Preoperative Ustekinumab Treatment Is Not Associated With Increased Postoperative Complications in Crohn’s Disease: A Canadian Multi-Centre Observational Cohort Study

Preoperative Ustekinumab Treatment Is Not Associated With Increased Postoperative Complications... Background: Ustekinumab (UST), an anti-IL12/23 inhibitor is indicated for moderate-to-severe Crohn’s disease (CD). However, it is unclear if patients treated with UST are at increased risk for post- operative complications. Aim: To evaluate the postoperative safety outcomes in UST-treated CD patients. Methods: A multicentre cohort study of UST-treated CD patients at two tertiary care centres (University of Calgary, University of Alberta, Canada) undergoing abdominal surgery between 2009 and 2016 was performed. Postoperative outcomes were compared against a control cohort of anti- TNF-treated patients over the same time-period. The primary outcome was occurrence of postop - erative complications up to six months postoperatively, stratified by timing (early <30  days vs. late complications ≥30 days). Results: Twenty UST-treated patients and 40 anti-TNF-treated patients were included with a median preoperative treatment exposure of 6.5 months and 18 months, respectively (p=0.01). Bowel obstruction was the most common surgical indication in both cohorts. UST-treated patients were more likely to require an ostomy (70.0% vs. 12.5%, p<0.001) and be on combination therapy with either systemic corticosteroids or concurrent immunomodulators (azathioprine or methotrexate) (25.0% vs. 2.5%, p=0.01). Despite the increased concomitant use of immunosuppression in the UST- treated cohort, there were no significant differences in early or late postoperative wound infections (1/20 in UST-cohort, 2/40 in anti-TNF cohort, p=1.00), anastomotic leak (0/20 in UST-cohort, 3/40 in anti-TNF cohort, p=0.54), or postoperative ileus/obstruction (3/20 in UST-cohort, 4/40 in anti-TNF cohort, p=0.67). Conclusions: CD patients receiving preoperative UST did not experience an increase in postopera- tive complications, despite increased use of concurrent immunosuppression. Keywords: Ustekinumab, Crohn’s disease, Surgery, Postoperative complications © The Author(s) 2018. Published by Oxford University Press on behalf of the Canadian Association of Gastroenterology. 115 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/jcag/article-abstract/1/3/115/4994946 by guest on 17 October 2018 116 Journal of the Canadian Association of Gastroenterology, 2018, Vol. 1, No. 3 Perioperative outcomes among UST-treated CD patients is INTRODUCTION unclear. This is of paramount clinical relevance in view of the Crohn’s disease (CD) is a chronic progressive inflammatory expected increasing use of UST for the treatment of refractory condition of the gastrointestinal tract.(1–3) In the pre-bio- CD. Therefore, we report our clinical experience with the use of logic era before the approval of infliximab in 1998, up to 80% UST in CD patients preoperatively and compare the postopera- of patients required surgical intervention for management of tive outcomes to those treated with anti-TNF therapy. disease-related complications including strictures, fistulae, and abscesses.(4,5) Since the introduction of biologic agents tar- geting tumor necrosis factor (TNF) alpha into the therapeutic METHODS armamentarium, there has been a paradigm shift in the natural Study Design and Patient Population history of CD with reduced need for surgery and hospitaliza- tion when treatment is used early, prior to the development A retrospective observational cohort study of CD patients of irreversible bowel damage and fibrostenotic disease.(6–10) treated with UST from two tertiary academic care centres In the Randomised Evaluation of an Algorithm for Crohn’s (University of Calgary, Calgary, Canada and University of Treatment (REACT 1)  cluster randomised controlled trial, Alberta, Edmonton, Canada) was performed. Adult (≥18 years) early anti-TNF initiation in combination with an immunomod- CD patients were eligible for inclusion if they met the following ulator was superior to conventional therapy for reducing surgi- criteria: (i) had a confirmed diagnosis of CD by standard endo - cal rate, hospitalization, or serious disease related complication scopic, radiologic, and histologic parameters; (ii) received UST (27.7% vs. 35.1%, p=0.0003) at 24  months.(6) However, one therapy within four months of abdominal surgery, and (iii) third of patients do not respond to anti-TNF agents due to non- subsequently underwent abdominal surgery between January TNF mediated pathways of inflammation and among respond - 1, 2009 and August 1, 2016. Abdominal surgery was defined ers, another third subsequently lose response due to insufficient as any surgery that was performed within the intra-abdom- drug levels or the development of anti-drug antibodies.(11,12) inal compartment, but did not have to be specifically for CD Non-anti-TNF biologic therapies for the treatment of CD management. Patients undergoing exclusive perianal surgery, have been limited until 2014, when the United States Food and including incision and drainage, examination under anesthesia, Drug Administration (FDA) approved vedolizumab, an α β or seton placement, were excluded. Minimum UST exposure 4 7 integrin inhibitor. Subsequently, ustekinumab (UST), a mono- time was not an inclusion criterion. clonal antibody targeting IL -12 and IL -23 through the common UST-treated patients were then compared in a 1:2 ratio to p40 subunit, was approved in 2016 by the FDA, the European a control group of CD patients treated with anti-TNF agents Medicines Agency (EMA), and Health Canada. UST has been undergoing abdominal surgery over the same time period. available since 2009 for use in patients with psoriasis. Prior to Control patients were identified using the University of Calgary its approval in 2016 for the treatment of moderate-to-severe Gastrointestinal Research Group (GIRG) database and the CD, UST had been available off-label for the compassionate University of Alberta Centre of Excellence for Gastrointestinal treatment of CD patients failing anti-TNF therapy in view of Inflammation and Immunity Research (CEGIIR) database. the favourable therapeutic response in clinical trials.(13) Matching on baseline covariates was not performed due to Approximately 30–50% of CD patients are likely to be on the small sample size; however, we restricted the selection of concurrent biologics at the time of surgery.(14) Data on the risk control patients to those undergoing surgery during the same of perioperative infections and complications with the use of time-period to control for potential temporal differences in sur - anti-TNF agents are conflicting, largely related to the significant gical and nursing-related care. heterogeneity of individual studies, patient cohorts, and nature Data were collected independently by authors (HHS and of surgery.(15–22) A  meta-analysis of eight studies reported CM) from a provincial electronic medical record system and via a trend towards an increased risk of total complications with chart review. Patient demographics including age, gender, dis- preoperative anti-TNF use.(23) No strong recommendations ease phenotype as defined by the Montreal classification,(26) with regards to perioperative use of anti-TNF therapy have tobacco exposure, body mass index (BMI) at time of surgery, been made in either the 2015 Crohn’s and Colitis Foundation serum albumin level (g/L) within one month preoperatively, of America (CCFA) position statement or the 2016 European date of surgery, nature of surgery (emergency vs. elective, lapa- Crohn’s and Colitis Organization (ECCO) consensus.(24,25) rotomy vs. laparoscopic, types and indications for surgery) were W hile it is often a joint decision with the surgeon, unnecessary collected. Medication history including biologic exposure and suspension of anti-TNF therapy and then subsequently restart- perioperative immunosuppression (corticosteroids, azathio- ing treatment ae ft r surgery may predispose patients to anti-drug prine, or methotrexate) were recorded. Systemic corticosteroid antibody formation, infusion reactions, and loss of clinical exposure was defined as a dose of ≥ 20mg per day of prednisone response. (or equivalent) given within four weeks perioperatively. Downloaded from https://academic.oup.com/jcag/article-abstract/1/3/115/4994946 by guest on 17 October 2018 Journal of the Canadian Association of Gastroenterology, 2018, Vol. 1, No. 3 117 treated with systemic corticosteroids (35% vs. 15%, p=0.10), Outcomes have stricturing disease phenotype (50% vs. 27.5%, p=0.13), The primary outcome of interest was the occurrence of post - and have disease affecting the upper gastrointestinal tract (35% operative complications, up to six months aeft r surgery. vs. 10%, p=0.53), although these associations were not statisti- Postoperative complications were defined by the follow - cally significant. ing events: (a) wound infection; (b) anastomotic leak; (c) All patients from the UST cohort were infliximab-experi - intra-abdominal abscess; (d) non-surgical site infection; (e) enced (either intolerant, primary non-responders, or developed delayed wound healing at one month post-surgery; (f ) need secondary loss of response to maintenance anti-TNF therapy). for readmission or reoperation; (g) median duration of hospi- Seventy percent (14/20) were intolerant or had lost response to tal admission; and (h) postoperative mortality. Outcomes of at least two anti-TNF therapies. In comparison, the majority of interest were defined by clinical assessment and where appro - anti-TNF-treated patients (77.5%, 31/40) were previously bio- priate, supplemented by diagnostic imaging. Postsurgical out- logic naïve and were on their first biologic at the time of surgery. comes for both cohorts were stratified by time to occurrence: Disease duration was numerically but not statistically longer early (<30 days post-surgery) and late (≥30 days and up to six in the UST-treated cohort compared to the anti-TNF-treated months post-surgery). cohort (median disease duration 14.5 years [IQR 8.5–19.5] vs. 7.0 [IQR 3.0–15.5] years, p=0.07). UST-treated patients were Statistical analysis also more likely to be smokers (50% vs. 5%, p<0.001) and had Baseline patient characteristics were analysed using standard a higher burden of concomitant methotrexate (45% vs. 15%, descriptive statistics; medians with interquartile ranges (IQR) p=0.02) and combination corticosteroid with immunomod- were calculated for continuous data and percentage were calcu- ulator (either azathioprine or methotrexate) (25% vs. 2.5%, lated for categorical data. Comparisons between baseline char- p=0.01). Previous treatment history of both cohorts is summa- acteristics and postoperative outcomes between UST-treated rized in Table 2. and anti-TNF-treated patients were performed using the Mann-W hitney U test for non-parametric continuous variables Surgical Details and Fisher exact test for categorical data. A  p-value <0.05 was Surgical details, including surgical indication, nature of surgery, considered to be statistically significant. Statistical analysis was and surgical type are summarized in Table 3. The predominant performed using SPSS 24.0 (Armonk, NY: IBM Corporation). indication for surgery in both cohorts was bowel obstruction (12/20 for UST and 26/40 for anti-TNF cohort, p=0.19). Ethical Considerations However, UST-treated patients were more likely to undergo This study was approved by the Human Research Ethics Board surgery in the emergent setting (55% vs. 25%, p=0.04) and at both the University of Calgary and the University of Alberta. require a postoperative ostomy (70.0% vs. 12.5%, p<0.001). Although not statistically significant, UST-treated patients were RESULTS also more likely to have undergone either proctocolectomy Patient Population (10% vs. 0%, p=0.10) or subtotal colectomy (20.0% vs. 7.5%, p=0.21). A similar proportion of patients treated with UST and Twenty-one UST-treated CD patients who underwent abdom- anti-TNF required ileal and ileocolonic resections (30.0% vs. inal surgery between January 1, 2009 and August 1, 2016 were 22.5%, p=0.54 and 35.0% vs. 42.5%, p=0.78, respectively). identified. One patient required emergency abdominal sur - gery outside of the study centres and due to incomplete data Postoperative Outcomes was excluded from the cohort. Forty anti-TNF treated CD patients who underwent abdominal surgery during the same There were no significant differences across both cohorts for all time period were included in the control group. Half of these postoperative complications, followed out to six months ae ft r patients (20/40) received adalimumab, 18/40 (45%) received surgery (Table  4). There were no significant differences in the infliximab, and 2/40 (5%) received golimumab as their most rate of anastomotic leak, intra-abdominal abscess, non-surgi- immediate pre-operative anti-TNF agent. Although golimumab cal site infection, delayed wound heaing, need for readmission is not listed for the treatment of CD in Canada, it was used or reoperation, or median days of total hospital stay for both off-label for both the patients as salvage therapy ae ft r they lost cohorts. No deaths were reported in both cohorts at six months. response to infliximab and adalimumab. Baseline patient demo - Only a single postoperative wound infection was reported in graphics are summarized in Table  1. There were no significant the UST-treated cohort. differences between both cohorts based on age, gender, BMI, UST was continued in 13 patients (65%) and anti-TNF coexistent diabetes mellitus, or pre-operative serum albumin therapy was continued in 28 patients (70%) postoperatively. level. UST-treated patients were nominally more likely to be Immunomodulator therapy with methotrexate or azathioprine Downloaded from https://academic.oup.com/jcag/article-abstract/1/3/115/4994946 by guest on 17 October 2018 118 Journal of the Canadian Association of Gastroenterology, 2018, Vol. 1, No. 3 Table 1. Baseline patient demographics Ustekinumab cohort (n=20) Anti-TNF cohort (n=40) P value Median age (years, IQR) 34.5 (26.3–51.5) 32.5 (22–42.5) 0.34 Male gender (n, %) 5 (25%) 15 (37.5%) 0.39 Current smoker (n, %) 10 (50%) 2 (5%) <0.001 Median BMI (IQR) 23.6 (19.6–27.6) 23.6 (20.2–25.7) 1.00 Median duration of postsurgical follow up (months, IQR) 14.5 (6.3–21.8) 39.5 (22–56.8) <0.001 Median duration of CD prior to surgery (years, IQR) 14.5 (8.5–19.5) 7 (3–15.5) 0.07 Median duration of biologics prior to surgery (months, IQR) 6.5 (3–12) 18 (5–33) 0.007 Montreal classification Age: 10 (50%) 13 (32.5%) 0.26 A1 A2 7 (35%) 23 (57.5%) A3 3 (15%) 4 (10%) Behaviour: 2 (10%) 2 (5%) 0.13 B1 B2 10 (50%) 11 (27.5%) B3 8 (40%) 27 (67.5%) P 7 (35%) 12 (30%) 0.77 Location: 5 (25%) 17 (42.5%) 0.53 L1 L2 3 (15%) 3 (7.5%) L3 9 (45%) 16 (40%) L3+ L4 3 (35%) 4 (10%) Previous history of intestinal resection (%, range) 60% (0–3) 47.5% (0–9) 0.36 Median preoperative serum albumin (g/L, IQR) 34.0 (28–42.2) 34.0 (30.5–38) 0.53 Concomitant diabetes mellitus 0% 0% - Perioperative immunosuppression (n, %) Corticosteroid ≥ 20mg/day 7 (35%) 6 (15%) 0.10 Azathioprine 4 (20%) 10 (25%) 0.75 Methotrexate 9 (45%) 6 (15%) 0.02 Combination corticosteroid and azathioprine/ 5 (25%) 1 (2.5%) 0.01 methotrexate was added in 5 patients in the UST group (25%) and 11 patients we anticipate an increase in the number of patients who are on in the anti-TNF group (27.5%). Therapy was changed in two UST preoperatively. A fundamental question with any biologic patients (10%) in UST group to vedolizumab postoperatively; therapy is whether exposure adversely influences post-opera - therapy was changed in three patients (7.5%) in the anti-TNF tive outcomes. In this multicenter cohort study, we demonstrate group to UST postoperatively. All medical therapy was discon- no increased risk of either early or late postoperative compli- tinued ae ft r surgery in two patients (10%) in the UST-treated cations in UST-treated patients undergoing intra-abdominal group and seven patients (17.5%) in the anti-TNF group. surgery as compared to patients treated with anti-TNF agents. This is despite UST-treated patients experiencing a significantly greater burden of immunosuppression preoperatively but may DISCUSSION also be confounded by a significantly higher proportion requir - Although the introduction of biologic therapy has ushered in ing postoperative ostomy creation. a new era in the management of CD, surgery continues to hold The impact of preoperative biologic therapy on postoperative a fundamental role in the treatment paradigm for patients with outcomes and in particular, postoperative infections, remains medically refractory or complicated CD. Indeed, approximately controversial.(27–29) Previous meta-analyses have demon- half of CD patients will require bowel resection within 10 years strated a modestly increased risk of postoperative infectious of diagnosis.(9) With the increasing adoption of UST for CD, complications associated with preoperative anti-TNF exposure Downloaded from https://academic.oup.com/jcag/article-abstract/1/3/115/4994946 by guest on 17 October 2018 Journal of the Canadian Association of Gastroenterology, 2018, Vol. 1, No. 3 119 Table 2. Treatment exposure history Ustekinumab cohort (n=20) Anti-TNF cohort (n=40) Immunomodulators Azathioprine 11 (55%) 11 (27.5%) Methotrexate 6 (30%) 9 (22.5%) Previous anti-TNF therapy Infliximab 20 (100%) 7 (17.5) Adalimumab 13 (65%) 4 (10%) Certolizumab 1 (5%) 0 Golimumab 3 (15%) 0 Previously biologic naive 0 31 (77.5%) Failed 1 anti-TNF therapies 6 (30%) 7 (17.5%) Failed 2 anti-TNF therapies 11 (55%) 2 (5%) Failed 3 anti-TNF therapies 3 (15%) 0 Other previous biologics exposure (commercial/clinical trials) Vedolizumab 1 (5%) 0 Ustekinumab - 1 (2.5%) Briakinumab (ABT-894) 0 1 (2.5%) CCR-9 inhibitor 1 (5%) 0 Table 3. Surgical details Ustekinumab cohort (n=20) Anti-TNF cohort (n=40) P value Indication of surgery: Medical refractory disease ^5 (25%) ^^3 (7.5%) 0.19 Obstruction 12 (60%) 26 (65%) Free bowel perforation 2 (10%) 2 (5%) Intraabdominal abscess 0 2 (5%) Closure of ostomy 0 3 (7.5%) Others *1 (5%) **4 (10%) Nature of surgery: Emergency 11 (55%) 10 (25%) 0.04 Open laparotomy 13 (65%) 20 (50%) 0.40 Type of surgery (n,%): Ileal resection 6 (30%) 9 (22.5%) 0.54 Ileocolonic resection 7 (35%) 17 (42.5%) 0.78 Subtotal colectomy 4 (20%) 3 (7.5%) 0.21 Proctocolectomy 2 (10%) 0 0.10 Ostomy 14 (70%) 5 (12.5%) <0.001 Primary anastomosis 9 (45%) 26 (65%) 0.17 Stricturoplasty 1 (5%) 2 (5%) 1.00 Fistula repair 2 (10%) 3 (7.5%) 1.99 Hernia repair 1 (5%) 1 (2.5%) 1.00 Cholecystectomy 1 (5%) 4 (10%) 0.66 Appendectomy 0 1 (2.5%) 1.00 Adhesiolysis 0 7 (17.5%) 0.08 ^inflammatory (ileo)colitis refractory to treatment x5 ^^ inflammatory colitis refractory to treatment x 2, defunctioning loop ileostomy for refractory perianal disease x1 *cholecystectomy for cholecystitis **cholecystectomy for porcelain gallbladder; cholecystectomy for gall bladder cancer; cholecystectomy for biliary colic x2 Downloaded from https://academic.oup.com/jcag/article-abstract/1/3/115/4994946 by guest on 17 October 2018 120 Journal of the Canadian Association of Gastroenterology, 2018, Vol. 1, No. 3 Table 4. Postoperative outcomes Ustekinumab cohort (n=20) Anti-TNF cohort (n=40) P value Postoperative complications: Wound infection ≤ 30 days 1 (5%) 2 (5%) 1.00 Wound infection > 30 days 0 0 - Anastomotic leakage ≤ 30 days 0 3 (7.5%) 0.54 Anastomotic leakage > 30 days 0 0 - Abscess ≤ 30 days 0 4 (10%) 0.29 Abscess > 30 days 0 2 (5%) 0.54 Nonsurgical site infection ≤ 30 days 0 3 (7.5%) 0.54 Nonsurgical site infection > 30 days 0 0 - Postoperative ileus /bowel obstruction 3 (15%) 4 (10%) 0.67 Delayed wound healing 0 5 (12.5%) 0.16 Need for reoperation/readmission 2 (10%) 6 (15%) 0.59 Median preoperative hospital stay (days, IQR) 0 (0–4) 0 (0–2) 0.59 Median total hospital stay (days, IQR) 7 (5–14) 7 (4–9) 0.45 Mortality at 6 months 0 0 - (OR 1.45–1.56), with a magnitude of associated risk similar to conventional biologics including various anti-TNF agents and that of systemic corticosteroids.(30–32) Furthermore, it has vedolizumab. Not unexpectedly, there was greater use of corti- been shown in animal models that TNF inhibition reduces costeroids, methotrexate, and combination corticosteroid and angiogenesis and collagen production. It has therefore been immunomodulator in UST-treated patients. While periopera- hypothesized to potentially inhibit wound healing in postop- tive use of immunomodulators appears to be safe, perioperative erative patients.(33) Biologically, UST blocks upstream Th1 corticosteroid use has previously been associated with increased and Th17 cytokine signalling involved in the proinflammatory total complications.(32,37,38) UST-treated patients in this response, and does not directly disrupt TNF pathways. cohort also tended to be smokers, have a significantly longer CD In the clinical trial development programs, there were duration, require emergent surgery, and have medical refractory no increased risks of serious adverse events or infections in disease: all are predictors of poor postoperative outcomes, but patients who received UST when compared to placebo.(13,34) despite these poor prognostics factors, our pilot data did not Although there is no direct head-to-head comparison, a sys- appear to have biased findings towards increased risk in UST- tematic review with network meta-analysis of 10 RCT reported treated patients. Our findings correlate with a recently published no significant difference in the safety profile between UST, retrospective cohort of 44 UST-treated patients undergoing anti-TNF agents and vedolizumab.(35) Fabiano et al. have also abdominal surgery: Lightner et al. also found no increased risk of reported the perioperative outcomes of a cohort of 131 patients surgical site infections or hospital readmission when comparing with psoriasis treated with various biologics (infliximab, adali - UST and anti-TNF treated patients.(39) mumab, UST and etanercept)(36). UST-treated patients were Of note, we observed a higher proportion of patients in however a minority (13/131, 10%) of the cohort and most sur- the UST cohort who received an ostomy (70% vs. 12.5%, geries in this study (73/131, 56%) were performed for minor p<0.001). We postulate there are multiple reasons for this dif- procedures (dermatologic and dental). There was no increased ference in ostomy creation, including: 1)  possible hesitancy risk of wound infection for those who continued with biologic from surgeons to create a primary anastomosis in patients on therapy compared to patients electively discontinuing therapy UST; 2) a greater need for emergency rather than elective sur- prior to surgery. gery among patients on UST; and 3)  more complex disease From our cohort of CD patients treated with UST, we did phenotype and longer disease duration among UST-treated not observe an increased risk of adverse perioperative out- patients compared to anti-TNF-treated patients precluding comes compared to CD patients treated with anti-TNF agents. primary anastomosis. The difference in ostomy creation intro - This was despite a greater exposure to immunosuppressants duces a potential source of bias in interpreting post-operative and more complicated disease phenotype in the UST-treated complication rates: ostomy creation may partially mitigate the cohort. Our UST-treated cohort was comprised of patients who risk of early post-surgical complications, such as wound dehis- were nominally more likely to have upper GI involvement, stric- cence, especially in complex CD patients with greater preoper- turing disease phenotype, and were unsuccessfully treated with ative immunosuppressant burden. However, if the decision for Downloaded from https://academic.oup.com/jcag/article-abstract/1/3/115/4994946 by guest on 17 October 2018 Journal of the Canadian Association of Gastroenterology, 2018, Vol. 1, No. 3 121 ostomy creation was driven by more aggressive CD phenotype, comparisons may be confounded by potentially important dif- this population would inherently be at increased risk for post- ferences in clinical characteristics between the two groups, such operative complications. as preoperative medication use and disease phenotype. Finally, Other confounders that we have considered, including we present a multicentre experience with UST-treated patients patient comorbidities such as age and diabetes mellitus, were requiring intra-abdominal surgery, but the study is underpow- comparable in both cohorts. To explore the effect of malnutri - ered due to 1)  small total cohort size and 2)  small number of tion as a confounder for occurrence of adverse perioperative postoperative complications. However, this study represents outcomes, we compared preoperative BMI and serum albumin the first uniquely Canadian experience with UST in a clini - levels in both cohorts as surrogate measures of overall nutri- cally important and understudied setting and we hope to stim- tional status, recognizing the inherent limitations that serum ulate collaborative efforts from other authors to confirm these albumin is a negative phase reactant in acute inflammation and findings. obese patients are not precluded from malnturtion.(40,41) In conclusion, in this multicentre cohort study, we found pre- Regardless, these markers were comparable for both cohorts. operative UST exposure to be associated with an increased risk Elderly age and longer preoperative hospital stay were noted to of requiring postoperative ostomy but not associated with an be potential risk factors for post-colectomy complications in a increased risk of early or late perioperative complications com- study by Bartels et al.(42) However, these factors were not con- pared to preoperative anti-TNF therapy. However, larger pro- firmed to be significant predictors in our cohort. For the single spective studies will be needed to confirm these findings. Funding Support: Christopher Ma was supported by a Canadian UST-treated patient who developed an early wound infection, Association of Gastroenterology Resident Research Award and by a there were multiple potential confounders, including presenta- Clinician Fellowship from the Canadian Institutes for Health Research. tion with a perforated viscus, operation in an emergency set- Writing Assistance: None ting, open laparotomy, and significant corticosteroid exposure (≥ 20mg/day).(32,43) Interestingly, we observed a relatively low rate of postopera- ACKNOWLEDGEMENTS tive complications in this cohort, especially in comparison to None declared. previous reports where complication rates approached 20% on Conflict of Interest anti-TNF therapy.(44) Possible explanations of our low com- HHS: Advisory board ( Janssen, Ferring) plication rates may include the selection of a relatively young CM, HA, AKA, JXQP: nil patient cohort without a substantial burden of comorbid ill- PGK : Consulting (Abbvie, Takeda, Pfizer), speaker’s bureau ( Janssen, Abbvie, Takeda, Ferring, Pfizer, UCB) ness predisposing to postoperative complications, improve- CHS: Advisory board (Janssen, Abbvie, Shire, Takeda, Actavis), ments in surgical technique (particularly less invasive surgical speaker’s bureau ( Janssen, Abbvie) approaches) over time, and optimized post-surgical care and RNF: Advisory board (Abbott/AbbVie, Celltrion, Ferring, Janssen, nursing support. However, our low postoperative event rate in Shire, VSL#3), consulting fees (Abbott/AbbVie, Celltrion, Ferring, the anti-TNF cohort may limit our ability to detect true differ - Janssen, Shire, VSL#3), research grants (Abbott/AbbVie, Alba ences from the UST-treated group. Therapeutics, BMS, Celltrion, Centocor, Genentech, GSK, Janssen, There are some limitations to our study. Due to the retrospec - Merck, Millennium, Novartis, Pfizer, Proctor & Gamble, Roche, tive nature, there are inherent limitations with respect to recall VSL#3) bias and incomplete data reporting. For example, periopera- SMD: Advisory board (Takeda, Shire, AbbVie, Janssen, Ferring, tive drug level testing was not routinely available for analysis. Hospira), speaker’s bureau (AbbVie, Janssen, Shire, Ferring, Takeda) Furthermore, exact quantification of preoperative UST expo - LAD: Consulting fees (AbbVie, Janssen), speaker’s bureau (AbbVie, sure is challenging: UST and adalimumab are self-administered Janssen) GGK: Advisory board ( Janssen, Abbott, Merck, Schering-Plough, and we could not ensure compliance with medical therapy prior Shire, UCB Pharma), research support (Merck, Abbott, GlaxoSmith to surgery. Therefore, reliable confirmation of last dose of bio - Kline, Shire), speaker’s bureau (Janssen, Merck, Schering-Plough, logic preoperatively to determine the washout period and date Abbott, UCB Pharma) of restarting biologic therapy postoperatively were only partially KLN: Advisory board (AbbVie, Janssen, Pfizer, Ferring), research sup - available and not included in the analysis to minimize obser- port (AbbVie, Janssen), speaker’s bureau (Abbvie, Janssen) vation bias. They are however, unlikely to be significant con- KIK: Consulting fees (AbbVie, Janssen, Takeda, Ferring), speaker’s founders in view of the long half-life of biologics.(45) Further, bureau (AbbVie, Janssen) up to 55% of surgeries were performed in the emergency setting BPH: Consulting fees (AbbVie, Janssen), speaker’s bureau (AbbVie, for UST-treated patients, limiting the washout period. Due to Janssen, Shire, Pendopharm) small sample size, our UST-treated cohort was compared with RP: Advisory board (Abbott/AbbVie, Amgen, Janssen, Merck, Pfizer, a randomly selected anti-TNF-treated cohort rather than a Prometheus Laboratories, Salix Pharma, Shire, Takeda, Warner control group that was matched for covariates. Therefore, any Chilcott), consulting fees (Abbott/AbbVie, Amgen, Aptalis, Astra Downloaded from https://academic.oup.com/jcag/article-abstract/1/3/115/4994946 by guest on 17 October 2018 122 Journal of the Canadian Association of Gastroenterology, 2018, Vol. 1, No. 3 Zeneca, Baxter, BMS, Centocor, Elan/Biogen, Eisai, Ferring, GSK, 10. Frolkis AD, Lipton DS, Fiest KM, et  al. Cumulative incidence Janssen, Merck, Millennium, Pfizer, Proctor & Gamble, Prometheus of second intestinal resection in Crohn’s disease: a system- Therapeutics and Diagnostics, Schering-Plough, Shire, Takeda, UCB atic review and meta-analysis of population-based studies. Pharma, Warner Chilcott), research grants (Abbott/AbbVie, Amgen, Am J Gastroenterol. 2014;109(11):1739–1748. doi:10.1038/ Aptalis, Astra Zeneca, Baxter, BMS, Centocor, Eisai, Elan/Biogen, ajg.2014.297. Ferring, GSK, Janssen, Merck, Millennium, Pfizer, Proctor & Gamble, 11. Danese S, Vuitton L, Peyrin-Biroulet L. Biologic agents for Prometheus, Shire, Schering-Plough, Takeda, UCB Pharma, Warner IBD: practical insights. Nat Rev Gastroenterol Hepatol. Chilcott), speaker’s bureau (Abbott/AbbVie, Amgen, Aptalis, Astra 2015;12(9):537–545. doi:10.1038/nrgastro.2015.135. Zeneca, Baxter, BMS, Centocor, Eisai, Elan/Biogen, Ferring, GSK, 12. Hazlewood GS, Rezaie A, Borman M, et  al. Comparative effec - Janssen, Merck, Millennium, Pfizer, Proctor & Gamble, Prometheus, tiveness of immunosuppressants and biologics for inducing and Schering-Plough, Shire, Takeda, UCB Pharma, Warner Chilcott) maintaining remission in Crohn’s disease: A  network meta-anal- Authorship Statement ysis. Gastroenterology. 2015;148(2):344–354. doi:10.1053/ Guarantor of article: Remo Panaccione j.gastro.2014.10.011. Author Contributions 13. Feagan BG, Sandborn WJ, Gasink C, et  al. Ustekinumab as HHS and CM contributed to study design, data collection, data anal- Induction and Maintenance Therapy for Crohn’s Disease. 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Ustekinumab induction tumor necrosis factor and postoperative complications in Crohn’s and maintenance therapy in refractory Crohn’s disease. N Engl disease: Systematic review and meta-analysis. Inflamm Bowel Dis. J Med. 2012;367(16):1519–1528. doi:10.1056/NEJMoa1203572. 2012;18(12):2404–2413. doi:10.1002/ibd.22954. 35. Mocko P, Kawalec P, Pilc A. Pharmacological Reports Safety 24. Holubar SD, Holder-Murray J, Flasar M, Lazarev M. Anti-Tumor profile of biologic drugs in the therapy of Crohn disease : A sys- Necrosis Factor-a Antibody Therapy Management Before and tematic review and network meta-analysis. Pharmacol reports. Ae ft r Intestinal Surgery for Inflammatory Bowel Disease: A CCFA 2016;68:1237–1243. doi:10.1016/j.pharep.2016.07.013. Position Paper. Inflamm Bowel Dis. 2015;21(11):2658–2672. 36. Fabiano A, De Simone C, Gisondi P, et  al. Management of doi:10.1097/MIB.0000000000000603. Patients with Psoriasis Treated with Biological Drugs Needing a 25. 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Meta-analysis: peri-opera- 2013;15(11):1392–1398. doi:10.1111/codi.12328. tive anti-TNFα treatment and post-operative complications in 43. Crowell KT, Messaris E. Risk factors and implications of anas- tomotic complications ae ft r surgery for Crohn’s disease. World patients with inflammatory bowel disease. Aliment Pharmacol J Gastrointest Surg. 2015;7(10):237–242. doi:10.4240/wjgs. Ther. 2013;37(11):1057–1064. doi:10.1111/apt.12313. v7.i10.237. 32. Subramanian V, Saxena S, Kang J, Pollok RCG. Preoperative 44. Ali T, Yun L, Rubin DT. Risk of post-operative complications Steroid Use and Risk of Postoperative Complications in Patients associated with anti-TNF therapy in inflammatory bowel disease. With Inflammatory Bowel Disease Undergoing Abdominal World J Gastroenterol. 2012;18(3):197–204. Surgery. Am J Gastroenterol. 2008;103(9):2373–2381. 45. Vande Casteele N, Gils A. Pharmacokinetics of anti-TNF mono- doi:10.1111/j.1572-0241.2008.01942.x. clonal antibodies in inflammatory bowel disease: Adding value 33. Lee RH, Efron DT , T antr y U , et  al. Inhibition of tumor necrosis factor-a to current practice. J Clin Pharmacol. 2015;55(S3):S39-S50. ae tt nuates wound breaking strength in rats. Wound Repair Regen. doi:10.1002/jcph.374. 2000;8(6):547–553. doi:10.1046/j.1524-475X.2000.00547.x. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of the Canadian Association of Gastroenterology Oxford University Press

Preoperative Ustekinumab Treatment Is Not Associated With Increased Postoperative Complications in Crohn’s Disease: A Canadian Multi-Centre Observational Cohort Study

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Abstract

Background: Ustekinumab (UST), an anti-IL12/23 inhibitor is indicated for moderate-to-severe Crohn’s disease (CD). However, it is unclear if patients treated with UST are at increased risk for post- operative complications. Aim: To evaluate the postoperative safety outcomes in UST-treated CD patients. Methods: A multicentre cohort study of UST-treated CD patients at two tertiary care centres (University of Calgary, University of Alberta, Canada) undergoing abdominal surgery between 2009 and 2016 was performed. Postoperative outcomes were compared against a control cohort of anti- TNF-treated patients over the same time-period. The primary outcome was occurrence of postop - erative complications up to six months postoperatively, stratified by timing (early <30  days vs. late complications ≥30 days). Results: Twenty UST-treated patients and 40 anti-TNF-treated patients were included with a median preoperative treatment exposure of 6.5 months and 18 months, respectively (p=0.01). Bowel obstruction was the most common surgical indication in both cohorts. UST-treated patients were more likely to require an ostomy (70.0% vs. 12.5%, p<0.001) and be on combination therapy with either systemic corticosteroids or concurrent immunomodulators (azathioprine or methotrexate) (25.0% vs. 2.5%, p=0.01). Despite the increased concomitant use of immunosuppression in the UST- treated cohort, there were no significant differences in early or late postoperative wound infections (1/20 in UST-cohort, 2/40 in anti-TNF cohort, p=1.00), anastomotic leak (0/20 in UST-cohort, 3/40 in anti-TNF cohort, p=0.54), or postoperative ileus/obstruction (3/20 in UST-cohort, 4/40 in anti-TNF cohort, p=0.67). Conclusions: CD patients receiving preoperative UST did not experience an increase in postopera- tive complications, despite increased use of concurrent immunosuppression. Keywords: Ustekinumab, Crohn’s disease, Surgery, Postoperative complications © The Author(s) 2018. Published by Oxford University Press on behalf of the Canadian Association of Gastroenterology. 115 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/jcag/article-abstract/1/3/115/4994946 by guest on 17 October 2018 116 Journal of the Canadian Association of Gastroenterology, 2018, Vol. 1, No. 3 Perioperative outcomes among UST-treated CD patients is INTRODUCTION unclear. This is of paramount clinical relevance in view of the Crohn’s disease (CD) is a chronic progressive inflammatory expected increasing use of UST for the treatment of refractory condition of the gastrointestinal tract.(1–3) In the pre-bio- CD. Therefore, we report our clinical experience with the use of logic era before the approval of infliximab in 1998, up to 80% UST in CD patients preoperatively and compare the postopera- of patients required surgical intervention for management of tive outcomes to those treated with anti-TNF therapy. disease-related complications including strictures, fistulae, and abscesses.(4,5) Since the introduction of biologic agents tar- geting tumor necrosis factor (TNF) alpha into the therapeutic METHODS armamentarium, there has been a paradigm shift in the natural Study Design and Patient Population history of CD with reduced need for surgery and hospitaliza- tion when treatment is used early, prior to the development A retrospective observational cohort study of CD patients of irreversible bowel damage and fibrostenotic disease.(6–10) treated with UST from two tertiary academic care centres In the Randomised Evaluation of an Algorithm for Crohn’s (University of Calgary, Calgary, Canada and University of Treatment (REACT 1)  cluster randomised controlled trial, Alberta, Edmonton, Canada) was performed. Adult (≥18 years) early anti-TNF initiation in combination with an immunomod- CD patients were eligible for inclusion if they met the following ulator was superior to conventional therapy for reducing surgi- criteria: (i) had a confirmed diagnosis of CD by standard endo - cal rate, hospitalization, or serious disease related complication scopic, radiologic, and histologic parameters; (ii) received UST (27.7% vs. 35.1%, p=0.0003) at 24  months.(6) However, one therapy within four months of abdominal surgery, and (iii) third of patients do not respond to anti-TNF agents due to non- subsequently underwent abdominal surgery between January TNF mediated pathways of inflammation and among respond - 1, 2009 and August 1, 2016. Abdominal surgery was defined ers, another third subsequently lose response due to insufficient as any surgery that was performed within the intra-abdom- drug levels or the development of anti-drug antibodies.(11,12) inal compartment, but did not have to be specifically for CD Non-anti-TNF biologic therapies for the treatment of CD management. Patients undergoing exclusive perianal surgery, have been limited until 2014, when the United States Food and including incision and drainage, examination under anesthesia, Drug Administration (FDA) approved vedolizumab, an α β or seton placement, were excluded. Minimum UST exposure 4 7 integrin inhibitor. Subsequently, ustekinumab (UST), a mono- time was not an inclusion criterion. clonal antibody targeting IL -12 and IL -23 through the common UST-treated patients were then compared in a 1:2 ratio to p40 subunit, was approved in 2016 by the FDA, the European a control group of CD patients treated with anti-TNF agents Medicines Agency (EMA), and Health Canada. UST has been undergoing abdominal surgery over the same time period. available since 2009 for use in patients with psoriasis. Prior to Control patients were identified using the University of Calgary its approval in 2016 for the treatment of moderate-to-severe Gastrointestinal Research Group (GIRG) database and the CD, UST had been available off-label for the compassionate University of Alberta Centre of Excellence for Gastrointestinal treatment of CD patients failing anti-TNF therapy in view of Inflammation and Immunity Research (CEGIIR) database. the favourable therapeutic response in clinical trials.(13) Matching on baseline covariates was not performed due to Approximately 30–50% of CD patients are likely to be on the small sample size; however, we restricted the selection of concurrent biologics at the time of surgery.(14) Data on the risk control patients to those undergoing surgery during the same of perioperative infections and complications with the use of time-period to control for potential temporal differences in sur - anti-TNF agents are conflicting, largely related to the significant gical and nursing-related care. heterogeneity of individual studies, patient cohorts, and nature Data were collected independently by authors (HHS and of surgery.(15–22) A  meta-analysis of eight studies reported CM) from a provincial electronic medical record system and via a trend towards an increased risk of total complications with chart review. Patient demographics including age, gender, dis- preoperative anti-TNF use.(23) No strong recommendations ease phenotype as defined by the Montreal classification,(26) with regards to perioperative use of anti-TNF therapy have tobacco exposure, body mass index (BMI) at time of surgery, been made in either the 2015 Crohn’s and Colitis Foundation serum albumin level (g/L) within one month preoperatively, of America (CCFA) position statement or the 2016 European date of surgery, nature of surgery (emergency vs. elective, lapa- Crohn’s and Colitis Organization (ECCO) consensus.(24,25) rotomy vs. laparoscopic, types and indications for surgery) were W hile it is often a joint decision with the surgeon, unnecessary collected. Medication history including biologic exposure and suspension of anti-TNF therapy and then subsequently restart- perioperative immunosuppression (corticosteroids, azathio- ing treatment ae ft r surgery may predispose patients to anti-drug prine, or methotrexate) were recorded. Systemic corticosteroid antibody formation, infusion reactions, and loss of clinical exposure was defined as a dose of ≥ 20mg per day of prednisone response. (or equivalent) given within four weeks perioperatively. Downloaded from https://academic.oup.com/jcag/article-abstract/1/3/115/4994946 by guest on 17 October 2018 Journal of the Canadian Association of Gastroenterology, 2018, Vol. 1, No. 3 117 treated with systemic corticosteroids (35% vs. 15%, p=0.10), Outcomes have stricturing disease phenotype (50% vs. 27.5%, p=0.13), The primary outcome of interest was the occurrence of post - and have disease affecting the upper gastrointestinal tract (35% operative complications, up to six months aeft r surgery. vs. 10%, p=0.53), although these associations were not statisti- Postoperative complications were defined by the follow - cally significant. ing events: (a) wound infection; (b) anastomotic leak; (c) All patients from the UST cohort were infliximab-experi - intra-abdominal abscess; (d) non-surgical site infection; (e) enced (either intolerant, primary non-responders, or developed delayed wound healing at one month post-surgery; (f ) need secondary loss of response to maintenance anti-TNF therapy). for readmission or reoperation; (g) median duration of hospi- Seventy percent (14/20) were intolerant or had lost response to tal admission; and (h) postoperative mortality. Outcomes of at least two anti-TNF therapies. In comparison, the majority of interest were defined by clinical assessment and where appro - anti-TNF-treated patients (77.5%, 31/40) were previously bio- priate, supplemented by diagnostic imaging. Postsurgical out- logic naïve and were on their first biologic at the time of surgery. comes for both cohorts were stratified by time to occurrence: Disease duration was numerically but not statistically longer early (<30 days post-surgery) and late (≥30 days and up to six in the UST-treated cohort compared to the anti-TNF-treated months post-surgery). cohort (median disease duration 14.5 years [IQR 8.5–19.5] vs. 7.0 [IQR 3.0–15.5] years, p=0.07). UST-treated patients were Statistical analysis also more likely to be smokers (50% vs. 5%, p<0.001) and had Baseline patient characteristics were analysed using standard a higher burden of concomitant methotrexate (45% vs. 15%, descriptive statistics; medians with interquartile ranges (IQR) p=0.02) and combination corticosteroid with immunomod- were calculated for continuous data and percentage were calcu- ulator (either azathioprine or methotrexate) (25% vs. 2.5%, lated for categorical data. Comparisons between baseline char- p=0.01). Previous treatment history of both cohorts is summa- acteristics and postoperative outcomes between UST-treated rized in Table 2. and anti-TNF-treated patients were performed using the Mann-W hitney U test for non-parametric continuous variables Surgical Details and Fisher exact test for categorical data. A  p-value <0.05 was Surgical details, including surgical indication, nature of surgery, considered to be statistically significant. Statistical analysis was and surgical type are summarized in Table 3. The predominant performed using SPSS 24.0 (Armonk, NY: IBM Corporation). indication for surgery in both cohorts was bowel obstruction (12/20 for UST and 26/40 for anti-TNF cohort, p=0.19). Ethical Considerations However, UST-treated patients were more likely to undergo This study was approved by the Human Research Ethics Board surgery in the emergent setting (55% vs. 25%, p=0.04) and at both the University of Calgary and the University of Alberta. require a postoperative ostomy (70.0% vs. 12.5%, p<0.001). Although not statistically significant, UST-treated patients were RESULTS also more likely to have undergone either proctocolectomy Patient Population (10% vs. 0%, p=0.10) or subtotal colectomy (20.0% vs. 7.5%, p=0.21). A similar proportion of patients treated with UST and Twenty-one UST-treated CD patients who underwent abdom- anti-TNF required ileal and ileocolonic resections (30.0% vs. inal surgery between January 1, 2009 and August 1, 2016 were 22.5%, p=0.54 and 35.0% vs. 42.5%, p=0.78, respectively). identified. One patient required emergency abdominal sur - gery outside of the study centres and due to incomplete data Postoperative Outcomes was excluded from the cohort. Forty anti-TNF treated CD patients who underwent abdominal surgery during the same There were no significant differences across both cohorts for all time period were included in the control group. Half of these postoperative complications, followed out to six months ae ft r patients (20/40) received adalimumab, 18/40 (45%) received surgery (Table  4). There were no significant differences in the infliximab, and 2/40 (5%) received golimumab as their most rate of anastomotic leak, intra-abdominal abscess, non-surgi- immediate pre-operative anti-TNF agent. Although golimumab cal site infection, delayed wound heaing, need for readmission is not listed for the treatment of CD in Canada, it was used or reoperation, or median days of total hospital stay for both off-label for both the patients as salvage therapy ae ft r they lost cohorts. No deaths were reported in both cohorts at six months. response to infliximab and adalimumab. Baseline patient demo - Only a single postoperative wound infection was reported in graphics are summarized in Table  1. There were no significant the UST-treated cohort. differences between both cohorts based on age, gender, BMI, UST was continued in 13 patients (65%) and anti-TNF coexistent diabetes mellitus, or pre-operative serum albumin therapy was continued in 28 patients (70%) postoperatively. level. UST-treated patients were nominally more likely to be Immunomodulator therapy with methotrexate or azathioprine Downloaded from https://academic.oup.com/jcag/article-abstract/1/3/115/4994946 by guest on 17 October 2018 118 Journal of the Canadian Association of Gastroenterology, 2018, Vol. 1, No. 3 Table 1. Baseline patient demographics Ustekinumab cohort (n=20) Anti-TNF cohort (n=40) P value Median age (years, IQR) 34.5 (26.3–51.5) 32.5 (22–42.5) 0.34 Male gender (n, %) 5 (25%) 15 (37.5%) 0.39 Current smoker (n, %) 10 (50%) 2 (5%) <0.001 Median BMI (IQR) 23.6 (19.6–27.6) 23.6 (20.2–25.7) 1.00 Median duration of postsurgical follow up (months, IQR) 14.5 (6.3–21.8) 39.5 (22–56.8) <0.001 Median duration of CD prior to surgery (years, IQR) 14.5 (8.5–19.5) 7 (3–15.5) 0.07 Median duration of biologics prior to surgery (months, IQR) 6.5 (3–12) 18 (5–33) 0.007 Montreal classification Age: 10 (50%) 13 (32.5%) 0.26 A1 A2 7 (35%) 23 (57.5%) A3 3 (15%) 4 (10%) Behaviour: 2 (10%) 2 (5%) 0.13 B1 B2 10 (50%) 11 (27.5%) B3 8 (40%) 27 (67.5%) P 7 (35%) 12 (30%) 0.77 Location: 5 (25%) 17 (42.5%) 0.53 L1 L2 3 (15%) 3 (7.5%) L3 9 (45%) 16 (40%) L3+ L4 3 (35%) 4 (10%) Previous history of intestinal resection (%, range) 60% (0–3) 47.5% (0–9) 0.36 Median preoperative serum albumin (g/L, IQR) 34.0 (28–42.2) 34.0 (30.5–38) 0.53 Concomitant diabetes mellitus 0% 0% - Perioperative immunosuppression (n, %) Corticosteroid ≥ 20mg/day 7 (35%) 6 (15%) 0.10 Azathioprine 4 (20%) 10 (25%) 0.75 Methotrexate 9 (45%) 6 (15%) 0.02 Combination corticosteroid and azathioprine/ 5 (25%) 1 (2.5%) 0.01 methotrexate was added in 5 patients in the UST group (25%) and 11 patients we anticipate an increase in the number of patients who are on in the anti-TNF group (27.5%). Therapy was changed in two UST preoperatively. A fundamental question with any biologic patients (10%) in UST group to vedolizumab postoperatively; therapy is whether exposure adversely influences post-opera - therapy was changed in three patients (7.5%) in the anti-TNF tive outcomes. In this multicenter cohort study, we demonstrate group to UST postoperatively. All medical therapy was discon- no increased risk of either early or late postoperative compli- tinued ae ft r surgery in two patients (10%) in the UST-treated cations in UST-treated patients undergoing intra-abdominal group and seven patients (17.5%) in the anti-TNF group. surgery as compared to patients treated with anti-TNF agents. This is despite UST-treated patients experiencing a significantly greater burden of immunosuppression preoperatively but may DISCUSSION also be confounded by a significantly higher proportion requir - Although the introduction of biologic therapy has ushered in ing postoperative ostomy creation. a new era in the management of CD, surgery continues to hold The impact of preoperative biologic therapy on postoperative a fundamental role in the treatment paradigm for patients with outcomes and in particular, postoperative infections, remains medically refractory or complicated CD. Indeed, approximately controversial.(27–29) Previous meta-analyses have demon- half of CD patients will require bowel resection within 10 years strated a modestly increased risk of postoperative infectious of diagnosis.(9) With the increasing adoption of UST for CD, complications associated with preoperative anti-TNF exposure Downloaded from https://academic.oup.com/jcag/article-abstract/1/3/115/4994946 by guest on 17 October 2018 Journal of the Canadian Association of Gastroenterology, 2018, Vol. 1, No. 3 119 Table 2. Treatment exposure history Ustekinumab cohort (n=20) Anti-TNF cohort (n=40) Immunomodulators Azathioprine 11 (55%) 11 (27.5%) Methotrexate 6 (30%) 9 (22.5%) Previous anti-TNF therapy Infliximab 20 (100%) 7 (17.5) Adalimumab 13 (65%) 4 (10%) Certolizumab 1 (5%) 0 Golimumab 3 (15%) 0 Previously biologic naive 0 31 (77.5%) Failed 1 anti-TNF therapies 6 (30%) 7 (17.5%) Failed 2 anti-TNF therapies 11 (55%) 2 (5%) Failed 3 anti-TNF therapies 3 (15%) 0 Other previous biologics exposure (commercial/clinical trials) Vedolizumab 1 (5%) 0 Ustekinumab - 1 (2.5%) Briakinumab (ABT-894) 0 1 (2.5%) CCR-9 inhibitor 1 (5%) 0 Table 3. Surgical details Ustekinumab cohort (n=20) Anti-TNF cohort (n=40) P value Indication of surgery: Medical refractory disease ^5 (25%) ^^3 (7.5%) 0.19 Obstruction 12 (60%) 26 (65%) Free bowel perforation 2 (10%) 2 (5%) Intraabdominal abscess 0 2 (5%) Closure of ostomy 0 3 (7.5%) Others *1 (5%) **4 (10%) Nature of surgery: Emergency 11 (55%) 10 (25%) 0.04 Open laparotomy 13 (65%) 20 (50%) 0.40 Type of surgery (n,%): Ileal resection 6 (30%) 9 (22.5%) 0.54 Ileocolonic resection 7 (35%) 17 (42.5%) 0.78 Subtotal colectomy 4 (20%) 3 (7.5%) 0.21 Proctocolectomy 2 (10%) 0 0.10 Ostomy 14 (70%) 5 (12.5%) <0.001 Primary anastomosis 9 (45%) 26 (65%) 0.17 Stricturoplasty 1 (5%) 2 (5%) 1.00 Fistula repair 2 (10%) 3 (7.5%) 1.99 Hernia repair 1 (5%) 1 (2.5%) 1.00 Cholecystectomy 1 (5%) 4 (10%) 0.66 Appendectomy 0 1 (2.5%) 1.00 Adhesiolysis 0 7 (17.5%) 0.08 ^inflammatory (ileo)colitis refractory to treatment x5 ^^ inflammatory colitis refractory to treatment x 2, defunctioning loop ileostomy for refractory perianal disease x1 *cholecystectomy for cholecystitis **cholecystectomy for porcelain gallbladder; cholecystectomy for gall bladder cancer; cholecystectomy for biliary colic x2 Downloaded from https://academic.oup.com/jcag/article-abstract/1/3/115/4994946 by guest on 17 October 2018 120 Journal of the Canadian Association of Gastroenterology, 2018, Vol. 1, No. 3 Table 4. Postoperative outcomes Ustekinumab cohort (n=20) Anti-TNF cohort (n=40) P value Postoperative complications: Wound infection ≤ 30 days 1 (5%) 2 (5%) 1.00 Wound infection > 30 days 0 0 - Anastomotic leakage ≤ 30 days 0 3 (7.5%) 0.54 Anastomotic leakage > 30 days 0 0 - Abscess ≤ 30 days 0 4 (10%) 0.29 Abscess > 30 days 0 2 (5%) 0.54 Nonsurgical site infection ≤ 30 days 0 3 (7.5%) 0.54 Nonsurgical site infection > 30 days 0 0 - Postoperative ileus /bowel obstruction 3 (15%) 4 (10%) 0.67 Delayed wound healing 0 5 (12.5%) 0.16 Need for reoperation/readmission 2 (10%) 6 (15%) 0.59 Median preoperative hospital stay (days, IQR) 0 (0–4) 0 (0–2) 0.59 Median total hospital stay (days, IQR) 7 (5–14) 7 (4–9) 0.45 Mortality at 6 months 0 0 - (OR 1.45–1.56), with a magnitude of associated risk similar to conventional biologics including various anti-TNF agents and that of systemic corticosteroids.(30–32) Furthermore, it has vedolizumab. Not unexpectedly, there was greater use of corti- been shown in animal models that TNF inhibition reduces costeroids, methotrexate, and combination corticosteroid and angiogenesis and collagen production. It has therefore been immunomodulator in UST-treated patients. While periopera- hypothesized to potentially inhibit wound healing in postop- tive use of immunomodulators appears to be safe, perioperative erative patients.(33) Biologically, UST blocks upstream Th1 corticosteroid use has previously been associated with increased and Th17 cytokine signalling involved in the proinflammatory total complications.(32,37,38) UST-treated patients in this response, and does not directly disrupt TNF pathways. cohort also tended to be smokers, have a significantly longer CD In the clinical trial development programs, there were duration, require emergent surgery, and have medical refractory no increased risks of serious adverse events or infections in disease: all are predictors of poor postoperative outcomes, but patients who received UST when compared to placebo.(13,34) despite these poor prognostics factors, our pilot data did not Although there is no direct head-to-head comparison, a sys- appear to have biased findings towards increased risk in UST- tematic review with network meta-analysis of 10 RCT reported treated patients. Our findings correlate with a recently published no significant difference in the safety profile between UST, retrospective cohort of 44 UST-treated patients undergoing anti-TNF agents and vedolizumab.(35) Fabiano et al. have also abdominal surgery: Lightner et al. also found no increased risk of reported the perioperative outcomes of a cohort of 131 patients surgical site infections or hospital readmission when comparing with psoriasis treated with various biologics (infliximab, adali - UST and anti-TNF treated patients.(39) mumab, UST and etanercept)(36). UST-treated patients were Of note, we observed a higher proportion of patients in however a minority (13/131, 10%) of the cohort and most sur- the UST cohort who received an ostomy (70% vs. 12.5%, geries in this study (73/131, 56%) were performed for minor p<0.001). We postulate there are multiple reasons for this dif- procedures (dermatologic and dental). There was no increased ference in ostomy creation, including: 1)  possible hesitancy risk of wound infection for those who continued with biologic from surgeons to create a primary anastomosis in patients on therapy compared to patients electively discontinuing therapy UST; 2) a greater need for emergency rather than elective sur- prior to surgery. gery among patients on UST; and 3)  more complex disease From our cohort of CD patients treated with UST, we did phenotype and longer disease duration among UST-treated not observe an increased risk of adverse perioperative out- patients compared to anti-TNF-treated patients precluding comes compared to CD patients treated with anti-TNF agents. primary anastomosis. The difference in ostomy creation intro - This was despite a greater exposure to immunosuppressants duces a potential source of bias in interpreting post-operative and more complicated disease phenotype in the UST-treated complication rates: ostomy creation may partially mitigate the cohort. Our UST-treated cohort was comprised of patients who risk of early post-surgical complications, such as wound dehis- were nominally more likely to have upper GI involvement, stric- cence, especially in complex CD patients with greater preoper- turing disease phenotype, and were unsuccessfully treated with ative immunosuppressant burden. However, if the decision for Downloaded from https://academic.oup.com/jcag/article-abstract/1/3/115/4994946 by guest on 17 October 2018 Journal of the Canadian Association of Gastroenterology, 2018, Vol. 1, No. 3 121 ostomy creation was driven by more aggressive CD phenotype, comparisons may be confounded by potentially important dif- this population would inherently be at increased risk for post- ferences in clinical characteristics between the two groups, such operative complications. as preoperative medication use and disease phenotype. Finally, Other confounders that we have considered, including we present a multicentre experience with UST-treated patients patient comorbidities such as age and diabetes mellitus, were requiring intra-abdominal surgery, but the study is underpow- comparable in both cohorts. To explore the effect of malnutri - ered due to 1)  small total cohort size and 2)  small number of tion as a confounder for occurrence of adverse perioperative postoperative complications. However, this study represents outcomes, we compared preoperative BMI and serum albumin the first uniquely Canadian experience with UST in a clini - levels in both cohorts as surrogate measures of overall nutri- cally important and understudied setting and we hope to stim- tional status, recognizing the inherent limitations that serum ulate collaborative efforts from other authors to confirm these albumin is a negative phase reactant in acute inflammation and findings. obese patients are not precluded from malnturtion.(40,41) In conclusion, in this multicentre cohort study, we found pre- Regardless, these markers were comparable for both cohorts. operative UST exposure to be associated with an increased risk Elderly age and longer preoperative hospital stay were noted to of requiring postoperative ostomy but not associated with an be potential risk factors for post-colectomy complications in a increased risk of early or late perioperative complications com- study by Bartels et al.(42) However, these factors were not con- pared to preoperative anti-TNF therapy. However, larger pro- firmed to be significant predictors in our cohort. For the single spective studies will be needed to confirm these findings. Funding Support: Christopher Ma was supported by a Canadian UST-treated patient who developed an early wound infection, Association of Gastroenterology Resident Research Award and by a there were multiple potential confounders, including presenta- Clinician Fellowship from the Canadian Institutes for Health Research. tion with a perforated viscus, operation in an emergency set- Writing Assistance: None ting, open laparotomy, and significant corticosteroid exposure (≥ 20mg/day).(32,43) Interestingly, we observed a relatively low rate of postopera- ACKNOWLEDGEMENTS tive complications in this cohort, especially in comparison to None declared. previous reports where complication rates approached 20% on Conflict of Interest anti-TNF therapy.(44) Possible explanations of our low com- HHS: Advisory board ( Janssen, Ferring) plication rates may include the selection of a relatively young CM, HA, AKA, JXQP: nil patient cohort without a substantial burden of comorbid ill- PGK : Consulting (Abbvie, Takeda, Pfizer), speaker’s bureau ( Janssen, Abbvie, Takeda, Ferring, Pfizer, UCB) ness predisposing to postoperative complications, improve- CHS: Advisory board (Janssen, Abbvie, Shire, Takeda, Actavis), ments in surgical technique (particularly less invasive surgical speaker’s bureau ( Janssen, Abbvie) approaches) over time, and optimized post-surgical care and RNF: Advisory board (Abbott/AbbVie, Celltrion, Ferring, Janssen, nursing support. However, our low postoperative event rate in Shire, VSL#3), consulting fees (Abbott/AbbVie, Celltrion, Ferring, the anti-TNF cohort may limit our ability to detect true differ - Janssen, Shire, VSL#3), research grants (Abbott/AbbVie, Alba ences from the UST-treated group. Therapeutics, BMS, Celltrion, Centocor, Genentech, GSK, Janssen, There are some limitations to our study. Due to the retrospec - Merck, Millennium, Novartis, Pfizer, Proctor & Gamble, Roche, tive nature, there are inherent limitations with respect to recall VSL#3) bias and incomplete data reporting. For example, periopera- SMD: Advisory board (Takeda, Shire, AbbVie, Janssen, Ferring, tive drug level testing was not routinely available for analysis. Hospira), speaker’s bureau (AbbVie, Janssen, Shire, Ferring, Takeda) Furthermore, exact quantification of preoperative UST expo - LAD: Consulting fees (AbbVie, Janssen), speaker’s bureau (AbbVie, sure is challenging: UST and adalimumab are self-administered Janssen) GGK: Advisory board ( Janssen, Abbott, Merck, Schering-Plough, and we could not ensure compliance with medical therapy prior Shire, UCB Pharma), research support (Merck, Abbott, GlaxoSmith to surgery. Therefore, reliable confirmation of last dose of bio - Kline, Shire), speaker’s bureau (Janssen, Merck, Schering-Plough, logic preoperatively to determine the washout period and date Abbott, UCB Pharma) of restarting biologic therapy postoperatively were only partially KLN: Advisory board (AbbVie, Janssen, Pfizer, Ferring), research sup - available and not included in the analysis to minimize obser- port (AbbVie, Janssen), speaker’s bureau (Abbvie, Janssen) vation bias. They are however, unlikely to be significant con- KIK: Consulting fees (AbbVie, Janssen, Takeda, Ferring), speaker’s founders in view of the long half-life of biologics.(45) Further, bureau (AbbVie, Janssen) up to 55% of surgeries were performed in the emergency setting BPH: Consulting fees (AbbVie, Janssen), speaker’s bureau (AbbVie, for UST-treated patients, limiting the washout period. Due to Janssen, Shire, Pendopharm) small sample size, our UST-treated cohort was compared with RP: Advisory board (Abbott/AbbVie, Amgen, Janssen, Merck, Pfizer, a randomly selected anti-TNF-treated cohort rather than a Prometheus Laboratories, Salix Pharma, Shire, Takeda, Warner control group that was matched for covariates. Therefore, any Chilcott), consulting fees (Abbott/AbbVie, Amgen, Aptalis, Astra Downloaded from https://academic.oup.com/jcag/article-abstract/1/3/115/4994946 by guest on 17 October 2018 122 Journal of the Canadian Association of Gastroenterology, 2018, Vol. 1, No. 3 Zeneca, Baxter, BMS, Centocor, Elan/Biogen, Eisai, Ferring, GSK, 10. Frolkis AD, Lipton DS, Fiest KM, et  al. Cumulative incidence Janssen, Merck, Millennium, Pfizer, Proctor & Gamble, Prometheus of second intestinal resection in Crohn’s disease: a system- Therapeutics and Diagnostics, Schering-Plough, Shire, Takeda, UCB atic review and meta-analysis of population-based studies. Pharma, Warner Chilcott), research grants (Abbott/AbbVie, Amgen, Am J Gastroenterol. 2014;109(11):1739–1748. doi:10.1038/ Aptalis, Astra Zeneca, Baxter, BMS, Centocor, Eisai, Elan/Biogen, ajg.2014.297. Ferring, GSK, Janssen, Merck, Millennium, Pfizer, Proctor & Gamble, 11. Danese S, Vuitton L, Peyrin-Biroulet L. Biologic agents for Prometheus, Shire, Schering-Plough, Takeda, UCB Pharma, Warner IBD: practical insights. Nat Rev Gastroenterol Hepatol. Chilcott), speaker’s bureau (Abbott/AbbVie, Amgen, Aptalis, Astra 2015;12(9):537–545. doi:10.1038/nrgastro.2015.135. Zeneca, Baxter, BMS, Centocor, Eisai, Elan/Biogen, Ferring, GSK, 12. Hazlewood GS, Rezaie A, Borman M, et  al. Comparative effec - Janssen, Merck, Millennium, Pfizer, Proctor & Gamble, Prometheus, tiveness of immunosuppressants and biologics for inducing and Schering-Plough, Shire, Takeda, UCB Pharma, Warner Chilcott) maintaining remission in Crohn’s disease: A  network meta-anal- Authorship Statement ysis. Gastroenterology. 2015;148(2):344–354. doi:10.1053/ Guarantor of article: Remo Panaccione j.gastro.2014.10.011. Author Contributions 13. Feagan BG, Sandborn WJ, Gasink C, et  al. Ustekinumab as HHS and CM contributed to study design, data collection, data anal- Induction and Maintenance Therapy for Crohn’s Disease. 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Journal of the Canadian Association of GastroenterologyOxford University Press

Published: Sep 12, 2018

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