Session Type: ACR Concurrent Abstract Session
Session Time: 4:30PM-6:00PM
Background/Purpose: Treatment of polyarticular JIA with anti-TNFA biologics has experienced significant success, with up to 80% of patients demonstrating clinically meaningful efficacy. Yet concerns regarding medium/long term toxicities and costs, have driven the clinical need to locate predictors for successful drug discontinuation. Compelling evidence indicate that T cells play a paramount role in disease progression. Identification of these pathogenic subsets within the T cell immunome will likely help stratify patients in terms of clinical fate. JIA patients previously treated with anti-TNFA were recruited through the Understanding TNFA trial and segregated into flare, active and inactive arms after drug discontinuation. Utilising a high dimensional platform, CyToF, that is capable of phenotyping up to 41 markers at single cell resolution, we aim to identify the pathogenic subsets responsible for clinical relapse and signatures capable of distinguishing therapeutic outcomes.
Methods: Patients treated with anti-TNF-alpha 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 were followed 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 47 JIA patients (Flare= 18, Active= 11, Inactive= 18) and 10 healthy controls were stained and interrogated with CyToF. Patients destined to flare (vs inactive/healthy) prior to therapy withdrawal, displayed significant dysregulation in the CD4 Memory compartment (p< 0.05), enriched particularly in (a) CD4 CD45RA– TNFA+ , (b) CD4 CD45RA– CXCR5+, and were skewed towards (c) CD152– / PD1–. When contrasting against healthy controls, patients destined to flare additionally upregulated CD4 CD45RA– TNFA+ IL-6+, possibly a sub-clinical disease subset. Intriguingly we noted a migratory subset, CD4 CD45RA– CXCR3+ CCR6+ that was present in patients destined to develop active disease (vs inactive/healthy). Upon flaring, the sub-clinical subset CD4 CD45RA– TNFA+ IL-6+ surfaces and CD4 memory subsets are now upregulating expression of CD152/PD1 (vs inactive) in response to ongoing inflammation, but when compared to healthy controls are still inadequate. Parallel pathogenic subsets were also detected in the synovial microenvironment, reflecting targeting towards the joints.
Conclusion: For some patients (Flare), anti-TNFA therapy is merely suppressing disease activity and not curative. The persistence of CD4 memory cells are likely to play a pivotal role in disease relapse, that may be partially explained by a weaker control through immune checkpoints (CD152/PD1). These results suggest that clinical fate is immunologically predetermined and patients who will develop different clinical fates can be identified from prior biologic sampling.
To cite this abstract in AMA style:Leong JY, Yeo JG, Chen P, Lai L, Ally F, Bathi LDT, Tan JHT, Arkachaisri T, van Wijk F, Albani S, Lovell DJ, Mijnheer G. Persistence of Pathogenic CD4 Memory T Cells Revealed through Cytometry Time of Flight in Juvenile Idiopathic Arthritic Patients with Disease Resurgence upon Withdrawal of Anti-TNFA Biologics [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/persistence-of-pathogenic-cd4-memory-t-cells-revealed-through-cytometry-time-of-flight-in-juvenile-idiopathic-arthritic-patients-with-disease-resurgence-upon-withdrawal-of-anti-tnfa-biologics/. Accessed November 19, 2019.
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