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Background: TNF inhibitors (TNFi) including: adalimumab (ADA), certolizumab pegol, etanercept (ETN), golimumab (GOL) and infliximab (IFX) are used in the treatment of inflammatory arthropathies. TNFi products differ in their structure and signaling. An individual patient may respond to one TNFi but not to another. Moreover, 30–40% of the patients inadequately respond to TNFi. The different TNFi downstream signaling may lead to their clinical efficacy. TNFi binding to transmembrane TNF on monocytes/dendritic cells elicit reverse signaling that cause reduced inflammatory cytokines and T cell subsets modulation. Several reports showed that TNFi exhibited differential effect on Th17 cells. Th17 cells and IL-17 gene were down-modulated in TNFi responders, but not in non-responders. Objectives: To predict the response to TNFi in an ex-vivo setting. The different TNFi effect on IL-17A expression was analyzed in peripheral blood mononuclear cells (PBMCs) which mainly include lymphocytes and monocytes to evaluate the potential prediction of response to the different TNFi. Methods: PBMCs were co-cultured with the different TNFi or medium (control) and RNA was extracted 72 hours later. IL-17A mRNA level was analyzed with qPCR. Change in IL-17A expression level in response to each TNFi was compared to control. Figure 1A shows the assay method scheme. Patients' clinical response to TNFi therapy was categorized, according to the EULAR response criteria into complete response (CR), moderate response (MR), and no response (NR) 3 months after starting treatment with TNFi. The primary endpoint was to analyze the correlation between IL-17A expression and the clinical response. Results: The assay was validated in 135 patients (psoriatic (PsA), rheumatoid (RA) arthritis and ankylosing spondylitis (AS)). The first step was a retrospective analysis to assess the clinical response to 4 TNFi (ADA, IFX, ETN and GOL) therapy (n=79). Figure 1B shows that IL-17A expression levels were significantly low in CR (0.3±0.05) as compared to MR (1.0±0.3) and NR (1.7±0.3). The difference between the IL-17A expression level in response to each TNFi in the assay correlated significantly with the clinical response between CR and NR (pConclusion: We have developed an assay to predict response to TNFi in patients with rheumatic diseases. The assay may indicate whether a given patient may respond to a specific TNFi(s) or none of them, and identify differential suitability of the TNFi drugs in personalized manner. REFERENCES: NIL. Acknowledgements: NIL. Disclosure of Interests: Smadar Gertel This technology is covered by patent application number PCT/IL2022/050662, owned by Ichilov-Tech, Tel–Aviv Sourasky Medical Center, Israel, and listing SG and OE as co-inventors., Ari Polachek: None declared, David Levartovsky: None declared, Adi Broyde: None declared, Victoria Furer: None declared, Tali Ofir Dovrat: None declared, Jonathan Wollman: None declared, Ori Elkayam As above.
Gertel et al. (Sat,) studied this question.