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Keywords:

  • postoperative;
  • Crohn's disease;
  • complications;
  • adverse effective;
  • infectious;
  • anti-TNF;
  • infliximab

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
  8. APPENDIX: NOS: CODING MANUAL FOR COHORT STUDIES
  9. Supporting Information

Background:

Anti-tumor necrosis factor (TNF) antibodies are efficacious in patients with Crohn's disease (CD) but the influence of these medications on surgical outcomes in CD patients has been frequently debated. The aim was to evaluate the impact of preoperative treatment with anti-TNF antibodies on postoperative complications in CD patients undergoing abdominal surgery.

Methods:

A systematic review and meta-analysis of comparative cohort studies was performed assessing postoperative complication rates in CD patients who were treated with anti-TNF antibodies within 3 months before surgery versus patients who were not. The primary outcome was overall complication rate within 1 month of surgery. Secondary outcomes included the rate of infectious and noninfectious complications. The quality of studies was assessed based on selection of patients and controls, comparability of the study groups, and assessment of outcomes. Odds ratios (OR) with 95% confidence intervals (CIs) were computed.

Results:

A total of eight studies including 1641 patients were included in our meta-analysis. Preoperative infliximab therapy in CD patients undergoing abdominal surgery was associated with a trend toward an increased rate of total complications (OR 1.72, 95% CI, 0.93–3.19). Anti-TNF treatments were associated with a modestly increased risk of infectious complications (OR 1.50, 95% CI 1.08–2.08), mostly remote from the surgical site (OR 2.07 95% CI 1.30–3.30) and with a trend toward a higher rate of noninfectious complications (OR 2.00, 95% CI 0.89–4.46).

Conclusion:

Preoperative infliximab treatment is associated with an increased risk of postoperative infectious complications, mostly nonlocal. A trend toward an increased risk of noninfectious and overall complications was also observed. (Inflamm Bowel Dis 2012;)

Monoclonal anti-tumor necrosis factor (TNF) antibodies have been employed in the treatment of Crohn's disease (CD), ulcerative colitis (UC), and other inflammatory disorders for over a decade. Infliximab (IFX) therapy has proven to be effective in induction and maintenance of remission in CD patients.1 However, this medication has also been associated with diverse adverse effects such as an increased risk of infections, infusion reactions, and a possible increased incidence of lymphoma.2

Up to two-thirds of all CD patients are expected to require surgery at least once during the course of their disease,3, 4, 6 and ≈40% will undergo two or more surgical interventions. Surgery is an effective method for induction of remission and for treatment of CD complications. However, surgical procedures may be associated with considerable morbidity in CD patients, with a reported complication rate of up to 22%.7–10 Nonetheless, the data concerning the influence of IFX on surgical risk in patients with inflammatory bowel disease (IBD) are equivocal. For patients with UC, a meta-analysis by Yang et al11 pointed to an increased risk of short-term postoperative complications in patients who received preoperative IFX. Although several studies pertaining to complications of preoperative IFX therapy in CD patients have been published, the impact of anti-TNF therapy on the rate of postoperative complications in CD patients remains unclear.

The aim of our study was to evaluate the impact of preoperative use of anti-TNF antibodies on the rate of postoperative complications in patients with CD by conducting a systematic review and meta-analysis of the existing literature.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
  8. APPENDIX: NOS: CODING MANUAL FOR COHORT STUDIES
  9. Supporting Information

Search Strategy

We searched the PubMed database for publications from 1966 to September 2011. The search terms used were “IFX/anti-TNF; postoperative/perioperative complications (or risk), and Crohn's disease/IBD.” Their MeSH terms were crossed. We manually scanned references of all included studies to identify additional relevant publications.

Study Selection

We included prospective or retrospective cohort studies comparing postoperative complication rates (within 30 days) between two groups of patients with CD: those who were treated with anti-TNF antibodies in the preoperative period and those who were not. Studies evaluating the association between other preoperative medications and postoperative complications were included only if they compared between preoperative anti-TNF-treated and untreated patients. Studies were also included only if they incorporated results for both groups (treated and untreated) and were published as a full article. We excluded studies that did not distinguish CD patients from other IBD patients (i.e., studies that included UC and CD patients as one group).

Outcome Measures

The primary outcome assessed was the overall complication rate up to 30 days after surgery. Secondary outcomes were the rate of infectious and noninfectious complications in the above period. Infectious complications were further divided into anastomosis-related and nonrelated complications. Local (anastomosis-related) infectious complications were defined as abscess, anastomotic leak, or fistula.

Data Extraction and Quality of Data Assessment

Two reviewers (U.K., L.K.) independently applied inclusion criteria, selected the studies, and extracted data, outcomes, and quality. Cases of disagreement between the two reviewers were resolved by discussion. Authors of studies were contacted when clarification was needed. The following data were collected: years and location of the studies, year of publication, inclusion criteria for participants in each study, duration of follow-up after surgery, number of participants, demographic characteristics (gender, smoking status, age at operation, duration of disease), disease characteristics (location, phenotype, severity), dose and schedule of anti-TNF drugs, concomitant medications (in particular, steroids and immunomodulators), characteristics of the surgery (location, type: mainly open vs. laparoscopic, kind of procedure, anastomosis, stoma creation), and complications. Complications were divided into infectious (sepsis, wound infection or dehiscence, abscess, perforation, fistula, anastomotic leak, peritonitis, and others) and noninfectious (e.g., intestinal obstruction/prolonged ileus, thromboembolic complications, gastrointestinal bleeding, cardiovascular, respiratory, and renal complications). Length of hospital stay, rate of reoperation, and mortality rates were recorded as well.

Studies were assessed using the Newcastle Ottawa Scale (Supporting Material),12 adapted for this review (Appendix). The quality of the included studies was evaluated based on questions regarding the selection and comparability of the cohort (cases and controls) and the outcomes. A higher score out of a total of 8 points indicates higher methodological quality.

Statistical Analysis

Study results are expressed as odds ratio (OR) with 95% confidence intervals (CIs). We used a fixed-effect model to pool results.13 We assessed heterogeneity using the χ2 test of heterogeneity and the I2 measure of inconsistency. If significant heterogeneity had a χ2 test P value < 0.1 or an I2 measure >50% we conducted a random effects meta-analysis. Numbers needed to treat (NNT) were calculated as the inverse of the pooled risk differences generated by the meta-analysis. Sensitivity analysis was done without the less-qualified studies or the study which has shown the most significant difference, with the same statistical methods. Analyses were performed using RevMan 4.2 (Review Manager [computer program] v. 4.2 for Windows, Copenhagen: Nordic Cochrane Centre, Cochrane Collaboration, 2003).

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
  8. APPENDIX: NOS: CODING MANUAL FOR COHORT STUDIES
  9. Supporting Information

Search Results

Our search yielded 235 articles, of which 189 were excluded after titles and abstracts scanning because they were reviews or irrelevant publications. Thirty-six articles were excluded after full-text review (Fig. 1). A total of 10 studies were included after exclusion of all studies not meeting the inclusion criteria.14–23 Two studies22, 23 provided their data for a mixed cohort of IBD patients that included both CD and UC patients. The first and last authors of these studies were contacted for clarifications on risks in their CD population alone but the data could not be retrieved and these two studies were excluded. Thus, there remained eight studies, including 1641 participants, eligible for systematic review and meta-analysis. Overall complication rates could be accessed in six of these studies. Infectious and noninfectious complications were assessed in six and four studies, respectively.

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Figure 1. Selection of included studies.

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Characteristics of Included Studies and Patients

The characteristics of studies and patients in the included studies are depicted in Table 1. All included studies were retrospective comparative cohort studies.

Table 1. Characteristics of Included Studies and Patients
          Surgical Technique 
     No. of PatientsMales (%) Age at Operation (years) OpenLaparoscopicType of SurgeryConcomitant Medications
StudyYears of StudyCountryIFX Perioda (w)Follow- upb (d)scscscType of Anti-TNFscscs (%)c (%)s (%)c (%)
  • a

    Before (-) and after surgery.

  • b

    After surgery.

  • c

    Studies that included only one type of surgery.

  • d

    22% of patients in the infliximab group received it more than 12 weeks prior to surgery.

  • e

    The study included an additional historic control group comprising patients operated before introduction of ant-TNF medication (1991–1997). These patients were excluded from this meta-analysis.

  • f

    The study included 2 control groups, one including patients who received nonanti-TNF medications and patients who did not receive any medical treatments. The data for the control groups were pooled for analysis.

  • S, study group; c, control group; IFX, infliximab; ADA, adalimumab; CZ, certolizumab; SB, small bowel; CD, corticosteroids; IM, immunomodulators; AZA, azathioprine; MTX, methotrexate; NA, unavailable/irrelevant.

Tay141998–2002US8282278NANA  IFX22/22 (100)78/78 (100)0/220/78Segmental resection +primary anastomosis/ strictureplastycSegmental resection+ primary anastomosis/ strictureplastycAZA+6-MP- 12/22(54.5) MTX-1/22(4.5)AZA+6-MP- 37/78 (47.4) MTX-1/78 (1.3)
Marchal151998–2002Belgium12d10/90403910/40 (25)18/39 (46.2)36.0 (16–73)38.7 (16–73)IFXnanananaSB resection −6/40 (15) Ileocolonic resection −17/40 (42.5) Colonic resection −11/40 (27.5) Proctectomy −6/40 (15)SB resection −6/39 (15.5) Ileocolonic resection −17/39 (43.5) Colonic resection −11/39 (28.2) Proctectomy-5/39 (12.8)5-asa – 12/40 (30) CS-12/40 (30) AZA-18/40 (45) MTX −6/40 (15) CS+IM- 29/40 (72.5) AB-10/40(25)5-asa – 21/39 (53.8) CS-12/39 (30.8) AZA-10/39 (25.6) MTX −1/39 (2.6) CS+IM- 16/39 (41) ABX −11/39 (28.2)
Colombel161998–2001US8 ;43052218NANANANAIFXnanananaNANANANA
Appau171998–2007US123060329e29/60 (48.3)151/329 (45.9)35.83± 11.936.84± 14.37IFX41/60 (68.3)228/329 (69.4)18/60 (30)95/329 (28.9)Ileocolonic resection – 60/60 (100)cIleocolonic resection −329/329 (100)c5-ASA- 36/60 (60) IM- 37/60 (61.7) CS-39/60 (65)5-ASA- 196/329 (59.6) IM- 55/329 (16.7) CS-253/329(76.9)
Indar181999–2007US830179552/Na104/Na  IFXnanananaNANACS-7/17 (41.2) IM- 5/17 (29.4) CS+IM-3/17(17.7)CS-21/95 (22.1) IM- 15/95 (15.8) CS+IM- 16/95 (16.8)
Canedo192001–2008US123065160f29/65 (44.6%)83/160 (51.8)26 (16–72)32 (18–78)/ 51 (16–740IFX34/65 (53.8)99/160 (61.9%)31/65 (46.2)61/160 (38.1)Ileocolonic resection −33/65(50.8) Proctectomy – 9/65(13.8) Total colectomy – 11/65 (16.9) Others- 12/65 (18.5)Ileocolonic resection – 83/160 (51.8) Proctectomy – 24/160(15) Total colectomy – 25/160 (15.7) Others- 28/60 (17.5)NaNA
Nasir202005–2009US8 ;43011925152/119 (43.7)104/251 (41.4)38.2 (17–66)43.3 (17–77)IFX ADA CZ70/119 (58.2)136/251 954.2)41/119 (34.5)93/251 (37.1)Ileocecectomy-29/119 (24.3) Colectomy- 32/119 (26.8) SB resection- 26/119 (21.7) Stricturoplasty- 13/119 (10.8) Stoma reversal- 12/119 (10.7) Other- 7/119 (5.7)Ileocecectomy- 75 (29.9) Colectomy- 57 (22.8) SB resection- 69 (27.5) Stricturoplasty- 15 (5.9) Stoma reversal- 25 (9.9) Other- 10 (4.0)CS-37/119 (31.1) IM-32/119(26.9)CS-114 /251(45.4) IM- 83/251 (33.1)
Kasparek212001–2008Germany1213 /12484821/48 (43.7)24/48 (50)35 (17–66)39 (17–68)IFX32/48 (66.7)40/48 (83.3)16/48 (32.3)8/48 (16.7)SB resection −16 (33.3) Ileoceccal resection– 15(31.2) Colonic −2 (4.2) SB and colonic resection −15(31.3)SB resection −9/48 (18.8) Ileoceccal resection– 17/48(35.4) Colon resection- 2/48(4.2%) SB and colon resection-20/48(41.6)CS-45/48 (93.8) AZA-32/48 (66.7) MTX-3/48(6.3)CS-45/48 (93.8) AZA-33/48 (68.8) MTX −2/48 (4.2)

In all, 423 out of 1641 (25.8%) patients who were included in our meta-analysis received anti-TNF antibodies and 1219/1641 (74.2%) did not. IFX was the only anti-TNF used in all studies except one,16 which also included patients treated with adalimumab and certolizumab pegol (69/119 patients received IFX). Patients were included if IFX was given in the 3 months prior to surgery in four studies,11, 13, 15, 17 2 months in two studies,10, 14 and 2 months before surgery or 1 month after it in the last two studies.12, 16 The duration of postoperative follow-up was reported at 10 days and at 3 months in one study.11 We contacted the corresponding author of this study in order to obtain the complication rates at 30 days but no response was received. Therefore, we included only the complications reported for 10 postoperative days, reasoning that complications as remote as 90 days postoperatively are unlikely to result from exposure to IFX due to its pharmacokinetic properties.24

Quality of Studies

Table 2 summarizes the risk of bias assessment for the retrospective studies included according to the Newcastle Ottawa Scale12 (Supporting Material). The major limitation of the studies was the incomparability between cases and controls (based on the use of concomitant medications and the type of surgery performed). However, in cases when this resulted from incomparability in the concomitant medications it was resolved in the subgroup analysis (except in two studies16, 19 in which no data were given regarding concomitant medications). Based on this scale, the three studies that received the lowest points (4/7) were considered “low-quality studies” for further sensitivity analysis. It should be emphasized that not only did these studies receive lower points on our scale, their primary objective was not limited to IFX-treated versus untreated patients.

Table 2. Total and Infectious Complications in Postoperative Patients Treated in Infliximab vs. Control Group
Study IDDefinition of Infectious ComplicationsNoninfectious ComplicationsTotal ComplicationsInfectious ComplicationsNoninfectious Complications
s%c%s%c%s%c%
  • a

    Only anastomosis-related complications were reported as infectious complications, so, it was not included in the meta-analysis

  • b

    Only the data that was incorporated into the meta-analysis.

  • s, study group; c, control group; na, not applicable; UTI, urinary tract infection; MI, myocardial infarction; DVT, deep venous thrombosis; PE, pulmonary embolism.

Tay14Abscess, fistula, leaknana na 3/2213.68/7810.3na na 
Marchal15Yeast infection, fever, infectious diarrhea, upper airway infection, sepsis, wound infection, wound failure, local abscess recurrence, abscess , fecal peritonitis, anastomotic leaks, fistulaeIleus, anemia, idiopathic peritonititis, hematoma, arthritis, subobstruction, fissure, ulcer bleeding12/403010/3925.610/40255/3915.42/405%5/3915.39
Colombel16Wound infection, dehiscence, anastomotic leaks, abscess, fistula , sepsis and any other extra-abdominal infectionSmall bowel obstruction, bleeding, thromboembolism, CD recurrence12/5223.151/21823.49/5217.343/21819.73/525.88/2183.7
Appau17sepsis, intaabdominal abscess anastomotic leak, wound dehiscenseUrinary complications, reoperation43/6071.7102/32931.024/6041.761/32918.519/6031.741/32912.5
Indar18Anastomotic leak, abscess, pneumonia, wound infection, UTIBleeding, MI , gracilis flap necrosis, rectal stump leak, renal failure, thrombosis, ileus6/1735.327/9528.4na na na na 
Canedo19Wound infection, pulmonary infection, abscesses, leaksnana na 14/6521.530/16018.8na na 
Nasir20Infections related to the anastomosis, e.g., abscess/anastomotic leakaNonanastomotic septic complications (pneumonia, UTI etc), anemia, cardiac, DVT,PE, renal failure, respiratory failure, urinary retention, ileus, death36/11930.370/25127.92/119a2%8/251a3.36na na 
Kasparek21wound infection, UTI, anastomotic leak, intraabdominal abscess, leakage, enterocutaneous fistulaIleus, hemorrhage, stoma complications, reoperation, small bowel leakage s/p takedown of adhesions33/4868.924/485018/4837.518/4837.515/4831.36/4812.5
total  142/33642.3284/98030.078/287b27.2b165/872b18.9b39/20019.560/6349.5

Demographic and Clinical Data

Data about the gender of the included patients, stratified by IFX treatment, was available in five studies including 1159 patients (521/1159 [44.9%] males). Data on the type of surgical resection undertaken were available in six studies. Three studies included only one specific type of surgery (Colombel et al16 and Tay et al14: small bowel resection with anastomosis/strictureplasty; Appau et al17: ileocolonic resection). The other three studies included patients who underwent different types of intestinal surgeries. We could not conduct a meta-analysis for specific operative interventions due to the variability of definitions employed by the studies. Data on the operative technique (open/laparoscopic) were available in 5/8 studies including 1180 patients (778/1180 [65.9%], open surgery; 363/1180 [30.7%], laparoscopic surgery). No association of the operative technique with IFX treatment was demonstrated.

Data on concomitant medications were available in six studies. Patients in the IFX group had a trend for a more frequent use of immunomodulators (thiopurines, 1146 patients, OR 1.78, 95% CI 0.74–4.30, six studies; methotrexate, 664 patients, OR 2.99, 95% CI 0.85–10.47, four studies). Corticosteroids were less frequently used in IFX-treated patients (OR 0.68, 95% CI 0.50–0.93, five studies).

Complications

Table 2 describes the complication rates in each of the included studies. Figures 2–5 show the pooled results of overall complications, infectious complications, noninfectious complications, and infectious nonlocal complications, respectively.

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Figure 2. Estimates of ORs for development of overall complications in patients treated with IFX preoperatively vs. controls.

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Figure 3. Estimates of ORs for development of infectious complications in patients treated with IFX preoperatively vs. controls.

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Figure 4. Estimates of ORs for development of noninfectious complications in patients treated with IFX preoperatively vs. controls.

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Figure 5. Estimates of ORs for development of infectious nonlocal complications in patients treated with IFX preoperatively vs. controls.

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Overall Complications

Six out of the eight included studies reported an overall complication rate and incorporated 1316 patients (336 IFX-treated and 980 controls). When the results from all studies were pooled, a trend for increased risk of complications was observed but without statistical significance (OR 1.72, 95% CI 0.93–3.19, I2 = 76.1%). This trend persisted even after the three “low-quality studies” were removed from the meta-analysis and also after the study with the most significant difference between the treatment and control groups (Appau et al17) was excluded.

Infectious Postoperative Complications

Seven studies reported infectious complications. Nasir et al20 reported only anastomosis-related complications as infectious (all extraabdominal septic complications were pooled together with the noninfectious complications), leading to exclusion of this study from the analysis of infectious complications. The remaining six studies included a total of 1159 patients (287 received IFX and 872 controls). When results of all studies were pooled, the OR was found to be 1.50 (95% CI, 1.08–2.08, I2 = 43.0%), thereby demonstrating a significant association between preoperative IFX therapy and postoperative infections, with a number needed to harm (NNH) of 20. No significant association with preoperative IFX was demonstrated in an analysis of anastomosis-related infectious complications alone (OR 1.18, 95% CI 0.61–2.30, six studies, I2 = 43.4%). However, the rate of nonlocal infectious complications was significantly higher in the IFX-treated group (OR 2.07 95% CI 1.30–3.30, five studies, I2 = 0%).

When low-quality studies9–11 were excluded, a trend for association of preoperative IFX treatment with overall (OR 2.2, 95% CI, 0.96–5.04) and infectious complications (OR 1.62, 95% CI, 0.92–2.86) was demonstrated.

Noninfectious Complications

A trend toward a higher rate of noninfectious complications in the IFX-treated group was observed with OR 2.00 (95% CI 0.89–4.46, four studies, I2 = 52.7%). This OR did not reach statistical significance, probably due to the low number of patients included in the analysis (n = 834). No significant difference was found in the reoperation rate (OR 1.26, 95% CI 0.65–2.42, three studies, I2 = 40.9%).

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
  8. APPENDIX: NOS: CODING MANUAL FOR COHORT STUDIES
  9. Supporting Information

Anti-TNF medications are among the most valuable tools in the therapeutic arsenal in IBD. However, the use of these medications may be associated with significant adverse effects, including an increased incidence of infections. As the majority of patients with CD will undergo at least one operation during their lifetimes,1, 2, 4 this anti-TNF-related susceptibility to infection may raise concerns pertaining to perioperative management. A potential influence of TNF inhibitors on wound healing is another matter of concern for these patients. However, most of the data pertaining to this issue include in vitro and animal studies, with equivocal results regarding collagen synthesis, wound healing, and anastomotic strength.25–28

Despite a continuing debate on this subject, no prospective study analyzing the risk for postoperative complications in CD patients treated with TNF inhibitors has been published so far. Several observational studies pertaining to CD, UC, and rheumatoid arthritis (RA) patients have been published. Comparing these studies, however, poses a significant challenge due to small cohort sizes and multiple important confounders.

Studies assessing surgical risks in RA patients treated with TNF inhibitors were mostly small and retrospective.29–34 No statistically significant increase in surgical complications was noted in any but one retrospective study,32 which suggested an increased risk of surgical site infections and deep venous thrombosis. Importantly, rheumatological data reported so far included mixed cohorts of patients treated with IFX, adalimumab, and Etanercept, the latter frequently employed in RA but ineffective in IBD.

A meta-analysis focusing on a similar issue in patients with UC11 summarized the surgical outcomes of IFX-treated patients with UC from five observational studies.35–39 Perioperative treatment with IFX was associated with increased risk of total short-term complications (OR 1.80, 95% CI 1.12–2.87). A trend for increased risk of postoperative infectious complications was also demonstrated (OR 2.23, 95% CI, 0.63–7.95).

However, no such meta-analysis has been hitherto published on TNF inhibitors treatment in CD patients undergoing surgery. Our meta-analysis addressed the risk of postoperative complications following abdominal surgery in CD patients who received perioperative IFX. We found a small but statistically significant increased risk of infectious complications (OR 1.50, 95% CI 1.08–2.08) and a nonsignificant trend toward increased rate of noninfectious (OR 2.00, 95% CI 0.89–4.46) and overall complications (OR 1.72, 95% CI, 0.93–3.19). Interestingly, a subanalysis of the infectious complications showed them to be unrelated to local infectious complications such as anastomotic leak or intraabdominal abscess. These findings imply an increased rate of remote or systemic infections such as respiratory, urinary infections, and sepsis, which are in line with the systemic immune suppression conferred by anti-TNFs.

Similar to other meta-analyses in this field,6–7 the present meta-analysis has several limitations stemming from the retrospective design of the included studies and resulting primarily from different inclusion criteria and nonuniform definitions of the complications. Thus, six out of eight analyzed studies included patients who received IFX only before surgery, whereas two studies also included patients who received IFX up to 30 days after the procedure. Our analysis was underpowered to discern an influence of the timing of the last preoperative IFX effusion on the rate of complications. However, a sustained effect of IFX beyond 12 weeks is unlikely due to its pharmacokinetic characteristics.24 Heterogeneity in timing of the assessment of complications is yet another limitations, since the surgical complications were assessed at 4 weeks postoperatively in six studies, and at 10 days or 90 days in one study,15 and at an average of 12 days postoperatively in another study.21

Importantly, the definitions of infectious and noninfectious complications vary substantially between different studies. In our meta-analysis, we addressed all anastomotic leaks and wound failures as infectious complications, even if they were not classified as such by the primary authors. It is clear that discrepancies in the classification of the complications may have had an influence on the statistical analysis.

The type and technique of the surgical procedures are other important factors that could influence outcome. Interestingly, the only study that has demonstrated a significant increase in adverse outcomes11 included exclusively patients who underwent ileocolonic resection without a history of previous abdominal operations. All other studies included patients undergoing a variety of abdominal surgical procedures, with ileocecal resections comprising only 31% of the included surgical procedures.

An important limitation in our meta-analysis is the concomitant use of nonanti-TNF immunomodulators. Patients treated with IFX were more likely to be treated with immunomodulators (OR 2.00, 95% CI 0.95–4.2), but less likely to receive corticosteroids (OR 0.68, 95% CI 0.50–0.93). Corticosteroid treatment has been consistently reported to be associated with increased risk of surgical complications, while no such association has been reported for 6-mercaptopurine and azathioprine.40–42 In addition, our analysis is restricted by the fact that only one study included patients who were treated with adalimumab and certolizumab in addition to patients treated with IFX. To the best of our knowledge, there are no other published studies that have analyzed the effect of adalimumab and certolizumab on perioperative complications. Finally, CD patients frequently have additional risk factors for adverse surgical outcomes such as malnutrition, anemia, fistulae, past surgeries, and urgent indications for surgery. It is not unreasonable to assume that patients treated with anti-TNFs had more severe disease. However, it was impossible to stratify the meta-analysis results for these important confounders due to insufficient data.

Despite the aforementioned limitations, this is the first meta-analysis to summarize the impact of preoperative anti-TNF therapy on postoperative complications in CD. To date, this topic has been addressed only by retrospective studies and in most of them only a nonsignificant trend for an association could be demonstrated. However, pooling the data from these studies enabled us to reach meaningful conclusions on this important and common therapeutic dilemma. In addition, this is the first study to point out an increased susceptibility of IFX-treated CD patients to systemic (nonlocal) infectious complication. This association has not been previously reported.

This meta-analysis points out that surgery in patients treated with TNF inhibitors may be associated with an increased risk of complications, mostly attributed to nonanastomotic postoperative infectious complications. When the clinical condition of the patient allows, we suggest scheduling elective abdominal surgical interventions in CD patients as far from anti-TNF therapy as possible. The optimal interval from the last dose of anti-TNF antibody to a planned surgery remains to be defined and the potential adverse influence of treatment withdrawal should also be taken into consideration. When emergent surgery is required in a patient treated with anti-TNFs, a higher risk of complications should be expected, and prompt preventive measures should be considered. Currently, a case-by-case approach to this therapeutic dilemma should be recommended. Undoubtedly, there is a need for large randomized controlled trials stratified for patient-related, disease-related, and surgery-related confounders in order to define the best management approach for these patients.

Acknowledgements

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
  8. APPENDIX: NOS: CODING MANUAL FOR COHORT STUDIES
  9. Supporting Information

Conflict of interest: Dr. Ben-Horin has received consultancy fees from Abbott and Schering Plow. Author contributions: Dr. Kopylov and Dr. Katz collected and analyzed the data and drafted the article. Dr. Ben Horin participated in the design of the study and preparation of the article. Dr. Zmora, Prof. Eliakim, and Dr. Ben-Horin provided a critical review of the article and contributed important scientific input.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
  8. APPENDIX: NOS: CODING MANUAL FOR COHORT STUDIES
  9. Supporting Information
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APPENDIX: NOS: CODING MANUAL FOR COHORT STUDIES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
  8. APPENDIX: NOS: CODING MANUAL FOR COHORT STUDIES
  9. Supporting Information

Selection

  • 1)
    Representativeness of the Exposed Cohort (NB exposure = intervention)
    Item is assessing the representativeness of exposed individuals in the community, not the representativeness of the study sample from some general population. For example, subjects derived from groups likely to contain exposed people are likely to be representative of exposed individuals, while they are not representative of all people the community.
    Allocation of stars as per rating sheet
  • 2)
    Selection of the Nonexposed Cohort
    Allocation of stars as per rating sheet
  • 3)
    Ascertainment of Exposure
    Allocation of stars as per rating sheet
  • 4)
    Demonstration that Outcome of Interest Was Not Present at Start of Study
    In the case of mortality studies, outcome of interest is still the presence of a disease/ incident, rather than death. That is to say that a statement of no history of disease or incident earns a star.

Comparability

  • 1)
    Comparability of Cohorts on the Basis of the Design or Analysis
    Either exposed and nonexposed individuals must be matched in the design and/or confounders must be adjusted for in the analysis. Statements of no differences between groups or that differences were not statistically significant are not sufficient for establishing comparability. Note: If the relative risk for the exposure of interest is adjusted for the confounders listed, then the groups will be considered to be comparable on each variable used in the adjustment.
    A maximum of 2 stars can be allotted in this category.

Outcome

  • 2)
    Assessment of Outcome
    For some outcomes, reference to the medical record is sufficient to satisfy the requirement for confirmation. This may not be adequate for other outcomes where reference to specific tests or measures would be required.
    • a)
      Independent or blind assessment stated in the paper, or confirmation of the outcome by reference to secure records (health records, etc.).
    • b)
      Record linkage (e.g., identified through ICD codes on database records).
    • c)
      Self-report (i.e., no reference to original health records or documented source to confirm the outcome).
    • d)
      No description.
  • 3)
    Was Follow-up Long Enough for Outcomes to Occur
    An acceptable length of time should be decided before quality assessment begins.
  • 4)
    Adequacy of Follow-up of Cohorts
    This item assesses the follow-up of the exposed and nonexposed cohorts to ensure that losses are not related to either the exposure or the outcome.
    Allocation of stars as per rating sheet

Supporting Information

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
  8. APPENDIX: NOS: CODING MANUAL FOR COHORT STUDIES
  9. Supporting Information

Additional Supporting Information may be found in the online version of this article.

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