Evolution of cytokines and inflammatory biomarkers during infliximab induction therapy and the impact of inflammatory burden on primary response in patients with Crohn’s disease

Billiet, Thomas; Cleynen, Isabelle; Ballet, Vera; Claes, Karolien; Princen, Fred; Singh, Sharat; Ferrante, Marc; Assche, Gert Van; Gils, Ann; Vermeire, Séverine

doi:10.1080/00365521.2017.1339825

Cited by 40 publications

(40 citation statements)

References 21 publications

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“…However, no prior studies regarding sequential changes in the actual tissue concentration of TNF‐α and the complex are known, thus we examined previously reported results showing the concentration in serum. Previous studies have reported that the serum concentration of TNF‐α was increased after infliximab therapy in patients with Crohn's disease (Billiet et al, ; Candon et al, ; Cornillie et al, ; Eder et al, ; Ogawa, Matsumoto, Esaki, Torisu, & Iida, ), as well as in those with rheumatoid arthritis (RA) (Charles et al, ; Cuchacovich et al, ) and juvenile idiopathic arthritis (JIA) (Levalampi et al, ). Furthermore, the serum concentration of TNF‐α has also been shown to be positively associated with both the dose and the serum concentration of infliximab (Candon et al, ; Charles et al, ).…”

Section: Discussionmentioning

confidence: 99%

Prediction of clinical effects of infliximab administered for inflammatory bowel disease based on pharmacokinetic and pharmacodynamic modeling

Kimura

Yoshida

Katagiri

et al. 2019

Biopharm & Drug Disp

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Infliximab (IFX) is used as a therapeutic agent for ulcerative colitis (UC) and Crohn's disease (CD). Although the dosage regimen has been established through clinical trial experience, it has yet to be assessed with a pharmacokinetic and pharmacodynamic model. The present study analysed sequential changes of clinical response in patients with ulcerative colitis and Crohn's disease following repeated administrations of infliximab using the pharmacokinetic/pharmacodynamic model. In addition, the dosage regimen presently used for patients with ulcerative colitis was evaluated, as well as the potential efficacy gained by increasing the dose and/or reducing the interval of administration for patients with Crohn's disease. Furthermore, the possibility of evaluating the difference between both diseases with regard to the efficacy of infliximab was investigated. Sequential changes in the clinical response values obtained with our model were in good agreement with the observed values following administration of infliximab in patients with ulcerative colitis and Crohn's disease. The results showed the importance of a loading dose for patients with ulcerative colitis, as well as the efficacy of increasing the dose and reducing the interval for patients with Crohn's disease. Also, the efficacy of infliximab for both diseases is suggested to be similar. In conclusion, our results show a possible modeling scenario that can accommodate the clinical response to infliximab administered for ulcerative colitis and Crohn's disease. Furthermore, it provides confirmation for the present dosage regimens given for these diseases.

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Section: Discussionmentioning

confidence: 99%

Prediction of clinical effects of infliximab administered for inflammatory bowel disease based on pharmacokinetic and pharmacodynamic modeling

Kimura

Yoshida

Katagiri

et al. 2019

Biopharm & Drug Disp

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“…IL-8 concentrations at baseline were higher in primary non-responders compared to responders in CD patients treated with infliximab. Multiple logistic regression identified TNF/CRP ratio at baseline as predictive for primary non-response to infliximab at week 14 ( 112 ).…”

Section: Blood Markersmentioning

confidence: 99%

Personalizing Treatment in IBD: Hype or Reality in 2020? Can We Predict Response to Anti-TNF?

2020

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The advent of anti-TNF agents as the first approved targeted therapy in the treatment of inflammatory bowel disease (IBD) patients has made a major impact on our existing therapeutic algorithms. They have not only been approved for induction and maintenance treatment in IBD patients, but have also enabled us to define and achieve novel therapeutic outcomes, such as combination of clinical symptom control and endoscopic remission, as well as mucosal healing. Nevertheless, approximately one third of treated patients do not respond to initiated anti-TNF therapy and these treatments are associated with sometimes severe systemic side-effects. There is therefore the currently unmet clinical need do establish predictive markers of response to identify the subgroup of IBD patients, that have a heightened probability of response. There have so far been approaches from different fields of IBD research, to descry markers that would empower us to apply TNF-inhibitors in a more rational manner. These markers encompass findings from disease-related and clinical factors, pharmacokinetics, biochemical markers, blood and stool derived parameters, pharmacogenomics, microbial species, metabolic compounds, and mucosal factors. Furthermore, changes in the intestinal immune cell composition in response to therapeutic pressure of anti-TNF treatment have recently been implicated in the process of molecular resistance to these drugs. Insights into factors that determine resistance to anti-TNF therapy give reasonable hope, that a more targeted approach can then be utilized in these non-responders. Here, IL-23 could be identified as one of the key factors determining resistance to TNF-inhibitors. Growing insights into the molecular mechanism of action of TNF-inhibitors might also enable us to derive critical molecular markers that not only mediate the clinical effects of anti-TNF therapy, but which level of expression might also correlate with its therapeutic efficacy. In this narrative review, we present an overview of currently identified possible predictive markers for successful anti-TNF therapy and discuss identified molecular pathways that drive resistance to these substances. We will also point out the necessity and difficulty of developing and validating a diagnostic marker concerning clinically relevant outcome parameters, before they can finally enter daily clinical practice and enable a more personalized therapeutic approach.

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“…The TNF/CRP ratio was associated with clinical response (OR 2.8 [1.4‐5.5], P = 0.003), which may underscore the contribution of TNF‐independent inflammation. An elevated IL‐8 concentration at baseline was also associated with nonresponse . Finally, a decrease in serum IL‐9 between baseline and week 14 could accurately predict both clinical remission and mucosal healing at week 30 (AUC 0.803 and 0.752 respectively) …”

Section: Resultsmentioning

confidence: 94%

“…In the absence of additional pharmacokinetic data, it remains uncertain whether these proteins reflect true nonresponders or an increased inflammatory load that requires intensified treatment to obtain adequate drug levels. Several studies have attempted to discriminate nonresponse based on TNF‐driven from TNF‐independent disease . However, biomarkers to identify true anti‐TNF nonresponse unrelated to underlying pharmacokinetics are still coveted and further research is warranted.…”

Section: Discussionmentioning

confidence: 99%

Systematic review: predictive biomarkers of therapeutic response in inflammatory bowel disease—personalised medicine in its infancy

Stevens

Matheeuwsen

Lönnkvist

et al. 2018

Aliment Pharmacol Ther

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Summary Background Inflammatory bowel disease (IBD) is characterised by substantial heterogeneity in treatment response. With an expanding number of therapeutic agents, identifying optimal treatment at the patient level remains a major challenge. Aim To systematically review the available literature on predictive biomarkers of therapeutic response in IBD. Methods An electronic literature search was performed on 30 January 2018 using MEDLINE, EMBASE and the Cochrane Library. Retrospective, prospective, uncontrolled and controlled studies reporting on biomarkers predicting therapeutic response in paediatric and adult IBD populations were eligible for inclusion. The methodological quality of the included studies was assessed using the QUIPS tool. Due to anticipated heterogeneity and limited data, a qualitative, rather than quantitative, assessment was planned. Results Of the 10 638 citations identified, 92 articles met the inclusion criteria. Several potential DNA, mRNA and protein markers were evaluated as predictive biomarkers. Most studies focused on predicting response to anti‐TNF agents. Substantial between‐study heterogeneity was identified with respect to both the biomarkers studied and the definition of response. None of the included studies received a low risk of bias rating for all six domains. Currently, none of the biomarkers is sufficiently predictive for clinical use. Conclusions The search for predictive biomarkers is still in its infancy and current evidence is limited. Future research efforts should take into account the high patient heterogeneity within prospective trials with objective response assessment. Predictive models will most likely comprise a combination of several molecular markers from integrated omics‐levels and clinical characteristics.

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Evolution of cytokines and inflammatory biomarkers during infliximab induction therapy and the impact of inflammatory burden on primary response in patients with Crohn’s disease

Cited by 40 publications

References 21 publications

Prediction of clinical effects of infliximab administered for inflammatory bowel disease based on pharmacokinetic and pharmacodynamic modeling

Prediction of clinical effects of infliximab administered for inflammatory bowel disease based on pharmacokinetic and pharmacodynamic modeling

Personalizing Treatment in IBD: Hype or Reality in 2020? Can We Predict Response to Anti-TNF?

Systematic review: predictive biomarkers of therapeutic response in inflammatory bowel disease—personalised medicine in its infancy

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