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Tissue and serum markers of inflammation during the follow-up of patients with giant-cell arteritis--a prospective longitudinal study.

Visvanathan S, Rahman MU, Hoffman GS, Xu S, García-Martínez A, Segarra M, Lozano E, Espígol-Frigolé G, Hernández-Rodríguez J, Cid MC - Rheumatology (Oxford) (2011)

Bottom Line: In post-treatment biopsies, mRNA expression of pro-inflammatory cytokines decreased, while vascular remodelling factors increased relative to baseline biopsies.Despite prior findings of high concentrations of TNF-α in temporal artery biopsies of GCA patients, infliximab plus glucocorticosteroids did not result in improved clinical outcomes.Increased measures of this biomarker did not provide useful insight into the relative importance of TNF-α in the pathogenesis of GCA.

View Article: PubMed Central - PubMed

Affiliation: Centocor Research and Development, Malvern, PA, USA.

ABSTRACT

Objective: To evaluate the association between inflammatory markers and relapse in GCA patients longitudinally assessed in a clinical trial of infliximab and glucocorticosteroids.

Methods: Forty-four newly diagnosed GCA patients in glucocorticosteroid-induced remission were randomized to receive infliximab 5 mg/kg or placebo plus daily glucocorticosteroids, tapered using a standardized schedule. Sera were analysed for inflammatory markers at multiple, pre-defined time points. Temporal artery biopsies were performed in four patients before and after treatment to analyse changes in inflammatory and vascular remodelling marker expression.

Results: Thirteen of 44 patients relapsed. Similar proportions of relapsed patients were present in both treatment arms. ESR, CRP, intercellular adhesion molecule (ICAM)-1, TNF-α, and IL-12p40 were significantly elevated near relapse. In post-treatment biopsies, mRNA expression of pro-inflammatory cytokines decreased, while vascular remodelling factors increased relative to baseline biopsies. Tissue IL-12p40 and IFN-γ mRNA remained elevated in relapsing vs remitting patients.

Conclusion: Despite prior findings of high concentrations of TNF-α in temporal artery biopsies of GCA patients, infliximab plus glucocorticosteroids did not result in improved clinical outcomes. Increased measures of this biomarker did not provide useful insight into the relative importance of TNF-α in the pathogenesis of GCA. Gene expression analysis in paired temporal artery biopsies pre- and post-treatment revealed decreased inflammatory activity and active vascular remodelling following treatment. In relapsing patients, increased expression of IFN-γ and IL-12p40 in post-treatment biopsies suggests a role in sustaining disease and setting the stage for relapse during treatment withdrawal.

Trial registration: ClinicalTrials.gov; http://www.clinicaltrials.gov; NCT00076726.

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Related in: MedlinePlus

mRNA concentrations (Th1 cytokines) in post-treatment temporal artery biopsies from patients who relapsed and those who did not relapse. Values are relative to those found in a normal temporal artery. In addition to gluccocorticosteroids, Patient 1 received placebo and Patients 2–4 received infliximab.
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Figure 1: mRNA concentrations (Th1 cytokines) in post-treatment temporal artery biopsies from patients who relapsed and those who did not relapse. Values are relative to those found in a normal temporal artery. In addition to gluccocorticosteroids, Patient 1 received placebo and Patients 2–4 received infliximab.

Mentions: A survey of 90 genes expressed in second biopsies revealed that patients with more frequent relapses had higher concentrations of IL-12p40 and IFN-γ mRNA in their post-treatment biopsies than patients who were more responsive to treatment (Fig. 1). IL-12p40 mRNA remained elevated in frequent relapsing patients but was undetectable in patients in remission. IL-12p35 mRNA was present in low concentrations in frequently relapsing patients. These levels suggested that persistence of IL-12p40 might be partly related to IL-23 (the IL-23p19 subunit is shared with the IL-12p40 subunit), which was not included in the gene-expression card. IL-23p19 mRNA and its related cytokine IL-17 were subsequently analysed by real-time PCR and found to be over-expressed in pre-treatment biopsies and decreased with treatment (Table 3). Although other mRNAs were elevated, no additional genes clearly differentiated between frequently relapsing and remitting patients.Fig. 1


Tissue and serum markers of inflammation during the follow-up of patients with giant-cell arteritis--a prospective longitudinal study.

Visvanathan S, Rahman MU, Hoffman GS, Xu S, García-Martínez A, Segarra M, Lozano E, Espígol-Frigolé G, Hernández-Rodríguez J, Cid MC - Rheumatology (Oxford) (2011)

mRNA concentrations (Th1 cytokines) in post-treatment temporal artery biopsies from patients who relapsed and those who did not relapse. Values are relative to those found in a normal temporal artery. In addition to gluccocorticosteroids, Patient 1 received placebo and Patients 2–4 received infliximab.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3198905&req=5

Figure 1: mRNA concentrations (Th1 cytokines) in post-treatment temporal artery biopsies from patients who relapsed and those who did not relapse. Values are relative to those found in a normal temporal artery. In addition to gluccocorticosteroids, Patient 1 received placebo and Patients 2–4 received infliximab.
Mentions: A survey of 90 genes expressed in second biopsies revealed that patients with more frequent relapses had higher concentrations of IL-12p40 and IFN-γ mRNA in their post-treatment biopsies than patients who were more responsive to treatment (Fig. 1). IL-12p40 mRNA remained elevated in frequent relapsing patients but was undetectable in patients in remission. IL-12p35 mRNA was present in low concentrations in frequently relapsing patients. These levels suggested that persistence of IL-12p40 might be partly related to IL-23 (the IL-23p19 subunit is shared with the IL-12p40 subunit), which was not included in the gene-expression card. IL-23p19 mRNA and its related cytokine IL-17 were subsequently analysed by real-time PCR and found to be over-expressed in pre-treatment biopsies and decreased with treatment (Table 3). Although other mRNAs were elevated, no additional genes clearly differentiated between frequently relapsing and remitting patients.Fig. 1

Bottom Line: In post-treatment biopsies, mRNA expression of pro-inflammatory cytokines decreased, while vascular remodelling factors increased relative to baseline biopsies.Despite prior findings of high concentrations of TNF-α in temporal artery biopsies of GCA patients, infliximab plus glucocorticosteroids did not result in improved clinical outcomes.Increased measures of this biomarker did not provide useful insight into the relative importance of TNF-α in the pathogenesis of GCA.

View Article: PubMed Central - PubMed

Affiliation: Centocor Research and Development, Malvern, PA, USA.

ABSTRACT

Objective: To evaluate the association between inflammatory markers and relapse in GCA patients longitudinally assessed in a clinical trial of infliximab and glucocorticosteroids.

Methods: Forty-four newly diagnosed GCA patients in glucocorticosteroid-induced remission were randomized to receive infliximab 5 mg/kg or placebo plus daily glucocorticosteroids, tapered using a standardized schedule. Sera were analysed for inflammatory markers at multiple, pre-defined time points. Temporal artery biopsies were performed in four patients before and after treatment to analyse changes in inflammatory and vascular remodelling marker expression.

Results: Thirteen of 44 patients relapsed. Similar proportions of relapsed patients were present in both treatment arms. ESR, CRP, intercellular adhesion molecule (ICAM)-1, TNF-α, and IL-12p40 were significantly elevated near relapse. In post-treatment biopsies, mRNA expression of pro-inflammatory cytokines decreased, while vascular remodelling factors increased relative to baseline biopsies. Tissue IL-12p40 and IFN-γ mRNA remained elevated in relapsing vs remitting patients.

Conclusion: Despite prior findings of high concentrations of TNF-α in temporal artery biopsies of GCA patients, infliximab plus glucocorticosteroids did not result in improved clinical outcomes. Increased measures of this biomarker did not provide useful insight into the relative importance of TNF-α in the pathogenesis of GCA. Gene expression analysis in paired temporal artery biopsies pre- and post-treatment revealed decreased inflammatory activity and active vascular remodelling following treatment. In relapsing patients, increased expression of IFN-γ and IL-12p40 in post-treatment biopsies suggests a role in sustaining disease and setting the stage for relapse during treatment withdrawal.

Trial registration: ClinicalTrials.gov; http://www.clinicaltrials.gov; NCT00076726.

Show MeSH
Related in: MedlinePlus