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Regulation of IFN response gene activity during infliximab treatment in rheumatoid arthritis is associated with clinical response to treatment.

van Baarsen LG, Wijbrandts CA, Rustenburg F, Cantaert T, van der Pouw Kraan TC, Baeten DL, Dijkmans BA, Tak PP, Verweij CL - Arthritis Res. Ther. (2010)

Bottom Line: Gene expression analysis revealed that anti-TNF antibody treatment induced a significant increase in type I IFN response gene activity in a subset of RA patients, whereas expression levels remained similar or were slightly decreased in others.Regulation of IFN response gene activity upon TNF blockade in RA is not as consistent as previously described, but varies between patients.The differential changes in IFN response gene activity appear relevant to the clinical outcome of TNF blockade in RA.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pathology, VU University Medical Center, De Boelelaan 1118, 1081 HZ, Amsterdam, The Netherlands. e.g.vanbaarsen@amc.uva.nl

ABSTRACT

Introduction: Cross-regulation between TNF and type I IFN has been postulated to play an important role in autoimmune diseases. Therefore, we determined the effect of TNF blockade in rheumatoid arthritis (RA) on the type I IFN response gene activity in relation to clinical response.

Methods: Peripheral blood from 33 RA patients was collected in PAXgene tubes before and after the start of infliximab treatment. In a first group of 15 patients the baseline expression of type I IFN-regulated genes was determined using cDNA microarrays and compared to levels one month after treatment. The remaining 18 patients were studied as an independent group for validation using quantitative polymerase chain reaction (qPCR).

Results: Gene expression analysis revealed that anti-TNF antibody treatment induced a significant increase in type I IFN response gene activity in a subset of RA patients, whereas expression levels remained similar or were slightly decreased in others. The findings appear clinically relevant since patients with an increased IFN response gene activity after anti-TNF therapy had a poor clinical outcome. This association was confirmed and extended for an IFN response gene set consisting of OAS1, LGALS3BP, Mx2, OAS2 and SERPING1 in five EULAR good and five EULAR poor responders, by qPCR.

Conclusions: Regulation of IFN response gene activity upon TNF blockade in RA is not as consistent as previously described, but varies between patients. The differential changes in IFN response gene activity appear relevant to the clinical outcome of TNF blockade in RA.

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Poor response to tumor necrosis factor blockade is accompanied by upregulation of interferon (IFN) response genes. For five European League Against Rheumatism (EULAR) (0) poor responder (red) and five EULAR (2) good responder (green) patients, the expression levels of 15 IFN response genes were measured by quantitative real-time polymerase chain reaction (PCR) (BioMark™) at baseline and 1, 2, 3, and 4 months after treatment. From two poor and one good responder patients, the 3-month time points are missing. The IFN response gene expression levels during treatment were compared between the two clinical response groups by means of two-way analysis of variance test. Treatment-induced changes in the expression levels of two genes, LGALS3BP (a) and OAS1 (b), were significantly different between the two response groups. (c) The mean expression level of five IFN response genes (LGALS3BP, OAS1, Mx2, SERPING1, and OAS2) showed the best significant difference between the two clinical response groups. Graphs show the mean and standard error of the mean expression levels for each clinical response group. RQ, relative quantity.
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Figure 3: Poor response to tumor necrosis factor blockade is accompanied by upregulation of interferon (IFN) response genes. For five European League Against Rheumatism (EULAR) (0) poor responder (red) and five EULAR (2) good responder (green) patients, the expression levels of 15 IFN response genes were measured by quantitative real-time polymerase chain reaction (PCR) (BioMark™) at baseline and 1, 2, 3, and 4 months after treatment. From two poor and one good responder patients, the 3-month time points are missing. The IFN response gene expression levels during treatment were compared between the two clinical response groups by means of two-way analysis of variance test. Treatment-induced changes in the expression levels of two genes, LGALS3BP (a) and OAS1 (b), were significantly different between the two response groups. (c) The mean expression level of five IFN response genes (LGALS3BP, OAS1, Mx2, SERPING1, and OAS2) showed the best significant difference between the two clinical response groups. Graphs show the mean and standard error of the mean expression levels for each clinical response group. RQ, relative quantity.

Mentions: To determine whether the IFN response to TNF blockade was sustained over time, five EULAR good and five EULAR poor responders were selected and the expression levels of 15 IFN response genes (selected from the set of 34 genes used above, Table 2) were measured at baseline and 1, 2, 3, and 4 months after treatment by qPCR (Additional file 3). The expression levels were averaged for the individual patients, and the treatment-induced changes (ratio post- versus pre-treatment) in IFN response gene expression levels over time were compared between the two clinical response groups using two-way ANOVA. Overall, the IFN response genes showed an upregulation in the poor responder group, which was most prominent at 2 months after the start of therapy (data not shown). At the single-gene level, the increased expression in poor versus good responders reached significance for the OAS1 and LGALS3BP genes (Figure 3a, b). For three other IFN response genes (Mx2, OAS2, and SERPING1), a trend (P = approximately 0.06, data not shown) was observed toward increased expression in the poor responder patients. Combining these five genes (OAS1, LGALS3BP, Mx2, OAS2, and SERPING1) into one IFN response gene set improved the significance (Figure 3c). These data demonstrate that poor response to infliximab treatment is associated with treatment-induced increase in type I IFN response gene activity.


Regulation of IFN response gene activity during infliximab treatment in rheumatoid arthritis is associated with clinical response to treatment.

van Baarsen LG, Wijbrandts CA, Rustenburg F, Cantaert T, van der Pouw Kraan TC, Baeten DL, Dijkmans BA, Tak PP, Verweij CL - Arthritis Res. Ther. (2010)

Poor response to tumor necrosis factor blockade is accompanied by upregulation of interferon (IFN) response genes. For five European League Against Rheumatism (EULAR) (0) poor responder (red) and five EULAR (2) good responder (green) patients, the expression levels of 15 IFN response genes were measured by quantitative real-time polymerase chain reaction (PCR) (BioMark™) at baseline and 1, 2, 3, and 4 months after treatment. From two poor and one good responder patients, the 3-month time points are missing. The IFN response gene expression levels during treatment were compared between the two clinical response groups by means of two-way analysis of variance test. Treatment-induced changes in the expression levels of two genes, LGALS3BP (a) and OAS1 (b), were significantly different between the two response groups. (c) The mean expression level of five IFN response genes (LGALS3BP, OAS1, Mx2, SERPING1, and OAS2) showed the best significant difference between the two clinical response groups. Graphs show the mean and standard error of the mean expression levels for each clinical response group. RQ, relative quantity.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2875639&req=5

Figure 3: Poor response to tumor necrosis factor blockade is accompanied by upregulation of interferon (IFN) response genes. For five European League Against Rheumatism (EULAR) (0) poor responder (red) and five EULAR (2) good responder (green) patients, the expression levels of 15 IFN response genes were measured by quantitative real-time polymerase chain reaction (PCR) (BioMark™) at baseline and 1, 2, 3, and 4 months after treatment. From two poor and one good responder patients, the 3-month time points are missing. The IFN response gene expression levels during treatment were compared between the two clinical response groups by means of two-way analysis of variance test. Treatment-induced changes in the expression levels of two genes, LGALS3BP (a) and OAS1 (b), were significantly different between the two response groups. (c) The mean expression level of five IFN response genes (LGALS3BP, OAS1, Mx2, SERPING1, and OAS2) showed the best significant difference between the two clinical response groups. Graphs show the mean and standard error of the mean expression levels for each clinical response group. RQ, relative quantity.
Mentions: To determine whether the IFN response to TNF blockade was sustained over time, five EULAR good and five EULAR poor responders were selected and the expression levels of 15 IFN response genes (selected from the set of 34 genes used above, Table 2) were measured at baseline and 1, 2, 3, and 4 months after treatment by qPCR (Additional file 3). The expression levels were averaged for the individual patients, and the treatment-induced changes (ratio post- versus pre-treatment) in IFN response gene expression levels over time were compared between the two clinical response groups using two-way ANOVA. Overall, the IFN response genes showed an upregulation in the poor responder group, which was most prominent at 2 months after the start of therapy (data not shown). At the single-gene level, the increased expression in poor versus good responders reached significance for the OAS1 and LGALS3BP genes (Figure 3a, b). For three other IFN response genes (Mx2, OAS2, and SERPING1), a trend (P = approximately 0.06, data not shown) was observed toward increased expression in the poor responder patients. Combining these five genes (OAS1, LGALS3BP, Mx2, OAS2, and SERPING1) into one IFN response gene set improved the significance (Figure 3c). These data demonstrate that poor response to infliximab treatment is associated with treatment-induced increase in type I IFN response gene activity.

Bottom Line: Gene expression analysis revealed that anti-TNF antibody treatment induced a significant increase in type I IFN response gene activity in a subset of RA patients, whereas expression levels remained similar or were slightly decreased in others.Regulation of IFN response gene activity upon TNF blockade in RA is not as consistent as previously described, but varies between patients.The differential changes in IFN response gene activity appear relevant to the clinical outcome of TNF blockade in RA.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pathology, VU University Medical Center, De Boelelaan 1118, 1081 HZ, Amsterdam, The Netherlands. e.g.vanbaarsen@amc.uva.nl

ABSTRACT

Introduction: Cross-regulation between TNF and type I IFN has been postulated to play an important role in autoimmune diseases. Therefore, we determined the effect of TNF blockade in rheumatoid arthritis (RA) on the type I IFN response gene activity in relation to clinical response.

Methods: Peripheral blood from 33 RA patients was collected in PAXgene tubes before and after the start of infliximab treatment. In a first group of 15 patients the baseline expression of type I IFN-regulated genes was determined using cDNA microarrays and compared to levels one month after treatment. The remaining 18 patients were studied as an independent group for validation using quantitative polymerase chain reaction (qPCR).

Results: Gene expression analysis revealed that anti-TNF antibody treatment induced a significant increase in type I IFN response gene activity in a subset of RA patients, whereas expression levels remained similar or were slightly decreased in others. The findings appear clinically relevant since patients with an increased IFN response gene activity after anti-TNF therapy had a poor clinical outcome. This association was confirmed and extended for an IFN response gene set consisting of OAS1, LGALS3BP, Mx2, OAS2 and SERPING1 in five EULAR good and five EULAR poor responders, by qPCR.

Conclusions: Regulation of IFN response gene activity upon TNF blockade in RA is not as consistent as previously described, but varies between patients. The differential changes in IFN response gene activity appear relevant to the clinical outcome of TNF blockade in RA.

Show MeSH
Related in: MedlinePlus