Background and Aims Ustekinumab, an anti-IL12/23p40 monoclonal antibody, has been approved for Crohn’s disease [CD]. Real-life data in CD patients receiving ustekinumab intravenously [IV] during induction, followed by subcutaneous [SC] maintenance, are lacking. We assessed efficacy of ustekinumab and studied exposure-response correlations. Methods We performed a prospective study in 86 CD patients predominantly refractory or intolerant to anti-tumour necrosis factor agents and/or vedolizumab. All received ustekinumab 6 mg/kg IV induction, with 90 mg SC every 8 weeks thereafter. Endoscopic response (50% decrease in Simple Endoscopic Score for CD [SES-CD] at Week 24), endoscopic remission [SES-CD ≤2], and clinical remission [daily stool frequency ≤2.8 and abdominal pain score ≤1] were assessed at weeks 4,8,16, and 24. Further serial analyses included patient-reported outcomes [PRO2], faecal calprotectin [fCal], and ustekinumab serum levels. Results SES-CD decreased from 11.5 [8.0–18.0] at baseline to 9.0 [6.0–16.0] at week [w]24 [p = 0.0009], but proportions of patients achieving endoscopic response [20.5%] or endoscopic remission [7.1%] were low. Clinical remission rates were 39.5% at w24. After IV induction, fCal dropped from baseline [1242.9 μg/g] to w4 [529.0 μg/g] and w8 [372.2 μg/g], but increased again by w16 [537.4 μg/g] and w24 [749.0 μg/g]. A clear exposure-response relationship was observed, both during induction and during maintenance therapy, with different thresholds depending on the targeted outcome. Conclusions In this cohort of refractory CD patients, ustekinumab showed good clinical remission rates but limited endoscopic remission after 24 weeks. Our data suggest that higher doses may be required to achieve better endoscopic outcomes.

Background and Objectives Vedolizumab has demonstrated efficacy and safety in patients with Crohn's disease [CD] and ulcerative colitis [UC]. Endoscopic outcome data are limited, especially in anti-tumour necrosis factor [TNF] naïve patients. The present study compared endoscopic outcome in anti-TNF naïve and exposed patients, and explored if this was affected by drug exposure. Methods We retrospectively analysed all patients initiating vedolizumab at our tertiary referral centre since 2015. For UC, endoscopic improvement was defined as a Mayo endoscopic subscore ≤1 at week 14. For CD, endoscopic remission was defined as absence of ulcerations at week 22. Vedolizumab trough concentrations were measured at week 6, week 14 and during maintenance. Results A total of 336 patients were identified [53.3% CD], 20% of them being anti-TNF naïve. Endoscopic improvement was achieved by 56.1% of UC patients and endoscopic remission by 39.1% of CD patients. Endoscopic outcomes were significantly better in anti-TNF naïve vs exposed patients [all: 67.2% vs 42.0%, p = 0.0002; UC: 74.4% vs 50.0%, p = 0.02; CD: 57.1% vs 35.8%, p = 0.03]. Achievement of endoscopic end points significantly impacted long-term treatment continuation [p = 9.7 × 10−13]. A better endoscopic outcome was associated with significantly higher drug exposure in both CD and UC. Conclusions The results of this observational, single-centre real-life study suggest that vedolizumab may induce endoscopic remission in both CD and UC. Although anti-TNF naïve patients had a significantly better outcome, 42% of anti-TNF exposed patients still benefited endoscopically. A clear exposure–endoscopic response relationship exists, but not all patients will benefit from treatment intensification. Hence, predictive biomarkers remain necessary. Podcast This article has an associated podcast which can be accessed at https://academic.oup.com/ecco-jcc/pages/podcast

Background and aims: Few data are available regarding the combination of biologics or small molecules in inflammatory bowel disease (IBD) patients. We report safety and efficacy of such combinations through a retrospective multicentre series.Methods: Combination therapy was defined as the concomitant use of two biologics or one biologic with a small molecule. Patient demographics, disease characteristics and types of combinations were recorded. Safety was evaluated according to the occurrence of serious infection, opportunistic infection, hospitalisation, lifethreatening event, worsening of IBD or immune-mediated inflammatory diseases (IMID), cancer and death. Efficacy was evaluated as the physician global assessment of the combination and comparison of clinical/endoscopic scores of IBD/IMID activity prior and during combination.Results: A total of 104 combinations were collected in 98 patients. Concomitant IMID were present in 41 patients. Reasons for starting combination therapy were active IBD (67%), active IMID or extra-intestinal manifestations (EIM) (22%), both (10%) and unclassified in 1. Median duration of combination was 8 months (interquartile range 5-16). During 122 patient-years of follow-up, 42 significant adverse events were observed, mostly related to uncontrolled IBD. There were 10 significant infections, 1 skin cancer and no death. IBD disease activity was clinically improved in 70% and IMID/EIM activity in 81% of the patients. Overall, combination was continued in 55% of the patients.Conclusions: Combination of biologics and small molecules in patients with IBD and IMID/EIM seems to be a promising therapeutic strategy but is also associated with a risk of opportunistic infections or infections leading to hospitalisation in 10%.

Background The pan-Janus kinase inhibitor tofacitinib (TFC) has recently been approved for treatment moderate-to-severe ulcerative colitis (UC). Real-life data are limited, especially on endoscopic and histologic outcome. We report the efficacy and safety of TFC in refractory UC patients, and assessed potential clinical predictors of response. Methods Thirty-five UC patients, all refractory to anti-TNF and vedolizumab, were prospectively included (Table 1). All received TFC 10mg BID till week 8, and were endoscopically assessed at baseline (Mayo endoscopic sub-score ≥2) and week 8. Biological response was defined as a 50% decrease in faecal calprotectin (fCal) or fCal <250 mg/g, and biological remission as a fCal <250 mg/g at week 8. The endoscopic response was defined as Mayo endoscopic sub-score of ≤1, endoscopic remission as a sub-score of 0. Histologic remission was defined as a numeric Geboes score ≤6 (similar to ≤2A.0). A non-response imputation and last observation carried forward analysis was applied. Results The Mayo endoscopic sub-score decreased significantly by week 8 (p = 0.004), resulting in an endoscopic response and remission rate of 22.9% and 17.2% respectively. Histological remission was seen in 14.8% of patients. Faecal calprotectin decreased from 1386 mg/g down to 568 mg/g by week 4 (p = 0.03) (Table 2), but not further down by week 8 (703 mg/g, p = 0.5) with a biological response and remission rate of 52.9% and 38.2%. Half of the patients with a PNR to one anti-TNF (10 out of 20) did discontinue TFC because of PNR. However, PNR to two anti-TNF agents almost exclusively (4 out of 5) resulted in PNR to TFC. In contrast, only 3 out of 8 vedolizumab PNR experienced PNR to TFC. Ultimately, 48.6% of all included patients discontinued TFC therapy after a median of 15.9 [12.4–26.6] weeks, all but one due to PNR, of whom 9/17 (52.9%) required colectomy. In multivariate analysis, a higher baseline albumin and a lower Mayo endoscopic sub-score were independent predictors of endoscopic (OR 1.06, p = 0.02; OR 0.59, p = 0.003) and biological remission (OR 1.06, p = 0.03; OR 0.57, p = 0.01). By week 8, creatinine kinase significantly increased (p = 0.001), whereas the lipid profile was not significantly affected. One patient suffered from vaginal herpes infection, and one patient treated with TFC and high dose steroids developed disseminated nocardia, pneumocystic jiroveci, cutaneous zoster and varicella pneumoniae. Conclusion TFC can induce biologic, endoscopic and histologic remission in refractory UC, though clinical and predictive molecular markers are required to identify the right patients. In patients with prior PNR to 2 anti-TNF agents, TFC does not seem an alternative treatment strategy.

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Infliximab dosage de-escalation without prior knowledge of drug concentrations may put patients at risk for underexposure and trigger the loss of response. A single-model approach for model-informed precision dosing during infliximab maintenance therapy has proven its clinical benefit in patients with inflammatory bowel diseases. We evaluated the predictive performances of two multimodel approaches, a model selection algorithm and a model averaging algorithm, using 18 published population pharmacokinetic models of infliximab for guiding dosage de-escalation. Data of 54 patients with Crohn's disease and ulcerative colitis who underwent infliximab dosage de-escalation after an earlier escalation were used. A priori prediction (based solely on covariate data) and maximum a posteriori prediction (based on covariate data and trough concentrations) were compared using accuracy and precision metrics and the classification accuracy at the trough concentration target of 5.0 mg/L. A priori prediction was inaccurate and imprecise, with the lowest classification accuracies irrespective of the approach (median 59%, interquartile range 59%-63%). Using the maximum a posteriori prediction, the model averaging algorithm had systematically better predictive performance than the model selection algorithm or the single-model approach with any model, regardless of the number of concentration data. Only a single trough concentration (preferably at the point of care) sufficed for accurate and precise prediction. Predictive performance of both single-and multi-model approaches was robust to the lack of covariate data. Model averaging using four models demonstrated similar predictive performance with a five-fold shorter computation time. This model averaging algorithm was implemented in the TDMx software tool to guide infliximab dosage de-escalation in the forthcoming prospective MODIFI study (NCT04982172).

Background and Aims Dose intensification of vedolizumab (VDZ) for moderate‐to‐severe ulcerative colitis (UC) and Crohn's disease (CD) may be effective in patients losing response. We aimed to assess the clinical and pharmacokinetic effect of VDZ dose intensification. Methods We performed a multicentre open‐label prospective study from June 2017 through December 2018 in patients on VDZ losing response, defined as total Mayo score >6 (UC) or Harvey‐Bradshaw Index >4 with inflammation (CD). Blood samples and clinical scores were collected at baseline and after VDZ infusion at Weeks 4 and 8. Clinical response was defined as a decrease of partial Mayo score ≥2 points or Harvey‐Bradshaw Index ≥3 points. Biological response was defined as a decrease of C‐reactive protein to ≤5 mg/L or of >50%. Results A total of 59 patients (31 UC and 28 CD) were included. Median (IQR) trough levels (TLs) increased from 8.7 (5.1‐12.7) µg/mL (baseline) to 19.1 (12.4‐22.4) µg/mL (Week 4) and 23.1 (16.7‐28.4) µg/mL (Week 8) (all P < 0.0001). Partial Mayo score decreased with 3 points from baseline to Week 4 (P = 0.001) but stabilised to Week 8 (P = 0.16). Harvey‐Bradshaw Index decreased with 4 points from baseline to Week 4 (P = 0.001) and 1 point to Week 8 (P = 0.04). Recapture of clinical and biological response was achieved in 49% and 27% at Week 4, and 54% and 37% at Week 8 respectively. Conclusion Dose escalation to VDZ every 4 weeks after loss of response resulted in higher TLs with regain of clinical response in half of the patients.

Background and Aims: The management of chronic inflammatory bowel diseases in youth is challenging. We aimed to determine health literacy (HL), quality of life (QoL) and clinical outcomes in young adults from the BELgian CROhn's disease registry (BELCRO) in comparison to type 1 diabetes mellitus (DM) as a control.Methods: In this prospective and observational study, young adults with Crohn's disease (CD) diagnosed &lt; 18 years and with &gt; 5 years disease duration and a comparable group of patients with DM completed validated HL, QoL and work productivity and activity impairment questionnaires (HLS-EU-Q16, EQ-5D-5L and WPAI). HL was scored as sufficient (13–16), problematic (9–12) or inadequate (0–8). QoL was dichotomized into “no problems” (EQ-5D level 1) or “problems” (EQ-5D levels 2 to 5). Non-parametric (Mann-Whitney U) analyses and Spearman correlations were performed.Results: A total of 52 CD (median [IQR] age of 25.0 [23.8-27.0], 64% male) and 50 DM (age 20.0 [19.0-22.0], 50% male) patients were included. HL was 14.0 [11.0-16.0] for CD and 14.0 [11.3-14.8] for DM (p = 0.6) with similar proportions of sufficient (60 vs. 68%, p = 0.4), problematic (34 vs. 26%, p = 0.3) and inadequate HL (both 6%, p = 1). Although QoL was comparable for CD and DM (77.0 [68.8-82.0] vs. 75.0 [65.0-80.0] %, p =0.4), CD had a trend for higher pain/discomfort (50 vs. 32%, p = 0.06). HL and QoL correlated in CD (r = 0.6, p &lt; 0.001) and DM patients (r = 0.6, p &lt; 0.001). Fewer CD patients with recent hospitalization/surgery had sufficient HL (31 vs. 69%, p = 0.01) and had lower QoL (70.0 [60.0-77.0] vs. 80.0 [70.0-85.0], p = 0.04) compared to those without.Conclusions: Selected young Belgian adults suffering from CD for &gt;5 years have similar and sufficient HL compared to DM patients. However, CD patients requiring hospitalization/surgery have lower HL, which indicates the need for targeted educational programs.