bluuebunny/crossref_metadata_2025 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

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

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

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 < 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 < 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

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

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

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

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 (<3, 3–6 and >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 <3 years, 3–6 years and >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 (<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 <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

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 < 0.001), neutrophils (r = -0.34;p < 0.001) and alanine aminotransferase (ALT) levels (r = -0.24;p < 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 < 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

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.
P497 Is mucosal healing sufficient paramater for anti-TNF discontinuation?
Authors: Knezevic T , Milic M , Kalaba A , Sreckovic S , Stopic B , Svorcan P , Markovic S
Published: January 2020

Background

Long-term treatment with biologic therapy alongside with immunomodulators in patients with inflammatory bowel disease (IBD) can be associated with severe side effects. Nowadays, there is not a clear recommendation for de-escalation of therapy in patients on biologic treatment. The aim of the study was to evaluate relapse rate in 4 ili 2 years follow-up in patients with mucosal healing after two years of anti-TNF treatment, regardless achieved histological remission.

Methods

52 patients with IBD after two years treatment with anti-TNF agents (Infliksimab (IFX) and Adalimumab (ADA)) and achieved mucosal healing, were enrolled in this retrospective study. Mayo endoscopic sub-score (0,1) and SES (<2) was used to define mucosal healing in UC and CD patients, respectively. For the assessment of histological activity Nancy and Global Histologic Disease Activity Score (GHAS) were used. Histologic remission was defined by Nancy’s score ≤ 1 and GHAS ≤ 4. Data were collected for 4 years follow-up period after discontinuation of anti-TNF agents. Statistical analysis was carried out using SPSS 20.0 (Chicago, IL).

Results

From 52 patients 40.38% (21/52) patients had UC, and 59.61 % (31/52) had CD with an average disease duration of 11.57 (SD ± 6.28) years. Gender distribution was relatively equal, 46% men (24/52), with an average age of 40.66 (SD ± 11.15) years. All of the patients were on anti-TNF therapy and had mucosal healing at the moment of discontinuation, 55% (29/52) were on IFX, 35% (23/52) were on ADA, respectively. 48.07% (25/52), were with pathohistological remission of disease. In 4 years follow-up after anti-TNF therapy discontinuation, 59.61% (31/52) relapsed, with an estimated period of relapse time of 15.4 (SD ± 9.83) months. Using Spearman`s correlation moderate relation was revealed between histological activity and relapse (rho 0.467, p < 0.001). Probability of relapse within 4 years in this group of patients with histologically active disease was higher (p < 0.01, OR 2.72, 95% Cl 1.24–5.92).

Conclusion

Achieving both, endoscopic and histological remission, may be a good parameter in making a decision when to de-escalate anti-TNF therapy.
P501 Thiopurine withdrawal in patients with Crohn’s disease: the SURESTE study
Authors: Sánchez Rodríguez E , Sánchez Aldehuelo R , Guardiola J , Gutiérrez Casbas A , Domènech E , Bermejo F , Van-Domselaar M , Mesonero Gismero F , Suris G , Muñoz Perez R , Mañosa M , Jiménez Márquez L , Algaba García A , López sanroman A
Published: January 2020

Background

Thiopurine (TP) withdrawal in patients with Crohn’s disease (CD) in clinical remission (CR) is controversial. Our aim was to describe the evolution of CD patients in CR who discontinued TP prescribed to maintain a remission previously achieved with medical treatment, and to detect predictors of reactivation after withdrawal.

Methods

Multicentric observational retrospective study including CD patients in RC under TP treatment, who electively discontinued TP. Relapse was defined as the need to start any specific treatment for CD, including surgery. Informed consent was obtained from the inclusion in the Eneida database.

Results

We included 78 patients (52.6% females, age 45(19–77) years) of whom 57 presented an inflammatory, 12 a stricturing and 9 a penetrating behaviour; 31 patients had terminal ileum involvement, 9 colonic, 36 ilecolonic, and 2 ileocolonic plus upper gastrointestinal involvement, whilst 17 also had perianal disease. Mean disease duration was 13.47 (3.02–35.02) years. 48.7% had never smoked whilst 24.4% were active smokers. TP was started to maintain remission previously achieved with medical therapies in 78 patients (100%). Median azathioprine dose was 2.11 (1.3–2.6) mg/kg/d, and of 6-mercaptopurine (6MP) 1.44 (1–2) mg/kg/day. The median duration of TP treatment was 52.79 (3–268) months and of steroid-free remission 49.41 (1–177) months. Reasons for TP withdrawal were: patient choice/request in 20 (25.6%), physician proposal in 28 (25.7%), drug-related adverse events in 19 (24.4%) and miscellaneous in 11 (14.1%). By the time of TP discontinuation, median CRP was 5.08 mg/l (0.1–157.9), fecal calprotectin(FC) 282.38 µg/g (2.4-4430) and a mean 0.45 (0–4) in Harvey–Bradshaw Index (HBI); those who relapsed presented median CRP of 15.31 mg/l (0.1–125.31), fecal calprotectin (FC) 462.22 µg/g (90–1240) and a mean 5.46 (0–15) in HBI. These differences were statistically significant. During a 5.08 (0.12–13.05) years follow-up, 38 (48.1%) patients relapsed, with treatment duration being the only factor associated to risk of relapse (Or = 0.659 IC95 0.43–0.98, p = 0.04) in the multivariant analysis (IMAGE1).

Conclusion

Thiopurine withdrawal in the context of sustained remission in CD is associated with relapse in almost half of the patients after a median follow-up of 5 years. Thiopurine treatment duration of shorter than 5 years was shown to carry greater risk for relapse.
P507 Ustekinumab: Medium-term outcomes from a UK multicentre real-world cohort
Authors: Gadhok R , Fragkos K , Honap S , Hassan J , Whiteley L , Ibarra A , Burgess N , Vega R , Seward E , Mehta S , McCartney S , Bloom S , Parkes G , Irving P , Lindsay J O , Kok K B , Rahman F
Published: January 2020

Background

Ustekinumab is effective at inducing and maintaining remission of Crohn’s disease (CD) in clinical trials. However real-world practice may vary regarding use of concomitant immunomodulator (IM), dosing schedule and patient selection. We present the largest UK real-world, multi-centre study of effectiveness.

Methods

The cohort comprised adult patients initiated on ustekinumab for CD from October 2016–18 at 3 tertiary London centres. Clinical endpoints were (i) remission (Harvey Bradshaw Index (HBI) ≤4) (ii) response, (reduction in HBI of ≥3 or sustained HBI≤4 points) at 3, 6 and 12 months. Biological endpoints were remission and response (CRP <5mg/l in patients with a baseline CRP>5mg/l, and 50% reduction in CRP, respectively).

Results

211 patients were included (Table 1), of whom 207 (98%) were biologic exposed and 59 (28%) had failed 3 biologics. All patients received i.v. induction and 203 (96%) received a s.c. dose at week 8. At 6 and 12 months, 133 (74.8%) and 109 (73.6%) patients, respectively, were on 8 weekly dosing. Dosing schedule did not impact clinical and biological outcome at 6 and 12 months.

Discontinuation occurred in 4 (1.9%), 20 (9.5%) and 50 (23.7%) patients by 3, 6 and 12 months respectively. Reasons for stopping included: drug reactions (4(1.9%)), partial response (4 (1.9%)), loss of response (10 (4.7%)) and primary non-response. (24 (11.4%)). Clinical and biological outcomes at 3, 6 and 12 months are shown in Figure 1. Adverse events occurred in 27 (12.8%) patients. IM were prescribed in 49 (23%) at baseline and continued in 46 (21.8%), 36 (17.1%), 27 (12.8%) at 3, 6 and12 months respectively. There was no significant difference in median persistence (months) on ustekinumab between patients who were on an IM at baseline vs. those not (15.2 (95% CI 0–32.2) vs. 23.3 (17.3–29.4) months, p = 0.4). Likewise, there was no significant difference in clinical or biological outcome between patients with colonic vs. ileocolonic or ileal disease. Finally, there was no significant difference in median persistence on ustekinumab between patients with and without a history of perianal disease (19.5 (95% CI 9.2–29.8) vs. 22.9 (18.6–27.2) months, p = 0.8).

Conclusion

Ustekinumab is effective in a real-world cohort. In keeping with trial data, we did not find evidence of improved outcomes with the use of a concomitant IM, nor differential outcomes when considering perianal and isolated colonic disease.
P518 Ulcerative colitis drug development success rates are higher than the industry average
Authors: Georgiev G , Hussain F , Copeman M , Delegge M , Gallagher M B , Stewart T , Reinisch W
Published: January 2020

Background

Given the increasing costs of drug development, coupled with low success rates, there is a need to both develop better predictive models and elucidate causes of failure. However, for indications such as ulcerative colitis, a baseline does not presently exist. In this paper, we review trends in drug development and establish a baseline for ulcerative colitis.

Methods

We used BiomedTracker to obtain information about the number of compounds, which were in development for ulcerative colitis between 2005 and 2018. We counted the number of compounds, which had reached a particular phase, had been discontinued during this phase, had successfully passed it or had been still in this phase. Success rates were derived for the different phases of drug development for all 73 candidate drugs and divided by type of molecule and type of company. A success rate was calculated by dividing the number of drugs successfully completing a particular phase by the sum of the number of drugs which were discontinued during this phase and the number of compounds that completed positively a phase. The likelihood for approval (LOA) for each phase was calculated by multiplying the success rate for the respective phase with the success rates of next stages of development.

Results

The success rate in phase I was 96 %, in phase II 53 % and in phase III 76%, while the respective LOA was 0.39, 0.4 and 0.76. Table 1 demonstrates the success rates and LOA by type of compound(New molecular entity (NME), Biologic, non-NME) and type of company (big, mid-size, emerging).

Conclusion

The general industry success rates and LOA for phase I is 64%, for Phase 2 30%, and for phase 3 60% while the LOA from phase I is 10%. These data are published by Michael Hay and co-authors in Nature in January 2014. The success rates in UC drug development are therefore higher than the overall industry success rates.
P523 Improvement of quality of life and continence in patients with distal ulcerative colitis treated by mesalazine: QUARTZ study
Authors: Paupard T , Gonzalez F , Siproudhis L , Peyrin-Biroulet L
Published: January 2020

Background

There is no robust data which analysed quality of life, functional disability and continence of patients with distal UC. QUARTZ is the first prospective study in this situation.

Methods

Observational, prospective and multicentric study involving public and private French gastroenterologist to recruit patients with mild to moderate (Mayo score ≥ 3 and ≤ 10) active proctitis or proctosigmoiditis (<20 cm) and under mesalazine for induction treatment. The patients followed for 12 months (±2 months). The primary objective was the quality of life evaluated by Short Inflammatory Bowel Disease (SIBDQ) at 8 weeks (±4 months). The functional disability and incontinence have been evaluated by IBD-Disability Index and Cleveland questionnaires.

Results

From December 2015 to November 2016, 117 patients were recruited. Data of 93 patients have been analysed and results are reported on Table 1. Among the 93 patients, 75 (81%) reached a clinical remission at week 8 with a SIBDQ score improvement of 6.7 ± 7.1 point (p < 0,001). Treatment adherence during the induction period was non-compliance for 76 patients (81%): 17 (18%) patients stopped treatment before W8 (all those patients received rectal formulation). After induction treatment, 72 (77%) patients received maintenance treatment. 11 (12%) patients reported adverse event not linked to the treatment.

Conclusion

For patients with distal ulcerative colitis treated by mesalazine, quality of life, functional disability and continence have been improved at 8 weeks of treatment despite a poor adherence.
P531 A retrospective audit of the inflammatory bowel disease specialist nurse-led telephone advice service
Authors: Watters C , Lloyd W , Porteous M , Mohamed M , Kari S , Nelson E , Saravanan R
Published: January 2020

Background

Inflammatory bowel disease affects more than 300 000 people in the UK. The aims of the audit were to review the current use of a telephone service provided by the IBD specialist nursing team in a DGH with a view to better funding and further development of the facility.

Methods

The letters generated from each phone call between January and February 2018 were collected and a sample assessed for outcomes directly related to the consultation. Outcomes were subtyped into a change in medical treatment, referral for investigation, referral to another specialist or arrangement of an urgent clinic appointment or hospital admission. Each phone consultation was also assessed as to whether it had avoided an attendance to the GP or hospital via A&E or acute medicine.

Results

The two-month period yielded 491 phone calls, of which 100 letters were reviewed of which 56 (56%) had ulcerative colitis (UC), 44 (44%) had Crohn’s disease (CD). Male users comprised 36% (vs. 64% females) and the age of callers ranged from 19 to 84 years (median age 44 years). Of the UC patients, 45 patients (80.4%) had been diagnosed over 2 years previously with two (3.6%) having been diagnosed within the preceding 3 months (CD patients 34 (77.3%) >2 years previously and three (6.8%) within the last 3 months). The phone consultations led to a change in medication in 49 cases (49%). Phlebotomy and/or faecal calprotectin testing was requested for 59 patients (59%) following the phone call and a further 17 (17%) were discussed with a consultant, although only 8 (8%) required an IBD nurse-led or gastroenterology consultant-led clinic (six and two patients, respectively). Nine patients (9%) went on to have cross-sectional imaging or ultrasound with contrast and 7 (7%) were referred for endoscopic assessment. The overall complexity of the consultation was assessed by the number of services referred to/requested. Thirty-four patients (34%) merely required reassurance or verbal advice whereas two cases (2%) led to five distinct referrals or investigation requests (one service 33 (33%), two service 20 (20%), three service 9 (9%), four service 3 (3%)). Each phone call was assessed as to whether it had likely avoided attendance elsewhere. This included general practice (25 cases (25%)), accident and emergency (2 (2%)), IBD nurse clinic appointment (41 (41%)) or consultant clinic appointment (6 (6%)).

Conclusion

(1) Our audit shows that the IBD nurse-led telephone service is extremely demanding, with a large volume of calls. (2) Remote management of patients could be facilitated by the telephone nurse-led hotline advice service leading to a reduction in healthcare costs, avoiding face-to-face consultations and managing patients as per their personalised needs.
P542 The effect of age on infliximab pharmacokinetics in patients with inflammatory bowel disease
Authors: Kantasiripitak W , Verstockt B , Lobatón T , Thomas D , Gils A , Vermeire S , Ferrante M , Dreesen E
Published: January 2020

Background

Data remain scarce in terms of efficacy and safety of infliximab (IFX) treatment in elderly patients with inflammatory bowel disease.1 Our aim was to employ a population pharmacokinetic (popPK) model to improve our understanding of factors impacting variability in IFX exposure in elderly patients with ulcerative colitis (UC) and Crohn’s disease (CD).

Methods

IFX concentration–time data during induction therapy (week 2, 6 and 14) of 104 patients were obtained from a retrospective case–control study2 (n = 79) and a single centre database search (n = 25) at our institution. Patients ≥65 years old were categorised as elderly. A popPK model was developed using NONMEM 7.4. Relationships between IFX exposure and the first endoscopic remission (ER) assessment after the start of IFX therapy (absence of ulceration [CD] and Mayo endoscopic sub-score ≤0 [UC]) were evaluated.

Results

Median age was 62 years (IQR 38–68). A total of 46 of 104 patients (44%) were elderly. A one-compartment model with linear clearance showed adequate descriptive and predictive ability. The estimated popPK parameters (typical value [%RSE]) were clearance CL (0.346 l/day [4%]) and volume of distribution V (6.42 l [5%]). The elimination half-life of IFX in the elderly was not significantly different from the non-elderly (12.6 days vs. 11.4 days, p = 0.356). IFX clearance was higher with the presence of antibodies to IFX (ATI; drug-tolerant assay; 32% higher), higher fat-free mass (FFM; 1.4% per kg), lower serum albumin (4.5% per g/l), and younger age (0.6% per year). These covariates explained 10% of interindividual variability (IIV) in IFX CL. However, 33% of the variability remained unexplained. Contrary to Paul et al.3, proportions of patients with ATI were not significantly different between elderly and non-elderly (13% [6/46] vs. 14% [8/58], p = 1.000). FFM and serum albumin were significantly lower in elderly patients (p = 0.007 and p = 0.0004, respectively). Due to the large remaining IIV, IFX exposures (trough concentrations and estimated area under the PK curve) were not significantly different between elderly and non-elderly (Figure 1). A total of 19/72 patients (26%, 32/104 had no endoscopy data) achieved ER. There was no significant difference between the proportion of elderly and non-elderly with ER (p = 1.000). IFX trough concentrations at w6 were significantly higher in patients achieving ER (p = 0.016).

Conclusion

Older age is an independent predictor of lower clearance. However, the effect of age did not pronounce on infliximab exposure in our elderly patient cohort as a result of confounding effects of fat-free mass and serum albumin.

References
P552 Withdrawal of immunomodulator medications (IM) in children with inflammatory bowel disease on combination therapy of IM and biologics
Authors: Chandrakumar A , Carroll M , deBruyn J , Jacobson K , Huynh H , Wine E , Lawrence S , El-Matary W
Published: January 2020

Background

Anti-tumor necrosis factor (anti-TNF) antagonists such as infliximab (IFX) are widely used for the treatment of inflammatory bowel disease (IBD). Early studies suggested that combination therapy with IFX and an immunomodulator drug (IM) such as azathioprine (AZA) or methotrexate (MTX) may help in optimising biologic pharmacokinetics, minimising immunogenicity, and improving outcomes. On the other hand, IM especially AZA, may increase infection and cancer risks with no clear evidence on long-term benefits of combination therapy. As such, stopping IM and continuation of an anti-TNF agent as a monotherapy in patients in remission seem to be a sensible strategy. However, there is no evidence to prove the efficacy of this strategy. The aim of this work was to examine frequency and factors associated with the first relapse after IM withdrawal in a cohort of children with IBD on combination therapy.

Methods

In a retrospective multicenter pediatric study, we determined the percentage of patients and investigated potential factors associated with the first relapse in a cohort of children and young adults with IBD on combination therapy of anti-TNF and IM after stopping IM. Cox regression analysis was used to assess factors associated with IBD relapse following IM withdrawal.

Results

A total of 79 patients (42, males, 62 Crohn’s disease) with 74 (93.7%) on IFX were included. In addition to the anti-TNF agent, 33 (41.8%) were on AZA and the rest were on MTX. The median duration of combination therapy was 2.0 (IQR 1.2–2.8) years. All participants were in clinical remission at the time of IM withdrawal. The median duration of follow-up after IM withdrawal was 11.0 (IQR 5.0–16.2) months. Only 8 (10.1%) patients relapsed over that period of follow-up. Age, sex, disease phenotype at diagnosis, family history of IBD, type of IM, and biochemical markers and clinical disease activity indices prior to IM stoppage did not predict a future relapse. Among those with CD on IFX who maintained remission, the median last IFX trough level before IM withdrawal was 6.25 Ug/ml (IQR: 4.04–8.70) vs. 3.8 Ug/ml (IQR: 2.40–11.6) in those who relapsed (p = 0.4).

Conclusion

Over short-term follow-up, the majority of children on combination therapy of IM and an anti-TNF agent remain in clinical remission after IM withdrawal.
P556 Long-term probability of retreatment with anti-TNF therapy after discontinuation based on mucosal healing in inflammatory bowel disease
Authors: Luque Carmona A M , García Ortíz J M , Nuñez Ortiz A , De la Cruz Ramírez M D , Herrera Justiniano J M , Leo Carnerero E
Published: January 2020

Background

To evaluate the need for retreatment with anti-TNF due to relapse after discontinuation based on mucosal healing in inflammatory bowel disease (IBD), as well as the influencing factors and the response to reintroduction.

Methods

Descriptive retrospective study of IBD patients in whom anti-TNF treatment was discontinued after mucosal healing had been proved, between June 2009 and May 2016. Demographic and phenotypic characteristics, biologic and immunomodulator (IM) therapy history, laboratory markers and histopathologic evaluation were noted. We evaluated the relapse rate after discontinuation of anti-TNF, as well as the need for reintroduction and its success rate.

Results

We included 100 patients, 69 of them affected by Crohn’s disease (CD), 29 with ulcerative colitis (UC) and 2 unclassified colitis. From those with CD, inflammatory behaviour (62%) and ileocolonic localisation (53%) were the most frequent conditions. Seventy-four per cent of UC patients had pancolonic involvement. Biological therapy had been indicated because of corticodependence in 66% (vs. 32% corticorefractoriness). The anti-TNF drug was infiliximab in 60 patients, adalimumab in 38, 1 certolizumab and one had been treated with golimumab. Endoscopic biopsies showed quiescent disease in 63 of 83 patients. Eighty-three per cent of patients were treated with IM after removal of anti-TNF. After a mean follow-up of 57 months, 63 patients relapsed, 52 of them needing anti-TNF reintroduction. Reintroduction rates at 12, 36 and 60 months were 19.5%, 43.5% and 52% respectively with a response after the re-treatment of 76,6%. Univariant analysis showed a higher risk in CD (61 vs. 31%, p = 0.008). Within the CD patients, the risk of reintroduction was lower in A3 (30 vs. 66%, p = 0.03) and B2 (31 vs. 69%, p = 0.006) patterns, and higher if the indication had been corticodependence (68% vs. 37%, p = 0.02). Multivariant analysis confirms the protective effect of B2 behaviour and worse outcomes for corticodependence antecedent. Considering UC, the retreatment probability was superior for those patients without IM therapy after anti-TNF discontinuation (57 vs. 22%), although this association did not reach statistical significance (p = 0.08).

Conclusion

The risk of needing reintroduction of anti-TNF therapy after mucosal healing in IBD is around 50% in 5 years, being superior in CD patients. Reintroduction success rate is 76%. In CD, this risk is higher when the reason for starting anti-TNF was corticodependence, and much lower when stricturing/fibrotic pattern predominates. For UC patients, anti-TNF drugs should not be stopped if IM therapy cannot be held.