P300 Crohn’s Disease Strictures Respond to Drug Treatment and Treat-to-Target Intense Combination Therapy is More Effective than Standard Anti-TNF Therapy. The STRIDENT Randomised Controlled Trial

Abstract Background Strictures are the commonest complication in Crohn’s disease. Surgery and endoscopic dilation are the main treatments; drug therapy has been considered contra-indicated. Given that most strictures have an inflammatory component we aimed to assess the efficacy of anti-inflammatory therapy, and to identify the optimal treatment. Methods In this randomised trial patients with symptomatic Crohn’s disease strictures and inflammation were assessed by imaging (MRI, colonoscopy, intestinal ultrasound) and for inflammation (faecal calprotectin and CRP). Symptoms were assessed using an Obstructive Symptom Score (OSS). Patients with short endoscopically-accessible strictures had a baseline endoscopic balloon dilation if indicated. Patients were then randomised 2:1 to high dose adalimumab induction (160mg weekly for 4 weeks) with 40mg fortnightly maintenance plus thiopurine, with therapy increased for ongoing inflammation at 4 and 8 months, versus standard dose adalimumab mono-therapy. At 12 months primary endpoint was improved OSS. Secondary outcomes: disease activity, treatment failure, stricture morphology, inflammation, psychological well-being, disability, and quality of life. MRI was assessed blindly. Results 52 patients were randomised to the intensive and 25 to the standard treatment arm. 27 of 52 (52%) intensive treatment patients dose escalated at 4 or 8 months. Improved OSS at 12 months occurred in 41 (79%) intensive treatment and 16 (64%) standard treatment arms (P=0.17). Treatment failure was less common in the intensive treatment arm (10%) versus the standard treatment arm (28%) (P=0·045). Faecal calprotectin normalised (<100mcg/g) in 32 (62%) v 11 (44%) (P=0.15), and CRP normalised in 32 (62%) v 11 (44%) (P=0.15), in intensive versus standard treatment arms respectively. MRI stricture morphology improvement (MaRIA score decrease ≥25%) was seen in 31 (61%) v 9 (28%) (P=0.009) and in 40 (78%) v 14 (56%) using the simplified MaRIA score (≥1 point improvement) (P=0.047). Improvement in bowel wall thickness by >25% on ultrasound was seen in 22/43 (51%) and 7/21 (33%) respectively (P=0.18). MRI complete stricture resolution was seen in 10/51 (20%) and 4/25 (16%) (P=0.7). At 12 month colonoscopy 22/48 (46%) v 9/25 (36%) strictures were passable (P=0.42). 12 month median drug levels were 13.2µg/ml and 6.6µg/ml respectively (P<0.0001). See summary results figure 1 and case example figure 2. Conclusion Crohn’s disease strictures are responsive to drug therapy. A majority of patients experience symptom improvement and many have improved stricture morphology. Treat-to-target therapy intensification results in less treatment failure, less stricture-associated inflammation, and greater improvement in stricture morphology.

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Week 6 Calprotectin Best Predicts Likelihood of Long-term Endoscopic Healing in Crohn’s Disease: A Post-hoc Analysis of the UNITI/IM-UNITI Trials

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjaa189 ◽

2020 ◽

Author(s):

Neeraj Narula ◽

Emily C L Wong ◽

Parambir S Dulai ◽

John K Marshall ◽

Jean-Frederic Colombel ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Predictive Performance ◽

Drug Level ◽

Symptom Improvement ◽

Faecal Calprotectin ◽

Post Hoc Analysis ◽

Post Hoc ◽

The Relationship

Abstract Objectives There is need for biomarkers as predictors of outcome of medical treatment in Crohn’s disease. The purpose of this study was to evaluate the predictive performance of faecal calprotectin for short- and long-term clinical and endoscopic outcomes. Methods This post-hoc analysis of the UNITI/IM-UNITI studies [NCT01369329, NCT01369342, and NCT01369355; YODA #2019–4026] included 677 patients to evaluate the relationship of Week 6 calprotectin cut-offs and changes from baseline assessments in calprotectin for prediction of outcomes at Weeks 8, 32, and 52, using receiver operating characteristic curves with comparisons of areas under the curve [AUC]. The relationship between clinical and biomarker assessments at Week 6 and endoscopic remission [ER] at Week 52 was evaluated using multivariate logistic regression models adjusted for confounders. Results A Week 6 calprotectin <250 mg/kg demonstrated a significant ability to predict Week 52 ER (AUC 0.709, 95% confidence interval [CI] 0.566–0.852, p = 0.014) with fair accuracy, and performed better than other calprotectin cut-offs and deltas from baseline for prediction of Week 52 ER. When adjusted for covariates, patients with a Week 6 faecal calprotectin <250 mg/kg had 3.48 times [95% CI 1.31–9.28, p = 0.013] increased odds of Week 52 ER. No other Week 6 clinical assessment [clinical remission or clinical response] or biomarker [CRP <5 or drug level] had an association with Week 52 ER. Conclusions In summary, the results of this post-hoc analysis suggest that Week 6 calprotectin levels < 250 mg/kg can be predictive of future endoscopic healing and may be more informative than clinical symptom improvement. Podcast This article has an associated podcast which can be accessed at https://academic.oup.com/ecco-jcc/pages/podcast

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DOP13 Clinical and endoscopic response to ustekinumab in Crohn’s disease: Week 16 interim analysis of the STARDUST trial

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz203.052 ◽

2020 ◽

Vol 14 (Supplement_1) ◽

pp. S049-S052 ◽

Cited By ~ 1

Author(s):

S Danese ◽

S Vermeire ◽

G D’Haens ◽

J Panés ◽

A Dignass ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Clinical Response ◽

Clinical Remission ◽

Disease Duration ◽

Activity Index ◽

Standard Of Care ◽

Treat To Target ◽

Faecal Calprotectin ◽

Intention To Treat

Abstract Background Treat-to-target (T2T) strategy may optimise IBD disease management. We describe interim clinical and endoscopic results of the STARDUST trial in Crohn’s disease (CD) patients, following 16 weeks (W) of ustekinumab (UST) induction. Methods STARDUST, an ongoing phase 3b randomised strategy trial, enrolled adults with moderate–severely active CD (CD activity index [CDAI] 220–450) and simple endoscopic index for CD [SES-CD] ≥3) who failed conventional therapy ±1 biologic. At W0, patients received intravenous, weight-based UST of ~6mg/kg (approved label) and at W8, subcutaneous UST 90mg. At W16, patients with CDAI reduction ≥70 points were randomised (1:1) to T2T or standard of care. Key endpoints (intention-to-treat [ITT] set, as observed) were analysed at W8 and W16: % patients in clinical remission (CDAI score <150); % patients with a clinical response (CDAI <150 or decrease vs. baseline [BL] ≥100 points); faecal calprotectin (FCal) and C-reactive protein (CRP) levels: normalisation of FCal or/and CRP; improvement ≥50% vs. BL (patients with elevated FCal and CRP subpopulations); change vs. BL in CDAI and Inflammatory Bowel Disease Questionnaire (IBDQ) total scores. Patients randomised to T2T underwent colonoscopy at W16 and were analysed for change in SES-CD score vs. BL, endoscopic response (decrease in SES-CD score ≥50% vs. BL) and endoscopic remission (SES-CD score ≤2) (central reading). Results The ITT full set included 500 patients with BL mean (SD) CDAI score 282.3 (65.8), SES-CD 13.1 (8.1), CRP 15.7 (23.4) mg/l, FCal 1741.9 (2932.1) mg/g and disease duration 9.4 (8.7) years; 58.4% previously failed 1 biologic. At W16, 79.4% of patients had a clinical response and 66.6% were in clinical remission. About half of the patients showed ≥50% improvement in FCal and CRP levels, which normalised in about 1/3 of patients. Results were similar irrespective of previous biologic (Table 1); 84% of patients in response at W16 were in clinical remission. Statistically significant changes from BL in CDAI, FCal, and CRP were observed at W8, and in IBDQ scores at W16 (Table 2). In the T2T set (n = 220; CDAI 70 responders), BL characteristics were similar to the full analysis set; SES-CD score was 13.4 (8.8). At W16, 36.8% and 11.4% of patients in the T2T set achieved endoscopic response and remission, respectively. The endoscopic response was independent of BL SES-CD score and disease duration, but numerically better for colonic vs. ileal disease. No new safety signals were reported. Conclusion STARDUST is the first T2T trial in CD patients. After 16 W following induction with UST, 2/3 of patients achieved clinical remission. Thirty-seven per cent of those randomised to the T2T arm (CDAI 70 responders) showed endoscopic response by central reading at W16. Results were similar irrespective of being bio-naïve or failing 1 biologic.

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OP023 Optimising post-operative Crohn's disease management: Best drug therapy alone versus endoscopic monitoring, disease evolution, and faecal calprotectin monitoring. The POCER study

Journal of Crohn s and Colitis ◽

10.1016/s1873-9946(14)60024-6 ◽

2014 ◽

Vol 8 ◽

pp. S13 ◽

Cited By ~ 9

Author(s):

M.A. Kamm ◽

P.P. De Cruz ◽

E.K. Wright ◽

A.L. Hamilton ◽

K.J. Ritchie ◽

...

Keyword(s):

Crohn’S Disease ◽

Drug Therapy ◽

Crohn's Disease ◽

Disease Management ◽

Faecal Calprotectin ◽

Disease Evolution

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Case of steroid-resistant Crohn’s-associated bronchiolitis in the setting of quiescent gastrointestinal disease treated with infliximab

BMJ Case Reports ◽

10.1136/bcr-2018-226934 ◽

2018 ◽

Vol 11 (1) ◽

pp. e226934 ◽

Cited By ~ 1

Author(s):

Cher Shiong Chuah ◽

Colin Noble ◽

Andrew Leitch

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Gastrointestinal Disease ◽

Forced Expiratory Volume ◽

High Dose ◽

Inflammatory Disorder ◽

Faecal Calprotectin ◽

Minimal Improvement ◽

Oral Steroids ◽

Dose Oral

A fit, 36-year-old man with a history of Crohn’s disease previously treated with azathioprine, presented acutely with progressive shortness of breath on exertion and pleuritic chest pain. At the time of presentation, his Crohn’s disease was quiescent, supported by a normal faecal calprotectin. The initial chest CT suggested the presence of a diffuse inflammatory disorder and he was subsequently started on high dose oral steroids. Despite 4 months of steroid therapy, there was minimal improvement. Following discussion at the inflammatory bowel disease multidisciplinary team meeting, a decision was made to commence infliximab. Subsequently, he made a dramatic clinical and physiological recovery. His forced expiratory volume in 1 s improved from 2.22 L/min (50% predicted) to 3.65 L/min (93% predicted) and he returned to baseline levels of exercise.

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OP40 Analysis of clinical features associated with favourable outcomes from ustekinumab treat-to-target strategy in Crohn’s Disease patients in the STARDUST trial

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjab075.039 ◽

2021 ◽

Vol 15 (Supplement_1) ◽

pp. S039-S039

Author(s):

S Danese ◽

S Vermeire ◽

A Dignass ◽

J Panés ◽

G D’Haens ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Activity Index ◽

Safety Data ◽

Standard Of Care ◽

Treat To Target ◽

Faecal Calprotectin ◽

Reactive Protein ◽

Moderate Disease ◽

Endoscopic Score

Abstract Background The 48-week (W) interventional STARDUST trial assessed whether a treat-to-target (T2T) strategy using ustekinumab (UST) may optimize Crohn’s disease (CD) outcomes; primary efficacy and safety data have been reported before.1 Here we assessed which patient (pt) subgroups may benefit from T2T vs standard of care (SoC) in achieving endoscopic response after 1 year of UST treatment. Methods Adult pts with moderate–severely active CD (CD activity index [CDAI] 220–450) and Simple Endoscopic Score in CD [SES-CD] ≥3) who failed conventional therapy and/or 1 biologic were included. Pts received iv, weight-based UST ~6 mg/kg at W0 (baseline [BL]); then SC UST 90 mg at W8. At W16, CDAI 70 responders were randomized (1:1) to T2T or SoC arms. Pts in the T2T arm were assigned to SC UST q12w or q8w based on 25% improvement in SES-CD score vs BL. From W16–48, UST dose was further intensified up to q4w if the following were not met: CDAI <220 and ≥70-point improvement from BL, and C-reactive protein ≤10 mg/L or faecal calprotectin (FCal) ≤250 µg/g. Pts who failed treatment target despite UST q4w were discontinued. In the SoC arm, UST dose was assigned based on EU SmPC (q12w or q8w). We report the treatment effect for the primary endpoint (endoscopic response [≥50% improvement in SES-CD score vs BL] at W48), evaluated for subgroups of pts, based on demographics at BL. For each subgroup, the odds ratio (OR) and 95% confidence interval (CI) of T2T vs SoC were provided based on the logistic regression model that included treatment arm and stratification factors (prior exposure to biologics [none or 1] and SES-CD score [≤16, > 16] at BL) as independent variables. Results Of 500 pts enrolled, 441 were randomized to T2T (n=220) or SoC (n=221); 79.1% and 87.3% completed W48. At W48, pts randomized to T2T were more likely to achieve endoscopic response compared to SoC (p<0.05), if they had at BL: (i) longer disease duration (>median [79.1 months]; OR 2.2; 95%CI 1.17–3.94); (ii) clinically moderate disease (CDAI ≤300; OR 1.7; 95%CI 1.03–2.76); (iii) normal FCal (≤250; OR 3.0; 95%CI 1.22–7.56), (iv) endoscopically active CD (SES-CD ≥4 for ileal or ≥6 for colonic and/or ileocolonic disease; OR 1.8; 95%CI 1.10–2.91); and (v) history or presence of strictures/fistula or occurrence of an intra-abdominal abscess (OR 2.3; 95%CI 1.06–5.01 and OR 3.5; 95%CI 1.07–11.19, respectively; Figure 1). Conclusion T2T was more effective than SoC (p<0.05) in achieving endoscopic response after 1 year of UST treatment in certain subgroups including pts with higher endoscopic scores at BL and those with history/presence of bowel damage. Reference

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Outcomes of Passable and Non-passable Strictures in Clinical Trials of Crohn’s Disease: A Post-hoc Analysis

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjab045 ◽

2021 ◽

Author(s):

Neeraj Narula ◽

Emily C L Wong ◽

Parambir S Dulai ◽

John K Marshall ◽

Jean-Frederic Colombel ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Activity Index ◽

Disease Activity Index ◽

Symptom Improvement ◽

Logistic Regression Models ◽

Post Hoc Analysis ◽

Endoscopic Remission ◽

Post Hoc ◽

The Impact

Abstract Background and Aims There is paucity of evidence on the reversibility of Crohn’s disease [CD]-related strictures treated with therapies. We aimed to describe the clinical and endoscopic outcomes of CD patients with non-passable strictures. Methods This was a post-hoc analysis of three large CD clinical trial programmes examining outcomes with infliximab, ustekinumab, and azathioprine, which included data on 576 patients including 105 with non-passable strictures and 45 with passable strictures, as measured using the Simple Endoscopic Score for Crohn’s Disease [SES-CD]. The impact of non-passable strictures on achieving clinical remission [CR] and endoscopic remission [ER] was assessed using multivariate logistic regression models. CR was defined as a Crohn’s Disease Activity Index [CDAI] <150, clinical response as a CDAI reduction of ≥100 points, and ER as SES-CD score <3. Results After 1 year of treatment, patients with non-passable strictures demonstrated the ability to achieve passable or no strictures in 62.5% of cases, with 52.4% and 37.5% attaining CR and ER, respectively. However, patients with non-passable strictures at baseline were less likely to demonstrate symptom improvement compared with those with passable or no strictures, with reduced odds of 1-year CR (adjusted odds ratio [aOR] 0.17, 95% CI 0.03–0.99, p = 0.048). No significant differences were observed between patients with non-passable strictures at baseline and those with passable or no strictures in rates of ER [aOR 0.82, 95% CI 0.23–2.85, p = 0.751] at 1 year. Conclusions Patients with non-passable strictures can achieve symptomatic and endoscopic remission when receiving therapies used to treat CD, although they are less likely to obtain CR compared with patients without non-passable strictures. These findings support the importance of balancing the presence of non-passable strictures in trial arms.

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