bluuebunny/crossref_metadata_2025_split huggingface dataset:
P278 Type IV collagen formation/degradation ratio predicts response to infliximab induction therapy in patients with Ulcerative Colitis
Authors: Bourgonje A R , Alexdottir M , Loveikyte R , Bay-Jensen A C , van Dullemen H M , Visschedijk M C , Festen E A M , Weersma R K , Karsdal M A , Faber K N , Mortensen J H , Dijkstra G 
Published: May 2021

Abstract

Background
Up to 50% of patients with ulcerative colitis (UC) do not respond to biological therapies, including TNF-α-antagonists (e.g., infliximab, IFX) and migration inhibitors (e.g., the α4β7-integrin inhibitor vedolizumab, VEDO). Therefore, serological biomarkers that predict therapy response are urgently needed. In this respect, biomarkers of extracellular matrix (ECM) remodeling, including basement membrane (BM) remodeling, and intestinal inflammation may hold promise as these processes play an important role in the pathophysiology of UC. In this study, we aimed to assess the predictive ability of serological biomarkers of ECM turnover and intestinal inflammation with regard to clinical response to IFX and VEDO therapy in patients with UC.

Methods
Serological biomarkers of collagen formation (PRO-C3, PRO-C4), matrix metalloproteinase (MMP)-mediated collagen degradation (reC1M, C3M, C4M, C4G, C6Ma3) and intestinal inflammation (macrophage activity marker [VICM] and calprotectin degradation fragments [CPa9-HNE]) were measured using neo-epitope solid-phase competitive enzyme-linked immunosorbent assay (ELISA) technology in 80 patients with UC who received either infliximab (IFX, n=26) or vedolizumab (VEDO, n=54) induction therapy. Clinical response to therapy was defined by composite assessment of available Simple Clinical Colitis Activity Index (SCCAI) scores and physician’s global assessments (PGA) derived from clinical records. Logistic regression modelling and receiver operating characteristics (ROC) statistics were used to assess discriminative capacity regarding response to IFX and VEDO.

Results
Only baseline ratios of type IV collagen formation and degradation (PRO-C4/C4M) were significantly elevated in patients with UC who clinically responded to IFX therapy (P&lt;0.05). In addition, PRO-C4/C4M ratios accurately discriminated responders and non-responders to IFX therapy (area under the curve [AUC]=0.77, P&lt;0.05), also after adjustment for confounding factors (AUC=0.88, P&lt;0.01). Serum VICM levels were elevated in patients not responding to IFX therapy, but did not reach statistical significance (AUC=0.76, P=0.06). None of the biomarkers predicted response to VEDO therapy.

Conclusion
The baseline ratio of type IV collagen formation/degradation demonstrated high predictive accuracy with regard to response to IFX therapy in patients with UC, which may imply that patients with increased BM formation vs. degradation are more likely to respond. Furthermore, VICM may hold promise as a predictor for non-response to IFX therapy. Serological biomarkers of ECM turnover and intestinal inflammation may aid in predicting response to biological therapy and deserve validation in larger, prospective cohort studies.
P285 A retrospective observational study on the effectiveness and safety of vedolizumab with or without budesonide induction therapy among patients with moderate-to-severe Crohn’s disease
Authors: Weisshof R , Vavricka S , Pouillon L , Braegger F , Roset M , Bent-Ennakhil N , Ferrante M 
Published: May 2021

Abstract

Background
The α4β7 integrin monoclonal antibody vedolizumab (VDZ) has been shown to be efficacious for patients with moderate-to-severe Crohn’s disease (CD). This study aimed to analyse the added value of budesonide in combination with VDZ as an induction treatment for this indication.

Methods
A multicentre, retrospective chart review study was conducted in Belgium, Israel, and Switzerland. Adult patients with moderately to severely active CD (defined as an abdominal pain [AP] score of ≥2 and/or a mean daily loose stool frequency [LSF] score of ≥4 for the previous 7 days) who initiated induction therapy with either VDZ monotherapy (mono) or a combination therapy (combo) of VDZ with budesonide (index date) between 1 January 2015 and 31 January 2019 were included. Patients who received VDZ by IV infusion at weeks 0, 2, 6, 10 (only some patients received VDZ during week 10), and 8 weeks thereafter were assessed for time to patient-reported outcome (PRO) clinical remission (Kaplan-Meier curves), defined as an average daily composite score of AP ≤1 and LSF ≤31 within 14 weeks. Regression models were used to assess differences and associations.

Results
Overall, 123 patients were included (mono, n=73; combo, n=50). Patients initiating combo presented with more severe disease at index date than patients initiating mono. PRO clinical remission rates were estimated at 71.4% (50/70) in the mono and 68.0% (34/50) in the combo groups, with a similar median time to PRO remission of 91 days (95% CI: 70–98) and 95 days (95% CI: 70–98), respectively (Figure 1). Figure 2 shows the mean % change in AP and LSF from baseline to week 14, which was comparable for mono and combo. The variables associated with mean % change were moderate and severe AP scores for AP and being a current smoker for LSF. One patient in each group discontinued VDZ before week 14 (due to lack of effectiveness [mono] and adverse event [AE; combo]); 68.0% of patients in the combo group discontinued budesonide by the end of the follow up period. The reasons for discontinuation were routine treatment regimen (8 weeks 9 mg/day+subsequent tapering-off) in 85.3% of the patients, lack of effectiveness in 5.9% and AEs in 2.9% (5.8% other reasons). Safety event rates were similar among the groups for overall AEs (mono, 23.3%; combo, 26.0%), with the majority designated as mild to moderate in severity, and 83.3% resolved within the follow-up period.

Conclusion
Comparable effectiveness and safety outcomes were observed with mono and combo therapy in patients with CD; however, disease state among patients receiving combo was more refractory/severe at baseline. Further evidence is needed to corroborate these findings.

Reference
P290 Impact of concomitant 5-aminosalicylic acid therapy on vedolizumab efficacy and safety in Inflammatory Bowel Disease
Authors: Ungaro R , Kadali H , Zhang W , Adsul S , Reinisch W 
Published: May 2021

Abstract

Background
Vedolizumab (VDZ), a gut-selective anti-lymphocyte trafficking monoclonal anti-a4β7-integrin antibody, has showed efficacy in multiple phase 3 clinical trials in patients (pts) with inflammatory bowel disease (IBD). Decreased likelihood of response to adalimumab was previously observed with concomitant 5-ASA.1 This post-hoc analysis assessed the impact of concomitant 5-ASA on efficacy and safety in VDZ-treated pts with IBD.

Methods
Pts with IBD treated with VDZ intravenous (IV) or subcutaneous (SC) in phase 3 trials who continued 5-ASA (at any dose) at the time of starting VDZ were compared with those who received no concomitant 5-ASA. Pts were also stratified by ulcerative colitis (UC) or Crohn’s disease (CD). Efficacy outcomes were the proportion of pts achieving clinical response, clinical remission and corticosteroid (CS)-free clinical remission at Wk 6 (end of induction phase) and Wk 52 (end of maintenance phase). Safety outcomes were the proportion of pts experiencing any infection and enteric infections. Studies included: GEMINI 1 and 2, and VISIBLE 1 and 2 in efficacy analyses; GEMINI 1, 2, 3 and long-term safety for VDZ IV, and VISIBLE 1, 2, and open-label extension (data cut-off 17 May 2019) for VDZ SC in safety analyses.

Results
At Wk 6, clinical response was achieved by 191 (70.0%) and 69 (61.6%) VDZ-treated pts with UC with and without 5-ASA, respectively, and by 139 (64.4%) and 161 (57.7%) pts with CD, respectively (Table 1). At week 52, clinical remission was achieved by 134 (46.0%) and 45 (38.8%) VDZ-treated pts with UC with or without 5-ASA, and by 116 (50.2%) and 132 (37.5%) pts with CD, respectively. CS-free clinical remission at Wk 52 was achieved by 55 (34.8%) and 19 (37.3%) VDZ-treated pts with UC with and without 5-ASA, respectively, and by 46 (41.4%) and 46 (31.5%) pts with CD, respectively. Multivariate analysis in general showed no differences in VDZ efficacy with or without 5-ASA. No new safety issues or signals were identified. A tendency towards lower incidence of all infections and enteric infections was observed in pts receiving VDZ (IV or SC) with versus without 5-ASA (Table 2).

Conclusion
In this post-hoc analysis of VDZ pivotal trial data, concomitant 5-ASA does not appear to significantly impact the efficacy of VDZ in pts with IBD. No new safety signals were identified. The safety profile of VDZ IV and SC, with and without 5-ASA was consistent with the known safety profile of VDZ. Although there was limited data in some subgroups, there was no evidence to suggest that concomitant 5-ASA usage was associated with higher infection rates. These data will be useful to inform risk-benefit assessments of continued 5-ASA in VDZ-treated pts.

Reference
P318 Intra-dermal with topical imiquimod pre-treatment versus intra-muscular hepatitis B vaccination in inflammatory bowel disease patients: a double-blind randomized controlled trial
Authors: Ko K L , Lam Y F , Cheung K S , Hung F N , Leung W K 
Published: May 2021

Abstract

Background
Patients with inflammatory bowel disease (IBD) are often immunocompromised and at risk of various opportunistic infections including viral hepatitis. Vaccination is recommended to prevent hepatitis B infection, but efficacy with conventional intra-muscular hepatitis B vaccination in IBD patients is suboptimal. Intra-dermal vaccination has been shown to be an effective way in augmenting immune response in poor vaccine responders. In addition, topical imiquimod, a synthetic agonist of toll-like receptor 7, has been shown to further boost the immunogenicity when applied to the injection site before intra-dermal vaccination. Our study compared the efficacy of intra-dermal hepatitis B vaccination with topical imiquimod with conventional intra-muscular hepatitis B vaccination in IBD patients.

Methods
This is a double-blind, randomized-controlled trial. IBD patients with no evidence of active or past infection nor history of vaccination i.e. negative serology to all HBsAg/Anti-HBc/Anti-HBs were recruited. They were randomized in 1:1 ratio to receive either intra-dermal recombinant hepatitis B vaccine with topical imiquimod pre-treatment to site of injection (ID) or intra-muscular recombinant hepatitis B vaccine with topical aqueous cream (IM). Same dose (20mcg) of vaccine (Engerix B, Glaxo Smith Klein) was administered to both groups at 0, 1, 6 month. The primary outcome was the sero-protection rate at 12-month, defined as percentage of recruited subjects with anti-HBs titre ≥ 10 mIU/mL.

Results
104 patients (mean age 46; 68% male; 50% Crohn’s and 50% UC) were enrolled, with 53 received ID and 51 received IM vaccine. The percentage of patients using steroids, immunomulators and biologics at the time of randomization was 15, 55 and 22 %, respectively. Baseline demographic, disease characteristic, and laboratory parameter were comparable between the ID and IM groups. Sero-protection rate at 12-month was significantly higher in the ID arm compared to the IM arm (91% vs. 69%, P=0.005; Figure). Percentage of good responders at 12 month (anti-HBs titre &gt; 100 mIU/mL) was also higher in the ID arm than in the IM (77% vs 59%, P=0.042). Multivariate analysis showed that use of ID vaccine (OR 4.45, 95% CI 1.40-14.47) and a higher albumin level (OR 1.30, 95% CI 1.06-1.58) are associated with better sero-protection rate. There was no significant difference in adverse effects reported in (64% in ID vs 55% in IM; Table).

Conclusion
ID hepatitis B vaccination with topical imiquimod is safe and offers superior seroprotection against hepatitis B among IBD patients.
P328 Ustekinumab is an effective and safe therapy in anti-TNF refractory Crohn’s Disease: a two year real-life observational study from Spain
Authors: Rueda Sanchez J , Cabello Ramirez M , Camara Baena S , Keco Huerga A , Garcia de la Borbolla Serres J , Castro Fernandez M , Grande Santamaria L 
Published: May 2021

Abstract

Background
Ustekinumab is a monoclonal antibody targeting IL-12/23 and was proved efficacious during the registration clinical trials. However real-world data in a day to day setting is still scarce. The aim of our study was to evaluate the effectiveness, durability and safety of ustekinumab in our real-life cohort.

Methods
We present a retrospective, observational study from a single tertiary center. We included adult CD patients that had received the standard ustekinumab intravenous induction and with at least 12-month follow-up. We assessed clinical (HBI) and biomarker (CRP, calprotectin) response at 3, 6, 12, 18 and 24 months. Adverse events, perianal disease response and corticosteroid (CS) use were also recorded.

Results
We observed a significant decrease in median HBI in all visits. Clinical response was observed in 72.7% of patients at 12 months and 66.7% at 24 months. Clinical remission was achieved in 57.6% and 58.3% of patients at 12 and 24 months respectively. CS-free clinical remission rates were 45.5% at 12 months and 54.2% at 24 months. The most frequent maintenance dose interval was q8w, with only 6/35 patients (17,14%) requiring dose escalation due to inefficacy of standard q8w interval. Drug survival at 2 years was 93.9%. Perianal disease clinical improvement was noted in 16 out of 17 patients with perianal disease at baseline. Fecal calprotectin decreased significantly from baseline, with a median change of -66 ug/g at 12 months and -253 ug/g at 24 months.
Ustekinumab was generally well-tolerated. Two adverse events were recorded during the follow-up period, an herpes zoster and an uveitis, none of them required Ustekinumab discontinuation.

Conclusion
According to our results, Ustekinumab was effective, durable, and safe for moderate-severe CD in a real-life clinical setting, with more than half of patients achieving CS-free clinical remission at 24 months in an anti-TNF refractory cohort.
P359 Influence of the nature of immunosuppressive therapy in patients with inflammatory bowel diseases on the level of immunoglobulins G after a Coronavirus Infection
Authors: Knyazev O , Kagramanova A , Lishchinskaya A , Noskova K , Chernova M , Shkurko T , Veselov A , Kulakov D , Li I , Parfenov A 
Published: May 2021

Abstract

Background
Currently, there are differences in the results of international studies and treatment outcomes in patients with inflammatory bowel disease (IBD) and COVID-19. Further research is needed to help answer the questions: do IBD patients have an increased risk of contracting SARS-CoV-2? Do IBD patients have more severe COVID-19 outcomes? Does IBD therapy increase the risk of infection? Do any IBD treatments protect against COVID-19?

Objective
To study the effect of immunosuppressors, genetically engineered biologics, and janus kinase blockers on the level of SARS-CoV-2 class G immunoglobulins in IBD patients who underwent COVID-19. .

Methods
The level of SARS-CoV-2 class G immunoglobulins was analyzed in 66 patients with IBD after COVID-19 infection. Male 28 (42.4%) of women 38 (57.6 per cent). The median age was 39±4.2 years. The duration of the anamnesis ranged from 1 to 8 years (Iu 4 years). The patients were divided into two groups, depending on the therapy performed: Group 1 (n=31) received long-term (more than 1 year) immunosuppressants (azathioprine/6-mercaptopurine/tofacitinib), group 2 (n=35) received anti-TNF-α therapy. The level of SARS-CoV-2 class G immunoglobulins was determined by the immunochemiluminescence method.

Results
After 4-6 weeks later, after a twice negative smear of PCR from the nose and oropharynx for SARS-CoV-2, in patients (n=31) receiving anti-relapse therapy with systemic IBD (azathioprine/6-mercaptopurine) and selective (tofacitinib) immunosuppressants, the average level of Ig G was 44.1±9.8 U/l. Among patients with IBD receiving anti-TNF-a drugs (n=35), the average level of class G immunoglobulins was 133.6±14.4 U/l. The difference was statistically significant (p=0.000003).

Conclusion
The level of class G immunoglobulins 3-4 weeks after the COVID-19 infection was significantly higher in IBD patients who received anti-TNF-α drugs.
P408 Anti-Drug Antibodies Detected in the Presence of Adequate Infliximab Drug Levels In IBD Patients in Clinical Remission have Limited Clinical Significance
Authors: Doherty J , Varley R , Healy M , Dunne C , Mac Carthy F , McKiernan S , Hartery K , Kevans D 
Published: May 2021

Abstract

Background
Immunogenicity, with the development of antibodies-to-infliximab (ATI) increases drug clearance and can lead to loss of infliximab (IFX) response in inflammatory bowel disease(IBD). Reporting of ATI is variable between commercial assays with some assays having high sensitivity for low-titre antibodies. Uniform thresholds for clinically relevant antibody titres are lacking. It is unclear how ATI affect treatment outcome when adequate trough IFX concentrations are present and ATI are detected.

Methods
We aimed to assess the impact of ATI detected in the presence of adequate IFX levels on the outcome of IFX therapy in IBD patients in clinical remission. A proactive therapeutic drug monitoring(TDM) strategy was utilized in our unit with IFX and ATI levels, assessed at trough, in all IBD patients receiving IFX. Baseline demographics were collected. Patients were grouped based on disease activity. An adequate trough IFX level was a concentration &gt; 3 µg/mL, with low levels defined as &lt; 3 µg/mL. ATI positivity was defined as a concentration &gt; 10 AU/mL. Receiver operating characteristic analysis was performed to evaluate the classifying performance of ATI concentration for low IFX levels. Survival analysis was performed to determine IFX persistence in patients with adequate IFX levels and positive ATI. Follow up TDM assessments, where available, were documented to determine changes in ATI concentration over time in patients with adequate IFX levels.

Results
108 patients were included. Median age 36years. 46% were female. 36% had ulcerative colitis, 60% Crohn’s disease. 35% were receiving concomitant immunomodulators. 56% of patients were in remission at the time of TDM assessment. 44%, 30% and 26% of patients had IFX levels &lt; 3 µg/mL, 3 – 7 µg/mL and &gt; 7 µg/mL. Median [range] ATI concentration was 11 AU/mL [0 – 800]. ATI positivity occurred in 25%, 19% and 8% of IFX groups with levels &lt; 3 µg/mL, 3 – 7 µg/mL and &gt; 7 µg/mL. There was a weak inverse correlation between trough ATI and IFX concentration (p=0.01)(Figure 1). ATI concentration performed poorly as a classifier of low IFX levels (AUC 0.568)(p=0.39). 83%(15/18) of IBD patients in remission with adequate IFX levels and positive ATI remained on IFX for the duration of follow up with a mean cumulative time on IFX of 111.2 weeks (95% CI 105.1 – 117.3)(Figure 2). In this group, there was no significant change in ATI titre comparing index with follow up TDM assessments (p=0.14)(Figure 3).

Conclusion
ATI positivity in the presence of adequate IFX levels is common with proactive TDM. For patients in clinical remission ATI positivity in the presence of adequate IFX levels has limited clinical significance. Care should be taken to avoid unnecessary therapy alterations in this patient subgroup.
P428 Early and Late Fecal Calprotectin Remission - Analysis of a proactive Therapeutic Drug Monitoring Treatment Protocol
Authors: Pedro J , Rodrigues I , Damião F , Fernandes S , Gonçalves A R , Bernardo S , Baldaia C , Valente A , Moura Santos P , Correia L , Tato Marinho R 
Published: May 2021

Abstract

Background
Fecal calprotectin (Fc) is an adequate surrogate marker for endoscopic activity in inflammatory bowel disease. The timing of Fc remission may have prognostic implications in patients under biologic therapy.

Methods
Using a prospectively maintained database we followed 135 patients under a proactive therapeutic drug monitoring (pTDM) protocol aiming at an Infliximab trough level (IFXTL) between 5-10 µg/mL with sequential measurements of Fc. We evaluated the rates of early (at week 14) and late (after week 14) Fc remission (&lt;250 µg/g) and associated clinical outcomes at 2-years of follow up.

Results
77 patients (57.0%) reached early Fc remission and 30 patients (22.2%) reached late Fc remission. Patients with late Fc remission presented higher Fc at baseline (1708.5 μg/g [681-3483] vs 803 μg/g [339-1477], P=0.006) and lower IFXTL at week 14 (2.71 µg/mL [1.24-6.30] vs 6.59 µg/mL [3.41-10.63], P=0.001) than patients with early Fc remission. However, by the end of follow-up, IFXTL were similar in both groups: 7.94 µg/mL (4.79-11.25) vs 8.54 µg/mL (6.49-11.07), P=0.514. In patients without early Fc remission, week 14 IFXTL did not differ between those with and without late Fc remission (2.71 µg/mL [1.24-6.30] vs 3.47 µg/mL [0.945-6.94], P=0.957), but significantly increased in late responders by the end of follow-up: 8.54 µg/mL (6.49-11.07) vs 4.37 µg/mL (1.77-7.49), P=0.002. Patients with early and late Fc remission presented similar rates of clinical remission (88.3% vs 83.0%, P=0.493), steroid-free clinical remission (79.1% vs 92.9% P=0.239), lower rates of IFX discontinuation (14.3% vs 16.7%, P=0.756), hospitalization (11.7% vs 13.3%, P=0.815), and surgery (1.3% vs 3.3%, P=0.485).

Conclusion
The magnitude of Fc at baseline and IFXTL at week 14 significantly influence the timing of Fc remission. The use of PTDM results in similar pharmacokinetics and clinical outcomes in both groups.
P429 Continued postoperative use of biologics for the prevention of recurrence of Crohn’s disease
Authors: Yu J , Hyun H K , Park J , Kang E A , Park S J , Park J J , Kim T I , Kim W H , Cheon J H 
Published: May 2021

Abstract

Background
Many patients with Crohn’s disease undergo major abdominal surgery during the disease course. Despite surgery, postoperative recurrence (POR) commonly occurs. Although postoperative use of biologic agents is known to be effective in preventing POR, few studies have evaluated the effectiveness of continuing the same biologic agents postoperatively in patients who received biologic agents preoperatively.

Methods
This retrospective observational study was performed in a single tertiary medical center. We retrospectively reviewed patients who underwent the first major abdominal surgery due to Crohn’s disease and divided them into two groups: biologics users both in the preoperative and postoperative periods and biologics users only in the preoperative period. We compared data between the groups according to endoscopic, clinical, and surgical recurrences.

Results
In total, 49 patients who used biologic agents preoperatively were recruited. Among them, biologics were used postoperatively in 24 patients (49.0%, Figure 1). Baseline characteristics except the median age and age at diagnosis were similar in both groups. Kaplan–Meier analysis revealed that the cumulative clinical recurrence rate was significantly lower in the postoperative biologics group (log-rank 0.012, Figure 2). On multivariate Cox regression analysis, postoperative biologics use was significantly associated with a decreased risk of clinical recurrence (adjusted hazard ratio 0.160, 95% confidence interval 0.037–0.692, p = 0.014).

Conclusion
Continuing biologics use postoperatively in patients who were receiving biologics preoperatively significantly reduced the rate of clinical recurrence. For patients with Crohn’s disease who were receiving biologic agents before surgery, continuing their use after surgery is recommended.