Abstract
IntroductionIn vitro apoptosis of peripheral monocytes in rheumatoid arthritis (RA) is disturbed and influenced by cytokine production and transmembrane TNF (tmTNF) reverse signaling. The goal of the study was the analysis of the predictive value of the rate of in vitro apoptosis for the therapeutic response to anti-TNF treatment.MethodsSpontaneous and tmTNF reverse signaling-induced apoptosis were determined in vitro in monocytes from 20 RA patients prior to initiation of therapeutic TNF inhibition with etanercept, and the subsequent clinical response was monitored.ResultsSpontaneous in vitro apoptosis was significantly reduced in RA patients compared to controls. Deficiency in spontaneous apoptosis was associated with an insufficient therapeutic response according to the European League Against Rheumatism (EULAR) response criteria and less reduction of the disease activity determined by disease activity score (DAS) 28. High susceptibility to reverse signaling-induced apoptosis was also associated with less efficient reduction in the DAS28. Of note, a strong negative correlation between the two apoptotic parameters was discernible, possibly indicative of two pathogenetically relevant processes counter-regulating each other.tmTNF reverse signaling induced in vitro production of soluble IL1-RI and IL-1RII only in monocytes not deficient in spontaneous apoptosis, and the levels of soluble IL1-RII were found to be predictive of a good clinical response to Etanercept.ConclusionAlthough tmTNF reverse signaling is able to induce apoptosis of RA monocytes in vitro, this process appears to occur in vitro preferentially in patients with suboptimal therapeutic response. Resistance to spontaneous in vitro apoptosis, in contrast, is a predictor of insufficient response to treatment.
Highlights
In vitro apoptosis of peripheral monocytes in rheumatoid arthritis (RA) is disturbed and influenced by cytokine production and transmembrane Tumor necrosis factor (TNF) reverse signaling
The soluble Ig tumor necrosis factor receptor 2 (TNFR2): Ig construct etanercept triggers transmembrane TNF (tmTNF) tmTNF-reverse signaling-induced apoptosis (RSA) in RA monocytes We have shown previously, that ligation of tmTNF by anti-TNF antibodies induces apoptosis in RA monocytes through triggering tmTNF reverse signaling (RS) [5]
An initial pre-study investigation confirmed the lower rate of spontaneous monocyte apoptosis in RA patients compared to healthy controls (RA: 18.92 ± 13.56% versus healthy donors (HD): 32.44 ± 10.52%, P = 0.016, Figure 1A,B)
Summary
In vitro apoptosis of peripheral monocytes in rheumatoid arthritis (RA) is disturbed and influenced by cytokine production and transmembrane TNF (tmTNF) reverse signaling. The goal of the study was the analysis of the predictive value of the rate of in vitro apoptosis for the therapeutic response to anti-TNF treatment. Our group was able to identify profound differences in monocyte apoptosis between RA patients and healthy donors. Monocytes from healthy controls undergo spontaneous apoptosis (SIA) in vitro at considerable rates during incubation over 16 hours. Deficient spontaneous in vitro apoptosis has been reported by other groups for peripheral monocytes from patients with systemic juvenile idiopathic arthritis [6] and for monocytic cells from the rheumatoid synovium [7,8]
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