Can We Predict the Efficacy of Anti-TNF-α Agents?

Lopetuso, Loris Riccardo; Gerardi, Viviana; Papa, Valerio; Scaldaferri, Franco; Rapaccini, Gian Lodovico; Gasbarrini, Antonio; Papa, Alfredo

doi:10.3390/ijms18091973

Cited by 80 publications

(73 citation statements)

References 92 publications

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“…The predictors of a response to anti‐TNFα have been widely studied . However, there are no published data on potential predictors of a response to the new drugs used in CD.…”

Section: Discussionmentioning

confidence: 99%

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Real‐world short‐term effectiveness of ustekinumab in 305 patients with Crohn’s disease: results from the ENEIDA registry

Iborra¹,

Beltrán²,

Fernández-Clotet³

et al. 2019

Aliment Pharmacol Ther

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Summary Background There are limited data of ustekinumab administered according to the doses recommended in the UNITI studies. Aim To assess the real‐world, short‐term effectiveness of ustekinumab in refractory Crohn's disease (CD) Methods Multicentre study of CD patients starting ustekinumab after June 2017 at the recommend dose (260, 390 or 520 mg based on weight ~6 mg/kg IV week 0 and 90 mg subcutaneously week 8). Values for Harvey‐Bradshaw Index (HBI), C‐reactive protein (CRP) and faecal calprotectin (FC) were recorded at baseline and at weeks 8 and 14. Demographic and clinical data, previous treatments, AEs and hospitalisations were documented. Possible predictors of clinical remission were examined. Results Three hundred and five patients were analysed (≥2 previous anti‐TNFα therapies 64% and vedolizumab 29%). At baseline, 217 (72%) had an HBI >4 points. Of these, 101 (47%) and 126 (58%) achieved clinical remission at weeks 8 and 14, respectively. FC levels returned to normal (<250 µg/g) in 46% and 54% of the patients at weeks 8 and 14 respectively. CRP returned to normal (<3 mg/L) in the 35% and 41% of the patients at week 8 and 14 respectively. AEs were recorded in 38, and 40 patients were hospitalised. Intolerance to the most recent anti‐TNF agent and fewer previous anti‐TNF agents were associated with clinical remission at week 14. Endoscopic severity was associated with poor response. Conclusion This is the first study to show the real‐world effectiveness and safety of ustekinumab administered according to the recommended induction regimen in a cohort of highly refractory CD patients.

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“…The predictors of a response to anti‐TNFα have been widely studied . However, there are no published data on potential predictors of a response to the new drugs used in CD.…”

Section: Discussionmentioning

confidence: 99%

“…The predictors of a response to anti-TNFα have been widely studied. 19,25 However, there are no published data on potential predictors of a response to the new drugs used in CD. Barré et al 26 recently published a review of various observational studies that analysed a response to SC ustekinumab in patients with CD.…”

Section: Discussionmentioning

confidence: 99%

Real‐world short‐term effectiveness of ustekinumab in 305 patients with Crohn’s disease: results from the ENEIDA registry

Iborra¹,

Beltrán²,

Fernández-Clotet³

et al. 2019

Aliment Pharmacol Ther

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“…In this study, we bring together decades of research on Tnf biology and its role in inflammation using this single screening approach. Anti-Tnf therapy remains one of the most effective methods for the treatment of various autoimmune diseases, including rheumatoid arthritis (RA) and irritable bowel disease (IBD) (39, 40), yet as many as 20-40% of patients don't respond to treatment (41). Our findings show that editing of Tnf resulted in elevated Il6 levels, which is another important pro-inflammatory cytokine and might explain lack in response to anti-Tnf therapy.…”

Section: Dissection the Complex Biology Of The Tumor Necrosis Factor mentioning

confidence: 76%

High throughput CRISPR screening identifies genes involved in macrophage viability and inflammatory pathways

Covarrubias

Vollmers

Capili

et al. 2019

Preprint

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Macrophages are critical cells of the innate immune system involved in the recognition and destruction of invading microbes in addition to the resolution of inflammation and maintenance of homeostasis. Understanding the genes involved in all aspects of macrophage biology is essential to gaining new insights into immune system dysregulation during diseases that range from autoinflammatory to cancer. Here we utilize high throughput clustered regularly interspaced short palindromic repeats (CRISPR) screening to generate a resource that identifies genes required for macrophage viability and function. First, we employ a pooled based CRISPR/Cas nuclease active screening approach to identify essential genes required for macrophage viability by targeting genes within coding exons. In addition, we also target 3'UTRs to gain insights into new cis-regulatory regions that control expression of these essential genes. Second, using our recently generated NF-κB reporter macrophage line, we perform a fluorescence-activated cell sorting (FACS)-based high-throughput genetic screen to identify regulators of inflammation. We identify a number of novel positive and negative regulators of the NF-κB pathway as well as unraveling complexities of the TNF signaling cascade showing it can function in an autocrine manner to negatively regulate the pathway. Utilizing a single complex library design we are capable of interrogating various aspects of macrophage biology, generating a resource for future studies. SignificanceExcess inflammation is associated with a variety of autoimmune diseases and cancers. Macrophages are important mediators of this inflammatory response. Defining the genes involved in their viability and effector function is needed to completely understand these two important aspects of macrophage biology. Here we screened over 21,000 genes and generated a resource guide of genes required for macrophage viability as well as novel positive and negative regulators of NF-κB signaling. We reveal important regulatory aspects of TNF signaling and showing that membrane-bound TNF primarily functions in an autocrine fashion to negatively regulate inflammation. /body

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“…Other patient-(age or genetic signature) and disease-(disease severity or duration) related factors have also been suggested to play a role. [59][60][61] In any case, current data show that a target concentration range, rather than a single value, may be preferable for the application of TDM in IBD clinical practice. Based on the published literature, proposed target trough ranges for infliximab are 3-7 μg/mL in IBD.…”

Section: Target Concentration In Tdmmentioning

confidence: 98%

Therapeutic Drug Monitoring of Biologics for Inflammatory Bowel Disease: An Answer to Optimized Treatment?

Hoseyni

Zhou

2018

The Journal of Clinical Pharma

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Therapeutic drug monitoring (TDM), or the measurement of drug concentrations in blood and antidrug antibodies, for biologic therapies used to treat inflammatory bowel disease (IBD) is an area of growing interest within the IBD community. When there is a definable relationship between drug concentration and clinical effect, blood concentration of biologics (and antidrug antibodies assessment) could be used to predict patient response and to titrate the biologics to maximize therapeutic benefit. This dose individualization has been proven to be more efficacious and cost-effective than empiric dose adjustment and can better guide therapeutic decisions regarding therapy withdrawal or switch. Appropriate implementation and interpretation of drug concentration measurement in TDM are essential to ensure full clinical benefit. Factors that need to be considered include sources of variability, timing of blood sampling, dosing history, analytical performance, immunogenicity, comedications, and clinical status of the patients. Desired target concentrations for biologics used in IBD have not been clearly determined yet. Published concentration thresholds differed widely for a given biologic, indicating a lack of consistent information. Factors other than drug concentration that may contribute to the dose-response variation are largely missing in the current TDM setting. A target range is likely preferable to a single value for TDM of biologics in IBD, and additional prospective research needs to be conducted in order to establish these ranges. Moving forward, TDM may be combined with pharmacodynamic end points and modeling and simulation tools for improved therapeutic benefit in IBD.

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Can We Predict the Efficacy of Anti-TNF-α Agents?

Cited by 80 publications

References 92 publications

Real‐world short‐term effectiveness of ustekinumab in 305 patients with Crohn’s disease: results from the ENEIDA registry

Real‐world short‐term effectiveness of ustekinumab in 305 patients with Crohn’s disease: results from the ENEIDA registry

High throughput CRISPR screening identifies genes involved in macrophage viability and inflammatory pathways

Therapeutic Drug Monitoring of Biologics for Inflammatory Bowel Disease: An Answer to Optimized Treatment?

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