Original article
Complications in surgery for Crohn’s disease after preoperative antitumour necrosis factor therapy P. Myrelid1,2 , M. Marti-Gallostra2,3 , S. Ashraf2 , M. L. Sunde4 , M. Tholin1 , T. Øresland4 , R. E. Lovegrove2 , A. Tøttrup5 , D. W. Kjær5 and B. D. George2 1
¨ Division of Surgery, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linkoping University, and Department of ¨ ¨ ¨ Surgery, County Council of Osterg otland, Linkoping, Sweden, 2 Department of Surgery, Unit of Colorectal Surgery, Oxford University Hospitals, Oxford, UK, 3 Department of Surgery, University Hospital of Valle de Hebron, Barcelona, Spain, 4 Clinic for Surgical Sciences, Faculty of Medicine, University of Oslo, Oslo, and Department of Gastrointestinal Surgery, Akershus University Hospital, Lorenskog, Norway, and 5 Surgical Gastroenterological Department P, Aarhus University Hospital, Aarhus, Denmark ¨ ¨ Correspondence to: Dr P. Myrelid, Department of Surgery, Linkoping University Hospital, S-58185 Linkoping, Sweden (e-mail: [email protected])
Background: The use of biological therapy (biologicals) is established in the treatment of Crohn’s
disease. This study aimed to determine whether preoperative treatment with biologicals is associated with an increased rate of complications following surgery for Crohn’s disease with intestinal anastomosis. Methods: All patients receiving biologicals and undergoing abdominal surgery with anastomosis or strictureplasty were identified at six tertiary referral centres. Demographic data, and preoperative, operative and postoperative details were registered. Patients who were treated with biologicals within 2 months before surgery were compared with a control group who were not. Postoperative complications were classified according to anastomotic, infectious or other complications, and graded according to the Clavien–Dindo classification. Results: Some 111 patients treated with biologicals within 2 months before surgery were compared with 187 patients in the control group. The groups were well matched. There were no differences between the treatment and control groups in the rate of complications of any type (34·2 versus 28·9 per cent respectively; P = 0·402), anastomotic complications (7·2 versus 8·0 per cent; P = 0·976) and nonanastomotic infectious complications (16·2 versus 13·9 per cent; P = 0·586). In univariable regression analysis, biologicals were not associated with an increased risk of any complication (odds ratio (OR) 1·33, 95 per cent confidence interval 0·81 to 2·20), anastomotic complication (OR 0·89, 0·37 to 2·17) or infectious complication (OR 1·09, 0·62 to 1·91). Conclusion: Treatment with biologicals within 2 months of surgery for Crohn’s disease with intestinal anastomosis was not associated with an increased risk of complications. Presented in part to the 2013 meeting of the European Crohn’s and Colitis Organization, Vienna, Austria, February 2013; published in abstract form as J Crohns Colitis 2013; 7(Suppl 1) S193–S194 Paper accepted 20 December 2013 Published online 26 February 2014 in Wiley Online Library (www.bjs.co.uk). DOI: 10.1002/bjs.9439
Introduction
Surgery for Crohn’s disease with intestinal anastomoses is associated with a high morbidity rate1 . The advent of antitumour necrosis factor (TNF) therapies such as infliximab and adalimumab has had a major impact on the treatment of patients with Crohn’s disease, with improvements in quality of life and a reduced need for hospitalization and possibly surgery2 – 4 . However, biological therapy (treatment with biologicals) is associated with an increased risk of infection, especially when used 2014 BJS Society Ltd Published by John Wiley & Sons Ltd
in combination with steroids5,6 . Biological therapy has raised concern among surgeons regarding the risk of postoperative complications and, in particular, the risk of anastomotic leakage. Studies addressing these concerns have conflicting results7 – 17 . The aim of this study was to assess the impact of antiTNF therapy on postoperative complications in patients undergoing surgery for Crohn’s disease with intestinal anastomoses without a diverting stoma. The study included patients who had ever been treated with biological therapy. The treatment group comprised patients who received BJS 2014; 101: 539–545
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biologicals within 2 months before surgery, who were compared with a control group of patients who did not. Methods
All patients undergoing surgery for Crohn’s disease involving one or more intestinal anastomoses and who received anti-TNF therapy either before or after surgery were identified from databases. Patients undergoing anastomoses protected by a proximal stoma were excluded. Patients were categorized into two groups: those in the treatment group received anti-TNF therapy within 2 months of surgery, whereas patients in the control group were treated with anti-TNF therapy, but had discontinued treatment more than 2 months before operation or started treatment at least 6 weeks after surgery. The cut-off period of 2 months was based on the half-life of the injected antibodies in vivo18 . Preoperative data recorded included: age and sex, body mass index, smoking history, duration of Crohn’s disease, Montreal classification (classification according to age at diagnosis as well as location and behaviour of Crohn’s disease)19 , indication for and urgency of surgery. Medical therapy at the time of surgery was recorded. Patients were considered to have ongoing treatment with steroids or immunomodulators if they received these drugs within 2 weeks or 1 month respectively before the surgical procedure1,20 . Operative procedures including surgical approach (open or laparoscopic), need for adhesiolysis and the method of anastomosis were recorded. Postoperative complications were recorded using the Clavien–Dindo21 classification. An anastomotic complication was recorded after an overt clinical leak, a leak found at repeat surgery or if leakage was verified radiologically. The primary endpoint of the study was the development of anastomotic complications within 30 days or during the postoperative hospital stay. Secondary endpoints were: infectious complications, other types of complication, need for intervention (radiological or surgical), length of hospital stay and severity of complications according to the Clavien–Dindo classification (Table S1, supporting information)21 . When multiple complications or interventions were present, only the one deemed most severe was included in the analysis. The Montreal classification19,21 of Crohn’s disease was used, which has three components: age at onset of disease (A), disease location (L) and behaviour of the disease (B). These components are further subclassified. Age of onset at 16 years or younger is denoted A1, age 17–40 years as A2 and age more than 40 years as A3. Location is classified as terminal ileal (L1), colonic (L2), ileocolonic 2014 BJS Society Ltd Published by John Wiley & Sons Ltd
(L3) or upper gastrointestinal (L4); the latter is defined as disease proximal to the terminal ileum. The L4 location may be used in combination with the other locations to classify more complex disease patterns. The disease behaviour is classified as non-stricturing, non-penetrating (B1), stricturing (B2) or penetrating (B3). The presence of perianal disease is denoted by a ‘P’ after the disease behaviour classification.
Statistical analysis Continuous data are presented as median (range) unless stated otherwise. The χ2 test, Fisher’s exact test, Mann–Whitney U test and univariable logistic regression were used as appropriate for statistical analysis. Factors previously shown to influence the risk of complications as well as factors found to be predictive on univariable analysis were entered into a multivariable logistic regression analysis. All P values were two-tailed and P < 0·050 was considered significant. SPSS version 15 (IBM, Armonk, New York, USA) was used for all statistical analyses. Results
During the study period 298 operations for Crohn’s disease with intestinal anastomoses without a covering stoma were undertaken in patients who received anti-TNF therapy. The proportion of all surgical patients who received biologicals differed slightly between centres (Table S2, supporting information), probably reflecting differing thresholds for use of anti-TNF therapy. Some 111 patients received anti-TNF within 2 months of surgery, whereas 187 did not. Most patients (229, 76·8 per cent) were diagnosed between the age of 17 and 40 years, 183 (61·4 per cent) had ileal or ileocaecal disease, and 74 (24·8 per cent) had ileocolonic disease (Table 1). Some 171 patients (57·4 per cent) had stricturing and 105 (35·2 per cent) penetrating, disease. Perianal disease was apparent before surgery in 79 patients (26·5 per cent) and 16 (5·4 per cent) had Crohn’s disease in the upper gastrointestinal tract as well. Some 164 patients (55·0 per cent) had undergone surgery for Crohn’s disease previously, and 27 (9·1 per cent) had a stoma before the index procedure. Seventy-one patients (23·8 per cent) were still smoking at the time of surgery. The most common indication for surgery was stenosis of an inflamed bowel segment or a previous anastomosis (183 patients, 61·4 per cent), followed by penetrating disease; bowel reconstruction and inflammation refractory to drug www.bjs.co.uk
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Characteristics of patients with Crohn’s disease ever treated with biological therapy and operated on with anastomosis or strictureplasty
Table 1
Median (range) age at surgery (years) Sex ratio (F : M) Montreal classification Age (years) A1 (≤ 16) A2 (17–40) A3 (> 40) Location L1 (ileal) L2 (colonic) L3 (ileocolonic) L4 (upper gastrointestinal) Behaviour B1 (inflammatory) B2 (stricturing) B3 (penetrating) Perianal disease (P) Previous abdominal operations for Crohn’s disease 0 1–2 ≥3 Previous permanent stoma (distal to later anastomosis/strictureplasty) Type of biological therapy* Infliximab Adalimumab Other medications Steroids Immunomodulation Azathioprine/6-mercaptopurine Methotrexate Mycophenolate mofetil Smoker Mean(s.d.) BMI (kg/m2 )† ASA fitness grade I II III Unknown
Biological therapy group (n = 111)
Control group (n = 187)
P‡
35·6 (12–82) 60 : 51
36·6 (12–76) 119 : 68
0·722§ 0·103
18 (16·2) 83 (74·8) 10 (9·0)
25 (13·4) 146 (78·1) 16 (8·6)
65 (58·6) 12 (10·8) 34 (30·6) 4 (3·6)
118 (63·1) 29 (15·5) 40 (21·4) 12 (6·4)
6 (5·4) 64 (57·7) 41 (36·9) 32 (28·8)
16 (8·6) 107 (57·2) 64 (34·2) 47 (25·1)
45 (40·5) 39 (35·1) 27 (24·3) 14 (12·6)
89 (47·6) 70 (37·4) 28 (15·0) 13 (7·0)
40 (36·0) 71 (64·0)
117 (62·6) 70 (37·4)
16 (14·4) 63 (56·8) 57 (51·4) 5 (4·5) 0 (0) 24 (21·6) 22·6(4·5)
25 (13·4) 110 (58·8) 98 (52·4) 8 (4·3) 4 (2·1) 47 (25·1) 23·4(4·0)
33 (29·7) 65 (58·6) 4 (3·6) 9 (8·1)
76 (40·6) 87 (46·5) 7 (3·7) 17 (9·1)
0·776
0·154
0·299 0·582
0·485 0·124
0·151 < 0·001
0·937 0·727
0·492 0·203§ 0·121
Values in parentheses are percentages. Patients in the biological therapy group had received biologicals within 2 months of surgery, whereas those in the control group had biologicals withheld for more than 2 months before surgery or received them after surgery. *Biological used closest in time to surgery (before and/or after operation). †Data missing for three patients. BMI, body mass index; ASA, American Society of Anesthesiologists. ‡χ2 test, except §Mann–Whitney U test.
treatment was less common (Table 2). The majority of the procedures (255, 85·6 per cent) were elective, and only 11 (3·7 per cent) were performed as an emergency. Even though laparoscopic surgery is increasingly being used for inflammatory bowel disease, open surgery was more frequent in this cohort (241 patients, 80·9 per cent). Intestinal resection was performed in 264 patients (88·6 per cent); ileocolonic resections were the most common, followed by colonic and small bowel resections. The use of strictureplasties is well described in Crohn’s disease22 . Strictureplasty was carried out together with a resection in 20 patients (6·7 per cent), whereas it was the only
procedure in five (1·7 per cent). There were no differences in preoperative or surgical parameters between the two groups (Tables 1 and 2). An increasing number of patients received biologicals during the study period, from 99 (19·5 per cent) of 508 during the first 3·5 years to 199 (45·9 per cent) of 434 during the last 3·5 years (P < 0·001). A change in favour of the use of adalimumab was seen during the second half of the study, increasing from 28 (28 per cent) of 99 to 113 (56·8 per cent) of 199, whereas 71 patients (72 per cent) were treated with infliximab during the first interval and 86 (43·2 per cent) during the second (P < 0·001). Only
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Characteristics of all abdominal operations (with anastomosis and/or strictureplasty) for Crohn’s disease, 2005–2011, in patients ever treated with biological therapy
Postoperative outcome (within 30 days) after abdominal operation
Table 2
Biological therapy group (n = 111) Surgical indication Inflammation Stricture Abscess/fistula Dysplasia/cancer Reconstruction Growth retardation Iatrogenic perforation* Urgency of surgery Elective Urgent (within 1 week) Emergency (within 24 h) Procedure performed Small bowel resection Ileocolic resection Colonic resection Stoma closure Strictureplasty alone Including strictureplasty Including severe adhesiolysis Surgical approach Open Laparoscopically assisted Type of anastomosis Handsewn Stapled
Control group (n = 187)
Table 3
Biological therapy group (n = 111) P†
0·831‡ 7 (6·3) 69 (62·2) 22 (19·8) 0 (0) 13 (11·7) 0 (0) 0 (0)
15 (8·0) 114 (61·0) 39 (20·9) 1 (0·5) 16 (8·6) 1 (0·5) 1 (0·5) 0·570‡
98 (88·3) 11 (9·9) 2 (1·8)
157 (84·0) 21 (11·2) 9 (4·8)
15 (13·5) 68 (61·3) 13 (11·7) 11 (9·9) 4 (3·6) 8 (7·2) 21 (18·9)
21 (11·2) 117 (62·6) 30 (16·0) 18 (9·6) 1 (0·5) 12 (6·4) 33 (17·6)
84 (75·7) 27 (24·3)
157 (84·0) 30 (16·0)
0·273‡
0·967 0·905 0·109
0·508 43 (38·7) 68 (61·3)
64 (34·2) 123 (65·8)
Values in parentheses are percentages. Patients in the biological therapy group had received biologicals within 2 months of surgery, whereas those in the control group had biologicals withheld for more than 2 months before surgery or received them after surgery. *Iatrogenic perforation during endoscopic dilatation of stricture. †χ2 test, except ‡Fisher’s exact test.
five (12 per cent) of 42 patients who underwent a primary operation for Crohn’s disease had received treatment with biologicals within 2 months before the procedure during the first half of the study, compared with 40 (43 per cent) of 92 during the second half (P < 0·001).
Postoperative outcome Postoperative complications occurred in 92 patients (30·9 per cent) (Table 3). Of these, 23 (7·7 per cent) had anastomotic complications and 44 (14·8 per cent) other infectious complications. The use of biologicals within 2 months before an operation with anastomosis or strictureplasty did not alter the rate or severity of complications. Serious complications (Clavien–Dindo grade III or higher) occurred in 32 patients (10·7 per cent). Some 22 patients (7·4 per cent) were reoperated and 2014 BJS Society Ltd Published by John Wiley & Sons Ltd
Median (range) postop. hospital stay (days) Any postop. complication Anastomotic postop. complication Infectious postop. complication (excluding anastomotic complications) Other postop. complication Need for repeat surgery Need for radiology-guided drainage Clavien–Dindo complication grade 0 I II III IIIA IIIB IV IVA IVB V ≥ III
7 (2–50)
Control group (n = 187) 6 (2–101)
P† 0·383‡
38 (34·2) 8 (7·2)
54 (28·9) 15 (8·0)
0·402 0·976
18 (16·2)
26 (13·9)
0·586
12 (10·8) 9 (8·1) 4 (3·6)
13 (7·0) 13 (7·0) 7 (3·7)
0·246 0·712 0·951§ 0·903§
56 (50·5) 20 (18·0) 23 (20·7) 11 (9·9) 3 (2·7) 8 (7·2) 1 (0·9) 1 (0·9) 0 (0) 0 (0) 12 (10·8)
101 (54·0) 35 (18·7) 31 (16·6) 18 (9·6) 6 (3·2) 12 (6·4) 1 (0·5) 1 (0·5) 0 (0) 1 (0·5) 20 (10·7)
0·975
Values in parentheses are percentages. Patients in the biological therapy group had received biologicals within 2 months of surgery, whereas those in the control group had biologicals withheld for more than 2 months before surgery or received them after surgery. †χ2 test, except ‡Mann–Whitney U test and §Fisher’s exact test.
11 (3·7 per cent) had radiological drainage. One patient (0·3 per cent) died. The median postoperative hospital stay was 7 (2–101) days and did not differ between the two groups (Table 3). The use of biologicals did not influence the length of stay among patients with an anastomotic complication: median 15 (7–50) versus 27 (7–101) days for treatment and control groups respectively (P = 0·103). In patients with a severe complication (at least Clavien–Dindo grade III), the median length of stay was 14 (7–50) and 26 (5–101) days respectively (P = 0·198). In univariable logistic regression analysis, extensive adhesiolysis was associated with an increased risk of anastomotic complications (odds ratio (OR) 3·29, 95 per cent confidence interval 1·34 to 8·05; P = 0·009) (Table 4). Proximal small bowel disease (Montreal classification L4) was associated with an increased risk of any complication (OR 3·03, 1·09 to 8·41; P = 0·033), anastomotic complication (OR 4·61, 1·36 to 15·69; P = 0·014) and infectious complication (OR 2·88, 1·03 to 8·05; P = 0·044). In the multivariable www.bjs.co.uk
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Univariable regression analysis of risk of postoperative complications after surgery for Crohn’s disease among patients treated with biological therapy
Table 4
Any complication
Biologicals within 2 months of surgery No Yes Steroids No Yes Immunomodulation No Yes Extensive adhesiolysis No Yes Montreal L4 No Yes
Anastomotic complication
Infectious complication
Odds ratio
P
Odds ratio
P
Odds ratio
P
1·00 1·33 (0·81, 2·20)
0·260
1·00 0·89 (0·37, 2·17)
0·799
1·00 1·09 (0·62, 1·91)
0·765
1·00 1·17 (0·59, 2·30)
0·655
1·00 1·68 (0·59, 4·79)
0·331
1·00 0·87 (0·40, 1·91)
0·727
1·00 1·14 (0·69, 1·88)
0·611
1·00 0·93 (0·40, 2·21)
0·877
1·00 1·09 (0·63, 1·90)
0·756
1·00 2·23 (1·22, 4·08)
0·009
1·00 3·29 (1·34, 8·05)
0·009
1·00 1·59 (0·82, 3·09)
0·167
1·00 3·03 (1·09, 8·41)
0·033
1·00 4·61 (1·36, 15·69)
0·014
1·00 2·88 (1·03, 8·05)
0·044
Values in parentheses are 95 per cent confidence intervals.
regression analysis, extensive adhesiolysis (OR 4·16, 1·53 to 11·31; P = 0·005) and L4 disease (OR 5·36, 1·41 to 20·47; P = 0·014) were predictive of anastomotic complications. Discussion
In present study, the use of anti-TNF drugs within 2 months before surgery for Crohn’s disease with intestinal anastomosis did not increase the risk of anastomotic, infectious or other complications. It was shown previously23 that long-term corticosteroid use was associated with adverse outcomes, and that preoperative intra-abdominal abscesses as well as steroid use were associated with severe complications. Anti-TNF agents can be considered to have a steroid-sparing effect and so the adverse outcomes associated with long-term medication with corticosteroid can be mitigated. In one study7 , treatment with infliximab within 8 weeks before surgery or 4 weeks after operation was not associated with an increase in septic or anastomotic complications. However, this analysis included 70 patients who had no anastomosis at the time of surgery. A more recent study24 concluded that preoperative infliximab therapy was associated with an increased risk of infectious complications, with an OR of 1·5. A systematic review and meta-analysis25 , focusing on a slightly different group of studies, concluded that there was no increased risk of complications associated with use of biologicals. A similar meta-analysis26 studied the influence of biologicals in surgery for ulcerative colitis, and showed an increase in short-term complications. 2014 BJS Society Ltd Published by John Wiley & Sons Ltd
Appau and colleagues10 studied 60 patients with Crohn’s disease undergoing ileocolic resections who were taking infliximab within 3 months before surgery. Two control groups, one from the preinfliximab era and the other consisting of patients not taking infliximab, were compared with the infliximab group. The group receiving infliximab had a higher rate of septic complications, intra-abdominal sepsis and readmission, although treatment with steroids and diverting stoma rates differed between the groups. One investigation12 showed no difference in complication rate between patients with Crohn’s disease treated with biologicals and patients receiving no drugs or those treated with immunomodulators. The groups, however, differed markedly, with a high stoma rate in the infliximab group. A recent large study from Canada17 , with matched control patients, showed no difference in short-term outcomes between patients who received biologicals within 180 days of surgery and those who did not. The study, however, included many patients not having intestinal anastomoses and it is unclear whether the groups were matched for anastomoses. The strength of the present study is that it included only patients treated with biologicals having surgery for Crohn’s disease with intestinal resection and anastomosis, providing a more homogeneous group than in previous investigations. The Clavien–Dindo classification was used for reporting postoperative complications, and anastomotic and infectious complications were reported separately to ensure a robust data set. A possible weakness of the study was the grouping of patients based on treatment with biologicals within www.bjs.co.uk
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2 months before surgery. In many other studies10 – 14,27,28 the cut-off time was at least 3 months before surgery. For patients with rheumatoid arthritis, before joint surgery it has been advised to stop therapy with biologicals for a time period equivalent to 3–5 times the half-life of the antibody29 . This interval would be approximately 60 days for adalimumab and 45 days for infliximab18 . In the present investigation a cut-off time of 2 months for preoperative biologicals was used, with a smaller number of patients in the treatment group but a potentially greater effect of the biological therapy on outcomes. One investigation17 analysed complication rates in patients with Crohn’s disease treated with biologicals for up to 180 days before surgery. No differences in complication rates were found between patients taking biologicals less than 14 days before operation compared with those receiving them 15–30 or 31–180 days before surgery. In this study, treatment with biologicals within 2 months of surgery for Crohn’s disease with intestinal anastomosis was not associated with an increased risk of complications. Acknowledgements
The authors thank the following for their contributions to the manuscript: V. Robles (Department of Gastroenterology, University Hospital of Valle de Hebron, Barcelona, Spain), and D. Humes and J. F. Abercrombie (Department of Surgery, Nottingham University Hospitals, Nottingham, UK). Disclosure: The authors declare no conflict of interest. References 1 Yamamoto T, Allan RN, Keighley MR. Risk factors for intra-abdominal sepsis after surgery in Crohn’s disease. Dis Colon Rectum 2000; 43: 1141–1145. 2 Danese S, Colombel JF, Reinisch W, Rutgeerts PJ. Review article: infliximab for Crohn’s disease treatment – shifting therapeutic strategies after 10 years of clinical experience. Aliment Pharmacol Ther 2011; 33: 857–869. 3 Hanauer S, Feagan B, Lichtenstein G, Mayer L, Schreiber S, Colombel J et al.; ACCENT I Study Group. Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet 2002; 359: 1541–1549. 4 Jones DW, Finlayson SR. Trends in surgery for Crohn’s disease in the era of infliximab. Ann Surg 2010; 252: 307–312. 5 Hansen RA, Gartlehner G, Powell GE, Sandler RS. Serious adverse events with infliximab: analysis of spontaneously reported adverse events. Clin Gastroenterol Hepatol 2007; 5: 729–735. 6 de Silva S, Devlin S, Panaccione R. Optimizing the safety of biologic therapy for IBD. Nat Rev Gastroenterol Hepatol 2010; 7: 93–101. 2014 BJS Society Ltd Published by John Wiley & Sons Ltd
7 Colombel JF, Loftus EV Jr, Tremaine WJ, Pemberton JH, Wolff BG, Young-Fadok T et al. Early postoperative complications are not increased in patients with Crohn’s disease treated perioperatively with infliximab or immunosuppressive therapy. Am J Gastroenterol 2004; 99: 878–883. 8 Tay GS, Binion DG, Eastwood D, Otterson MF. Multivariate analysis suggests improved perioperative outcome in Crohn’s disease patients receiving immunomodulator therapy after segmental resection and/or strictureplasty. Surgery 2003; 134: 565–572. 9 Marchal L, D’Haens G, Van Assche G, Vermeire S, Noman M, Ferrante M et al. The risk of post-operative complications associated with infliximab therapy for Crohn’s disease: a controlled cohort study. Aliment Pharmacol Ther 2004; 19: 749–754. 10 Appau KA, Fazio VW, Shen B, Church JM, Lashner B, Remzi F et al. Use of infliximab within 3 months of ileocolonic resection is associated with adverse postoperative outcomes in Crohn’s patients. J Gastrointest Surg 2008; 12: 1738–1744. 11 Kunitake H, Hodin R, Shellito PC, Sands BE, Korzenik J, Bordeianou L. Perioperative treatment with infliximab in patients with Crohn’s disease and ulcerative colitis is not associated with an increased rate of postoperative complications. J Gastrointest Surg 2008; 12: 1730–1736. 12 Canedo J, Lee SH, Pinto R, Murad-Regadas S, Rosen L, Wexner SD. Surgical resection in Crohn’s disease: is immunosuppressive medication associated with higher postoperative infection rates? Colorectal Dis 2011; 13: 1294–1298. 13 Kasparek MS, Bruckmeier A, Beigel F, Muller MH, Brand S, Mansmann U et al. Infliximab does not affect postoperative complication rates in Crohn’s patients undergoing abdominal surgery. Inflamm Bowel Dis 2012; 18: 1207–1213. 14 Rizzo G, Armuzzi A, Pugliese D, Verbo A, Papa A, Mattana C et al. Anti-TNF-alpha therapies do not increase early postoperative complications in patients with inflammatory bowel disease. An Italian single-center experience. Int J Colorectal Dis 2011; 26: 1435–1444. 15 Indar AA, Young-Fadok TM, Heppell J, Efron JE. Effect of perioperative immunosuppressive medication on early outcome in Crohn’s disease patients. World J Surg 2009; 33: 1049–1052. 16 Regadas FS, Pinto RA, Murad-Regadas SM, Canedo JA, Leal M, Nogueras JJ et al. Short-term outcome of infliximab and other medications on patients with inflammatory bowel disease undergoing ileostomy reversal. Colorectal Dis 2011; 13: 555–560. 17 Waterman M, Xu W, Dinani A, Steinhart AH, Croitoru K, Nguyen GC et al. Preoperative biological therapy and short-term outcomes of abdominal surgery in patients with inflammatory bowel disease. Gut 2013; 62: 387–394. 18 Tracey D, Klareskog L, Sasso EH, Salfeld JG, Tak PP. Tumor necrosis factor antagonist mechanisms of action: a
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Inflamm Bowel Dis 2012; 18: 2404–2413. 25 Rosenfeld G, Qian H, Bressler B. The risks of post-operative complications following pre-operative infliximab therapy for Crohn’s disease in patients undergoing abdominal surgery: a systematic review and meta-analysis. J Crohns Colitis 2013; 7: 868–877. 26 Yang Z, Wu Q, Wu K, Fan D. Meta-analysis: pre-operative infliximab treatment and short-term post-operative complications in patients with ulcerative colitis. Aliment Pharmacol Ther 2010; 31: 486–492. 27 Selvasekar CR, Cima RR, Larson DW, Dozois EJ, Harrington JR, Harmsen WS et al. Effect of infliximab on short-term complications in patients undergoing operation for chronic ulcerative colitis. J Am Coll Surg 2007; 204: 956–962. 28 Ferrante M, D’Hoore A, Vermeire S, Declerck S, Noman M, Van Assche G et al. Corticosteroids but not infliximab increase short-term postoperative infectious complications in patients with ulcerative colitis. Inflamm Bowel Dis 2009; 15: 1062–1070. 29 Ding T, Ledingham J, Luqmani R, Westlake S, Hyrich K, Lunt M et al.; Standards, Audit and Guidelines Working Group of BSR Clinical Affairs Committee; BHPR. BSR and BHPR rheumatoid arthritis guidelines on safety of anti-TNF therapies. Rheumatology (Oxford) 2010; 49: 2217–2219.
Supporting information
Additional supporting information may be found in the online version of this article: Table S1 Clavien–Dindo classification (Word document) Table S2 Distribution of patients with Crohn’s disease undergoing surgery, abdominal surgery for Crohn’s disease with anastomosis and/or strictureplasty, and treatment with biologicals by hospital, 2005–2011 (Word document)
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Complications in surgery for Crohn’s disease after preoperative antitumour necrosis factor therapy P. Myrelid1,2 , M. Marti-Gallostra2,3 , S. Ashraf2 , M. L. Sunde4 , M. Tholin1 , T. Øresland4 , R. E. Lovegrove2 , A. Tøttrup5 , D. W. Kjær5 and B. D. George2 1
¨ Division of Surgery, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linkoping University, and Department of ¨ ¨ ¨ Surgery, County Council of Osterg otland, Linkoping, Sweden, 2 Department of Surgery, Unit of Colorectal Surgery, Oxford University Hospitals, Oxford, UK, 3 Department of Surgery, University Hospital of Valle de Hebron, Barcelona, Spain, 4 Clinic for Surgical Sciences, Faculty of Medicine, University of Oslo, Oslo, and Department of Gastrointestinal Surgery, Akershus University Hospital, Lorenskog, Norway, and 5 Surgical Gastroenterological Department P, Aarhus University Hospital, Aarhus, Denmark ¨ ¨ Correspondence to: Dr P. Myrelid, Department of Surgery, Linkoping University Hospital, S-58185 Linkoping, Sweden (e-mail: [email protected])
Background: The use of biological therapy (biologicals) is established in the treatment of Crohn’s
disease. This study aimed to determine whether preoperative treatment with biologicals is associated with an increased rate of complications following surgery for Crohn’s disease with intestinal anastomosis. Methods: All patients receiving biologicals and undergoing abdominal surgery with anastomosis or strictureplasty were identified at six tertiary referral centres. Demographic data, and preoperative, operative and postoperative details were registered. Patients who were treated with biologicals within 2 months before surgery were compared with a control group who were not. Postoperative complications were classified according to anastomotic, infectious or other complications, and graded according to the Clavien–Dindo classification. Results: Some 111 patients treated with biologicals within 2 months before surgery were compared with 187 patients in the control group. The groups were well matched. There were no differences between the treatment and control groups in the rate of complications of any type (34·2 versus 28·9 per cent respectively; P = 0·402), anastomotic complications (7·2 versus 8·0 per cent; P = 0·976) and nonanastomotic infectious complications (16·2 versus 13·9 per cent; P = 0·586). In univariable regression analysis, biologicals were not associated with an increased risk of any complication (odds ratio (OR) 1·33, 95 per cent confidence interval 0·81 to 2·20), anastomotic complication (OR 0·89, 0·37 to 2·17) or infectious complication (OR 1·09, 0·62 to 1·91). Conclusion: Treatment with biologicals within 2 months of surgery for Crohn’s disease with intestinal anastomosis was not associated with an increased risk of complications. Presented in part to the 2013 meeting of the European Crohn’s and Colitis Organization, Vienna, Austria, February 2013; published in abstract form as J Crohns Colitis 2013; 7(Suppl 1) S193–S194 Paper accepted 20 December 2013 Published online 26 February 2014 in Wiley Online Library (www.bjs.co.uk). DOI: 10.1002/bjs.9439
Introduction
Surgery for Crohn’s disease with intestinal anastomoses is associated with a high morbidity rate1 . The advent of antitumour necrosis factor (TNF) therapies such as infliximab and adalimumab has had a major impact on the treatment of patients with Crohn’s disease, with improvements in quality of life and a reduced need for hospitalization and possibly surgery2 – 4 . However, biological therapy (treatment with biologicals) is associated with an increased risk of infection, especially when used 2014 BJS Society Ltd Published by John Wiley & Sons Ltd
in combination with steroids5,6 . Biological therapy has raised concern among surgeons regarding the risk of postoperative complications and, in particular, the risk of anastomotic leakage. Studies addressing these concerns have conflicting results7 – 17 . The aim of this study was to assess the impact of antiTNF therapy on postoperative complications in patients undergoing surgery for Crohn’s disease with intestinal anastomoses without a diverting stoma. The study included patients who had ever been treated with biological therapy. The treatment group comprised patients who received BJS 2014; 101: 539–545
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biologicals within 2 months before surgery, who were compared with a control group of patients who did not. Methods
All patients undergoing surgery for Crohn’s disease involving one or more intestinal anastomoses and who received anti-TNF therapy either before or after surgery were identified from databases. Patients undergoing anastomoses protected by a proximal stoma were excluded. Patients were categorized into two groups: those in the treatment group received anti-TNF therapy within 2 months of surgery, whereas patients in the control group were treated with anti-TNF therapy, but had discontinued treatment more than 2 months before operation or started treatment at least 6 weeks after surgery. The cut-off period of 2 months was based on the half-life of the injected antibodies in vivo18 . Preoperative data recorded included: age and sex, body mass index, smoking history, duration of Crohn’s disease, Montreal classification (classification according to age at diagnosis as well as location and behaviour of Crohn’s disease)19 , indication for and urgency of surgery. Medical therapy at the time of surgery was recorded. Patients were considered to have ongoing treatment with steroids or immunomodulators if they received these drugs within 2 weeks or 1 month respectively before the surgical procedure1,20 . Operative procedures including surgical approach (open or laparoscopic), need for adhesiolysis and the method of anastomosis were recorded. Postoperative complications were recorded using the Clavien–Dindo21 classification. An anastomotic complication was recorded after an overt clinical leak, a leak found at repeat surgery or if leakage was verified radiologically. The primary endpoint of the study was the development of anastomotic complications within 30 days or during the postoperative hospital stay. Secondary endpoints were: infectious complications, other types of complication, need for intervention (radiological or surgical), length of hospital stay and severity of complications according to the Clavien–Dindo classification (Table S1, supporting information)21 . When multiple complications or interventions were present, only the one deemed most severe was included in the analysis. The Montreal classification19,21 of Crohn’s disease was used, which has three components: age at onset of disease (A), disease location (L) and behaviour of the disease (B). These components are further subclassified. Age of onset at 16 years or younger is denoted A1, age 17–40 years as A2 and age more than 40 years as A3. Location is classified as terminal ileal (L1), colonic (L2), ileocolonic 2014 BJS Society Ltd Published by John Wiley & Sons Ltd
(L3) or upper gastrointestinal (L4); the latter is defined as disease proximal to the terminal ileum. The L4 location may be used in combination with the other locations to classify more complex disease patterns. The disease behaviour is classified as non-stricturing, non-penetrating (B1), stricturing (B2) or penetrating (B3). The presence of perianal disease is denoted by a ‘P’ after the disease behaviour classification.
Statistical analysis Continuous data are presented as median (range) unless stated otherwise. The χ2 test, Fisher’s exact test, Mann–Whitney U test and univariable logistic regression were used as appropriate for statistical analysis. Factors previously shown to influence the risk of complications as well as factors found to be predictive on univariable analysis were entered into a multivariable logistic regression analysis. All P values were two-tailed and P < 0·050 was considered significant. SPSS version 15 (IBM, Armonk, New York, USA) was used for all statistical analyses. Results
During the study period 298 operations for Crohn’s disease with intestinal anastomoses without a covering stoma were undertaken in patients who received anti-TNF therapy. The proportion of all surgical patients who received biologicals differed slightly between centres (Table S2, supporting information), probably reflecting differing thresholds for use of anti-TNF therapy. Some 111 patients received anti-TNF within 2 months of surgery, whereas 187 did not. Most patients (229, 76·8 per cent) were diagnosed between the age of 17 and 40 years, 183 (61·4 per cent) had ileal or ileocaecal disease, and 74 (24·8 per cent) had ileocolonic disease (Table 1). Some 171 patients (57·4 per cent) had stricturing and 105 (35·2 per cent) penetrating, disease. Perianal disease was apparent before surgery in 79 patients (26·5 per cent) and 16 (5·4 per cent) had Crohn’s disease in the upper gastrointestinal tract as well. Some 164 patients (55·0 per cent) had undergone surgery for Crohn’s disease previously, and 27 (9·1 per cent) had a stoma before the index procedure. Seventy-one patients (23·8 per cent) were still smoking at the time of surgery. The most common indication for surgery was stenosis of an inflamed bowel segment or a previous anastomosis (183 patients, 61·4 per cent), followed by penetrating disease; bowel reconstruction and inflammation refractory to drug www.bjs.co.uk
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Characteristics of patients with Crohn’s disease ever treated with biological therapy and operated on with anastomosis or strictureplasty
Table 1
Median (range) age at surgery (years) Sex ratio (F : M) Montreal classification Age (years) A1 (≤ 16) A2 (17–40) A3 (> 40) Location L1 (ileal) L2 (colonic) L3 (ileocolonic) L4 (upper gastrointestinal) Behaviour B1 (inflammatory) B2 (stricturing) B3 (penetrating) Perianal disease (P) Previous abdominal operations for Crohn’s disease 0 1–2 ≥3 Previous permanent stoma (distal to later anastomosis/strictureplasty) Type of biological therapy* Infliximab Adalimumab Other medications Steroids Immunomodulation Azathioprine/6-mercaptopurine Methotrexate Mycophenolate mofetil Smoker Mean(s.d.) BMI (kg/m2 )† ASA fitness grade I II III Unknown
Biological therapy group (n = 111)
Control group (n = 187)
P‡
35·6 (12–82) 60 : 51
36·6 (12–76) 119 : 68
0·722§ 0·103
18 (16·2) 83 (74·8) 10 (9·0)
25 (13·4) 146 (78·1) 16 (8·6)
65 (58·6) 12 (10·8) 34 (30·6) 4 (3·6)
118 (63·1) 29 (15·5) 40 (21·4) 12 (6·4)
6 (5·4) 64 (57·7) 41 (36·9) 32 (28·8)
16 (8·6) 107 (57·2) 64 (34·2) 47 (25·1)
45 (40·5) 39 (35·1) 27 (24·3) 14 (12·6)
89 (47·6) 70 (37·4) 28 (15·0) 13 (7·0)
40 (36·0) 71 (64·0)
117 (62·6) 70 (37·4)
16 (14·4) 63 (56·8) 57 (51·4) 5 (4·5) 0 (0) 24 (21·6) 22·6(4·5)
25 (13·4) 110 (58·8) 98 (52·4) 8 (4·3) 4 (2·1) 47 (25·1) 23·4(4·0)
33 (29·7) 65 (58·6) 4 (3·6) 9 (8·1)
76 (40·6) 87 (46·5) 7 (3·7) 17 (9·1)
0·776
0·154
0·299 0·582
0·485 0·124
0·151 < 0·001
0·937 0·727
0·492 0·203§ 0·121
Values in parentheses are percentages. Patients in the biological therapy group had received biologicals within 2 months of surgery, whereas those in the control group had biologicals withheld for more than 2 months before surgery or received them after surgery. *Biological used closest in time to surgery (before and/or after operation). †Data missing for three patients. BMI, body mass index; ASA, American Society of Anesthesiologists. ‡χ2 test, except §Mann–Whitney U test.
treatment was less common (Table 2). The majority of the procedures (255, 85·6 per cent) were elective, and only 11 (3·7 per cent) were performed as an emergency. Even though laparoscopic surgery is increasingly being used for inflammatory bowel disease, open surgery was more frequent in this cohort (241 patients, 80·9 per cent). Intestinal resection was performed in 264 patients (88·6 per cent); ileocolonic resections were the most common, followed by colonic and small bowel resections. The use of strictureplasties is well described in Crohn’s disease22 . Strictureplasty was carried out together with a resection in 20 patients (6·7 per cent), whereas it was the only
procedure in five (1·7 per cent). There were no differences in preoperative or surgical parameters between the two groups (Tables 1 and 2). An increasing number of patients received biologicals during the study period, from 99 (19·5 per cent) of 508 during the first 3·5 years to 199 (45·9 per cent) of 434 during the last 3·5 years (P < 0·001). A change in favour of the use of adalimumab was seen during the second half of the study, increasing from 28 (28 per cent) of 99 to 113 (56·8 per cent) of 199, whereas 71 patients (72 per cent) were treated with infliximab during the first interval and 86 (43·2 per cent) during the second (P < 0·001). Only
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Characteristics of all abdominal operations (with anastomosis and/or strictureplasty) for Crohn’s disease, 2005–2011, in patients ever treated with biological therapy
Postoperative outcome (within 30 days) after abdominal operation
Table 2
Biological therapy group (n = 111) Surgical indication Inflammation Stricture Abscess/fistula Dysplasia/cancer Reconstruction Growth retardation Iatrogenic perforation* Urgency of surgery Elective Urgent (within 1 week) Emergency (within 24 h) Procedure performed Small bowel resection Ileocolic resection Colonic resection Stoma closure Strictureplasty alone Including strictureplasty Including severe adhesiolysis Surgical approach Open Laparoscopically assisted Type of anastomosis Handsewn Stapled
Control group (n = 187)
Table 3
Biological therapy group (n = 111) P†
0·831‡ 7 (6·3) 69 (62·2) 22 (19·8) 0 (0) 13 (11·7) 0 (0) 0 (0)
15 (8·0) 114 (61·0) 39 (20·9) 1 (0·5) 16 (8·6) 1 (0·5) 1 (0·5) 0·570‡
98 (88·3) 11 (9·9) 2 (1·8)
157 (84·0) 21 (11·2) 9 (4·8)
15 (13·5) 68 (61·3) 13 (11·7) 11 (9·9) 4 (3·6) 8 (7·2) 21 (18·9)
21 (11·2) 117 (62·6) 30 (16·0) 18 (9·6) 1 (0·5) 12 (6·4) 33 (17·6)
84 (75·7) 27 (24·3)
157 (84·0) 30 (16·0)
0·273‡
0·967 0·905 0·109
0·508 43 (38·7) 68 (61·3)
64 (34·2) 123 (65·8)
Values in parentheses are percentages. Patients in the biological therapy group had received biologicals within 2 months of surgery, whereas those in the control group had biologicals withheld for more than 2 months before surgery or received them after surgery. *Iatrogenic perforation during endoscopic dilatation of stricture. †χ2 test, except ‡Fisher’s exact test.
five (12 per cent) of 42 patients who underwent a primary operation for Crohn’s disease had received treatment with biologicals within 2 months before the procedure during the first half of the study, compared with 40 (43 per cent) of 92 during the second half (P < 0·001).
Postoperative outcome Postoperative complications occurred in 92 patients (30·9 per cent) (Table 3). Of these, 23 (7·7 per cent) had anastomotic complications and 44 (14·8 per cent) other infectious complications. The use of biologicals within 2 months before an operation with anastomosis or strictureplasty did not alter the rate or severity of complications. Serious complications (Clavien–Dindo grade III or higher) occurred in 32 patients (10·7 per cent). Some 22 patients (7·4 per cent) were reoperated and 2014 BJS Society Ltd Published by John Wiley & Sons Ltd
Median (range) postop. hospital stay (days) Any postop. complication Anastomotic postop. complication Infectious postop. complication (excluding anastomotic complications) Other postop. complication Need for repeat surgery Need for radiology-guided drainage Clavien–Dindo complication grade 0 I II III IIIA IIIB IV IVA IVB V ≥ III
7 (2–50)
Control group (n = 187) 6 (2–101)
P† 0·383‡
38 (34·2) 8 (7·2)
54 (28·9) 15 (8·0)
0·402 0·976
18 (16·2)
26 (13·9)
0·586
12 (10·8) 9 (8·1) 4 (3·6)
13 (7·0) 13 (7·0) 7 (3·7)
0·246 0·712 0·951§ 0·903§
56 (50·5) 20 (18·0) 23 (20·7) 11 (9·9) 3 (2·7) 8 (7·2) 1 (0·9) 1 (0·9) 0 (0) 0 (0) 12 (10·8)
101 (54·0) 35 (18·7) 31 (16·6) 18 (9·6) 6 (3·2) 12 (6·4) 1 (0·5) 1 (0·5) 0 (0) 1 (0·5) 20 (10·7)
0·975
Values in parentheses are percentages. Patients in the biological therapy group had received biologicals within 2 months of surgery, whereas those in the control group had biologicals withheld for more than 2 months before surgery or received them after surgery. †χ2 test, except ‡Mann–Whitney U test and §Fisher’s exact test.
11 (3·7 per cent) had radiological drainage. One patient (0·3 per cent) died. The median postoperative hospital stay was 7 (2–101) days and did not differ between the two groups (Table 3). The use of biologicals did not influence the length of stay among patients with an anastomotic complication: median 15 (7–50) versus 27 (7–101) days for treatment and control groups respectively (P = 0·103). In patients with a severe complication (at least Clavien–Dindo grade III), the median length of stay was 14 (7–50) and 26 (5–101) days respectively (P = 0·198). In univariable logistic regression analysis, extensive adhesiolysis was associated with an increased risk of anastomotic complications (odds ratio (OR) 3·29, 95 per cent confidence interval 1·34 to 8·05; P = 0·009) (Table 4). Proximal small bowel disease (Montreal classification L4) was associated with an increased risk of any complication (OR 3·03, 1·09 to 8·41; P = 0·033), anastomotic complication (OR 4·61, 1·36 to 15·69; P = 0·014) and infectious complication (OR 2·88, 1·03 to 8·05; P = 0·044). In the multivariable www.bjs.co.uk
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Univariable regression analysis of risk of postoperative complications after surgery for Crohn’s disease among patients treated with biological therapy
Table 4
Any complication
Biologicals within 2 months of surgery No Yes Steroids No Yes Immunomodulation No Yes Extensive adhesiolysis No Yes Montreal L4 No Yes
Anastomotic complication
Infectious complication
Odds ratio
P
Odds ratio
P
Odds ratio
P
1·00 1·33 (0·81, 2·20)
0·260
1·00 0·89 (0·37, 2·17)
0·799
1·00 1·09 (0·62, 1·91)
0·765
1·00 1·17 (0·59, 2·30)
0·655
1·00 1·68 (0·59, 4·79)
0·331
1·00 0·87 (0·40, 1·91)
0·727
1·00 1·14 (0·69, 1·88)
0·611
1·00 0·93 (0·40, 2·21)
0·877
1·00 1·09 (0·63, 1·90)
0·756
1·00 2·23 (1·22, 4·08)
0·009
1·00 3·29 (1·34, 8·05)
0·009
1·00 1·59 (0·82, 3·09)
0·167
1·00 3·03 (1·09, 8·41)
0·033
1·00 4·61 (1·36, 15·69)
0·014
1·00 2·88 (1·03, 8·05)
0·044
Values in parentheses are 95 per cent confidence intervals.
regression analysis, extensive adhesiolysis (OR 4·16, 1·53 to 11·31; P = 0·005) and L4 disease (OR 5·36, 1·41 to 20·47; P = 0·014) were predictive of anastomotic complications. Discussion
In present study, the use of anti-TNF drugs within 2 months before surgery for Crohn’s disease with intestinal anastomosis did not increase the risk of anastomotic, infectious or other complications. It was shown previously23 that long-term corticosteroid use was associated with adverse outcomes, and that preoperative intra-abdominal abscesses as well as steroid use were associated with severe complications. Anti-TNF agents can be considered to have a steroid-sparing effect and so the adverse outcomes associated with long-term medication with corticosteroid can be mitigated. In one study7 , treatment with infliximab within 8 weeks before surgery or 4 weeks after operation was not associated with an increase in septic or anastomotic complications. However, this analysis included 70 patients who had no anastomosis at the time of surgery. A more recent study24 concluded that preoperative infliximab therapy was associated with an increased risk of infectious complications, with an OR of 1·5. A systematic review and meta-analysis25 , focusing on a slightly different group of studies, concluded that there was no increased risk of complications associated with use of biologicals. A similar meta-analysis26 studied the influence of biologicals in surgery for ulcerative colitis, and showed an increase in short-term complications. 2014 BJS Society Ltd Published by John Wiley & Sons Ltd
Appau and colleagues10 studied 60 patients with Crohn’s disease undergoing ileocolic resections who were taking infliximab within 3 months before surgery. Two control groups, one from the preinfliximab era and the other consisting of patients not taking infliximab, were compared with the infliximab group. The group receiving infliximab had a higher rate of septic complications, intra-abdominal sepsis and readmission, although treatment with steroids and diverting stoma rates differed between the groups. One investigation12 showed no difference in complication rate between patients with Crohn’s disease treated with biologicals and patients receiving no drugs or those treated with immunomodulators. The groups, however, differed markedly, with a high stoma rate in the infliximab group. A recent large study from Canada17 , with matched control patients, showed no difference in short-term outcomes between patients who received biologicals within 180 days of surgery and those who did not. The study, however, included many patients not having intestinal anastomoses and it is unclear whether the groups were matched for anastomoses. The strength of the present study is that it included only patients treated with biologicals having surgery for Crohn’s disease with intestinal resection and anastomosis, providing a more homogeneous group than in previous investigations. The Clavien–Dindo classification was used for reporting postoperative complications, and anastomotic and infectious complications were reported separately to ensure a robust data set. A possible weakness of the study was the grouping of patients based on treatment with biologicals within www.bjs.co.uk
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2 months before surgery. In many other studies10 – 14,27,28 the cut-off time was at least 3 months before surgery. For patients with rheumatoid arthritis, before joint surgery it has been advised to stop therapy with biologicals for a time period equivalent to 3–5 times the half-life of the antibody29 . This interval would be approximately 60 days for adalimumab and 45 days for infliximab18 . In the present investigation a cut-off time of 2 months for preoperative biologicals was used, with a smaller number of patients in the treatment group but a potentially greater effect of the biological therapy on outcomes. One investigation17 analysed complication rates in patients with Crohn’s disease treated with biologicals for up to 180 days before surgery. No differences in complication rates were found between patients taking biologicals less than 14 days before operation compared with those receiving them 15–30 or 31–180 days before surgery. In this study, treatment with biologicals within 2 months of surgery for Crohn’s disease with intestinal anastomosis was not associated with an increased risk of complications. Acknowledgements
The authors thank the following for their contributions to the manuscript: V. Robles (Department of Gastroenterology, University Hospital of Valle de Hebron, Barcelona, Spain), and D. Humes and J. F. Abercrombie (Department of Surgery, Nottingham University Hospitals, Nottingham, UK). Disclosure: The authors declare no conflict of interest. References 1 Yamamoto T, Allan RN, Keighley MR. Risk factors for intra-abdominal sepsis after surgery in Crohn’s disease. Dis Colon Rectum 2000; 43: 1141–1145. 2 Danese S, Colombel JF, Reinisch W, Rutgeerts PJ. Review article: infliximab for Crohn’s disease treatment – shifting therapeutic strategies after 10 years of clinical experience. Aliment Pharmacol Ther 2011; 33: 857–869. 3 Hanauer S, Feagan B, Lichtenstein G, Mayer L, Schreiber S, Colombel J et al.; ACCENT I Study Group. Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet 2002; 359: 1541–1549. 4 Jones DW, Finlayson SR. Trends in surgery for Crohn’s disease in the era of infliximab. Ann Surg 2010; 252: 307–312. 5 Hansen RA, Gartlehner G, Powell GE, Sandler RS. Serious adverse events with infliximab: analysis of spontaneously reported adverse events. Clin Gastroenterol Hepatol 2007; 5: 729–735. 6 de Silva S, Devlin S, Panaccione R. Optimizing the safety of biologic therapy for IBD. Nat Rev Gastroenterol Hepatol 2010; 7: 93–101. 2014 BJS Society Ltd Published by John Wiley & Sons Ltd
7 Colombel JF, Loftus EV Jr, Tremaine WJ, Pemberton JH, Wolff BG, Young-Fadok T et al. Early postoperative complications are not increased in patients with Crohn’s disease treated perioperatively with infliximab or immunosuppressive therapy. Am J Gastroenterol 2004; 99: 878–883. 8 Tay GS, Binion DG, Eastwood D, Otterson MF. Multivariate analysis suggests improved perioperative outcome in Crohn’s disease patients receiving immunomodulator therapy after segmental resection and/or strictureplasty. Surgery 2003; 134: 565–572. 9 Marchal L, D’Haens G, Van Assche G, Vermeire S, Noman M, Ferrante M et al. The risk of post-operative complications associated with infliximab therapy for Crohn’s disease: a controlled cohort study. Aliment Pharmacol Ther 2004; 19: 749–754. 10 Appau KA, Fazio VW, Shen B, Church JM, Lashner B, Remzi F et al. Use of infliximab within 3 months of ileocolonic resection is associated with adverse postoperative outcomes in Crohn’s patients. J Gastrointest Surg 2008; 12: 1738–1744. 11 Kunitake H, Hodin R, Shellito PC, Sands BE, Korzenik J, Bordeianou L. Perioperative treatment with infliximab in patients with Crohn’s disease and ulcerative colitis is not associated with an increased rate of postoperative complications. J Gastrointest Surg 2008; 12: 1730–1736. 12 Canedo J, Lee SH, Pinto R, Murad-Regadas S, Rosen L, Wexner SD. Surgical resection in Crohn’s disease: is immunosuppressive medication associated with higher postoperative infection rates? Colorectal Dis 2011; 13: 1294–1298. 13 Kasparek MS, Bruckmeier A, Beigel F, Muller MH, Brand S, Mansmann U et al. Infliximab does not affect postoperative complication rates in Crohn’s patients undergoing abdominal surgery. Inflamm Bowel Dis 2012; 18: 1207–1213. 14 Rizzo G, Armuzzi A, Pugliese D, Verbo A, Papa A, Mattana C et al. Anti-TNF-alpha therapies do not increase early postoperative complications in patients with inflammatory bowel disease. An Italian single-center experience. Int J Colorectal Dis 2011; 26: 1435–1444. 15 Indar AA, Young-Fadok TM, Heppell J, Efron JE. Effect of perioperative immunosuppressive medication on early outcome in Crohn’s disease patients. World J Surg 2009; 33: 1049–1052. 16 Regadas FS, Pinto RA, Murad-Regadas SM, Canedo JA, Leal M, Nogueras JJ et al. Short-term outcome of infliximab and other medications on patients with inflammatory bowel disease undergoing ileostomy reversal. Colorectal Dis 2011; 13: 555–560. 17 Waterman M, Xu W, Dinani A, Steinhart AH, Croitoru K, Nguyen GC et al. Preoperative biological therapy and short-term outcomes of abdominal surgery in patients with inflammatory bowel disease. Gut 2013; 62: 387–394. 18 Tracey D, Klareskog L, Sasso EH, Salfeld JG, Tak PP. Tumor necrosis factor antagonist mechanisms of action: a
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Supporting information
Additional supporting information may be found in the online version of this article: Table S1 Clavien–Dindo classification (Word document) Table S2 Distribution of patients with Crohn’s disease undergoing surgery, abdominal surgery for Crohn’s disease with anastomosis and/or strictureplasty, and treatment with biologicals by hospital, 2005–2011 (Word document)
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BJS 2014; 101: 539–545
