Receiving Infliximab Maintenance Research Articles

Identifying risk factors of anti-TNF induced skin lesions and other adverse events in paediatric patients with inflammatory bowel disease.

While higher infliximab (IFX) trough concentrations (TCs) are associated with better outcomes in patients with inflammatory bowel disease (IBD), they could pose a risk for adverse events (AEs), including IFX-induced skin lesions. Therefore, we studied correlations between IFX TCs and occurrence of AEs in paediatric IBD patients. In this single-centre study, all children with Crohn's disease (CD) and ulcerative colitis (UC) receiving IFX maintenance therapy who underwent proactive drug monitoring between March 2015 and August 2022 were included. IFX doses/intervals/TCs and patient characteristics were systematically registered, as well as AEs and skin lesions appearance. A total of 109 patients (72 CD and 37 UC) contributed 2913 IFX TCs. During a median follow-up of 3.0 [1.5-4.5] years, we observed 684 AEs in 101 patients and 49 skin lesions in 35 patients. There was no significant difference (p = .467) in median TCs between patients with and without skin lesions. However, higher median IFX doses were associated with an increased hazard rate of skin lesions [HR 1.084 (1.024-1.148), p = .005], in addition to female sex [2.210 (1.187-5.310), p = .016] and diagnosis of CD [1.695 (1.241-1.877), p = .011]. Considering IFX therapeutic TC cut-offs of 5.0 and 9.0 µg/mL, there was no significant difference in AE rate (p = .749 and p = .833, respectively). Also, no significant association between IFX doses and AE rate (p = .159). Increasing the IFX dose to achieve therapeutic TCs may not increase the overall risk of AEs in paediatric IBD patients. However, concerns arise regarding the risk of skin lesions, especially in female CD patients.

Free antibodies-to-infliximab are biomarker for predicting the effect of dose intensification in pediatric Crohn's disease patients with secondary loss of response.

Immunogenicity to antitumor necrosis factor alpha agents, such as infliximab (IFX), may lead to therapeutic failure. This study evaluated the relationship between free and total antibodies-to-infliximab (ATIs), trough levels (TLs) of IFX, and the response to dose intensification. We performed a prospective, observational study including pediatric patients with Crohn's disease (CD) receiving IFX maintenance therapy without dose intensification. We compared clinical and laboratory outcomes according to the presence of free and total ATIs. Factors associated with response to IFX dose intensification were investigated by analyzing IFX TLs and free and total ATIs. Of the 98 patients, 9 patients had detectable free ATIs and 38 patients had total ATIs. Patients with free ATIs had significantly lower TLs (0.7 versus 5.1 µg/mL, p < 0.001) than patients without free ATIs. However, there was no difference in the IFX TLs according to the presence of total ATIs (p = 0.2523). Analysis of the 38 samples with total ATIs showed that response to dose intensification was significantly lower in patients with free ATIs than those without free ATIs (22.2% versus 65.5%, p < 0.001). In addition, free ATIs were the only factor with poor response to dose intensification [odds ratio (OR): 14.15, 95% confidence interval (CI): 1.31-151.97, p = 0.0140]. According to the receiver operating characteristic analysis, the optimal cutoff level indicating non-response to IFX dose intensification was 30.0 AU/mL for free ATIs concentration (area under curve, 0.792; 95% CI: 0.590-0.942; sensitivity, 60.0%; specificity, 96.7%; p = 0.0241). Free ATIs, but not total ATIs, have a negative impact on the course of CD. Free ATIs are potential reliable biomarker for predicting the effect of dose intensification in patients with loss of response to IFX. Future studies based on serial and proactive therapeutic drug monitoring are required in the future.

Efficacy of dashboard driven dosing of infliximab in inflammatory bowel disease patients; a randomized controlled trial

Objectives Loss of response (LOR) to infliximab (IFX) remains a challenge in the management of inflammatory bowel diseases (IBD). Proactive dosing strategies to achieve and maintain predefined IFX trough levels (TL) may prevent LOR. We aimed to investigate the efficacy of dashboard driven IFX dosing compared to standard dosing in a prospective trial in IBD patients. Methods In this multicentre 1:1 ‘PRECISION’ trial, we randomized IBD patients in clinical remission (Harvey Bradshaw Index ≤4 for Crohn’s disease (CD) or a partial Mayo score ≤2 for ulcerative colitis (UC)) receiving IFX maintenance treatment. The precision group (PG) received IFX dosing guided by a Bayesian pharmacokinetic model, aiming to achieve and maintain a TL of 3 µg/ml by treatment (de)escalation as indicated by the dashboard. Patients in the control group (CG) continued treatment without dose adaptations. The primary endpoint was the proportion of patients in sustained clinical remission after 1 year. Results Eighty patients were enrolled (66 CD, 14 UC), and the median [interquartile range] age was 37 years [27–51]). After one year, 28/32 (88%) of patients in the PG were in sustained clinical remission versus 25/39 (64%) in the CG (p = .017). PG patients had lower median faecal calprotectin levels after 1 year (p = .031), whereas no significant differences in median CRP levels were found. Conclusion We demonstrated that the use of a Bayesian dashboard for IFX dosing in maintenance treatment for IBD reduced the incidence of LOR compared to standard dosing. Precision dosing also resulted in lower FCP levels. ClinicalTrials.gov number NCT02453776.

Implementation of infliximab standardized doses after pharmacokinetic modelization in a cohort of patients with Crohn’s disease

BackgroundAccording to infliximab (IFX) license in Crohn’s disease (CD), infusion doses are based on patient’s body-weight. Dose banding providing standardized doses (SD) has been implemented in parenteral chemotherapy in order to optimize aseptic unit capacity and reduce drug expenditure, duration of hospital stay and costs without decreasing efficacy. Material and methodThe first part was a single-center retrospective analysis of consecutive CD patients receiving IFX maintenance therapy to determine standardized doses covering more than 50% of infusions. The second part was a prospective cohort study assessing the impact of SD compared to body-weight doses (BWD) on admission duration and costs. ResultsSix IFX SD covering more than 90% of infusion doses were implemented for dose banding. According to the Monte-Carlo simulation, there was no significant difference between IFX SD and BWD maintenance regimens. When assessed prospectively in 116 patients (75 patients treated with SD and 41 with BWD) corresponding to 128 infusions, hospitalization duration was shortened by 70 min per patient (p < 0.001). ConclusionAccording to a pharmacokinetic model, IFX SD has a pharmacokinetic profile close to BWD and is associated with reduced length of hospitalization in a cohort of patients with CD. IFX SD implementation could optimize infusion units functioning and, save time and costs without decreasing efficacy.

Infliximab Therapeutic Drug Monitoring Changes Clinical Decisions in a Virtual Biologics Clinic for Inflammatory Bowel Disease.

Virtual biologics clinics are often used to review patients with inflammatory bowel disease receiving biological therapy, with decisions whether to continue, switch, or stop therapy made based on review of symptoms, disease history, and investigations. We aimed to investigate whether therapeutic drug monitoring of infliximab (IFX) trough levels and anti-drug antibodies influences decision making within a virtual biologics clinic. For all patients with inflammatory bowel disease receiving IFX maintenance therapy, 2 decisions were recorded in a preset format. The first decision was based on assessment of clinical details, with clinicians blinded to IFX trough levels and anti-drug antibodies. The second decision was made after unblinding of these data. Among 191 patients (mean age 40 years; 106 (55.5%) male), IFX trough levels were sub-therapeutic in 53 (27.7%) (<2 mg/L), therapeutic in 100 (52.4%), and supra-therapeutic in 38 (19.9%) (>6 mg/L). Anti-drug antibodies were detected in 58 (30.4%), and were >50 AU/mL in 26 (13.6%). Blinded treatment decisions were changed on unblinding these data in 56 cases (29.3%; P < 0.0001). Knowledge of these data led to 7 (3.7%) patients receiving intensified IFX, whereas 33 (17.3%) patients were able to either dose de-escalate or stop IFX. Basing decisions on therapeutic drug monitoring, rather than clinical acumen alone, led to a change in almost one-third of decisions made, offering considerable cost savings and reducing exposure to potentially toxic therapies. Routine therapeutic drug monitoring should be considered an integral part of annual biologics assessment (see Video Abstract, Supplemental Digital Content 1, http://links.lww.com/IBD/B629).

The association of infliximab trough levels with disease activity in pediatric inflammatory bowel disease

Objective. Low serum trough levels (TLs) of infliximab (IFX) and antibodies to IFX (ATIs) are associated with the loss of therapeutic response in adults with inflammatory bowel disease (IBD) receiving IFX. Until now, pediatric data are scarce. Therefore, we aimed to cross-sectionally investigate the association between ATIs and IFX TLs, and clinical and biochemical disease activity in children receiving IFX for IBD. Material and methods. Children aged <18 years receiving IFX maintenance treatment for Crohn’s disease (CD) or ulcerative colitis (UC) at three Dutch hospitals were included. Prior to two consecutive IFX infusions, IFX TLs and ATI levels were measured. Clinical disease activity was determined by Pediatric Crohn’s Disease Activity Index (PCDAI) and Pediatric Ulcerative Colitis Activity Index (PUCAI), for CD and UC, respectively. Biochemical disease activity was assessed by serum C-reactive protein (CRP) and fecal calprotectin (FC). Clinical remission was defined as a PUCAI or PCDAI score of <10. Therapeutic range of IFX was considered 3–7 µg/ml. Results. Thirty-nine patients were included (31 CD; 16 females). Median age was 15 years. Median IFX TL was 3.5 µg/ml [IQR 2–7]. Subtherapeutic and supratherapeutic TLs were found in 38% and 23% of children, respectively. ATIs were detected in four patients. A correlation was found between IFX TL and CRP [rs = −0.51; p < 0.01] and FC [rs = −0.49; p < 0.01]. However, when only clinical disease activity was considered, no difference in median TL was found between remission and active disease (resp. 3.5 µg/ml [IQR 2–5] and 2.3 µg/ml [IQR 0.3–4.6]; p = 0.2). Conclusions. IFX TLs are related to biochemical markers of disease activity. This could provide a rationale for monitoring TLs in children receiving IFX for IBD.

Anti-tumor Necrosis Factor Therapy for Crohn Disease: Friend or Foe to the Surgeon?

Anti-tumor Necrosis Factor Therapy for Crohn Disease: Friend or Foe to the Surgeon?

Predictors of Loss of Response to Infliximab in Pediatric Crohn’s Disease

Introduction: Our aim was to determine the proportion of children with Crohn’s disease (CD) who lose clinical response to infliximab and to identify any demographic, clinical, or laboratory variables that predict this loss of response. Methods: This study was a retrospective chart review. Thirty-one pediatric CD patients who received infliximab maintenance therapy between January 2003 and December 2013 at the St. John Pediatric Gastroenterology Clinic were included. Demographics, clinical variables, and laboratory markers before induction were obtained and compared between patients who lost response and patients who had sustained remission. Predictors of time to loss of response were also assessed. Data were analyzed using chi-square, student t test, and multivariate logistic regression. Results: The mean age of the study group was 17.5 ± 3.1 years, 61.3% (19/31) were male, and 87.1% (27/31) were white. During the maintenance phase of therapy, 48% of patients (15/31) lost response to Infliximab. Univariate analysis showed that patients who lost response tended to be older at induction than those who did not lose response (14.7 ± 2.2 vs. 12.9 ± 3.0 years; p=0.06). Patients with ileocolonic disease were also significantly more likely to lose response than patients with non-ileocolonic disease (60.9% vs. 12.5%; p=0.018). From multivariate logistic regression, both age at induction (OR 1.66; p=0.024) and ileocolonic disease (OR 34.25; p=0.013) were significant predictors of loss of response. Mean time from induction to loss of response was 318.0 ± 197.3 days. Male patients lost response earlier than females (213.8 ± 124.7 days compared to 437 ± 204.4 days; p=0.02, respectively). Conclusion: In our pediatric population with CD, ileocolonic disease and age at induction predicted the loss of response to infliximab during the maintenance phase. Males lost response earlier than females. Larger studies are needed to further evaluate these findings.Table 1: Predictors of Loss of Response to Infliximab

Mucosal healing of ileal lesions is associated with long-term clinical remission after infliximab maintenance treatment in patients with Crohn's disease.

The aim of the present study was to endoscopically evaluate ileal mucosal healing during maintenance therapy with infliximab in order to investigate the clinical significance of endoscopic examination of ileal lesions in Crohn's disease patients. This study retrospectively analyzed 54 patients who mainly had active ulcers of the ileum on endoscopy at baseline who were responsive to infliximab induction and who received infliximab maintenance therapy. Mucosal healing was defined as no ulcer or only ulcer scar. At the time of follow-up endoscopy after starting infliximab, endoscopic score, mucosal healing, and clinical remission were evaluated. On long-term follow up, correlations between mucosal healing and long-term clinical remission, and between mucosal healing and the need for major abdominal surgery, were also evaluated. Ileal mucosal healing and complete mucosal healing were significantly correlated with clinical remission (P = 0.046, P = 0.0001, respectively). The rate of long-term clinical remission was significantly higher in patients with complete mucosal healing (P = 0.025). The rate of major abdominal surgery for strictures was significantly lower in patients with complete mucosal healing (P = 0.044). Complete mucosal healing after 1-2 years was a predictive factor for long-term clinical remission up to 4 years after starting infliximab. A lack of complete mucosal healing was a predictive factor for major abdominal surgery for strictures. The present study suggests that endoscopic evaluation of ileal lesions is useful for long-term prognosis of Crohn's disease patients.

Consecutive Fecal Calprotectin Measurements to Predict Relapse in Patients with Ulcerative Colitis Receiving Infliximab Maintenance Therapy

This study examined whether fecal calprotectin can be used in daily practice as a marker to monitor patients with ulcerative colitis (UC) receiving infliximab maintenance therapy. This prospective multicenter study enrolled adult patients with UC in clinical remission under infliximab maintenance therapy. Fecal calprotectin levels were measured every 4 weeks. Sigmoidoscopies were performed at inclusion and at study end. Relapse was defined as a clinical need for change in treatment or an endoscopic Mayo subscore of ≥2 at week 52. Sustained deep remission was defined as a partial Mayo score <3 at all points and an endoscopic Mayo score 0 at week 52. Full analysis was possible for 87 of 113 included patients with UC (77%). Of these patients, 30 (34.4%) were considered to be in sustained deep remission and 13 (14.9%) to have relapsed. Calprotectin levels in patients with sustained deep remission remained very low (median < 40 mg/kg at all time points). Patients who flared had significantly higher calprotectin levels (median > 300 mg/kg) already 3 months before the flare. Further receiver operator curve analysis suggested that a calprotectin level >300 mg/kg had a reasonable sensitivity (58.3%) and specificity (93.3%) to model flare. Two consecutive calprotectin measurements of >300 mg/kg with 1-month interval were identified as the best predictor of flare (61.5% sensitivity and 100% specificity). Fecal calprotectin can be used in daily practice to monitor patients with UC receiving infliximab maintenance therapy. Two consecutive measurements >300 mg/kg is more specific than a single measurement for predicting relapse.

Infliximab and Azathioprine for Crohn's Disease: A Super-Sonic Combination?

Infliximab and Azathioprine for Crohn's Disease: A Super-Sonic Combination?

Usefulness of co-treatment with immunomodulators in patients with inflammatory bowel disease treated with scheduled infliximab maintenance therapy

Background and aimsConcomitant use of immunosuppressants (IS) with scheduled infliximab (IFX) maintenance therapy for Crohn's disease (CD) or ulcerative colitis (UC) is debated. The aim of this study was to...

Factors Associated With the Development of Intestinal Strictures or Obstructions in Patients With Crohn's Disease

OBJECTIVE Theoretical concern exists that rapid luminal healing in Crohn's disease (CD) with therapies like infliximab increases the risk of intestinal stenosis, stricture, or obstruction (SSOs). METHODS Data were analyzed from the ongoing observational TREAT (the Crohn's Therapy, Resource, Evaluation, and Assessment Tool) Registry and ACCENT I (A Crohn's Disease Clinical Trial Evaluating Infliximab in a New Long-Term Treatment Regimen) study. Investigators reported SSOs as adverse events or serious adverse events. RESULTS In TREAT, SSOs occurred at a significantly higher rate in patients treated with infliximab compared with patients who received other treatments only (1.95 events/100 patient-years vs 0.99 events/100 patient-years; p < 0.001). Using multivariable analyses, however, infliximab therapy was not associated with SSO development. CD severity at the time of event onset (hazard ratio (HR) = 2.35, 95% confidence internal (CI) 1.35–4.09); CD duration (HR = 1.02, 95% CI 1.00–1.04); ileal disease (HR = 1.56, 95% CI 1.04–2.36); and new corticosteroid use (HR = 2.85, 95% CI 1.23–6.57) were associated with SSOs. In ACCENT I, no increase in SSOs was reported in patients who received infliximab maintenance therapy compared with those who received episodic therapy, despite higher median cumulative infliximab exposure. Additionally, there was no increase in SSO development with rapid mucosal healing (healing at week 10). CONCLUSIONS Although unadjusted analyses suggested that patients who received infliximab were twice as likely to develop SSOs, multivariable analysis adjusting for other factors demonstrated that only disease duration, disease severity, ileal disease, and new corticosteroid use were significantly associated with SSO development.

Factors Associated with the Development of Intestinal Strictures or Obstructions in Patients with Crohn's Disease

Theoretical concern exists that rapid luminal healing in Crohn's disease (CD) with therapies like infliximab increases the risk of intestinal stenosis, stricture, or obstruction (SSOs). Data were analyzed from the ongoing observational TREAT (the Crohn's Therapy, Resource, Evaluation, and Assessment Tool) Registry and ACCENT I (A Crohn's Disease Clinical Trial Evaluating Infliximab in a New Long-Term Treatment Regimen) study. Investigators reported SSOs as adverse events or serious adverse events. In TREAT, SSOs occurred at a significantly higher rate in patients treated with infliximab compared with patients who received other treatments only (1.95 events/100 patient-years vs 0.99 events/100 patient-years; p < 0.001). Using multivariable analyses, however, infliximab therapy was not associated with SSO development. CD severity at the time of event onset (hazard ratio (HR) = 2.35, 95% confidence internal (CI) 1.35-4.09); CD duration (HR = 1.02, 95% CI 1.00-1.04); ileal disease (HR = 1.56, 95% CI 1.04-2.36); and new corticosteroid use (HR = 2.85, 95% CI 1.23-6.57) were associated with SSOs. In ACCENT I, no increase in SSOs was reported in patients who received infliximab maintenance therapy compared with those who received episodic therapy, despite higher median cumulative infliximab exposure. Additionally, there was no increase in SSO development with rapid mucosal healing (healing at week 10). Although unadjusted analyses suggested that patients who received infliximab were twice as likely to develop SSOs, multivariable analysis adjusting for other factors demonstrated that only disease duration, disease severity, ileal disease, and new corticosteroid use were significantly associated with SSO development.

Infliximab maintenance treatment reduces hospitalizations, surgeries, and procedures in fistulizing Crohn’s disease

Infliximab is effective in closing fistulas in patients with Crohn's disease. We examined the effect of infliximab maintenance treatment on hospitalizations, surgeries, and procedures in patients with fistulizing Crohn's disease enrolled in the ACCENT II study. After 5 mg/kg infliximab at weeks 0, 2, and 6, a total of 282 patients were separately randomized at week 14 as responders (at least a 50% reduction from baseline in the number of draining fistulas at both weeks 10 and 14) or nonresponders to receive placebo or 5 mg/kg infliximab maintenance every 8 weeks. At week 22 and later, patients who lost response could be treated with a maintenance dose 5 mg/kg higher. Data on Crohn's disease-related hospitalizations, surgeries, and procedures were compared between the treatment groups for responders and all randomized patients. A total of 282 patients were randomized at week 14, of whom 195 were randomized as responders. Among patients randomized as responders, those who received infliximab maintenance had significantly fewer mean hospitalization days (0.5 vs. 2.5 days; P < .05), mean numbers (per 100 patients) of hospitalizations (11 vs. 31; P < .05), all surgeries and procedures (65 vs. 126; P < .05), inpatient surgeries and procedures (7 vs. 41; P < .01), and major surgeries (2 vs. 11; P < .05), compared with those who received placebo maintenance. In patients with fistulizing Crohn's disease, infliximab 5 mg/kg every 8 weeks significantly reduced hospitalizations, surgeries, and procedures compared with placebo.