Secondary loss of miR-3607 reduced cortical progenitor amplification during rodent evolution

Expression of miR-3607 in embryonic mammalian cerebral cortex was lost in rodents, limiting progenitor cell proliferation.

MRI-Based Radiomic Signature Identifying Secondary Loss of Response to Infliximab in Crohn's Disease

Up to 50% of patients with Crohn's disease (CD) experience secondary loss of response (SLR) to infliximab. Patients with SLR may show clinical signs of iron deficiency as a result of inflammation despite being iron-replete. The magnetic resonance imaging (MRI)-based radiomic index, R2*, can detect changes in iron metabolism. Therefore, the R2* parameter has considerable potential for detection of SLR to infliximab. The aims of this study were to explore the correlation between R2* and inflammation and to develop a non-invasive nomogram based on R2* to identify SLR to infliximab in patients with CD. Three hundred and twenty-two infliximab-treated patients with CD who underwent magnetic resonance enterography within 2 weeks before or after 54 weeks of infliximab therapy were divided into training and validation datasets at a ratio of 8:2. Point-biserial analysis was conducted to confirm the relationship between R2* and inflammation. A multivariate logistic regression model was created using R2*, CRP and hemoglobin (OR, 1.10, 1.04 and 0.98; P < 0.05). Receiver-operating characteristic curves and the Hosmer-Lemeshow test were used to assess the performance of the model. A correlation between R2* and inflammation was identified. Different trends in R2* and iron status indices were observed between patients with responsive and non-responsive CD, which is worthy of further study. The model was converted to a visualized nomogram that had a good ability to discriminate the outcomes of infliximab therapy with an area under the curve of 0.723 (95% CI, 0.661–0.785) in the training dataset and 0.715 (95% CI, 0.587–0.843) in the validation dataset. We confirmed a correlation between R2* and inflammation in patients with CD. Based on the MRI-based radiomic signature, a novel nomogram was established and validated to facilitate individualized identification of SLR to infliximab in patients with CD.

Swapping Versus Dose Optimization in Patients Losing Response to Adalimumab With Adequate Drug Levels

Background In cases of loss of response due to mechanistic failure under antitumor necrosis factor agents, it is recommended to switch to another class of biologics. Two different strategies were compared in patients with inflammatory bowel disease (IBD) who were treated with nonoptimized adalimumab (ADA) and experienced a loss of response despite therapeutic trough levels of adalimuma—either ADA dose optimization or switching to vedolizumab or ustekinumab. Methods Patients under maintenance therapy with ADA monotherapy (40 mg every 14 days) and who experienced a secondary loss of response with trough levels > 4.9 μg/mL were included prospectively in this nonrandomized study. The primary end point was the survival rate without therapeutic discontinuation after ADA dose optimization or switching to another class of biologics. Results Adalimumab was optimized (n = 61 patients, 42 Crohn’s disease, 19 ulcerative colitis) or swapped for vedolizumab (n = 40, 20 ulcerative colitis) or ustekinumab (n = 30, 30 Crohn’s disease). At 24 months, 11 out of 70 patients (14.8%) in the swap group discontinued treatment compared with 36 out of 61 (59.6%) patients in the optimization group (P < 0.001). The median time without therapeutic discontinuation was significantly longer in the swap group (>24 months) than in the optimization group (13.3 months, P < 0.001). In the optimization group, treatment discontinuation was positively associated with baseline fecal calprotectin >500 μg/g (HR, 3.53; 95% CI, 1.16–10.72; P = 0.026) and inversely associated with variation of trough levels of adalimumab (>2 µg/mL from baseline to week 8 after optimization; HR, 0.51; 95% CI, 0.13–0.82; P = 0.03). In the swap group, no factor was associated with treatment discontinuation. Conclusion In IBD patients under ADA maintenance therapy who experience a secondary loss of response and in whom trough levels are >4.9µg/mL, swapping to another class is better than optimizing ADA, which is, however, appropriate in a subgroup of patients.

P297 HLA-DQA1*05 allele and its association with the secondary loss of response to infliximab in patients with Inflammatory Bowel Disease

Background It is estimated that around 40-50% of patients with Inflamatory Bowel Disease (IBD) will experience a secondary loss of response (SLR) to infliximab, being the immunogenicity a fundamental mechanism. The HLA class II allele, DQA1*05, that codifies the adaptative immune response, is present in approximately 40% of patients treated with anti-TNF, and has been recently associated with a higher probability of immunogenicity, secondary loss of response and discontinuation of anti-TNF therapy. The aim of this study was to evaluate if the presence of one o more copies of this allele is associated with a higher chance of SLR in patients with IBD treated with infliximab in our project study area. Methods Retrospective observational cohort study. We conducted a review of our unit’s database, including in the study patients with IDB treated with infliximab that responded to the induction, in which the presence of HLA-DQA1*05 had been tested. SLR was defined as the recurrence or worsening of symptoms that entailed a treatment change or intensification, hospitalization or surgery. The predictive factors for SLR were identified through a uni and multivariate Cox regression analysis. Results 88 patients with IDB were included (63 with Crohn’s Disease and 25 with Ulcerative Colitis), followed up to the SLR (52,3%) or a median of 35 months (IQR=58). 42% of these patients were carriers of the HLA-DQA1*05 allele. Patients’ clinical features are gathered in table 1. In the univariate analysis the disease duration in years (HR=0,9, IC 95% 0,85-0,97, p=0,008) and the presence of HLA-DQA1*05 (HR=2,27, IC 95% 1,07-4.83, P=0,03) were associated with the SLR. In the multivariate analysis, adjusted for smoking, previous restrictive surgery, years of evolution of the disease and the presence of combined immunosuppressive therapy, only the presence of HLA-DQA1*05 remained associated to the SLR (HR=2,32, IC 95% 1,07-5,02, p=0,03). Figure 1. Conclusion The presence of the HLA-DQA1*05 allele is frequent in patients with IBD, and it is associated with a secondary loss of response to infliximab. If confirmed with prospectively designed studies, the determination of this allele could guide physicians on the therapeutic decision making, advancing towards a more accurate medicine.

P461 Vedolizumab Dose Escalation in a Real-World Cohort of IBD Patients

Background Vedolizumab (VDZ) effectively induces and maintains remission in inflammatory bowel disease (IBD). The loss of response to VDZ has been shown to be recaptured with dose escalation but the data in this field are still scarce. In addition, data on pharmacokinetics (PK) of dose escalation are limited and it is unclear whether PK should used in decision-making algorithm in adjusting VDZ dose regimen. Therefore, the aim of our study was to assess clinical efficacy and pharmacokinetic profile of VDZ dose escalation. Methods All IBD patients treated with VDZ in one tertiary IBD centre were retrospectively retrieved from the database. According to local protocol, non-responders to standard dosing of 300 mg i.v. of VDZ every 8 weeks, received escalated dose of 300mg i.v. every 6 or 4 weeks. Disease activity was assessed by Harvey-Bradshaw index (HBI) and partial Mayo score in Crohn’s disease (CD) and ulcerative colitis (UC) pts; respectively. VDZ dose was escalated in case of clinically assessed primary non response by week 22 of the treatment or in case of secondary loss of response. Response to dose escalation was defined as a decrease of HBI of ≥2 points, partial Mayo score ≥3 points or endoscopic improvement. VDZ through levels were assessed at the completion of induction and in dose escalated patients after at least two VDZ administrations in shortened interval. Results In total, 75 IBD patients were included (mean age 47 years, range 20–90; 36 men; 35 CD/39UC/1 IBD-U). Fifty two pts (69%) were primary responders, out of these 23 pts (44%) required dose escalation at some point of the treatment due to secondary loss of response. Out of 23 primary non-responders, 10 stopped the treatment, the remaining 13 received escalated dose of VDZ. Altogether, dose escalation was used in 36 pts (48%). There were no differences in the proportion of CD and UC between conventional and escalated dose regimen groups. Among secondary loss of response, the response was recaptured in 15 out of 23 pts (65%} while only two out of thirteen primary non-responders responded to dose escalation. There were no significant differences in VDZ levels between pts requiring dose escalation and pts with stable response to conventional regimen (mean levels 9,97±1,276 vs. 12,79±1,771 µg/mL; p=n.s.). VDZ levels increased significantly in patients who responded to dose escalation (from 10,12±3,460 to 20,81±3,326 µg/mL; p=0.0497). Conclusion Response to vedolizumab can be successfully recaptured in two thirds of secondary non responders by dose escalation. Patients requiring dose escalation do not seem to differ from stable responders with regards to vedolizumab pharmacokinetics.

P270 Mesenchymal stromal cells contribute to the recovery of secondary loss of response to infliximab in patients with ulcerative colitis

Background Long-term experience with infliximab (IFХ) shows that within a year, 20–30% of patients with ulcerative colitis (UC) develop acquired drug resistance (secondary inefficiency). Aim To establish the possibility of overcoming the secondary inefficiency of IFX in UC patients using mesenchymal stromal cells (MSC). Methods In the IBD treatment Department, the clinical status of 84 UC patients receiving IFX therapy was evaluated. Secondary loss of response was registered in 28 UC patients, which required optimization of IFX therapy. 12 patients (group 1), in order to overcome the secondary loss of response, were administered MSCS three times every 4 weeks, 16 patients with UC (group 2) received standard optimized IFX therapy. The effectiveness of therapy was evaluated after 12 weeks of therapy (reduction of the Mayo score) and normalization of laboratory parameters (ESR, C-reactive protein (CRP), hemoglobin, fecal calprotectin (FCP). The comparative analysis was carried out using the method of four-field tables using nonparametric statistical criteria. Results In 10 (83.3%) of 12 patients of group 1, a significant positive dynamics was observed after 12 weeks: a decrease in the Mayo index and normalization of laboratory parameters (ESR, CRP, hemoglobin, FCP). In 4 (25.0%) patients with UC from group 2, against the background of optimized IFX therapy, a significant positive dynamics was also observed with a decrease in the meio index and an improvement in ESR, CRP, hemoglobin and FCP levels. However, 12 patients from group 2 were transferred to therapy with other anti-TNF-α drugs and drugs with a different mechanism of action (RR-0.222, 95% CI 0.061–0.812; x2 - 7.146; p=0.00334). Conclusion The use of mesenchymal stromal cells of the bone marrow helps to overcome the secondary loss of response to infliximab in patients with ulcerative colitis.