ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 1662

Using Circulating Soluble Serum Mediator Profiles to Understand the Mechanisms Driving Disease Flare and Drug-free Remission in Rheumatoid Arthritis

Amy Anderson1, Fiona Rayner2, Abbie Degnan1, Imogen Wilson1, Julie Diboll1, Jasmine Sim1, Andrew Melville3, Stefan Siebert3, Iain McInnes4, Carl Goodyear3, Catharien Hilkens1, Andrew Filer5, Karim Raza5, Christopher Buckley6, Kenneth Baker1, Arthur Pratt2 and John Isaacs1, 1Translational and Clinical Research Institute, NIHR Newcastle Biomedical Research Centre, Newcastle University and The Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom, 2Translational and Clinical Research Institute, NIHR Newcastle Biomedical Research Centre, Newcastle University and The Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, England, United Kingdom, 3School of Infection and Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom, 4University of Glasgow, College of Medical Veterinary and Life Sciences, Glasgow, United Kingdom, 5Rheumatology Research Group, Institute for Inflammation and Ageing, NIHR Birmingham Biomedical Research Center and Clinical Research Facility, University of Birmingham, Birmingham, United Kingdom, 6Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom

Meeting: ACR Convergence 2024

Keywords: , ,

Session Information

Date: Sunday, November 17, 2024

Title: Abstracts: RA – Etiology and Pathogenesis I

Session Type: Abstract Session

Session Time: 1:00PM-2:30PM

Background/Purpose: Little is known of the factors that trigger disease relapses/flares in patients with rheumatoid arthritis (RA). The underpinning mechanisms have been difficult to study because of the unpredictable nature of flare. The BIOlogical Factors that Limit sustAined Remission in rhEumatoid arthritis (BIO-FLARE) study1 is an experimental medicine study of ‘synchronised’ RA flares. This is achieved by stopping treatment in RA patients in clinical remission receiving conventional synthetic (cs)DMARDs.  Subsequently, approximately 50% flare within 6 months, the remainder maintaining drug-free remission (DFR). In the current analysis we have measured circulating proteins in sequential blood samples following treatment cessation.

Methods: Individuals with RA receiving methotrexate, sulfasalazine and hydroxychloroquine, singly or in combinations, in clinician-defined remission with a DAS28-CRP < 2.4 were recruited into BIO-FLARE. Treatment was stopped and participants monitored over 24 weeks, and serum stored at 0, 2, 5, 8, 12 and 24 weeks. Flare was defined as DAS28-CRP ≥3.2 at any study visit, or DAS28-CRP ≥2.4 on two occasions within a 14-day period. Soluble serum mediators were detected by the NULISAseq™ Inflammation Panel 250 (Alamar Biosciences)2. Following data normalisation and quality control, differential expression analysis was performed using the NULISAseqR package. An unadjusted significance threshold (p< 0.05) was used in the baseline analysis for discovery purposes, whereas a false discovery rate (FDR) adjusted p value < 0.05 was deemed significant in the longitudinal data.

Results: At baseline, participants who subsequently flared and those who maintained DFR were well matched clinically, with the exception of RF/ACPA titres (Table 1). In contrast, NULISAseq analysis revealed differences in a number of inflammatory mediators, such as CXCL13 and soluble PD-1 (PDCD1), and immunoregulatory molecules, such as soluble CD83 and CTLA-4, all of which were elevated in the flare group at baseline (Figure 1). When assessing changes in soluble mediators across time from the point of DMARD withdrawal, few changes were detected in the DFR group (Figure 2A), whereas a number of inflammatory mediators, such as CXCL9, CXCL10, granzyme B and IL-6, increased in the flare group (Figure 2B).

Conclusion: Even prior to DMARD cessation, individuals who subsequently flare following csDMARD withdrawal display a unique soluble proteome, indicative of immune activation and regulation. Other mediators increase towards the point of flare, providing potential insights into flare physiology. Our ultimate goal is to develop biomarkers that will facilitate targeted treatment withdrawal in patients in remission, and to generate knowledge that may aid relapse prevention by appropriately targeted therapeutics.

References

  1. Rayner F et al. BMC Rheumatol. 2021
  2. Feng W et al. Nat Commun. 2023

Supporting image 1

Table 1: BIO-FLARE cohort clinical characteristics. Values are stated as median (range) for continuous variables, and n (%) for binary variables. § Mann-Whitney test for continuous variables, and Chi-square for binary variables. * p < 0.05, ** p < 0.01, **** p < 0.0001.

Supporting image 2

Figure 1: RA patients who flare following DMARD withdrawal have a unique soluble mediator profile at baseline. Serum was  analysed using the NULISAseq™ Inflammation Panel 250 and the NULISAseqR package. Upregulated mediators in the flare group are highlighted in red, whereas downregulated mediators are highlighted in blue as compared to DFR. For discovery purposes an unadjusted significance threshold (p<0.05) was used.

Supporting image 3

Figure 2: RA patients who flare following DMARD withdrawal have a distinct longitudinal change in soluble mediators towards the point of flare. Serum was analysed using the NULISAseq™ Inflammation Panel 250 and the NULISAseqR package. Differential changes in mediator abundance across time in the DFR group (A) and flare group (B) using a linear mixed effect model with co-variates – fixed effect of time and random effect of participant ID. Mediators highlighted in red show a significant change in time with a FDR adjusted p value < 0.05.

Disclosures: A. Anderson: None; F. Rayner: None; A. Degnan: None; I. Wilson: None; J. Diboll: None; J. Sim: None; A. Melville: None; S. Siebert: AbbVie, 6, Amgen, 6, AstraZeneca, 6, Boehringer-Ingelheim, 5, Bristol-Myers Squibb, 5, Eli Lilly, 5, GlaxoSmithKline, 5, Janssen, 5, 6, Teijin Pharma, 6, UCB, 5; I. McInnes: AbbVie, 2, 5, 6, Amgen, 2, Bristol Myers Squibb, 2, 5, Cabaletta, 2, Celgene, 2, Compugen, 2, Dextera, 2, Eli Lilly, 2, 5, Janssen, 2, 5, Moonlake, 2, Novartis, 2, 5, Pfizer, 2, UCB, 2, 5, 6; C. Goodyear: None; C. Hilkens: None; A. Filer: None; K. Raza: None; C. Buckley: None; K. Baker: Pfizer, 5; A. Pratt: None; J. Isaacs: AbbVie/Abbott, 2, 6, AnaptysBio, 2, Annexon, 2, AstraZeneca, 2, Bristol-Myers Squibb(BMS), 2, Dragonfly, 2, Eli Lilly, 1, Galapagos, 2, GlaxoSmithKlein(GSK), 2, 5, Istesso, 2, Janssen, 5, Kira Biotech, 2, Ono Pharma, 2, Pfizer, 5, Revelo, 2, Sanofi, 2, Sonoma Biotherapeutics, 2, Topas, 2, UCB, 1.

To cite this abstract in AMA style:

Anderson A, Rayner F, Degnan A, Wilson I, Diboll J, Sim J, Melville A, Siebert S, McInnes I, Goodyear C, Hilkens C, Filer A, Raza K, Buckley C, Baker K, Pratt A, Isaacs J. Using Circulating Soluble Serum Mediator Profiles to Understand the Mechanisms Driving Disease Flare and Drug-free Remission in Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2024; 76 (suppl 9). https://acrabstracts.org/abstract/using-circulating-soluble-serum-mediator-profiles-to-understand-the-mechanisms-driving-disease-flare-and-drug-free-remission-in-rheumatoid-arthritis/. Accessed .

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