Durability of Infliximab Is Associated With Disease Extent in Children With Inflammatory Bowel Disease

Shapiro, Jason; Subedi, Shova D.; Machan, Jason T.; Cerezo, Carolina S.; Ross, Albert M.; Shalon, Linda; Silverstein, Jared; Herzlinger, Michael; Kasper, Vania; Leleiko, Neal S.

doi:10.1097/mpg.0000000000001034

Cited by 14 publications

(19 citation statements)

References 29 publications

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“…To the best of our knowledge, this is the first study to address differences in the therapeutic effects in CD according to NUDT15 activity. The factors associated with LOR are colonic involvement, young age at IFX initiation, smoking, concomitant immunomodulators, IFX TLs and development of ATIs 23,24 . In this study, no significant differences were found in variables reported to affect LOR, as well as in treatment outcomes such as CR, BR and MH at 1 year according to NUDT15 phenotype.…”

Section: Discussioncontrasting

confidence: 54%

NUDT15 intermediate metabolisers are associated with lower loss of response in paediatric Crohn’s disease patients treated by combination treatment with infliximab and azathioprine

Kim

Choi

et al. 2022

Aliment Pharmacol Ther

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Background: NUDT15 polymorphisms are associated with leukopenia during treatment with thiopurines. However, data regarding its effect on treatment outcomes are scarce. Aims: To investigate the outcomes between NUDT15 normal and intermediate metabolisers in paediatric patients with Crohn's disease (CD) treated with a combination therapy of infliximab (IFX) and azathioprine (AZA). Methods: In this retrospective observational study, 143 patients categorised into the NUDT15 normal and intermediate metaboliser groups were compared based on clinical remission (CR), biochemical remission (BR), mucosal healing (MH) at 1 year treatment, IFX trough levels (TLs), antibodies to IFX (ATIs), 6-thioguanine nucleotide (6-TGN) levels, loss of response (LOR) and IFX durability.Results: No significant differences were observed between the groups in CR, BR, MH at 1 year, whereas IFX TLs and ATIs and 6-TGN levels were comparable. However, LOR (6.5% vs 27.7%, P = 0.025) was significantly lower and IFX durability significantly higher (96.8% vs 80.4% P = 0.027) in the intermediate group. Multivariable Cox proportional hazard regression analysis showed that ATI positivity (hazard ratio (HR): 4.76, 95% CI: 2.25-10.07, P < 0.001) and the NUDT15 metaboliser group was associated with LOR (HR: 0.18, 95% CI: 0.04-0.76, P = 0.019). The Kaplan-Meier survival curves showed that the LOR-free survival rate was significantly lower in normal metabolisers (log-rank test P = 0.009). Conclusion: NUDT15 intermediate metabolisers were associated with lower LOR in paediatric patients with CD treated with IFX and AZA combination therapy. This finding may partially explain the longer durability of IFX in Korean children than their counterparts in Western countries.

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Section: Discussioncontrasting

confidence: 54%

NUDT15 intermediate metabolisers are associated with lower loss of response in paediatric Crohn’s disease patients treated by combination treatment with infliximab and azathioprine

Kim

Choi

et al. 2022

Aliment Pharmacol Ther

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“…Recent reports have described potential benefits of accelerated infliximab induction regimens for optimal disease control and reducing the early colectomy rate in severe UC ( 24 , 25 ). Shapiro et al suggest that an initial intensive regimen is necessary in extensive disease (90% of the patients in this study) to maintain sustained efficacy ( 26 ). Therapeutic drug monitoring may be a useful adjunct to clinical judgment to identify which patients need therapy escalation with infliximab ( 27 ).…”

Section: Discussionmentioning

confidence: 86%

Outcomes of a National Cohort of Children with Acute Severe Ulcerative Colitis

et al. 2018

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AimAll Irish children with ulcerative colitis (UC) attend the National Centre for Paediatric Gastroenterology at Our Lady’s Children’s Hospital, Crumlin. The aim of this study was to determine the outcomes of children with acute severe ulcerative colitis (ASC) and the impact of infliximab on these outcomes following its introduction for this indication in 2011.MethodsA retrospective chart review of all patients admitted with ASC between January 1, 2009 and December 31, 2015 was undertaken. Patients were identified from the departmental database cross-referenced with the hospital inpatient enquiry system. Inpatients with a paediatric ulcerative colitis activity index (PUCAI) of ≥65 were included. Data collected included baseline demographic and laboratory data, concomitant treatments, PUCAI scores on days 3 and 5, second-line treatments, surgery, and discharge outcomes. Infliximab dose, frequency, and available therapeutic drug monitoring results were recorded, along with clinical response outcomes (remission, primary, and secondary loss of response). The cohort was sub-analysed to determine if there was any era effect pre- and post-introduction of infliximab (2009–2010 and 2011–2015, respectively).ResultsFifty-five patients (M:F = 1.4:1) were treated for acute severe colitis over the study period (8 in the pre-infliximab and 47 in the post-infliximab era) and 46/55 (86%) had steroid-refractory disease. Of these, 7/8 (88%) required colectomy in the pre-infliximab era, compared with 15/47 (36%) in the post-infliximab era. The remission rate with second-line infliximab was 61% at maximal follow-up. There were no identifiable factors that predicted likely success or failure of infliximab, including gender, CRP, day-3 and day-5 PUCAI scores. Of the 33 patients treated with infliximab, dose increase was required in 23/33 (70%); 21/33 (64%) received an accelerated dose schedule, and 9/33 (27%) eventually needed colectomy. Primary and secondary loss of response to infliximab was seen in one and nine patients, respectively.ConclusionThis is the first population-based study of the outcomes of severe UC in Irish children, and suggests a higher burden of steroid-refractory disease compared with previous international studies. While infliximab treatment has led to reduction in colectomy rates, a significant proportion of patients lose therapeutic effect.

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“…1 The incidence of IBD is rapidly increasing worldwide and approximately 25% of IBD patients are diagnosed in early ages. 1,2 I Extra-intestinal manifestations including oral cavity are more commonly seen at the disease onset in pediatric IBD patients than adults. 3 The prevalence of oral manifestations of IBD ranges widely from 7% to 23% in children (up to 41% in children with CD).…”

Section: Introductionmentioning

confidence: 99%

“…5 The main mechanisms of IBD pathogenesis are dysregulated host immune response to commensal microbiota and disruption of pro-and antiinflammatory cytokines' balance in genetically predisposed individuals. 1,2,6 Although UC is limited to the superficial mucosa of the colon, CD progresses with transmural inflammation in any part of the gastrointestinal system from mouth to anus. 1 Although the main focus of studies have been oral mucosal lesions rather than periodontal disease, there are some studies demonstrating the increased risk of periodontitis in patients with IBD.…”

Section: Introductionmentioning

confidence: 99%

“…1,2,6 Although UC is limited to the superficial mucosa of the colon, CD progresses with transmural inflammation in any part of the gastrointestinal system from mouth to anus. 1 Although the main focus of studies have been oral mucosal lesions rather than periodontal disease, there are some studies demonstrating the increased risk of periodontitis in patients with IBD. 7,8 Similar to IBD, the pathogenesis of periodontitis comprises the interaction of microbial challenge and host response resulting in cytokine production.…”

Section: Introductionmentioning

confidence: 99%

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Cytokine profile in serum and gingival crevicular fluid of children with inflammatory bowel disease: A case‐control study

Acar

Gümüş

Özcan-Bulut

et al. 2021

Journal of Periodontology

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Background: To evaluate the cytokine profile in gingival crevicular fluid (GCF) and serum of pediatric inflammatory bowel disease (IBD) patients and determine the cluster patterns of cytokines. Methods: Fifty IBD patients and 21 systemically healthy children were enrolled in the study. The GCF samples were collected from the participants during periodontal examination and periodontal indices were recorded. Based on activity indexes and response to conventional treatment, patients with IBD were further categorized into subgroups as: remission, active disease, and treatment-resistant.Serum samples were obtained from IBD patients to determine serum levels of cytokines. The levels of pro-(interleukin (IL)-1β, IL-12, IL-21, IL-22, IL-23, IL-17A, IL-17F) and anti-inflammatory (IL-4, IL-10) cytokines in serum and GCF were measured using Enzyme-linked Immunosorbent Assay (ELISA) kits. Results: Among 50 IBD patients, 58% were in remission, 20% had active disease, and 22% were defined as treatment-resistant. The severity of gingival inflammation measured by the criteria of Löe had increasing trends in IBD patients with active disease and treatment resistance. GCF IL-1β level was lower and GCF IL-4 and GCF IL-23 levels were higher in IBD patients compared to healthy controls.In the active disease group, more cytokine clusters occurred compared to the control group and other IBD subgroups, as explained by increased cytokine-cytokine interactions. Conclusions:Considering the increased complexity of cytokine interactions and the increased severity of gingival inflammation in patients with active disease, it can be concluded that disease activity might have an impact on gingival inflammation in pediatric patients with IBD.

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Durability of Infliximab Is Associated With Disease Extent in Children With Inflammatory Bowel Disease

Cited by 14 publications

References 29 publications

NUDT15 intermediate metabolisers are associated with lower loss of response in paediatric Crohn’s disease patients treated by combination treatment with infliximab and azathioprine

NUDT15 intermediate metabolisers are associated with lower loss of response in paediatric Crohn’s disease patients treated by combination treatment with infliximab and azathioprine

Outcomes of a National Cohort of Children with Acute Severe Ulcerative Colitis

Cytokine profile in serum and gingival crevicular fluid of children with inflammatory bowel disease: A case‐control study

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