Background/Purpose: Sustained disease remission is the treatment goal for Rheumatoid Arthritis (RA) leading patients to be eligible to treatment tapering or discontinuation. However, disease flare is an unpredictable event after treatment change representing a burden for RA. The study aims were to assess the impact of clinical classification on synovial tissue (ST) inflammation in sustained remission RA and to identify biomarkers of disease flare after treatment modification.

Methods: 152 RA in sustained clinical (84 RA with DAS< 1.6 and 68 RA fulfilling Boolean remission criteria for at least 9 months, respectively) and ultrasound (US) remission (PDneg) under Methotrexate with or without biological-Disease Modifying Anti-Rheumatic Drug (bDMARD) underwent US guided ST biopsy and were enrolled in the study. 240 naive RA were enrolled as comparison group. For each patient, synovitis degree was determined using a H&E-based semiquantitative score¹. Some ST samples of naive RA and RA in remission were used for digital spatial profiling (GeoMx DSP, Nanostring) to quantitate transcript abundance in spatially distinct regions of interest (ROIs) within ST. RA in remission were randomly assigned to tapering/discontinuation (TAP/DISC) group (tapering c- or b-DMARD treatment for 6 months first and discontinuing c- or bDMARD afterwards) or maintaining the therapy unchanged (CONT). Each RA was followed every 3 months to assess disease flare rate after treatment modifications for at least 6 months.

Results: Considering the whole RA cohort, despite either DAS- and Boolean-defined remission RA had significantly lower KSS than naive RA (p< 0.0001 for both), RA in Boolean remission had lower KSS compared to RA in DAS-defined remission (p< 0.0001). In particular, ST of RA in Boolean remission showed lower stromal density (p< 0.0001) and inflammatory infiltrate scores (p=0.0003) together with lower lymphocytes (p=0.003) and plasmacells presence rates (p=0.015) than ST of RA with DAS-defined remission. Among the whole cohort, 54(35.5%) RA had a disease flare regardless the treatment change. Moreover, RA with DAS-defined remission who had a disease flare within at least 6 months follow-up had, at study entry, significantly higher KSS (p=0.0005) than RA who maintained a sustained remission, regardless to the treatment change (CONT:p=0.0275 and TAP/DISC:p=0.0112, respectively). Conversely, RA in Boolean-defined remission did not differ in terms of ST inflammation at study entry in the CONT (p >0.05) as well as in the TAP/DISC (p >0.05) subgroup. However, DSP analysis revealed that ROIs in ST of RA in Boolean remission had a unique transcriptomic signature characterized by 298 differentially expressed genes belonging to 26 pathways compared with RA in DAS-defined remission, whose over-expression, identifies ROIs from ST of RA who had disease flare.

Conclusion: DAS- and Boolean-based remission definitions in RA mirror differential degree of residual subclinical synovitis and are characterized by distinct ST transcriptomic signature which identifies RA in remission at higher risk of disease flare after treatment modification.

References.

1. Alivernini S, et al. A&R 2021;Mar 22. doi:10.1002/art.41726.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/digital-spatial-profiling-reveals-distinct-synovial-tissue-transcriptomic-signature-of-sustained-disease-remission-in-rheumatoid-arthritis-patients-at-risk-of-disease-flare-after-treatment-tapering-or/