Background/Purpose: Clinical management of polyarticular JIA with anti-TNF-alpha has been met with moderate success, with up to 50% of patients demonstrating clinically meaningful efficacy. Concerns with medium/long term drug toxicities has driven the clinical need to find predictors for successful drug discontinuation. Based on a solid foundation of preliminary and published data, our hypothesis is that adaptive T cell immunity plays a pivotal role in the pathogenic mechanisms which determine clinical fate in JIA. To distill this pathogenic signal located within the T cell immunome, a high dimensional single cell resolution platform, CyToF, was deployed to phenotype activated antigen experienced T cells. Patients treated with anti-TNF-alpha were recruited in the Understanding TNF-alpha trial and segregated into flare, active and inactive arms after discontinuation of therapy. The central aim of the project is to identify pathogenic immune mechanisms of clinical relapse and signatures capable of distinguishing clinical fates.

Methods: Patients treated with anti-TNF-alpha biologics were recruited into the study (Improved Understanding of the Biology and Use of TNF inhibition in Children with JIA Trial) with clinically inactive disease on treatment (Wallace criteria) and initiated with therapy discontinuation. The patients are followed up and evaluated as flare, inactive and active based on 6 JIA core set parameters; number of joints with active arthritis and/or loss of motion, MD global assessment of current disease activity, patient/parent global assessment of overall disease severity in prior week, a validated measure of physical function and ESR.

Results: PBMCs from n=17 JIA patients (n= 6 flare, 5 active and 6 inactive) were stained with a 37 markers CyToF panel designed to interrogate the T cell compartment. Cluster analysis was achieved through dimensional reduction of 37 markers onto a bivariate X-Y plane via T-SNE algorithm (ACCENSE). Binary comparison of clinical fates with the clustered dimensions revealed that patients experiencing flare within 6 months of drug discontinuation, were enriched with these striking characteristics: pro-inflammatory, recently antigen stimulated, and, most importantly, pre-existing withdrawal of therapy. The phenotype comprised of CD3⁺ CD4⁺ memory (CD45RA^–) antigen experienced (CD40L⁺, CD69⁺) T cells, expressing co-stimulatory markers (CD28⁺, ICOS⁺), immune checkpoints (CTLA4⁺) capable of secreting high levels of TNF-alpha (p < 0.0 5). Intriguingly within the Treg compartment, CD3⁺CD4⁺CD25^hi Foxp3^hi CD45RA^–CTLA4^hiCD28⁺ICOS⁺were found to be significantly (p < 0.05) up-regulated in flare patients.

Conclusion: These results are striking, in our opinion, as they define some important concepts: i) Teff mechanisms which lead to clinical relapse are pre-existing withdrawal from therapy; ii) Tregs cells, are significantly elevated in patients who flare, representing probably a mechanism of overcompensation, probably ineffective due to resistance to suppression by Teff; iii) that the clinical fate is immunologically predetermined; iv) patients who achieve different clinical fates can be stratified immunologically.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/high-dimensional-interrogation-of-the-t-cell-immunome-in-polyarticular-juvenile-idiopathic-arthritis-patients/