Adherence to Adalimumab Was Not Improved by a Reminder-Based Intervention with an Electronic Needle Container

Background: Adherence to adalimumab in inflammatory bowel disease (IBD) patients is reported to be below par. Non-adherence may result in loss-of-response and increased hospitalization. We analyzed the effect of an electronic needle container (ENC) on adherence to adalimumab. Methods: In this multicenter, 12-months observational study, we included adalimumab treated IBD patients. All patients were invited to receive an ENC. Patients who declined or did not complete the registration for an ENC served as controls. Primary endpoint was whether an ENC increased adherence, calculated from pharmacy refills as proportion of days covered (PDC). Secondary endpoints were clinical outcomes, including loss-of-response, identification of predictors of adherence and correlation between different modalities for measuring adherence. Loss-of-response was defined as a disease flare, dose-escalation or IBD-related hospitalization or surgery. Results: The pharmacies’ records identified 198 eligible patients, of whom 32 were excluded. The ENC was supplied to 69 patients, the remaining 97 patient formed the control group. Median baseline PDC (98.4% vs. 96.1%, p = 0.047) and the proportion of adherent (PDC ≥ 86%) patients (87.0% vs. 74.2%, p = 0.045) was higher for the ENC group. The ENC did not improve the adherence of patients during follow-up (odds ratio 1.26, 95% CI 0.55–2.86). During follow-up, five (7.2%) patients in the ENC group and 13 (13.4%) in the control group discontinued adalimumab (log-rank p = 0.22). Loss-of-response occurred in 12 (17.4%) and 14 (14.4%) patients, respectively (log-rank p = 0.66). Conclusions: Our results show no beneficial effect of a reminder-based intervention on adherence or treatment outcomes

Does the 5-Aminosalicylate Concentration Correlate with the Efficacy of Oral 5-Aminosalicylate and Predict Response in Patients with Inflammatory Bowel Disease?: A Systematic Review

BACKGROUND: Oral 5-aminosalicylic acid (5-ASA, mesalazine) is the first choice therapeutic agent for treating mild-to-moderate ulcerative colitis (UC). Unfortunately a significant group of patients fail to respond. Therapeutic drug monitoring might help to maintain or induce remission by providing a tool for optimization of 5-ASA therapy. However, plasma and urine concentrations of 5-ASA reflect systemic uptake and are not useful to evaluate therapeutic effect. OBJECTIVES: To explore if mucosal and faecal 5-ASA values correlate with disease activity and/or therapeutic effects in patients with inflammatory bowel disease, especially UC. METHOD: We identified studies that analysed 5-ASA in faeces or mucosa of humans using an oral 5-ASA formulation, using PubMed and Embase. RESULTS: In total, 39 studies (n = 939) were included, 27 on faecal 5-ASA, 9 on mucosal concentrations, and 3 on both faecal and mucosal values. We included 33 cross-sectional studies, 3 randomised clinical trials, 2 longitudinal cohorts and 1 randomized cross-over study. Mucosal 5-ASA concentrations in healthy subjects and patients on equivalent doses of 5-ASA were not found to differ remarkably. In the sub-analysis of mucosal 5-ASA concentrations in patients with active or quiescent UC, a higher concentration was seen during remission. Faecal concentrations were associated with 5-ASA doses but not with disease activity. Differences in faecal or mucosal 5-ASA values could not be ascribed to different 5-ASA formulations. CONCLUSIONS: An increase of the mucosal 5-ASA concentrations was observed during remission in patients with UC. No clear relationship between the faecal 5-ASA excretion and the therapeutic efficacy was identified

Loss of response to anti-TNF alpha agents depends on treatment duration in patients with inflammatory bowel disease

Background: Inflammatory bowel disease (IBD) is often managed with anti-tumour necrosis factor-α therapy (anti-TNFα), but treatment efficacy is compromised by high annual rates of loss of response (13%-21% per patient-year). Aims: To assess whether the incidence of loss of response decreases with longer treatment duration. Methods: This was a multicentre, retrospective cohort study of patients with ulcerative colitis (UC) or Crohn's disease (CD) who received anti-TNFα for at least 4 months between 2011 and 2019. We studied the incidence of loss of response as a function of treatment duration, employing parametric survival modelling. Predictors of loss of response were identified by Cox regression analysis. Secondary outcomes included overall anti-TNFα discontinuation and dose escalation. Results: We included 844 anti-TNFα treatment episodes in 708 individuals. Loss of response occurred in 211 (25.0%) episodes, with anti-drug antibodies detected in 66 (31.3%). During the first year, the incidence of loss of response was three-fold higher than after four years of treatment (17.2% vs 4.8% per patient-year, P < 0.001). The incidence of anti-TNFα discontinuation (28.6% vs 14.0% per patient-year, P < 0.001) and dose escalations (38.0% vs 6.8% per patient-year, P < 0.001) also decreased significantly from the first year to after four years, respectively. Predictors of loss of response included UC (vs CD, adjusted hazard ratio [aHR] 1.53, 95% CI 1.10-2.15) and, among patients with CD, stricturing or penetrating disease (aHR 1.68, 95% CI 1.15-2.46) and male sex (aHR 0.55, 95% CI 0.38-0.78). Immunomodulators were protective against loss of response with anti-drug antibodies (aHR 0.42, 95% CI 0.24-0.74). Conclusions: Patients with sustained benefit to anti-TNFα after 2 years are at low risk of subsequent loss of response

Outcome of Reverse Switching From CT-P13 to Originator Infliximab in Patients With Inflammatory Bowel Disease

BACKGROUND: Patients suffering from inflammatory bowel diseases (IBD) and treated with originator infliximab are increasingly being switched to biosimilars. Some patients, however, are "reverse switched" to treatment with the originator. Here we assess the prevalence of reverse switching, including its indication and outcomes. METHODS: In this retrospective multicenter cohort study, data on patients with IBD from 9 hospitals in the Netherlands were collected. All adult patients with IBD were included if they previously had been switched from originator infliximab to the biosimilar CT-P13 and had a follow-up time of at least 52 weeks after the initial switch. The reasons for reverse switching were categorized into worsening gastrointestinal symptoms, adverse effects, or loss of response to CT-P13. Drug persistence was analyzed through survival analyses. RESULTS: A total of 758 patients with IBD were identified. Reverse switching was observed in 75 patients (9.9%). Patients with reverse switching were predominantly female (70.7%). Gastrointestinal symptoms (25.5%) and dermatological symptoms (21.8%) were the most commonly reported reasons for reverse switching. In 9 patients (12.0%), loss of response to CT-P13 was the reason for reverse switching. Improvement of reported symptoms was seen in 73.3% of patients after reverse switching and 7 out of 9 patients (77.8%) with loss of response regained response. Infliximab persistence was equal between patients who were reverse-switched and those who were maintained on CT-P13. CONCLUSIONS: Reverse switching occurred in 9.9% of patients, predominantly for biosimilar-attributed adverse effects. Switching back to originator infliximab seems effective in patients who experience adverse effects, worsening gastrointestinal symptoms, or loss of response after switching from originator infliximab to CT-P13

Instructions for Authors

Nonadherence to medical therapy is frequently encountered in patients with inflammatory bowel disease (IBD). We aimed to identify predictors for future (non)adherence in IBD

Autologous bone marrow-derived mesenchymal stromal cell treatment for refractory luminal Crohn’s disease: results of a phase I

Mesenchymal stromal cells (MSCs) are pluripotent cells that have immunosuppressive effects both in vitro and in experimental colitis. Promising results of MSC therapy have been obtained in patients with severe graft versus host disease of the gut. Our objective was to determine the safety and feasibility of autologous bone marrow derived MSC therapy in patients with refractory Crohn's disease. 10 adult patients with refractory Crohn's disease (eight females and two males) underwent bone marrow aspiration under local anaesthesia. Bone marrow MSCs were isolated and expanded ex vivo. MSCs were tested for phenotype and functionality in vitro. 9 patients received two doses of 1-2×10(6) cells/kg body weight, intravenously, 7 days apart. During follow-up, possible side effects and changes in patients' Crohn's disease activity index (CDAI) scores were monitored. Colonoscopies were performed at weeks 0 and 6, and mucosal inflammation was assessed by using the Crohn's disease endoscopic index of severity. MSCs isolated from patients with Crohn's disease showed similar morphology, phenotype and growth potential compared to MSCs from healthy donors. Importantly, immunomodulatory capacity was intact, as Crohn's disease MSCs significantly reduced peripheral blood mononuclear cell proliferation in vitro. MSC infusion was without side effects, besides a mild allergic reaction probably due to the cryopreservant DMSO in one patient. Baseline median CDAI was 326 (224-378). Three patients showed clinical response (CDAI decrease ≥70 from baseline) 6 weeks post-treatment; conversely three patients required surgery due to disease worsening. Administration of autologous bone marrow derived MSCs appears safe and feasible in the treatment of refractory Crohn's disease. No serious adverse events were detected during bone marrow harvesting and administratio

Limited predictive value of the gut microbiome and metabolome for response to biological therapy in inflammatory bowel disease

Emerging evidence suggests the gut microbiome's potential in predicting response to biologic treatments in patients with inflammatory bowel disease (IBD). In this prospective study, we aimed to predict treatment response to vedolizumab and ustekinumab, integrating clinical data, gut microbiome profiles based on metagenomic sequencing, and untargeted fecal metabolomics. We aimed to identify predictive biomarkers and attempted to replicate microbiome-based signals from previous studies. We found that the predictive utility of the gut microbiome and fecal metabolites for treatment response was marginal compared to clinical features alone. Testing our identified microbial ratios in an external cohort reinforced the lack of predictive power of the microbiome. Additionally, we could not confirm previously published predictive signals observed in similar sized cohorts. Overall, these findings highlight the importance of external validation and larger sample sizes, to better understand the microbiome's impact on therapy outcomes in the setting of biologicals in IBD before potential clinical implementation

Methotrexate accumulation in target intestinal mucosa and white blood cells differs from non-target red blood cells of patients with Crohn's disease

BACKGROUND: Intracellular methotrexate polyglutamates (MTX-PGs) concentrations are measurable in red blood cells (RBCs) during MTX treatment. MTX-PG 3 concentrations correlate with efficacy in patients with Crohn's disease (CD). Since RBCs are not involved in pathogenesis of CD and lack extended MTX metabolism, we determined MTX-PGs accumulation in peripheral blood mononuclear cells (PBMCs: effector cells) and intestinal mucosa (target cells) and compared those with RBCs as a potential more precise biomarker. METHODS: In a multicentre prospective cohort study, blood samples of patients with CD were collected during the first year of MTX therapy. Mucosal biopsies were obtained from non-inflamed rectum and/or inflamed intestine. MTX-PGs concentrations in mucosa, PBMCs and RBCs were measured by liquid chromatography-tandem mass spectrometry. RESULTS: From 80 patients with CD, a total of 27 mucosal biopsies, 9 PBMC and 212 RBC samples were collected. From 12 weeks of MTX therapy onwards, MTX-PG 3 was the most predominant species (33%) in RBCs. In PBMCs, the distribution was skewed towards MTX-PG 1 (48%), which accounted for an 18 times higher concentration than in RBCs. Long-chain MTX-PGs were highly present in mucosa: 21% of MTX-PG total was MTX-PG 5. MTX-PG 6 was measurable in all biopsies. CONCLUSIONS: MTX-PG patterns differ between mucosa, PBMCs and RBCs of patients with CD