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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

Distribution of IL-12p40, IL-12p35, IL-23p19 and IFN-γ expression in pre- and post-treatment temporal artery biopsies from two relapsing patients. The first three rows correspond to one patient and the fourth row to the other.
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Figure 3: Distribution of IL-12p40, IL-12p35, IL-23p19 and IFN-γ expression in pre- and post-treatment temporal artery biopsies from two relapsing patients. The first three rows correspond to one patient and the fourth row to the other.

Mentions: A substantial reduction in the intensity of inflammatory infiltrates was observed in biopsies collected post-treatment with glucocorticosteroids plus infliximab or placebo compared with those obtained at the time of diagnosis. Only scattered foci of inflammatory cells persisted in second biopsies. Immunohistochemical scores for all of the markers tested were reduced in proportion to the decrease in inflammatory cells (Fig. 2). Figure 3 shows the topographic distribution of the products associated with relapse in pre- and post-treatment biopsies. As with other markers, IFN-γ, IL-12p35, IL-23p19 and IL-12p40 immunohistochemical expression decreased. Intense expression of these markers was observed in a cluster of infiltrating cells located in the adventitia in post-treatment biopsies. Smooth muscle cells immunostained slightly positive for IL-12p35 (Fig. 3), reflecting the constitutive expression of this IL-12 subunit in normal arteries (Fig. 1).Fig. 2


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)

Distribution of IL-12p40, IL-12p35, IL-23p19 and IFN-γ expression in pre- and post-treatment temporal artery biopsies from two relapsing patients. The first three rows correspond to one patient and the fourth row to the other.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

Figure 3: Distribution of IL-12p40, IL-12p35, IL-23p19 and IFN-γ expression in pre- and post-treatment temporal artery biopsies from two relapsing patients. The first three rows correspond to one patient and the fourth row to the other.
Mentions: A substantial reduction in the intensity of inflammatory infiltrates was observed in biopsies collected post-treatment with glucocorticosteroids plus infliximab or placebo compared with those obtained at the time of diagnosis. Only scattered foci of inflammatory cells persisted in second biopsies. Immunohistochemical scores for all of the markers tested were reduced in proportion to the decrease in inflammatory cells (Fig. 2). Figure 3 shows the topographic distribution of the products associated with relapse in pre- and post-treatment biopsies. As with other markers, IFN-γ, IL-12p35, IL-23p19 and IL-12p40 immunohistochemical expression decreased. Intense expression of these markers was observed in a cluster of infiltrating cells located in the adventitia in post-treatment biopsies. Smooth muscle cells immunostained slightly positive for IL-12p35 (Fig. 3), reflecting the constitutive expression of this IL-12 subunit in normal arteries (Fig. 1).Fig. 2

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