Background IL-6, one of the causes of key molecule in RA pathogenesis, is signaling through the two receptor systems, one is IL-6 binding molecule (IL-6R) and the other is gp130 molecule (gp130), a signal transducer. And we know the presence of soluble form of IL-6 receptor (sIL-6R) and gp130 (sgp130). SIL-6R is an IL-6 functional accelerator; however less is known about the function of sgp130.
Objectives We want to know whether sgp130 is a regulator of IL-6 both in vitro and vivo. Tocilizumab, an anti-IL-6 receptor antibody, shows good effect as well as TNF-a inhibitors for the treatment of RA. However the efficacy is variable to each of patient. We want to know the reason of this variety caused by sgp130 molecule.
Methods [In vitro] Hep3B, a hepatoma derived cell line, was stimulated with IL-6 or Hyper IL-6 (complex of IL-6/sIL-6R) and co-cultured with tocilizumab or complex of gp130-Fc. CRP mRNA induction was accessed after two days culture by real-time RT-PCR.
[In vivo] We performed with observation study. 88 RA patients (48 biologics naïve, 40 biologics non-naïve) were treated with tocilizumab over 16 weeks by every 4 week injection at dose 8mg/kg. 41 biologics in pretreatment serum was measured by Bio-Prex27 and Milliplex. The disease activity at 16 week was scored on DAS28-CRP. Multiple linear regression analysis were used to determine if any relationship existed between biologics and patient's week 16 DAS 28-CRP score.
Results [In vitro] Gp130-Fc did not inhibited the IL-6 induced CRP, however inhibited the Hyper IL-6 induced CRP productions. This means, gp130-Fc specifically inhibited the stimulation with complex of IL-6/sIL-6R which stimulation could not be inhibited with tocilizumab.
[In vivo] 7 biomarker including sgp130 were predictive of the week 16 DAS28-CRP in naïve tocilizumab patients (R2=0.646, P<0.0001) while gp130, GM-CSF, IP-10 were predictive in non-naïve patients (R2=0.486, P<0.001). The most reliable marker is sgp130 (Estimated value -5.34).
Conclusions 1) Sgp130 is a natural IL-6 inhibitor both in vitro and in vivo.
2) Higher level of sgp130 predicts the better outcome to tocilizumab therapy
3) Clinical efficacy might be resulted in the additive effects by the inhibition with tocilizumab (IL-6 binding inhibition on IL-6R) and the inhibition with sgp130, (IL-6/sIL-6R binding inhibition on gp130).
4) Prediction of individual RA patient's outcome to tociizumab therapy can be recognized by measuring biologics including sgp130 (most reliable marker) in pretreatment serum.
5) Opening the personalized medicine in RA field by measuring biomarker before therapy.
Disclosure of Interest None declared
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