Background/Purpose: Multiple biomarker disease activity (MBDA) cytokine panels identify RA subsets with continuing inflammation despite fulfilling clinical and acute phase reactants (APR) parameters of low disease activity or remission. However, the characteristics of MDBA in the RA subset of discordant disease, (clinically active, normal APR), are yet to be defined. Herein, we compared clinical characteristics and cytokine assays in RA concordant and discordant disease subsets.

Methods: RA patients enrolled in a longitudinal observational registry (VARA) were studied and clinical and disease status characteristics documented. Patients with high joint counts (TJC + SJC>3) and APR (ESR ≥ 28 + CRP ≥ 1.5) were categorized as Concordant (C1), those with TJC+SJC ≤3 and normal APR (ESR < 28 + CRP < 1.5) were C2, while those with TJC+SJC>3, but with ESR < 28 and CRP < 1.5 were categorized as Discordant (D). Discordant patients were further stratified into Low, Medium, High disease activity (DL, DM, DH), based on TJC+SJC of 4 or 5, 6-8, 9 or higher, respectively. Cytokines and chemokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 (p70), IL-13, IL-17, GCSF, GM-CSF), IFN-γ, MCP-1, MIP-1β, TNF-α) were measured via bead-based multiplex assay and a cytokine score calculated (weighted average). Chi-square tests compared categorical measures by concordance status, t-, Wilcoxon rank sum and Kruskal-Wallis tests, ANOVA models, ordinary least squares regressions compared continuous measures. 

Results: 1467, predominantly male, VARA patients had cytokine assays. Compared to C1 patients (n=434), D patients (n=174) were younger (62[11] vs 66[11] years), less frequently seropositive (RF [75% vs 91%], ACPA [72% vs 86%), with lower TJC (8.1 [7.1] vs. 10.0 [8.0] , SJC (6.1 [5.4] vs. 9.5 [6.9]) and DAS28-3v scores (3.8 [1.1] vs. 5.5 [1.1]. p<0.001). Cytokine scores at all levels of discordance were significantly lower than in C1 patients (p<0.001) (Table). DL, DM and DH subsets were not significantly different in cytokine scores, and were similar to C2 (n=356) patients. In multivariable analyses comparing C1 vs D patients, log CK Score was associated with RF status (p=0.037) and DAS28-3v scores (p=0.012). In the OLS model including C2 patients (mean log cytokine score = 1.99), there was significant association with RF (p=0.042), ACPA (p=0.031), but only a trend towards DAS28-3v scores (p=0.066).

Conclusion:  In our RA discordant subset, cytokine scores were congruent with APR levels and disease status suggesting this particular MBDA at a single time point was not useful in delineating active disease. Prospective studies assessing disease outcomes in this RA subset may argue for less aggressive DMARD therapies.

Table: Associations of TJC+SJC >3 with cytokine assays/quartiles in RA patients with

Elevated and Normal Acute phase reactants

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/limited-utility-of-cytokine-profiles-in-rheumatoid-arthritis-patients-with-clinically-active-disease-and-normal-inflammatory-indices/