bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract

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&lt;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 &lt;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

Abstract

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

Abstract

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

Abstract

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&lt;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&lt;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 &gt; 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

Abstract

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 &lt; 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

Abstract

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

Abstract

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&lt; 0.01). Blood count parameters failed to show that (P &gt;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

Abstract

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 &gt;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&lt;0.001). In multivariable models, use of TNF-α-antagonists (percentage decrease -88%, P&lt;0.001), age (&gt;50 years) (-54%, P&lt;0.01) and CD (vs. UC) (-39%, P&lt;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&lt;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.