bluuebunny/crossref_metadata_2025_split huggingface dataset:
P299 Loss-of-response to anti-tumour necrosis factor-α critically depends on treatment duration in patients with Inflammatory Bowel Disease
Authors: Schultheiss J , Mahmoud R , Louwers J , van der Kaaij M , van Hellemondt B , van Boeckel P , Mahmmod N , Jharap B , Fidder H , Oldenburg B 
Published: May 2021

Abstract

Background
Inflammatory bowel disease (IBD) is often managed with anti-tumour necrosis factor-α (anti-TNFα) compounds, but only few studies have reported on long-term outcomes. We aimed to determine whether the incidence of loss-of-response decreases with longer treatment duration.

Methods
In a multicentre, retrospective cohort study of patients with IBD who received anti-TNFα for at least 4 months between 2011-2019, we compared incidence rates of loss-of-response between different intervals of treatment duration and performed parametric survival modelling to assess changes with longer treatment duration. Cox regression analysis was performed to identify predictors of loss-of-response. Secondary outcomes included overall anti-TNFα discontinuation and dose escalation.

Results
We included 900 anti-TNFα treatment episodes in 746 individual patients, with up to 9 years of follow-up. During follow-up, the most frequently observed reason for anti-TNFα discontinuation was loss-of-response (Figure 1), which occurred in 231 (25.7%) episodes, with presence of anti-drug antibodies in 67/231 (29%). Within the first year, the incidence of loss-of-response was threefold higher than after four years of treatment (17.3% versus 4.7% per patient-year, p&lt;0.001). The incidence of overall drug discontinuation (28.6% versus 14.0% per patient-year, p&lt;0.001) and dose escalations (36.5% versus 6.4% per patient-year, p&lt;0.001) also decreased significantly from the first year to after four years, respectively. Risk factors for loss-of-response included stricturing or penetrating Crohn’s disease (adjusted hazard ratio [aHR] 1.67, 95% CI 1.14 – 2.44), while male sex (aHR 0.74, 95% CI 0.56 – 0.98) and concomitant immunomodulators (aHR 0.73, 95% CI 0.54 – 0.98) were protective.

Conclusion
Long-term use of anti-TNFα maintenance treatment is associated with a reduced risk of loss-of-response in patients with IBD.
P304 Rational infliximab induction dosing to achieve long-term deep remission in children with Inflammatory Bowel Diseases
Authors: Kantasiripitak W , van Hoeve K , Sabino J , Vermeire S , Hoffman I , Declerck P , Thomas D , Ferrante M , Dreesen E 
Published: May 2021

Abstract

Background
Adequate infliximab (IFX) trough concentrations (TCs) during induction treatment are predictive for long-term clinical and endoscopic remission in paediatric patients with inflammatory bowel diseases (IBD). However, under the approved weight-based dosing (5 mg/kg), children often have low IFX TCs, since the relationship between bodyweight and the IFX pharmacokinetic (PK) parameters is nonlinear. Therefore, there is a need to optimise paediatric dosing to engage optimal IFX TCs during induction treatment.

Methods
Fifty-two paediatric patients with IBD (34 Crohn’s disease (CD), 18 ulcerative colitis (UC)) contributed IFX samples (246 intermediate and 150 trough samples) during either induction treatment (n=32) or maintenance treatment (n=20). A population PK (popPK) model was developed to describe the relationship between IFX dose and exposure. The previously published IFX popPK model based on data of 112 children with CD in the Phase 3 REACH trial was used as a frequentist prior to inform parameter estimation using NONMEM. Our popPK model was used to simulate IFX TCs during induction treatment under different induction dosing regimens (5 mg/kg, 7.5 mg/kg, and 10 mg/kg IFX at weeks 0, 2, and 6). Probabilities of TC target attainment (PTA) were compared. The TC target, associated with a 75% probability of achieving deep remission (DR) at six months after initiating IFX treatment, was identified using a logistic regression model and a ROC analysis. DR was defined as combined endoscopic remission (Simple Endoscopic Score for CD &lt;3 or Mayo endoscopic sub-score 0) and corticosteroid-free clinical remission (Paediatric CD or UC Activity Index &lt;10).

Results
The median boyweight was 44 kg (range 15-92 kg). A 2-compartment popPK model with first-order elimination described IFX concentrations well (Table 1). The IFX clearance by weight increased with decreasing bodyweight, decreasing serum albumin and absence of immunomodulator combo-therapy. Also, the IFX volume of distribution in the central and peripheral compartment by weight increased with decreasing bodyweight. A total of 18/32 (56%) patients in the induction treatment achieved DR at six months. An IFX TC of 23.0 mg/L at week 6 was identified as the TC target (100% sen, 33% spe, 100% npv, and 50% ppv). Children with a bodyweight less than 30 kg could only reach a 50% PTA when receiving 10 mg/kg IFX combo-therapy during induction (Figure 1). While children with a bodyweight above 30 kg had more than 50% PTA when receiving either 10 mg/kg IFX monotherapy or 7.5 mg/kg IFX combo-therapy (Table 2).

Conclusion
IFX doses higher than 5 mg/kg are needed during induction in children with IBD to facilitate the attainment of the TC target, thereby increasing the chance of long-term DR.
P311 Intensive dried blood spot sampling shows a higher drug exposure throughout the first 24 weeks of therapy in ustekinumab-treated Crohn’s disease patients achieving endoscopic remission
Authors: Van den Berghe N , Verstockt B , Ballet V , Gils A , Sabino J , Ferrante M , Vermeire S , Declerck P , Thomas D 
Published: May 2021

Abstract

Background
Various studies have shown an association between ustekinumab serum concentrations and treatment response in patients with Crohn’s disease (CD). However, the time point at which this concentration is most informative for long-term outcome is unknown. Dried blood spot (DBS) sampling allows remote collection of blood for measurements at various time points. By use of this sampling method, the current study aimed to evaluate the exposure-response relationship of ustekinumab throughout the first 24 weeks of treatment and to investigate the time points at which ustekinumab levels could identify patients achieving endoscopic remission.

Methods
This interim-analysis included DBS (n = 332) and serum (n = 60) samples collected from 13 ustekinumab-treated CD patients at 25 time points during the first 6 months of therapy. All patients received an intravenous infusion of ~6 mg/kg ustekinumab followed by subcutaneous dosing of 90 mg every 8 weeks. Ustekinumab concentrations were measured in serum and DBS extracts using an ustekinumab ELISA (apDia, Turnhout, Belgium). Endoscopic remission was defined as simple endoscopic score for CD (SES-CD) ≤3 after 6 months of therapy. The Mann-Whitney U-test was used to compare unpaired data.

Results
Three out of 13 patients (23.1%) achieved endoscopic remission. Ustekinumab concentrations in serum correlated with those in DBS extracts (Spearman r = 0.97, p &lt;0.0001). Measurement of the ustekinumab concentration in 38 simultaneously collected DBS and serum samples showed an average DBS-to-serum conversion factor of 2.5±0.7 (mean±SD) with an acceptable interpatient variability (CV ≤29%). Concentration-time profiles showed that patients in remission have a higher area under the curve (AUC), hence a higher drug exposure, than patients not achieving remission (906 vs 466 μg*day/mL, p=0.007, Figure). A negative correlation was observed between the AUC and SES-CD at week 24 (Spearman r = -0.74, p=0.0048). Ustekinumab concentrations in DBS extracts at the intermediate time points week 6, week 11 and week 12 after treatment start exhibited the most significant difference between remitters and non-remitters (Table). In contrast, no significant difference was observed in ustekinumab levels in DBS extracts at week 8, week 16 and week 24 between remitters and non-remitters.

Conclusion
Intensive DBS sampling showed that ustekinumab-treated CD patients in endoscopic remission have a higher drug exposure throughout the first 24 weeks of treatment than patients not in remission. DBS is an easy sampling method that allows accurate monitoring of ustekinumab exposure over time and could help to identify underexposed patients which might benefit from treatment optimization.
P329 Comparative Assessment of Adalimumab Trough Levels between Point-of-Care Testing and current Standard of Care (enzyme linked immunosorbent assay) in patients with Inflammatory Bowel Disease
Authors: Marsilio I , Maniero D , Lorenzon G , Rigo A , Cardin R , Facchin S , Barberio B , D’Incà R , Zingone F , Bahur B , Bray K B , Savarino E V 
Published: May 2021

Abstract

Background
Adalimumab (ADL) is a therapeutic monoclonal antibody that targets the proinflammatory cytokine tumor necrosis factor-alpha (TNF-α) and has been shown to effectively induce and maintain disease remission in patients with Inflammatory Bowel Disease (IBD). However, some patients fail to respond to this treatment, experiencing primary failure (no response to induction therapy), while others initially respond but lose efficacy over time (secondary failure). Therapeutic Drug Monitoring (TDM), in clinical practice, may lead to maintain therapeutic drug concentration thereby optimizing individual dosage regimen and improving treatment response. Recently, a point of care testing (POCT) has been developed to rapidly measure trough levels in patients taking ADL. Comparative data with current gold standard are lacking.

Aim
To determine the degree of analytical correlation between a recently developed POCT (ProciseDx) ADL assay which analyze capillary whole blood and the comparative enzyme linked immunosorbent assays (ELISA) from serum samples.

Methods
From December 2020 to February 2021, consecutive patients (aged ≥ 18 years) taking ADA (Humira, Amgevita, Imraldi) were recruited at Gastroenterology Unit, Padua University Hospital, during outpatient visits. In each patient, ADL levels from capillary whole blood collected by finger stick were performed using the ProciseDx ADL assay with reportable range between 1.3 µg/mL - 51.5 µg/mL; at the same time, a serum sample from venous blood was collected to carry out Grifols’ Promonitor ELISA test (range ≤ 0.024 – 12 µg/mL). A Deming regression test was used to identify the correlation between the two methods.

Results
Sixty patients were enrolled (67% males with mean age of 3±14), with 80% of them having CD, 17% UC and 3% an undetermined-Inflammatory Bowel Disease (IBD-U). The assessment with ProciseDx POCT was feasible and required a turnaround time of 3±0.2 minutes while serum ELISA analysis required the collection of at least 40 samples (around three weeks at our centre) and 3 hours to be performed. Thirty patients (63% males with mean age of 41±14) had therapeutic levels as assessed by ProciseDx ADL assay lower than 1.3 or greater than 12 µg/mL, in accordance with ELISA assessment. Among the remaining 30 patients (70% males with mean age of 43±15), the correlation between the two tests was high (r of 0.858 (95% CI 0.720 – 0.930)).

Conclusion
The ProciseDx POCT has similar accuracy but was more rapid and easy to be performed in providing the results of TDM in outpatients taking ADL. This could lead to a more rapid and effective optimization of the biological drug, thus avoiding treatment failure.
P334 Tofacitinib for the treatment of Ulcerative Colitis: Analysis of malignancy rates from the Ulcerative Colitis clinical programme
Authors: Ungaro R C , Ciorba M A , Rogler G , Sharara A I , Sunna N , Connelly S B , Mundayat R , Lawendy N , Panés J 
Published: May 2021

Abstract

Background
Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). We present an updated analysis of adjudicated malignancies in the tofacitinib UC clinical programme, including final data from the open-label, long-term extension (OLE) study (as of 24 Aug 2020).

Methods
Malignancies were evaluated from 3 randomised, placebo-controlled studies (2 Phase [P]3 induction studies [NCT01465763; NCT01458951]; 1 P3 maintenance study [NCT01458574]) and an OLE study (NCT01470612). Three cohorts were analysed: Induction (P3 induction studies), Maintenance (P3 maintenance study) and Overall (patients receiving tofacitinib 5 or 10 mg twice daily [BID] in P3 or OLE studies; data from the previous data cut [May 2019] are also reported for comparison). Analysis was by predominant dose (PD) 5 or 10 mg BID, based on average daily dose &lt;15 mg or ≥15 mg, respectively (82.1% of patients received PD 10 mg BID). An independent adjudication committee reviewed potential malignancies. Proportions and incidence rates (IRs; unique patients with events per 100 patient-years of exposure) were evaluated for malignancies (excluding non-melanoma skin cancer [NMSC]) and NMSC.

Results
1124 patients were evaluated for malignancies (2809.4 patient-years of tofacitinib exposure; up to 7.8 years of treatment; median duration of 685.5 days). No malignancies (excluding NMSC) occurred in Induction Cohort patients. Malignancies (excluding NMSC) occurred in 1 Maintenance Cohort patient (who was receiving placebo) and in 25 Overall Cohort patients (IR 0.86 [95% confidence interval (CI) 0.56, 1.27]: PD tofacitinib 5 mg BID n=5, IR 0.63 [95% CI 0.20, 1.47]; PD tofacitinib 10 mg BID n=20, IR 0.95 [95% CI 0.58, 1.46]); 5 new cases since May 2019 (Table).1 NMSC events in the Induction and Maintenance Cohorts were previously reported (Table).1 NMSC events occurred in 21 Overall Cohort patients (IR 0.73 [95% CI 0.45, 1.12]): PD tofacitinib 5 mg BID n=5, IR 0.63 (95% CI 0.21, 1.48); PD tofacitinib 10 mg BID n=16, IR 0.77 (95% CI 0.44, 1.25); 2 new cases since May 2019 (Table).1

Conclusion
There was no apparent clustering of types of malignancy, excluding NMSC. Malignancies (excluding NMSC) and NMSC IRs remained stable over time, being comparable to those previously reported in the tofacitinib UC clinical programme.1 In this analysis, malignancies (excluding NMSC) and NMSC IRs were similar to those in patients with UC treated with tumour necrosis factor inhibitors, as reported from claims data (IRs of 0.63 and 1.69, respectively).2

References
P436 SPOSAB ABP 501 - A Sicilian Prospective Observational Study of Patients with Inflammatory Bowel Disease Treated with Adalimumab Biosimilar ABP 501
Authors: Macaluso F , Cappello M , Busacca A , Fries W , Viola A , Costantino G , Magnano A , Vinci E , Ferracane C , Privitera A C , Piccillo G , Belluardo N , Giangreco E , Romano C , Citrano M , Graziano F , Garufi S , Bertolami C , Scrivo B , Renna S , Casà A , Rizzuto G , Ventimiglia M , Orlando A 
Published: May 2021

Abstract

Background
Clinical data on the use of Adalimumab (ADA) biosimilar ABP 501 in inflammatory bowel disease (IBD) are lacking.

Methods
SPOSAB ABP 501 is a multicenter, observational, prospective study performed among the cohort of the Sicilian Network for Inflammatory Bowel Disease (SN-IBD). All consecutive patients with Crohn’s Disease (CD) or Ulcerative Colitis (UC) treated with ABP 501 from the introduction of the drug in Sicily (February 2019) to February 2020 (12 months) were enrolled. Patients were divided into 3 groups (group A: naive to ADA and naive to anti-TNFs; group B: naive to ADA and previously exposed to anti-TNFs; group C: switch from ADA originator to ABP 501). The primary end-point was the assessment of safety, in terms of rate of serious adverse events (SAEs). Secondary end-point was the evaluation of effectiveness, in terms of clinical response and steroid-free clinical remission at 12 weeks for group A and B, and as treatment persistency for all 3 groups.

Results
559 patients (median age 39 years; CD 88.0%, UC 12.0%) were included [group A: 189 (33.8%); group B: 30 (5.4%); group C: 340 (60.8]. Overall, the mean follow-up was 8.7 months (median 10.0 months, interquartile range: 6.0–12.0 months), and the total follow-up time was 403.4 patient-years. 36 SAEs occurred in 36 patients (6.4%), with an incidence rate of 8.9 per 100 person-years (PY), and 22 of them caused the withdrawal of the drug (incidence rate: 5.5 per 100 PY). The incidence rate of SAEs was higher among patients in group A compared with group C (17.4 vs. 4.8 per 100 PY; incidence rate ratio=3.61; p&lt;0.001) and among patients in group B compared with group C (16.4 vs. 4.8 per 100 PY; incidence rate ratio=3.42; p=0.041). The effectiveness of ABP 501 after 12 weeks of treatment was assessed in patients naïve to ADA (group A + B; n=219): 188 patients (85.8%) had a clinical response, including 165 (75.3%) who achieved a steroid-free remission. Among the patients who responded at 12 weeks, a subsequent loss of response was reported in 17 subjects (9.0%). At the end of follow-up, 56 patients (10.0%) interrupted the treatment, with higher treatment persistency estimations for patients in group C compared with group A and B (log-rank p&lt;0.001).

Conclusion
This is the first prospective study on the use of ADA biosimilar ABP 501 in IBD. Safety and effectiveness of ABP 501 seem to be overall similar to those reported for ADA originator. Switching from originator to ABP 501 was safe and effective.
P439 Effectiveness of Ustekinumab on Crohn’s disease associated spondyloartropathy: real-world data from the Sicilian Network for Inflammatory Bowel Diseases (SN-IBD)
Authors: Macaluso F , Fries W , Viola A , Costantino G , Muscianisi M , Cappello M , Guida L , Giuffrida E , Magnano A , Pluchino D , Ferracane C , Magrì G , Di Mitri R , Mocciaro F , Privitera A C , Camilleri S , Garufi S , Renna S , Casà A , Scrivo B , Ventimiglia M , Orlando A 
Published: May 2021

Abstract

Background
The efficacy of Ustekinumab (UST) on Crohn’s disease (CD) associated spondyloarthropathy (SpA) was evaluated neither in randomized controlled trials nor in real-world studies. Web-based data from the cohort of the Sicilian Network for Inflammatory Bowel Disease (SN-IBD) were extracted to perform a multicentre, real-world assessment of the effectiveness of UST on CD-associated SpA

Methods
All consecutive CD patients with active SpA at the initiation of the treatment with UST from January 2019 (the date on which the drug became available for clinical practice in Sicily) to August 2019 were extracted from the SN-IBD cohort. The study outcomes were evaluated at 8 and 24 weeks. The primary outcome was the articular response, defined as the disappearance of objective signs of arthritis (swelling and/or articular stiffness) and resolution of pain. As ancillary end-points, the clinical response (reduction of Harvey-Bradshaw Index ≥ 3 compared with baseline with a concomitant reduction of at least ≥ 50% of steroid dosage compared with baseline) and the steroid-free remission (Harvey-Bradshaw Index &lt; 5 without steroids use) were assessed.

Results
Out of 131 total patients treated with UST, 30 consecutive patients (22.9%) had active SpA at baseline (axial SpA: 3/30; peripheral SpA: 18/30; axial plus peripheral SpA: 9/30). After 8 weeks, 10 patients (33.3%) reported an articular response [0/3 patients with axial SpA, 7/18 patients (38.9%) with peripheral SpA, and 3/9 patients (33.3%) with axial and peripheral SpA]. After 24 weeks, 13 patients (43.3%) had an articular response [0/3 patients with axial SpA, 10/18 patients (55.5%) with peripheral SpA, and 3/9 patients (33.3%) with axial and peripheral SpA]. None of these 13 responders was taking systemic steroids at 24 weeks. The concomitant presence of a clinical response on intestinal symptoms was associated with the articular response at 24 weeks at univariable analysis (OR 5.14, CI 1.09-32.70, p=0.038).

Conclusion
UST obtained a response on articular symptoms in nearly half of the patients with CD and active SpA at baseline after 24 weeks. The rate of response was higher in case of peripheral arthropathy. The articular response was associated with the clinical response on intestinal symptoms.
P448 Safety of anti-TNF introduction following tuberculosis treatment in Inflammatory Bowel Disease patients in an endemic area
Authors: Azevedo M F C D , Justus F F , Lima C C G , Garcia K S , Barros L L , Oba J , Carlos A D S , Milani L R , Sipahi A M , Damião A O M C , Queiroz N S F 
Published: May 2021

Abstract

Background
Patients with inflammatory bowel diseases (IBD) have a greater risk of developing opportunistic infections, especially if they are under immunosuppressants and biological agents. Anti-tumor necrosis factor alpha (anti-TNF) has considerably increased the risk of tuberculosis (TB) in IBD patients. Brazil is considered an endemic area for TB and the safety of anti-TNF agents in IBD patients previous diagnosed with TB infection remains to be elucidated. The aim of this study was to evaluate the safety of anti-TNFs in patients with previous TB infection at a tertiary center in São Paulo, Brazil.

Methods
We retrospectively reviewed IBD patients with active TB followed in our center between January 2010 and December 2020. Data regarding disease phenotype, TB clinical presentation, IBD treatment at TB diagnosis and following TB treatment were collected from electronic medical records. TB diagnosis was based on symptoms, identification of the bacillus in body secretions, sample cultures, radiologic, endoscopic and histopathologic exams.

Results
Among 1040 IBD patients, we identified 37 patients with active TB (mean age at TB diagnosis 41.2 [25–69]; 59.4% male). Overall, 33 patients (89.2%) were under immunosuppressive medications. Of them, 27 (72.9%) were under anti-TNF drugs, 8 (29.6%) in monotherapy and 19 (70.3%) in combination with thiopurines or methotrexate. Pulmonary TB was the most common clinical presentation (40.5%) followed by disseminated TB (37.8%). Only 4 patients (10.8%) were not under immunosuppressant drugs and all of them were smokers. Sixteen (43.2%) patients received anti-TNF therapy after TB treatment, 4 of them had not been previously exposed to biologics. Median interval from TB diagnosis and anti-TNF initiation was 8 months (interquartile range [IQR] 4–24) and patients have been followed for a median of 34 months (IQR 7–108). Only one patient developed “de novo” tuberculosis, ten years after the first infection and after 48 months of treatment with infliximab and azathioprine.

Conclusion
Our findings suggest that treatment with anti-TNF following antituberculosis treatment is probably safe, even in endemic areas. TB occurred infrequently and after long-term follow-up, suggesting “de novo” infection rather than TB reactivation. This data emphasize the importance of periodic TB screening in IBD patients living in endemic areas.