Disease-related Surgery Research Articles

JINLING (Judicious INdex of Luminal INflammation Grade) score, an effective indicator to assess inflammation severity in Crohn's disease.

With the increasing demand for individualized treatment in Crohn's disease, a score for accurate evaluation of inflammation grade will be of great significance. We have developed the JINLING score to assess inflammation severity for Crohn's disease, which incorporates an endoscopic score (SES-CD) and a 2-item patient-reported outcome (PRO2). The aim of this study was to examine the performance of JINLING score in evaluating inflammation grade and the correlation with the clinical outcomes. The correlation between JINLING score and Global Histologic Disease Activity Score (GHAS), fecal calprotectin (FCP), and C-reactive protein (CRP) level was performed in an exploration phase with a retrospective data set. The data on clinical outcomes including medication effects, Crohn's disease-related surgery and biochemical results were collected from a single-center prospective validation cohort. JINLING score correlated significantly with FCP, CRP, and hemoglobin in the exploration cohort (all P < 0.05). The receiver operating characteristic (ROC) curves based on a threshold Crohn's disease activity index value of 150, GHAS of 4, and FCP of 60 μg/g to identify disease activity, all showed a higher area under the curve with JINLING score than SES-CD or PRO2 alone. In the validation cohort, patients with high inflammation grade (JINLING ≥4) had higher GHAS, CRP, and FCP than low inflammation grade patients. High JINLING score was associated with an increased risk of treatment failure (hazard ratio 2.93; 95% confidence interval 1.13-7.61, P = 0.021). This newly developed index served well for quantifying inflammation grade and predicting clinical outcomes. JINLING score has the potential to facilitate clinical decision-making and personalized therapy for Crohn's disease patients.

S0871 Costs of Inflammatory Bowel Disease-Related Hospitalizations and Surgeries: A Retrospective Analysis in a Commercially Insured Population

S0871 Costs of Inflammatory Bowel Disease-Related Hospitalizations and Surgeries: A Retrospective Analysis in a Commercially Insured Population

Objectively assessed disease activity and drug persistence during ustekinumab treatment in a nationwide real-world Crohn's disease cohort.

ObjectiveLong-term evidence on ustekinumab treatment response and persistence in patients with Crohn’s disease in a real-world setting is scarce. We performed a retrospective nationwide chart review study of long-term clinical outcomes in Crohn’s disease patients treated with ustekinumab.MethodsThe study was conducted in 17 Finnish hospitals and included adult Crohn’s disease patients who received an initial intravenous dose of ustekinumab during 2017–2018. Disease activity data were collected at baseline, 16 weeks, and 1 year from health records.ResultsThe study included 155 patients. The disease was stricturing or penetrating in 69 and 59% had prior Crohn’s disease-related surgeries, and 97% had a treatment history of at least one biologic agent. Of 93 patients with ≥1 year of follow-up, 77 (83%) were still on ustekinumab at 1 year. In patients with data available, from baseline to the 1-year follow-up the simple endoscopic score for Crohn’s disease (SES-CD) decreased from 10 to 3 (P = 0.033), C-reactive protein from 7 to 5 mg/L, (P < 0.001) and faecal calprotectin from 776 to 305 μg/g (P < 0.001).ConclusionsUstekinumab treatment in patients with highly refractory Crohn’s disease resulted in high long-term treatment persistence and significantly reduced disease activity, assessed with objective markers for intestinal inflammatory activity.

Perioperative Surgical Home Model Improves Outcomes in Crohn's Disease Patients Undergoing Disease-Related Surgery.

Background To evaluate Perioperative Surgical Home (PSH) practice model implementation in Crohn's disease (CD) patients undergoing disease-related surgery. Methods A retrospective analysis of CD patients requiring disease-related surgery in the Shanghai Ninth People's Hospital was undertaken. Subjects were divided into a non-PSH group consisting of 49 patients (June 2016 to November 2017) and a PSH group consisting of 72 patients (December 2017 until May 2019). Conventional treatment was used for the non-PSH group, while in the PSH group, a standardized pre- and postoperative management routine was employed. The postoperative lengths of stay and incidences of postoperative complications were analyzed. Results There were no significant differences in demographics, reasons for surgery, preoperative BMIs, and preoperative hemoglobin between the two groups (P > 0.05). The overall incidence of complications in the PSH group was dramatically lower than that in the non-PSH group (26.4% vs. 44.9%, P = 0.035). In the PSH group, postoperative length of stay was significantly shorter than that in the non-PSH group (11.5 ± 5.7 vs. 9.0 ± 6.8, P < 0.001). Conclusions The PSH conditioning routine in CD patients undergoing disease-related surgeries suggests a trend of fewer postoperative complications and shorter lengths of hospital stay. The PSH model may have clinical advantages when applied to CD patients.

The role of coexisting cardiovascular disease on disease severity in patients with inflammatory bowel disease.

Chronic inflammation has been implicated in the pathogenesis of atherosclerosis and cardiovascular disease. Data linking the severity of inflammatory bowel disease to coexisting cardiovascular disease are scarce. The aim of the present study was to investigate whether inflammatory bowel disease patients with coexistent cardiovascular disease have more severe disease. We included 103 inflammatory bowel disease patients with coexisting cardiovascular disease compared to 206 age- and sex-matched inflammatory bowel disease patients without cardiovascular disease derived from three referral inflammatory bowel disease Centers. Traditional cardiovascular disease factors and parameters of inflammatory bowel disease severity were compared between the two groups. Cardiovascular disease was diagnosed after the inflammatory bowel disease diagnosis in 56.6% of cases. No significant difference was found in the prevalence of surrogate markers of severity (inflammatory bowel disease-related surgeries, hospitalizations, biologics or immunosuppressants' use, and persistent CRP elevation) between inflammatory bowel disease patients with and without cardiovascular disease. There was no difference between cardiovascular disease patients diagnosed before and after inflammatory bowel disease onset. All traditional risk factors (hypertension, dyslipidemia, smoking, obesity, diabetes mellitus) were significantly more common in cardiovascular disease patients. Cardiovascular disease patients had a trend for lower rates of multiple hospitalizations (16.5% vs. 24.3%, P = 0.05) and inflammatory bowel disease-related surgeries (P = 0.09). The inflammatory burden possibly plays a less important role in the development of cardiovascular disease in inflammatory bowel disease patients but future larger prospective studies are needed.

P644 Post-operative Crohn’s disease recurrence in Glasgow: How common is it and does deprivation matter?

Abstract Background 50% of patients with Crohn’s disease (CD) will have surgery within the first 10 years, with 35% requiring additional surgery in the following decade. The REMIND cohort-linked male gender, smoking and previous resection to recurrence1. The link between CD and deprivation is debated, while its influence on recurrence is unknown. We aimed to define our local post-operative CD population, highlighting recurrence rates and associated risk factors. Methods CD resections between 2008 and 2014 were identified from NHS Greater Glasgow and Clyde Pathology Archive. Data including gender, age at diagnosis/resection, Montreal classification and smoking status was obtained from the Electronic Patient Record (EPR). Scottish Index of Multiple Deprivation (SIMD) score was determined by postcode and was ranked 1–5 (most to least deprived). Five years of follow-up data were collected. The type of recurrence was recorded as clinical recurrence - symptom flare requiring a course of steroids or inpatient admission; biochemical recurrence—faecal calprotectin &amp;gt;250 µg/l; endoscopic recurrence; or surgical recurrence—the need for further Crohn’s disease-related surgery. Results 304 patients (59.5% female) were included. Median age at diagnosis was 29 (range 3–82 years) and at resection was 43 (range 17–85 years). 52.9% of patients were never-smokers, 16.5% were ex-smokers and 30.6% were current smokers. 33.6% of patients had a SIMD score of 1. Eighty-two per cent had ileal, colonic or ileocolonic involvement. 46.7% of patients had clinical recurrence, 48.7% biochemical recurrence and 31.6% endoscopic recurrence. 15.8% required further surgery for CD. For clinical recurrence, younger age at diagnosis (p = 0.012, and younger age at resection (p = 0.002) were significant determinants. Gender, smoking and SIMD were not significantly associated with recurrence. Chemical recurrence showed similar associations. Similarly, for surgical recurrence, younger age at diagnosis (p = 0.030, and younger age at resection (p = 0.003) were significant determinants. Male gender was the only risk factor for endoscopic recurrence (OR=1.88, 95% CI: 1.13–3.08). Conclusion Our data suggest rates of post-operative recurrence in line with published data. Risk factors were similar to those identified in the REMIND study, with younger age at diagnosis/resection associated with higher rates of recurrence. Our data suggest sociodemographic deprivation does not influence recurrence rates; however,, more work is needed to validate this. References

P419 Clinical effectiveness and safety of first-line biologic vedolizumab as a monotherapy or combination therapy in ulcerative colitis and Crohn’s disease patients: results from the EVOLVE study

Abstract Background There is little long-term research (≥12 months) in ulcerative colitis (UC) and Crohn’s disease (CD) patients investigating the impact on clinical effectiveness of combined (combo) therapy of vedolizumab (VDZ) plus immunomodulators/immunosuppressants (IMMs) compared with VDZ monotherapy. Research suggests the use of concomitant aminosalicylates [5-ASAs] in UC may not bolster effectiveness. Finally, it is unclear if the safety profile differs between VDZ monotherapy and combo therapy. This study described clinical effectiveness and safety outcomes in patients with UC or CD treated with first-line biologic VDZ as monotherapy or combo therapy with IMMs or 5-ASAs (UC only). Methods This was a real-world, multi-country (Canada, Greece and the USA), retrospective chart review study of biologic-naïve UC and CD patients (≥18 years old) treated with VDZ (initiated Tx May 2014–March 2018). Data were collected from Tx initiation to the earliest of death and chart abstraction date. Cumulative rates of clinical effectiveness outcomes over 24 months (Tx persistence, clinical response and clinical remission) were estimated using the Kaplan-Meier method with unadjusted comparisons conducted using the log-rank test. Clinical response and remission were assessed from standard disease measures reported in medical records. Analyses of unadjusted incidence rates (per 100 person-years [PYs]) of disease exacerbations, disease-related surgeries, serious adverse events (SAEs) and serious infections (SIs) were performed. For these analyses in monotherapy vs. VDZ+IMMs, UC and CD patients were combined due to restrictions of sample size and a number of events. Results This analysis included 318 patients treated with VDZ (monotherapy: UC = 53, CD = 108; VDZ+IMMs: UC = 22, CD = 24; VDZ+5-ASAs: UC = 111). There were no observed differences in age, sex or disease duration between patients on monotherapy vs. VDZ+IMMs or vs. VDZ+5-ASAs. Data trends in effectiveness outcomes were similar in monotherapy vs. VDZ+IMMs over 24 months (Figure 1). Tx persistence (monotherapy: 71.6%; VDZ+5-ASAs: 82.7%; p = 0.40), clinical remission (monotherapy: 54.3%; VDZ+5-ASAs: 87.7%; p = 0.37) and clinical response (monotherapy: 81.7%; VDZ+5-ASAs: 92.2%; p = 0.54) were also similar between monotherapy and VDZ+5-ASAs over 24 months. Safety outcomes were similar between groups (Figure 2). Conclusion Though sample sizes were small, the unadjusted trends in the results of this long-term real-world study suggest that biologic-naïve UC or CD patients treated with VDZ alone may have similar clinical effectiveness outcomes to patients receiving VDZ+IMMs. Trends in data also suggest that in patients with UC, VDZ+5-ASAs may not be more effective than VDZ alone.

DOP55 A real-world comparison of the effectiveness and safety of vedolizumab and anti-TNF therapies in early treatment initiation with first-line biologic therapy in ulcerative colitis: Results from EVOLVE

Abstract Background Evidence suggests that early treatment (Tx) with biologic agents in Crohn’s disease improves long-term clinical outcomes. However, there is less evidence in ulcerative colitis (UC), and data comparing early Tx with first-line biologic vedolizumab (VDZ) to anti-tumour necrosis factor (anti-TNF) in real-world settings is needed. This study compared the clinical effectiveness and safety of UC patients who initiated VDZ or an anti-TNF as a first-line biologic within 2 years following diagnosis. Methods This was a real-world, multi-country, retrospective chart review study in Canada, Greece and the United States where biologic-naïve UC patients (≥18 years old) were treated with VDZ or an anti-TNF (adalimumab, infliximab, golimumab) agent within 2 years following diagnosis (initiated Tx May 2014–March 2018). Clinical effectiveness and safety data were collected from Tx initiation to earliest of chart abstraction date, death, or 6 months post-Tx discontinuation (Canada only). Tx persistence was defined as the duration of time from treatment initiation to discontinuation. Analyses of cumulative rates of Tx persistence, clinical response, clinical remission and mucosal healing over 24 months were estimated using Kaplan–Meier analyses. Clinical response, remission and mucosal healing were assessed using pre-defined hierarchical algorithms of standard disease measures reported in the medical records. Analyses of incidence rates (per 100 person-years [PYs]) of disease exacerbations, disease-related surgeries, serious adverse events (SAEs) and serious infections (SIs) were performed. Adjusted analyses used inverse probability weighting to balance cohorts. Results This analysis included 176 UC patients (VDZ: 86; anti-TNF: 90) from 37 sites. Mean (SD) age at index date: VDZ, 41.4 (18.9); anti-TNF, 36.8 (15.6) years (p = 0.20) and the proportion male: VDZ, 58.1%; anti-TNF, 56.7% (p = 0.84). At 12 months, 72.9% and 58.1% continued VDZ and anti-TNF respectively (p = 0.03) (Figure 1A). Though there were no differences in clinical response, clinical remission or mucosal healing between VDZ and anti-TNF groups; VDZ patients were significantly less likely to experience disease exacerbations (HR = 0.47 [95% CI: 0.32–0.69]) and SAEs (HR = 0.37 [95% CI: 0.19–0.72]) (Figure 2). Adjusted outcomes (Figures 1C and D, and 2B) were similar to unadjusted outcomes. Conclusion EVOLVE is one of the first studies that compared early VDZ Tx to early anti-TNF Tx in biologic-naïve UC patients. Results showed VDZ was associated with higher persistence, lower likelihood of experiencing disease exacerbations and a more favourable safety profile. Thus, in early UC, Tx with VDZ may improve long-term clinical outcomes. Sample size limitations warrant further study.

P267 Validation of the short inflammatory bowel disease questionnaire as an outcome measure in Crohn’s disease patients

Abstract Background Health-related quality-of-life by the self-report, disease-specific Short Inflammatory Bowel Disease Questionnaire (SIBDQ) is increasingly used as an outcome measure in Crohn`s disease (CD) patients in clinical trials. Higher SIBDQ scores indicate better quality-of-life; the range is 10 to 70. However, the construct validity of SIBDQ and its responsiveness to change of disease status require validation. Methods Adult (≥18 years) CD patients (n = 108) with Harvey–Bradshaw Index (HBI) &amp;gt;4 and &amp;lt;16 prospectively filled in the SIBDQ at two time-points (T1, T2) 3 months apart. Medical data at T1 and T2 were collected, and recorded by their physicians in the HBI. Biomarkers of disease activity included Calprotectin and C-reaction protein (CRP), measured at T1 and T2. The construct validity of SIBDQ in relation to biomarkers and HBI was determined by Pearson correlations and group comparisons using Student`s t-test. Statistical significance was taken as p &amp;lt; 0.05. Patients’ medications were prescribed without regard to the study protocol. Results Demographic and medical characteristics (median, %) of the cohort were: age 30 years; females 65%, married/partner 48%; higher education 83%; BMI 22; non-smokers/past-smokers 92%; disease duration 5 years; past Crohn’s disease-related surgery 17%; Montreal classification A2 89%, L2+L3 89%, B1+B2 89%, perianal disease 18%; medications: corticosteroids 4%, 5-ASA 5%, immunomodulators 21%, biologicals 43%. HBI and SIBDQ median scores at T1 and T2 were: HBI: 9 and 4 (p &amp;lt; 0.001); SIBDQ: 43 and 49 (p &amp;lt; 0.001). SIBDQ scores correlated inversely with Calprotectin (r = −0.395, p = .002), CRP (r = −0.208, p = .046), and HBI (r = −0.345, p &amp;lt; 0.001). Baseline HBI scores were used to divide the cohort into two groups for comparison: mild disease (5–7) vs. moderate disease (8–16). Mild disease patients reported higher SIBDQ scores than those with moderate disease (42.7 vs. 39.7, t = 1.96, p = 0.05). Regarding sensitivity of SIBDQ to clinical changes between T1 and T2, we found that change in SIBDQ correlated significantly with change in CRP across these two administrations (r = −0.232, p = 0.042). Finally, defining clinical response in CD as a decrease from baseline HBI score by ≥3 points, SIBDQ change scores were significantly larger in treatment responders (n = 51, M = 6.25) than non-responders (n = 30, M = 1.13, t = −3.042, p = 0.003). Conclusion The SIBDQ measure is a valid assessment of quality-of-life in CD, correlating with biomarkers and sensitive to change of disease activity, with potential for use as a patient-reported outcome in both clinical practice and as a primary end-point in clinical trials.

Follow-Up Ileocolonoscopy Is Underused in Crohn’s Disease Patients after Ileocecal Resection despite Higher Total and Inpatient Health-Care Costs Compared to Controls

Background: Postoperative recurrence is frequently observed after ileocecal resection in Crohn’s disease (CD) patients. Since 2010, endoscopy within 1 year is considered the gold standard for its diagnosis. However, if and how frequent such endoscopies are performed in clinical practice remains unknown. Methods: We analyzed 1-year follow-up data on CD patients who underwent ileocecal resection between 2012 and 2014 and compared them with hospitalized, non-resected CD controls. Data were extracted from the Helsana database. Helsana is one of the largest Swiss health insurance companies providing coverage for 1.2 million individuals. Results: A total of 645 CD patients were identified with ≥1 hospitalization between 2012 and 2014 and a follow-up of 1 year. Of these, 79 (12.2%) underwent ileocecal resection. Although endoscopy rates increased over time and were higher in patients with resection versus controls (p = 0.029), in only 54.4% a 1-year follow-up ileocolonoscopy was performed. Postoperative prophylaxis with anti-tumor necrosis factor or azathioprine was prescribed in 63.3%. Female sex and age >60 years were independent predictors for not receiving prophylaxis (odds ratio [OR] 0.36, p = 0.048, and OR 0.2, p = 0.022). Patients with resection had significantly lower numbers of rehospitalizations (1.2 vs. 1.8, p = 0.021), with resection being an independent negative predictor for number of rehospitalizations in a Poisson regression model (incident risk ratio 0.64, p = 0.029). However, disease-related surgery was more often the cause for rehospitalization after resection versus controls (47.6 vs. 22.1%, p = 0.015). Total and inpatient health-care costs were higher in these patients. Conclusion: Endoscopies are underused after ileocecal resection. This contrasts current guidelines. Physicians should be aware of this underuse and perform follow-up examinations more often.

Stoma formation for Crohn’s disease in the post‐biologic era, Ma et al.

Up to one-third of patients with Crohn’s disease will require major abdominal surgery over the first 5 years of their disease and most Crohn’s patients will have a Crohn’s related operation at some time in their lifetime 1. Nonetheless, as surgeons we notice a trend towards less referrals for operations for Crohn’s disease, where the patients tend to present later and often in a poorer condition. It has been suggested that this change in surgical practice is due to the introduction of biologic medications for Crohn’s disease in the first half of the 2000s. However, despite the increasing use of novel biologic agents, counterintuitively the incidence of Crohn’s disease related surgery does not appear to be reducing 2. A recent large population based cohort study from Alberta, Canada, showed a decrease in emergency surgery but an increase in elective surgery 3. This might explain why surgeons get the sense that the burden for Crohn’s related surgery is less. One could expect that more elective surgery is related to earlier referral, a better condition of the patient at the time of surgery and therefore less stoma formation. In this month’s Editor’s choice study, Ma et al., from the same Canadian group, are looking at trends in stoma formation after the introduction of biologics in management of Crohn’s disease 4. In order to assess the need for stoma creation in the biological era, the authors queried an administrative population database from their area, serving 1.4 million inhabitants. They identified 545 patients who underwent bowel resection and stoma formation for Crohn’s disease between 2002 and 2011. They found a time based reduction in stoma rates from 2.30 stomas per 100 person-years to 1.51 stomas per 100 person-years. The number of emergency and temporary stomas decreased over time, whereas the number of elective permanent stomas remained stable. Except for severe perianal fistulising disease, elective stoma formation for Crohn’s disease becomes necessary where primary anastomosis is technically impossible or if there is a high risk for anastomotic breakdown. Unfortunately, this study was not able to identify the reason the stoma was indicated 4. Well-known risk factors for anastomotic complications in Crohn’s patients include recurrent clinical episodes, steroid use, and malnutrition 5. Nowadays, gastroenterologists have a wide range of medical therapies available to avoid intestinal resection. This might cause a delay to progress to surgery, which may result in a progressively more complex disease phenotype at the time of surgery. If this delay occurs, the patient’s condition deteriorates, and this forces the surgeon to elect for a stoma to avoid an anastomotic complication. The study by Ma et al. reminds us of the importance of appropriate and timely surgery, especially in the biologic era. Therefore, the IBD surgeon should be involved in the management of the Crohn’s patient from the first onset of the disease, as a member of an IBD multidisciplinary team.

692 Low Levels of Ustekinumab Despite Dose Escalation Is a Risk Factor for Surgery

INTRODUCTION: Ustekinumab is an IL-12/23 inhibitor used for the treatment of Crohn's disease (CD). Previous studies have suggested that dose escalation to every 4-week intervals can be beneficial in patients who do not achieve a clinical response on every 8-week maintenance dosing. However, safety and efficacy is unknown in CD patients escalated to more frequently than every 4-week intervals in patients who continue to have low trough drug levels. METHODS: We performed a retrospective chart review of patients on ustekinumab for CD who had dosing escalation to every two weeks (Q2) due to persistent low drug levels (&lt;5 µg/mL) despite being on q4 weeks (Q4) maintenance dosing and clinically losing response. RESULTS: Out of 200 CD patients on ustekinumab 90 mg subcutaneous (SQ) maintenance in our IBD program, 112 underwent reactive therapeutic drug monitoring for loss of response or incomplete response to therapy. Of the 112 with drug levels, none had anti-drug antibodies, but 80 patients had levels &lt;5 mcg/mL. All 80 patients were frequency escalated to q4 week dosing. Of these, 12 patients continued to have low ustekinumab trough levels at week 4 (&lt;5 mcg/mL) and thus were escalated to Q2 week dosing. Eight of the 12 patients had IV reinduction dosing prior to dose escalation to Q2 frequency. Of the 12 patients, 6 (50%) required surgery for their active Crohn's disease. These patients were on Q2 week dosing for median of 16 weeks (range 1-68) prior to surgery. All 6 (100%) were able to be de-escalate to less frequent dosing after surgery. Two patients that were unable to de-escalate their dosing frequency are planning for surgery in the near future. The remaining four patients were able to de-escalate to Q4 dosing after clinical response. See full details in Table 1. No adverse events unrelated to their Crohn's disease, including infections or other safety markers were noted. CONCLUSION: Low levels of ustekinumab despite escalation of dosing to every 2 weeks may suggest a need for Crohn's disease related surgery. In our study, all patients who underwent surgery were able to de-escalate to lower dosing frequency suggesting that high inflammatory disease burden contributed to the low levels of ustekinumab. Further studies are needed to assess the safety and efficacy of high frequency dosing of ustekinumab.

1690 Management of Non-Malignant Enterocutaneous Fistula Using Fully Covered Stent

INTRODUCTION: Postoperative enterocutaneous fistula (ECF) has a reported prevalence of 3.6% in general surgery, and up to 35% in Crohn disease-related surgery. ECFs can be of low-output, drain &lt; 200 mL/day, or of high-output, drain &gt; 500 mL/day, which unlikely to heal spontaneously. ECFs can cause metabolic disturbances, fluid loss, and malnutrition. CASE DESCRIPTION/METHODS: Case 1: A 54-year-old man with a history of colonic transmural necrosis status post multiple surgeries and end transverse colostomy placement, presented with a two-week history of passing stool from the lateral aspect of his peristomal incision, consistent with enterocutaneous fistula. The 2 fistulae ends were seen on the skin, laterally to the stoma (Figure 2c), and both other ends were identified in the stoma lumen. CT fistulogram confirmed the fistulae. After advancing the endoscope into the stoma, a 2 cm friable stenosis was seen (Figure 1a). The fistulae tracts were treated with silver nitrate and were injected with fibrin glue. A 20 mm × 6 cm fully-covered stent was placed (Figure 1b) and sutured in place. A month later the fistulae had healed (Figure 2d), with no recurrence reported. Case 2: A 64-year-old man with a history of metastatic mucinous appendiceal cancer status post multiple abdominal surgeries, referred for his recurrent ECF. CT scan showed air tracking outside the colon at the level of the cutaneous fistula site. Water-soluble contrast pushed through the rectum showed an occlusion with contrast extravasation is seen in the fistula (Figure 3e). Sigmoidoscopy confirmed the site of obstruction and the area of leakage. A fully covered stent was placed to relieve the obstruction and cover the fistula (Figure 3f). Initially, the fistula output resolved, but when the stent was removed a month later, the fistula output returned. So, a stent was placed again and was sutured to the colon. The patient is now asymptomatic and having normal bowel movements. DISCUSSION: ECF can cause significant morbidity and affect the quality of life. Surgical repair of ECF has a recurrence rate as high as 36% and is associated with high mortality especially in malnourished patients. Thus, endoscopic intervention using fully-covered stents can be helpful in healing the fistulae. In these 2 cases, the placement of a fully-covered stent relieved the coexisting obstruction, diverted the flow away from the fistula, and simultaneously covered the fistula end. The patients experienced relief of fistula symptoms and avoided them major surgical intervention. Watch the video: http://bit.ly/30BIvtw.

Early combined immunosuppression may be effective and safe in older patients with Crohn's disease: post hoc analysis of REACT.

Physicians may be reluctant to prescribe combined immunosuppression in older patients with Crohn's disease due to perceived risk of treatment-related complications. To evaluate the impact of age on risk of Crohn's disease-related complications in patients treated with early combined immunosuppression vs conventional management in a post hoc analysis of the randomised evaluation of an algorithm for Crohn's treatment (REACT), a cluster-randomised trial. We compared efficacy (time to major adverse outcome of Crohn's disease-related surgery, hospitalisation or serious complications; corticosteroid-free clinical remission) and safety outcomes at 24months, between patients aged <60 vs ≥60years randomised to early combined immunosuppression or conventional management, using Cox proportional hazard analysis or modified Poisson model. In the early combined immunosuppression arm, patients with failure to achieve clinical remission within 4-12weeks of corticosteroids were treated with a combination of tumour necrosis factor-α antagonist plus anti-metabolite and sequentially escalated in a stepwise algorithm. Of 1981 patients, 311 were ≥60years (15.7%; 173 randomised to early combined immunosuppression and 138 to conventional management). Over 24months, 10% of older patients developed Crohn's disease-related complications (early combined immunosuppression vs conventional management: 6.4% vs 14.5%) and 14 patients died (3.5% vs 5.8%). There was no difference between younger and older patients in risk of achieving corticosteroid-free clinical remission (<60years, early combined immunosuppression (72.6%) vs conventional management (64.4%): relative risk [RR], 1.06 [95% CI, 0.98-1.15] vs ≥60years, early combined immunosuppression (74.8%) vs conventional management (63.0%): RR, 1.09 [0.90-1.33], P-interaction=0.78) or time to major adverse outcome (<60years: hazard ratio [HR], 0.71 [0.53-0.96] vs ≥60years: HR, 0.69 [0.31-1.51], P-interaction=0.92) with early combined immunosuppression vs conventional management. We observed no difference in efficacy and safety of early combined immunosuppression compared to conventional management in older and younger patients. Early combined immunosuppression may be considered as a treatment option in selected older patients with Crohn's disease with suboptimal disease control. Clinical Trial Identifier: NCT01030809.

Predictors of anti-TNF treatment failure in anti-TNF-naive patients with active luminal Crohn's disease: a prospective, multicentre, cohort study

Anti-TNF drugs are effective treatments for the management of Crohn's disease but treatment failure is common. We aimed to identify clinical and pharmacokinetic factors that predict primary non-response at week 14 after starting treatment, non-remission at week 54, and adverse events leading to drug withdrawal. The personalised anti-TNF therapy in Crohn's disease study (PANTS) is a prospective observational UK-wide study. We enrolled anti-TNF-naive patients (aged ≥6 years) with active luminal Crohn's disease at the time of first exposure to infliximab or adalimumab between March 7, 2013, and July 15, 2016. Patients were evaluated for 12 months or until drug withdrawal. Demographic data, smoking status, age at diagnosis, disease duration, location, and behaviour, previous medical and drug history, and previous Crohn's disease-related surgeries were recorded at baseline. At every visit, disease activity score, weight, therapy, and adverse events were recorded; drug and total anti-drug antibody concentrations were also measured. Treatment failure endpoints were primary non-response at week 14, non-remission at week 54, and adverse events leading to drug withdrawal. We used regression analyses to identify which factors were associated with treatment failure. We enrolled 955 patients treated with infliximab (753 with originator; 202 with biosimilar) and 655 treated with adalimumab. Primary non-response occurred in 295 (23·8%, 95% CI 21·4-26·2) of 1241 patients who were assessable at week 14. Non-remission at week 54 occurred in 764 (63·1%, 60·3-65·8) of 1211 patients who were assessable, and adverse events curtailed treatment in 126 (7·8%, 6·6-9·2) of 1610 patients. In multivariable analysis, the only factor independently associated with primary non-response was low drug concentration at week 14 (infliximab: odds ratio 0·35 [95% CI 0·20-0·62], p=0·00038; adalimumab: 0·13 [0·06-0·28], p<0·0001); the optimal week 14 drug concentrations associated with remission at both week 14 and week 54 were 7 mg/L for infliximab and 12 mg/L for adalimumab. Continuing standard dosing regimens after primary non-response was rarely helpful; only 14 (12·4% [95% CI 6·9-19·9]) of 113 patients entered remission by week 54. Similarly, week 14 drug concentration was also independently associated with non-remission at week 54 (0·29 [0·16-0·52] for infliximab; 0·03 [0·01-0·12] for adalimumab; p<0·0001 for both). The proportion of patients who developed anti-drug antibodies (immunogenicity) was 62·8% (95% CI 59·0-66·3) for infliximab and 28·5% (24·0-32·7) for adalimumab. For both drugs, suboptimal week 14 drug concentrations predicted immunogenicity, and the development of anti-drug antibodies predicted subsequent low drug concentrations. Combination immunomodulator (thiopurine or methotrexate) therapy mitigated the risk of developing anti-drug antibodies (hazard ratio 0·39 [95% CI 0·32-0·46] for infliximab; 0·44 [0·31-0·64] for adalimumab; p<0·0001 for both). For infliximab, multivariable analysis of immunododulator use, and week 14 drug and anti-drug antibody concentrations showed an independent effect of immunomodulator use on week 54 non-remission (odds ratio 0·56 [95% CI 0·38-0·83], p=0·004). Anti-TNF treatment failure is common and is predicted by low drug concentrations, mediated in part by immunogenicity. Clinical trials are required to investigate whether personalised induction regimens and treatment-to-target dose intensification improve outcomes. Guts UK, Crohn's and Colitis UK, Cure Crohn's Colitis, AbbVie, Merck Sharp and Dohme, Napp Pharmaceuticals, Pfizer, and Celltrion.

Visceral Adipose Tissue Is Associated With Stricturing Crohn's Disease Behavior, Fecal Calprotectin, and Quality of Life.

Visceral adipose tissue (VAT) has been proposed to play a pathogenic role in Crohn's disease (CD); however, prospective clinical data are lacking. The aim was to evaluate whether VAT, beyond body mass index (BMI), is associated with CD behavior, disease activity, quality of life (QoL), or outcomes. Body composition data and clinical, anthropometric, disease activity (fecal calprotectin [FC]), and QoL scores were gathered prospectively on adults with CD at 0, 12, and 24 months. BMI and, VAT metrics (visceral adipose tissue volume [cm3]/height [m2] index and VAT:subcutaneous adipose tissue [SAT] ratio) were calculated. Inflammatory bowel disease-related surgery and hospitalization were recorded over extended follow-up (median, 51 months). Multivariable linear mixed effects and logistic regression analyses were performed. Ninety-seven participants were assessed at baseline (55% male; median age, 31 years), 84 at 12 months, and 72 at 24 months. VAT:SAT was positively associated with stricturing disease behavior (log odds ratio [OR], 1.7; 95% confidence interval [CI], 0.32 to 3; P = 0.01) and elevated FC in patients with ileocolonic disease (β, 1.3; 95% CI, 0.32 to 2.3; P = 0.01). VAT:SAT was associated with lower QoL, particularly in those with ileal disease (β, -12; 95% CI, -19 to -4.5; P = 0.05). However, no prospective associations were observed between serial VAT measurements and time to surgery or hospitalization. No correlations were found between BMI and disease behavior, activity, or QoL. VAT:SAT, rather than BMI, is associated with stricturing CD behavior, elevated FC, and reduced QoL in a disease distribution-dependent manner. Further studies are required to substantiate the role of VAT as a useful biomarker in CD.

Early drug and anti-infliximab antibody levels for prediction of primary nonresponse to infliximab therapy.

Primary nonresponse, defined as lack of clinical benefit during the induction phase, occurs in up to 30% of IBD patients treated with infliximab. The mechanisms underlying primary nonresponse have not yet been clearly defined. To evaluate the association of early (week 2 and week 6) induction infliximab and anti-infliximab antibody levels with primary nonresponse. A retrospective observational case-control study of inflammatory bowel disease patients treated with infliximab and followed at Sheba Medical Center between 2009 and 2016 was performed. Pre-infusion infliximab and antibodies to infliximab (ATI) levels were measured by our previously described drug-tolerant ELISA assay. Thirty-five primary nonresponders have been identified and matched with 105 primary responders (1:3 ratios). Both week 2 and week 6 infliximab levels were significantly lower among primary nonresponders compared to responders (week 2, 6: median level 7.2, 2.2μg/mL vs 13.5, 9.5μg/mL, P=.0019, P<.0001 respectively). Antibodies to infliximab appeared more frequently (either week 2 or 6, 68% vs 28% prevalence, P=.0004) and at higher levels in nonresponders compared to responders (week 2, 6: median ATI 7.3, 10.8μg/mL-eq vs 3.8, 4.4μg/mL-eq, P=.005, P=.008 respectively). Moreover, week 2 infliximab levels <6.8μg/mL (AUC=0.68, P=.002, sensitivity 50%, specificity 86%) and antibodies to infliximab levels >4.3μg/mL-eq (AUC=0.78, P=.0004, sensitivity 77%, specificity 71%) were predictive of primary nonresponse. Among the other clinical and demographic variables, higher baseline ulcerative colitis clinical score, infliximab monotherapy, prior adalimumab therapy and previous Crohn's disease-related surgeries were also associated with an increased risk of primary nonresponse. Infliximab levels below 6.8μg/mL and antibodies to infliximab levels above 4.3μg/mL-eq before the second infusion are associated with primary nonresponse, especially among Crohn's disease patients.

Delayed Diagnosis is Associated with Early and Emergency Need for First Crohn's Disease-Related Intestinal Surgery.

BackgroundIncreasing evidence suggests that delayed diagnosis in Crohn’s disease is associated with a complicated disease course. The aim of this study was to explore the association between delayed diagnosis and the timing of the first Crohn’s disease-related intestinal surgery.Material/MethodsA retrospective study included 215 Crohn’s disease patients with previous surgical history in the Department of General Surgery of Jinling Hospital, China, between January 2013 and March 2016. Data were collected on demographics, clinical characteristics, medication history, and operation history.ResultsThe time from the first appearance of Crohn’s disease-related symptoms to the first intestinal surgery in the delayed diagnosis group was obviously shorter than in the non-delayed diagnosis group (26.4±28.7 months vs. 42.6±58.4 months, respectively, p=0.032). Patients in the delayed diagnosis group tended to receive more ileal resections (47.8% vs. 26.4%, respectively, p=0.002) and less ileocecal resections (22.4% vs. 37.2%, respectively, p=0.032). More patients in the delayed diagnosis group received the first Crohn’s disease-related intestinal surgery as an emergency one (20.9% vs. 4.7%, respectively, p=0.001).ConclusionsDelayed diagnosis is associated with early and emergency need for the first Crohn’s disease-related intestinal surgery.

Development of Clinical Prediction Models for Surgery and Complications in Crohn's Disease.

Crohn's disease-related complications account for a substantial proportion of inflammatory bowel disease-associated health care expenditure. Identifying patients at risk for complications may allow for targeted use of early therapeutic interventions to offset this natural course. We aimed to develop risk prediction models for Crohn's disease-related surgery and complications. Using data from the Randomised Evaluation of an Algorithm for Crohn's Disease cluster-randomised clinical Trial [REACT], which involved 1898 patients from 40 community practices, separate prediction models were derived and internally validated for predicting Crohn's disease-related surgery and disease-related complications [defined as the first disease-related surgery, hospitalisation, or complication within 24 months]. Model performance was assessed in terms of discrimination and calibration, decision curves, and net benefit analyses. There were 130 [6.8%] disease-related surgeries and 504 [26.6%] complications during the 24-month follow-up period. Selected baseline predictors of surgery included age, gender, disease location, Harvey-Bradshaw Index [HBI] score, stool frequency, antimetabolite or 5-aminosalicylate use, and the presence of a fistula, abscess, or abdominal mass. Selected predictors of complications included those same factors for surgery, plus corticosteroid or anti-tumour necrosis factor use, but excluded 5-aminosalicylate use. Discrimination ability, as measured by validated c-statistics, was 0.70 and 0.62 for the surgery and complication models, respectively. Score charts and nomograms were developed to facilitate future risk score calculation. Separate risk prediction models for Crohn's disease-related surgery and complications were developed using clinical trial data involving community gastroenterology practices. These models could be used to guide Crohn's disease management. External validation is warranted.

Outcomes After Primary Infliximab Treatment Failure in Inflammatory Bowel Disease.

Primary infliximab treatment failure is common in patients with inflammatory bowel disease and represents a challenge to clinicians. Treatment options are limited. This study assessed the prognosis, defined as surgery-free survival, in patients with primary infliximab treatment failure as compared to patients without primary failure (initial responders). Furthermore, this study assessed the specter of medical therapies used after primary infliximab treatment failure along with treatment outcomes. Retrospective, observational, cohort study of patients with inflammatory bowel disease treated with infliximab as first-line anti-tumor necrosis factor treatment at a tertiary center. Primary infliximab treatment failure was defined as no clinical improvement during infliximab induction therapy resulting in discontinuation of infliximab therapy. A total of 560 patients (Crohn's disease n = 353 and ulcerative colitis n = 207) were treated with infliximab. Among these, 81 (15%) had primary infliximab treatment failure after a median of 3 infusions (weeks 0, 2, and 6) (interquartile range 2-4). The median surgery-free survival was 196 days from first infusion. One year after primary infliximab treatment failure, the majority of patients (n = 51, 63%) had inflammatory bowel disease-related surgery (Crohn's disease n = 19, 58%; ulcerative colitis n = 32, 67%; P = 0.49). There was a markedly increased risk of surgery in patients with primary infliximab treatment failure as compared to initial responders: odds ratio 6.3 (3.8-10.6), P < 0.0001. Among 30 patients handled by medical therapies, 16 (53%) still had active disease 1 year after primary infliximab treatment failure. Primary infliximab treatment failure is associated with poor outcome including high risk of surgery or sustained active disease despite medical interventions.