SP0054 DECONVOLUTION OF THE IMMUNE RESPONSE
Authors: Lars Rogge
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Anti-TNF therapy has revolutionized treatment of many chronic inflammatory diseases, including rheumatoid arthritis, Crohn"s disease and spondyloarthritis (SpA). However, clinical efficacy of TNF-inhibitors (TNFi) is limited by a high rate of non-responsiveness (30-40%) both in SpA and other diseases, which exposes a substantial fraction of patients to important side-effects without clinical benefit. Despite TNFi having been used extensively for many years, it is still not possible to determine which patients will respond to TNFi before treatment initiation. <h3>Objectives:</h3> In this study, we have tested the hypothesis that the functional analysis of immune responses of patients before and after anti-TNF therapy may not only improve our understanding of the molecular mechanisms of TNF-blocker activity, but also identify correlates of therapeutic responses in SpA patients. <h3>Methods:</h3> To facilitate the potential translation of our findings into a clinical setting, we have used standardized whole-blood stimulation assays ("TruCulture" assays; Duffy et al., 2014), and have minimized sources of pre-analytical variability, implementing a highly sensitive and robust pipeline to assess immune functions in patients. <h3>Results:</h3> We show that anti-TNF therapy induces profound changes in patients' immune responses, affecting predominantly several innate immune pathways. Of note, all these effects could be measured in stimulated, but not in resting immune cells, and were already detectable early, after a single TNFi injection. Modular transcriptional repertoire analysis revealed that TNFi affect immune responses via multiple mechanisms, such as directing monocyte/macrophage polarization and the inhibition of a TNF- and IL-1-dependent feed-forward loop of NF-kB activation. On the other hand, the action of anti-TNF treatment was surprisingly selective, in that it did not affect the IL-6/Th17 or Th1 arm of the patients' immune response. These findings have important implications for therapy, given the recent approval of anti-IL-17 antibodies as an alternative agent for the treatment of several chronic inflammatory diseases. To investigate the concept that the immune status of a patient will define their response to TNFi treatment, we have used machine-learning algorithms to identify, in whole-blood stimulation assays, immunological transcripts that correlate with clinical efficacy of TNFi. We found that high expression, before treatment initiation, of molecules associated with leukocyte invasion/migration and inflammatory processes predisposes to favorable outcome of anti-TNF therapy, while high-level expression of cytotoxic molecules was associated with poor therapeutic responses to TNF-blockers. <h3>Conclusion:</h3> These findings suggest that SpA patients whose immune response is characterized by strong, NF-kB-mediated inflammation are more likely to benefit from TNFi treatment than patients with an active T/NK-cell component. This proof-of-concept study establishes a new framework to explore patient stratification in chronic inflammatory diseases according to the patients' immune phenotype. <h3>Reference:</h3> [1] Duffy, D., et al. Functional Analysis via Standardized Whole-Blood Stimulation Systems Defines the Boundaries of a Healthy Immune Response to Complex Stimuli. Immunity 40, 436-450 (2014). <h3>Disclosure of Interests:</h3> None declared