Dataset Information

Whole Transcription Profile of Responders to Anti-TNF Drugs in Pediatric Inflammatory Bowel Disease.

ABSTRACT:

Background

Up to 30% of patients with pediatric inflammatory bowel disease (IBD) do not respond to anti-Tumor Necrosis Factor (anti-TNF) therapy. The aim of this study was to identify pharmacogenomic markers that predict early response to anti-TNF drugs in pediatric patients with IBD.

Methods

An observational, longitudinal, prospective cohort study was conducted. The study population comprised 38 patients with IBD aged < 18 years who started treatment with infliximab or adalimumab (29 responders and nine non-responders). Whole gene expression profiles from total RNA isolated from whole blood samples of six responders and six non-responders taken before administration of the biologic and after two weeks of therapy were analyzed using next-generation RNA sequencing. The expression of six selected genes was measured for purposes of validation in all of the 38 patients recruited using qPCR.

Results

Genes were differentially expressed in non-responders and responders (32 before initiation of treatment and 44 after two weeks, Log2FC (Fold change) >0.6 or <-0.6 and p value < 0.05). After validation, FCGR1A, FCGR1B, and GBP1 were overexpressed in non-responders two weeks after initiation of anti-TNF treatment (Log2FC 1.05, 1.21, and 1.08, respectively, p value < 0.05).

Conclusion

Expression of the FCGR1A, FCGR1B, and GBP1 genes is a pharmacogenomic biomarker of early response to anti-TNF agents in pediatric IBD.

SUBMITTER: Salvador-Martin S

PROVIDER: S-EPMC7830359 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Publications

Whole Transcription Profile of Responders to Anti-TNF Drugs in Pediatric Inflammatory Bowel Disease.

Salvador-Martín Sara S Kaczmarczyk Bartosz B Álvarez Rebeca R Navas-López Víctor Manuel VM Gallego-Fernández Carmen C Moreno-Álvarez Ana A Solar-Boga Alfonso A Sánchez Cesar C Tolin Mar M Velasco Marta M Muñoz-Codoceo Rosana R Rodriguez-Martinez Alejandro A Vayo Concepción A CA Bossacoma Ferrán F Pujol-Muncunill Gemma G Fobelo María J MJ Millán-Jiménez Antonio A Magallares Lorena L Martínez-Ojinaga Eva E Loverdos Inés I Eizaguirre Francisco J FJ Blanca-García José A JA Clemente Susana S García-Romero Ruth R Merino-Bohórquez Vicente V González de Caldas Rafael R Vázquez Enrique E Dopazo Ana A Sanjurjo-Sáez María M López-Fernández Luis A LA

Pharmaceutics 20210108 1

<h4>Background</h4>Up to 30% of patients with pediatric inflammatory bowel disease (IBD) do not respond to anti-Tumor Necrosis Factor (anti-TNF) therapy. The aim of this study was to identify pharmacogenomic markers that predict early response to anti-TNF drugs in pediatric patients with IBD.<h4>Methods</h4>An observational, longitudinal, prospective cohort study was conducted. The study population comprised 38 patients with IBD aged < 18 years who started treatment with infliximab or adalimumab ...[more]

PMID: 33429950

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Project description:Although initially described as an anti-tumor mediator, tumor necrosis factor-alpha (TNF) is generally considered as the master pro-inflammatory cytokine. It plays a crucial role in the pathogenesis of inflammatory diseases, such as rheumatoid arthritis (RA), inflammatory bowel disease, ankylosing spondylitis (AS), and psoriasis. Consequently, anti-TNF therapy has become mainstay treatment for autoimmune diseases. Historically, anti-inflammatory agents were developed before the identification of TNF. Salicylates, the active components of Willow spp., were identified in the mid-19th century for the alleviation of pain, fever, and inflammatory responses. Study of this naturally occurring compound led to the discovery of aspirin, which was followed by the development of non-steroidal anti-inflammatory drugs (NSAIDs) due to the chemical advances in the 19th-20th centuries. Initially, the most of NSAIDs were organic acid, but the non-acidic compounds were also identified as NSAIDs. Although effective in the treatment of inflammatory diseases, NSAIDs have some undesirable and adverse effect, such as ulcers, kidney injury, and bleeding in the gastrointestinal tract. In the past two decades, anti-TNF biologics were developed. Drugs belong to this class include soluble TNF receptor 2 fusion protein and anti-TNF antibodies. The introduction of anti-TNF therapeutics has revolutionized the management of autoimmune diseases, such as RA, psoriatic arthritis (PsA), plaque psoriasis (PP), AS, CD and ulcerative colitis (UC). Nevertheless, up to 40% of patients have no response to anti-TNF treatment. Furthermore, this treatment is associated with some adverse effects such as increased risk of infection, and even triggered the de novo development of autoimmune diseases. Such harmful effect of anti-TNF treatment is likely caused by the global inhibition of TNF biological functions. Therefore, specific inhibition of TNF receptor (TNFR1 or TNFR2) may represent a safer and more effective treatment, as proposed by some recent studies. In this review article, the historical development of anti-inflammatory drugs after World War II as briefly described above will be reviewed and analyzed. The future trend in the development of novel TNF receptor-targeting therapeutics will be discussed in the context of latest progress in the research of TNF biology.

Project description:BackgroundVaccination against SARS-CoV-2 is a highly effective strategy to protect against infection, which is predominantly mediated by vaccine-induced antibodies. Postvaccination antibodies are robustly produced by those with inflammatory bowel disease (IBD) even on immune-modifying therapies but are blunted by anti-TNF therapy. In contrast, T-cell response which primarily determines long-term efficacy against disease progression,, is less well understood. We aimed to assess the post-vaccination T-cell response and its relationship to antibody responses in patients with inflammatory bowel disease (IBD) on immune-modifying therapies.MethodsWe evaluated IBD patients who completed SARS-CoV-2 vaccination using samples collected at four time points (dose 1, dose 2, 2 weeks after dose 2, 8 weeks after dose 2). T-cell clonal analysis was performed by T-cell Receptor (TCR) immunosequencing. The breadth (number of unique sequences to a given protein) and depth (relative abundance of all the unique sequences to a given protein) of the T-cell clonal response were quantified using reference datasets and were compared to antibody responses.ResultsOverall, 303 subjects were included (55% female; 5% with prior COVID) (Table). 53% received BNT262b (Pfizer), 42% mRNA-1273 (Moderna) and 5% Ad26CoV2 (J&J). The Spike-specific clonal response peaked 2 weeks after completion of the vaccine regimen (3- and 5-fold for breadth and depth, respectively); no changes were seen for non-Spike clones, suggesting vaccine specificity. Reduced T-cell clonal depth was associated with chronologic age, male sex, and immunomodulator treatment. It was preserved by non-anti-TNF biologic therapies, and augmented clonal depth was associated with anti-TNF treatment. TCR depth and breadth were associated with vaccine type; after adjusting for age and gender, Ad26CoV2 (J&J) exhibited weaker metrics than mRNA-1273 (Moderna) (p=0.01 for each) or BNT262b (Pfizer) (p=0.056 for depth). Antibody and T-cell responses were only modestly correlated. While those with robust humoral responses also had robust TCR clonal expansion, a substantial fraction of patients with high antibody levels had only a minimal T-cell clonal response.ConclusionAge, sex and select immunotherapies are associated with the T-cell clonal response to SARS-CoV-2 vaccines, and T-cell responses are low in many patients despite high antibody levels. These factors, as well as differences seen by vaccine type may help guide reimmunization vaccine strategy in immune-impaired populations. Further study of the effects of anti-TNF therapy on vaccine responses are warranted.

Dataset Information

Whole Transcription Profile of Responders to Anti-TNF Drugs in Pediatric Inflammatory Bowel Disease.

Background

Methods

Results

Conclusion

Publications

Whole Transcription Profile of Responders to Anti-TNF Drugs in Pediatric Inflammatory Bowel Disease.

Similar Datasets

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