Molecular discrimination of responders and nonresponders to anti-TNFalpha therapy in rheumatoid arthritis by etanercept

Koczan, Dirk; Drynda, Susanne; Hecker, Michael; Drynda, Andreas; Guthke, Reinhard; Kekow, J; Thiesen, Hans‐Juergen

doi:10.1186/ar2419

Cited by 114 publications

(100 citation statements)

References 27 publications

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“…In addition, lower expression levels of A20 seem predictive of primary response to infliximab, while non-responders display significantly higher and stable A20 expression levels. These data are in line with studies in rheumatoid arthritis patients 52 and Crohn's disease patients 53 where low A20 expression has been correlated to good anti-TNF response. Taken together, we identified A20 as a potential biomarker for the prognosis of anti-TNF therapy.…”

Section: Discussionsupporting

confidence: 78%

A20 controls intestinal homeostasis through cell-specific activities

et al. 2014

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The transcription factor NF-kB is indispensable for intestinal immune homeostasis, but contributes to chronic inflammation and inflammatory bowel disease (IBD). A20, an inhibitor of both NF-kB and apoptotic signalling, was identified as a susceptibility gene for multiple inflammatory diseases, including IBD. Despite absence of spontaneous intestinal inflammation in intestinal epithelial cell (IEC) specific A20 knockout mice, we found additional myeloid-specific A20 deletion to synergistically drive intestinal pathology through cell-specific mechanisms. A20 ensures intestinal barrier stability by preventing cytokine-induced IEC apoptosis, while A20 prevents excessive cytokine production in myeloid cells. Combining IEC and myeloid A20 deletion induces ileitis and severe colitis, characterized by IEC apoptosis, Paneth and goblet cell loss, epithelial hyperproliferation and intestinal microbiota dysbiosis. Continuous epithelial cell death and regeneration in an inflammatory environment sensitizes cells for neoplastic transformation and the development of colorectal tumours in aged mice.

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Section: Discussionsupporting

confidence: 78%

A20 controls intestinal homeostasis through cell-specific activities

et al. 2014

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“…The few pharmacogenomics studies published so far were conducted to find genes predictive for clinical response to TNF-blocking therapy. [13][14][15][16][17] Overall, the identification of predictive biomarkers for clinical response to treatment has not yet led to consistent results, although synovial TNF expression may explain approximately 10% of the effect. 6 As indicated by the small sample size per clinical response group, this study was not designed to identify predictors of clinical response to treatment.…”

Section: Discussionmentioning

confidence: 99%

Pharmacogenomics of infliximab treatment using peripheral blood cells of patients with rheumatoid arthritis

et al. 2010

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“…38 Moreover, PPP1R15A was recently linked to responsiveness to TNF inhibitor therapy in rheumatoid arthritis. 39 Among the genes induced by P. gingivalis LPS is I B␣, which can re-exert control over NF-B, along with I B ⑀ and particularly, I B , which binds to NF-B p50 in the nucleus and has both negative (IL-8, TNF-␣) and positive (IL-6, IL12p40, GM-CSF, G-CSF) regulatory actions. 40,41 Although rapid NF-B activation is necessary for host defense against microbial invasion, failure to re-exert control with persistent NF-B activation may result in tissue injury, and in the extreme, to organ failure, systemic disease, and death.…”

Section: Discussionmentioning

confidence: 99%

Rapid Myeloid Cell Transcriptional and Proteomic Responses to Periodontopathogenic Porphyromonas gingivalis

Nares

Moutsopoulos

Angelov

et al. 2009

The American Journal of Pathology

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Long-lived monocytes, macrophages, and dendritic cells (DCs) are Toll-like receptor-expressing, antigenpresenting cells derived from a common myeloid lineage that play key roles in innate and adaptive immune responses. Based on immunohistochemical and molecular analyses of inflamed tissues from patients with chronic destructive periodontal disease, these cells, found in the inflammatory infiltrate, may drive the progressive periodontal pathogenesis. To investigate early transcriptional signatures and subsequent proteomic responses to the periodontal pathogen, Porphyromonas gingivalis, donor-matched human blood monocytes, differentiated DCs, and macrophages were exposed to P. gingivalis lipopolysaccharide (LPS) and gene expression levels were measured by oligonucleotide microarrays. In addition to striking differences in constitutive transcriptional profiles between these myeloid populations, we identify a P. gingivalis LPS-inducible convergent, transcriptional core response of more than 400 annotated genes/ESTs among these populations, reflected by a shared, but quantitatively distinct, proteomic response. Nonetheless, clear differences emerged between the monocytes, DCs, and macrophages. The finding that long-lived myeloid inflammatory cells, particularly DCs, rapidly and aggressively respond to P. gingivalis LPS by generating chemokines, proteases, and cytokines capable of driving T-helper cell lineage polarization without evidence of corresponding immunosuppressive pathways highlights their prominent role in host defense and progressive tissue pathogenesis. The shared, unique, and/or complementary transcriptional and proteomic profiles may frame the context of the host response to P. gingivalis, contributing to the destructive nature of periodontal inflammation.

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Molecular discrimination of responders and nonresponders to anti-TNFalpha therapy in rheumatoid arthritis by etanercept

Abstract: Introduction About 30% of rheumatoid arthritis patients fail to respond adequately to TNFα-blocking therapy. There is a medical and socioeconomic need to identify molecular markers for an early prediction of responders and nonresponders.

Cited by 114 publications

References 27 publications

A20 controls intestinal homeostasis through cell-specific activities

A20 controls intestinal homeostasis through cell-specific activities

Pharmacogenomics of infliximab treatment using peripheral blood cells of patients with rheumatoid arthritis

Rapid Myeloid Cell Transcriptional and Proteomic Responses to Periodontopathogenic Porphyromonas gingivalis

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