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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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Differential regulation of interferon (IFN) response genes upon tumor necrosis factor (TNF) blockade and clinical response to treatment. Patients were divided into two groups (ratio < 1 and ratio > 1) on the basis of their IFN response upon TNF blockade and compared with each other with respect to clinical response to treatment. The ratio is determined by the T = 1/T = 0 expression levels of the IFN response genes as demonstrated in Figure 1a. Data are shown as box plots; each box represents the 25th to 75th percentiles. The lines inside represent the median, and the ends of the whiskers represent the smallest and largest observations. Patients with an upregulation in IFN response genes displayed a significantly (unpaired t test, * P < 0.05; **P < 0.01) worse clinical response to treatment as assessed by change in disease activity score (DAS) (DAS before treatment minus DAS 16 weeks after treatment) (a), European League Against Rheumatism (EULAR) response (b), tender joint count (TJC) (c), and Health Assessment Questionnaire-Disability Index (HAQ) (d) after treatment.
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Figure 2: Differential regulation of interferon (IFN) response genes upon tumor necrosis factor (TNF) blockade and clinical response to treatment. Patients were divided into two groups (ratio < 1 and ratio > 1) on the basis of their IFN response upon TNF blockade and compared with each other with respect to clinical response to treatment. The ratio is determined by the T = 1/T = 0 expression levels of the IFN response genes as demonstrated in Figure 1a. Data are shown as box plots; each box represents the 25th to 75th percentiles. The lines inside represent the median, and the ends of the whiskers represent the smallest and largest observations. Patients with an upregulation in IFN response genes displayed a significantly (unpaired t test, * P < 0.05; **P < 0.01) worse clinical response to treatment as assessed by change in disease activity score (DAS) (DAS before treatment minus DAS 16 weeks after treatment) (a), European League Against Rheumatism (EULAR) response (b), tender joint count (TJC) (c), and Health Assessment Questionnaire-Disability Index (HAQ) (d) after treatment.

Mentions: Finally, we investigated whether the treatment-induced changes in type I IFN response gene expression levels were associated with clinical response to treatment. Therefore, the patients (n = 15) were divided into two groups on the basis of their change in mean expression level for the 34 IFN response genes (ratio > 1 and ratio < 1) as demonstrated in Figure 1a. Next, clinical parameters were compared between these two groups. Clinical response to treatment was determined after 16 weeks of treatment. Interestingly, the patients who showed an increase in type I IFN response gene expression levels after 1 month of treatment had a poor clinical response to treatment. This was reflected by less improvement in disease activity scores (P = 0.013) and higher tender joint counts (P = 0.015) and higher Health Assessment Questionnaire-Disability Index scores (P = 0.008) after treatment (Figure 2). Accordingly, all patients without an anti-TNF-induced increase in type I IFN gene activity had a good or moderate response to treatment as assessed by the EULAR response criteria (P = 0.018) (Figure 2). From a total of 29 patients, both the EULAR and the qPCR expression data were available for the three IFN response genes RSAD2, IFI44L, and OAS1. Analysis of the pre- versus post-treatment ration of OAS1 revealed that the change in gene expression of OAS1 is significantly associated with clinical response to treatment (P < 0.013).


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)

Differential regulation of interferon (IFN) response genes upon tumor necrosis factor (TNF) blockade and clinical response to treatment. Patients were divided into two groups (ratio < 1 and ratio > 1) on the basis of their IFN response upon TNF blockade and compared with each other with respect to clinical response to treatment. The ratio is determined by the T = 1/T = 0 expression levels of the IFN response genes as demonstrated in Figure 1a. Data are shown as box plots; each box represents the 25th to 75th percentiles. The lines inside represent the median, and the ends of the whiskers represent the smallest and largest observations. Patients with an upregulation in IFN response genes displayed a significantly (unpaired t test, * P < 0.05; **P < 0.01) worse clinical response to treatment as assessed by change in disease activity score (DAS) (DAS before treatment minus DAS 16 weeks after treatment) (a), European League Against Rheumatism (EULAR) response (b), tender joint count (TJC) (c), and Health Assessment Questionnaire-Disability Index (HAQ) (d) after treatment.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2875639&req=5

Figure 2: Differential regulation of interferon (IFN) response genes upon tumor necrosis factor (TNF) blockade and clinical response to treatment. Patients were divided into two groups (ratio < 1 and ratio > 1) on the basis of their IFN response upon TNF blockade and compared with each other with respect to clinical response to treatment. The ratio is determined by the T = 1/T = 0 expression levels of the IFN response genes as demonstrated in Figure 1a. Data are shown as box plots; each box represents the 25th to 75th percentiles. The lines inside represent the median, and the ends of the whiskers represent the smallest and largest observations. Patients with an upregulation in IFN response genes displayed a significantly (unpaired t test, * P < 0.05; **P < 0.01) worse clinical response to treatment as assessed by change in disease activity score (DAS) (DAS before treatment minus DAS 16 weeks after treatment) (a), European League Against Rheumatism (EULAR) response (b), tender joint count (TJC) (c), and Health Assessment Questionnaire-Disability Index (HAQ) (d) after treatment.
Mentions: Finally, we investigated whether the treatment-induced changes in type I IFN response gene expression levels were associated with clinical response to treatment. Therefore, the patients (n = 15) were divided into two groups on the basis of their change in mean expression level for the 34 IFN response genes (ratio > 1 and ratio < 1) as demonstrated in Figure 1a. Next, clinical parameters were compared between these two groups. Clinical response to treatment was determined after 16 weeks of treatment. Interestingly, the patients who showed an increase in type I IFN response gene expression levels after 1 month of treatment had a poor clinical response to treatment. This was reflected by less improvement in disease activity scores (P = 0.013) and higher tender joint counts (P = 0.015) and higher Health Assessment Questionnaire-Disability Index scores (P = 0.008) after treatment (Figure 2). Accordingly, all patients without an anti-TNF-induced increase in type I IFN gene activity had a good or moderate response to treatment as assessed by the EULAR response criteria (P = 0.018) (Figure 2). From a total of 29 patients, both the EULAR and the qPCR expression data were available for the three IFN response genes RSAD2, IFI44L, and OAS1. Analysis of the pre- versus post-treatment ration of OAS1 revealed that the change in gene expression of OAS1 is significantly associated with clinical response to treatment (P < 0.013).

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