Tumour brain: pre‐treatment cognitive and affective disorders caused by peripheral cancers

People that develop extracranial cancers often display co-morbid neurological disorders, such as anxiety, depression and cognitive impairment, even before commencement of chemotherapy. This suggests bidirectional crosstalk between non-CNS tumours and the brain, which can regulate peripheral tumour growth. However, the reciprocal neurological effects of tumour progression on brain homeostasis are not well understood. Here, we review brain regions involved in regulating peripheral tumour development and how they, in turn, are adversely affected by advancing tumour burden. Tumour-induced activation of the immune system, blood–brain barrier breakdown and chronic neuroinflammation can lead to circadian rhythm dysfunction, sleep disturbances, aberrant glucocorticoid production, decreased hippocampal neurogenesis and dysregulation of neural network activity, resulting in depression and memory impairments. Given that cancer-related cognitive impairment diminishes patient quality of life, reduces adherence to chemotherapy and worsens cancer prognosis, it is essential that more research is focused at understanding how peripheral tumours affect brain homeostasis

P711 Carriage of the HLA-DQA1*05 allele is associated with a high risk of loss of response to adalimumab in patients with Crohn’s disease

Abstract Background Loss of response (LOR) to tumour necrosis factor antagonists (anti-TNF) occurs in up to 50% of patients with inflammatory bowel disease (IBD). The ability to predict which patients are likely to lose response would allow therapies to be tailored to the patient’s characteristics. Immunogenicity is a common cause of LOR. Recently, a GWAS performed using the PANTS cohort demonstrated that carriage of one or more HLA-DQA1*05 alleles confers an increased risk of immunogenicity to anti-TNF therapy (Sazonovs et al. Gastroenterology 2019). We found that HLA-DQA1*05 carriage also identified patients at increased risk of clinical LOR to infliximab (Guardiola et al. ECCO 2019). The aim of our study was to know if carriage of a HLA-DQA1*05 allele is also associated with secondary LOR to adalimumab (ADA) in patients with Crohn’s disease (CD). Methods This is a retrospective cohort study from a prospectively maintained data base. Patients were included if they had achieved response to ADA. LOR was defined as recurrence or worsening of IBD-related symptoms that required a change or intensification in treatment, hospitalisation or surgery. Independent predictors of LOR were identified using univariate and multivariable Cox proportional hazard regression. Results We included 53 patients with Crohn’s disease, followed up to LOR (n = 31, 58%) or a median of 51 months (IQR 35–74). Forty-five per cent were carriers of an HLA-QA1*05 allele. HLA-DQA1*05 carriage was associated with LOR both, upon univariate analysis (HR 2.1 (95% CI 1.1–4.3), p = 0.04) and upon multivariate analysis, after adjusting for immunomodulators use, smoking status and BMI (HR 2.74 (95% CI 1.2–6.2), p = 0.02) (Figure 1). The cumulative persistence rates of ADA after adjusting for immunomodulators use was significantly lower in HLA-DQA1*05 carriers compared with non-carriers (HR 4 (95% CI 1.2–15.5), p = 0.02) (Figure 2). Conclusion HLA-DQA1*05 carriage is frequent and it is associated with a marked increase in the risk of LOR to ADA. HLA-DQA1*05 may become a clinically meaningful genetic marker that could allow for treatment to be tailored according to the risk of LOR, which is a step towards personalised medicine. </jats:sec

P642 Serum adalimumab levels measured between days 9 and 13 from drug injection can be interpreted clinically in a similar way to trough levels in patients with inflammatory bowel disease

Abstract Background AntiTNF therapeutic drug monitoring is currently performed at trough, immediately before drug administration. However, in clinical practice when subcutaneous medications are used, blood extractions often do not coincide with that moment. The aim of this study was to know if adalimumab levels measured between injections are sufficiently similar to trough levels to be used in clinical practice in a similar way. Methods 295 adalimumab level determinations performed at different time points of 99 injection cycles in 55 patients with inflammatory bowel disease (IBD) were included in the study. 51 patients received 40mg every 2 weeks and 4 patients received 80mg every 2 weeks. Results Median adalimumab levels (IQR) at trough, between days 1–4, 5–8 and 9–13 were 10.6 (6–12), 12.3 (7–18), 13 (7–19) and 10.8 (8–12), respectively. The median differences between trough level and days 1–4, 5–8 and 9–13 were 1.7 (IC 95% 1–2.3) (p &amp;lt; 0.001), 2.3 (IC 95% 1.5–3.1) (p &amp;lt; 0.001), 0.6 (IC 95% –0.2–1.3) (p = 0.13), respectively. Conclusion Adalimumab levels between days 9 and 13 from drug injection are very similar to trough level and could be interpreted clinically at the same way. Adalimumab levels between days 1 and 8 are significantly higher, although, differences are small. </jats:sec

P675 Real world evidence of tofacinitib in ulcerative colitis: short and long-term effectiveness, safety and impact of extraintestinal manifestations and immunomediated diseases

Abstract Background Main aim: To assess the durability of tofacitinib treatment in patients with ulcerative colitis (UC). Secondary aims: To assess the short and long-term effectiveness; the tolerability of tofacitinib in clinical practice; and to evaluate the evolution of extraintestinal manifestations (EIMs) and immunomediated inflammatory diseases (IMIDs). Methods Retrospective, multicenter study including UC patients who had received the first tofacitinib dose at least 8 weeks before the inclusion. Patients were followed-up from the first tofacitinib dose to treatment discontinuation or last visit, whichever came first. Only patients with active disease [Partial Mayo Score (PMS)&amp;gt;2] at tofacitinib start were considered in the effectiveness analysis. Clinical effectiveness was based on PMS. In patients who stopped tofacitinib before their last visit, the last observation carried forward method was used to impute missing values at subsequent time points. Results 408 patients were included (figure 1). Incidence rate of tofacitinib discontinuation was 41% per patient-year of follow-up. The probability of maintaining tofacitinib is shown in figure 2a. Main reasons for tofacitinib withdrawal were primary non-response (44%) and loss of response (26%). Age at the start of tofacitinib (older) (HR=0.98, 95%CI=0.97-0.99) and the severity of clinical activity were associated with tofacitinib withdrawal (mild vs. remission: HR=1.5, 95%CI=0.5-4; and moderate-severe vs. remission: HR=3.0, 95%CI=1.2-7.4). Short-term effectiveness is shown in figure 3a. To have moderate-severe vs. mild disease activity at baseline (OR=0.2, 95%CI=0.1-0.4) and age at tofacitinib start (older) (OR=1.01, 95%CI=1.002-1.03) were associated with clinical remission at week 8. The probability of maintaining response in shown in figure 2b. Tofacitinib dose was escalated in 55 patients (66%) of those who had lost response, and 82% of them improved (60% regained remission). The proportion of patients on 10 mg b.i.d was over 40% in all timepoints during follow-up. The proportion of patients in clinical remission during follow-up in shown in figure 3b. Adverse events during tofacitinib treatment are summarized in figure 4. There was not any signal of negative impact of tofacitinib on EIM o IMIDs. Conclusion Tofacitinib is effective in inducing remission even in highly refractory UC patients. A relevant proportion of patients discontinue the treatment, mostly due to primary failure. Dose escalation is effective to regain response after loss of efficacy. The safety profile is similar to that previously reported </jats:sec

P545 Safety of ustekinumab in pregnant patients with inflammatory bowel disease and in their offspring: results from the DUMBO registry of GETECCU

Abstract Background The safety of ustekinumab in pregnant patients with inflammatory bowel disease (IBD) and in their offspring has been barely studied. Aims Primary: To know the risk of serious adverse events (SAEs) in women exposed to ustekinumab during pregnancy and in their offspring. Secondary: To assess the risk of complications of the mothers and their offspring. To describe the patterns of use of ustekinumab during pregnancy in these patients Methods Patients with IBD exposed to ustekinumab during pregnancy from DUMBO registry of GETECCU were included. DUMBO is a prospective, observational and multicentre registry, which enrols pregnant women with IBD over 5 years in 70 centres in Spain. The registry was kicked off in September 2019. SAE definition was based on “Clinical Safety Data Management: Definitions and Standards for Expedited Reporting by European Medicines Agency”. Study protocol is summarized in figure 1. Results 49 pregnant patients have been exposed to ustekinumab during pregnancy so far (table 1). All pregnancies were singleton. Two patients were lost of follow-up (1st and 2nd trimester) but had uneventful pregnancies up-to last visit. There were 2 miscarriages (4%) at 1st trimester of gestation, 34 newborns and 11 pregnancies that were still on-going at the time of this analysis. All patients were on ustekinumab at conception (57% of them 90 mg/8 weeks). A total of 12 patients (24%) withdrawn ustekinumab during pregnancy: 1 (8%) due to disease flare, 1 (8%) underwent surgery due to intestinal obstruction, 2 (17%) due to patient’s choice (at 1st and 2nd trimester), and 8 (67%) due to clinicians’ decision (1 at 1st, 5 at 2nd and 2 at 3rd trimesters). No patient flared up after ustekinumab discontinuation. 10 (20%) patients had SAEs: 2 miscarriages, 1 intestinal infection, 1 subcorionic hematoma, 3 preterm birth, 1 intestinal obstruction and perforation (underwent surgery), 1 preeclapmsia, and 1 stoma obstruction. A total of 34 women gave birth after a median of 39 weeks gestation [interquartile range (IQR)=38–40], 3 (9%) preterm births, 55% by caesarean section (82% obstetric reasons and 18% perianal fistulae). Of the 34 newborns, 53% were female, median birth weight was 3,110 g (IQR=2,820–3,325), 3 (9%) low-birth weight, and 50% were breastfed exclusively. Median babies’ follow-up was 12 months (IQR=7–16). During follow-up, 3 children (9%) had severe infections (2 urinary infections, and 1 bronchiolitis by respiratory syncytial virus). In addition, 4 (13%) children were hospitalized: 1 cardiorespiratory arrest, 1 prematurity, 1 jaundice, and 1 vesicoureteral reflux Conclusion Ustekinumab seems to be safe during pregnancy in patients with IBD and their offspring. </jats:sec

DOP52 Safety of Inflammatory Bowel Disease drugs during pregnancy and breastfeeding: Mothers and babies’ outcomes (DUMBO registry)

Abstract Background Prospective registries are necessary to evaluate the safety of inflammatory bowel disease (IBD) treatment during pregnancy and in children in the long term. Aims The overall aim of DUMBO registry is to know the risk of serious adverse events (SAEs) during pregnancy and in children up to 4 years of age exposed during pregnancy to drugs for IBD (mainly focused on biologics), compared to unexposed children. In this analysis we aim to evaluate the risk of SAEs during pregnancy and the predictive factors of it (mainly focused on IBD drugs). Methods Prospective, observational and multicentre registry, which enrols pregnant women with IBD (Crohn’s disease, ulcerative colitis, IBD-unclassified) over 5 years in 70 centres in Spain. The registry was kicked off in September 2019. SAE was defined based on “Clinical Safety Data Management: Definitions and Standards for Expedited Reporting by European Medicines Agency”. Study protocol is summarized in figure 1. Results 433 women have been included so far; 241 got pregnant at least 9 months before this interim analysis (table 1). Mean age was 34 years, and 17% of women had active disease at any time during pregnancy. 23% of pregnancies were exposed to immumodulators (thiopurines), 25% to biologics and 10% to combo therapy (biologics and immunomodulators). 85 pregnancies (35%) were exposed to biologics (60 anti-TNF, 17 ustekinumab, and 8 vedolizumab) either in combo or in monotherapy. There were 237 newborns (227 singleton and 5 pair of twins), 9 miscarriages and 1 abortion. 72% of patients had vaginal delivery and 28% C-sections (18% due to perianal CD or active disease). A total of 59 pregnancies (24.5%) reported at least one SAE: 32% in exposed to biologics and 20.5% in non-exposed group (p&amp;gt;0.05) (figure 2). Four out of 17 pregnancies exposed to ustekinumab and 3 out of 8 exposed to vedolizumab had SAEs (non-related with the drug). In the multivariate analysis, adjusted by disease activity, in comparison with no immunosuppressive treatment, neither immunosuppressants [Odds ratio (OR)=1.1, 95% confidence interval (CI)=0.3–4.3] nor biologics in monotherapy or in combo (OR=0.8; 95%CI=0.2–3) were associated with higher risk of SAEs. 40 patients (17%) were hospitalised due to complications during pregnancy or delivery (figure 3). Two patients underwent surgery during pregnancy due to IBD complications Conclusion IBD treatment (either immunomodulators or biologics) does not increase the risk of SAEs during pregnancy. Nevertheless, one-quarter of IBD women suffer SAEs during pregnancy and about 20% need hospitalisation, which should be taken into account when managing IBD during pregnancy. </jats:sec