Long-Term Results and Recurrence-Related Risk Factors for Crohn Disease in Patients Undergoing Side-To-Side Isoperistaltic Strictureplasty

Research

Original Investigation Long-term Results and Recurrence-Related Risk Factors for Crohn Disease in Patients Undergoing Side-to-Side Isoperistaltic Strictureplasty

Marilena Fazi, MD; Francesco Giudici, MD, PhD; Cristina Luceri, PhD; Micaela Pronestì, MD; Francesco Tonelli, MD

Invited Commentary page 461 IMPORTANCE Side-to-side isoperistaltic strictureplasty (SSIS) is useful in patients undergoing surgery for Crohn disease (CD) to avoid wide small-bowel resections. To our knowledge, there are no definitive data regarding its recurrence risk factors.

OBJECTIVE To evaluate the results obtained in a monocentric population of patients with CD who have undergone SSIS.

DESIGN, SETTING, AND PARTICIPANTS From August 1996 to March 2010, 91 patients with CD underwent SSIS in our center. In this prospective observational study, side-to-side isoperistaltic strictureplasty was according the Michelassi technique in 69 patients and the Tonelli technique in 22 patients. Factors relating to the patient and the CD, surgery, and pharmacological therapy during the preoperative and perioperative periods were evaluated in association with medical or surgical recurrence.

EXPOSURE Side-to-side isoperistaltic strictureplasty.

MAIN OUTCOMES AND MEASURES The recurrence-free curve was estimated using Kaplan-Meier analysis. Patients were stratified into cohorts in relation to the considered categorical variables and data were compared by using the Mantel-Cox log-rank test. Cox proportional hazard regression analysis was used to set up a predictive model simultaneously exploring the effects of all independent variables on a dichotomous outcome recurrence in relation to time.

RESULTS Among the 91 patients, the mean (SD) age was 39.5 (11.2) years and preoperative disease duration was 97.9 (85.8) months; 83 patients (91.2%) were followed up, of whom 37 (44.58%) experienced a recurrence at a mean (SD) of 55.46 (36.79) months after surgery (range, 9-140 months). The recurrence in the SSIS site at a mean (SD) of 48.25 (29.94) months after surgery affected 24 of 83 patients (28.9%), 9 being medical and 15 being surgical recurrence. Recurrence in the SSIS was statistically significantly associated with the time elapsed between diagnosis and surgery (P = .03). A borderline association between family history of CD and surgical recurrence (P = .054) was also found. Multivariate analysis identified the age at diagnosis (χ2 = 5.56; P = .02) and at surgery (χ2 =7.77;P = .005), family history (χ2 = 6.26; P = .01), and smoking habit (χ2 = 10.06; P = .007) as independent risk factors for recurrence.

CONCLUSIONS AND RELEVANCE In the short-term, SSIS leads to a resolution of symptoms in more than 90% of cases and the recurrence rate in the SSIS area is acceptable, even after Author Affiliations: Department of Surgery and Translational Medicine, long-term follow-up. University of Florence, Careggi University Hospital, Florence, Italy (Fazi, Giudici, Pronestì, Tonelli); Section of Pharmacology and Toxicology, Department of NEUROFARBA, University of Florence, Florence, Italy (Luceri). Corresponding Author: Marilena Fazi, MD, Department of Surgery and Translational Medicine, University of JAMA Surg. 2016;151(5):452-460. doi:10.1001/jamasurg.2015.4552 Florence, Largo Brambilla 3, 50134 Published online December 30, 2015. Florence, Italy ([email protected]).

452 (Reprinted) jamasurgery.com

Downloaded From: http://archsurg.jamanetwork.com/ by a UNIEVERSITA DEGLI STUDI DI FIRENZE User on 08/05/2016 Results and Risk Factors of Side-to-Side Isoperistaltic Strictureplasty in Crohn Disease Original Investigation Research

he surgical outcome of Crohn disease (CD) is character- Table 1. Demographics and Clinical Characteristics of the Patients ized by recurrence even after “radical” operations, T which remove both microscopically and macroscopi- Characteristic No. (%) cally affected bowel. Although the surgical approach in the past Age, mean (SD), y 39.5 (11.2) has been characterized by radical resections of the affected Preoperative disease duration, mean (SD), mo 97.9 (85.8) areas, the present therapeutic approach is to perform conser- Age at diagnosis, mean (SD), y 29 (11.2) vative operations and reduce the risk for short-bowel syn- Sex drome. Included in this approach are techniques such as mini- Male 48 (52.7) mal resection and strictureplasty (SXPL). Lee and Papaioannou Female 43 (47.3) were the first to use SXPL in patients with CD in 1982.1 Over Family history of IBD the last 30 years, the SXPL method has further expanded and Yes 18 (19.8) been performed even in long strictures. No 73 (80.2) 2 In 1996, Michelassi described a new type of SXPL known Smoking habit as side-to-side isoperistaltic strictureplasty (SSIS). In 2000, a Yes 34 (37.4) variation in the original technique in the section of the neo- No 34 (37.4) terminal ileum and colic cul-de-sac at the level of a previous Former smoker 23 (25.2) side-to-side or end-to-side ileo-colic anastomosis performed Disease location for CD was described by one of the authors (F.T.).3 Duodenum-jejunum 5 (5.5) In 2004, our center evaluated patients who had under- Jejunum-ileum 40 (44) gone SSIS, but at the time, the cases were still limited (n = 21) Distal ileum-colon 46 (50.5) and the follow-up relatively short.4 In 2007, a retrospective ob- Associated perianal disease servational, multicenter international study was conducted Yes 16 (17.5) with the purpose of assessing the results achieved with SSIS No 75 (82.5) in its first 10 years of use in treating CD. The evidence ob- Abdominal fistula/abscess tained proved how it could be considered a safe technique, with very low morbidity and mortality rates and an acceptable risk Yes 12 (13.2) for recurrence.5 No 79 (86.8) Because the evaluation of risk factors implicated in the Associated disease recurrence of CD in the strictureplasted bowel is still Celiac disease 3 (3.3) extremely limited, the purpose of this study was to evaluate Hepatitis 4 (4.4) the results obtained in a large population of patients with CD Osteopenia/osteoporosis 2 (2.2) who have undergone SSIS, after long-term follow-up, and Psoriasis 2 (2.2) especially to identify possible recurrence-related factors at Sacroileitis/polyarthritis 2 (2.2) the SSIS site. Nodosum erythema 1 (1.1) Recurrent venous thrombosis 2 (2.2) Cholelithiasis 1 (1.1) Methods More than 1 of the above 4 (4.4) Malnutrition From August 1996 to March 2010, 91 patients with CD (48 men Yes 39 (42.8) and 43 women; median age, 39 years; range, 20-71 years) con- No 45 (57.2) secutively underwent SSIS in our center; the operations were Preoperative therapy performed by the same surgeon. The study was approved by 5-ASA ± CCS 56 (61.5) the local ethics committee of Azienda Ospedaliera Careggi. Oral Immunosuppressants 28 (30.8) informed consent was obtained from the study participants. Biological therapies 7 (7.7) At the time of first surgery, 34 patients were smokers, 23 were former smokers, and 34 had never smoked. The main indica- Abbreviations: 5-ASA, 5-amino-salicylic acid; CCS, corticosteroids; IBD, inflammatory bowel disease. tion for surgery was bowel obstruction in 68 cases, malnutrition in 11 patients, and fistula and/or abscess in 12 patients. Of those patients with fistulizing CD, 7 had entero-enteric fistulae, 1 had entero-colic fistulae, 2 had entero-sigmoideal fistu- ried out simultaneously during the same operation in 3 lae, and 3 had multiple fistulae (between the ileum and the patients. The clinical characteristics of the patients are shown bladder, vagina, skin, colon, and sigma). Seven of these pain Table 1. tients also had an abscess: mesenteric in 5, pelvic in 1, and near The mean extent of diseased bowel was 69.97 cm (range, the bladder in 1. 20-150 cm). Strictures were classified as short (≤6 cm in length) Fifty-two patients had already undergone 1 (n = 30), 2 or long (>6 cm in length). The strictures involved in the SSIS (n = 12), 3 (n = 4), 4 (n = 5), or 5 (n = 1) operations for CD. were long and continuous in 18 patients, short and multiple Appendectomy had been previously performed in 17 patients. in 54, and both short and long in 19. The median length of the A total of 94 SSISs had been performed, as 2 SSISs were car- long continuous strictures was 15 cm (range, 7-80 cm) and 2.5

jamasurgery.com (Reprinted) JAMA Surgery May 2016 Volume 151, Number 5 453

Downloaded From: http://archsurg.jamanetwork.com/ by a UNIEVERSITA DEGLI STUDI DI FIRENZE User on 08/05/2016 Research Original Investigation Results and Risk Factors of Side-to-Side Isoperistaltic Strictureplasty in Crohn Disease

cm for the short ones (range, 0.5-6 cm). The median thick- of each variable among patients in the recurrence and nonre- ness of the intestinal wall at the section where the SSIS was currence categories were evaluated using the χ2 test or t test, performed was 8.5 mm (range, 5-16 mm). The mean length of as appropriate. residual small bowel was 263.53 cm (range, 120-450 cm). The recurrence-free curve was estimated using Kaplan- Meier analysis of different outcomes. Patients were stratified Surgical Technique into cohorts in relation to the considered categorical vari- Side-to-side isoperistaltic strictureplasty was performed with ables and data were compared using the Mantel-Cox log-rank the technique described by Michelassi in 1996 in 69 patients, test. Cox proportional hazard regression analysis was used to whereas we used the previously described personal tech- set up a predictive model simultaneously exploring the nique in the remaining 22 patients who had an ileal relapse at effects of all independent variables on a dichotomous out- a previous ileo-colic anastomosis.2,3 come recurrence in relation to time (dependent variable val- Side-to-side isoperistaltic strictureplasty was performed ues: censored/complete). The quantitative variables were at the level of the duodenum-jejunum in 5 patients, at the je- transformed into dichotomous categorical ones, and hazard juno-ileum in 40 patients, and on the distal ileum-colon in 46 ratios (HRs) and 95% CIs were calculated using standard patients. methods. The median length of the diseased bowel where the SSIS The univariate analysis included the following indepen- was performed was 55 cm (range, 10-140 cm), and the me- dent variables: patient factors (sex, age at diagnosis and at sur- dian length of the SSIS was 28.41 cm (range, 8-72 cm). A syn- gery, smoking habits, number of cigarettes per day, years of chronous intestinal resection was necessary in 41 patients; in smoking, and family history of inflammatory bowel disease 28 of these, the diseased bowel resected was located in the [IBD]); disease factors (time between diagnosis and first sur- middle of the tract where SSIS had to be performed with a mean gery, number of previous surgical procedures, presence of fis- length of 28.5 cm (range, 3-92 cm). Resection was performed tulae and/or abscesses, and presence of associated perianal dis- at different disease locations cranially or distally from the SSIS eases); surgery factors (technique, number of strictures in SSIS, site in the remaining 12 patients. number of SXPLs, final length of the SSIS, disease location, and A total of 41 patients had undergone additional SXPLs (16 associated appendectomy); pharmacological therapy factors singles and 25 multiples, up to a maximum of 11). The fistu- (presurgical and postsurgical therapy); and perioperative fac- lizing diseased bowel was resected in 6, whereas the fistula was tors (blood transfusions and total parenteral nutrition). Other sutured without resection in 5 patients. Abdominal abscess was preoperative factors included the presence of anemia, in- drained intraoperatively in 4 of 7 patients, whereas the ab- crease in inflammatory indexes, and malnutrition. scesses were included in the resection in the remaining 3. Side- All the independent variables of the univariate analysis to-side isoperistaltic strictureplasty was performed together were forced in the Cox proportional hazard model with back- with appendectomy in 12 cases, cholecystectomy in 2 cases, ward elimination applied to select the most promising subset hemicolectomy in 2 cases, and a subtotal colectomy in 1 case. of predictors by multiple regression. Every patient was biopsied to exclude the presence of neo- plastic tissue at the SSIS site. Results Early Postoperative Treatment At discharge, 5-amino-salicylic acid (5-ASA) by mouth was None of the 91 patients died during surgery but 24 experi- prescribed, while corticosteroid therapy administered pre- enced postoperative complications. Four patients had an operatively was gradually decreased. No prophylactic immu- enterorrhagia between the third and eighth postoperative nosuppressive or biological therapy were scheduled in these days treated with medical therapy and 1 developed a hema- patients. toma in the rectal abdominal muscles that was drained percu- taneously. One patient had anastomotic dehiscence of the Follow-up SSIS; another patient had dehiscence of associated restricture- Patients were scheduled for outpatient clinical assessment 1, plasty (Heineke-Mikulicz [HM]) SXPL. Both patients were 3, 6, and 12 months and then every 6 months following sur- reoperated on the second and seventh postoperative days gery to evaluate the symptoms, bowel habit, body weight, and with suture of the dehiscence and peritoneal toilette, respec- results of laboratory examinations and imaging studies tively. One patient had dehiscence of 2 associated short SXPLs performed. with peritonitis requiring ileal resection and temporary termi- We considered CD recurrence to be the relapse of disease nal ileostomy. One patient had a pelvic abscess treated with symptoms in the presence of radiologically and/or endoscopi- computed tomography–guided drainage. cally confirmed stricturing and/or inflammatory lesions re- Ten patients had a bloodstream infection from the cen- quiring medical treatment or surgery. tral venous catheter, 3 patients developed suppuration of the surgical wound, and 2 cases had prolonged postoperative para- Statistical Analysis lytic ileum. Statistical analysis was carried out using the STATGRAPHICS Patients’ intestinal activity restarted between the third and Centurion XV statistical package (StatPoint Inc) and the use of 13th postoperative days (mean, day 5), and nutrition was re- GRAPHPAD Prism 5 software. Differences in the distribution sumed gradually from postoperative day 2.

454 JAMA Surgery May 2016 Volume 151, Number 5 (Reprinted) jamasurgery.com

The median postoperative stay was 12 days (range, 7-87 Patients with recurrence received postoperative therapy days); 13 patients needed 1 or more blood transfusions due to that was significantly different; in particular, none of them had serious anemia, 6 of whom during the preoperative period, 6 received mesalazine alone while most of them had therapies during the postoperative period, and 1 during surgery. with corticosteroids, immunosuppressant drugs, or biologi- After surgery, all patients had resolution of obstructive cal therapies. symptoms. During the third month after surgery, 85% of pa- Moreover, recurrent patients had a family history of CD or tients (n = 77) had increased body weight, and 68% (n = 62) ex- IBD at higher frequency compared with the no recurrence cases perienced normalization of inflammation indexes. Obstruc- (32.4% vs 13%) but this difference did not reach statistical sig- tive symptoms relapsed within 2 weeks after discharge in only nificance (P = .06). 1 patient who was rehospitalized and the symptoms were con- Instead, patients with surgical recurrence in SSIS had a sig- servatively treated with medical therapy. nificantly shorter time between diagnosis and surgery Sevenof91patients(7.7%)diedowingtocausesnotre- (P = .002). lated to CD during the follow-up. The estimation of the actuarial curves according to the Eight patients were lost to follow-up. The remaining 83 pa- Kaplan-Meier method was calculated with the log-rank test to tients were regularly followed up with laboratory and instru- evaluate the relationship between the examined variables and mental tests. The mean duration of follow-up was 85.97 months postoperative recurrence. The global risk for recurrence was (range, 6-180 months). moderately lower in patients without family history of CD During long-term follow-up, most patients reported 1 to 2 (HR, 0.45; P = .06) and higher for those with diseases located semisolid evacuations per day. Five patients (without recur- in the jejunum-ileum compared with the distal ileum-colon rence) had 3 to 4 evacuations per day with mild abdominal pain. localizations (HR, 2.45; 95% CI, 1.15-5.22; P = .002) (Figure, Eleven patients were treated with 5-ASA, 23 with 5-ASA A; Table 3). Moreover, former smokers had a significantly associated with corticosteroids, 19 with immunosuppres- lower risk for recurrence compared with smokers and those sants, 20 with biological drugs (anti–tumor necrosis factor patients who had never smoked (Figure, A). When analyzing α), and 10 patients with a combination of all the previous the risk factors associated with surgical recurrence in SSIS drugs. A total of 47 patients periodically took vitamins, folic alone, we found a reduced risk in patients without a family acid, and probiotics. Four patients developed iron-defi- history of CD (HR, 0.13; P = .006) and with a disease local- ciency anemia. ization in the distal part of the small bowel (HR, 0.23; P = .002) (Figure, B). Recurrence Multivariate analysis identified age at diagnosis (χ2 = 5.56; Among the 83 patients regularly followed up, 37 (44.6%) had P = .02) and at surgery (χ2 =7.77;P = .005), family history a clinical recurrence at a mean (SD) of 55.46 (36.79) months (χ2 = 6.26; P = .01), and smoking habit (χ2 = 10.06; P = .007) after surgery (range, 9-140 months). Global recurrence was con- as independent risk factors for postoperative recurrence. These trolled with medical therapy in 15 patients (40.5%) and surgi- risk factors were more relevant in men because in women, the cally (reoperation) in 22 (59.5%). only statistically significant risk factor was age at surgery The recurrent disease was outside of the SSIS site in 13 pa- (Table 4). tients (15.7%), being medical in 6 cases and surgical in 7 patients. In the other 24 patients (28.9%), recurrence occurred Discussion after a mean of 48.25 months (range, 9-140 months) inside the SSIS site, being medical in 9 and surgical in 15 patients. Our study indicated that the following factors were related to The surgical recurrence affected the SSIS body in 8 patients global recurrence of CD in our patients who had undergone (in 2 with long stricture and in 6 with short ones), the inlet in SSIS: smoking habit, a short time between diagnosis and sur- 4 patients, and the outlet in 3 cases; it was treated with SSIS gery, and postoperative therapy. Moreover, a family history of removal in 2 cases (both affected by more than 2 long stric- IBD was a borderline risk factor. tures at SSIS body) and strictureplasty (HM) of the stricture in It is of interest that former smokers (patients who had 13 patients. stopped smoking after surgery) had a significantly lower re- Twelve patients (50%) of 24 experienced recurrence after currence rate. Cigarette smoking is considered both an etio- more than 5 years, during which they experienced well-being logical risk factor for the disease as well as its recurrence, with and good condition. studies showing that smokers not only have a higher risk for developing a postoperative recurrence compared with non- Recurrence-Related Risk Factors smokers (around 2.5 times more), but also that this risk in- The postoperative global recurrence and the surgical or medi- creases in relation to the number of cigarettes smoked (espe- cal recurrence at the SSIS site were analyzed (Table 2). cially for heavy smokers, >10 cigarettes a day).6-10 Our data The frequency of global recurrence was lower in former suggest that smoking probably plays a decisive role in the de- smokers compared with active smokers or those who had never velopment of CD but when these patients quit, they may have smoked (P < .01). Those with recurrence also had a signifi- significantly reduced the risk for recurrence, as the “aggres- cantly shorter time between diagnosis and surgery (mean [SD], siveness” of the disease in their case may have been strongly 55.46 [36.79] vs 122.30 [17.20] months; P =.02). influenced by smoking. Literature evidence is rare on this point,

jamasurgery.com (Reprinted) JAMA Surgery May 2016 Volume 151, Number 5 455

Table 2. Univariate Analysis of Variables in Relation to Postoperative Recurrence in 83 Patientsa

No. (%) Cases SSIS Surgical No Recurrence Recurrence Recurrence Recurrence Variable (n = 46) (n = 37) (n = 24) (n = 15) Sex Male 26 (56.5) 18 (48.6) 11 (45.8) 8 (53.3) Female 20 (43.5) 19 (51.4) 13 (54.2) 7 (46.7) Age at surgery, mean (SD), y 41.22 (1.71) 37.02 (1.74) 39.38 (2.34) 40.27 (2.47) Age at diagnosis, mean (SD), y 31.48 (1.63) 30.10 (1.96) 32.46 (2.81) 33.00 (2.97) Family history of IBD Yes 6 (13.0) 12 (32.4) 7 (29.2) 6 (40.0) No 40 (87.0) 25 (67.6) 17 (70.8) 9 (24.3) Smoking habit Yes 15 (32.6) 18 (48.6)b 11 (45.8) 7 (46.7) No 14 (30.4) 16 (43.2)b 10 (41.7) 6 (16.2) Former smokers 17 (37.0) 3 (8.1)b 3 (12.5) 2 (13.3) No. of cigarettes/d (in smokers), 16.38 (3.13) 18.28 (2.86) 15.91 (2.98) 14.86 (2.47) mean (SD), y Duration of smoking (in 19.00 (2.31) 17.11 (2.37) 17.64 (3.42) 14.86 (3.13) smokers), mean (SD), y Quit smoking after surgery (in smokers) Yes 3 (23.1) 4 (23.5) 3 (27.3) 1 (14.3) No 10 (76.9) 13 (76.5) 8 (72.7) 6 (85.7) Time between diagnosis and 122.30 (17.20) 55.46 (36.79)c 48.25 (29.94)c 53.6 (16.4)c surgery, mean (SD), mo No. of previous surgical procedures 0-1 37 (80.4) 26 (70.3) 17 (70.8) 10 (66.7) ≥2 9 (19.6) 11 (29.7) 7 (29.2) 5 (13.5) Perianal disease Yes 7 (15.2) 7 (18.9) 4 (16.7) 3 (20.0) No 39 (84.8) 30 (81.1) 20 (83.3) 12 (80.0) Presence of fistulae and/or abscesses Yes 9 (19.6) 3 (8.1) 1 (4.2) 0 No 37 (80.4) 34 (91.9) 23 (95.8) 15 (100) Surgical technique SSIS 14 (30.4) 10 (27) 7 (29.2) 4 (26.7) Resection+SSIS 14 (30.4) 9 (24.3) 5 (20.8) 4 (26.7) Resection+SXPL+SSIS 11 (23.9) 9 (24.3) 6 (25.0) 5 (33.3) SSIS+SXPL 7 (15.2) 9 (24.3) 6 (25.0) 2 (13.3) Resection Within SSIS 14 (41.2) 14 (37.8) 10 (43.5) 9 (60.0) No resection 20 (58.8) 19 (51.4) 13 (56.5) 6 (40.0) No. of strictures in SSIS 1 14 (30.4) 11 (29.7) 7 (29.2) 3 (20.0) 2 6 (13.0) 3 (8.1) 2 (8.3) 1 (6.7) 3-5 12 (26.1) 6 (16.2) 3 (12.5) 2 (13.3) 6-10 10 (21.7) 12 (32.4) 9 (37.5) 7 (46.7) 11-20 4 (8.7) 5 (13.5) 3 (12.5) 2 (13.3) No. of SXPLs 0 28 (60.9) 19 (51.4) 12 (50.0) 8 (53.3) 1-2 11 (23.9) 13 (35.1) 8 (33.3) 4 (26.7) >2 7 (15.2) 5 (13.56) 4 (16.7) 3 (20.0)

(continued)

456 JAMA Surgery May 2016 Volume 151, Number 5 (Reprinted) jamasurgery.com

Table 2. Univariate Analysis of Variables in Relation to Postoperative Recurrence in 83 Patientsa (continued)

No. (%) Cases SSIS Surgical No Recurrence Recurrence Recurrence Recurrence Variable (n = 46) (n = 37) (n = 24) (n = 15) Final length of the SSIS, mean 49.45 (14.6) 52.98 (14.9) 54.60 (15.6) 59.10 (16.8) (SD), cm Disease location Duodenum-jejunum 2 (4.3) 3 (8.1) 3 (12.5) 2 (13.3) Jejunum-ileum 16 (34.8) 16 (43.2) 10 (41.7) 7 (46.7) Ileum-colon 28 (60.9) 18 (48.6) 11 (45.8) 6 (40.0) Appendectomy Yes 8 (17.4) 8 (21.6) 7 (29.2) 4 (26.7) No 38 (82.6) 29 (78.4) 17 (70.8) 11 (73.3) Anemia Yes 21 (48.8) 17 (45.9) 13 (54.2) 8 (53.3) No 22 (51.2) 19 (51.4) 11 (45.8) 7 (46.7) Inflammatory indexes Yes 17 (39.5) 18 (48.6) 13 (54.2) 10 (66.7) No 26 (60.5) 19 (51.4) 11 (45.8) 5 (33.3) Malnutrition Yes 24 (52.2) 15 (40.5) 11 (45.8) 8 (53.3) No 22 (47.8) 22 (59.5) 13 (54.2) 7 (46.7) Blood transfusions Yes 8 (17.4) 5 (13.3) 2 (8.3) 2 (13.3) No 38 (82.6) 32 (86.7) 22 (91.7) 13 (86.7) Abbreviations: CCS, corticosteroids; Total parenteral nutrition IBD, inflammatory bowel disease; Yes 25 (55.6) 22 (59.5) 13 (54.2) 9 (64.3) SSIS, side-to-side isoperistaltic strictureplasty; SXPL, strictureplasty. No 20 (44.4) 14 (37.8) 11 (45.8) 5 (35.7) a Differences in the distribution of Postoperative use variables among patients with and Mesalazine 11 (23.9) 0 (0.0)d 0 (0.0)b 0 (0.0)c without recurrences were evaluated 2 CCS+mesalazine 11 (23.9) 12 (32.4)d 8 (33.3)b 6 (40.0)c using the χ test or 1-way analysis of variance, as appropriate. Immunosuppressant 10 (21.7) 9 (24.3)d 7 (29.2)b 3 (20.0)c b P < .01. Biological therapies 5 (10.9) 15 (40.5)d 9 (37.5)b 6 (40.0)c c P <.05. Others 9 (19.6) 1 (2.7)d 0 (0.0)b 0 (0.0)c d P < .001 vs no recurrence cases.

and the most recent contributions do not seem to show a sig- We observed that the risk for relapse was significantly nificant difference between former smokers and nonsmokers.11 lower in patients without a family history of IBD; 35.7% of Sex, age at diagnosis or surgery, number of previous op- the SSIS patients who had a surgical recurrence also had a erations, duration of the disease, localization of the disease and family history of IBD compared with 13% of the no recur- of the SSIS, number of strictures and associated small-bowel rence cases. resection within the SSIS, other resections, perianal CD, fis- Another risk factor seems to be the disease location, with tulizing disease, anemia, inflammatory index, blood transfu- an increased recurrence in patients with the disease located sion, and malnutrition or total parenteral nutrition did not seem in the upper part of the intestine (2.5-fold higher) than those related to recurrence. with diseases located in the distal ileum and colon.12-14 Univariate analysis of patients with medical or surgical re- A previous retrospective study by Greenstein et al15 in 2009 currence at the SSIS site identified similar risk factors: the time found that the number of strictures and SXPLs was associ- between diagnosis and surgery and the postoperative therapy. ated with postoperative recurrence risk. However, the au- Specifically, patients with a surgical recurrence in the SSIS site thors examined only HM and/or Finney SXPLs. Our data sug- showed a significantly shorter time between the diagnosis and gest that the situation is different for SSIS because a higher surgery (mean [SD], 45.64 [13.01] compared with 122.3 [17.20] number of strictures found on the SSIS segment (11-20 steno- months for patients without recurrence). This finding was not sis) is not related to a higher rate of recurrence. unexpected because patients undergoing surgery with a short The association between age at diagnosis or at first sur- time between diagnosis and surgery usually have a more ag- gery and recurrence risk is still controversial16,17; our data gressive form of the disease. indicated that the age at diagnosis or at surgery are indepen-

jamasurgery.com (Reprinted) JAMA Surgery May 2016 Volume 151, Number 5 457

Figure. Kaplan-Meier Time-to-Event Estimate Plots

A Global recurrence B Surgical recurrence in SSIS Family history Family history 150 100 No No P = .006 Yes Yes 80

100 60

Recurrence, % Recurrence, 50

20 Surgical Recurrence in SSIS, % in SSIS, Surgical Recurrence

0 0 0 50 100 150 200 0 50 100 150 200 Follow-up, mo Follow-up, mo No. at risk No. at risk No 65 53 44 40 No 49 40 33 32 Yes 18 11 8 6 Yes 12 7 4 4

Smoke habit Disease location 150 100 Yes Distal ileum-colon P = .002 No Jejunum-ileum Ex-smokers 80

100 60

Recurrence, % Recurrence, 50

20 Surgical Recurrence in SSIS, % in SSIS, Surgical Recurrence

0 0 0 50 100 150 200 0 50 100 150 200 Follow-up, mo Follow-up, mo No. at risk No. at risk No 30 21 17 14 Distal ileum-colon 23 16 12 12 Yes 33 25 18 15 Jejunum-ileum 34 29 24 23 Ex-smokers 20 18 17 17

Disease location 150 Jejunum-ileum Ileum-colon

100

Recurrence, % Recurrence, 50

0 0 50 100 150 200 Follow-up, mo No. at risk Jejunum-ileum 32 23 18 16 Ileum-colon 46 38 32 28

A, Global recurrence based on family history, smoking, and disease location. (SSIS) based on family history of inflammatory bowel disease and disease Recurrence events were significantly negatively associated with cessation of location. Surgical recurrence in SSIS alone was associated with significant smoking (P < .05) and with distal ileum-colon localization of the disease reduction in patients without a family history and with a disease localization in (P < .01). B, Surgical recurrence in side-to-side isoperistaltic strictureplasty the distal part of the bowel.

dent risk factors only in men. Our results showed a lower per- sants, or anti–tumor necrosis factor α drugs. This is likely centage of global recurrence and surgical recurrence in because 5-ASA alone was administered only in patients with patients treated with 5-ASA alone after surgery compared no symptoms or mild disease, while immunosuppressive or with those treated with corticosteroids, immunosuppres- biological therapies were administered in the presence of

458 JAMA Surgery May 2016 Volume 151, Number 5 (Reprinted) jamasurgery.com

Table 3. Global Recurrence-Free Survivala Table 4. Independent Risk Factors for Postoperative Recurrence

Variable HR (95% CI) P Value Factor χ2 P Value Sex Age at surgery 7.77 .005 Male vs female 0.93 (0.48-1.79) .83 Age at diagnosis 5.56 .02 Age at diagnosis, y Family history of IBD 6.26 .01 < 30 vs > 30 1.66 (0.85-3.22) .14 Smoking habit 10.06 .007 Age at surgery, y Women < 40 vs > 40 1.61 (0.82-3.18) .17 Age at surgery 5.52 .02 Family history of IBD Men No vs yes 0.45 (0.20-1.03) .06 Age at diagnosis 4.24 .04 Smokers vs nonsmokers Family history of IBD 7.89 .005 Yes vs no 0.82 (0.41-1.66) .59 Smoking habit 12.63 .002

Yes vs former smokers 3.16 (1.26-7.95) .01 Abbreviation: IBD, inflammatory bowel disease. No vs former smokers 3.51 (1.44-8.57) .006 No. of cigarettes/d No smoking vs <15 1.15 (0.47-2.86) .76 Currently, to our knowledge, there are no standard indi- No smoking vs >15 0.98 (0.40-2.38) .97 cations for SSIS and, therefore, the experience of the surgeon Duration of smoking, y plays a fundamental role. Studies carried out so far, aiming at No smoking vs <20 1.49 (0.70-3.19) .30 identifying specific risk factors associated with recurrences in No smoking vs >20 0.75 (0.26-2.12) .59 patients treated with SSIS, have not provided homogeneous Quit smoking after surgery results.5,6,17,26,27 Furthermore, these few studies, owing to the No smoking vs yes 1.15 (0.37-3.62) .81 relatively recent introduction of SSIS, included small cohorts No. of previous surgical procedures of patients. Our relatively long experience with this tech- 0 vs ≥1 0.86 (0.44-1.66) .64 nique, performed for more than 15 years, provides us with the Perianal disease opportunity of evaluating possible recurrence risk factors over No vs yes 0.75 (0.30-1.87) .54 long-term follow-up. Disease location Furthermore, our data are discordant regarding previous Jejunum-ileum vs ileum-colon 2.45 (1.15-5.22) .002 experiences28,29 about the site of the surgical recurrence in Inflammatory indexes SSIS. In 8 of our patients (53.7%), the recurrence affected the No vs yes 0.70 (0.35-1.39) .30 body of the SSIS, which was successfully treated with HM stric- Abbreviations: IBD, inflammatory bowel disease; HR, hazard ratio. tureplasty in 75% of them. a Calculated using actuarial (Kaplan-Meier) analysis with follow-up time (time at Moreover, we followed up by endoscopy the patients with risk) beginning at first reoperation or at last available follow-up. an SSIS on the neoterminal ileum and we observed normal or mild erythematous mucosa in most of these patients. With time only, 27.3% (6 of 22 patients who had undergone SSIS on the clinical relapse. However, 10 patients treated with a combina- neoterminal ileum) of them developed mucosal edema with tion of all the drugs did not show any recurrence. aphthae or ulcers and subsequently stricture that required sur- Many prospective studies18-21 or meta-analysis22 evaluat- gical treatment only in 2 cases. ing global CD recurrence after ileo-cecal resection are present A possible limitation of the study is the lack of uniformity but clinical trials evaluating the efficacy of prophylactic medi- in the postoperative medical therapy. cal therapies in reducing postoperative recurrence after SSIS are still lacking. 23 Only a randomized study by Ardizzone et al evaluated, Conclusions after conservative surgery (SXPL or minimal resection), the postoperative prophylactic use of azathioprine, showing af- Our work shows that SSIS, in the short-term, leads to a reso- ter 24 months of follow-up that there was no significant dif- lution of symptoms in more than 90% of cases; only 5 pa- ference in terms of clinical and surgical recurrence compared tients (6%) all with a strictureplasted small bowel wider than with the control group treated with 5-ASA. 70 cm required a longer follow-up for resolution of anemia. We Only rarely is there described an association between can- have noticed that some factors influence the recurrence of the cer and SXPL24-26 and in the present study, we had no case of disease, including the habit of cigarette smoking and the age intestinal cancer in SSIS, even after a long-term follow-up. How- at diagnosis, especially in men. A family history of IBD is an- ever, careful surveillance of these patients is desirable. other positive correlation with recurrence risk, as is the loca- Side-to-side isoperistaltic strictureplasty can be consid- tion of the disease in the upper part of the bowel. The other ered a useful alternative to resection, especially in extended examined factors did not show any significance, but in some or multioperated on patients with CD who might have short- cases, this could depend on the relatively small size of our bowel syndrome. sample.

jamasurgery.com (Reprinted) JAMA Surgery May 2016 Volume 151, Number 5 459

ARTICLE INFORMATION 8. Yamamoto T, Keighley MR. The association of 20. Ewe K, Herfarth C, Malchow H, Jesdinsky HJ. Accepted for Publication: September 16, 2015. cigarette smoking with a high risk of recurrence Postoperative recurrence of Crohn’s disease in after ileocolonic resection for ileocecal Crohn’s relation to radicality of operation and sulfasalazine Published Online: December 30, 2015. disease. Surg Today. 1999;29(6):579-580. prophylaxis: a multicenter trial. Digestion. 1989; doi:10.1001/jamasurg.2015.4552. 9. Yamamoto T. Factors affecting recurrence after 42(4):224-232. Author Contributions: Dr Fazi had full access to all surgery for Crohn’s disease. World J Gastroenterol. 21. Wenckert A, Kristensen M, Eklund AE, et al. of the data in the study and takes responsibility for 2005;11(26):3971-3979. The long-term prophylactic effect of the integrity of the data and the accuracy of the 10. Sutherland LR, Ramcharan S, Bryant H, Fick G. salazosulphapyridine (Salazopyrin) in primarily data analysis. resected patients with Crohn’s disease: a controlled Study concept and design: Fazi, Giudici, Pronestì, Effect of cigarette smoking on recurrence of Crohn’s disease. Gastroenterology. 1990;98(5, pt 1): double-blind trial. Scand J Gastroenterol. 1978;13(2): Tonelli. 161-167. Acquisition, analysis, or interpretation of data: Fazi, 1123-1128. Giudici, Luceri, Pronestì. 11. Reese GE, Nanidis T, Borysiewicz C, Yamamoto 22. Peyrin-Biroulet L, Deltenre P, Ardizzone S, et al. Drafting of the manuscript: Fazi, Giudici, Pronestì. T, Orchard T, Tekkis PP. The effect of smoking after Azathioprine and 6-mercaptopurine for the Critical revision of the manuscript for important surgery for Crohn’s disease: a meta-analysis of prevention of postoperative recurrence in Crohn’s intellectual content: Fazi, Giudici, Luceri, Tonelli. observational studies. Int J Colorectal Dis. 2008;23 disease: a meta-analysis. Am J Gastroenterol. 2009; Statistical analysis: Luceri, Pronestì. (12):1213-1221. 104(8):2089-2096. Obtained funding: Fazi. 12. Tonelli F, Alemanno G, Bellucci F, Focardi A, 23. Ardizzone S, Maconi G, Sampietro GM, et al. Administrative, technical, or material support: Fazi, Sturiale A, Giudici F. Symptomatic duodenal Crohn’s Azathioprine and mesalamine for prevention of Giudici. disease: is strictureplasty the right choice? J Crohns relapse after conservative surgery for Crohn’s Study supervision: Fazi, Giudici, Tonelli. Colitis. 2013;7(10):791-796. disease. Gastroenterology. 2004;127(3):730-740. Conflict of Interest Disclosures: None reported. 13. Borley NR, Mortensen NJ, Jewell DP. Preventing 24. Marchetti F, Fazio VW, Ozuner G. postoperative recurrence of Crohn’s disease. Br J Adenocarcinoma arising from a strictureplasty site REFERENCES Surg. 1997;84(11):1493-1502. in Crohn’s disease: report of a case. Dis Colon Rectum. 1996;39(11):1315-1321. 1. Lee EC, Papaioannou N. Minimal surgery for 14. Louis E, Belaiche J, Reenaers C. Do clinical chronic obstruction in patients with extensive or factors help to predict disease course in 25. Jaskowiak NT, Michelassi F. Adenocarcinoma at universal Crohn’s disease. Ann R Coll Surg Engl. inflammatory bowel disease? World J Gastroenterol. a strictureplasty site in Crohn’s disease: report of a 1982;64(4):229-233. 2010;16(21):2600-2603. case. Dis Colon Rectum. 2001;44(2):284-287. 2. Michelassi F. Side-to-side isoperistaltic 15. Greenstein AJ, Zhang LP, Miller AT, et al. 26. Michelassi F, Hurst RD, Melis M, et al. strictureplasty for multiple Crohn’s strictures. Dis Relationship of the number of Crohn’s strictures Side-to-side isoperistaltic strictureplasty in Colon Rectum. 1996;39(3):345-349. and strictureplasties to postoperative recurrence. extensive Crohn’s disease: a prospective 3. Tonelli F, Ficari F. Strictureplasty in Crohn’s J Am Coll Surg. 2009;208(6):1065-1070. longitudinal study. Ann Surg. 2000;232(3): 401-408. disease: surgical option. Dis Colon Rectum. 2000; 16. Yamamoto T, Bain IM, Allan RN, Keighley MR. 43(7):920-926. An audit of strictureplasty for small-bowel Crohn’s 27. Fazio VW, Marchetti F, Church M, et al. Effect of 4. Tonelli F, Fedi M, Paroli GM, Fazi M. Indications disease. Dis Colon Rectum. 1999;42(6): resection margins on the recurrence of Crohn’s and results of side-to-side isoperistaltic 797-803. disease in the small bowel: a randomized controlled trial. Ann Surg. 1996;224(4):563-571. strictureplasty in Crohn’s disease. Dis Colon Rectum. 17. Yamamoto T, Fazio VW, Tekkis PP. Safety and 2004;47(4):494-501. efficacy of strictureplasty for Crohn’s disease: 28. Sasaki I, Shibata C, Funayama Y, et al. New 5. Michelassi F, Taschieri A, Tonelli F, et al. An a systematic review and meta-analysis. Dis Colon reconstructive procedure after intestinal resection international, multicenter, prospective, Rectum. 2007;50(11):1968-1986. for Crohn’s disease: modified side-to-side isoperistaltic anastomosis with double observational study of the side-to-side isoperistaltic 18. Poggioli G, Laureti S, Selleri S, et al. Factors strictureplasty in Crohn’s disease. Dis Colon Rectum. Heineke-Mikulicz procedure. Dis Colon Rectum. affecting recurrence in Crohn’s disease: results of a 2004;47(6):940-943. 2007;50(3):277-284. prospective audit. Int J Colorectal Dis. 1996;11(6): 6. Yamamoto T, Keighley MR. Factors affecting the 294-298. 29. Poggioli G, Laureti S, Pierangeli F, Ugolini F. incidence of postoperative septic complications A new model of strictureplasty for multiple and long 19. Rutgeerts PJ, Peters M, Hiele M, et al. A placebo stenoses in Crohn’s ileitis: side-to-side diseased to and recurrence after strictureplasty for jejunoileal controlled trial of metronidazole for recurrence Crohn’s disease. Am J Surg. 1999;178(3):240-245. disease-free anastomosis. Dis Colon Rectum. 2003; prevention of Crohn’s disease after resection of the 46(1):127-130. 7. Yamamoto T, Keighley MR. Smoking and disease terminal ileum. Gastroenterology. 1992;102: recurrence after operation for Crohn’s disease. Br J A688. Surg. 2000;87(4):398-404.

460 JAMA Surgery May 2016 Volume 151, Number 5 (Reprinted) jamasurgery.com

Downloaded From: http://archsurg.jamanetwork.com/ by a UNIEVERSITA DEGLI STUDI DI FIRENZE User on 08/05/2016