Personalized Healthcare in Autoimmune Diseases - Genomic Biomarkers for Pharmaceutical Development - page 63

(A) (B)

IFN-induced gene cluster (28)

IFN-induced gene set (15)

4 4

3
2
1

3
2
1

− 2 − 1 1 2 3 − 2 − 1 1 2 3

− 1 − 1

− 2
− 3
− 4

− 2
− 3
− 4

Baseline (t=0) Baseline (t=0)

Pearson R = − 0.6657
p-value = 0.0049

Pearson R = − 0.7208
p-value = 0.0016

RSAD2

(C)

RSAD2

(D)

1024

4096

32

64

1

1

0.03125

0.015625

Baseline (t=0)

Baseline (t=0)

Spearman R = − 0.7383
p-value = 0.0027

Spearman R = − 0.8154
p-value = 0.0004

FIGURE 3.7 Correlation between baseline and pharmacological response to IFN-β therapy. Pharmacological
responses were calculated for the indicated follow-up periods relative to the baseline expression levels using a set
of 28 (A) or 15 (B) IFN-induced genes or RSAD2 as a single IFN-induced gene (C and D). The results reveal in sig-
nificant negative correlations between the pharmacological response at 1, 3 and 6 months after the start with IFN-β
treatment for the measurement of IFN response gene activity (IFN signature expression). In C and D the expression
levels of RSAD2 are measured by quantitative real-time PCR and normalized to the expression levels of GAPDH.
(A) Pharmacological response after 1 month using a 28 gene IFN cluster; (B) Pharmacological response using a
selection of 15 IFN response genes; (C) Pharmacological response after three months, using RSAD2 gene expression
levels; (D) Pharmacological response after six months using RSAD2 gene expression levels. (Adapted with permission
from: van Baarsen LG, et al. [62] .)

results, which revealed that in the IFN high patients the type I IFN pathway is fully activated
prior to therapy and cannot be activated further [62] . Remarkably, LPS (via TLR4) triggered
induction of IFN-α was significantly increased in non-responders compared to respond-
ers. This effect is most likely also mediated by the monocytes and suggests an uncoupling of
IFN-α and IFN-β production.
In accordance with an increased IFN activity at baseline, Axtell and colleagues reported
that non-responders had a significantly elevated serum concentration of IFN-β compared to
the responders [69] . High IFN-β concentration correlated with increased IL17F in the serum
suggesting a tight biological association between these two cytokines. One hypothesis for the