bluuebunny/crossref_metadata_2025 huggingface dataset:
P472 Changes in colectomy for Ulcerative Colitis during the last two decades: an in-depth retrospective analysis
Authors: Le Cosquer G , Capirchio L , Rivière P , de Suray N , Poullenot F , De Vroey B , Berger A , Denis M A , Zerbib F , Bachmann R , Remue C , Celerier B , Leonard D , Denost Q , Kartheuser A , Laharie D , Dewit O
Published: January 2022

Background

The management of ulcerative colitis (UC) has been improved due to progresses in medical and surgical practices during the past twenty years. Yet the impact of new therapies on the evolution of the three colectomy’s indications in UC (severe acute colitis, refractory ulcerative colitis and (pre-)neoplastic complication) is still not well established. The aim of this study was to compare the evolution of the surgical indications within the last two decades.

Methods

This was an observational retrospective study carried out in two tertiary hospitals. All patients with UC who underwent total or segmental colectomy between 2001 and 2020 were included, without age restriction. Two periods were compared: 2001–2010 and 2011–2020. Endpoints were to compare the colectomy indications, patients’ characteristics, surgical procedures, and rates of postoperative complication between the two cohorts.

Results

Among the 286 patients included (57% were men; median age of 40 years; 60.5% of extensive and 35.7% of distal colitis), 87 (30.4%) underwent colectomy in 2001–2010 and 199 patients (69.6%) in 2011–2020. Patients’ characteristics were similar between the two periods, including duration of UC and the severity according to the global Mayo score. Colectomy rate for refractory UC significantly decreased over time (n=119) (50.6% vs. 37.7%; p=0.042), while it increased for acute severe colitis (n=116) (36.8% vs. 42.2%; p=0.390) and (pre-)neoplastic indication (n=51) (12.6% vs. 20.1%; p=0.130) (Figure 1).

Regarding surgery, there was an increased use of laparoscopic colectomy (47.7% vs. 81.4%; p<0.001) during the latter period and the median length of stay in hospital after surgery has decreased from 13 to 10 days (p=0,098). There were less early (12.6% vs. 5.5%; p=0.038) and late severe complications (1.6% vs. 0.8%; p< 0.001) and less surgical revisions (38.6% vs. 19.5%; p<0.001) without change on 30-day mortality rate (2.3% vs. 1%; p=0.391). The rate of extraintestinal postoperative infections (especially urinary, pulmonary and catheters infections) increased during the second period (27% vs; 45.7%; p=0.018).

As expected, the mean number of past biotherapies was higher during the second period (1.2 versus 0.6; p<0.001), as well as the rate of pre-operative exposition to TNFα antagonists (68.4% vs. 50.6%; p=0.016).

Conclusion

The rate of surgery for refractory colitis has significantly decreased while the rate of colectomy for cancer and acute severe colitis has risen during the last twenty years. In the same time, surgical technics have changed with more laparoscopic surgeries associated with a reduction of postoperative morbidity despite the larger use of biotherapies.
P474 Prevalence of fecal incontinence and clinical characteristics of IBD patients in remission and treated with biologics – experience from a tertiary referral center
Authors: Jelakovic M , Turk N , Brinar M , Barisic A , Grgic D , Cukovic-Cavka S , Krznaric Z
Published: January 2022

Background

Fecal incontinence (FI) is a debilitating disorder highly prevalent in inflammatory bowel disease (IBD) patients with reports in literature ranging from 20–80%. There is limited data on FI prevalence in IBD patients who are in remission, treated with biologics and their clinical characteristics.

Methods

In this cross-sectional observational study we have included IBD patients in remission, treated with biologics. Demographics and medical data were collected from electronic medical charts while patients were screened for FI using the St. Mark’s incontinence score (SMIS). Significant FI was characterized as SMIS ³6. Descriptive statistical analysis was used.

Results

We included 57 patients (24 female/33 male) in clinical remission treated with biologics, median age 41 years (18–70), 23 patients had ulcerative colitis (UC) and 34 had Crohn’s disease (CD). Median disease duration was 8 years (1–31). Significant FI was identified in 41 patient (71.9%) out of which 87.8% were in biochemical and 34.1% in endoscopical remission. FI was more prevalent among CD patients (76.4%) compared to UC (65.2%), but the difference did not reach statistical significance. FI was not significantly correlated to gender, type or number of biologics but there was significant positive correlation with disease duration (r=0.3139; p<0.05), especially for patients with disease duration longer than 5 years who had significantly higher mean SMIS score (9.1±4.6 vs 5.2±2.6; t-2.86; p<0.05). Furthermore, patients older than 50 years of age also had significantly higher average SMIS scores compared to younger patients (10.6±4.6 vs 7.6±4.3;t-2.09;p<0.05)

Conclusion

FI is highly prevalent in IBD patients treated with biologics, even in those who have reached endoscopical remission. Clinicians should be aware of this disorder and use available screening tools especially in older patients with longer disease duration in order to further improve quality of life of these patients.
P476 Disease recurrence patterns in patients undergoing bowel resections for Crohn’s disease
Authors: Ahmed M , Chacko J , Zimerly S , Patel A
Published: January 2022

Background

Despite numerous advances in the medical management of IBD, it is estimated that 70–90% of patients with Crohn’s disease require surgical intervention with a significant proportion requiring repeat surgery. There is evidence to suggest that biologic agents may reduce the incidence of disease recurrence and may delay progression to further surgery. We aim to compare disease progression in biologic-naïve patients with patients on established biologic therapy

Methods

A retrospective single-centre UK study including patients who underwent primary Ileo-caecal resections for Crohn’s disease between 01/01/2014 to 31/12/2019. Patients were classified according to the Montreal classification. Electronic case records used to obtain patient data. Disease recurrence was defined as active disease on radiological imaging or endoscopic visualisation up until 01/11/2021. Prophylactic treatment included medical therapy initiated postoperatively prior to disease recurrence.

Results

In total, 88 patients, with a median follow-up of 54 months (IQR: 1–104 months), were included (Table 1). Of these, 69 patients had been started on medical therapy prior to surgery and 21 had Biologic treatment. Nearly half of the patients (36/88) underwent emergency resections (Table 2).

Postoperative prophylaxis was given to 28 patients (31.8%), of which 8 were given Biologics. Patients who were smokers were more likely to be offered post-operative prophylaxis (55.56% vs 22.9%). 58 patients (65.9%) developed disease recurrence and 9 patients (15.5%) required further resections. Use of biologic therapy preoperatively was associated with an increased risk of requiring further resections (20.8% vs 6.8% with alternative agents; OR: 3.684, p-value: 0.030). Biologics were continued postoperatively in 5/21 patients and none of these required further resections. Discontinuation of biologics postoperatively was associated with a higher risk of recurrence (68.75%) and further bowel resection (25%). Prophylactic use of biologics had an overall net preventive effect on disease recurrence compared to alternative agents (62.5% vs 89%; OR: 0.417).

Conclusion

Preoperative biologic therapy can be a marker of more severe disease at presentation and may indicate need for repeat resection. In addition, patients on biologic therapy preoperatively have significantly worse outcomes if this is discontinued in the postoperative period.
P477 Rectal bleeding and stool frequency improvement with tofacitinib retreatment in patients with Ulcerative Colitis after treatment interruption: Results from OCTAVE Open
Authors: Allegretti J R , Gecse K B , Chiorean M V , Argollo M , Guo X , Lawendy N , Su C , Mundayat R , Paulissen J , Salese L , Irving P M
Published: January 2022

Background

Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Patients may require retreatment following treatment interruption for reasons such as adverse events or pregnancy.1 In the tofacitinib UC clinical programme, patients who responded to tofacitinib 10 mg BID during induction, and experienced treatment failure whilst receiving placebo during maintenance (OCTAVE Sustain) and subsequently received tofacitinib 10 mg BID in the open-label, long-term extension (OLE) study (OCTAVE Open; NCT01470612), comprised the retreatment subpopulation. The efficacy and safety of tofacitinib in the retreatment subpopulation have previously been reported.1 Here, we evaluated patient-reported outcomes to assess rectal bleeding and stool frequency improvement in the retreatment subpopulation in OCTAVE Open.

Methods

The following efficacy endpoints based on the Mayo subscores were analysed in the overall retreatment subpopulation and by prior tumour necrosis factor inhibitor (TNFi) failure status: rectal bleeding improvement (≥1 point decrease in rectal bleeding subscore [RBS] from OLE study baseline), and stool frequency improvement (≥1 point decrease in stool frequency subscore [SFS] from OLE study baseline), up to Month (M)6 in the OLE study (full analysis set, non-responder imputation). Changes from baseline in partial Mayo score (PMS), RBS and SFS at M1, by M2 clinical response status, were also analysed (as observed).

Results

In OCTAVE Open, 101 patients were included in the retreatment subpopulation, of which 46 (45.5%) had prior TNFi failure. Overall, at M1 and M6 of OCTAVE Open, 83.2% and 76.2% of patients had rectal bleeding improvement, respectively (Figure 1). Corresponding values for stool frequency improvement were 70.3% and 75.2%. At most time points, rates of rectal bleeding and stool frequency improvements were similar in patients with and without prior TNFi failure. Mean decrease from baseline in PMS, RBS and SFS at M1 was similar in patients with and without a clinical response at M2 (Figure 2).

Conclusion

In this post hoc analysis, in patients with UC who had loss of response after 8–52 weeks of treatment interruption, retreatment with tofacitinib 10 mg BID resulted in rectal bleeding and stool frequency improvement in the majority of patients by M1, which was maintained to M6, regardless of prior TNFi failure status.

Reference

1. Panés J et al. J Crohns Colitis 2021. Epub ahead of print.
P478 The role of proactive measurement of adalimumab trough levels and antibodies to adalimumab in Greek patients with Inflammatory Bowel Disease
Authors: Orfanoudaki E , Gazouli M , Theodoraki E , Foteinogiannopoulou K , Andreou N P , Koutroubakis I E
Published: January 2022

Background

Therapeutic drug monitoring (TDM) of adalimumab trough levels (ADA-TLs) and antibodies to adalimumab (ADA-Abs) in patients with inflammatory bowel disease (IBD) is usually performed in a reactive setting when the disease flares. There is not enough evidence in favor of proactive TDM in these patients.

Methods

We aimed to evaluate the role of proactive measurement of ADA-TLs and ADA-Abs in IBD patients under treatment with adalimumab. Consecutive IBD patients on maintenance treatment with ADA, were included. ADA-TLs and Abs were measured using ELISA (Immunoguide, Aybayteche, Turkey) on serum samples drawn before ADA administration. At the same time serum biomarkers [Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), white blood cells (WBC), hemoglobin (Hgb), platelets (PLT)] as well as home-based fecal calprotectin (FC) ±3 months from blood sampling were assessed. After the measurements patients were followed and treatment changes made were recorded.

Results

A total of 52 patients receiving ADA maintenance therapy [48 CD, 4 UC, 31 males, mean age (±SD) 42.1±12.6 years, 8 on combination therapy with immunomodulators (IMMs), 23 under intensified dose (either 40mg/w or 80mg/2w)] were included. Median (IQR) time since ADA initiation was 31 (17.5–38.5) months and median value (IQR) of serum ADA-TLs was 8.24 μg/ml (3.32–10.02). Five out 52 (9.6%) were positive for ATIs (>3 AU/ml). Patients with positive Abs had median (IQR) ADA-TLs 0.41 μg/ml (0.10–0.71) statistically lower compared to those with negative Abs [8.86μg/ml (5.6–10.0) (p=0.0004)]. The correlations of ADA-TLs with disease characteristics, treatment and biomarkers in IBD patients are presented in Table 1. Elevated CRP was negatively associated with ADA-TLs. No other significant correlations were observed except a trend towards significance for body mass index (BMI) and ADA treatment duration (both p=0.09). After a median (IQR) follow up of 15 (11.5–16) months treatment optimization became necessary in 4 patients (8%) [adalimumab dose intensification in 2, change to a clinical trial medication in 1 and 1 underwent surgery] who initially had significantly lower ADA-TLs than the rest patients [median (IQR) ADA-TLs 0.51μg/ml (0.26-5.09-10.04) vs 8.62 (4.48–10.04); p=0.0362].

Conclusion

Proactive measurement of ADA-TLs and Abs in patients under maintenance treatment with adalimumab may be worth using along with other parameters in the management of IBD patients. Additional long term research in larger populations focused on the optimal use of proactive TDM is needed.
P491 Efficacy and safety outcomes of long-term treatment with filgotinib 200 mg among patients with Ulcerative Colitis: An interim analysis of SELECTIONLTE
Authors: Feagan Senior Scientific Officer B G , Matsuoka K , Rogler G , Faes M , Oortwijn A , de Haas A , Rudolph C , Patel H , Peyrin-Biroulet L
Published: January 2022

Background

Filgotinib (FIL) is a once-daily, oral, Janus kinase 1 preferential inhibitor in development as an ulcerative colitis (UC) therapy. In the phase 2b/3 SELECTION trial, FIL 200 mg (FIL200) was well tolerated and effective in inducing and maintaining clinical remission vs placebo (PBO) in patients with UC.1 We assessed the efficacy and safety of continued FIL200 therapy in the SELECTION long-term extension (LTE) study.

Methods

The SELECTION programme comprised SELECTION (NCT02914522)1 and an ongoing LTE study, SELECTIONLTE (NCT02914535). Adults with moderately to severely active UC received induction (IND) FIL200 or FIL100 or PBO for 11 weeks in SELECTION. Patients in clinical remission or Mayo Clinic Score (MCS) response at week 10 (responders) could enter the 47-week Maintenance (MNT) Study. Patients who completed the SELECTION IND and MNT studies (completers), IND non-responders and patients with disease worsening during MNT could enter SELECTIONLTE. This interim analysis assessed the efficacy of open-label FIL200 among completers and non-responders in SELECTIONLTE up to LTE weeks 48 and 96, respectively. Partial MCS (pMCS) and achievement of the minimal clinically important difference (MCID) in total health-related quality of life (HRQoL) IBDQ score (≥16-point increase vs baseline) were assessed over time. Exposure-adjusted incidence rates per 100 patient-years of exposure (PYE) of treatment-emergent adverse events (TEAEs) and TEAEs of interest were assessed in patients treated with open-label FIL200 in the LTE.

Results

These analyses included 147 completers and 372 non-responders (IND FIL200, n=160; IND FIL100, n=212). Data were available for 136 completers at LTE week 48 and for 97 IND FIL200 and 139 IND FIL100 non-responders at LTE week 96. Among completers, the mean pMCS reductions observed in SELECTION were maintained up to LTE week 48 (Figure 1). Among IND FIL200 and FIL100 non-responders, mean pMCS decreased from LTE baseline to week 96 (Figure 2). The proportion of patients achieving the MCID in total IBDQ score increased over time among completers (IND week 10, 90.4%; LTE week 48, 96.1%) and IND FIL200 non-responders (LTE week 48, 60.6%; LTE week 96, 66.7%) (Table 1). Safety events among patients treated with open-label FIL200 in the LTE study (total PYE, 970.9) to the date analysed are reported in Table 2.

Conclusion

FIL200 was effective in maintaining long-term improvements in UC symptoms and HRQoL among patients who completed SELECTION. Among non-responders, initiating open-label FIL200 in the LTE study led to improvements in UC symptoms and HRQoL that were sustained over time. Safety events were as expected in the LTE study based on initial data.

Reference

1. Feagan BF et al. Lancet 2021;397:2372–84.
P512 Vedolizumab is effective in the prevention and treatment of postoperative recurrence in patients with Crohn′s disease
Authors: Kadleckova B , Podmanicky D , Lipovska A , Zelinkova Z
Published: January 2022

Background

Vedolizumab (VDZ), an anti-integrin monoclonal antibody has demonstrated its efficacy in inducing and maintaining response in patients with luminal Crohn`s disease (CD). Postoperative recurrence (POR) affects over half of the patients with CD and currently, majority of these patients undergo surgery due to primary or secondary failure of anti-tumor necrosis factor (antiTNF) biologics. Thus, data on efficacy of other agents in this setting are needed. Considering the slow onset of action of VDZ together with its favorable safety profile in older and co-morbid patients, VDZ would represent a good candidate for preventing and treating POR but the data on its efficacy in this specific clinical situation are scarce. Therefore, the aim of this study was to evaluate the efficacy of VDZ in preventing and treating of Crohn`s disease postoperative recurrence.

Methods

In this retrospective single-center cohort study, we included all patients with CD treated with VDZ between May 2015 and August 2020. Patients who started with VDZ immediately postoperatively or continued from the pre-operative period (prevention of POR) or patients who started VDZ because of clinical or endoscopic POR (treatment of POR) with a minimal follow-up of one year were eligible for further analysis. The effect of VDZ was determined by Harvey-Bradshaw Index ≤ 4 in case of prevention of POR, or as any decrease of 3 or more points in case of treatment of POR. Endoscopic response was evaluated by Rutgeerts` score as any decrease of the score. All patients underwent the colonoscopy at 6 months postoperatively and further follow-up colonoscopy one year after treatment adjustment.

Results

In the defined period, a total of 54 patients with Crohn`s disease were treated with VDZ. Of these 54 patients, sixteen (11 women; median age 57 years, range 25–75) receive VDZ for prevention (6) or treatment (10) of postoperative recurrence. Six patients received first-line VDZ due to high risk profile for systemic biologics (age and/or co-morbidities), the remaining ten patients all had previously failed at least one anti-tumor necrosis factor biologic agent.

During the median follow-up of 24 months (range 12 to 70), thirteen patients (81%) had clinical response or achieved remission, eleven (69%) had endoscopic response. Three patients with no response had to change the treatment to another biologic. Out thirteen responders, seven (54%) necessitated intensification of dosing regimen to every 4 or 6 weeks in order to achieve clinical and/or endoscopic response.

Conclusion

Vedolizumab is effective in preventing and treating of Crohn`s disease postoperative recurrence in a difficult-to-treat population of patients.
P525 A prospective interventional study to evaluate the effect of hypoxia on healthy volunteers and patients with inflammatory bowel disease: The altitude IBD study
Authors: Vavricka S , Zeitz J , Madanchi M , Biedermann L , Morsy Y , Scharl M , Gassmann M , Lutz T , Kunz A , Bron D , Rogler G , Greuter T
Published: January 2022

Background

It is unknown how high altitude exposure causes inflammatory bowel disease (IBD) flares. We assessed disease activity in healthy controls, IBD patients after 3h exposure in a hypobaric pressure chamber (imitating an altitude of 4000m above sea level).

Methods

In a prospective study, 11 Crohn’s disease (CD, 6 males, 35.6y±13.7), 9 ulcerative colitis (UC, 3 males, 31.4y±10.8) patients and 10 healthy controls (7 males, 27.7y±4.9) underwent rectosigmoidoscopy in our outpatient clinic (490m, baseline T1) and after 3h exposure in a hypobaric pressure chamber (follow-up day 1 T2 and day 7 T3). Symptoms were assessed using the Harvey Bradshaw Index and the partial Mayo Score before and after hypobaric pressure chamber exposure (baseline T1, day 1 T2, day 7 T3 and day 30 T4). Disease activity was further assessed using CRP levels and fecal calprotectin. Intestinal mucosa-associated microbial composition was analyzed using high-throughput sequencing.

Results

The 3h exposure in a hypobaric pressure chamber was well tolerated in all subjects. Mean oxygen saturation decreased from 97.5%±1.3 to 80.9%±4.1, and increased back to normal levels (98.8%±1.2%) after the hypobaric intervention (p<0.0001). Clinical and endoscopic disease activity were not significantly changed before vs. after intervention. However, mild flare was seen in 2 UC patients and another UC patient was lost to follow-up due to a disease flare. New endoscopic lesions were detected in one healthy subject and one UC patient. Fecal calprotectin levels significantly increased in CD patients during the follow-up period (p=0.031), but not in UC and healthy controls. No changes in CRP levels were observed. Percentage of calprotectin-based disease remission (fecal calprotectin <100ug/g) decreased in all groups after hypobaric pressure chamber exposure, and increased thereafter (Figure 1) with a significant decrease in the control group (100% at baseline vs. 50% at day 1, p=0.029) and all patients combined (73.3% at baseline vs. 36.7% at day 7, p=0.013). No differences in alpha and beta diversity of stool microbiota composition before vs. after hypobaric pressure chamber exposure were observed.

Conclusion

In this prospective study involving IBD patients and healthy controls, a 3h exposure in a hypobaric pressure chamber (corresponding to an altitude of 4000m) did not result in higher disease activity. However, mild flares and development of endoscopic lesions were seen in a subset of patients. Calprotectin-based remission rates significantly decreased between baseline and day 7 suggesting a subclinical effect of short-term hypoxia, not explained by changes in the microbiome.

(Clinicaltrials.gov number, NCT02849821)
P544 Patients with moderate to severe Crohn’s disease with and without prior biologic failure demonstrated improved clinical outcomes with risankizumab: Results from phase 3 induction and maintenance trials
Authors: D’Haens G , Beaton M , Bossuyt P , Dotan I , Sands B , Sugimoto K , Neimark E , Song A , Wallace K , Zhou Q , Kligys K , Ferrante M
Published: January 2022

Background

Risankizumab (RZB), a selective interleukin-23 inhibitor, demonstrated superior efficacy over placebo (PBO) as induction and maintenance therapy in patients with moderate to severe Crohn’s disease (CD). Here we compared the efficacy and safety of RZB in inducing and maintaining clinical remission and clinical response in patients with CD who demonstrated intolerance and/or inadequate response (IR) to biologic therapies (with prior bio-failure) versus those who demonstrated IR to conventional therapies only (without prior bio-failure).

Methods

This subgroup analysis included pooled induction data from patients randomized to receive intravenous (IV) RZB 600mg (N=527) or placebo (PBO) IV (N=362) every 4 weeks (wks) for 12wks in the ADVANCE+MOTIVATE studies, and maintenance data from IV RZB responders who were randomized to subcutaneous (SC) RZB 360mg (N=141) or withdrawn from RZB to receive PBO SC (withdrawal [PBO SC], N=164) every 8wks for 52wks in FORTIFY. Clinical remission (per CDAI and per stool frequency [SF]/abdominal pain score [APS]), CDAI clinical response, enhanced SF/APS clinical response, and maintenance of clinical remission were evaluated in the overall population, and in subgroups with and without prior bio-failure, using non-responder imputation. Only descriptive statistics were used for the subpopulations (Endpoints are defined in Table footnotes). Safety was assessed throughout the studies.

Results

Approximately three-quarters of randomized patients included in the subgroup analyses had prior bio-failure (ADVANCE+MOTIVATE: 75.4%; FORTIFY: 73.8%). Among the subpopulations, numerically higher rates of clinical remission (CDAI and SF/APS), CDAI clinical response, and enhanced SF/APS clinical response were observed at the end of induction (wk12) among patients receiving RZB 600mg IV versus PBO IV (Figure); rates were numerically higher in the subpopulation without prior bio-failure than with prior bio-failure. FORTIFY Wk52 response rates for these endpoints, along with maintenance of clinical remission, were higher in the RZB 360mg SC arm compared to the withdrawal (PBO SC) arm in both subpopulations, with numerically higher rates observed for the subgroup without prior bio-failure (Figure). RZB maintenance treatment was well-tolerated and no new safety signals were observed. The safety profile of RZB has been reported previously.1,2

Conclusion

Across the induction and maintenance studies, compared to PBO, RZB treatment led to greater clinical remission and clinical response in patients with CD independent of prior biologic experience. The subpopulation without prior bio-failure achieved higher rates of symptomatic remission.
P574 Population pharmacokinetic and exposure-response analyses for efficacy and safety of risankizumab in subjects with active Crohn‘s disease
Authors: Suleiman A , Goebel A , Bhatnagar S , D’Cunha R , Liu W , Pang Y
Published: January 2022

Background

In order to support risankizumab dose recommendation for the treatment of Crohn’s disease (CD), population pharmacokinetic (PPK) and exposure-response (ER) analyses were conducted for risankizumab using data from Phases 2 & 3 studies in moderate to severely active CD patients to characterise PK and its relationship with clinical efficacy and safety.

Methods

PPK analyses used non-linear mixed-effects modelling, leveraging a previously developed PPK model for plaque psoriasis & CD, with additional evaluation of covariates relevant to CD. ER relationships were evaluated for efficacy endpoints (clinical remission/response based on CDAI or stool frequency/abdominal pain, endoscopic endpoints, etc.) at Week 12 (induction), Week 24 (re-induction; exploratory only), and Week 52 (maintenance), using graphical analyses at Week 12, 24 and 52 and logistic regression analyses at Week 12 and 52. ER analyses for safety evaluated key safety variables through Week 12, 24 and 52 using graphical analyses.

Results

Observed risankizumab concentrations in CD patients were adequately described by the risankizumab PK model. PK in subjects with CD was linear and time-independent, similar to healthy subjects and plaque psoriasis. The majority of the evaluated intrinsic and extrinsic factors showed no statistically significant effect on risankizumab PK, including age, race, country/region, liver function markers, creatinine, baseline CDAI, baseline SES-CD, duration of disease, prior biological therapies, immunosuppressant use, and immunogenicity. Sex, baseline fecal calprotectin, corticosteroid use, baseline creatinine clearance, body weight, and baseline albumin were statistically correlated with risankizumab clearance but their impact on exposure was not clinically relevant for efficacy or safety. ER analyses for induction demonstrated that exposures associated with 600 mg IV at Week 0, 4 and 8 achieved a near maximal response for all evaluated efficacy endpoints at Week 12, with negligible added benefit from 1200 mg IV. ER analyses for maintenance showed higher efficacy response at higher exposures for most of the Week 52 endpoints, particularly the more stringent endoscopic endpoints. ER analyses for safety indicated no apparent relationship between exposure and incidence of any AE, SAE, infection or serious infection over the 12 or 24 weeks of induction or 52 weeks of maintenance treatment.

Conclusion

PPK and ER analyses of risankizumab in subjects with CD supported the final dose recommendation of 600 mg IV at Week 0, 4, 8 followed by 360 mg SC at Week 12 and Q8W thereafter for the treatment of moderate to severely active CD.
P577 Mucosal eosinophil abundance in non-inflamed colonic tissue predict response to vedolizumab induction therapy in inflammatory bowel disease
Authors: Gabriëls R Y , Bourgonje A R , von Martels J , Blokzijl T , Weersma R , Galinsky K , Julius J , Faber K N , Kats-Ugurlu G , Dijkstra G
Published: January 2022

Background

Vedolizumab has shown efficacy, safety and tolerability as treatment for patients with inflammatory bowel disease (IBD). However, vedolizumab induction therapy only shows clinical response and remission in roughly 55% and 30% of IBD patients, respectively. Vedolizumab binds and blocks migration of T-lymphocytes and eosinophils. In this study, we aimed to explore the predictive value of mucosal eosinophils and serum eotaxin-1, an eosinophil chemoattractant, regarding response to vedolizumab induction therapy.

Methods

84 IBD patients treated within the University Medical Center Groningen (UMCG) (37 Crohn’s disease [CD], 47 ulcerative colitis [UC]) were included. In a subset of 24 IBD patients (9 CD, 15 UC) histopathological data were analyzed for eosinophil counts in high power fields (hpf) in non-inflamed colon ascendens tissue prior to vedolizumab treatment. In another subset of 64 IBD patients, (28 CD, 36 UC) baseline serum eotaxin-1 was quantified prior to vedolizumab treatment. Clinical response or remission was defined as a decrease of the Harvey Bradshaw Index (HBI) for CD or Simple Clinical Colitis Activity Index (SCCAI) for UC together with physician’s global assessment (PGA). Serum eotaxin-1 was externally assessed as a biomarker for response to vedolizumab induction therapy in 100 IBD patients derived from the GEMINI 1 & 2 trials.

Results

Baseline eosinophil mucosal count was significantly higher in vedolizumab induction therapy responders, compared to primary non responders (69[34–138] vs. 24[18–28] eosinophils/hpf respectively, P<0.01). Baseline serum eotaxin-1 levels in the UMCG cohort were significantly elevated in therapy responders, compared to primary non-responders (0.33 vs. 0.20 ng/mL, P<0.01). The final prediction model based on mucosal eosinophil count showed an area under the curve (AUC) of 0.90 and serum eotaxin-1 an adjusted AUC of 0.79 The optimal with balanced cut-off value for eosinophil count was > 30 eosinophils/hpf with a sensitivity of 90.9% and specificity of 92.3% (Youden’s index 0.83). Results derived from the GEMINI I & II cohorts did not show any associations between eotaxin-1 levels and therapy response.

Conclusion

Mucosal eosinophil abundance in non-inflamed colon ascendens biopsies can predict vedolizumab induction therapy response in IBD patients. More studies are warranted to confirm these preliminary results and further investigate the additional value of eotaxin-1 regarding predicting vedolizumab therapy response.
P587 Disease severity in the INFLAMMATORY BOWEL DISEASES: Do patients and physicians agree?
Authors: Timmer A , de Sordi D , Neuser J , Seibel K , Hensel A , Schmidt-Lauber M , Allgayer H , Klebl F , Obermeier F , Jessen P , Schnoy E , Helwig U , Morgenstern J , Leifeld L , Schmidt S , Meinhardt C , Maaser C , Bästlein E , Bokemeyer A , Graefe U , Kühbacher T , Kaltz B , Sander C , Wolfgang K
Published: January 2022

Background

Evaluation of disease severity (DS) in the Inflammatory Bowel Diseases (IBD) requires comprehensive consideration of disease course and health status of individual patients. It is not clear how well physician assessment covers disease impact as perceived by patients. We compared patient and physician global assessment of disease severity in relation to standardized assessment using a clinical disease severity score (DSI, Siegel 2018).

Methods

Patients with ulcerative colitis (UC) and Crohn’s disease (CD) were prospectively recruited from the national patient organization (DCCV) and by participating physicians. Physicians (IBD experts) were approached via the DCCV advisory board and other professional contacts. Both groups graded disease severity for a random selection of written standard short cases (1 page, maximum 5 CD, 3 UC) on a simple visual analogue scale (VAS) (online survey). For analysis, VAS were transferred to a 0 (minimal severity) to 100 (maximal severity) scale, in analogy to the range of the DSI. We present graphs of mean scores by rater group with 95% CI. Differences between mean patient and physician assessments were calculated per case. In addition, we examined the difference from the DSI.

Results

We included 824 ratings from 319 patients (168 CD, 151 UC), and 143 ratings from 34 physicians (20 ISS, 14 external)(recruitment ongoing). UC cases received on average 124 patient ratings (range 122–125), and 21 physician ratings (range 17–26). Means from both rater groups discriminated well between disease severity as scored by the DSI. Mean physician ratings were consistently and substantially lower than patient ratings for all three UC cases. Differences between means ranged from 8.5 (95% CI 0.5 to 16.5) for mild disease to 10.1 (95% CI 1.3 to 18.9) for moderate disease (p < 0.001) (Figure 1). In contrast, deviations from the DSI did not show a clear pattern.

CD cases were rated by a mean of 91 patients (77–125) and 16 physicians (13–21). Mean physician and mean patient ratings were very close, in particular in those with medium DSI (Figure 2).

Conclusion

Physicians agreed, on average, very well with patient grading on disease severity grading of exemplary cases of CD. Lower scores were given for UC cases, and mild CD, but the overall trend remained intact. In contrast, correlation with DSI scores was poor and will need further analysis.
P589 Total thiopurine exposure and impact on the development of keratinocyte carcinomas in Inflammatory Bowel Disease patients; a case control study
Authors: Jansen F M , Lubeek S , den Broeder N , Savelkoul E , Marcus C , Hoentjen F , van Dop W
Published: January 2022

Background

Keratinocyte skin cancer (KSC) including basal-cell carcinomas (BCC) and cutaneous squamous cell carcinomas (SCC), is the most prevalent cancer-type in the Netherlands with an increasing incidence and impact on morbidity. In addition to ultraviolet radiation (UVR), thiopurines used in patients with inflammatory bowel disease (IBD), are associated with KSC development. It is unclear whether this is a dose response relationship. The aim of this study was to investigate the association between the cumulative dose of thiopurines and the development of KSCs in IBD patients.

Methods

A single-center retrospective case control study was conducted and we included patients with IBD on thiopurines and a history of KSC (n=50, cases) as well as without KSC (n= 150, controls). For each patient we calculated the cumulative dose of azathioprine (AZA), 6-mercaptopurine (6-MP) and tioguanine (6-TG) as primary outcome, and of methotrexate (MTX) as secondary outcome. Univariable and multivariable regression analyses were performed, the latter corrected for known risk factors and potential confounders: age and smoking.

Results

200 IBD patients were included (see Table 1). There were more cases (24%) using azathioprine at time of KSC onset compared to 11.3% of controls at time of inclusion (p= 0.028). Independent variables including age at inclusion (OR 1.065, CI 1.038–1.092) and IBD disease duration (OR 1.040, CI 1.016–1.065) were significantly associated with KSC. No significant association was found between KSC development and smoking, cumulative thiopurine use, nor between KSC development and cumulative MTX use. To account for possible non-linear effects, cut-offs at the registered 1- and 3-years- cumulative doses were assessed. Here, no significant results were found for any of the distinct thiopurines or MTX, the 3-years cumulative use of AZA had the highest odds ratio of 1.085 (CI 0.795–1.482). In multivariate logistic regression analyses (see Table 2), age per 10 years remained significant associated (p=0.005) (OR 1.666, CI 1.165–2.381).

Conclusion

This study showed that in IBD-patients IBD duration (only in univariable regression analysis) and age (in both uni- and multivariable regression analyses) are important risk factors for KSC development while cumulative exposure of thiopurines and MTX did not show an association. The dose response association between KSC and thiopurines requires further research.
P596 Adalimumab use in Paediatric Inflammatory Bowel Disease: A single centre real-life experience
Authors: El-Lababidi N , Frühauf P
Published: January 2022

Background

Anti-TNF-α, including infliximab and adalimumab (ADA), plays a crucial role in the treatment of Paediatric Inflammatory Bowel Disease (PIBD). This study evaluates the efficacy of ADA in children ≤ 19 years in a single European centre.

Methods

A 6-year retrospective analysis of prospectively collected data of PIBD patients treated with ADA (10/2015 onward). Wellbeing, clinical and laboratory findings were assessed at each visit. A mean, median and a standard deviation were calculated were applicable. ANOVA (analysis of variances) was used for evaluation of presence of statistically significant differences and a P-value ≤ 0.05 was regarded as such.

Results

ADA, all originator, was used in 31 patients. All of them were diagnosed with Crohn’s Disease (CD). The mean age at diagnosis was 14.6±2.8 years (range 6.6–18.2 years). The mean interval from diagnosis till commencement of ADA was 6.9 months (0.25–36 months). Step-up was used 17x and top-down 15x. A top-down approach was indicated in patients with extraintestinal manifestations, fistulizing disease, severe growth impairment and affections of the proximal gastrointestinal tract. Adjacent treatments at the time of commencement of ADA were azathioprine (18/31), CD exclusion diet (7/31), exclusive enteral nutrition (6/31), steroids (4/31), methotrexate and 5-aminosalicylates (both 3/31).

Mean CRP at the time of ADA commencement was 8.8 mg/l (1.0–44.4 mg/l), ESR 21 mm/hour (1–66 mm/hour), leukocytes 8.3x109/l (3.3–22.0x109/l), haemoglobin 118.3 g/l (68–150 g/l), platelets 422x109/l (232–828 x109/l) and faecal calprotectin (FC) 901.1 μg/g (95.2–5041.9 μg/g). At the end of induction period, CRP, ESR and FC showed a significant decrease (P< 0.01). Blood count parameters failed to show that (P >0.05). Mean ADA trough levels at the end of induction period were 18.4±2.3 μg/ml. For maintenance of trough levels (≥7.5 μg/ml), weekly administration was required in 5 cases. During the follow-up period, surgical intervention was required 2x (ileocecal resection 1x and stricturoplasty 1x). Adverse side effects consisted of a skin reaction 1x and reversible hair loss 1x. Due to loss of response, 3 patients had to be switched out-of-class to ustekinumab. The mean time to loss of response since ADA commencement was 23.3 months (16–30 months). Antibody formation after 23 months of treatment led to switching one patient to infliximab. One patient was lost to follow-up.

Conclusion

These data show that ADA is effective in achieving laboratory and clinical remission in PIBD patients. Maintenance of trough levels may sometimes requite weekly administration of ADA. Loss of response may occur. Adverse reactions were minimal.
P606 Use of TNF-α-antagonists and systemic steroids is associated with attenuated immunogenicity against SARS-CoV-2 in fully vaccinated patients with Inflammatory Bowel Disease
Authors: Otten A T , Bourgonje A R , Horinga P P , van der Meulen H H , van Leer-Buter C C , Dijkstra G , Visschedijk M C
Published: January 2022

Background

Patients with Inflammatory Bowel Disease (IBD) frequently use immunomodulating treatment, which may render them at increased risk of attenuated immunogenicity after vaccination. Immunosuppressive drugs, such as TNF-α-antagonists, have shown an attenuating effect on serological response after SARS-CoV-2 infection. Here we assessed the effects of different types of immunosuppressive medications on the serological response after vaccination against SARS-CoV-2 in patients with IBD.

Methods

This was a prospective observational cohort study in patients with IBD of whom IgG antibody titers were measured after 2–10 weeks after full vaccination against SARS-CoV-2. Patient demographics, clinical characteristics as well as a previous history of SARS-Cov-2 infection, type of vaccine (mRNA or vector), and medication use were recorded at time of sampling. The primary study outcome was the anti-SARS-CoV-2 spike (S) antibody concentrations, measured using chemiluminescence microparticle immunoassay (CMIA) after full vaccination.

Results

312 IBD patients were included (172 Crohn’s disease [CD] and 140 ulcerative colitis [UC]). Seroconversion (defined as titer of >50 AU/ml) was achieved in 98,3% of patients. Antibody concentrations were significantly lower in patients treated with TNF-α-antagonists vs. non-users of TNF-α-antagonists (geometric mean [95% confidence interval]: 2204 [1655–2935] vs. 5002 [4089–6116] AU/ml, P<0.001). In multivariable models, use of TNF-α-antagonists (percentage decrease -88%, P<0.001), age (>50 years) (-54%, P<0.01) and CD (vs. UC) (-39%, P<0.05) were independently associated with anti-SARS-CoV-2 antibody titers. In patients who received mRNA vaccines, users of systemic steroids demonstrated significantly lower antibody titers compared to patients who were steroid-free (geometric mean [95% CI]: 3410 [2233;5210] vs. 5553 [4686–6580], P<0.05).

Conclusion

TNF-α-antagonist use is strongly associated with an attenuated serological response after vaccination, independent of the type of vaccination (mRNA/vector), the time interval between vaccination and sampling, prior SARS-CoV-2 infection and patient age. Patients treated with systemic steroids who received mRNA vaccines demonstrated lower anti-SARS-CoV-2 antibody titers compared with patients who were steroid-free at time of serology.
P622 Comparison of long-term outcomes of infliximab and adalimumab in biologic-naïve patients with ulcerative colitis
Authors: Durak M B , Baspınar B , Guven I E , Kivrakoglu F , Kilic V , Kosar K , Erdogan C , Yüksel I
Published: January 2022

Background

The comparative efficacy and safety of infliximab (IFX) and adalimumab (ADA) have revealed variable results in biologic-naïve patients with ulcerative colitis (UC), and long-term comparison studies between IFX and ADA with or without immunomodulator therapy are still needed in patients with UC.

Methods

The aim of this study was to evaluate the long-term effectiveness and safety of IFX compared to ADA in biologic-naïve adult patients with UC. All data of patients between June 2007 and March 2021 were collected retrospectively. We compared UC-related hospitalisation, colectomy, steroid use, and serious infections leading to treatment cessation.

Results

Out of 86 UC patients, 41 started IFX first (mean age at onset: 34.4 years, 61.0% male) and 45 started ADA first (mean age at onset: 31.4 years, 60.0% male). Disease duration was 7.2 years for IFX and 8.1 years for ADA. There were no significant differences between the two groups with respect to age, gender, smoking, extraintestinal manifestations, immunomodulator usage, or disease extent at the onset of anti-TNF therapy (p > 0.05). Concomitant rates of medication including mesalazine, sulphapyridine, thiopurine, and steroids were the same in both groups (p > 0.05). In the IFX group, baseline haemoglobin (11.7 vs 13.2, p = 0.05) and albumin (3.8 vs 4.2, p = 0.02) levels were lower than those of the ADA group, while C-reactive protein was higher (14.0 vs 6.0, p = 0.04) than in the ADA group. Total MAYO score at baseline was similar in both groups (p = 0.10).

During anti-TNF therapy, steroid use was significantly higher in the ADA group (44.4%) compared to IFX (14.6%, p = 0.003). The rates of UC-related hospitalisation (IFX 9.8% vs ADA 13.3%, p=0.74) and colectomy (IFX 4.9% vs ADA 2.2%, p = 0.60) were similar in IFX and ADA groups. Serious infection leading to treatment cessation was not different between the two groups (IFX 2.4% vs ADA 4.4%, p=0.54). These outcomes were similar in UC patients treated with IFX or ADA monotherapy or in combination with an immunomodulator within each group, and there was no significant difference between IFX and ADA in combination with an immunomodulator regarding those outcomes (p > 0.05).

Conclusion

In this study, steroid use in the ADA group was significantly higher than in the IFX group, although UC-related hospitalisation, colectomy, and serious infections were not different in biologic-naïve adult patients with UC. We also observed that outcomes were similar in patients treated with IFX and ADA monotherapy or in combination with an immunomodulator. In the present study, IFX revealed better long-term outcomes for first-time treatment of UC patients.
P630 Systematic review and meta-analysis: Diagnostic delay and the subsequent impact on the disease course of adult Inflammatory Bowel Disease
Authors: Jayasooriya N , Ballie S , Blackwell J , Creese H , Bottle R , Petersen I , Saxena S , Pollok R C
Published: January 2022

Background

Diagnosis of inflammatory Bowel disease (IBD) can be challenging and time consuming. There is substantial variation in the reported time to diagnosis and the impact of diagnostic delay on disease course. We therefore conducted a systematic review to evaluate the length of time to diagnosis and a meta-analysis of the impact of delay on the disease course of IBD.

Methods

The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed, and final papers were assessed for risk of bias. We searched MEDLINE and Embase for retrospective and prospective studies, published up to December 2020, that reported diagnostic interval, from the time of symptom onset or first consultation to a confirmed diagnosis of IBD, in adults (age ≥18 years). We extracted data from published studies and calculated the weighted median and interquartile range (IQR) of the reported diagnosis interval. Delay was defined as a time period greater than the 75th centile. From eligible studies, we extracted risk estimates and, using random-effects meta-analysis, calculated the pooled odds ratios (OR) and 95% confidence intervals (CI) of studies that examined the association of diagnostic delay with subsequent clinical outcomes, including disease phenotype and surgical intervention. Statistical heterogeneity was assessed, I2 >50% indicating substantial heterogeneity.

Results

Of 1,533 studies identified, 28 fulfilled the eligibility criteria, including 25,764 patients diagnosed with IBD: Crohn’s disease (CD) = 13,206 and ulcerative colitis (UC) = 12,558. In CD, the pooled weighted median for the diagnostic interval was 8.8 months (IQR 3.0–61.1 months). In UC, the pooled weighted median was 15.2 months (IQR 2.4–62.8). Considering studies from high income countries alone, the pooled weighted median was 6.4 months (IQR 1.7–46.7) in CD, and 2.5 months (IQR 0.3–23.0) in UC.

11 studies were eligible for inclusion in the meta-analysis, representing 6,403 patients diagnosed with IBD (CD; n = 4,902 and UC; n = 1,501). In CD, pooled analysis showed an association between delayed diagnosis and stricturing disease (OR:1.77, CI 1.28–2.46; I2 =61%), penetrating disease (OR: 1.48, CI 1.21–1.82; I2=0%) and intestinal surgery (OR:1.88, CI 1.45–2.44; I2 =34%; figure 1a). In UC, delayed diagnosis was associated with an increased risk of colectomy (OR:4.13, CI 1.04–16.40; I2 =0%; figure 1b).

Conclusion

Measures are required to reduce delay in the diagnosis of IBD, which is associated with an increase in stricturing and penetrating disease phenotype in CD and a substantially increased risk of surgery in both CD and UC.