bluuebunny/crossref_metadata_2025_split huggingface dataset:
P447 No severe neonatal and maternal complications in inflammatory bowel diseases patients treated with ustekinumab or vedolizumab during pregnancy
Authors: Wils P , Seksik P , Stefanescu C , Nancey S , Allez M , Laharie D , Pineton De Chambrun G , Altwegg R , Gilletta C , Vuitton L , Viennot S , Serrero M , Fumery M , Savoye G , Collins M , Goutorbe F , Brixi H , Bouguen G , Tavernier N , Boualit M , Amiot A , Abitbol V , Pariente B 
Published: January 2020

Abstract

Background
Inflammatory bowel diseases (IBD) have a high incidence in the female population of childbearing age. Ustekinumab (UST) and vedolizumab (VDZ) are used in IBD after failure of immunosuppressants and//or anti-TNF therapy. Data on the use and safety of these novel biologics in pregnancy are rare.

Methods
We conducted a retrospective cohort study in the GETAID and identified female IBD patients who received at least one injection of UST or VDZ during pregnancy or within the 2 months before conception. The aims of the study were to assess the maternal and neonatal complications in these patients and to assess the management of VDZ or UST during pregnancy.

Results
Seventy-three pregnancies in 68 patients were reported in 21 centres. The median time between UST or VDZ introduction and pregnancy was 11.8 months (IQR: 5.2–17.6) and 10 months (IQR: 5.7–19.5), respectively. Twenty-nine pregnancies occurred in 27 patients on UST resulting in 26 (90%) live births, two (7%) spontaneous abortions, and one (3%) elective termination. Maternal complications were reported in two patients (gestational diabetes and threat of preterm birth). Five (19%) neonatal complications were reported (3 preterm deliveries, one low birth weight and one cardiac malformation). Six (21%) patients received UST in the 2 months before conception and stopped UST with a relapse in one patient (17%). UST was maintained during pregnancy in 22 (79%) patients: 13 patients discontinued UST in the first trimester with a relapse in 4 (31%) patients and 9 patients maintained UST during all pregnancy with a relapse in 3 (33%) patients. Forty-four pregnancies occurred under VDZ resulting in 38 (86%) live births, 5 (11%) spontaneous abortions and one (3%) medical interruption. Maternal complications were reported in 5 women (4 pre-eclampsia and one pregnancy cholestasis). Fourteen (37%) neonatal complications were reported: 7 (18%) premature births, 6 (16%) low birth weights and one (3%) congenital corpus callosum hypoplasia. Fifteen (34%) patients received VDZ in the 2 months before conception and discontinued VDZ with a relapse in 8 (53%) patients. VDZ was maintained during pregnancy in 29 (66%) patients: 16 patients discontinued VDZ in the 1st trimester with a relapse in 8 (50%) patients and 13 patients maintained VDZ during all the pregnancy with a relapse in one (8%) patient.

Conclusion
We reported 73 pregnancies under VDZ or UST. Except one cardiac malformation on UST and one congenital corpus callosum hypoplasia on VDZ, no serious neonatal or maternal complications were observed. However, additional prospective evaluations regarding pregnancy outcomes with new biologics are needed.
P452 Biologic use patterns and predictors for non-persistence and switching of biologics in patients with inflammatory bowel disease: a nationwide population-based study
Authors: Jung Y S , Han M , Park S , Cheon J H 
Published: January 2020

Abstract

Background
Data on real-life patterns of biologic use for inflammatory bowel disease (IBD) are scarce. We aimed to examine the patterns of biologic use and the factors associated with non-persistence and switching of biologics in Korean IBD patients.

Methods
Using National Health Insurance claims, we collected data on patients who were diagnosed with IBD and exposed to biologics between 2010 and 2016.

Results
Among 1838 patients with Crohn’s disease (CD), 1237 and 601 started with infliximab and adalimumab, respectively. Among 1125 patients with ulcerative colitis (UC), 774, 294, and 57 initiated infliximab, adalimumab, and golimumab, respectively. Rates of non-persistence and switching were higher in UC than in CD. One- and 3-year non-persistence rates were 14.2% and 26.5% in CD and 35.4% and 53.4% in UC, respectively. One- and 3-year switching rates were 3.7% and 10.1% in CD and 15.6% and 22.0% in UC, respectively. In both CD and UC, infliximab and adalimumab initiators showed similar persistence rates, whereas adalimumab initiators had a higher risk of switching than infliximab initiators. In UC, golimumab initiators had a higher risk of non-persistence and switching than infliximab initiators. Steroid use at biologic initiation was associated with an increased risk of non-persistence and switching in both CD and UC. UC patients who started biologic treatment at tertiary hospitals were more likely to continue treatment than those who started at general hospitals/community hospitals/clinics.

Conclusion
In real-world clinical practice settings, discontinuation of biologics occurred frequently in IBD patients, and switching of biologics was common in UC patients.
P453 Comparison of therapeutic effects between groups of thiopurine alone and combination of thiopurine with 5-ASA after remission introduced by oral tacrolimus for patients with severe ulcerative colitis
Authors: Sato T , Kojima K , Koshiba R , Fujimoto K , Kawai M , Kamikoduru K , Yokoyama Y , Miyazaki T , Watanabe K , Hida N , Nakamura S 
Published: January 2020

Abstract

Background
Although thiopurine is recommended to be used for maintenance after remission, the reliable data of maintenance introduced by tacrolimus is limited for patients with ulcerative colitis (UC). 5-aminosalicylic acid (5-ASA) is reported to induce 6-thioguanine nucleotides (6-TGN) levels higher in patients with inflammatory bowel diseases. However, the data of 5-ASA are few reported among East Asians.

Methods
A retrospective cohort study was conducted evaluating the 70 patients with severe UC who were primary responders to oral tacrolimus from April 2015 to March 2018. Twenty-seven patients were administered maintenance treatment with thiopurine. We evaluated the efficacy of thiopurines with and without 5-ASA in these patients, using ΔMCV, lowest WBC, highest 6TGN between groups of thiopurine alone and thiopurine+ 5-ASA. Kaplan–Meier analysis was used to assess time to relapse between groups of thiopurine and thiopurine+5-ASA.

Results
The median follow-up period was 430 days (interquartile range 207–952 days). The statistical significances were not found in patients background between groups of thiopurine and thiopurine+5-ASA. ΔMCV were significantly greater (p &lt; 0.01), lowest WBC were significantly lower (p = 0.02) in the thiopurines+5-ASA group than in thiopurines alone group. The highest 6-TGN levels tended to be higher in thiopurine+5-ASA group than in thiopurine alone group (p = 0.09). The rate of relapse was significantly higher in the thiopurine alone group than in thiopurines+5-ASA group (p = 0.03). Kaplan–Meier curves confirmed that thiopurine+5-ASA group appeared to protect against relapse (log-rank test, p &lt; 0.01).

Conclusion
Thiopurine+5-ASA induced significantly lower relapse than thiopurine alone after remission introduced by tacrolimus in the patients with severe UC, along with significantly greater the ΔMCV and lower the lowest WBC.
P457 IBD couples and their offspring: a European survey
Authors: Oliveira A , Costa-Santos M P , Frias Gomes C , Sabino J , Sampaio A , Avedano L , Leone S , Colombel J F , Torres J 
Published: January 2020

Abstract

Background
Small studies have shown that the frequency of inflammatory bowel disease (IBD) is significantly increased after marriage to an individual with the disease relative to what would be expected by chance alone. Furthermore, the offspring of these couples have a significantly increased risk of developing the disease. The aim of this study was to identify couples where both spouses have IBD and their offspring in a larger cohort and to characterise their phenotype.

Methods
This was a cross-sectional study including couples where both members were affected with IBD and their offspring. An electronic survey in seven languages was distributed by the European Crohn’s and Colitis Organization (ECCO), European Federation of Crohn’s and Ulcerative Colitis Associations (EFCCA) and national patient′s associations from June 2018 to December 2019.

Results
We identified 51 couples where both members had IBD. There was consanguinity in one couple. There was a representation of couples living in nine different countries. Thirty (59%) couples were concordant for IBD, 14 for Crohn’s disease (CD) and 16 for ulcerative colitis (UC). Within 49 couples, 21 (43%) were diagnosed prior to cohabitation, in 7 (14%) one spouse was diagnosed before and the other after a mean of 7.2 ± 8.9 years after cohabitation, and in 21 (43%) the onset of disease was after cohabitation for both (the first member developed IBD after a mean of 8.3 ± 8.4 years of cohabitation and the second one 4.1 ± 4.5 years after the first). The prevalence of IBD in the 58 children born from these couples was 9%. The cumulative probability of developing disease in the progeny was 3% at 10 years, 11% at 15 years and 15% at 20 years of age.

Conclusion
This survey identified 51 couples with IBD across Europe; 59% were concordant for IBD type and in 57% the diagnosis of at least one spouse was made after cohabitation. In a wider population, the risk for the progeny was at most 15% at the age of 20, lower than previously reported.
P460 Evaluation of potential mechanisms underlying the safety observations of filgotinib in clinical studies in rheumatoid arthritis
Authors: Clarke A , Di Paolo J , Downie B , Meng A , Mollova N , Yu Y , Han P 
Published: January 2020

Abstract

Background
Inhibitors of the Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway have demonstrated efficacy in the treatment of rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). Differences in selectivity of JAK inhibitors for JAK1, JAK2, JAK3 and TYK2 may influence their respective safety profiles, and the mechanisms responsible are not currently known. Filgotinib (FIL), a JAK1 inhibitor, did not negatively impact haemoglobin, LDL:HDL ratios or natural killer (NK) cell counts in clinical trials. Here, we compare the in vitro mechanistic profiles of four JAK inhibitors at clinically relevant doses.

Methods
JAK inhibitors (FIL, FIL metabolite [GS-829845], baricitinib [BARI], tofacitinib [TOFA], and upadacitinib [UPA]) were evaluated in vitro in human-cell-based assays. Growth of erythroid progenitors from human cord blood CD34+ cells was assessed using a HemaTox™ liquid expansion assay, NK cell proliferation was induced by IL-15 and LXR agonist-induced cholesteryl ester transfer protein (CETP) expression was assessed in the hepatic cell line, HepG2. Using assay-generated IC50 values and the reported human plasma concentrations from clinical studies, we calculated the target coverage for each JAK inhibitor at clinically relevant doses. The activity of FIL in humans was based on PK/PD modelling of FIL + GS-829845.

Results
Inhibition of cellular activity was calculated for each JAK inhibitor based on in vitro dose-response data, human exposure data and modelled PK/PD relationships. At clinically relevant doses, FIL resulted in lower calculated inhibition of NK cell proliferation compared with other JAK inhibitors. FIL 100 mg and 200 mg also reduced CETP expression, whereas other JAK inhibitors had no effect. There was no difference in the effect of FIL vs. other JAK inhibitors on erythroid progenitor cell differentiation or maturation.

Conclusion
FIL, a JAK1 inhibitor, resulted in less inhibition of NK cell proliferation compared with BARI, TOFA, and UPA. FIL also reduced LXR agonist-induced CETP expression, while the other inhibitors did not alter these levels. These results provide a potential mechanistic link between the observed reduction of CETP concentration following FIL treatment and the previously observed reduction in the LDL:HDL ratio in RA patients.
P466 Is it possible avoid colectomy with rescue dual therapy with vedolizumab plus tacrolimus in ulcerative colitis that losing response to anti-tumour necrosis factor?
Authors: Sanchis L , Molés J R , Borrás J , Rodriguez J , Cortés X 
Published: January 2020

Abstract

Background
There is an increasing number of ulcerative colitis (UC) patients that losing response to anti-tumour necrosis factor (TNF) drugs. There is low evidence about combining Tacrolimus (TAC) with vedolizumab (VED) for UC patients, who have failed treatment with anti-TNF therapy. The aim of the present study was to assess the efficacy and safety of TAC with VED in UC patient refractory to anti-TNF therapies.

Methods
Inclusion criteria: patients with moderately to severely active UC and who failed or showed intolerance to at least one TNF antagonists that received dual therapy with VED and oral TAC (Envarsus®). TAC blood levels were monitored at weeks 2,4,8 and then every 2 months. Rates of clinical response and remission were evaluated in November 2019 using the Mayo score. Clinical response was considered when PCR and calprotectin were decreased ³50% and biological remission was considered when PCR and calprotectin achieved normal values.

Results
Seven UC patients (1 proctitis, 3 left colon disease, 2 Pancolitis and 1 pouchitis) had sufficient dTNF for analysis. Demographic dTNF: age 51 ± years and 10.4 ± years since UC was diagnosed. All patients received thiopurine therapy and 86% received corticosteroids. 43% of patients were corticodependent and 43% were corticosteroid-refractory. 29% of patients failed to one TNF antagonists and 71% of patients failed to two TNF antagonists. Previous to started dual therapy; 29% of patients with moderate endoscopic activity and 71% of patients with severe endoscopic activity. Thiopurine treatment was suspended and 3 corticosteroid-refractory patients received IV cyclosporine therapy. The median dual therapy follow-up was 12.8 months (range 6–30 months). At the end of the study period; all patients presented clinical response, 86% of patients were corticosteroids free and biological remission was achieved in 71% of patients and any patient required colectomy. Fifty-seven per cent of patients needed VED dose intensification. Side effects were mild; abdominal pain (1), tremor (4), hypertension (1), moderate decrease creatinine clearance (1), insomnia (1) and arthralgías (1). Any patient discontinued dual therapy by adverse drug effect. At the end of the study, 4 patients continued with the dual therapy and 3 patients TAC was discontinued due to maintained clinical remission

Conclusion
In UC patients that losing response to anti-tumour necrosis factor (TNF) drugs and corticosteroid-refractory, the dual therapy with VED plus TAC could be an alternative, effective and safe therapy.
P475 Association between disease duration and degree of endoscopic improvement in patients with ulcerative colitis treated with tofacitinib
Authors: Sandborn W J , Gisbert J P , Modesto I , Su C , Quirk D , Mundayat R , Guo X , Chiorean M , Reinisch W 
Published: January 2020

Abstract

Background
Tofacitinib is an oral, small-molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Efficacy and safety of tofacitinib in patients with UC were evaluated in two Phase 3 induction studies (OCTAVE Induction 1 and 2; NCT01465763, NCT01458951), a 52-week, Phase 3 maintenance study (OCTAVE Sustain, NCT01458574), and an ongoing, open-label, long-term extension study (NCT01470612) [1,2]. Here, we evaluate the association between disease duration and the likelihood of achieving an endoscopic subscore of either 0 or 1 in OCTAVE Induction 1 and 2 and OCTAVE Sustain.

Methods
The degree of mucosal healing (Mayo endoscopic subscore of 0 or 1) achieved at Week 8 of OCTAVE Induction 1 and 2 (tofacitinib 10 mg twice daily [BID] or placebo) and at Week 52 of OCTAVE Sustain (responders from OCTAVE Induction 1 and 2; tofacitinib 5 or 10 mg BID or placebo) was evaluated in relation to UC disease duration at OCTAVE Induction 1 and 2 baseline (ie prior to study treatment). The association between disease duration category (&lt;3, 3–6 and &gt;6 years) and endoscopic subscore (centrally read) was assessed using the Cochran–Mantel–Haenszel chi-square test. Patients who did not achieve mucosal healing (as observed) were excluded.

Results
A total of 303/1139 (26.6%) patients achieved mucosal healing at Week 8 of OCTAVE Induction 1 and 2, and 190/593 (32.0%) at Week 52 of OCTAVE Sustain. Of patients who achieved mucosal healing at Week 8 of OCTAVE Induction 1 and 2 (with tofacitinib or placebo), 89 (29.4%), 76 (25.1%) and 138 (45.5%) had baseline disease durations of &lt;3 years, 3–6 years and &gt;6 years, respectively. Overall (among patients who achieved mucosal healing, treated with tofacitinib or placebo), no statistically significant association between disease duration and endoscopic subscore was observed, either at Week 8 of OCTAVE Induction 1 and 2 or at Week 52 of OCTAVE Sustain (chi-squared p = 0.13 and p = 0.23, respectively). In both OCTAVE Induction 1 and 2 and OCTAVE sustain, a numerically higher proportion of patients with shorter disease duration (&lt;3 years) had complete mucosal healing (endoscopic subscore of 0) with tofacitinib vs. patients with longer disease duration (tofacitinib 10 mg BID and/or tofacitinib all groups) (Table).

Conclusion
Among patients with endoscopic improvement after induction and maintenance therapy with tofacitinib, rates of complete mucosal healing were numerically higher among those with UC for &lt;3 years before starting treatment than among those with a longer disease duration. These analyses are post hoc and limited by the small sample size.

References
P478 Thiopurines’ metabolites levels and drug toxicity: a systematic review and meta-analysis
Authors: Sousa P C , Estevinho M , Dias C C , Martins D , Cancela E , Pires F , Carvalho C , Ministro P , Magro F 
Published: January 2020

Abstract

Background
Besides Inflammatory Bowel Disease, thiopurines are used in a broad range of clinical conditions. Even though therapeutic drug monitoring (TDM) is widely used with biologics, there are still many unanswered questions regarding TDM for thiopurines. This study aimed to establish a relationship between the levels of thiopurines’ metabolites and treatment toxicity.

Methods
Literature search was carried out in 3 databases (Pubmed, Web of Science and Scopus) following PRISMA guidelines. Studies evaluating the relationship between the levels of thiopurines’ metabolites and their toxicity (haematological and hepatoxicity, pancreatitis, intolerance and infection), regardless of the disease to which they were prescribed, were included.

Results
From the 16194 identified records 74 were eligible for further analysis. A meta-analysis of mean comparisons, correlations and odds ratio (OR) were performed. The levels of 6-thioguanine nucleotides (6-TGN) were significantly higher in patients with general toxicity and leukopenia when the Lennard method was used for quantification (Figure 1). Significant correlations were obtained between the 6-TGN levels and leucocytes (r = -0.21;p &lt; 0.001), neutrophils (r = -0.34;p &lt; 0.001) and alanine aminotransferase (ALT) levels (r = -0.24;p &lt; 0.001). The pooled OR (95%IC) for general toxicity, haematological toxicity and leukopenia in patients with 6-TGN concentrations above the predefined thresholds was 2.78(1.54–5.00), 8.54(3.55–20.56) and 5.26(3.34–8.15), respectively. Regarding 6-methylmercaptopurine metabolites (6-MMP), there was a significant correlation of their levels with general toxicity and leukopenia when the Lennard method was used for quantification (Figure 2), and with hepatotoxicity. 6-MMP levels were significantly correlated with ALT (r = 0.35;p &lt; 0.001). The pooled OR (95%IC) for haematological toxicity, leukopenia and hepatotoxicity in patients with 6-MMP above the predefined thresholds was 4.12(1.80–9.47), 4.09(1.98–8.45) and 4.31(3.21–5.78), respectively. The studies evaluating the relationship between the ratio 6-MMP/TGN and thiopurines’ toxicity did not find differences between the mean ratio in patients with haematological toxicity and leukopenia. The pooled OR for hepatotoxicity in patients with a ratio above the predefined threshold was 4.44(IC 95%2.92–6.75).

Conclusion
These results reinforce that TDM may be used to prevent the occurrence of toxicity during thiopurines’ treatment. However, the cut-off values for this association may depend on the method used to measure metabolites’ levels.
P493 Segmental colectomy vs. extended colectomy for colonic Crohn’s disease: results from 112 consecutive patients
Authors: Frontali A , Chierici A , Treton X , Maggiori L , Bouhnik Y , Panis Y 
Published: January 2020

Abstract

Background
According to recent literature, extended colectomy (EC) and segmental colectomy (SC) are equally effective for colonic Crohn’s disease (CCD), with no differences in terms of postoperative morbidity, incidence of long-term recurrence and definitive stoma, but earlier recurrence is observed in patients with SC. Our objective was to evaluate our comparative results between EC and SC.

Methods
All consecutive patients undergoing surgery for CCD (EC vs. SC) in our Centre were included and compared and we evaluated postoperative morbidity, long-term clinical and surgical recurrence.

Results
One hundred and twelve patients (mean age at diagnosis of CD, 31 ± 17 years, mean age at surgery 42 ± 17 years) with CCD underwent EC (n = 45) or SC (n = 67); 62 (55%) patients presenting concomitant small bowel disease, 10 (9%) an extra-intestinal manifestation and 16 (14%) were active smokers. Postoperative morbidity was 8/45 (18%) in case of EC vs. 9/67 (13%) in case of SC (NS). In EC group, 8/8 (100%) complicated patients vs. 16/37 (43%) uncomplicated patients were under anti-TNF before surgery (p = 0.04). This significant difference was not showed in SC group. After a median follow-up of 40 ± 34 months (range 1–130), clinical recurrence incidence was 15/45 (33%) in EC vs. 27/67 (40%) in SC patients (NS) and surgical recurrence was 8/45 (18%) in CE vs. 13/67 (19%) in CS patients (NS). Recurrence of the disease occurred after 19 ± 20 months (range, 1–74) in EC vs. 14 ± 26 months (range, 1–130) in CS patients (p = NS).

Conclusion
Our study confirms that in case of surgery for CCD, EC and SC are equally safe and feasible but recurrence happens earlier after SC than EC. Additionally, the role of anti-TNF is confirmed for postoperative complications.