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Current guidelines on Crohn’s perianal fistulas recommend anti-TNF treatment and suggest to consider surgical closure in amendable patients. However, long-term outcome of both treatments have not been directly compared. The aim of this study was to assess MRI healing in a patient preference RCT comparing both treatment modalities.

This multicentre, international trial compared surgical closure following anti-TNF induction (4 months) to anti-TNF therapy without surgery. Patients were counselled for both treatment arms and randomised if there was no preference. Due to the combination of a preference and randomised cohort, the appropriate sample size to detect a clinically relevant increase of 25% closure (from 15% to 40%) was flexible and adjusted for a possible skewed distribution (86 patients in case of 1:1 treatment allocation).

All Crohn’s patients ≥ 18 years with a (re)active high perianal fistula and a single internal opening were eligible. Exclusion criteria were previous failure of anti-TNF, recto-vaginal fistula, proctitis, or stoma. Patients received seton placement prior to treatment. Primary outcome was MRI healing after 18 months (defined as a complete fibrotic fistula or MAGNIFI-CD score of 0-5). Secondary outcomes included clinical healing, re-interventions and fistula recurrence.

Between September 2013 and December 2019, 7 hospitals in the Netherlands and Italy included 93 patients (59% females, median age 34 years) of which 32 were randomised. Thirty-seven patients were treated in the surgical closure group and 56 in the anti-TNF group, with comparable baseline characteristics.

After 18 months, MRI healing was significantly higher after surgical closure (41% vs 11%; P=0.002). Although a trend was seen in favour of surgical closure, clinical healing rates and surgical re-interventions were not significantly different between groups (65% vs 45%, P=0.07 and 19% vs 34%, P=0.1). After median 38 months follow-up, 12 patients in the anti-TNF group crossed over to surgical closure. Both long-term MRI healing and clinical closure in the per protocol analysis remained significantly higher for the surgical closure group (46% vs 11%, P=0.002 and 65% vs 29%, P=0.006). One patient (4%) with a MAGNIFI-CD score ≤5 developed a recurrent fistula after 46 months, whereas recurrences occurred in 37% of patients with MAGNIFI-CD score >5 (P=0.004).

These results demonstrate that surgical closure following anti-TNF induction treatment induces MRI healing more frequently than anti-TNF alone. This is associated with increased long-term clinical closure and reduced recurrences. These data suggest that Crohn’s perianal fistula patients amendable for surgical closure should be counselled for this therapeutic approach.

Limited resective surgery is used as a primary therapeutic option in patients with Crohn’s disease (CD) who present with severe symptoms or fibrostenotic complications. Recent studies suggest that surgery represents a valid alternative of biological therapy in subgroups of CD patients.¹ However, only few studies have described the disease course in early resected CD patients regardless of disease location. This study aimed to investigate disease course in all early resected CD patients.

Using the Danish National Patient Registry (NPR), we identified 9739 patients who were diagnosed with CD between January 1^st, 1997 and December 31^st, 2015. Of those, 499 patients underwent a major abdominal surgery within 30 days before or after their diagnosis. Data on re-operation, hospitalization and medication use were retrieved from the NPR and the National Prescription Registry. Trends in treatment outcomes over time were assessed using Chi-square test, Kaplan Meier survival analysis and log-rank test.

Overall, 217 (43.5%) patients had an initial ileocecal resection, 154 (30.9%) had a colonic resection and 112 (22.4%) had a small bowel resection and 16(3.2%) patients without classification of  surgery. The cumulative risk of reoperation was 16.4% at five years after the initial surgery. Five-year risk of hospitalization and need for medical therapy was 66.1% and 61.7% (Figure 1). Among 326 (65.3%) patients who received medical therapy during follow-up, 216 (66.3%) were treated with an immunomodulator and 62 (19.0%) with a biological drug. There was no difference in the risk of re-operation (p=0.11), hospitalization (p=0.70) or medication use (p=0.37) in relation to the anatomic location of the initial surgery.

When comparing patients diagnosed before and after 2005, five-year risk of hospitalization decreased from 76.9% to 56.1% (p<0.001, Figure 2), while five-year risk of medication use decreased from 65.9% to 58.5% (p=0.01, Figure 2). In contrast, five-year risk of re-operation showed an increasing, but insignificant trend from 13.7% to 18.6% (p=0.18).

Figure 1. Cumulative risk of re-operation, hospitalization and medication use

The risk of re-operation and hospitalization after the initial surgery in this cohort of early resected CD patients are lower when compared to other CD cohorts. Furthermore, hospitalization risk and need for medical therapy decreased over time.

¹.Stevens TW, Haasnoot ML, D’Haens GR, Buskens CJ, de Groof EJ, Eshuis EJ, et al. Laparoscopic ileocaecal resection versus infliximab for terminal ileitis in Crohn’s disease: retrospective long-term follow-up of the LIR!C trial. Lancet Gastroenterol Hepatol. 2020 Oct 1;5(10):900–7.

Background

Endoscopic remission is associated with better outcomes in ulcerative colitis (UC). However, colonoscopy (CS) is invasive and poorly tolerated by patients. Recently, we developed and externally validated non-invasive ultrasonography based criteria [Milan ultrasound criteria (MUC)] to assess and grade endoscopic activity in UC. We also confirmed that a MUC score > 6.2 is a valid cut-off to discriminate endoscopic activity, defined by a Mayo endoscopic subscore > 2.
Aim of this study was to assess the predictive role of MUC on disease course in a prospective cohort of UC patients.

Methods

UC consecutive patients were followed for at least 12 months after performing baseline bowel US. UC-related outcomes, including need of treatment escalation (defined as the need of corticosteroids or change/optimization of immunosuppressants), hospitalization and surgery, were assessed at 1 year by logistic regression analysis, and were analyzed after long term follow-up (5 years) using Kaplan-Meier survival analysis.

Results

87 UC consecutive patients were included in the study, 31 (36%) were in endoscopic remission (Mayo endoscopic subscore 0-1) and 56 (64%) in endoscopic activity (Mayo endoscopic subscore 2-3). MUC and Mayo endoscopic subscore significantly correlated at baseline (Spearman’s rank correlations [rho]= 0.642; 95% confidence interval (CI) 0.499 to 0.751; p < 0.001). The multivariable analysis identified as independent predictors of need of treatment escalation throughout the 12-month period as being: MUC > 6.2 (OR: 5.95, 95% CI: 1.32–26.76, p < 0.020) and a partial Mayo score (PMS) > 2 (OR: 26.88, 95% CI: 5.01–144.07, p < 0.001). Kaplan-Meier survival analysis of long-term follow up demonstrated a lower cumulative probability of need for surgery and hospitalization in patients with MUC < 6.2 compared to MUC > 6.2 (Fig. 1A and 1B), as well as in patients with a Mayo endoscopic subscore of < 1 compared to Mayo endoscopic subscore of 2-3 (Fig. 1C and 1D).

Conclusion

MUC is a novel non invasive tool that predicts the course of UC in the short and long term follow-up. 

Fatigue is one of the most common symptoms in IBD resulting in decreased quality of life, impaired work productivity, and higher societal costs. However, little is known about its etiology and pathophysiology. We aimed to estimate the prevalence of fatigue and to identify predictive factors for fatigue.

The PREdiCCt study (https://www.predicct.co.uk) is the largest prospective study of the causes of IBD flare. 2629 patients in clinical remission were recruited from 48 UK sites. 1946 (74%) patients completed the baseline questionnaires. We assessed the prevalence of fatigue at baseline using a single item from the IBD Control questionnaire. To identify predictors for fatigue, we performed univariable and multivariable analyses including demographic, biochemical, environmental and psychosocial factors such as anxiety and depression [HADS], sleep quality [PSQI] and physical exercise [GPAQ]).

759/1919 IBD patients in clinical remission (39.6%) reported fatigue in the past 2 weeks, while 1034 patients (53.9%) did not report fatigue. Patients who reported fatigue were more frequently female, had more frequently CD, and were more frequently smokers (Table 1). Univariable comparisons showed higher inflammatory markers in the fatigued group, with fewer patients in clinical remission. Multivariable analyses identified female sex (OR 2.4), CRP>5 (OR 2.1), bad sleep quality (OR 2.5), anxiety (OR 1.8) and depression (OR 6.2) as independent factors associated with fatigue (Table 2).

Table 1

We show the significant burden of fatigue in IBD patients and describe putative causes which demonstrate both the impact of residual gut inflammation and the relationship between fatigue and psychological well-being. The impact of environmental and dietary factors on fatigue is being further investigated with ongoing longitudinal data collection in the PREdiCCt study.

Upadacitinib (UPA) is a selective and reversible Janus kinase inhibitor.U-ACCOMPLISH is one of two phase 3 induction trials that evaluated the safety and efficacy of UPA 45 mg once daily (QD) in adults with ulcerative colitis (UC).

U-ACCOMPLISH was a multicentre, randomized, double-blind, placebo-controlled trial (NCT03653026) that enrolled patients with moderate-to-severe UC (defined as adapted Mayo score 5–9 with centrally read endoscopic score 2–3) who had inadequate response, loss of response, or intolerance to aminosalicylates, immunosuppressants, corticosteroids and/or biologics. Patients were randomized 2:1 to UPA 45 mg QD or placebo (PBO) for 8 weeks. At week 8, responders entered the maintenance phase and non-responders entered the extended treatment period to receive open-label UPA 45 mg QD for additional 8 weeks.The primary endpoint (clinical remission per adapted Mayo Score) and ranked secondary endpoints including symptomatic, endoscopic– histologic evaluations from the 8-week PBO-controlled period are reported here. Non-responder imputation incorporating multiple imputation for missing data due to COVID-19 are reported.

522 patients were randomized (UPA, n=345; PBO, n=177);the intent-to-treat population included 341 patients in UPA and 174 patients in PBO group. Baseline demographics and disease characteristics were similar between groups; 50.7% and 51.1% were biologic inadequate responders in UPA and PBO groups, respectively (Table 1). A significantly higher proportion of patients receiving UPA 45 mg QD (33.5%) versus PBO (4.1%) achieved the primary endpoint (adjusted treatment difference: 29.0% [23.2, 34.7]; P<0.001). A significantly higher proportion of patients receiving UPA versus PBO also achieved all ranked secondary endpoints (all P<0.001; Figure 1).Serious adverse events were reported by 3.2% and 4.5% of patients in UPA and PBO groups, respectively (Table 2). Similar rates of serious infection were observed in both groups (0.6%); 2 events each of herpes zoster and opportunistic infection were reported in UPA group. No active tuberculosis, malignancy, adjudicated major adverse cardiovascular events, or deaths were reported in the study. One patient with venous thromboembolism (deep vein thrombosis and pulmonary embolism) and 1 patient with gastrointestinal perforation were reported in the placebo group.

In U-ACCOMPLISH, 8-week UPA 45 mg QD induction treatment led to statistically significant improvements in clinical, endoscopic, and combined endoscopic-histologic endpoints.The treatment was well tolerated, and the safety profile and AE prevalence was comparable with previous studies of UPA with no new safety signals identified.