4455; No. of Pages 5
ARTICLE IN PRESS Joint Bone Spine xxx (2016) xxx–xxx
Available online at
ScienceDirect www.sciencedirect.com
Original article
Infectious risk associated to orthopaedic surgery for rheumatoid arthritis patients treated by anti-TNFalpha Charlotte Mabille a , Yannick Degboe a , Arnaud Constantin a , Thomas Barnetche b , Alain Cantagrel a , Adeline Ruyssen-Witrand a,∗ a b
Centre de Rhumatologie, Hôpital Pierre Paul Riquet, CHU Toulouse Purpan, 31000 Toulouse, France Service de Rhumatologie, Hôpital Pellegrin, CHU Bordeaux, 33000 Bordeaux, France
a r t i c l e
i n f o
Article history: Accepted 22 June 2016 Available online xxx Keywords: Surgery Rheumatoid arthritis Infection Anti-TNF␣
a b s t r a c t Introduction: Although biotherapy has greatly improved the prognosis of RA many patients have still recourse to an orthopaedic surgery. The current recommendation for scheduled surgery is to discontinue administration of the biological agent two to six weeks before surgery. Reinitiating anti-TNF therapy is proposed when the patient has healed. We wanted to know whether patients treated with anti-TNF␣ were exposed to an infectious risk undergoing a surgical procedure and if discontinuation of anti-TNF␣ therapy altered the risk of surgical infection. Methods: We conducted a systematic review of the literature in PubMed, Embase and Cochrane until March 2014. We selected studies that reported post-operative infections by comparing patients treated with anti-TNF␣ to patients treated with csDMARD without biological treatment, or patients who continued anti-TNF␣ therapy to the patients who discontinued treatment prior to surgery. Results: A first meta-analysis of 12 studies evaluating postoperative infection risk in patients treated with anti-TNF␣ showed that the postoperative infection risk doubled (RR = 1.81 [1.31–2.50]). Seven studies were grouped into a second meta-analysis to evaluate the benefit of the preventive discontinuation of anti-TNF␣. Discontinuation of treatment did not alter the post-operative infection risk significantly: RR = 0.69 [0.39–1.21]. Conclusion: This study showed that patients treated with anti-TNF␣ were more at risk of post-operative infection undergoing orthopaedic surgery. Preventive discontinuation of anti-TNF␣ does not seem to change this risk. ´ e´ franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved. © 2016 Societ
1. Introduction Over the past 15 years, anti-TNF␣ has made major therapeutic progress in the treatment of rheumatoid arthritis (RA) by enabling better clinical and structural control and improving prognosis. However in spite of the improvement, patients still need orthopaedic surgery at the early stage of the disease with synovectomy or later in the course of the disease for arthrodesis or prosthesis. TNF inhibitors are thought to increase the risk of developing infections and RA is a risk factor for septic complications undergoing prosthetic surgery [1]. Data on post-operative infections in patients treated with methotrexate (MTX) have not revealed any increased risk of infection even if treatment is continued
∗ Corresponding author at: Centre de Rhumatologie, Hôpital Pierre Paul Riquet, CHU Toulouse Purpan, 1 place du Dr Baylac, 31000 Toulouse, France. E-mail address: [email protected] (A. Ruyssen-Witrand).
perioperatively [2,3]. Continuation of MTX during any surgery is the daily practice. The known increased risk of infection related to anti-TNF␣ has led to recommend its discontinuation before surgery and its reinitiation only after the patient has healed completely. These recommendations are based on caution. The French Society of Rheumatology recommends in case of elective surgery at least two weeks of preoperative discontinuation for etanercept, and four weeks for adalimumab, certolizumab, golimumab and infliximab [4]. Reinitiation is proposed when the patient has healed completed. The American College of Rheumatology recommends discontinuation of the biological agent at least a week before surgery and reinitiation one week later [5]. To assess the risk of infection undergoing the surgery, we conducted a systematic literature review to answer two questions: 1. Is RA treated with anti-TNF␣ exposed to an infectious risk undergoing a surgical procedure compared to patients treated with csDMARDs alone?
http://dx.doi.org/10.1016/j.jbspin.2016.06.011 ´ e´ franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved. 1297-319X/© 2016 Societ
Please cite this article in press as: Mabille C, et al. Infectious risk associated to orthopaedic surgery for rheumatoid arthritis patients treated by anti-TNFalpha. Joint Bone Spine (2016), http://dx.doi.org/10.1016/j.jbspin.2016.06.011
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2. Does discontinuation of anti-TNF␣ preoperatively modify the post-operative infection risk? 2. Methods 2.1. Identifications of articles We used the term “rheumatoid arthritis AND surgery AND infection AND (adalimumab OR certolizumab OR etanercept OR golimumab OR infliximab)”. We researched in the Cochrane, Pubmed and Embase databases for articles published until March 2014. Our search was limited to articles in English and French. We selected observational studies measuring the frequency of post-operative infections in orthopaedic surgery in a population of patients with inflammatory arthritis treated with anti-TNF␣ compared to a similar population not exposed to biological agents. We also included articles comparing the frequency of post-operative infections in patients treated with anti-TNF␣ but the treatment was discontinued before surgery to the frequency of post-operative infections in patients who continued anti-TNF␣ therapy.
• The second compared in patients treated with anti-TNF␣ the frequency of post-operative infections according to whether the biological agent was discontinued or not before surgery. The endpoint studied was the number of infectious events in each group of patients (treated with anti-TNF␣ vs. treated without biological agent) or between patients who continued the anti-TNF␣ therapy and those who discontinued biological treatment before surgery. A relative risk was calculated for each study. The calculations were made by the inverse of variance method according to a fixed pattern or a random pattern, depending on the level of heterogeneity. This method provides an overall relative risk with a 95% confidence interval, taking into account the weight of each study. Statistical heterogeneity amongst the included studies was assessed using the Cochrane Q test (2 ), using a significance level of 5%, and carrying forward the value of the I2 statistic for which important values are associated with a level significant heterogeneity. Publication bias was assessed with the Egger test. Meta-analyses were performed with the Revman 5.1.6 software. 3. Results
2.2. Data acquisition
3.1. Identification of articles
In these articles, we extracted the definition of infection, type of surgery, number of surgeries in the control and anti-TNF␣ arms, the number of surgeries performed without discontinuation of antiTNF␣ therapy or after discontinuation of anti-TNF␣ therapy, and the number of infections in each group of patients. 2.3. Statistical analysis From the extracted data, we conducted two meta-analyses: • The first compared the incidence of post-operative infections in patients treated with anti-TNF␣ compared to patients treated with csDMARD.
We identified 215 articles (Fig. 1). After reading the title and abstract, we retained 15 studies to which we added three articles from a manual search. We excluded three articles after reading them completely as two did not involve surgery and one had no control group. We retained a total of 15 articles. Four studies were relevant to answer both questions. Twelve studies compared the number of post-operative infections in patients treated with anti-TNF␣ to patients treated with csDMARDs alone. These 12 publications were used to answer the first question [6–17]. In the other three studies [18–20] and four studies common to both questions [6,13,14,16] amongst patients treated with anti-TNF␣, a group of patients continued taking the biological agent before surgery and another group discontinued treatment.
Fig. 1. Publications selection process used for the literature analysis.
Please cite this article in press as: Mabille C, et al. Infectious risk associated to orthopaedic surgery for rheumatoid arthritis patients treated by anti-TNFalpha. Joint Bone Spine (2016), http://dx.doi.org/10.1016/j.jbspin.2016.06.011
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Fig. 2. Meta-analysis comparing the number of post-operative infections observed in patients treated with anti-TNF␣ compared to patients treated with csDMARDS.
Fig. 3. Meta-analysis comparing the number of post-operative infection in patients treated with anti-TNF␣ who continued or discontinued treatment before surgery.
These seven studies were used to answer the second question [6,13,14,16,18–20]. All these studies are observational retrospective or prospective studies and there were no randomised controlled trials. Some information is often missing as coprescription of steroids, the exact dose and time of withdrawal anti-TNF. 3.2. Patients treated with anti-TNF˛ have an increased risk of post-operative infection The 12 studies identified described infections after orthopaedic surgery. A total of 124 infections occurred for 4975 surgeries performed in patients treated with anti-TNF␣ (2.49%) and 731 infections of 61,090 surgeries performed in the control population (1.19%). Individually, only four of these studies identified a significantly higher incidence of post-operative infections in patients treated with anti-TNF␣ [6–9]. Six others showed a trend, but without reaching the significance level, in favour of a high risk of infection [10–15]. At the opposite, the studies by Berthold et al. [16] and Bibbo et al. [17], which represented 1694 patients, no differences were found between the two populations. Meta-analysis of the 12 studies (Fig. 2) showed a significant risk of infection amongst patients treated with anti-TNF␣ compared to those treated with csDMARD without biological agents (RR = 1.81 [1.31–2.50]) 3.3. Discontinuing anti-TNF˛ therapy before surgery does not alter significantly the post-operative risk of infection Seven articles compared the frequency of superficial or deep surgical site infections whether anti-TNF␣ therapy was discontinued before the intervention or not [6,13,14,16,18–20]. Two of these
studies were uninformative since no infectious event occurred after a 12- and 14-month follow-up [19,20]. Overall, amongst the 501 patients who discontinued anti-TNF␣ therapy before surgery, 20 (3.99%) had a post-operative infection compared to 586 patients who continued their anti-TNF␣ therapy, 37 (6.3%). After meta-analysis (Fig. 3), we found no significant change in the risk of infection by prior discontinuation or continuation of biological treatment (RR = 0.69 [0.39–1.21]). 4. Discussion Our work demonstrated that patients treated with anti-TNF␣ are more exposed to a risk of infection undergoing surgery (RR = 1.88 [1.32–2.66]). This high risk is very similar to that reported by Goodman et al.: 2.47 [95% CI: 1.66–3.68] [21]. Compared to the meta-analysis published recently, our work covered a greater number of patients with 3681 patients treated with anti-TNF␣ while Goodman et al. only included 598. Similarly, the control population was larger. Indeed, we included in our meta-analysis the work of Suzuki et al., which included nearly 60,000 individuals of which 3468 RA were treated with anti-TNF␣, representing 23% of all data [10]. The first part of our work focused on RA and all surgeries performed were orthopaedic surgeries, while the meta-analysis of Goodman et al. retained the work by Ruyssen-Witrand et al. [18], which included other types of surgery. Increased risk of infection associated with TNF␣ inhibitors occurs undergoing any type of surgery. However, several studies observed a different infection frequency according to the surgical site. For den Broeder et al. [14], high risk of infection increased for foot, ankle and elbow surgeries with about 9% of infection for each of these locations against 3% for hand surgery, 4% for total knee prostheses and 1% for hip fractures. Similarly, the study by Scherrer et al. described high risk of infection in RA for elbow and foot surgeries, and less risk for hand
Please cite this article in press as: Mabille C, et al. Infectious risk associated to orthopaedic surgery for rheumatoid arthritis patients treated by anti-TNFalpha. Joint Bone Spine (2016), http://dx.doi.org/10.1016/j.jbspin.2016.06.011
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surgeries [6]. It may be interesting to adapt the advice on the discontinuation period of anti-TNF␣ therapies depending on the type of orthopaedic surgery. An important factor associated with the risk of infection during RA is corticosteroids [22]. We investigated in 12 studies of our first meta-analysis, the main confounding factor. In five studies [9,11,12,15,16], no difference was found in the frequency of use and dose of cortisone between the two groups. In both studies, the consumption of steroids was more frequent and greater in patients treated with anti-TNF␣ compared to patients treated with csDMARDS [8,10]. In these two studies, one of them showed no significant difference in terms of infection between the two populations [14]. However, the study of Kawakami et al. concluded a high risk of infection in patients treated with anti-TNF␣; these patients also received more steroids than control patients [8]. In this study, the high risk of infection could be attributed to anti-TNF␣ or cortisone. Three studies used univariate and multivariate analyses, including corticosteroids as an infection risk factor [6,8,13]. They did not reveal a high risk associated with taking cortisone. The studies of Bibbo et al. and Suzuki et al. did not include cortisone treatment when assessing the risk of postoperative infection [10,17]. Other factors, such as the duration of disease progression, tobacco abuse, diabetes, comorbidities and in particular, disease activity were not taken into account in all studies and could not be analysed. Indeed, patients with RA treated with anti-TNF␣ had more severe inflammatory arthritis that patients treated with csDMARDS. No adjustment type propensity score was achieved. Another difficulty in interpreting these studies was the definition of an infection that is not homogeneous. Six studies were based on US CDC criteria [23] to conclude the infection diagnosis [7,8,11,12,14,16]. In the study of Bibbo et al., the definition of infection was not described [17]. In the other five studies, the infection definition varies. One of them documented bacteria as the only evidence of infection. We also analysed the impact of discontinuing anti-TNF␣ therapy before surgery on the incidence of post-operative infections. Discontinuing anti-TNF␣ therapy before surgery did not change significantly the risk generated by taking anti-TNF␣ (RR = 0.70 [0.39–1.25]). In the articles selected for this second meta-analysis, all patients were treated with anti-TNF␣ and a small group received another biotherapy. In the study of Suzuki et al., 2.9% (102/3468) of the surgeries were performed in patients treated with tocilizumab and 0.6% (23/3468) with abatacept [12]. In the study of Kubota et al., 6.5% (18/276) of the surgeries involved patients treated with toclizumab [11]. In the studies of Giles et al. and Bongartz et al., some patients received anakinra, but their number was not specified [9,13]. In any case, we considered these cases as minimal and analysed all patients as being treated with anti-TNF␣. Significant heterogeneity existed during the period of discontinuation of anti-TNF␣ before surgery. Some studies defined discontinuing anti-TNF␣ therapy before surgery as stopping etanercept for seven days, adalimumab for 28 days and infliximab for 56 days [16]. In other studies, treatment was considered terminated if discontinuation respected four half-lives of anti-TNF␣, or 12 days for etanercept, 39 days infliximab and 56 days for adalimumab [14], and reinitiation was sometimes proposed one week after surgery, sometimes after the patient healed. These differences in discontinuation periods are an additional difficulty when interpreting the studies. The work of Ruyssen-Witrand et al. showed that the percentage of post-operative complications (infections, disunity and dehiscence) was 30% when biotherapy was discontinued less than five half-lives before surgery and 19% if anti-TNF␣ treatment was discontinued for more than five half-lives before surgery [18]. The study by Scherrer et al. emphasised the importance of the time interval between two injections. It showed that the risk was particularly high if the last dose of anti-TNF␣ was received within
one dosing interval before surgery: OR = 10.05 [95% CI 1.17–86.29] (P = 0.035) [6]. However, a risk of discontinuing anti-TNF␣ therapy is the occurrence of an inflammatory flare, requiring corticosteroid treatment, risk of infection and exposing the patient to a loss of efficiency when reinitiating the biological agent. In the study of Kawakami et al., 30% of patients treated with etanercept and 10% of patients treated with infliximab showed recurring arthralgias in the off-treatment period [8]. Other studies did not find any joint flares on discontinuing anti-TNF␣ therapy. In conclusion we showed that patients treated with anti-TNF␣ had about twice as many post-operative infections as patients treated with csDMARDs. Discontinuation of anti-TNF␣ therapy did not seem to decrease the high risk of infection caused by anti-TNF␣. This high risk should be weighed against that of corticosteroids, often necessary to control flares caused by discontinuing the biological agent. Various parameters such as the type of surgery, history (smoking, diabetes, history of infection, morbidity) and inflammatory arthritis severity (inflammatory activity, difficulty in controlling the disease, cortisone treatment) must be taken into account when assessing the need for and modalities of discontinuation of the biological agent. Disclosure of interest The authors declare that they have no competing interest. Acknowledgments Abbvie France pharmaceutical company provided logistic support by organising a meta-analysis methods workshop, but played no further role in the project. References [1] Luessenhop CP, Higgins LD, Brause BD, et al. Multiple prosthetic infections after total joint arthroplasty. Risk factor analysis. J Arthroplasty 1996;11:862–8. [2] Scanzello CR, Figgie MP, Nestor BJ, et al. Perioperative management of medications used in the treatment of rheumatoid arthritis. HSS J 2006;2:141–7. [3] Krause ML, Matteson EL. Perioperative management of the patient with rheumatoid arthritis. World J Orthop 2014;5:283–91. [4] Goeb V, Ardizzone M, Arnaud L, et al. Recommendations for using TNFalpha antagonists and French Clinical Practice Guidelines endorsed by the French National Authority for Health. Joint Bone Spine 2013;80:574–81. [5] Saag KG, Teng GG, Patkar NM, et al. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum 2008;59:762–84. [6] Scherrer CB, Mannion AF, Kyburz D, et al. Infection risk after orthopaedic surgery in patients with inflammatory rheumatic diseases treated with immunosuppressive drugs. Arthritis Care Res (Hoboken) 2013;65:2032–40. [7] Momohara S, Kawakami K, Iwamoto T, 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;21:469–75. [8] Kawakami K, Ikari K, Kawamura K, et al. Complications and features after joint surgery in rheumatoid arthritis patients treated with tumour necrosis factoralpha blockers: perioperative interruption of tumour necrosis factor-alpha blockers decreases complications? Rheumatology (Oxford) 2010;49:341–7. [9] Giles JT, Bartlett SJ, Gelber AC, et al. Tumor necrosis factor inhibitor therapy and risk of serious postoperative orthopaedic infection in rheumatoid arthritis. Arthritis Rheum 2006;55:333–7. [10] Suzuki M, Nishida K, Soen S, 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. [11] Kubota A, Nakamura T, Miyazaki Y, et al. Perioperative complications in elective surgery in patients with rheumatoid arthritis treated with biologics. Mod Rheumatol 2012;22:844–8. [12] Johnson BK, Goodman SM, Alexiades MM, et al. Patterns and associated risk of perioperative use of anti-tumor necrosis factor in patients with rheumatoid arthritis undergoing total knee replacement. J Rheumatol 2013;40:617–23. [13] Bongartz T, Halligan CS, Osmon DR, et al. Incidence and risk factors of prosthetic joint infection after total hip or knee replacement in patients with rheumatoid arthritis. Arthritis Rheum 2008;59:1713–20.
Please cite this article in press as: Mabille C, et al. Infectious risk associated to orthopaedic surgery for rheumatoid arthritis patients treated by anti-TNFalpha. Joint Bone Spine (2016), http://dx.doi.org/10.1016/j.jbspin.2016.06.011
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[14] den Broeder AA, Creemers MC, Fransen J, 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;34:689–95. [15] Hirano Y, Kojima T, Kanayama Y, et al. Influences of anti-tumour necrosis factor agents on postoperative recovery in patients with rheumatoid arthritis. Clin Rheumatol 2010;29:495–500. [16] Berthold E, Geborek P, Gulfe A. Continuation of TNFa blockade in patients with inflammatory rheumatic disease. An observational study on surgical site infections in 1,596 elective orthopaedic and hand surgery procedures. Acta Orthop 2013;84:495–501. [17] 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;25:331–5. [18] Ruyssen-Witrand A, Gossec L, Salliot C, et al. Complication rates of 127 surgical procedures performed in rheumatic patients receiving tumor necrosis factor alpha blockers. Clin Exp Rheumatol 2007;25:430–6.
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[19] Talwalkar SC, Grennan DM, Gray J, et al. Tumour necrosis factor alpha antagonists and early postoperative complications in patients with inflammatory joint disease undergoing elective orthopaedic surgery. Ann Rheum Dis 2005;64:650–1. [20] Wendling D. Surgery in rheumatoid arthritis patients under anti-TNF-alpha therapy: what is the risk? Clin Rheumatol 2007;26:1396–7. [21] Goodman SM, Menon I, Christos PJ, et al. Management of perioperative tumour necrosis factor alpha inhibitors in rheumatoid arthritis patients undergoing arthroplasty: a systematic review and meta-analysis. Rheumatology (Oxford) 2016;55:573–82. [22] Doran MF, Crowson CS, Pond GR, et al. Predictors of infection in rheumatoid arthritis. Arthritis Rheum 2002;46:2294–300. [23] Mangram AJ, Horan TC, Pearson ML, et al. Guideline for prevention of surgical site infection, 1999. Hospital Infection Control Practices Advisory Committee. Infect Control Hosp Epidemiol 1999;20:250–78, quiz 79-80.
Please cite this article in press as: Mabille C, et al. Infectious risk associated to orthopaedic surgery for rheumatoid arthritis patients treated by anti-TNFalpha. Joint Bone Spine (2016), http://dx.doi.org/10.1016/j.jbspin.2016.06.011
ARTICLE IN PRESS Joint Bone Spine xxx (2016) xxx–xxx
Available online at
ScienceDirect www.sciencedirect.com
Original article
Infectious risk associated to orthopaedic surgery for rheumatoid arthritis patients treated by anti-TNFalpha Charlotte Mabille a , Yannick Degboe a , Arnaud Constantin a , Thomas Barnetche b , Alain Cantagrel a , Adeline Ruyssen-Witrand a,∗ a b
Centre de Rhumatologie, Hôpital Pierre Paul Riquet, CHU Toulouse Purpan, 31000 Toulouse, France Service de Rhumatologie, Hôpital Pellegrin, CHU Bordeaux, 33000 Bordeaux, France
a r t i c l e
i n f o
Article history: Accepted 22 June 2016 Available online xxx Keywords: Surgery Rheumatoid arthritis Infection Anti-TNF␣
a b s t r a c t Introduction: Although biotherapy has greatly improved the prognosis of RA many patients have still recourse to an orthopaedic surgery. The current recommendation for scheduled surgery is to discontinue administration of the biological agent two to six weeks before surgery. Reinitiating anti-TNF therapy is proposed when the patient has healed. We wanted to know whether patients treated with anti-TNF␣ were exposed to an infectious risk undergoing a surgical procedure and if discontinuation of anti-TNF␣ therapy altered the risk of surgical infection. Methods: We conducted a systematic review of the literature in PubMed, Embase and Cochrane until March 2014. We selected studies that reported post-operative infections by comparing patients treated with anti-TNF␣ to patients treated with csDMARD without biological treatment, or patients who continued anti-TNF␣ therapy to the patients who discontinued treatment prior to surgery. Results: A first meta-analysis of 12 studies evaluating postoperative infection risk in patients treated with anti-TNF␣ showed that the postoperative infection risk doubled (RR = 1.81 [1.31–2.50]). Seven studies were grouped into a second meta-analysis to evaluate the benefit of the preventive discontinuation of anti-TNF␣. Discontinuation of treatment did not alter the post-operative infection risk significantly: RR = 0.69 [0.39–1.21]. Conclusion: This study showed that patients treated with anti-TNF␣ were more at risk of post-operative infection undergoing orthopaedic surgery. Preventive discontinuation of anti-TNF␣ does not seem to change this risk. ´ e´ franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved. © 2016 Societ
1. Introduction Over the past 15 years, anti-TNF␣ has made major therapeutic progress in the treatment of rheumatoid arthritis (RA) by enabling better clinical and structural control and improving prognosis. However in spite of the improvement, patients still need orthopaedic surgery at the early stage of the disease with synovectomy or later in the course of the disease for arthrodesis or prosthesis. TNF inhibitors are thought to increase the risk of developing infections and RA is a risk factor for septic complications undergoing prosthetic surgery [1]. Data on post-operative infections in patients treated with methotrexate (MTX) have not revealed any increased risk of infection even if treatment is continued
∗ Corresponding author at: Centre de Rhumatologie, Hôpital Pierre Paul Riquet, CHU Toulouse Purpan, 1 place du Dr Baylac, 31000 Toulouse, France. E-mail address: [email protected] (A. Ruyssen-Witrand).
perioperatively [2,3]. Continuation of MTX during any surgery is the daily practice. The known increased risk of infection related to anti-TNF␣ has led to recommend its discontinuation before surgery and its reinitiation only after the patient has healed completely. These recommendations are based on caution. The French Society of Rheumatology recommends in case of elective surgery at least two weeks of preoperative discontinuation for etanercept, and four weeks for adalimumab, certolizumab, golimumab and infliximab [4]. Reinitiation is proposed when the patient has healed completed. The American College of Rheumatology recommends discontinuation of the biological agent at least a week before surgery and reinitiation one week later [5]. To assess the risk of infection undergoing the surgery, we conducted a systematic literature review to answer two questions: 1. Is RA treated with anti-TNF␣ exposed to an infectious risk undergoing a surgical procedure compared to patients treated with csDMARDs alone?
http://dx.doi.org/10.1016/j.jbspin.2016.06.011 ´ e´ franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved. 1297-319X/© 2016 Societ
Please cite this article in press as: Mabille C, et al. Infectious risk associated to orthopaedic surgery for rheumatoid arthritis patients treated by anti-TNFalpha. Joint Bone Spine (2016), http://dx.doi.org/10.1016/j.jbspin.2016.06.011
G Model BONSOI-4455; No. of Pages 5
ARTICLE IN PRESS C. Mabille et al. / Joint Bone Spine xxx (2016) xxx–xxx
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2. Does discontinuation of anti-TNF␣ preoperatively modify the post-operative infection risk? 2. Methods 2.1. Identifications of articles We used the term “rheumatoid arthritis AND surgery AND infection AND (adalimumab OR certolizumab OR etanercept OR golimumab OR infliximab)”. We researched in the Cochrane, Pubmed and Embase databases for articles published until March 2014. Our search was limited to articles in English and French. We selected observational studies measuring the frequency of post-operative infections in orthopaedic surgery in a population of patients with inflammatory arthritis treated with anti-TNF␣ compared to a similar population not exposed to biological agents. We also included articles comparing the frequency of post-operative infections in patients treated with anti-TNF␣ but the treatment was discontinued before surgery to the frequency of post-operative infections in patients who continued anti-TNF␣ therapy.
• The second compared in patients treated with anti-TNF␣ the frequency of post-operative infections according to whether the biological agent was discontinued or not before surgery. The endpoint studied was the number of infectious events in each group of patients (treated with anti-TNF␣ vs. treated without biological agent) or between patients who continued the anti-TNF␣ therapy and those who discontinued biological treatment before surgery. A relative risk was calculated for each study. The calculations were made by the inverse of variance method according to a fixed pattern or a random pattern, depending on the level of heterogeneity. This method provides an overall relative risk with a 95% confidence interval, taking into account the weight of each study. Statistical heterogeneity amongst the included studies was assessed using the Cochrane Q test (2 ), using a significance level of 5%, and carrying forward the value of the I2 statistic for which important values are associated with a level significant heterogeneity. Publication bias was assessed with the Egger test. Meta-analyses were performed with the Revman 5.1.6 software. 3. Results
2.2. Data acquisition
3.1. Identification of articles
In these articles, we extracted the definition of infection, type of surgery, number of surgeries in the control and anti-TNF␣ arms, the number of surgeries performed without discontinuation of antiTNF␣ therapy or after discontinuation of anti-TNF␣ therapy, and the number of infections in each group of patients. 2.3. Statistical analysis From the extracted data, we conducted two meta-analyses: • The first compared the incidence of post-operative infections in patients treated with anti-TNF␣ compared to patients treated with csDMARD.
We identified 215 articles (Fig. 1). After reading the title and abstract, we retained 15 studies to which we added three articles from a manual search. We excluded three articles after reading them completely as two did not involve surgery and one had no control group. We retained a total of 15 articles. Four studies were relevant to answer both questions. Twelve studies compared the number of post-operative infections in patients treated with anti-TNF␣ to patients treated with csDMARDs alone. These 12 publications were used to answer the first question [6–17]. In the other three studies [18–20] and four studies common to both questions [6,13,14,16] amongst patients treated with anti-TNF␣, a group of patients continued taking the biological agent before surgery and another group discontinued treatment.
Fig. 1. Publications selection process used for the literature analysis.
Please cite this article in press as: Mabille C, et al. Infectious risk associated to orthopaedic surgery for rheumatoid arthritis patients treated by anti-TNFalpha. Joint Bone Spine (2016), http://dx.doi.org/10.1016/j.jbspin.2016.06.011
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ARTICLE IN PRESS C. Mabille et al. / Joint Bone Spine xxx (2016) xxx–xxx
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Fig. 2. Meta-analysis comparing the number of post-operative infections observed in patients treated with anti-TNF␣ compared to patients treated with csDMARDS.
Fig. 3. Meta-analysis comparing the number of post-operative infection in patients treated with anti-TNF␣ who continued or discontinued treatment before surgery.
These seven studies were used to answer the second question [6,13,14,16,18–20]. All these studies are observational retrospective or prospective studies and there were no randomised controlled trials. Some information is often missing as coprescription of steroids, the exact dose and time of withdrawal anti-TNF. 3.2. Patients treated with anti-TNF˛ have an increased risk of post-operative infection The 12 studies identified described infections after orthopaedic surgery. A total of 124 infections occurred for 4975 surgeries performed in patients treated with anti-TNF␣ (2.49%) and 731 infections of 61,090 surgeries performed in the control population (1.19%). Individually, only four of these studies identified a significantly higher incidence of post-operative infections in patients treated with anti-TNF␣ [6–9]. Six others showed a trend, but without reaching the significance level, in favour of a high risk of infection [10–15]. At the opposite, the studies by Berthold et al. [16] and Bibbo et al. [17], which represented 1694 patients, no differences were found between the two populations. Meta-analysis of the 12 studies (Fig. 2) showed a significant risk of infection amongst patients treated with anti-TNF␣ compared to those treated with csDMARD without biological agents (RR = 1.81 [1.31–2.50]) 3.3. Discontinuing anti-TNF˛ therapy before surgery does not alter significantly the post-operative risk of infection Seven articles compared the frequency of superficial or deep surgical site infections whether anti-TNF␣ therapy was discontinued before the intervention or not [6,13,14,16,18–20]. Two of these
studies were uninformative since no infectious event occurred after a 12- and 14-month follow-up [19,20]. Overall, amongst the 501 patients who discontinued anti-TNF␣ therapy before surgery, 20 (3.99%) had a post-operative infection compared to 586 patients who continued their anti-TNF␣ therapy, 37 (6.3%). After meta-analysis (Fig. 3), we found no significant change in the risk of infection by prior discontinuation or continuation of biological treatment (RR = 0.69 [0.39–1.21]). 4. Discussion Our work demonstrated that patients treated with anti-TNF␣ are more exposed to a risk of infection undergoing surgery (RR = 1.88 [1.32–2.66]). This high risk is very similar to that reported by Goodman et al.: 2.47 [95% CI: 1.66–3.68] [21]. Compared to the meta-analysis published recently, our work covered a greater number of patients with 3681 patients treated with anti-TNF␣ while Goodman et al. only included 598. Similarly, the control population was larger. Indeed, we included in our meta-analysis the work of Suzuki et al., which included nearly 60,000 individuals of which 3468 RA were treated with anti-TNF␣, representing 23% of all data [10]. The first part of our work focused on RA and all surgeries performed were orthopaedic surgeries, while the meta-analysis of Goodman et al. retained the work by Ruyssen-Witrand et al. [18], which included other types of surgery. Increased risk of infection associated with TNF␣ inhibitors occurs undergoing any type of surgery. However, several studies observed a different infection frequency according to the surgical site. For den Broeder et al. [14], high risk of infection increased for foot, ankle and elbow surgeries with about 9% of infection for each of these locations against 3% for hand surgery, 4% for total knee prostheses and 1% for hip fractures. Similarly, the study by Scherrer et al. described high risk of infection in RA for elbow and foot surgeries, and less risk for hand
Please cite this article in press as: Mabille C, et al. Infectious risk associated to orthopaedic surgery for rheumatoid arthritis patients treated by anti-TNFalpha. Joint Bone Spine (2016), http://dx.doi.org/10.1016/j.jbspin.2016.06.011
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surgeries [6]. It may be interesting to adapt the advice on the discontinuation period of anti-TNF␣ therapies depending on the type of orthopaedic surgery. An important factor associated with the risk of infection during RA is corticosteroids [22]. We investigated in 12 studies of our first meta-analysis, the main confounding factor. In five studies [9,11,12,15,16], no difference was found in the frequency of use and dose of cortisone between the two groups. In both studies, the consumption of steroids was more frequent and greater in patients treated with anti-TNF␣ compared to patients treated with csDMARDS [8,10]. In these two studies, one of them showed no significant difference in terms of infection between the two populations [14]. However, the study of Kawakami et al. concluded a high risk of infection in patients treated with anti-TNF␣; these patients also received more steroids than control patients [8]. In this study, the high risk of infection could be attributed to anti-TNF␣ or cortisone. Three studies used univariate and multivariate analyses, including corticosteroids as an infection risk factor [6,8,13]. They did not reveal a high risk associated with taking cortisone. The studies of Bibbo et al. and Suzuki et al. did not include cortisone treatment when assessing the risk of postoperative infection [10,17]. Other factors, such as the duration of disease progression, tobacco abuse, diabetes, comorbidities and in particular, disease activity were not taken into account in all studies and could not be analysed. Indeed, patients with RA treated with anti-TNF␣ had more severe inflammatory arthritis that patients treated with csDMARDS. No adjustment type propensity score was achieved. Another difficulty in interpreting these studies was the definition of an infection that is not homogeneous. Six studies were based on US CDC criteria [23] to conclude the infection diagnosis [7,8,11,12,14,16]. In the study of Bibbo et al., the definition of infection was not described [17]. In the other five studies, the infection definition varies. One of them documented bacteria as the only evidence of infection. We also analysed the impact of discontinuing anti-TNF␣ therapy before surgery on the incidence of post-operative infections. Discontinuing anti-TNF␣ therapy before surgery did not change significantly the risk generated by taking anti-TNF␣ (RR = 0.70 [0.39–1.25]). In the articles selected for this second meta-analysis, all patients were treated with anti-TNF␣ and a small group received another biotherapy. In the study of Suzuki et al., 2.9% (102/3468) of the surgeries were performed in patients treated with tocilizumab and 0.6% (23/3468) with abatacept [12]. In the study of Kubota et al., 6.5% (18/276) of the surgeries involved patients treated with toclizumab [11]. In the studies of Giles et al. and Bongartz et al., some patients received anakinra, but their number was not specified [9,13]. In any case, we considered these cases as minimal and analysed all patients as being treated with anti-TNF␣. Significant heterogeneity existed during the period of discontinuation of anti-TNF␣ before surgery. Some studies defined discontinuing anti-TNF␣ therapy before surgery as stopping etanercept for seven days, adalimumab for 28 days and infliximab for 56 days [16]. In other studies, treatment was considered terminated if discontinuation respected four half-lives of anti-TNF␣, or 12 days for etanercept, 39 days infliximab and 56 days for adalimumab [14], and reinitiation was sometimes proposed one week after surgery, sometimes after the patient healed. These differences in discontinuation periods are an additional difficulty when interpreting the studies. The work of Ruyssen-Witrand et al. showed that the percentage of post-operative complications (infections, disunity and dehiscence) was 30% when biotherapy was discontinued less than five half-lives before surgery and 19% if anti-TNF␣ treatment was discontinued for more than five half-lives before surgery [18]. The study by Scherrer et al. emphasised the importance of the time interval between two injections. It showed that the risk was particularly high if the last dose of anti-TNF␣ was received within
one dosing interval before surgery: OR = 10.05 [95% CI 1.17–86.29] (P = 0.035) [6]. However, a risk of discontinuing anti-TNF␣ therapy is the occurrence of an inflammatory flare, requiring corticosteroid treatment, risk of infection and exposing the patient to a loss of efficiency when reinitiating the biological agent. In the study of Kawakami et al., 30% of patients treated with etanercept and 10% of patients treated with infliximab showed recurring arthralgias in the off-treatment period [8]. Other studies did not find any joint flares on discontinuing anti-TNF␣ therapy. In conclusion we showed that patients treated with anti-TNF␣ had about twice as many post-operative infections as patients treated with csDMARDs. Discontinuation of anti-TNF␣ therapy did not seem to decrease the high risk of infection caused by anti-TNF␣. This high risk should be weighed against that of corticosteroids, often necessary to control flares caused by discontinuing the biological agent. Various parameters such as the type of surgery, history (smoking, diabetes, history of infection, morbidity) and inflammatory arthritis severity (inflammatory activity, difficulty in controlling the disease, cortisone treatment) must be taken into account when assessing the need for and modalities of discontinuation of the biological agent. Disclosure of interest The authors declare that they have no competing interest. Acknowledgments Abbvie France pharmaceutical company provided logistic support by organising a meta-analysis methods workshop, but played no further role in the project. References [1] Luessenhop CP, Higgins LD, Brause BD, et al. Multiple prosthetic infections after total joint arthroplasty. Risk factor analysis. J Arthroplasty 1996;11:862–8. [2] Scanzello CR, Figgie MP, Nestor BJ, et al. Perioperative management of medications used in the treatment of rheumatoid arthritis. HSS J 2006;2:141–7. [3] Krause ML, Matteson EL. Perioperative management of the patient with rheumatoid arthritis. World J Orthop 2014;5:283–91. [4] Goeb V, Ardizzone M, Arnaud L, et al. Recommendations for using TNFalpha antagonists and French Clinical Practice Guidelines endorsed by the French National Authority for Health. Joint Bone Spine 2013;80:574–81. [5] Saag KG, Teng GG, Patkar NM, et al. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum 2008;59:762–84. [6] Scherrer CB, Mannion AF, Kyburz D, et al. Infection risk after orthopaedic surgery in patients with inflammatory rheumatic diseases treated with immunosuppressive drugs. Arthritis Care Res (Hoboken) 2013;65:2032–40. [7] Momohara S, Kawakami K, Iwamoto T, 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;21:469–75. [8] Kawakami K, Ikari K, Kawamura K, et al. Complications and features after joint surgery in rheumatoid arthritis patients treated with tumour necrosis factoralpha blockers: perioperative interruption of tumour necrosis factor-alpha blockers decreases complications? Rheumatology (Oxford) 2010;49:341–7. [9] Giles JT, Bartlett SJ, Gelber AC, et al. Tumor necrosis factor inhibitor therapy and risk of serious postoperative orthopaedic infection in rheumatoid arthritis. Arthritis Rheum 2006;55:333–7. [10] Suzuki M, Nishida K, Soen S, 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. [11] Kubota A, Nakamura T, Miyazaki Y, et al. Perioperative complications in elective surgery in patients with rheumatoid arthritis treated with biologics. Mod Rheumatol 2012;22:844–8. [12] Johnson BK, Goodman SM, Alexiades MM, et al. Patterns and associated risk of perioperative use of anti-tumor necrosis factor in patients with rheumatoid arthritis undergoing total knee replacement. J Rheumatol 2013;40:617–23. [13] Bongartz T, Halligan CS, Osmon DR, et al. Incidence and risk factors of prosthetic joint infection after total hip or knee replacement in patients with rheumatoid arthritis. Arthritis Rheum 2008;59:1713–20.
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[14] den Broeder AA, Creemers MC, Fransen J, 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;34:689–95. [15] Hirano Y, Kojima T, Kanayama Y, et al. Influences of anti-tumour necrosis factor agents on postoperative recovery in patients with rheumatoid arthritis. Clin Rheumatol 2010;29:495–500. [16] Berthold E, Geborek P, Gulfe A. Continuation of TNFa blockade in patients with inflammatory rheumatic disease. An observational study on surgical site infections in 1,596 elective orthopaedic and hand surgery procedures. Acta Orthop 2013;84:495–501. [17] 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;25:331–5. [18] Ruyssen-Witrand A, Gossec L, Salliot C, et al. Complication rates of 127 surgical procedures performed in rheumatic patients receiving tumor necrosis factor alpha blockers. Clin Exp Rheumatol 2007;25:430–6.
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[19] Talwalkar SC, Grennan DM, Gray J, et al. Tumour necrosis factor alpha antagonists and early postoperative complications in patients with inflammatory joint disease undergoing elective orthopaedic surgery. Ann Rheum Dis 2005;64:650–1. [20] Wendling D. Surgery in rheumatoid arthritis patients under anti-TNF-alpha therapy: what is the risk? Clin Rheumatol 2007;26:1396–7. [21] Goodman SM, Menon I, Christos PJ, et al. Management of perioperative tumour necrosis factor alpha inhibitors in rheumatoid arthritis patients undergoing arthroplasty: a systematic review and meta-analysis. Rheumatology (Oxford) 2016;55:573–82. [22] Doran MF, Crowson CS, Pond GR, et al. Predictors of infection in rheumatoid arthritis. Arthritis Rheum 2002;46:2294–300. [23] Mangram AJ, Horan TC, Pearson ML, et al. Guideline for prevention of surgical site infection, 1999. Hospital Infection Control Practices Advisory Committee. Infect Control Hosp Epidemiol 1999;20:250–78, quiz 79-80.
Please cite this article in press as: Mabille C, et al. Infectious risk associated to orthopaedic surgery for rheumatoid arthritis patients treated by anti-TNFalpha. Joint Bone Spine (2016), http://dx.doi.org/10.1016/j.jbspin.2016.06.011