Discontinuation of Anti-Tumour Necrosis Factor Therapy in Patients with Perianal Fistulizing Crohn's Disease: Individual Participant Data Meta-Analysis of 309 Patients from 12 Studies.

BACKGROUND: The risk of relapse after anti-tumour necrosis factor [TNF] therapy discontinuation in Crohn's disease patients with perianal fistulas [pCD] is unclear. We aimed to assess this risk. METHODS: A systematic literature search was conducted to identify cohort studies on the incidence of relapse following anti-TNF discontinuation in pCD patients. Individual participant data were requested from the original study cohorts. Inclusion criteria were age ≥16 years, pCD as a (co)indication for start of anti-TNF therapy, more than three doses, and remission of luminal and pCD at anti-TNF discontinuation. The primary outcome was the cumulative incidence of CD relapse using Kaplan-Meier estimates. Secondary outcomes included response to re-treatment and risk factors associated with relapse as assessed by Cox regression analysis. RESULTS: In total, 309 patients from 12 studies in ten countries were included. The median duration of anti-TNF treatment was 14 months [interquartile range 5.8-32.5]. Most patients were treated for pCD without active luminal disease [89%], received first-line anti-TNF therapy [87%], and continued immunomodulatory therapy following anti-TNF discontinuation [78%]. The overall cumulative incidence of relapse was 36% (95% confidence interval [CI] 25-48%) and 42% [95% CI 32-53%] at 1 and 2 years after anti-TNF discontinuation, respectively. Risk factors for relapse included smoking (hazard ratio [HR] 1.5 [1.0, 2.1]) and history of proctitis (HR 1.7 [1.1, 2.5]). The overall re-treatment response rate was 82%. CONCLUSIONS: This individual participant data meta-analysis, on predominantly patients with pCD without active luminal disease and first-line anti-TNF therapy, shows that over half of patients remain in remission 2 years after anti-TNF discontinuation. Therefore, anti-TNF discontinuation may be considered in this subgroup.

Prognostic Value of the Modified Rutgeerts Score for Long-Term Outcomes After Primary Ileocecal Resection in Crohn's Disease.

INTRODUCTION: The prognostic value of the modified Rutgeerts score (mRS) in patients with Crohn's disease (CD) needs to be further elucidated. This study assessed the prognostic value of the mRS for long-term outcomes after primary ileocecal resection in patients with CD. METHODS: Patients with CD after primary ileocecal resection with an available mRS at first postoperative ileocolonoscopy (index mRS) were retrospectively included. The primary outcome was surgical recurrence. Secondary outcomes were clinical recurrence and progression to severe endoscopic recurrence (≥i3). Cox proportional hazard models were used to assess the association between index mRS and outcomes. RESULTS: Six hundred fifty-two patients were included (mean follow-up: 6.4 years, SD: 4.6). Surgical recurrence rates were 7.7%, 5.3%, 12.9%, 19.1%, 28.8%, 47.8% for index mRS i0, i1, i2a, i2b, i3, and i4, respectively. Clinical recurrence occurred in 42.2% (i0), 53.7% (i1), 58.5% (i2a), 80.2% (i2b), 79.4% (i3), and 95.3% (i4) of patients. Progression to severe endoscopic recurrence occurred in 21.1% (i0), 33.9% (i1), 26.8% (i2a), and 33.3% (i2b) of patients. An index mRS of i2b (adjusted hazard ratio [aHR] 3.0; 1.5-5.6), i3 (aHR 4.0; 2.0-7.9) and i4 (aHR 8.0; 4.0-16.0) were associated with surgical recurrence. An index mRS of i1 (aHR 1.7; 1.2-2.4), i2a (aHR 1.7; 1.2-2.4), i2b (aHR 4.4; 3.2-6.0), i3 (aHR 3.6; 2.5-5.2), and i4 (aHR 7.3; 4.8-10.9) were associated with clinical recurrence. An index mRS of i1 (aHR 2.0; 1.1-3.7) or i2b (aHR 2.5; 1.4-4.6) was associated with progression to severe endoscopic recurrence. DISCUSSION: The increasing mRS corresponds closely with the risk of surgical and clinical recurrence. An index mRS ≥ i2b is associated with surgical recurrence, an index mRS ≥ i1 is associated with clinical recurrence, and i1 or i2b with progression to severe endoscopic recurrence. These results support tight monitoring of disease activity and treatment optimization in patients with ileal lesions and a more conservative management in patients with anastomotic lesions.

Early fecal calprotectin levels at week 8 may guide therapeutic decisions on Ustekinumab therapy in patients with Crohn's disease.

BACKGROUND: Response evaluation after induction therapy with ustekinumab (UST) in Crohn's disease (CD) is important for decisions on maintenance therapy. We aimed to assess the potential of fecal calprotectin (FC) levels to predict endoscopic response at week 16. METHODS: CD patients with FC >100 µg/g and endoscopic active disease (SES-CD> 2, Rutgeerts' score ≥ i2) at initiation of UST therapy were enrolled. FC was determined at weeks 0, 2, 4, 8 and 16 and patients underwent a colonoscopy at week 16. The primary outcome was an endoscopic response at week 16 (SES-CD score ≥50% decrease or a decrease of ≥1 points in Rutgeerts' score). The optimal cut-off levels of FC and change in FC to predict endoscopic response were determined using ROC statistics. RESULTS: 59 CD patients were included. Endoscopic response was observed in 21/59 (36%) patients. The diagnostic accuracy for FC levels at week 8 to predict endoscopic response at week 16 showed a predictive value of 0.71. A decrease in FC levels ≥500 µg/g between baseline at week 8 indicates endoscopic response (PPV = 89%), whereas absence of any decrease indicates endoscopic non-response after induction (NPV = 81%). CONCLUSIONS: Continuation of UST therapy without endoscopic response evaluation may be considered in patients with a decrease in FC levels of ≥500 µg/g at week 8. The decision on continuation of UST therapy or therapy optimization needs reconsideration in patients without a decrease of FC level. In all other patients, endoscopic response evaluation of induction therapy remains essential for therapeutic decisions.

Retreatment with anti-tumor necrosis factor therapy in combination with an immunomodulator for recurrence of Crohn's disease after ileocecal resection results in prolonged continuation as compared to anti-tumor necrosis factor monotherapy.

BACKGROUND: A considerable proportion of Crohn's disease patients that undergo ileocecal resection (ICR) have failed anti-tumor necrosis factor (TNF) therapy preoperatively. This study aimed to assess the effectiveness of retreatment of anti-TNF therapy in patients with postoperative recurrence. METHODS: A real-world cohort study was performed on Crohn's disease patients who underwent primary ICR after anti-TNF therapy failure, and who were retreated with anti-TNF therapy for postoperative symptomatic Crohn's disease. The primary outcome was treatment failure (the need for (re)introduction of corticosteroids, immunosuppressants, or biologicals or the need for re-resection). Sub-analyses were performed on the nature of preoperative anti-TNF failure (primary non-response, secondary loss of response, intolerance), indication for ICR (refractory, stricturing, penetrating disease), combination therapy with immunomodulators, retreatment with the same anti-TNF agent and preoperative exposure to 1 vs. >1 anti-TNF agents. RESULTS: In total, 66 of 364 patients retreated with anti-TNF therapy following ICR. Cumulative rates of treatment failure at 1 and 2 years were 28% and 47%. Treatment failure rate at 2 years was significantly lower in patients receiving combination therapy as compared to anti-TNF monotherapy (30% vs. 49%, P = 0.02). No difference in treatment failure was found with regards to the nature of preoperative anti-TNF failure (P = 0.76), indication for ICR (P = 0.88) switch of anti-TNF agent (P = 0.55) agent, and preoperative exposure to 1 vs. >1 anti-TNF agents (P = 0.88). CONCLUSION: Retreatment with anti-TNF therapy for postoperative Crohn's disease recurrence is a valid strategy after preoperative failure. Combination therapy is associated with a lower rate of treatment failure.

Validation and update of a prediction model for risk of relapse after cessation of anti-TNF treatment in Crohn's disease.

BACKGROUND: Anti-tumor necrosis factor (TNF) therapy is effective for the treatment of Crohn's disease. Cessation may be considered in patients with a low risk of relapse. We aimed to externally validate and update our previously developed prediction model to estimate the risk of relapse after cessation of anti-TNF therapy. METHODS: We performed a retrospective cohort study in 17 Dutch hospitals. Crohn's disease patients in clinical, biochemical or endoscopic remission were included after anti-TNF cessation. Primary outcome was a relapse necessitating treatment. Discrimination and calibration of the previously developed model were assessed. After external validation, the model was updated. The performance of the updated prediction model was assessed in internal-external validation and by using decision curve analysis. RESULTS: 486 patients were included with a median follow-up of 1.7 years. Relapse rates were 35 and 54% after 1 and 2 years. At external validation, the discriminative ability of the prediction model was equal to that found at the development of the model [c-statistic 0.58 (95% confidence interval (CI) 0.54-0.62)], though the model was not well-calibrated on our cohort [calibration slope: 0.52 (0.28-0.76)]. After an update, a c-statistic of 0.60 (0.58-0.63) and calibration slope of 0.89 (0.69-1.09) were reported in internal-external validation. CONCLUSION: Our previously developed and updated prediction model for the risk of relapse after cessation of anti-TNF in Crohn's disease shows reasonable performance. The use of the model may support clinical decision-making to optimize patient selection in whom anti-TNF can be withdrawn. Clinical validation is ongoing in a prospective randomized trial.

Re-induction with intravenous Ustekinumab after secondary loss of response is a valid optimization strategy in Crohn's disease.

BACKGROUND AND AIM: Re-induction with intravenous ustekinumab after secondary loss of response in Crohn's disease is a relatively new strategy to regain efficacy. This real-world cohort study aimed to evaluate its effectiveness and safety. METHODS: Crohn's disease patients with loss of response after initial response to ustekinumab and treated with a second intravenous dose of ustekinumab were included. Clinical, biochemical and endoscopic data were collected. Primary outcome was drug survival. Secondary effectiveness outcomes included clinical remission, primary nonresponse and adverse events. RESULTS: In total, 31 Crohn's disease patients were included after re-induction with intravenous ustekinumab. All patients had failed prior biologic therapy, that is 77% were exposed to two or more antitumor necrosis factor agents and 65% were exposed to vedolizumab prior to initiation of ustekinumab treatment. Median treatment duration between initial treatment and re-induction with intravenous ustekinumab was 11.1 months (interquartile range 6.9-19.5). Ustekinumab therapy after a second dose of intravenous ustekinumab was maintained in 74 and 71% of the patients at weeks 20 and 52. Clinical remission rates after re-induction at weeks 8, 20 and 52 were 37, 56 and 45%, respectively. Nonresponse occurred in 16% of the patients. Adverse events were reported in four patients. CONCLUSIONS: Re-induction with intravenous ustekinumab after secondary loss of response results in continuation of ustekinumab treatment for at least 1 year in almost three-quarters of patients and in clinical remission in half of patients after 1 year. Therefore, ustekinumab re-induction may be considered an important rescue treatment option in patients with refractory Crohn's disease.

Measuring Diet Intake and Gastrointestinal Symptoms in Irritable Bowel Syndrome: Validation of the Food and Symptom Times Diary.

INTRODUCTION: Patients with irritable bowel syndrome (IBS) identify food as a trigger for the onset or worsening of gastrointestinal symptoms. Despite this, there is no published validated contemporaneous food and symptom diary to investigate the association between diet and IBS symptoms. The objective of this prospective observational study was to assess the construct validity of a novel food diary and symptom questionnaire, the Food and Symptom Times (FAST) diary, and the predictive validity of the food diary component with relation to fiber and fermentable oligosaccharides, disaccharides, monosaccharides, and polyols consumption and subsequent gastrointestinal symptoms. METHODS: Fifty-one participants with IBS completed the FAST diary and several legacy instruments. The relationship between the FAST gastroenterological symptoms and legacy instruments was examined using Spearman correlation coefficients. Further statistical analysis investigated the relationship between diet and postprandial gastrointestinal symptoms. RESULTS: Consistent with a priori predictions, the FAST symptoms showed moderate correlations with the most similar Patient-Reported Outcome Measurement Information System gastrointestinal scales (0.328-0.483, P < 0.05) and the most similar Gastrointestinal Symptom Rating Scale questions (0.303-0.453, P < 0.05), with the exception of the weakly correlated subscale constipation for both instruments (-0.050 to -0.119, P > 0.05). The IBS-Quality of Life instrument showed moderate correlations with the FAST symptom abdominal swelling/distension (0.313-0.416, P < 0.05). The consumption of a high fermentable oligosaccharides, disaccharides, monosaccharides, and polyols meal was associated with participants with IBS-D experiencing abdominal bloating and participants with IBS-C not experiencing abdominal swelling (P < 0.05). The consumption of fiber was correlated with abdominal fullness and bloating in participants with IBS-C (P < 0.05). DISCUSSION: The FAST diary validly measures gastrointestinal symptoms as they occur in people with IBS and correlates these symptoms with specific aspects of diet.

Low-FODMAP Diet Is Associated With Improved Quality of Life in IBS Patients-A Prospective Observational Study.

BACKGROUND: The low fermentable oligosaccharide, disaccharide, monosaccharide, and polyol (FODMAP) diet is effectively manages irritable bowel syndrome (IBS) symptoms. Long-term low-FODMAP studies rarely report quality of life (QoL). We aimed to determine the effect of low-FODMAP diet on long-term QoL, gastrointestinal (GI) and non-GI symptoms in IBS patients. METHODS: A prospective observational study of IBS patients referred for low-FODMAP dietary advice was performed. The primary outcome of QoL and secondary outcomes of GI symptoms, anxiety/depression, fatigue, sleep quality, and happiness were obtained at baseline, 6 weeks (T6), and 6 months (T26). RESULTS: 111 patients were recruited. 91.0%, 71.6%, and 50.5% of participants completed baseline, T6, and T26 assessments, respectively. There were significant improvements in QoL from baseline at T6 and T26 (both P < 0.001). Significant reductions were seen in GI symptoms at T6 and T26 (both P < 0.001), fatigue at T6 and T26 (both P < 0.003), and anxiety at T6 and T26 (both P < 0.007), compared with baseline. A significant reduction was seen for depression (P < 0.010) from baseline at T26, and a significant increase was seen for both happiness and vitality (both P < 0.04) from baseline at T26. There was a significant correlation between GI symptom response and change in QoL, anxiety, depression, and fatigue (all P < 0.034). CONCLUSION: Low-FODMAP diet was associated with improved long-term QoL and GI symptoms, reduced fatigue and anxiety/depression, and increased happiness and vitality. These data support a wider range of benefits for IBS patients consuming a low-FODMAP diet.

Observational Study of Perspectives of Inflammatory Bowel Disease Patients Concerning the Use of Corticosteroids.

AIM: We aimed to investigate the factors that make inflammatory bowel disease (IBD) patients more or less likely to be willing to take corticosteroids. METHODS: Respondents completed a questionnaire. The primary outcome was whether the respondents would or would not use corticosteroids again to treat their IBD. Three separate univariate and multivariate analyses were performed to examine which variables predicted willingness to take steroids, including specific side effects. RESULTS: Four hundred fifty three respondents (321 with Crohn's disease, 115 with ulcerative colitis; mean age 40 years, 297 [66%] female) completed the questionnaire. Corticosteroid efficacy (OR 6.83, 95% CI 3.67-12.7), lack of previous negative side effects (OR 0.11, 95% CI 0.04-0.32), and positive side effects (OR 2.96, 95% CI 1.63-5.40) were associated with a willingness to use corticosteroids in the future. In multivariate analysis, weight gain (OR 0.53, 95% CI 0.29-0.98) and hallucinations (OR 0.28, CI 0.09-0.89) were associated with an unwillingness to use corticosteroids again, whereas increased energy (OR 2.30, 95% CI 1.20-4.42) was the only significant positive side effect in a multivariate model. CONCLUSIONS: Past experiences with corticosteroids influence whether patients will take corticosteroids again. Clinicians should enquire about side effects and positive psychological symptoms associated with corticosteroid use.