Early Infliximab Trough Levels Predict Remission at one Year in Pediatric IBD Patients

Crohn’s disease and ulcerative colitis are chronic inflammatory disorders of the gastrointestinal tract. Treatment options include biologic therapies; however, a proportion of patients lose response to biologics, partly due to the formation of anti-drug antibodies (ADAbs). Concomitant immunosuppressive agents reduce the development of ADAbs. This review article aims to assess the immunogenicity of biologic therapies and their clinical implications. A comprehensive literature search was conducted for articles published January 2009 to August 2015 reporting immunogenicity to adalimumab (ADM), certolizumab pegol (CZP), golimumab, infliximab (IFX), ustekinumab, and vedolizumab in inflammatory bowel disease (IBD). Eligible articles were reviewed and quality assessed by independent reviewers. Overall, 122 publications reporting 114 studies were assessed. ADAbs were reported for all agents, but the percentage of patients developing ADAbs was extremely variable, with the highest (65.3%) being for IFX administration to patients with IBD. ADAb presence was frequently associated with a reduction in primary efficacy and a loss of response, and, for IFX, an increase in adverse events (AEs). Lower serum levels of ADM, CZP and IFX were seen in ADAbs-positive rather than ADAbs-negative patients; pharmacokinetic data were unavailable for other therapies. Little information was available regarding the timing of ADAb development; studies reported their detection from as early as 10–14 days up to months after treatment initiation. Biologic therapies carry an intrinsic risk of immunogenicity, although reported rates of ADAbs vary considerably. The clinical implications of immunogenicity are a concern for effective treatment; further research, particularly into the more recently approved biologics, is required.

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“…However, ADAbs can also take months to reach detectable levels ( Table 3 ). 26 , 37 , 38 , 41 , 47 , 49 – 61 …”

Section: Resultsmentioning

confidence: 99%

Immunogenicity of biologics in inflammatory bowel disease

Vermeire

Gils

Accossato

et al. 2018

Therap Adv Gastroenterol

181

146

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“…The electronic search yielded 2558 potentially relevant articles. An additional 11 articles were identified from reference lists in review articles (19)(20)(21)(22)(23)(24). After removal of duplicates, 2033 FIGURE 1.…”

Section: Resultsmentioning

confidence: 99%

“…Of the 32 studies that were selected, 23 were full text manuscripts and 9 were abstracts. Regarding study design, 4 were randomized controlled trials (7,25-27), 2 were cross-sectional studies (28,29), and 26 were cohort studies, of which 14 were retrospective (23,(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42), 11 were prospective (19)(20)(21)24,(43)(44)(45)(46)(47)(48)(49), and 1 partially retrospective and prospective (22) as listed in Supplemental Table 1 (Supplemental Digital Content, http:// links.lww.com/MPG/B781).…”

Section: Resultsmentioning

confidence: 99%

“…On the contrary, achieving higher IFX-TLs by increasing IFX dose or dosing interval can potentially prevent ATI formation (Table 2), because in adults both prolonged low IFX-TLs and low IFX-TLs at week 14 may precede ATI formation (68,69). Similarly to adult data, Rosenthal et al (21) reported an inverse association between IFX-TL at week 14 and ATIs at week 54 (P ¼ 0.003) in pediatric patients with IBD. Several studies reported a reduction of ATI formation and ATI concentration with concomitant IM therapy, and an increase of IFX-TL.…”

Section: Discussionmentioning

confidence: 96%

“…Van Hoeve et al (42) reported that median TLs during maintenance treatment were significantly higher in children in clinical, biological, and endoscopic remission compared to patients not in remission. Two studies reported that week 14 TLs may have predictive value for clinical remission without dose intensification during maintenance or deep remission (clinical remission with normal CRP) (21,46). Hofmekler et al (37) defined clinical outcome as the need for dose optimization and reported that 37% of children who required dose optimization had low TLs during maintenance (<3 mg/mL).…”

Section: Clinical Outcome: Pharmacodynamicsmentioning

confidence: 99%

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Pharmacokinetics, Pharmacodynamics, and Immunogenicity of Infliximab in Pediatric Inflammatory Bowel Disease

Winter

Joosse

Taminiau

et al. 2020

J. pediatr. gastroenterol. nutr.

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Objectives: Infliximab (IFX), a monoclonal antibody directed against tumor necrosis factor alpha is a potent treatment option for inflammatory bowel disease (IBD). Dosing regimens in children are extrapolated from adult data using a fixed, weight-based dose, which is often not adequate. While clinical trials have focused on safety and efficacy, there is limited data on pharmacokinetic characteristics and immunogenicity of IFX in children. The objective was to provide a systematic overview of current literature on pharmacokinetic and immunogenicity of IFX in children with IBD, to assess the validity of current adult to pediatric dosing extrapolation. Methods: A literature search identified publications up to October 2018. Eligibility criteria were study population consisting of children and/or adolescents with IBD, report of IFX trough levels and/or antibodies-to IFX, full text article or abstract, article in English, and original data. Results: Initial electronic search yielded 2360 potentially relevant articles, with 1831 remaining after removal of duplicates. An additional search yielded another 202 potentially relevant articles. Of the 2033 retrieved articles, 2000 articles were excluded based on title, abstract, or eligibility criteria. Clearance of IFX was increased in young children and children with extensive disease, leading to lower trough levels after extrapolated dosing of 5 mg/kg, antibodies-to IFX emergence, and subsequent reduced efficacy. Conclusions: Adult to pediatric weight-based dosing extrapolation is often inadequate. We provide several considerations for optimal dosing of IFX in children and adolescents with IBD.

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Biomarkers predicting the effect of anti‐TNF treatment in paediatric and adult inflammatory bowel disease

Winter,

de Bruyne,

van der Woude

et al. 2024

J. pediatr. gastroenterol. nutr.

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ObjectivesPaediatric and adult inflammatory bowel disease (pIBD, aIBD) patients may lose response to anti‐TNF treatment within the first year. Adult‐extrapolated weight‐based dosing is incorrect in children, due to age‐related pharmacokinetic differences. We investigated biomarkers for initial and maintenance of response to infliximab (IFX) or adalimumab (ADA), comparing pIBD and aIBD patients.MethodsIn this prospective, observational study, pIBD (n = 24) and aIBD (n = 21) patients were included when initiating anti‐TNF. Escalation from standard dosing and continued anti‐TNF at 12 and 18 months were assessed. Biomarkers included clinical laboratory parameters, faecal calprotectin (FCP) and IFX trough levels (TLs). Plasma proteomics was performed in pIBD.ResultsDuring our study, treatment escalation (in clinical loss of response) occurred more common in pIBD versus aIBD (p = 0.02). We established that IFX therapy escalation in pIBD patients was not due to low infliximab levels. We identified 9 pro‐inflammatory proteins that were elevated in patients losing response.ConclusionAnti‐TNF exposure‐response relationship may be different in pIBD versus aIBD. No biomarkers for maintained response were identified, but 9 inflammatory proteins were of interest as potential predictors for loss of response in pIBD.

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Early Infliximab Trough Levels Predict Remission at one Year in Pediatric IBD Patients

Cited by 5 publications

References 0 publications

Immunogenicity of biologics in inflammatory bowel disease

Immunogenicity of biologics in inflammatory bowel disease

Pharmacokinetics, Pharmacodynamics, and Immunogenicity of Infliximab in Pediatric Inflammatory Bowel Disease

Biomarkers predicting the effect of anti‐TNF treatment in paediatric and adult inflammatory bowel disease

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