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.

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.

Loss of response to anti-TNFα 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.

Earlier discontinuation of TNF-α inhibitor therapy in female patients with inflammatory bowel disease is related to a greater risk of side effects.

BACKGROUND: In rheumatoid arthritis and psoriasis female sex has been shown to be associated with discontinuation of anti-tumour necrosis factor-α (TNF-α) therapy. AIM: To retrospectively assess the association between sex and TNF-α drug persistence in patients with inflammatory bowel disease (IBD). METHODS: All IBD patients on anti-TNF-α therapy with a minimum follow-up of 12 months in a single tertiary centre were identified. Patient and treatment characteristics and reasons for anti-TNF-α discontinuation were recorded. Overall and cause-specific drug persistence was analysed with Kaplan-Meier followed by Cox proportional hazards regression models. RESULTS: We included 529 patients (49.9% male) with 631 treatment episodes (2280 anti-TNF-α treatment years) and 289 discontinuations of therapy. Female sex (adjusted hazard ratio [aHR] 1.42, 95% confidence interval [CI] 1.16-1.74), greater age at start of therapy per decade (aHR 1.15, 95% CI 1.04-1.27] and dose escalation (aHR 3.74, 95% CI 2.78-5.02) were associated with TNF-α inhibitor discontinuation. Total cohort cause-specific analysis identified female sex to be associated with side effects (aHR 4.05, 95% CI 2.36-6.98) but not to other discontinuation reasons. Adalimumab (aHR 1.70, 95% CI 1.11-2.60) and golimumab (aHR 4.97, 95% CI 2.30-10.74) use and dose-escalation (aHR 7.71, 95% CI 5.28-11.26) were associated with secondary loss of response. CONCLUSION: Drug persistence of anti-TNF-α therapy is lower in females as compared to males, mainly because of higher rates of side effects in females. Understanding the sex specific differences in effectiveness and safety of anti-TNF-α compounds can aid physicians in clinical decision-making.