bluuebunny/crossref_metadata_2025 huggingface dataset:
P469 Infliximab for induction of medically-induced remission in Crohn’s disease: a Cochrane systematic review
Authors: Radford S , Sinopoulou V , Gordon M , Eldragini M E A A , Darie A M , Akobeng A , Moran G W
Published: January 2022

Background

Infliximab is a monoclonal antibody that binds and neutralizes tumour necrosis factor-alpha, which is present in high levels in the blood serum, mucosa and stool of patients with Crohn’s disease (CD). We sought to determine the effectiveness and safety of infliximab in inducing remission in patients with CD.

Methods

On 31 August 2021, we searched CENTRAL, CINAHL, ClinicalTrials.gov, Embase, MEDLINE, and WHO ICTRP with no language, date, publication status, or document type limitations. We included randomized controlled trials (RCTs) in which infliximab was compared to placebo or another active comparator in adult (18 and over) patients with active CD. The review authors independently conducted data extraction and ‘Risk of bias’ assessment of the included studies. We expressed dichotomous and continuous outcomes as risk ratios and mean differences with 95% confidence intervals. We assessed the certainty of the evidence using GRADE methodology. The primary outcome was the proportion of patients who achieved clinical remission.

Results

We included 9 RCTs (1130 participants). Three studies compared multiple arms with different infliximab doses (between 5mg and 20mg/kg) to placebo. Two studies each with three arms compared azathioprine and placebo, infliximab and placebo, or infliximab and azathioprine combined. One study compared infliximab with biosimilar CT-P13. One study compared infliximab and azathioprine with steroids and azathioprine and only infliximab if no response. The final study compared a single dose (5mg/kg) of infliximab to placebo. In all trials that didn’t require a purine analogue to be given to both study groups, they allowed such concomitant use in both groups. There is evidence that infliximab combined with azathioprine is superior to azathioprine combined with placebo in inducing clinical remission for CD (RR 1.97, 95% CI 1.60–2.42, moderate certainty evidence downgraded due to risk of bias, NNT = 3). Sensitivity analysis considering a fixed effects model and then removing a study where most received azathioprine in both groups instead of all, had no impact on the result, which remained significant. There is evidence that there may be no difference in withdrawals from adverse events between infliximab combined with azathioprine and azathioprine combined with placebo when inducing clinical remission for CD (RR 0.74, 95% CI 0.29–1.86, low certainty evidence downgraded due to serious imprecision). The evidence is uncertain for all other comparisons and outcomes due to imprecision from small sample sizes.

Conclusion

There is evidence that infliximab with azathioprine is probably better than azathioprine, however the remaining data is based on limited total patient numbers and offers limited scope for meta-analysis.
P480 Comparison of executive functioning profiles among adults with Crohn’s disease and Ulcerative colitis
Authors: Zelnik Yovel D , Meyer S , Richter V , Shirin H , Broide E
Published: January 2022

Background

Psychological factors that influence inflammatory bowel disease (IBD) outcome can impact patients’ ability to cope and aid the management of the disease. Executive functions (EFs) are cognitive processes, which enable the achievement of selected goals and overcoming new challenges. The role of EFs in the management of IBD is still not fully understood.

We assess the EFs in IBD patients and compare EFs between patients with Crohn’s disease (CD) and ulcerative colitis (UC).

Methods

An anonymous online survey, including demographic, clinical data and the validated self-report BRIEF-A questionnaire, was sent to adult IBD patients. BRIEF-A score above 65 is considered an impaired EF. Logistic regression was used to study the association between disease type (UC vs CD) and suspected EF deficits, while controlling for potential cofounders by use of a propensity score.

Results

148 IBD patients (34% UC) with mean age of 31.5 years old (50% females) were included. BRIEF-A scale and index scores were within the normal range (<65). Most of the scores were significantly better in CD than UC patients: shift (57.9 vs 52.7, p=0.015), monitor (50.54 vs 46.24, p=0.029), working memory (57.83 vs 52.18, p=0.03), plan (54.97 vs 49.2, p=0.005), organization of materials (52.95 vs 48.98, p=0.019). CD patients had a better Global Executive Composite (59.27 vs 53.7, p=0.008).

Conclusion

IBD patients in the study had normal EF profiles assessed by the BRIEF-A questionnaire. However, UC and CD patients presented different executive profiles. Understanding these differences can enable interventions that may improve patient’s quality of life.
P482 Pre-screening IBD patients starting biologic therapies, a positive single centre quality improvement project
Authors: Colclough J , Ali M , Shami N , Aitchison L , Hurst A , Shams-Khan H
Published: January 2022

Background

Biologic therapies have revolutionised the management of IBD however their use can be associated with opportunistic infections and malignancy. BSG guidance1 outlines the necessary pre-screening investigations required before starting these treatments. We assessed our compliance with these guidelines before and after implementing a proforma led SOP to evaluate whether there was any improvement in clinical practice.

Methods

A pre-screening checklist proforma was created for all IBD patients starting biologic therapies at Southport and Ormskirk hospital and compliance with BSG guidelines was measured before and after its implementation. Data was collected retrospectively using electronic patient records over two 12-month cycles; pre-implementation (Nov 2018 – Oct 2019) and post-implementation (Feb 2020 – Jan 2021).

Results

31 patients (42% female, median age 48, range 19–84) were started on biologics before the checklist was implemented and 25 after (40% female, median age 40, range 17–73). Compliance with screening tests for baseline bloods and infections improved from 58.1% to 100%, with the largest improvements in Hep B and TB. See figure 1. Checking patient’s vaccination history improved from 0% to 88% and adequate cervical screening improved from 3.2% to 66.7%. Overall, 80% of patients met full BSG pre-screening guidelines following implementation of the proforma, compared to 0% prior to this.

Conclusion

The use of a pre-screening checklist has drastically improved the pre-screening process from 0% compliance to 88%, therefore improving patient safety prior to starting biologic therapies. This data compares favourably with national audit data where only 60% of patients had adequate pre-screening2. It has allowed us to standardise care to screen for contraindications to treatment, especially opportunistic infections. There is still room for improvement when assessing patients’ vaccination and cervical screening histories, however these rely on documentation of the discussion in notes and may underestimate the number of patients receiving this advice.

Overall we have shown a dramatic improvement in the quality of our care and therefore patient safety. We will continue to use the checklist as well as educating staff within the hospital about the importance of pre-screening before starting patients on biologic therapies.

References

1. Lamb CA, et al. British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults. Gut 2019;68:s1-s106.

2. Arnott I, et al. 2016. National clinical audit of biological therapies. Royal College of Physicians. https://www.rcplondon.ac.uk/projects/outputs/national-clinical-audit-biological-therapies-annual-report-2016.
P483 Patient-reported quality of life, anxiety, and depression associated with switching originator infliximab to biosimilar
Authors: Ritter T E , Mehta S A , Van Anglen L J
Published: January 2022

Background

Non-medical switching from biologics to biosimilars is becoming increasingly common. Previous studies have demonstrated efficacy and safety of switching originator to biosimilar infliximab in inflammatory bowel disease (IBD) patients. Limited data exist on patient-reported quality of life (QOL) and possible emotional duress associated with these switches. The purpose of this study was to describe the impact of non-medical switches to infliximab biosimilars on QOL, anxiety, and depression.

Methods

This was a retrospective review of all IBD patients switched from originator to infliximab biosimilar at a large multicenter gastroenterology private practise in Texas. Patients were asked to complete standardised questionnaires on a quarterly basis beginning 3/2021, concurrent with large US payor policy changes mandating non-medical biosimilar switches. The Short Inflammatory Bowel Disease Questionnaire (SIBDQ) was used to assess disease-specific QOL. The Hospital Anxiety and Depression Scale (HADS) was used to determine anxiety and depression. All questionnaires through 10/2021 were collected and designated as “pre” or “post” based on the date of the patient’s non-medical switch to infliximab biosimilar. Wilcoxon rank sum test was used to compare scores. We also performed subset analyses on patients with both “pre” and “post” questionnaires with paired t-test.

Results

From 3/2021 to 10/2021, a total of 81 questionnaires were submitted by 54 patients who underwent non-medical switches to an infliximab biosimilar. 30 questionnaires were submitted prior to (“pre”) and 51 questionnaires were submitted after (“post”) the non-medical switch. Median “pre” SIBDQ score was 58 (IQR 53–63). Median “pre” HADS-Anxiety and HADS-Depression score were 3.5 (IQR 1–6) and 1 (IQR 0–5), respectively. As shown in Figure 1, “post” scores were unchanged [SIBDQ 59 (IQR 54–63); HADS-Anxiety 3 (IQR 1–7); HADS-Depression 2 (IQR 1–4)]. Subset analyses included 14 patients who submitted both “pre” and “post” questionnaires. Similarly, no significant changes were observed [Figure 2].

Conclusion

Non-medical switches to infliximab biosimilar did not affect QOL or mental health. To our knowledge, this is the first biosimilar switch study to incorporate anxiety and depression measures. These relationships should continue to be assessed.
P490 Patients with inflammatory bowel disease should be vaccinated against pneumococcus and influenza despite immunosuppressive therapy
Authors: Dohos D , Müller K E , Sipos Z , Kiss S , Dembrovszky F , Kovács N , Solymár M , Erőss B , Hegyi P , Sarlós P
Published: January 2022

Background

Patients with inflammatory bowel disease (IBD) have a high risk for infection. Pneumonia related to influenza and pneumococcal infection is one of the most common infection-related complication in IBD. Our aim was to evaluate the immunogenicity of pneumococcal and influenza vaccination in patients with IBD receiving different treatment.

Methods

We searched four databases for studies evaluating seroprotection and seroconversion rates after influenza or pneumococcal vaccination in IBD. In meta-analysis, odds ratios (OR) were calculated with 95% confidence intervals (CI).

Results

Twelve studies (1429 patients) were included in this meta-analysis. The seroconversion rate after pneumococcal vaccination was significantly lower in the immunosuppressed group and in the subgroup of patients with anti-TNF mono- or combination therapy compared to the non-immunosuppressed patients (OR = 0.38, 95% CI: 0.23–0.62, OR = 0.28, 95% CI: 0.15–0.53, and OR = 0.27, 95% CI: 0.15–0.49, p < 0.001, respectively). Following influenza vaccination there was no significant difference in the seroprotection rate between immunosuppressed and non-immunosuppressed patients (OR = 0.59, 95% CI: 0.34–1.03, p = 0.065). Seroprotection rate was not significantly reduced in patients with immunomodulator compared to anti-TNF monotherapy or combination therapy (OR = 1.45, 95% CI: 0.62–3.38, p = 0.84 and OR = 0.91 95% CI: 0.37–2.22, p = 0.391, respectively). Following both vaccinations, the seroresponse was not significantly reduced in patients treated with immunomodulator monotherapy compared to non-immunosuppressed patients.

Conclusion

Our results suggest that response rate is reduced in patients treated with anti-TNF therapy but not in patients treated with immunomodulator monotherapy. Patients treated with immunosuppressive treatment should be vaccinated against pneumococcus and influenza despite immunosuppressive therapy.
P492 A comparison of treatment effects for clinical, endoscopic and histological remission in ulcerative colitis clinical trials
Authors: Sedano R , Hogan M , Zou G , Narula N , Singh S , Ma C , Jairath V
Published: January 2022

Background

Clinical remission, defined by the Mayo Clinic Score (MCS) or modified MCS, is the accepted regulatory endpoint in drug development for ulcerative colitis (UC). Whilst histologic remission is a more stringent outcome, recent trials have reported numerically higher rates compared to endoscopic or clinical remission rates at the same timepoint, suggesting that histologic remission may be a more sensitive endpoint for detecting treatment response

Methods

A systematic review was performed from inception to December 2020, including all placebo-controlled drug trials for adults with UC. Clinical, endoscopic, and histologic induction remission rates for active treatment and placebo arms were pooled on the logit scale using a random-effects model to account for both between- and within-study variability. Risk ratios (RR) and risk differences comparing the rate of remission in active treatment arms to the rate of remission in placebo arms were also pooled using a random-effects model.

Results

For induction trials, 15/84 reported clinical, endoscopic, and histologic remission rates at the same timepoint. Clinical remission was mostly defined as a MCS≤2 with no individual subscore>1 (10/15;66.6%), and endoscopic remission as MES=0 (6/15; 40%) or MES≤1 (9/15; 60%). Histologic remission was defined using Geboes score in 10/15(66.7%) trials, with a score≤1.0 in 4/10(40%), score=0 in 3/10(30%), and score<3.0 in 3/10(30%) trials. For placebo/active treatment arms, the pooled clinical, endoscopic, and histologic remission rates were 11.3%(95% CI 7.4–16.9%) /17.8%(95% CI 13.7–22.8%), 13.4%(95% CI 8.5–20.5%) /18.7% (95% CI 12.2–27.5%), and 18.2%(95% CI 13.8–23.6%) /27%(95% CI 20.6–34.7%), respectively(Figure 1). The differences in pooled clinical, endoscopic, and histologic remission rates between active treatment and placebo were 7.2%(95% CI 4.3%–10.1%), 6.6% (95% CI 2.5%–10.7%), and 8.4% (95% CI 4.3%–12.4%), respectively(Figure 2A), and the pooled RR comparing clinical, endoscopic, and histologic remission rates in the active treatment and placebo arms were 1.59 (95%CI 1.19–2.13), 1.49 (95%CI 1.16–1.90), and 1.47 (95%CI 1.20–1.81), respectively(Figure 2B)

Conclusion

Histologic remission has been proposed as a treatment target for patients with UC, given an association between this outcome and lower rates of clinical relapse.1 Although we found numerically higher pooled histologic remission rates for active treatment and placebo arms, compared to pooled clinical and endoscopic remission rates, we found no difference in the pooled RR for clinical, endoscopic, and histologic remission rates in the active treatment and placebo arms. Whilst histology has the potential to serve as a more efficient endpoint for drug development, more studies are needed.
P506 Rates of clinical remission among patients with Ulcerative Colitis from real-world clinical practice settings from Germany
Authors: Bokemeyer B , Picker N , Kromer D , Rosin L , Patel H
Published: January 2022

Background

Patients with Ulcerative Colitis (UC) may not equally respond to advanced therapies. Therapy modifications such as dose adjustments, augmentation, and use of corticosteroids (CS) are required to achieve remission. This study aimed to examine the rates of clinical remission requiring adjustments with advanced therapies among UC patients from real-world clinical practices in Germany.

Methods

Using a retrospective chart review, patients with UC treated with an advanced therapy (adalimumab, infliximab, golimumab, vedolizumab, and tofacitinib) between 01/2017 through 09/2019 were selected from 18 outpatient gastroenterology practices across Germany. Patients with at least 12 months of data before (baseline) and after initiating an advanced therapy (Index Date) were included. Data was collected up to 24 months after index date. Clinical remission was assessed based on a partial Mayo score ≤1. Among patients with remission, therapy adjustments were assessed based on the following: Dose escalation, augmentation with conventional therapies, CS use for ≥12 weeks, or any use of CS during the maintenance phase. Time to remission was analysed using Kaplan-Meier analysis and associated factors were assessed within a multivariate Cox regression model. Patients were censored at end of the study period or if they discontinued or switched the index therapy.

Results

Among 149 patients included (females: 50.3%; median age: 40 years; median follow-up: 25.9 months), 75 (50.3%) received an anti-TNF agent, 48 (32.2%) vedolizumab, and 26 (17.4%) tofacitinib. Of these, 96 (64.4%) patients were biologic-naïve, and 42 patients (28.2%) were receiving concurrent CS at the index date. Within one year, remission was achieved in 49 out of 134 patients (46.1%; median time: 19.3 months [95%-CI: 7–24 months]; Figure 1). Among patients with remission at 24 months, therapy adjustments were required in 35.8% of patients. Most common adjustments included dose escalation (9.0%) and use of CS during the maintenance phase (11.9%). In an adjusted model, chances of remission were halved in biologic-experienced patients vs. naïve patients (hazard ratio [HR]: 0.49; p<0.05), while patients with concurrent use of conventional therapy at baseline were associated with a higher chance of achieving remission (HR: 1.82; p<0.05).

Conclusion

Less than half of UC patients treated with advanced therapies in Germany achieved clinical remission after one year. More than half of the patients required 1.5 years to achieve clinical remission. Among those who achieved remission within two years, one third required additional therapy modifications. More effective therapies are needed to achieve earlier and better outcomes among patients with UC in Germany.
P517 Re-treatment with filgotinib in patients with Ulcerative Colitis following treatment interruption: Analysis of the SELECTION and SELECTIONLTE studies
Authors: Vermeire S , Feagan B , Peyrin-Biroulet L , Oortwijn A , Faes M , de Haas A , Rogler G
Published: January 2022

Background

Long-term treatment regimens for ulcerative colitis (UC) present challenges for patients who may need to interrupt therapy for various reasons.1 Filgotinib (FIL) is an oral Janus kinase 1 preferential inhibitor. We performed a post hoc analysis of data collected from patients with UC treated with FIL in the phase 2b/3 SELECTION programme to assess the efficacy and safety of re-treatment following treatment interruption.

Methods

The SELECTION programme comprises two Induction Studies and a Maintenance Study (NCT02914522) and a long-term extension (LTE) study (NCT02914535). Adults aged 18–75 years with moderately to severely active UC, who had clinical remission or Mayo Clinic Score (MCS) response to FIL 200 mg or 100 mg at week 10 of SELECTION were re-randomized 2:1 to continue assigned FIL treatment or placebo (PBO) from week 11 to week 58. Patients with disease worsening (DW) in the Maintenance Study could enter the LTE study to receive open-label FIL 200 mg once daily. We assessed the efficacy of FIL in patients treated with induction FIL 200 mg or 100 mg who were randomized to PBO in the Maintenance Study and were re-treated with open-label FIL in the LTE study. Efficacy endpoints included partial MCS (pMCS) response and remission at LTE baseline and weeks 2, 4, 12 and 24. Non-responder imputation was used to analyse efficacy results.

Results

This analysis evaluated 50 patients treated with FIL 200 mg and 35 treated with FIL 100 mg in the Induction Study, who were withdrawn and re-treated upon DW. Baseline characteristics were similar among patients in the 200 mg and 100 mg treatment groups, with a median time to DW of 16.9 and 13.3 weeks, respectively. Mean pMCS declined rapidly in both groups from LTE baseline to week 2, reaching pMCS <2 at week 24 (Figure 1). By as early as week 2 of re-treatment, over 60% of patients in both groups had achieved pMCS response (Figure 2). By week 12, 78% of the 200 mg group and 94% of the 100 mg group achieved a pMCS response. Median time to response was 2.4 and 2.1 weeks in the 200 mg and 100 mg groups, respectively. Figure 3 shows that pMCS remission was achieved in 42% of the 200 mg group and 45% of the 100 mg group by week 24. Median time to pMCS remission was 23.6 and 12.1 weeks in the 200 mg and 100 mg groups, respectively. The number of adverse events upon re-treatment in the LTE was consistent with that reported in SELECTION (Table 1).

Conclusion

The majority of patients re-treated with FIL achieved pMCS response and remission within 12 weeks, with onset as early as week 2. Good disease control was maintained over the course of 24 weeks. Re-treatment was well tolerated, with no new safety signals observed among these patients.

Reference

1. Rubin DT. Gastroenterol Hepatol 2019;15:612–5.
P543 Point-of-care testing in therapeutic drug monitoring of infliximab
Authors: Šahinović I , Orsic Fric V , Konjik V , Pavela J , Borzan V , Šerić V
Published: January 2022

Background

Within the past 20 years infliximab (IFX), a monoclonal antibody targeting tumor necrosis factor-alpha, has become an established therapy for inducing and maintaining remission in inflammatory bowel disease (IBD). IFX therapeutic drug monitoring (TDM) using the point-of-care (POC) methods showed to be able to produce results fast enough to allow IFX dose adjustments before drug infusion. This study aimed to compare IFX quantification using two POC tests, Procise IFX (Procise Dx) and Quantum Blue Infliximab assay (Bühlmann Laboratories AG).

Methods

Serum samples from 22 IBD patients (M=64%) on IFX maintenance therapy were collected immediately before drug infusion. Capillary blood was also collected from 6 IBD patients by finger prick using whole blood pipettes (Procise Dx). Crohn’s disease (CD) was diagnosed in 12 patients and ulcerative colitis (UC) in 10 patients. For method comparison, a Passing Bablok regression was used and for qualitative comparison weighted kappa statistic was obtained after stratification of results by therapeutic range (<3 mg/l, ≥3 to 7 mg/L, and ≥7 mg/L).

Results

Both methods measured lower IFX concentrations in CD patients (4,95 (0,65 – 5,80) mg/L) than in UC patients (8,50 (4,80 – 12,20) mg/L). In two patients with confirmed IFX antibodies, both methods showed immeasurably low IFX concentrations. Passing Bablok regression analysis of IFX concentration in serum sample has showed a proportional deviation between two POC methods (y=0.416 (-0.654 to 1.279) + 0.753 (0.648 to 0.923)x). A good comparison has been observed for capillary blood measured using Procise IFX test and serum samples measured using Quantum Blue Infliximab assay (y=-2.732 (-4.315 to 1,867) + 1.263 (0.278 to 1.566)x), although IFX concentration was lower in capillary blood. Classification of results according to therapeutic interval showed good agreement for serum samples and serum and whole capillary blood measurements (κ=0.79 (0.59–0.999 and κ=0.80 (0.45–1.00), respectively).

Conclusion

Because of proportional differences, two POC tests can’t be used interchangeably for longitudinal TDM of IFX in IBD patients. There is a need for caution in the interpretation of IFX in whole blood, due to its possibly lower concentration.
P556 The effect of multiple doses of upadacitinib 45 mg on the pharmacokinetics of cytochrome P450 substrates in healthy adult subjects
Authors: Ibrahim M , Pangan A , Feng T , Mohamed M E
Published: January 2022

Background

Upadacitinib is a selective Janus kinase 1 inhibitor, which is approved for treatment of several inflammatory diseases. Upadacitinib 45 mg QD dose was evaluated for induction treatment in ulcerative colitis Phase 3 studies and is currently being evaluated in Crohn’s disease Phase 3 studies. A prior clinical study demonstrated that upadacitinib 30 mg QD dose resulted in no clinically relevant effects on plasma exposures of sensitive probe substrates for cytochrome P450 (CYP) enzymes. The objective of this study was to evaluate the effect of repeated doses of upadacitinib 45 mg on the pharmacokinetics of sensitive probe substrates of CYP enzymes in healthy adult subjects.

Methods

This was an open-label, multiple-dose, two-period study using the modified Cooperstown 5 + 1 cocktail drugs (midazolam [CYP3A], caffeine [CYP1A2], warfarin + vitamin K [CYP2C9], omeprazole [CYP2C19], and dextromethorphan [CYP2D6]). Twenty healthy adults received single oral doses of the cocktail drugs without upadacitinib in Period 1, followed by daily dosing of upadacitinib 45 mg for 16 days and administration of the cocktail drugs on Day 11 (for midazolam) and Day 12 (rest of substrates) in Period 2. A washout period of 6 days separated each Period. Serial blood samples and 12-hour urine samples (for dextromethorphan and dextrorphan) were collected. Pharmacokinetic parameters were estimated using noncompartmental analysis and repeated-measures analyses were performed for the natural logarithms of Cmax and AUC to assess the effect of upadacitinib on the probe substrates.

Results

The ratio (90% confidence interval) of area under the plasma concentration-time curve from time 0 to infinity (AUCinf) central values when the cocktail drugs were administered with upadacitinib 45 mg relative to when administered alone were 0.76 (0.69–0.83) for midazolam, 1.04 (0.95–1.13) for caffeine, 1.12 (1.05–1.20) for S-warfarin, 1.35 (1.18–1.54) for dextromethorphan, and 0.98 (0.85–1.13) for omeprazole. The 5-hydroxy-omeprazole to omeprazole plasma AUC ratio was unchanged (90% confidence interval within the no effect limits of 0.8 to 1.25).

Conclusion

Administration of daily upadacitinib 45 mg doses resulted in a limited effect on midazolam (CYP3A) and dextromethorphan (CYP2D6) exposures and had no relevant effects on the sensitive probe substrates for CYP1A2, CYP2C9 and CYP2C19. These limited effects are not expected to be clinically relevant or necessitate dose adjustment of CYP3A or CYP2D6 substrates. These results are consistent with a previous drug interaction evaluation for upadacitinib 30 mg and support lack of relevant effects of upadacitinib on drugs metabolized by CYP enzymes.
P579 Rates, predictive factors and effectiveness of ustekinumab intensification to 4- or 6-weekly intervals in Crohns’s disease
Authors: Derikx L , Plevris N , Su S , Gros B , Lyons M , Siakavellas S , Constantine-Cook N , Jenkinson P , O’Hare C , Merchant L , Noble C , Arnott I , Jones G , Lees C
Published: January 2022

Background

The efficacy and safety of ustekinumab (UST) intravenous induction followed by 8- and 12- weekly maintenance was established in the UNITI controlled trial. These data report dose intensification for 12- to 8-weekly but not 4-weekly. The effectiveness of this strategy is an important, unanswered real-world question. We aimed 1) to assess the cumulative incidence of UST dose intensification to 4- or 6-weekly in patients with Crohn’s disease (CD), 2) to identify factors associated with dose intensification, and 3) to assess the effectiveness and safety of this strategy.

Methods

We performed a retrospective, observational cohort study in a tertiary IBD referral centre. All CD patients treated with UST between 22 January 2015 and 28 October 2020 were identified from a prospective biologic prescription database. Subsequently, data on IBD phenotype, UST interval, drug survival, and corticosteroid-free remission were collected. Dose intensification and drug survival were established with (one minus) Kaplan Meier curves. Logistic regression models were used to identify factors independently associated with dose intensification.

Results

163 CD patients (male: 71/163 [43.6%]; median disease duration 9.5 years [IQR 4.8–17.1]) were treated with UST, with median follow-up time of 20.3 months (13.4–38.4). 21/163 patients (12.9%) were biologic naïve, whereas 142 patients (87.1%) were previously treated with one (n=100, 61.3%) or two biologic therapies (n=42, 25.8%). During follow-up, 55/163 patients (33.7%) underwent dose intensification to a 4-weekly (n=50, 30.7%) or 6-weekly (n=5, 3.1%) interval. Median time to dose intensification was 6.1 months (3.9–11.0); after 1 year 29.9% were escalated to 4- or 6-weekly UST. Prior exposure to both anti-TNF and vedolizumab (HR 9.5; 1.3–70.9) as well as concomitant steroid use at start of UST (HR 1.8; 1.0–3.1) were independently associated with dose intensification (Figure 1; non-significant: age, CD behaviour, perianal disease activity and UST start dose).

Following dose intensification 62.6% patients (29/55) remained on UST beyond 1 year (median time to discontinuation 5.2 months; Figure 2). No licensed treatment options remained in 12/29 patients. At the end of follow-up, (median 8.9 months [4.3–14.8] following dose intensification) 27.8% (15/54) were in corticosteroid-free and clinical remission.

Figure 1

Conclusion

One third of CD patients treated with UST will undergo dose intensification to a 4- or 6-weekly interval within the first year. Patients who failed two or more biologics were more likely to dose intensify. These are a very refractory group of CD patients, the majority of whom have no licensed treatment options available.
P581 Transmural remission improves clinical outcomes up to 5 years in patients with Crohn’s Disease
Authors: Pedro J , Botto I , Fernandes S , Lemos J , Neves J , Campelo P , Carvalho D , Bernardo S , Gonçalves A R , Valente A , Moura Santos P , Rosa I , Tavares de Sousa H , Ramos J , Venâncio J , Leitão J , Claro I , Correia L , Tato Marinho R
Published: January 2022

Background

Endoscopic remission (ER) is currently endorsed as one of the main treatment targets in Crohn’s Disease (CD). In a previous study, we have shown that transmural remission (TR) is associated with better clinical outcomes up to 1-year. It is unknown if these results still hold over a longer follow-up

Methods

This was a multicenter study, including 333 CD patients with magnetic resonance enterography (MRE) and colonoscopy evaluation performed within a 6-month interval and at least 5-years of follow-up. Patients were classified as having TR (inactive MRE and colonoscopy), ER (active MRE and inactive colonoscopy), and no remission (NR) (active colonoscopy). The need for surgery, hospitalization, steroids, and biologics was evaluated at 5-years of follow-up.

Results

Patients with TR presented lower rates of surgery (1.9% vs 17.9% vs 23.7%, P<0.001 and P=0.008), hospitalization (13.2% vs 30.4% vs 37.9%, P=0.001 and P=0.038), steroids (11.3% vs 21.4% vs 33.0%, P=0.001 and P=0.2), biologics (18.9% vs 51.8% vs 66.5%, P<0.001 and P=0.001), and any adverse outcome (26.4% vs 64.3% vs 78.6%, P<0.001) compared to ER and NR. Comparisons between ER and NR were mostly non-significant in respect to surgery (P=0.474), hospitalization (P=0.352), steroids (P=0.106), biologics (P=0.045), and any adverse outcome (P=0.036). The time until reaching any individual outcome was also significantly longer for TR. In multivariate analysis, endoscopic remission (OR 0.234 95%CI 0.135–0.405, P<0.001) and MRE remission (OR 0.316 95%CI 0.187–0.536, P<0.001) were independently associated with a lower likelihood of reaching any adverse outcome.

Conclusion

TR was associated with improved clinical outcomes over 5-years of follow-up. Going beyond ER appears to provide significant clinical benefits in the short and long-term.
P584 Systematic Review and Meta-analysis Evaluating the Real-World Effectiveness and Safety of Ustekinumab in Crohn’s Disease
Authors: Hosack T , Gadhok R , Lindsay J O
Published: January 2022

Background

The landmark UNITI trials 1 of Ustekinumab (UST, an anti-p40IL12/23 mAb) in treating Crohn’s disease (CD) demonstrated 6-week clinical response and 44-week clinical remission rates of 38% and 41% in TNF experienced and 52% and 62.5% in TNF naive patients. Clinical trials may not however reflect real world experience.

Methods

A systematic review and meta-analysis was conducted according to PRISMA guidelines to assess the real-world effectiveness and safety of UST in luminal CD based on current licensing approvals. A systematic literature search was performed using MEDLINE, EMBASE and conference proceedings from inception to 17 March 2021. Random-effects meta-analysis was used to assess clinical response, clinical remission, corticosteroid-free clinical remission (CFCR), biochemical remission and mucosal healing (MH) at weeks 8, 14, 26 and 52. Safety profile as well as rates of primary non-response (NR), secondary loss of response (LOR) and dose-intensification were also evaluated.

Results

4,957 studies were screened with 36 studies (22 full text articles and 14 abstracts) meeting inclusion criteria, comprising 3,821 patients in total. Pooled outcome measures for clinical response, clinical remission, CFCR and biochemical remission at weeks 8, 14, 26 and 52 as well as MH at weeks 26 and 52 are reported in Table 1. UST was discontinued in 12.0% (95%CI, 7.3%-17.8%) during the follow-up period with over half attributable to failure of response. The overall safety profile was favourable compared to clinical trials, with a pooled adverse events rate of 14.6% (95%CI, 9.8%-20.2%). Primary NR and LOR were observed in 10.7% (95%CI, 6.6%-15.6%) and 12.7% (95%CI, 3.5%-26.5%), respectively. UST dose was intensified in 25.6% (95%CI, 11.3%-43.4%) of patients during follow-up.

Conclusion

This systematic review and meta-analysis of real-world studies demonstrates clinical effectiveness and safety of UST for CD comparable to that observed in clinical trials, supporting the use of UST in CD.

Reference

1. Feagan BG et al. N Engl J Med 2016; 375:1946–1960 DOI: 10.1056/NEJMoa1602773
P595 Validation of a predictive algorithm for thiopurine induced hepatotoxicity in IBD patients
Authors: Van Moorsel F , Deben D , Creemers R , Winkens B , Pierik M , Bus P , Simsek M , de Boer N , van Bodegraven A , Wong D
Published: January 2022

Background

The thiopurines, azathioprine (AZA) and mercaptopurine (MP), are effective and remain standard treatment options in steroid sparing and maintaining remission in patients with inflammatory bowel disease (IBD). Approximately 25% of patients discontinue within three months after treatment initiation due to adverse events, of which about half due to hepatotoxicity. We hypothesise that identification of patients with an increased risk of adverse events and timely treatment optimisation (e.g. dose adjustment, adjuvant allopurinol) can prevent treatment failure due to adverse events.

The primary objective of this prospective observational multicentre study was to optimise and validate a proposed hepatotoxicity predictive algorithm in IBD patients starting AZA or MP therapy.

Methods

We adapted an algorithm from a previous study to predict the risk of developing hepatotoxicity in thiopurine drug treatment using multivariable logistic regression and a receiver operating characteristic curve. The determinants age, BMI and 6-MMPR-concentration one week after start of treatment (T=1) were inserted as continuous variables in this algorithm. Sex was inserted as a dichotomous variable.

Inclusion criteria were adult thiopurine-naive IBD patients initiating AZA or MP treatment. Subjects were treated according to guidelines and followed for 12 weeks. The primary study outcome was hepatotoxicity within 12 weeks, defined as ALAT > 2x ULN or an R value ((ALAT / ULN ALAT)/(AP / ULN ALP)) ≥ 5. The hepatotoxicity- and no-hepatotoxicity groups were compared using the Mann-Whitney U-test.

Results

In total, 255 patients were included from Dec 2015 to June 2019, of whom 26 were excluded because of no actual start with AZA or MP (n=18), loss to follow up (n=7) or no IBD diagnosis (n=1). Out of 229 patients 21 (9%) developed hepatotoxicity. Five out of 21 patients (24%) in the hepatotoxicity-group and 123 out of 208 patients (59%) in the no-hepatotoxicity-group had to be excluded for analysis (see Figure 1).

Ninety-three % of patients received MP with a median dose of 0.7 mg/kg (95%CI 0.3–1.4 mg/kg). Median dose of AZA (7%) was 2.0 mg/kg (95%CI 1.1 - 2.6 mg/kg).

There was a difference between the hepatotoxicity and no-hepatotoxicity group in BMI (28 versus 24, p=0.022) and 6-MMPR/6-TGN ratio at T=1 (16 versus 9, p=0.027). In Table 1, the number of true positives, true negatives, false positives and false negatives are presented. The diagnostic values are shown in Table 2. A specificity of 77% (95%CI 66–85%) and a sensitivity of 50% (95%CI 26–75%) was obtained.

Conclusion

In conclusion, the adapted algorithm does not accurately predict hepatotoxicity in this cohort of patients on relatively low-dose thiopurine treatment.
P598 Indicators for inadequate response among patients with Ulcerative Colitis treated with advanced therapies in German clinical practice
Authors: Bokemeyer B , Picker N , Kromer D , Rosin L , Patel H
Published: January 2022

Background

Management of Ulcerative Colitis (UC) is challenging, and clinicians are often obliged to attempt a variety of therapies in sequence until an adequate clinical response is achieved. This study examined the rates of inadequate response to advanced therapies among UC patients in clinical practice in Germany.

Methods

Using a retrospective chart review, patients with UC treated with an advanced therapy (adalimumab, infliximab, golimumab, vedolizumab, and tofacitinib) between 01/2017 through 09/2019 were selected from 18 outpatient gastroenterology practices across Germany. Patients with at least 12 months of data before (baseline) and after initiating an advanced therapy (Index Date) were included. Data was collected up to 24 months after index date. Inadequate response was defined as at least one of the following events: index therapy discontinuation due to lack of response, therapy escalation, augmentation with newly prescribed conventional therapies, corticosteroid (CS) dependency (use for ≥12 weeks), CS use during the maintenance phase, UC-related hospitalisations, surgery or emergency visit. Subgroups included patients with prior exposure to biologics, with and without remission (clinical remission defined as partial Mayo Score ≤1) at one year, and concurrent use of CS at the index date. Kaplan-Meier analysis was used to examine the rates over time. Patients were censored at the end of the study period.

Results

Among 149 patients (females: 50.3%; median age: 40 years; median follow-up: 25.9 months), 96 (64.4%) patients were biologic-naïve. Nearly half of the patients (45.5%) had ≥1 indicator for an inadequate response within two years after the index date (Figure 1). Among those who discontinued (N=43), 82.0% had switched to another advanced therapy. Therapy escalation was observed in 20 (16.3%) patients, and augmentation with conventional therapies was observed in 19 (15.6%) patients. 14 patients (11.3%) received CS during the maintenance phase of the index therapy, and 14 patients (10.1%) were CS dependent for ≥12 weeks. Inadequate response rates were significantly higher in patients without (n=80) vs. with remission (n=54) after one year (53.4% vs. 35.5%; p<0.05, Figure 2) and in patients with (n=42) vs. without concurrent CS (n=107) at the index date (67.0% vs. 36.9%; p<0.05). There was no significant difference between biologic-naïve and biologic-experienced patients.

Conclusion

Nearly half of the patients with UC experienced an inadequate response to their advanced therapy within two years. Higher rates of inadequate response were observed in patients without remission and in those with concurrent use of CS at baseline. More effective therapies are needed to achieve better outcomes in UC.
P611 Serological biomarkers of type VI and XXII collagen formation predict and monitor infliximab treatment response in patients with Crohn’s disease
Authors: Sorokina Alexdóttir M , Bourgonje A R , Karsdal M A , Bay-Jensen A C , Pehrsson M , Loveikyte R , van Dullemen H M , Visschedijk M C , Festen E A M , Weersma R K , Faber K N , Dijkstra G , Mortensen J H
Published: January 2022

Background

Crohn’s disease (CD) is a chronic inflammatory disease of the gastrointestinal (GI) tract characterized by excessive protease activity and extracellular matrix (ECM) remodeling. Although biologics such as TNF-α antibodies have improved the management of disease, up to 30–50% of patients still experience non-response to treatment. Biomarkers may be useful to improve therapeutic decision-making and monitor treatment response, thereby optimizing biological therapy and decreasing the risk of surgical intervention. This study assessed whether serological biomarkers of ECM turnover could monitor or predict response to TNF-α-antagonists in patients with and without surgical history.

Methods

Using protein fingerprint technology, serum biomarkers of type VI (PRO-C6) and XXII (PRO-C22) collagen formation were measured in 63 patients with CD undergoing infliximab (IFX) induction therapy. Disease activity was defined by a composite of the Harvey-Bradshaw Index (HBI) and physician’s global assessments (PGA). Response to treatment was defined as steroid-free remission (HBI<5) at week 14. Patients were stratified according to history of prior surgery. Patients with history of prior surgery (n=18) were 10 responders and 8 non-responders. Patients without history of prior surgery (n=45) were 40 responders and 5 non-responders. Differences in marker levels between groups were determined using Mann-Whitney U-tests. Area under the curve (AUC) values were generated using receiver operating characteristics (ROC) statistics.

Results

In patients with history of prior surgery, PRO-C22 was higher at baseline in responders than non-responders (P=0.004). At week 14, responders had higher levels of PRO-C6 than non-responders (P<0.05). Biomarkers PRO-C6 and PRO-C22 demonstrated predictive value at baseline (AUC [95% CI]: PRO-C6 0.78 [0.55–1.0], P=0.012; PRO-C22 0.90 [0.73–1.0], P<0.001). At week 14, PRO-C6 was also able to discriminate between responders and non-responders (AUC [95% CI]: 0.82 [0.54–1.0], P<0.01). No significant differences were observed in patients without history of prior surgery (Figure 1).

Conclusion

In patients with a history of prior surgery, higher baseline levels of PRO-C22 predict treatment response to IFX, whereas PRO-C6 levels were higher at week 14 after treatment initiation. These biomarkers demonstrated promising results in predicting response to anti-TNFα treatment, as well as separating responders from non-responders at week 14. Together, these markers could be used to predict and monitor treatment response to IFX in patients with CD with surgical history and may shed light on different profiles of ECM turnover. Future studies are warranted to further validate the potential utility of these biomarkers in larger patient cohorts.
P613 Comparative objective effectiveness of vedolizumab and ustekinumab in a real-life cohort of active Crohn’s disease patients failure to TNF inhibitors
Authors: Onali S , Pugliese D , Caprioli F A , Orlando A , Biancone L , Nardone O M , Imperatore N , Fiorino G , Cappello M , Viola A , Principi M B , Bezzio C , Aratari A , Carparelli S , Mazzuoli S , Manguso F , Grossi L , Bodini G , Ribaldone D , Mocci G , Minerba L , Favale A , Grova M , Scucchi L , Segato S , Fries W , Castiglione F , Armuzzi A , Fantini M C
Published: January 2022

Background

The use of ustekinumab (UST) and vedolizumab (VDZ) as second line therapy in Crohn’s disease (CD) patients failing tumour necrosis factor alpha inhibitors is still debated. The aim of the study was to compare in a large multicentre observational retrospective cohort, the effectiveness of UST and VDZ as second line therapy as assessed by clinical and objective outcomes including endoscopy and gastro intestinal (GI)-imaging.

Methods

Clinical response, remission and steroid-free remission at week 26 and 52 were evaluated in a retrospective cohort of CD patients previously experienced TNF-alpha inhibitors (primary or secondary failure, and intolerant). Objective response and remission were evaluated by one or more techniques including ileocolonoscopy, magnetic resonance (MR)/computer tomography (CT) enteroclysis and small bowel ultrasound (US) performed within 3 months before the beginning of the treatment and after one year of therapy. Inverse propensity of treatment weighting (IPTW) and propensity score matching (PMS) methods were used for statistical analysis.

Results

470 CD patients (239 UST and 231 VDZ) were included in the study. At week 26 clinical response, clinical remission and steroid free remission were similar between the two groups (Figure 1) At week 52, clinical remission and steroid-free remission rates were significantly higher in VDZ-treated patients (clinical remission: UST 42.5% vs VDZ 55.5%, p=0.01; steroid-free clinical remission UST 40.6% vs VDZ 51.1%, p=0.038; Figure 1). 302 patients (135 UST and 167 VDZ) had objective evaluation of disease activity at baseline and week 52. At week 52 objective response and remission rates were similar between the groups. (Figure 2). Clinical response at week 26 predicted steroid-free remission at week 52 in both UST- and VDZ-treated patients. Safety profiles were similar between the two groups.

Conclusion

One-year treatment with VDZ was associated with higher rate of clinical remission as compared to UST, but no difference was observed between the two groups when objective outcomes were investigated
P615 Improving IBD monitoring by understanding preanalytical faecal calprotectin variability
Authors: Schröder O , Farrag K , Böcher A , Helmschrodt A , Aksan A , Ehehalt R , Stein J M
Published: January 2022

Background

Currently, faecal calprotectin (fCal) is considered the best available biomarker for both diagnosing and monitoring IBD. However, little is known about the stability of this protein in stool: The few studies available are contradictory. Our aim was to investigate the pre-analytical and biological variability of fCal in order to provide tools for its interpretation in the clinical setting.

Methods

Samples from 36 patients with IBD were collected to verify the preanalytical stability of fCal. Aliquots of homogenised stool were stored at room temperature and 37°C and fCal concentration measured for 7 consecutive days. In addition, fCal stability was assessed at each respective temperature in assay-specific extraction buffer.

Results

Baseline fCal concentration in stool samples varied from 14 to 2210µg/g. In aliquots or raw stool samples kept at room temperature, mean change from baseline on days 1, 4 and 7 was -30,95%, -43,66%, and -58,68%, respectively. This decline was irrespective of fCal concentration at baseline, but significantly reduced by using an assay-specific extraction buffer (Fig.1).

Figure 1.

Conclusion

fCal is not stable at room temperature. Patients with IBD and their carers may be falsely reassured by low calprotectin values. Our results indicate that for preanalytical fCal handling, samples should only be stored at room temperature in the short term (up to 24 h). While refrigeration may be suitable for up to 48 h, the use of special extraction fluids improves fCal stability for a longer period. The sending of stool samples by post should therefore be avoided unless extraction buffer is used.