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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 24 months) than in the optimization group (13.3 months, P 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.

Background Two scores have shown their interest in evaluating the luminal activity of CD in magnetic resonance (MR), the MARIA and Clermont scores, but their calculation can be complicated in clinical practice. Recently, the Spanish authors validated a new simplified MARIA score (MARIAs) and retrospectively showed a very good correlation with the initial MARIA score (1). The purpose of this study was to validate this correlation in an independent cohort and to compare its feasibility with other scores. Methods This was a retrospective analysis of all MR performed in our department to evaluate the luminal activity of CD. Two independent radiologists each calculated the MARIA, Clermont and MARIAs scores (wall thickness > 3mm, oedema, comb sign, ulcerations), each blind to the other and blind to clinical activity. In case of disagreement between the two radiologists, a third reader analyzed MR activity. Correlations were calculated between these three tests for the entire cohort. In addition, concordance tests were performed for predetermined thresholds of 7 to 11 for the MARIA score, 8.5 to 12.5 for the Clermont score and 1 to 2 for the MARIAs score. The duration of the analysis was reported for each reading. Isolated colonic CD were excluded from the study. Results One hundred and twenty-one CD were included (65 in clinical and biological activity, 33% ileal phenotype, mean age: 38.5 years, sex ratio M/F = 54.5%). The agreement between the MARIA score between 7 and 11, the Clermont score between 8.5 and 12.5 and the MARIAs score between 1 and 2 was 0.92 (Fleiss kappa test). The correlation between the MARIA score and its simplified score was very strong (r = 0.93; 95% CI: 0.9–0.95) as well as between the Clermont score and the MARIAs score (r = 0.92 95% CI: 0.89–0.95). Inter-observer agreement was significantly higher in the calculation of the MARIAs score (96%) compared with 80% for the MARIA and Clermont scores (p = 0.04). Reading time was significantly faster for the MARIAs score (3.45 ± 0.4 min) compared with the MARIA (10.05 ± 1.2 min) and Clermont (13.5 ± −3.5 min) scores (p < 0.01). Positive predictive values for deep remission (clinical remission and calprotectin < 250 µg/g stool) were 95% at thresholds Conclusion In this independent cohort, we confirm the very strong correlation between the simplified MARIA score and the two reference scores (MARIA and Clermont) in the analysis of MC luminal activity as well as its rapid calculation and strong inter-observer agreement.

Background Nearly 40% of patients who failed on ADA have therapeutic residual trough levels (pharmacodynamic failure). It is then recommended to change the therapeutic class to a non-anti-TNF biological. In this situation, however, a quarter of patients respond to an ADA dose optimisation. The purpose of this work was to compare these two strategies and identify predictors of response for each strategy. Methods This is a bi-centre, retrospective study based on a clinical and biological database that included patients followed from 2015 to 2016 with an IBD in maintenance treatment with ADA as monotherapy (40 mg/sc/14 days) and in loss of response (CDAI > 220 with faecal calprotectin > 250 µg/g stool for CD and Mayo score > 6 with endoscopic sub-score > 1 for UC). All patients included had residual trough ADA levels > 5 µg/ml. Relapsed patients were treated either with dose optimisation (ADA: 40 mg/sc/7 days) or other biotherapy (ustekinumab or vedolizumab, according to classic regimens and dosages). The primary endpoint was the relapse-free survival rate (defined as clinical and biological or endoscopic activity requiring therapeutic change). The survival curve analysis was performed using the Kaplan–Meier method and the log-rank test. Results In total, 125 patients (mean age: 38 years, 75% CD, sex ratio M/F = 57%, previous infliximab = 42%) were included and 50 were treated with another biological (Vedolizumab: 30 patients, Ustekinumab: 20 patients). The characteristics of the two groups were comparable except for significantly higher levels of CRP and faecal calprotectin at inclusion in the biological change arm. The duration without relapse was significantly longer after the class change (p = 0.0005; HR = 0.39[0.23–0.68]). The relapse-free survival rates at 54 weeks were 35% for the optimised arm and 66% for a class change (p = 0.04). In multivariate analysis, the only long-term response predictor was biotherapy class change vs. ADA dose optimisation (p = 0.042; HR = 0.3[0.02–0.95]). Previous use of IFX or type of IBD were not associated with relapse. For the dose optimisation strategy, in multivariate analysis, only age < 40 years was associated with a progression without relapse (p = 0.007; HR = 0.09[0.01–0.52]). Residual ADA levels were not predictive of response to optimisation (p = 0.73) and no ADA quartile was significantly associated with a more favourable clinical response. For the class change strategy, no relapse predictors were isolated in univariate analysis. Conclusion In patients on ADA who are losing response despite therapeutic rates, the change of class to non-anti-TNF biotherapy allows a significantly greater lasting response than a dose optimisation strategy for ADA.

Background Several studies have shown a link between circulating anti-TNF levels during induction and clinical progression during IBD. There are less data on the detection of anti-drug antibodies at induction because it requires the use of so-called ‘drug-tolerant’ techniques. The purpose of our study was to investigate in two distinct cohorts (IBD patients on IFX or ADA) whether the early appearance of anti-drug antibodies measured using a drug-tolerant test was associated with clinical progression. Methods In a retrospective study, we included all patients followed in our department for at least 3 months and having had an anti-TNF dosage from W2 of induction under ADA or IFX. At follow-up, therapeutic failure was defined by the obligation to optimise, a change in biotherapy, the use of corticosteroids or surgery. IFX and ADA levels were measured routinely (Lisa-Tracker; Theradiag) and anti-medicine antibodies were detected by ‘drug-sensitive’ ELISA technique (Lisa-Tracker; Theradiag) or ‘drug-tolerant’ as previously described [1]. Patients with a positive rheumatoid factor were excluded. Results 54 patients were included in ADA (mean age: 36 years, sex ratio M/F = 54%, CD: 65%, combotherapy: 10%) and 54 treated with IFX (mean age: 35 years, sex ratio M/F: 46%, CD: 62%, combotherapy: 65%). The search for anti-drug antibodies to W2 using a ‘drug-sensitive’ technique did not reveal any antibodies, whereas 74% of patients on ADA (AAA > or = 2.5 µg/ml eq) and 55% of patients on IFX (ATI > or = 4µg/ml eq). Under ADA, the duration of treatment until loss of response was significantly shorter in the presence of AAA at W2: 6 months vs. 24 months (HR = 18.51; 95CI = 4.35–78.11; p < 0.001). In multivariate analysis, the only independent factor associated with failure was the rate of ADA antibodies to W2 (HR = 18.17; 95CI: 4.27–77.45; p < 0.001). Under IFX, the treatment time to loss of response was significantly shorter in the presence of ATI to W2 (ATI > or = 4µg/ml eq): 5.5 months vs. >24 months (HR = 13.89; 95CI = 4.08–47.31; p < 0.001). In multivariate analysis, the only independent factor associated with failure was the level of anti-IFX antibodies to W2 (> or = 4 µg/ml eq) (HR = 8.07; 95CI: 3.13–20.82; p < 0.001). The higher quartiles of ATI and AAA were significantly associated with poor outcomes (p < 0.001 for each anti-TNF). Conclusion The early onset of anti-drug antibodies in the induction phase as early as W2 is the only isolated independent factor associated with loss of response. Anti-drug antibody frequencies are very high when measured with a drug-tolerant test and these Abs may be more neutralising with ADA than with IFX.

Background In a recent prospective, randomised trial, we showed that the rates of clinical failure and occurrence of unfavourable pharmacokinetics using a drug-sensitive assay after a switch of anti-TNF were significantly higher in monotherapy compared with combination therapy (Log-rank test p < 0.0001), whatever the anti-TNF used in IBD patients. We aimed in a post hoc analysis to assess the time-course of antidrug antibodies in the two groups of patients using a drug-tolerant assay previously described (1). Methods After switching of anti-TNF under mono or combotherapy, blood samples were uptake at various time-points (6, 12, 18 and 24 months). Using a drug-tolerant assay, we defined pharmacokinetic failure when antidrug antibodies were detected (> 2.5 μg/ml Eq). Transient anti-drug antibodies were defined as antibodies that appeared during the course of anti-TNF therapy with no clinical worsening, and finally that disappeared after 2 consecutive measurements. Results Ninety patients were analysed. According to a drug-tolerant assay, the occurrence of antibodies against anti-TNF was significantly higher in patients under monotherapy (log-rank test p < 0.0001 (HR = 3.36 [1.94–5.86]) than under combination therapy. The rates of anti-drug antibody were significantly lower under IFX-AZA combotherapy compared with ADA-AZA combotherapy or under monotherapy. Monotherapy ADA (HR = 5.55[2.46–12.34]) or IFX (HR = 6.05[2.67–13.70]) and combination therapy ADA-AZA (HR = 3.34 [1.407.98]) increased significantly the rates of pharmacokinetic failure using a drug-tolerant assay compared with IFX-AZA combotherapy. The time-course without pharmacokinetic failure was significantly different between the 4 groups of patients from 15 months (p = 0.04) but was not significantly different at 6 months (p = 0.12). Overall, 9% of patients developed transient antibodies. Detection of antibodies against anti-TNF at 6 months using a drug-tolerant assay predicted significantly an immunogenic failure assessed previously by a drug-sensitive assay with a sensitivity of 57.1%, a specificity of 92.7%, a positive predictive value of 90.3%. In contrary to the association between clinical failure and immunogenic failure using drug-sensitive assay, the association of detectable drug and positive antibodies using a drug-tolerant assay was not significantly associated with clinical failure (HR = 1.3[0.3–6.8], p = 0.51). Conclusion Pharmacokinetic failure using a drug-tolerant assay was significantly lower under combotherapy, especially for IFX-AZA. Detection of anti-drug antibodies could predict pharmacokinetic failure. Reference