POS0076 S100A8/A9 AND S100A12 AS POTENTIAL PREDICTIVE BIOMARKERS OF ABATACEPT RESPONSE IN POLYARTICULAR JUVENILE IDIOPATHIC ARTHRITIS
Authors: N. Ruperto, G. Schulert, A. Sproles, S. Thornton, G. Vega Cornejo, J. Anton, R. Cuttica, M. Henrickson, I. Foeldvari, D. Kingsbury, M. Askelson, J. Liu, S. Mukherjee, R. Wong, D. J. Lovell, A. Martini, A. Grom, H. Brunner
Journal: Annals of the Rheumatic Diseases (2021)

Background: The calcium-binding proteins S100A8/A9 (calprotectin) and S100A12 (extracellular newly identified receptor for advanced glycation end-products binding protein [EN-RAGE]) are involved in multiple signalling pathways to mediate inflammation, can be secreted by activated monocytes/macrophages and exhibit cytokine-like extracellular functions. Circulating levels of these proteins have been associated with disease and clinical responses in systemic juvenile idiopathic arthritis (sJIA), including treatment response. 1 Studies suggest that serum S100A8/A9 and S100A12, which are released at inflammation sites, are more specific biomarkers of local inflammation (e.g. in the synovium) than systemic biomarkers such as CRP and ESR. 2,3 Objectives: To investigate if baseline S100A8/A9 and S100A12 predict clinical response to abatacept treatment in polyarticular JIA (pJIA), and to assess whether changes from baseline in S100A8/A9 or S100A12 can be better prognostic markers for response to abatacept treatment than CRP in pJIA. Methods: Data are from a phase III trial of SC abatacept for the treatment of pJIA ( NCT01844518 ). 4 This 24-month, single-arm, open-label, international, multicentre, two-part study included male and female patients with pJIA aged 2–17 years. This analysis examined the correlation between biomarkers (S100A8/A9, S100A12 and high-sensitivity CRP [hsCRP]) and disease activity (measured using Juvenile Arthritis Disease Activity Score [JADAS]) at baseline, baseline biomarker values as predictors of future treatment response (ACR and JADAS endpoints), and the correlation between change from baseline in biomarker values and treatment response at Day 113. Results: Of 219 total patients, 158 (72%) had S100A8/A9 values and 155 (71%) had S100A12 values at baseline. Median S100A8/A9 and S100A12 values were 3295 ng/mL (normal range, 716–3004 ng/mL) and 176 ng/mL (normal range, 32–385 ng/mL), respectively. S100A8/A9, S100A12 and hsCRP (median 0.20 mg/dL; normal ≤0.6 mg/dL) had a low-to-moderate but significant association with disease activity at baseline; coefficients for associations between JADAS71-CRP low disease activity (LDA) and the biomarkers S100A8/A9, S100A12 and hsCRP were 0.23 (p=0.0038), 0.16 (p=0.0448) and 0.26 (p=0.0001), respectively. Baseline S100A8/A9 level above the median was associated with lower odds of ACR100 at Day 113 (p=0.0052). Figure 1 shows the associations of baseline biomarker values with Day 113 ACR and JADAS scores in the overall population. Baseline S100A8/A9 or S100A12 did not significantly influence ACR50 or ACR70 responses at Day 113, but high baseline values were associated with reduced odds of ACR90 (p=0.01), ACR100 (p=0.005), ACR-inactive disease (ID) (p=0.0001), and JADAS71-CRP (LDA) (p=0.02). By Day 477, elevated baseline S100A12 was still significantly associated with lower odds of ACR100 overall (0.467; p=0.0248) but baseline S100A8/A9 was not; at Day 645, neither was significantly associated with ACR100 response. At Day 113, changes from baseline in S100A8/A9 and S100A12 were correlated with ACR100 (coefficients of 0.22 [p=0.0082] and 0.26 [p=0.0015], respectively) and with ACR-ID (0.22 [p=0.0067] and 0.26 [p=0.0014], respectively); change in hsCRP was not significantly correlated with disease response. Conclusion: S100A8/A9 and S100A12 may serve as prognostic biomarkers to predict response to abatacept treatment at Day 113. Changes from baseline S100A8/A9 and S100A12 levels were more highly correlated with efficacy outcomes including ACR100 and ACR-ID at Day 113 compared with hsCRP. References: [1]Aljaberi N, et al. Pediatr Rheumatol Online J 2020;18:7. [2]Hammer H, et al. Arthritis Res Ther 2011;13:R178. [3]Nordal HH, et al. BMC Musculoskelet Disord 2014;15:335. [4]Brunner H, et al. Arthritis Rheumatol 2018;70:1144–1154. Acknowledgements: Professional medical writing and editorial assistance was provided by Rob Coover, MPH, at Caudex and was funded by Bristol Myers Squibb. Disclosure of Interests: Nicolino Ruperto Speakers bureau: NR has received honoraria for consultancies or speaker bureaus (&lt; 10.000 USD each) from the following pharmaceutical companies in the past 3 years: Ablynx, Astrazeneca-Medimmune, Bayer, Biogen, Boehringer, Bristol Myers Squibb, Celgene, Eli Lilly, EMD Serono, GlaxoSmithKline, Hoffmann-La Roche, Janssen, Merck, Novartis, Pfizer, R-Pharma, Sinergie, Sobi and UCB, Consultant of: NR has received honoraria for consultancies or speaker bureaus (&lt; 10.000 USD each) from the following pharmaceutical companies in the past 3 years: Ablynx, Astrazeneca-Medimmune, Bayer, Biogen, Boehringer, Bristol Myers Squibb, Celgene, Eli Lilly, EMD Serono, GlaxoSmithKline, Hoffmann-La Roche, Janssen, Merck, Novartis, Pfizer, R-Pharma, Sinergie, Sobi and UCB, Grant/research support from: The IRCCS Istituto Giannina Gaslini (IGG), where NR works as full-time public employee has received contributions (&gt;10.000 USD each) from the following industries in the last 3 years: Bristol Myers Squibb, Eli Lilly, F Hoffmann-La Roche, GlaxoSmithKline, Janssen, Novartis, Pfizer, Sobi. This funding has been reinvested for the research activities of the hospital in a fully independent manner, without any commitment with third parties., Grant Schulert Speakers bureau: Novartis, Consultant of: SOBI, Alyssa Sproles: None declared, Sherry Thornton: None declared, Gabriel Vega Cornejo Speakers bureau: AbbVie, Grant/research support from: Bristol Myers Squibb, Eli Lilly, Janssen, Parexel, Sanofi, Jordi Anton Speakers bureau: AbbVie, Gebro, GlaxoSmithKline, Novartis, Pfizer, Roche, Sobi, Consultant of: AbbVie, Gebro, GlaxoSmithKline, Novartis, Pfizer, Roche, Sobi, Grant/research support from: AbbVie, Amgen, Gebro, GlaxoSmithKline, Lilly, Novartis, Novimmune, Pfizer, Roche, Sanofi, Sobi, Ruben Cuttica Speakers bureau: AbbVie, Bristol Myers Squibb, GlaxoSmithKline, Lilly, Novartis, Pfizer, Roche, UCB, Paid instructor for: AbbVie, Novartis, Pfizer, Roche, Consultant of: AbbVie, Bristol Myers Squibb, GlaxoSmithKline, Lilly, Novartis, Pfizer, Roche, UCB, Michael Henrickson: None declared, Ivan Foeldvari Consultant of: Bristol Myers Squibb, Gilead, Hexal, MEDAC, Novartis, Pfizer, Sanofi, Daniel Kingsbury Consultant of: Pfizer, Margarita Askelson Consultant of: Currently working for Syneos Health providing services to Bristol Myers Squibb, Jinqi Liu Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Sumanta Mukherjee Shareholder of: Bristol Myers Squibb, GlaxoSmithKline, Employee of: Bristol Myers Squibb, GlaxoSmithKline, Robert Wong Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Daniel J Lovell Speakers bureau: Genentech, Wyeth Pharm, Consultant of: Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Celgene, GlaxoSmithKline, Hoffman-La Roche, Novartis, Pfizer, Regeneron, Takeda, UBC, Wyeth Pharma, Xoma, Alberto Martini Speakers bureau: AbbVie, Novartis, Consultant of: AbbVie, Eli Lilly, EMD Serono, Idorsia, Janssen, Novartis, Pfizer, Alexei Grom Consultant of: AB2Bio, Novartis, Sobi (NovImmune), Grant/research support from: AB2Bio, Novartis, Sobi (NovImmune), Hermine Brunner Speakers bureau: GlaxoSmithKline, Novartis, Pfizer, Roche, Paid instructor for: Novartis, Pfizer (funds go to CCHMC/employer), Consultant of: Boehringer Ingelheim, Bristol Myers Squibb, GlaxoSmithKline, Janssen, Merck, Novartis, Pfizer, Roche, UCB (funds go to CCHMC/employer), Grant/research support from: Bristol Myers Squibb, Pfizer (funds go to CCHMC/employer).