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The perioperative use of biologic agents in patients with rheumatoid arthritis
Autoimmunity Reviews 12 (2012) 164–168
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Review
The perioperative use of biologic agents in patients with rheumatoid arthritis Ari Polachek, Dan Caspi, Ori Elkayam ⁎ Department of Rheumatology, Tel-Aviv "Sourasky" Medical Center and the "Sackler" Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
a r t i c l e
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Article history: Received 15 March 2012 Accepted 4 April 2012 Available online 12 April 2012 Keywords: Perioperative period Infection Wound healing Biological therapy Rheumatoid arthritis
a b s t r a c t Biologic drugs have gained an important place in the treatment of rheumatic diseases. These medications may, however, pose a higher risk of infections in rheumatic patients who a priori are prone to infections. The potential consequences of the immunosuppressive effects of the biologics raise concern about their safety in the perioperative setting. This article reviews the scientific literature that examines the influence of biologic drugs on post-surgical complications. According to these studies, it is apparently safe to use tumor necrosis factor-α blockers and the IL-6 receptor blocker, although a few study limitations, such as small sample size, retrospective design and differences in the comparison groups weaken the conclusions. In addition, the recommendations for some of the biologic drugs are based solely on pharmacological parameters due to the absence of trials, and larger randomized controlled studies are needed to establish the safety of their use by patients with rheumatic diseases. © 2012 Elsevier B.V. All rights reserved.
Contents 1. 2. 3. 4.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The pathophysiologic role of specific cytokines and B cells in wound healing Evidence of perioperative consequences of biologic drugs . . . . . . . . . 4.1. TNFα blockers . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Tocilizumab . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Other biologics . . . . . . . . . . . . . . . . . . . . . . . . . 5. Limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. Recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . 7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction The use of biologic agents has revolutionized the treatment of patients with rheumatoid arthritis (RA). This group of drugs has been constantly expanding and includes a variety of agents, such as tumor necrosis factor-α (TNFα) antagonists, interleukin (IL) 6 and 1 receptor antagonists, B cell depleting agents, CTLA-4 co-stimulator of T cells while new modalities are being developed and others are expected to be soon introduced into practice [1–4]. Although earlier studies
⁎ Corresponding author at: Department of Rheumatology, Tel Aviv Medical Center, 6 Weizman Street, Tel Aviv 64239, Israel. Tel.: + 972 3 6973668; fax: + 972 3 6974577. E-mail address: [email protected] (O. Elkayam). 1568-9972/$ – see front matter © 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.autrev.2012.04.001
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have questioned an increased risk for infections in patients with RA, recent reports have clearly shown a higher rate of infections in comparison with healthy controls, both in ambulatory and hospitalized patients [5,6]. This risk is further increased by the continuous use of biologic drugs [7–10]. Bongartz et al.'s meta analysis of nine randomized controlled studies on the use of infliximab and adalimumab in RA showed an odds ratio (OR) of 2.0 (95% CI, 1.3–3.1) for severe infections [11]. Their findings, however, were not confirmed by others (OR 1.21; 95% CI, 0.89–1.63) [12]. Data from most registries of RA patients treated with biologics support an increased rate of severe infections in patients treated with biologics [13–15]. Surgery is not infrequently required by patients treated with biologics. One example is inflammatory bowel disease patients who receive TNF antagonists and undergo abdominal surgery. Interestingly, most studies on Crohn's disease patients treated with TNFα blockers
A. Polachek et al. / Autoimmunity Reviews 12 (2012) 164–168
showed that they did not have more infections or impaired wound healing than non-treated Crohn's disease patients [16,17], while the results for ulcerative colitis patients are conflicting [18–20]. Rheumatologic patients often undergo orthopedic procedures, each of them carrying a postoperative complication rate, which can potentially be higher in patients who are being treated with immunosuppressive agents. The reported rate of infection after total joint replacement surgery in the general population ranges between 1% and 2.5% [21], compared to reports that suggest a rate of up to 4% for RA patients from the pre-TNFα blockers era [22,23]. Rheumatologists must often face the dilemma of whether or not and for how long to stop biologics before elective surgeries risking possible flare-up of the rheumatic disease. The aim of this article was to review the literature related to the perioperative complications in rheumatologic patients treated with biologic drugs and to establish a set of recommendations for the perioperative use of these agents based on the results of this search. 2. Methods We conducted a literature search up to April 2011 (PubMed database, National Library of Medicine, Bethesda, MD) using the Medline subheadings and key words “rheumatoid arthritis”, “RA”, “psoriatic arthritis”, “ankylosing spondylitis”, “biologic”, “infliximab”, “adalimumab”, “etanercept”, “IL-6 antagonist”, “tocilizumab”, “IL-1 antagonist”, “anakinra”, “rituximab”, “ abatacept”, “surgery”, “orthopedic operation”, “hip replacement”, “knee replacement”, as well as post-surgical complications, such as “ wound healing” and “infections.” We also included terms associated with the role of cytokines in wound healing, such as TNFα, IL-1, IL-6 and B-cells. 3. The pathophysiologic role of specific cytokines and B cells in wound healing Wound healing is a critical component of perioperative patient care. Surgical wounds recruit local repair mechanisms and a systemic defense response in which various parts of the immunologic system participate. Among them are cytokines and cells that are inhibited by specific biologic drugs. TNFα has been implicated in regulating cells which play an important role in wound healing, such as fibroblast proliferation [24], prostaglandin production [25] and angiogenesis [26]. In addition, TNF mediates chemotaxis and adhesion of macrophages and neutrophils during the initial phases of inflammation [27]. However, the results of experimental studies on the possibilities of modulating TNF activity in wound healing are contradictory. Some reports suggest that the addition of exogenous TNF may improve impaired healing [28], while others show that the inhibition of TNF attenuates wound breaking strength [29]. On the other hand, Salomon et al. demonstrated that local application of recombinant TNF had an inhibitory effect on wound strength and on the gene that controls new collagen synthesis [30]. In contrast, Cowin et al. showed the ability of etanercept to reduce the chronicity of venous leg ulcers and promote wound healing by inhibiting TNF activity in chronic wound fluids [31]. IL-1 is another cytokine with regulating ability of the production of wound inflammatory mediators, as demonstrated in vivo in a murine model [32]. The results of an in vitro study suggested that acute exposure to exogenous IL-1 may slow down the repair of an injured meniscus [33]. Furthermore, wound healing in vivo was improved in IL-1 receptor knockout mice [34]. Likewise, periodontal wound healing was enhanced when an IL-1 inhibitor was added for a short term in an in vivo primate model [35]. IL-6 has been demonstrated to have an essential role in promoting wound healing. Galluci et al. observed that knockout mice for IL-6 exhibited impaired skin wound healing, and that the process was reversed when recombinant IL-6 was added [36]. Similarly, it has been shown that wound healing
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is delayed in IL-6-deficient mice as well as in wild type mice treated with IL-6 antibodies [37]. Lastly, while the modulatory role of T lymphocytes in wound healing was demonstrated in several studies [38–40], it is less clear whether B lymphocytes play any role [41]. However, Iwata et al. showed that CD19 (a B cell regulator) deficiency was related to impaired cutaneous wound healing, while overexpression of CD19 was related to enhanced healing in a mice model [42]. 4. Evidence of perioperative consequences of biologic drugs The evidence for the relationship between biologic drugs and surgery that we present herein is based on a total of 11 clinical studies (Table 1) [43–53]. All of them had a retrospective design, except for Bibbo and Goldberg's prospective study [43]. The majority of the patient populations consisted of RA patients, with a minority of patients with ankylosing spondylitis and psoriatic arthritis. Most of these studies examined the perioperative consequences of orthopedic surgery, mainly large joint arthroplasties (hip, knee, shoulder, wrist and ankle). The single exception was a study by Ruyseen-Witrand et al. that also included a small number of patients who underwent abdominal surgery [48]. The biologic drugs that were examined included the TNFα antagonists in ten studies and IL-6 antagonist (tocilizumab) in one. 4.1. TNFα blockers All 10 studies on TNFα blockers evaluated the risk for infections, while only five of them addressed the issue of impaired wound healing. In seven studies, including the prospective study by Bibbo and Goldberg [43], the rate of infections was not found to be significantly increased and whether or not the patient was being treated with TNFα blockers. In contrast, this risk was found to be significantly higher in three of the studies, with an odds ratio (OR) ranging between 5.3 and 5.7 [46,50,52]. Ruyseen-Witrand et al. showed an increased infection rate of 6.5%, but without significant differences between patients who interrupted TNF blocker use before undergoing the surgical procedure and those who did not [48]. Most of the studies did not report any significant difference in the rate of wound healing complications, while the study by den Broeder et al. was the only one to demonstrate a significantly higher risk of wound dehiscence and bleeding in patients receiving anti-TNFα therapies (RR 2.4, 95% CI 1.1–5) [47]. Flare-up of the basic rheumatologic disease while anti-TNF treatment was being withheld had been mentioned in two studies [45,50]. Kawakami et al., however, were the only ones who showed a significant rate (p = 0.009) of RA flare-ups (11 patients) following the interruption of TNFα blockers use [50]. 4.2. Tocilizumab The only study on this drug was by Hirano et al. who retrospectively compared 22 patients who were treated with tocilizumab to 22 patients who were treated with conventional disease modifying antirheumatic drugs (DMARDs). Their results did not show the occurrence of infections or delayed wound healing in either group [53]. 4.3. Other biologics We did not find any study that examined the effect of other biologics, such as IL-1 inhibitor, abatacept, and rituximab. 5. Limitations This review has some limitations. First, most of the studies had a retrospective design, which may have led to an information bias since descriptions of the rates of wound healing and of rheumatic
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A. Polachek et al. / Autoimmunity Reviews 12 (2012) 164–168
Table 1 Clinical trials on the perioperative use of biologic drugs. Reference
Study design
Main type of surgery
Biologics
Study groups
Bibbo et al. [43]
P
Foot and ankle
Wendling et al. [44]
R
16 15 32 18
Talwalker et al. [45]
R
THA/TKA TSA/TEA Foot and ankle THA/TKA TWR
Giles et al. [46]
R
Orthopedic procedures
den Broeder et al. [47]
R
Wrist/hand ankle/foot Knee/hip
Ruyssen-Witrand et al. [48]
R
Orthopedic, abdominal
Bongartz et al. [49]
R
THA TKA
Kawakami et al. [50]
R
THA/TKA
ETN INF ETN INF ADA ETN INF ADA ETN INF ADA ETN INF ADA ETN INF ADA ETN INF ADA ETN
Hirano et al. [51]
R
TAA/TSA TEA/Foot THA/TKA TAA/TSA TEA/Ankle
Momohara et al. [52]
R
THA
ETN
TKA
INF ADA TCZ
Hirao et al. [53]
R
THA/TKATSA/TRA Hand and foot
Infections
Wound healing
Similar
Similar
Similar
NA
4 pts — cont TNFα inh 12 pts — discont TNFα inh
Similar
Similar
35 pts — cont TNFα inh 56 pts — cont conv DMARDs
Increased risk (p b 0.05), OR 5.3 CI 1.1–24.9 Similar
NA
pts pts pts pts
— cont TNFα inh — cont conv DMARDs — cont TNFα inh — discont TNFα inh
92 pts — cont TNFα inh 104 pts — discont TNFα inh 10 55 36 38 12
pts pts pts pts pts
— discont TNFα inh b 2hla — discont TNFα inh2–5hl — discont TNFα inh > 5 hl — cont TNFα inh — discont TNF α inh
64 pts — cont TNFα inh
INF
64 pts — cont conv DMARDs
ETN INF
39 24 15 74 48
pts pts pts pts pts
— TNFα inh group: — discont INF 3–4wb — discont ETN1–2w — cont conv DMARDs — cont TNFα inh
372 pts — cont conv DMAR's 22 pts — cont TNFα inh 22 pts — cont conv DMARDs
Increased but not significant
Increased risk OR 11.2, 95% CI 1.4–90 Increased but not significant
Similar
NA
Increased risk (p b 0.05), OR 21.8 CI 1.23–386.1
NA
Similar
Similar
Increased risk (p b 0.05), OR 5.69 CI 2.07–15.6
NA
Similar
Similar
Legend: NA = not available; P = prospective; R = retrospective; THA = total hip arthroplasty; TKA = total knee arthroplasty; TEA = total elbow arthroplasty; TSA = total shoulder arthroplasty; TWA = total wrist arthroplasty; TAA = total ankle arthroplasty; INF = infliximab; ETN = etanercept; ADA = adalimumab; Cont = continuous; Discont = discontinuous; DMARD = disease-modifying antirheumatic drug; Pts = patients; Inh = inhibitor; Conv = conventional; hl = half-life; OR = odds ratio; and W = week. a Discontinue TNFα inhibitor before surgery as per half-life. b Discontinue TNFα inhibitor before surgery as per week.
disease flare-ups in patients whose biologic drugs were withheld were not available in most reports. In addition, the comparisons between the various groups' study were not uniform: some studies compared patients who continued on TNFα blockers to those who stopped them, while other studies used a different control group (e.g., conventional DMARD-treated patients who were naïve to TNFα blockers treatment). Another limitation is the time of withholding the TNFα blockers before surgery, which differed among the studies or was not mentioned at all. Likewise, the population samples were small and lacked sufficient statistical power to enable comparisons between the study groups, the different rheumatologic diseases, and the variety of drugs used (even within the same group). Finally, the majority of studies were on RA patients who were treated with TNF antagonists, making it difficult to apply their conclusions to patients with other rheumatologic conditions.
6. Recommendations The recommendations for perioperative handling of biologic drugs are a matter of controversy. Unfortunately, there are no unifying guidelines on the withholding of biologic drugs, and the various prestigious associations suggest different recommendations, most of them based on expert opinion (Table 2). Specifically, The British Society for Rheumatology as well as the Japanese College of Rheumatology guidelines recommend withholding TNFα blocking agents for 2 to 4 weeks before major surgical procedures [54,55]. Treatment may be restarted postoperatively if there is no evidence of infection and when wound healing is satisfactory. The French Rheumatologic Society guidelines are more stringent, recommending that patients with “septic risk” (the type of risk relevant to total joint replacement) stop TNFα blocker use for 5 half-lives: infliximab for 8 weeks, adalimumab for 4–6 weeks
Table 2 Recommendation of various rheumatology associations for withholding biologic drugs in perioperative periods. Rheumatology association
Biologic agent
Recommendation
British Society for Rheumatology and Japanese College of Rheumatology
{TNF α inhibitors
French Society for Rheumatologya (Club Rheumatisms et Inflammation — CRI)
Infliximab Adalimumab Etanercept TNF alpha blockers Abatacept Rituximabg
Hold 2–4 weeks before surgery Reinstitution — good wound healing and no infection Hold 8 weeks before surgery Hold 4–6 weeks before surgery Hold 2–3 weeks before surgery Hold for at least 1 week before to 1 week after surgery (consider the pharmacokinetic properties and the infectious risk of the specific surgery)
American College of Rheumatology
a
The recommendation pertaining to surgery with septic risk (e.g., hip/knee arthroplasty).
A. Polachek et al. / Autoimmunity Reviews 12 (2012) 164–168 Table 3 Recommendations for the perioperative use of biologics. Drug
Perioperative recommendationa
TNF alpha blockers Tocilizumab (IL-6 receptor antagonist) Anakinra (IL-1 antagonist) Abatacept (CTL4Ig blocker) Rituximab (CD20 antibody)
Withhold Withhold Withhold Withhold Withhold
one dose before surgery one dose before surgery for 1 week before surgery for 1 month before surgery for 3–6 months before surgery
a All the drugs should be restarted after surgery in the absence of infection and when wound healing is satisfactory.
and etanercept for 2–3 weeks [56]. The American College of Rheumatology recommends withholding biologic agents for at least 1 week prior to and 1 week after surgery [57]. In addition, they suggest tailoring the management to each case, taking into consideration the pharmacokinetic properties of each drug and the infectious risk of the specific surgery [57]. Based on this review and on the pharmacokinetics of biologics, we have established a series of recommendations which are presented in Table 3. Generally, the data in the current article tend to demonstrate that the perioperative use of TNFα blockers in RA patients is safe. However, given the limitations mentioned above and the contradictory data from a minority of studies, we recommend some caution in decision-making and the withholding of one dose of TNFα blocker treatment before surgery. The evidence from clinical trials on other biological drugs is less well established. Although tocilizumab was found to be safe in the single study performed on it, the experimental data indicating the important role of IL-6 in wound healing leads us to recommend withholding 1 dose preoperatively. In accordance with the experimental trials that point to the deleterious role of IL-1 in wound healing and to the benefits achieved from blocking it, it seems reasonable to withhold anakinra for one week before surgery. Finally, the timing of surgery for abatacept and rituximab is based on the pharmacological parameters of half-life and duration of effect. 7. Conclusions Recommendations on the perioperative management of TNFα blocker use in patients with rheumatic diseases must meet the goals of avoiding surgical complications that could be caused by the uninterrupted use of biologic agents, such as impaired wound healing and infections, while maintaining disease control. In general, the accumulated data on the safety of TNFα blockers and IL-6 receptor antagonists in the perioperative setting are reassuring. The limitations of the currently available studies call for caution when deciding individual patient management. Larger prospective studies on the effect of TNFα blockers and other biologics on perioperative complications in patients with rheumatic diseases are clearly warranted. Take-home messages • The use of biologics during the perioperative period seems to be safe. • In most studies, the rate of infection and impaired wound healing was not increased in rheumatic patients continuing biologics. • Withhold one dose of TNFα blockers and Tocilizumab before surgery. • Withhold Rituximab for 3–6 months before surgery. • Further studies are needed to establish evidence-based recommendations on the use of biologics during the perioperative period.
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[45] Talwalkar SC, Grennan DM, Gray J, Johnson P, Hayton MJ. Tumor necrosis factor alpha antagonists and early postoperative complications in patients with inflammatory joint disease undergoing elective orthopedic surgery. Ann Rheum Dis 2005;64:650–1. [46] Giles JT, Bartlett J, 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;55:333–7. [47] den Broeder AA, Creemers MCW, 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: 689–95. [48] Ruyssen-Witrand A, Gossec L, Salliot C, Luc M, Duclos M, Guignard S, et al. Complications rate of 127 surgical procedures performed in rheumatic patients receiving tumor necrosis factor alpha blockers. Clin Exp Rheumatol 2007;25:430–6. [49] Bongartz T, Halligan CS, Osmon DR, Reinalda MS, Bamlet WR, Crowson CS, et al. Incidence and risk factors of prosthetic joint infection after hip or knee replacement in patients with rheumatoid arthritis. Arthritis Rheum 2008;12:1713–20. [50] Kawakami K, Ikari K, Kawumura K, Tsukahara S, Iwamoto T, Yano K, et al. Complications and features after joint surgery in rheumatoid arthritis patients treated with tumor necrosis factor-alpha blockers: perioperative interruption of tumor necrosis factor-alpha blockers decreases complications? Rheumatology 2010;49: 341–7. [51] Hirano Y, Kojima T, Kanayama Y, Shioura T, Hayashi M, Kida D, et al. Influences of anti-tumor necrosis factor agents on postoperative recovery in patients with rheumatoid arthritis. Clin Rheumatol 2010;29:495–500. [52] Momohara S, Kawakami K, Iwamoto T, Yano K, Sakuma Y, Hiroshima R, et al. Prosthetic joint infections after total hip or knee arthroplasty in rheumatoid arthritis patients treated with non biologic and biologic disease-modifying antirheumatic drugs. Mod Rheumatol 2011;21(5):469–75 [Electronic publication ahead of print 2011 Feb 12]. [53] Hirano 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;68:654–7. [54] Ledingham J, Deighton C. Update on the British Society of Rheumatology guidelines for prescribing TNF alpha blockers in adults with rheumatoid arthritis. (update of previous guidelines of April 2001). Rheumatology 2005;44:157–63. [55] Koike R, Takeuchi K, Eguchi K, Miyasaka N. Update on the Japanese guidelines for the use of infliximab and etanercept in rheumatoid arthritis. Mod Rheumatol 2007;17:451–8. [56] Club Rheumatisms et Inflammation (CRI). Anti-TNF-alpha therapy and safety monitoring. Clinical situation: management in the case of surgery and dental care. Joint Bone Spine 2005;72:49–50 (Suppl.). [57] Saag KG, Teng GG, Patkar NM, Anuntiyo J, Finney C, Curtis JR, 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.
Contents lists available at SciVerse ScienceDirect
Autoimmunity Reviews journal homepage: www.elsevier.com/locate/autrev
Review
The perioperative use of biologic agents in patients with rheumatoid arthritis Ari Polachek, Dan Caspi, Ori Elkayam ⁎ Department of Rheumatology, Tel-Aviv "Sourasky" Medical Center and the "Sackler" Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
a r t i c l e
i n f o
Article history: Received 15 March 2012 Accepted 4 April 2012 Available online 12 April 2012 Keywords: Perioperative period Infection Wound healing Biological therapy Rheumatoid arthritis
a b s t r a c t Biologic drugs have gained an important place in the treatment of rheumatic diseases. These medications may, however, pose a higher risk of infections in rheumatic patients who a priori are prone to infections. The potential consequences of the immunosuppressive effects of the biologics raise concern about their safety in the perioperative setting. This article reviews the scientific literature that examines the influence of biologic drugs on post-surgical complications. According to these studies, it is apparently safe to use tumor necrosis factor-α blockers and the IL-6 receptor blocker, although a few study limitations, such as small sample size, retrospective design and differences in the comparison groups weaken the conclusions. In addition, the recommendations for some of the biologic drugs are based solely on pharmacological parameters due to the absence of trials, and larger randomized controlled studies are needed to establish the safety of their use by patients with rheumatic diseases. © 2012 Elsevier B.V. All rights reserved.
Contents 1. 2. 3. 4.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The pathophysiologic role of specific cytokines and B cells in wound healing Evidence of perioperative consequences of biologic drugs . . . . . . . . . 4.1. TNFα blockers . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Tocilizumab . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Other biologics . . . . . . . . . . . . . . . . . . . . . . . . . 5. Limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. Recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . 7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction The use of biologic agents has revolutionized the treatment of patients with rheumatoid arthritis (RA). This group of drugs has been constantly expanding and includes a variety of agents, such as tumor necrosis factor-α (TNFα) antagonists, interleukin (IL) 6 and 1 receptor antagonists, B cell depleting agents, CTLA-4 co-stimulator of T cells while new modalities are being developed and others are expected to be soon introduced into practice [1–4]. Although earlier studies
⁎ Corresponding author at: Department of Rheumatology, Tel Aviv Medical Center, 6 Weizman Street, Tel Aviv 64239, Israel. Tel.: + 972 3 6973668; fax: + 972 3 6974577. E-mail address: [email protected] (O. Elkayam). 1568-9972/$ – see front matter © 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.autrev.2012.04.001
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have questioned an increased risk for infections in patients with RA, recent reports have clearly shown a higher rate of infections in comparison with healthy controls, both in ambulatory and hospitalized patients [5,6]. This risk is further increased by the continuous use of biologic drugs [7–10]. Bongartz et al.'s meta analysis of nine randomized controlled studies on the use of infliximab and adalimumab in RA showed an odds ratio (OR) of 2.0 (95% CI, 1.3–3.1) for severe infections [11]. Their findings, however, were not confirmed by others (OR 1.21; 95% CI, 0.89–1.63) [12]. Data from most registries of RA patients treated with biologics support an increased rate of severe infections in patients treated with biologics [13–15]. Surgery is not infrequently required by patients treated with biologics. One example is inflammatory bowel disease patients who receive TNF antagonists and undergo abdominal surgery. Interestingly, most studies on Crohn's disease patients treated with TNFα blockers
A. Polachek et al. / Autoimmunity Reviews 12 (2012) 164–168
showed that they did not have more infections or impaired wound healing than non-treated Crohn's disease patients [16,17], while the results for ulcerative colitis patients are conflicting [18–20]. Rheumatologic patients often undergo orthopedic procedures, each of them carrying a postoperative complication rate, which can potentially be higher in patients who are being treated with immunosuppressive agents. The reported rate of infection after total joint replacement surgery in the general population ranges between 1% and 2.5% [21], compared to reports that suggest a rate of up to 4% for RA patients from the pre-TNFα blockers era [22,23]. Rheumatologists must often face the dilemma of whether or not and for how long to stop biologics before elective surgeries risking possible flare-up of the rheumatic disease. The aim of this article was to review the literature related to the perioperative complications in rheumatologic patients treated with biologic drugs and to establish a set of recommendations for the perioperative use of these agents based on the results of this search. 2. Methods We conducted a literature search up to April 2011 (PubMed database, National Library of Medicine, Bethesda, MD) using the Medline subheadings and key words “rheumatoid arthritis”, “RA”, “psoriatic arthritis”, “ankylosing spondylitis”, “biologic”, “infliximab”, “adalimumab”, “etanercept”, “IL-6 antagonist”, “tocilizumab”, “IL-1 antagonist”, “anakinra”, “rituximab”, “ abatacept”, “surgery”, “orthopedic operation”, “hip replacement”, “knee replacement”, as well as post-surgical complications, such as “ wound healing” and “infections.” We also included terms associated with the role of cytokines in wound healing, such as TNFα, IL-1, IL-6 and B-cells. 3. The pathophysiologic role of specific cytokines and B cells in wound healing Wound healing is a critical component of perioperative patient care. Surgical wounds recruit local repair mechanisms and a systemic defense response in which various parts of the immunologic system participate. Among them are cytokines and cells that are inhibited by specific biologic drugs. TNFα has been implicated in regulating cells which play an important role in wound healing, such as fibroblast proliferation [24], prostaglandin production [25] and angiogenesis [26]. In addition, TNF mediates chemotaxis and adhesion of macrophages and neutrophils during the initial phases of inflammation [27]. However, the results of experimental studies on the possibilities of modulating TNF activity in wound healing are contradictory. Some reports suggest that the addition of exogenous TNF may improve impaired healing [28], while others show that the inhibition of TNF attenuates wound breaking strength [29]. On the other hand, Salomon et al. demonstrated that local application of recombinant TNF had an inhibitory effect on wound strength and on the gene that controls new collagen synthesis [30]. In contrast, Cowin et al. showed the ability of etanercept to reduce the chronicity of venous leg ulcers and promote wound healing by inhibiting TNF activity in chronic wound fluids [31]. IL-1 is another cytokine with regulating ability of the production of wound inflammatory mediators, as demonstrated in vivo in a murine model [32]. The results of an in vitro study suggested that acute exposure to exogenous IL-1 may slow down the repair of an injured meniscus [33]. Furthermore, wound healing in vivo was improved in IL-1 receptor knockout mice [34]. Likewise, periodontal wound healing was enhanced when an IL-1 inhibitor was added for a short term in an in vivo primate model [35]. IL-6 has been demonstrated to have an essential role in promoting wound healing. Galluci et al. observed that knockout mice for IL-6 exhibited impaired skin wound healing, and that the process was reversed when recombinant IL-6 was added [36]. Similarly, it has been shown that wound healing
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is delayed in IL-6-deficient mice as well as in wild type mice treated with IL-6 antibodies [37]. Lastly, while the modulatory role of T lymphocytes in wound healing was demonstrated in several studies [38–40], it is less clear whether B lymphocytes play any role [41]. However, Iwata et al. showed that CD19 (a B cell regulator) deficiency was related to impaired cutaneous wound healing, while overexpression of CD19 was related to enhanced healing in a mice model [42]. 4. Evidence of perioperative consequences of biologic drugs The evidence for the relationship between biologic drugs and surgery that we present herein is based on a total of 11 clinical studies (Table 1) [43–53]. All of them had a retrospective design, except for Bibbo and Goldberg's prospective study [43]. The majority of the patient populations consisted of RA patients, with a minority of patients with ankylosing spondylitis and psoriatic arthritis. Most of these studies examined the perioperative consequences of orthopedic surgery, mainly large joint arthroplasties (hip, knee, shoulder, wrist and ankle). The single exception was a study by Ruyseen-Witrand et al. that also included a small number of patients who underwent abdominal surgery [48]. The biologic drugs that were examined included the TNFα antagonists in ten studies and IL-6 antagonist (tocilizumab) in one. 4.1. TNFα blockers All 10 studies on TNFα blockers evaluated the risk for infections, while only five of them addressed the issue of impaired wound healing. In seven studies, including the prospective study by Bibbo and Goldberg [43], the rate of infections was not found to be significantly increased and whether or not the patient was being treated with TNFα blockers. In contrast, this risk was found to be significantly higher in three of the studies, with an odds ratio (OR) ranging between 5.3 and 5.7 [46,50,52]. Ruyseen-Witrand et al. showed an increased infection rate of 6.5%, but without significant differences between patients who interrupted TNF blocker use before undergoing the surgical procedure and those who did not [48]. Most of the studies did not report any significant difference in the rate of wound healing complications, while the study by den Broeder et al. was the only one to demonstrate a significantly higher risk of wound dehiscence and bleeding in patients receiving anti-TNFα therapies (RR 2.4, 95% CI 1.1–5) [47]. Flare-up of the basic rheumatologic disease while anti-TNF treatment was being withheld had been mentioned in two studies [45,50]. Kawakami et al., however, were the only ones who showed a significant rate (p = 0.009) of RA flare-ups (11 patients) following the interruption of TNFα blockers use [50]. 4.2. Tocilizumab The only study on this drug was by Hirano et al. who retrospectively compared 22 patients who were treated with tocilizumab to 22 patients who were treated with conventional disease modifying antirheumatic drugs (DMARDs). Their results did not show the occurrence of infections or delayed wound healing in either group [53]. 4.3. Other biologics We did not find any study that examined the effect of other biologics, such as IL-1 inhibitor, abatacept, and rituximab. 5. Limitations This review has some limitations. First, most of the studies had a retrospective design, which may have led to an information bias since descriptions of the rates of wound healing and of rheumatic
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A. Polachek et al. / Autoimmunity Reviews 12 (2012) 164–168
Table 1 Clinical trials on the perioperative use of biologic drugs. Reference
Study design
Main type of surgery
Biologics
Study groups
Bibbo et al. [43]
P
Foot and ankle
Wendling et al. [44]
R
16 15 32 18
Talwalker et al. [45]
R
THA/TKA TSA/TEA Foot and ankle THA/TKA TWR
Giles et al. [46]
R
Orthopedic procedures
den Broeder et al. [47]
R
Wrist/hand ankle/foot Knee/hip
Ruyssen-Witrand et al. [48]
R
Orthopedic, abdominal
Bongartz et al. [49]
R
THA TKA
Kawakami et al. [50]
R
THA/TKA
ETN INF ETN INF ADA ETN INF ADA ETN INF ADA ETN INF ADA ETN INF ADA ETN INF ADA ETN
Hirano et al. [51]
R
TAA/TSA TEA/Foot THA/TKA TAA/TSA TEA/Ankle
Momohara et al. [52]
R
THA
ETN
TKA
INF ADA TCZ
Hirao et al. [53]
R
THA/TKATSA/TRA Hand and foot
Infections
Wound healing
Similar
Similar
Similar
NA
4 pts — cont TNFα inh 12 pts — discont TNFα inh
Similar
Similar
35 pts — cont TNFα inh 56 pts — cont conv DMARDs
Increased risk (p b 0.05), OR 5.3 CI 1.1–24.9 Similar
NA
pts pts pts pts
— cont TNFα inh — cont conv DMARDs — cont TNFα inh — discont TNFα inh
92 pts — cont TNFα inh 104 pts — discont TNFα inh 10 55 36 38 12
pts pts pts pts pts
— discont TNFα inh b 2hla — discont TNFα inh2–5hl — discont TNFα inh > 5 hl — cont TNFα inh — discont TNF α inh
64 pts — cont TNFα inh
INF
64 pts — cont conv DMARDs
ETN INF
39 24 15 74 48
pts pts pts pts pts
— TNFα inh group: — discont INF 3–4wb — discont ETN1–2w — cont conv DMARDs — cont TNFα inh
372 pts — cont conv DMAR's 22 pts — cont TNFα inh 22 pts — cont conv DMARDs
Increased but not significant
Increased risk OR 11.2, 95% CI 1.4–90 Increased but not significant
Similar
NA
Increased risk (p b 0.05), OR 21.8 CI 1.23–386.1
NA
Similar
Similar
Increased risk (p b 0.05), OR 5.69 CI 2.07–15.6
NA
Similar
Similar
Legend: NA = not available; P = prospective; R = retrospective; THA = total hip arthroplasty; TKA = total knee arthroplasty; TEA = total elbow arthroplasty; TSA = total shoulder arthroplasty; TWA = total wrist arthroplasty; TAA = total ankle arthroplasty; INF = infliximab; ETN = etanercept; ADA = adalimumab; Cont = continuous; Discont = discontinuous; DMARD = disease-modifying antirheumatic drug; Pts = patients; Inh = inhibitor; Conv = conventional; hl = half-life; OR = odds ratio; and W = week. a Discontinue TNFα inhibitor before surgery as per half-life. b Discontinue TNFα inhibitor before surgery as per week.
disease flare-ups in patients whose biologic drugs were withheld were not available in most reports. In addition, the comparisons between the various groups' study were not uniform: some studies compared patients who continued on TNFα blockers to those who stopped them, while other studies used a different control group (e.g., conventional DMARD-treated patients who were naïve to TNFα blockers treatment). Another limitation is the time of withholding the TNFα blockers before surgery, which differed among the studies or was not mentioned at all. Likewise, the population samples were small and lacked sufficient statistical power to enable comparisons between the study groups, the different rheumatologic diseases, and the variety of drugs used (even within the same group). Finally, the majority of studies were on RA patients who were treated with TNF antagonists, making it difficult to apply their conclusions to patients with other rheumatologic conditions.
6. Recommendations The recommendations for perioperative handling of biologic drugs are a matter of controversy. Unfortunately, there are no unifying guidelines on the withholding of biologic drugs, and the various prestigious associations suggest different recommendations, most of them based on expert opinion (Table 2). Specifically, The British Society for Rheumatology as well as the Japanese College of Rheumatology guidelines recommend withholding TNFα blocking agents for 2 to 4 weeks before major surgical procedures [54,55]. Treatment may be restarted postoperatively if there is no evidence of infection and when wound healing is satisfactory. The French Rheumatologic Society guidelines are more stringent, recommending that patients with “septic risk” (the type of risk relevant to total joint replacement) stop TNFα blocker use for 5 half-lives: infliximab for 8 weeks, adalimumab for 4–6 weeks
Table 2 Recommendation of various rheumatology associations for withholding biologic drugs in perioperative periods. Rheumatology association
Biologic agent
Recommendation
British Society for Rheumatology and Japanese College of Rheumatology
{TNF α inhibitors
French Society for Rheumatologya (Club Rheumatisms et Inflammation — CRI)
Infliximab Adalimumab Etanercept TNF alpha blockers Abatacept Rituximabg
Hold 2–4 weeks before surgery Reinstitution — good wound healing and no infection Hold 8 weeks before surgery Hold 4–6 weeks before surgery Hold 2–3 weeks before surgery Hold for at least 1 week before to 1 week after surgery (consider the pharmacokinetic properties and the infectious risk of the specific surgery)
American College of Rheumatology
a
The recommendation pertaining to surgery with septic risk (e.g., hip/knee arthroplasty).
A. Polachek et al. / Autoimmunity Reviews 12 (2012) 164–168 Table 3 Recommendations for the perioperative use of biologics. Drug
Perioperative recommendationa
TNF alpha blockers Tocilizumab (IL-6 receptor antagonist) Anakinra (IL-1 antagonist) Abatacept (CTL4Ig blocker) Rituximab (CD20 antibody)
Withhold Withhold Withhold Withhold Withhold
one dose before surgery one dose before surgery for 1 week before surgery for 1 month before surgery for 3–6 months before surgery
a All the drugs should be restarted after surgery in the absence of infection and when wound healing is satisfactory.
and etanercept for 2–3 weeks [56]. The American College of Rheumatology recommends withholding biologic agents for at least 1 week prior to and 1 week after surgery [57]. In addition, they suggest tailoring the management to each case, taking into consideration the pharmacokinetic properties of each drug and the infectious risk of the specific surgery [57]. Based on this review and on the pharmacokinetics of biologics, we have established a series of recommendations which are presented in Table 3. Generally, the data in the current article tend to demonstrate that the perioperative use of TNFα blockers in RA patients is safe. However, given the limitations mentioned above and the contradictory data from a minority of studies, we recommend some caution in decision-making and the withholding of one dose of TNFα blocker treatment before surgery. The evidence from clinical trials on other biological drugs is less well established. Although tocilizumab was found to be safe in the single study performed on it, the experimental data indicating the important role of IL-6 in wound healing leads us to recommend withholding 1 dose preoperatively. In accordance with the experimental trials that point to the deleterious role of IL-1 in wound healing and to the benefits achieved from blocking it, it seems reasonable to withhold anakinra for one week before surgery. Finally, the timing of surgery for abatacept and rituximab is based on the pharmacological parameters of half-life and duration of effect. 7. Conclusions Recommendations on the perioperative management of TNFα blocker use in patients with rheumatic diseases must meet the goals of avoiding surgical complications that could be caused by the uninterrupted use of biologic agents, such as impaired wound healing and infections, while maintaining disease control. In general, the accumulated data on the safety of TNFα blockers and IL-6 receptor antagonists in the perioperative setting are reassuring. The limitations of the currently available studies call for caution when deciding individual patient management. Larger prospective studies on the effect of TNFα blockers and other biologics on perioperative complications in patients with rheumatic diseases are clearly warranted. Take-home messages • The use of biologics during the perioperative period seems to be safe. • In most studies, the rate of infection and impaired wound healing was not increased in rheumatic patients continuing biologics. • Withhold one dose of TNFα blockers and Tocilizumab before surgery. • Withhold Rituximab for 3–6 months before surgery. • Further studies are needed to establish evidence-based recommendations on the use of biologics during the perioperative period.
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