Abstract
BackgroundTreatment with TNF inhibitors is very efficient in the majority of the patients with rheumatoid arthritis (RA), but it does not achieve a sufficient treatment response in 40–50% of the cases. Goal of the study was to assess functional ex vivo-tests of RA monocytes as prognostic parameters of the subsequent treatment response.Methods20 anti-TNF naïve RA patients were enrolled in a prospective, open-label trial, and Etanercept therapy was initiated. Prior to treatment, reverse signaling was induced in peripheral blood monocytes by tmTNF crosslinking via TNFR2:Ig construct Etanercept in a standardized ex vivo-assay. Released cytokine and cytokine receptor concentrations were determined as parameters of the monocyte response.ResultsCrosslinking of tmTNF and consecutive reverse signaling led to production of pro- and anti-inflammatory cytokines and of soluble cytokine decoy receptors such as sTNFR1 and sIL-1R2. Several of the measured concentrations were found to correlate with the treatment response according to the EULAR criteria. The correlation was most pronounced in sTNFR1 concentrations (r = −0.657, p = 0.0031), which also predicted a good clinical response with the highest sensitivity and specificity according to EULAR criteria.ConclusionsHerein we propose that the tmTNF crosslinking-triggered shedding of soluble decoy receptors and production of anti-inflammatory cytokines could contribute to the clinical efficacy of TNF inhibitors, and that in vitro quantification of this secretion by RA monocytes prior to treatment can be used to predict the clinical response. Further development of such standardized tests could be a step towards personalized medicine by providing rheumatologists with a rational choice for first line biological therapy in patients with RA.
Highlights
Treatment with tumor necrosis factor (TNF) inhibitors is very efficient in the majority of the patients with rheumatoid arthritis (RA), but it does not achieve a sufficient treatment response in 40–50% of the cases
A total of 33 consecutive, antiTNF naïve patients with RA according to the revised criteria of the American College of Rheumatology (ACR) [11], who were assessed by their rheumatologists to require treatment with Etanercept based on their clinical status, were screened for the study. 13 of them could not be initiated on anti-TNF treatment due to subsequently discovered various contraindications, newly diagnosed co-morbidities, requirement of surgery or withdrawal of patient’s consent
Cytokine decoy receptor levels induced by transmembrane TNF (tmTNF) crosslinking predict subsequent responses to anti‐TNF therapy In vivo, the effects of the pro-inflammatory monocytic cytokines TNF and IL-1β are counterbalanced by soluble cytokine decoy receptors released from the cell surface
Summary
Treatment with TNF inhibitors is very efficient in the majority of the patients with rheumatoid arthritis (RA), but it does not achieve a sufficient treatment response in 40–50% of the cases. The clinical efficacy of specific cytokine inhibitors in rheumatoid arthritis (RA) reveals the pivotal role of predominantly monocytic cytokines like IL-1β, TNF or IL-6 in the pathogenesis of the disease. We and others have extensively investigated the cellular signaling pathways initiated by tmTNF ligation with soluble tmTNF ligands like anti-TNF antibodies or TNFR2:Ig construct Etanercept [3,4,5,6,7]. This so-called reverse signaling inhibits the intrinsic NFkappaB activation and IL-1β secretion characteristic for RA monocytes, and induces apoptosis [3]. The rate of apoptosis induced by reverse signaling is not related to the therapeutic efficacy of TNF inhibitors [8].
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