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Perioperative Management of Patients with Rheumatoid Arthritis Treated with TNF-α Blocking Agents
Letter to the Editor Perioperative Management of Patients with Rheumatoid Arthritis Treated with TNF-␣ Blocking Agents
W
e read with interest the review by Pieringer and coworkers of published data on the perioperative medical management of rheumatic disease patients, especially those with rheumatoid arthritis (RA) (1). We were chiefly interested in their findings concerning the perioperative handling of TNF-␣ blocking agents, and we thank these authors for indicating that “The Club Rhumatismes et Inflammation (CRI), which is a working group of the French Society of Rheumatology, has issued the only available recommendations on this topic” (2). The authors describe a few small studies that addressed the use of TNF-␣ blocking agents in patients with RA undergoing surgery. We would like to add to this review a retrospective study (3), a case series (4), and the 2005 update of the British Society for Rheumatology (BSR) guidelines (5). Matthews and coworkers (3) performed a retrospective chart review of a series of RA patients who underwent orthopedic procedures (joint replacement surgery, reconstruction surgery, spinal surgery, or fracture repair) during a 12-month period (3). A total of 142 procedures were performed in 126 RA patients, of whom 30 (24%) were treated with TNF-␣ blocking agents. Overall, 9/30 (30%) anti-TNF-␣-treated patients developed complications (joint or wound infections, other infections) compared with 11/112 (10%) patients not treated with TNF-␣ blocking agents, despite the fact that the anti-TNF-␣ treatments had been withheld for 2 weeks before and after surgery. Corrao and coworkers (4) reported a case series of 5 RA patients who underwent various types of elective surgery (for knee or hip prosthesis, bilateral cataract, bilateral hallux valgus, bladder stone by cystoscopy, or left inguinal hernia) but did not discontinue etanercept therapy despite their physician’s advise. During the follow-up period (6 to 12 months), none of these patients suffered infective postsurgery complications. The 2005 updated BSR guidelines (5) recommend that treatment with infliximab, etanercept, and adalimumab should be withheld for 2 to 4 weeks before major surgical procedures and state that treatment may be restarted postoperatively if there is no evidence of infection and once wound healing is satisfactory. The CRI guidelines have been updated recently (6) for several reasons. First, TNF-␣ blocking agents have gained widespread use over the world and there is a larger clinical experience with their use in “real-life” conditions, especially regarding the perioperative management of surgery patients. Previous guidelines were very strict and cautious because of lack of experience with these drugs. Since then, 202
rheumatologists’ real-life clinical practice evolved necessitating an update of the guidelines. Second, the previous guidelines were mainly based on pharmacological reasoning (ie, on drug half-lives), which clearly has limitations. In fact, in addition to half-lives, it is important to take into account the time necessary to achieve infra-therapeutic concentrations. Third, it is difficult to specify a general duration for presurgery anti-TNF-␣ therapy discontinuation because it depends on the type of surgery (“sterile environment”— eg, cataract; “septic environment”— eg, sigmoiditis; or “septic risk” conditions— eg, joint prosthesis), on the drug used (and its pharmacological properties), on the risk inherent to the individual patient (infection history, joint prosthesis, diabetes, corticosteroid therapy, . . .), on the severity of the rheumatologic disease, and on the risk of flare when TNF-␣ blocking agents are withheld for a long period. The updated CRI guidelines now recommend shorter durations for presurgery discontinuation of TNF-␣ blocking agents that are not directly related to the drugs’ half-lives. The CRI experts recommend discontinuing anti-TNF-␣ treatment for at least 2 weeks before surgery for etanercept and for at least 4 weeks for infliximab and adalimumab (6). On the whole, the currently available data do not allow us to draw definitive conclusions about the perioperative handling of TNF-␣ blocking agents, and the updated CRI guidelines will have to be reassessed in the real-life conditions of rheumatologic clinical practice. Philippe Goupille,* Thao Pham,† Jean Sibilia,‡ and Xavier Mariette§ * For the CRI University Hospitals of Tours, † Marseille, ‡ Strasbourg, § Paris-Sud, France
REFERENCES 1. Pieringer H, Stuby U, Biesenbach G. Patients with rheumatoid arthritis undergoing surgery: how should we deal with antirheumatic treatment? Semin Arthritis Rheum 2007 [Epub ahead of print]. 2. Pham T, Claudepierre P, Deprez X, Fautrel B, Goupille P, Hilliquin P, et al. Anti-TNF alpha therapy and safety monitoring. Clinical tool guide elaborated by the Club Rhumatismes et Inflammations (CRI), section of the French Society of Rheumatology (SFR). Joint Bone Spine 2005;72(Suppl 1):1-58. 3. Matthews JLK, Martin L, Hu R. Post-operative complications in rheumatoid arthritis patients on anti-TNF therapies undergoing
0049-0172/07/$-see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.semarthrit.2007.04.006
Letter to the Editor orthopaedic procedures. Ann Rheum Dis 2006;65(Suppl 2):331 (Abstract). 4. Corrao S, Pistone G, Arnone S, Calvo L, Scaglione R, Licata G. Safety of etanercept therapy in rheumatoid patients undergoing surgery: preliminary report. Clin Rheumatol 2007 [Epub ahead of print]. 5. Ledingham J, Deighton C; British Society for Rheumatology Standards, Guidelines and Audit Working Group (SGAWG). Update on the British Society for Rheumatology guidelines for prescribing
203 TNF␣ blockers in adults with rheumatoid arthritis (update of previous guidelines of April 2001). Rheumatology 2005;44:157-63. 6. Pham T, Claudepierre P, Deprez X, Fautrel B, Goupille P, Hilliquin P, et al. Traitements anti-TNF␣ et suivi de la tolérance. Fiches pratiques élaborées par le Club Rhumatismes et Inflammation (CRI), section de la Société Française de Rhumatologie (SFR). Rev Rhum 2007;74:S1-73. Tools available in French on the website of the CRI: http://www.cri-net.com/prive/recherche/fiches_anti_ tnf.asp.
Reply
I
read with interest the letter by Goupille and cowork ers. The authors present 2 further (retrospective) studies which analyze the impact of tumor necrosis factor (TNF) blocking agents on the perioperative outcome; while Matthews and coworkers (1) found a higher rate of (total) complications in rheumatoid arthritis (RA) patients receiving TNF blocking agents (discontinued 2 weeks before and after surgery), the small case series by Corraro and coworkers (2) did not show postoperative infections in patients continuing treatment with etanercept perioperatively. The recommendations from the British Society for Rheumatology (BSR) are described in “Guidelines for prescribing TNF alpha blockers in adults with rheumatoid arthritis” (3). A few lines address the perioperative use of these drugs in case of “major surgical procedures” and solely follow the recommendations of the drug companies (“information provided by the drug companies”). “Minor surgeries” are not mentioned by the BSR. Of particular interest is the fact that the CRI (Club Rhumatismes et Inflammation) now has updated its recommendations on the time of perioperative discontinuation of TNF blocking agents, which is now somewhat shorter than before. Unfortunately, these recommendations are only available on a French website. I am looking forward to seeing these guidelines published in an English language journal. For the perioperative use of TNF blocking agents there are only a few (and mostly small and/or retrospective) studies published and these are by no means conclusive. This is also reflected in the 2 papers mentioned by Goupille and associates (1, 2). Matthews and coworkers (1) found an increased risk in patients with TNF blockers. However, we cannot be sure whether this is really related to the drugs themselves. RA patients who are treated with TNF blocking agents probably have more severe disease and therefore may be more likely to develop postoperative complications. In addition, surgeons may give more attention to wound healing in patients thought to be at higher risk for impaired wound healing. A retrospective analysis, therefore, may have the limitation of not using a uniform definition of complications (eg, delayed wound healing).
Summing up the results of published articles and abstracts, the feared risk of postoperative infections and impaired wound healing might be much less then initially expected. However, extrapolation from these small studies with TNF blocking agents to all RA patients has a number of limitations. Goupille and coworkers mention several reasons why recommendations for the perioperative handling of TNF alpha blockers are difficult to establish. I totally agree. So, it appears that— besides the small body of evidence concerning the perioperative use of biologics—mainly personal experience and opinions, as well as pharmacological reasoning have also led to the present form of CRI recommendations. As TNF blocking agents are a crucial part in daily clinical practice, rheumatologists have become familiar with these drugs. Today most rheumatologists usually discontinue TNF blocking agents perioperatively for a shorter time than they did some years earlier. However, this reflects conventional wisdom and lacks substantial proof. Retrospective studies and deliberate recommendations of experts are helpful, but, prospective trials are needed. These should not only focus on the time of discontinuation of the drugs, but should also evaluate a number of additional parameters (eg, number of flares, quality of life, need for additional amounts of corticosteroids, influence on postoperative rehabilitation, comorbidities, different surgical risk levels, etc). Until the results of such studies are available, the CRI recommendations deserve attention. Herwig Pieringer, MD
REFERENCES 1. Matthews JLK, Martin L, Hu R. Post-operative complications in rheumatoid arthritis patients on anti-TNF therapies undergoing orthopaedic procedures. Ann Rheum Dis 2006;65(Suppl 2):331 (Abstract). 2. Corrao S, Pistone G, Arnone S, Calvo L, Scaglione R, Licata G. Safety of etanercept therapy in rheumatoid patients undergoing surgery: preliminary report. Clin Rheumatol 2007 Jan 17; [Epub ahead of print]. 3. Ledingham J, Deighton C. British Society for Rheumatology Standards, Guidelines and Audit Working Group (SGAWG). Update on the British Society for Rheumatology guidelines for prescribing TNFa blockers in adults with rheumatoid arthritis (update of previous guidelines of April 2001). Rheumatology 2005;44:157-63.
W
e read with interest the review by Pieringer and coworkers of published data on the perioperative medical management of rheumatic disease patients, especially those with rheumatoid arthritis (RA) (1). We were chiefly interested in their findings concerning the perioperative handling of TNF-␣ blocking agents, and we thank these authors for indicating that “The Club Rhumatismes et Inflammation (CRI), which is a working group of the French Society of Rheumatology, has issued the only available recommendations on this topic” (2). The authors describe a few small studies that addressed the use of TNF-␣ blocking agents in patients with RA undergoing surgery. We would like to add to this review a retrospective study (3), a case series (4), and the 2005 update of the British Society for Rheumatology (BSR) guidelines (5). Matthews and coworkers (3) performed a retrospective chart review of a series of RA patients who underwent orthopedic procedures (joint replacement surgery, reconstruction surgery, spinal surgery, or fracture repair) during a 12-month period (3). A total of 142 procedures were performed in 126 RA patients, of whom 30 (24%) were treated with TNF-␣ blocking agents. Overall, 9/30 (30%) anti-TNF-␣-treated patients developed complications (joint or wound infections, other infections) compared with 11/112 (10%) patients not treated with TNF-␣ blocking agents, despite the fact that the anti-TNF-␣ treatments had been withheld for 2 weeks before and after surgery. Corrao and coworkers (4) reported a case series of 5 RA patients who underwent various types of elective surgery (for knee or hip prosthesis, bilateral cataract, bilateral hallux valgus, bladder stone by cystoscopy, or left inguinal hernia) but did not discontinue etanercept therapy despite their physician’s advise. During the follow-up period (6 to 12 months), none of these patients suffered infective postsurgery complications. The 2005 updated BSR guidelines (5) recommend that treatment with infliximab, etanercept, and adalimumab should be withheld for 2 to 4 weeks before major surgical procedures and state that treatment may be restarted postoperatively if there is no evidence of infection and once wound healing is satisfactory. The CRI guidelines have been updated recently (6) for several reasons. First, TNF-␣ blocking agents have gained widespread use over the world and there is a larger clinical experience with their use in “real-life” conditions, especially regarding the perioperative management of surgery patients. Previous guidelines were very strict and cautious because of lack of experience with these drugs. Since then, 202
rheumatologists’ real-life clinical practice evolved necessitating an update of the guidelines. Second, the previous guidelines were mainly based on pharmacological reasoning (ie, on drug half-lives), which clearly has limitations. In fact, in addition to half-lives, it is important to take into account the time necessary to achieve infra-therapeutic concentrations. Third, it is difficult to specify a general duration for presurgery anti-TNF-␣ therapy discontinuation because it depends on the type of surgery (“sterile environment”— eg, cataract; “septic environment”— eg, sigmoiditis; or “septic risk” conditions— eg, joint prosthesis), on the drug used (and its pharmacological properties), on the risk inherent to the individual patient (infection history, joint prosthesis, diabetes, corticosteroid therapy, . . .), on the severity of the rheumatologic disease, and on the risk of flare when TNF-␣ blocking agents are withheld for a long period. The updated CRI guidelines now recommend shorter durations for presurgery discontinuation of TNF-␣ blocking agents that are not directly related to the drugs’ half-lives. The CRI experts recommend discontinuing anti-TNF-␣ treatment for at least 2 weeks before surgery for etanercept and for at least 4 weeks for infliximab and adalimumab (6). On the whole, the currently available data do not allow us to draw definitive conclusions about the perioperative handling of TNF-␣ blocking agents, and the updated CRI guidelines will have to be reassessed in the real-life conditions of rheumatologic clinical practice. Philippe Goupille,* Thao Pham,† Jean Sibilia,‡ and Xavier Mariette§ * For the CRI University Hospitals of Tours, † Marseille, ‡ Strasbourg, § Paris-Sud, France
REFERENCES 1. Pieringer H, Stuby U, Biesenbach G. Patients with rheumatoid arthritis undergoing surgery: how should we deal with antirheumatic treatment? Semin Arthritis Rheum 2007 [Epub ahead of print]. 2. Pham T, Claudepierre P, Deprez X, Fautrel B, Goupille P, Hilliquin P, et al. Anti-TNF alpha therapy and safety monitoring. Clinical tool guide elaborated by the Club Rhumatismes et Inflammations (CRI), section of the French Society of Rheumatology (SFR). Joint Bone Spine 2005;72(Suppl 1):1-58. 3. Matthews JLK, Martin L, Hu R. Post-operative complications in rheumatoid arthritis patients on anti-TNF therapies undergoing
0049-0172/07/$-see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.semarthrit.2007.04.006
Letter to the Editor orthopaedic procedures. Ann Rheum Dis 2006;65(Suppl 2):331 (Abstract). 4. Corrao S, Pistone G, Arnone S, Calvo L, Scaglione R, Licata G. Safety of etanercept therapy in rheumatoid patients undergoing surgery: preliminary report. Clin Rheumatol 2007 [Epub ahead of print]. 5. Ledingham J, Deighton C; British Society for Rheumatology Standards, Guidelines and Audit Working Group (SGAWG). Update on the British Society for Rheumatology guidelines for prescribing
203 TNF␣ blockers in adults with rheumatoid arthritis (update of previous guidelines of April 2001). Rheumatology 2005;44:157-63. 6. Pham T, Claudepierre P, Deprez X, Fautrel B, Goupille P, Hilliquin P, et al. Traitements anti-TNF␣ et suivi de la tolérance. Fiches pratiques élaborées par le Club Rhumatismes et Inflammation (CRI), section de la Société Française de Rhumatologie (SFR). Rev Rhum 2007;74:S1-73. Tools available in French on the website of the CRI: http://www.cri-net.com/prive/recherche/fiches_anti_ tnf.asp.
Reply
I
read with interest the letter by Goupille and cowork ers. The authors present 2 further (retrospective) studies which analyze the impact of tumor necrosis factor (TNF) blocking agents on the perioperative outcome; while Matthews and coworkers (1) found a higher rate of (total) complications in rheumatoid arthritis (RA) patients receiving TNF blocking agents (discontinued 2 weeks before and after surgery), the small case series by Corraro and coworkers (2) did not show postoperative infections in patients continuing treatment with etanercept perioperatively. The recommendations from the British Society for Rheumatology (BSR) are described in “Guidelines for prescribing TNF alpha blockers in adults with rheumatoid arthritis” (3). A few lines address the perioperative use of these drugs in case of “major surgical procedures” and solely follow the recommendations of the drug companies (“information provided by the drug companies”). “Minor surgeries” are not mentioned by the BSR. Of particular interest is the fact that the CRI (Club Rhumatismes et Inflammation) now has updated its recommendations on the time of perioperative discontinuation of TNF blocking agents, which is now somewhat shorter than before. Unfortunately, these recommendations are only available on a French website. I am looking forward to seeing these guidelines published in an English language journal. For the perioperative use of TNF blocking agents there are only a few (and mostly small and/or retrospective) studies published and these are by no means conclusive. This is also reflected in the 2 papers mentioned by Goupille and associates (1, 2). Matthews and coworkers (1) found an increased risk in patients with TNF blockers. However, we cannot be sure whether this is really related to the drugs themselves. RA patients who are treated with TNF blocking agents probably have more severe disease and therefore may be more likely to develop postoperative complications. In addition, surgeons may give more attention to wound healing in patients thought to be at higher risk for impaired wound healing. A retrospective analysis, therefore, may have the limitation of not using a uniform definition of complications (eg, delayed wound healing).
Summing up the results of published articles and abstracts, the feared risk of postoperative infections and impaired wound healing might be much less then initially expected. However, extrapolation from these small studies with TNF blocking agents to all RA patients has a number of limitations. Goupille and coworkers mention several reasons why recommendations for the perioperative handling of TNF alpha blockers are difficult to establish. I totally agree. So, it appears that— besides the small body of evidence concerning the perioperative use of biologics—mainly personal experience and opinions, as well as pharmacological reasoning have also led to the present form of CRI recommendations. As TNF blocking agents are a crucial part in daily clinical practice, rheumatologists have become familiar with these drugs. Today most rheumatologists usually discontinue TNF blocking agents perioperatively for a shorter time than they did some years earlier. However, this reflects conventional wisdom and lacks substantial proof. Retrospective studies and deliberate recommendations of experts are helpful, but, prospective trials are needed. These should not only focus on the time of discontinuation of the drugs, but should also evaluate a number of additional parameters (eg, number of flares, quality of life, need for additional amounts of corticosteroids, influence on postoperative rehabilitation, comorbidities, different surgical risk levels, etc). Until the results of such studies are available, the CRI recommendations deserve attention. Herwig Pieringer, MD
REFERENCES 1. Matthews JLK, Martin L, Hu R. Post-operative complications in rheumatoid arthritis patients on anti-TNF therapies undergoing orthopaedic procedures. Ann Rheum Dis 2006;65(Suppl 2):331 (Abstract). 2. Corrao S, Pistone G, Arnone S, Calvo L, Scaglione R, Licata G. Safety of etanercept therapy in rheumatoid patients undergoing surgery: preliminary report. Clin Rheumatol 2007 Jan 17; [Epub ahead of print]. 3. Ledingham J, Deighton C. British Society for Rheumatology Standards, Guidelines and Audit Working Group (SGAWG). Update on the British Society for Rheumatology guidelines for prescribing TNFa blockers in adults with rheumatoid arthritis (update of previous guidelines of April 2001). Rheumatology 2005;44:157-63.