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Clinical Trial
. 2024 Jun 25;26(1):125.
doi: 10.1186/s13075-024-03347-0.

S100 proteins as potential predictive biomarkers of abatacept response in polyarticular juvenile idiopathic arthritis

Hermine I Brunner  1 , Grant S Schulert  2 , Alyssa Sproles  2 , Sherry Thornton  2 , Gabriel Vega Cornejo  3 , Jordi Antón  4 , Ruben Cuttica  5 , Michael Henrickson  2 , Ivan Foeldvari  6 , Daniel J Kingsbury  7 , Margarita Askelson  8 , Jinqi Liu  9 , Sumanta Mukherjee  9 , Robert L Wong  10 , Daniel J Lovell  2 , Alberto Martini  11 , Nicolino Ruperto  12 , Alexei A Grom  2 ; Pediatric Rheumatology Collaborative Study Group (PRCSG) and the Paediatric Rheumatology International Trials Organisation (PRINTO)
Affiliations
Clinical Trial

S100 proteins as potential predictive biomarkers of abatacept response in polyarticular juvenile idiopathic arthritis

Hermine I Brunner et al. Arthritis Res Ther. .

Erratum in

Abstract

Background: Juvenile idiopathic arthritis (JIA) comprises a heterogeneous group of conditions that can cause marked disability and diminished quality of life. Data on predictors of clinical response are insufficient to guide selection of the appropriate biologic agent for individual patients. This study aimed to investigate the propensity of S100A8/9 and S100A12 as predictive biomarkers of abatacept response in polyarticular-course juvenile idiopathic arthritis (pJIA).

Methods: Data from a phase 3 trial (NCT01844518) of subcutaneous abatacept in patients with active pJIA (n = 219) were used in this exploratory analysis. Association between biomarker levels at baseline and improvements in JIA-American College of Rheumatology (ACR) criteria responses or baseline disease activity (measured by Juvenile Arthritis Disease Activity Score in 27 joints using C-reactive protein [JADAS27-CRP]) were assessed. Biomarker level changes from baseline to month 4 were assessed for disease outcome prediction up to 21 months.

Results: At baseline, 158 patients had available biomarker samples. Lower baseline S100A8/9 levels (≤ 3295 ng/mL) were associated with greater odds of achieving JIA-ACR90 (odds ratio [OR]: 2.54 [95% confidence interval (CI): 1.25-5.18]), JIA-ACR100 (OR: 3.72 [95% CI: 1.48-9.37]), JIA-ACR inactive disease (ID; OR: 4.25 [95% CI: 2.03-8.92]), JADAS27-CRP ID (OR: 2.34 [95% CI: 1.02-5.39]) at month 4, and JIA-ACR ID (OR: 3.01 [95% CI: 1.57-5.78]) at month 16. Lower baseline S100A12 levels (≤ 176 ng/mL) were associated with greater odds of achieving JIA-ACR90 (OR: 2.52 [95% CI: 1.23-5.13]), JIA-ACR100 (OR: 3.68 [95% CI: 1.46-9.28]), JIA-ACR ID (OR: 3.66 [95% CI: 1.76-7.61]), JIA-ACR90 (OR: 2.03 [95% CI: 1.07-3.87]), JIA-ACR100 (OR: 2.14 [95% CI: 1.10-4.17]), and JIA-ACR ID (OR: 4.22 [95% CI: 2.15-8.29]) at month 16. From baseline to month 4, decreases in S100A8/9 and S100A12 generally exceeded 50% among JIA-ACR90/100/ID responders.

Conclusion: Lower baseline levels of S100A8/9 and S100A12 proteins predicted better response to abatacept treatment than higher levels and may serve as early predictive biomarkers in pJIA. Decreases in these biomarker levels may also predict longer-term response to abatacept in pJIA.

Keywords: Abatacept; Biomarkers; C-Reactive protein (CRP); Juvenile idiopathic arthritis; S100.

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Conflict of interest statement

HIB: consultant: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, GlaxoSmithKline, Janssen, Merck, Novartis, Pfizer, Roche, UCB (funds go to CCHMC/employer); grant/research support: Bristol Myers Squibb, Pfizer (funds go to CCHMC/employer). GSS: speakers bureau: Novartis; consultant: Sobi. GVC: speakers bureau: AbbVie; grant/research support: Bristol Myers Squibb, Eli Lilly, Janssen, Parexel, Sanofi. JA: speakers bureau: AbbVie, Gebro, GlaxoSmithKline, Novartis, Pfizer, Roche, Sobi; consultant: AbbVie, Gebro, GlaxoSmithKline, Novartis, Pfizer, Roche, Sobi; grant/research support: AbbVie, Amgen, Gebro, GlaxoSmithKline, Lilly, Novartis, Novimmune, Pfizer, Roche, Sanofi, Sobi. RC: speakers bureau: AbbVie, Bristol Myers Squibb, GlaxoSmithKline, Lilly, Novartis, Pfizer, Roche, UCB; paid instructor: AbbVie, Novartis, Pfizer, Roche; consultant: AbbVie, Bristol Myers Squibb, GlaxoSmithKline, Lilly, Novartis, Pfizer, Roche, UCB. IF: consultant: Bristol Myers Squibb, Gilead, Hexal, MEDAC, Novartis, Pfizer, Sanofi. DJK: consultant: Pfizer. MA: consultant: Bristol Myers Squibb (working for Syneos Health). JL: employee, shareholder: Bristol Myers Squibb. SM: shareholder: Bristol Myers Squibb; employee, shareholder: GlaxoSmithKline. RLW: employee (at the time of analysis): Bristol Myers Squibb; shareholder: Bristol Myers Squibb. DJL: speakers bureau: Genentech, Wyeth Pharm; consultant: Abbott, AstraZeneca, Boehringer Ingelheim, Celgene, F Hoffmann-La Roche, GlaxoSmithKline, Novartis, Pfizer, Regeneron, UBC, Wyeth Pharma. AM: speakers bureau: AbbVie, Novartis; consultant: AbbVie, Eli Lilly, EMD Serono, Idorsia, Janssen, Novartis, Pfizer. NR: honoraria, speakers bureau, consultant: Ablynx, AstraZeneca-Medimmune, Bayer, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, EMD Serono, F Hoffmann-La Roche, GlaxoSmithKline, Janssen, Merck, Novartis, Pfizer, R-Pharma, Sinergie, Sobi, UCB; grant/research support: The IRCCS Istituto Giannina Gaslini, where NR works as full-time public employee, has received contributions from: 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 to third parties. AAG: consultant, grant/research support: AB2Bio, Novartis, Sobi (NovImmune). AS, ST, MH: none declared.

Figures

Fig. 1
Fig. 1
Clinical response to abatacept over 21 months for A the biomarker cohort* and B by background MTX use. Values are given as n/m, where n is the number of responders at the corresponding time point for each baseline category and m is the number of patients in each baseline category. *All treated patients with available baseline data for S100 proteins (S100A8/9 or S100A12). At months 4, 16, and 21, patients who were still in the study but had missing JADAS27-CRP values were considered as non-responders at those respective time points in the analysis (n = 3, 4, 2, respectively). Patients who were not in the study and had no available efficacy assessments at those respective time points and later time points were also considered as non-responders (n = 9, 26, 32, respectively). CRP = C-reactive protein; ID = inactive disease; JADAS27-CRP = Juvenile Arthritis Disease Activity Score in 27 joints using C-reactive protein; JIA-ACR50/70/90/100 = 50/70/90/100% improvement in juvenile idiopathic arthritis-American College of Rheumatology criteria; LDA = low disease activity; MTX = methotrexate
Fig. 2
Fig. 2
Prediction of response to abatacept treatment by baseline biomarker level at A month 4 and B month 16. CI = confidence interval; ID = inactive disease; JADAS27-CRP = Juvenile Arthritis Disease Activity Score in 27 joints using C-reactive protein; JIA-ACR50/70/90/100 = 50/70/90/100% improvement in juvenile idiopathic arthritis-American College of Rheumatology criteria; LDA = low disease activity; OR = odds ratio
Fig. 3
Fig. 3
Percent mean change in biomarker levels of A S100A8/9, B S100A12, and C CRP from baseline to month 4 for responders versus non-responders across efficacy endpoints. CRP = C-reactive protein; ID = inactive disease; JADAS27-CRP = Juvenile Arthritis Disease Activity Score in 27 joints using C-reactive protein; JIA-ACR50/70/90/100 = 50/70/90/100% improvement in juvenile idiopathic arthritis-American College of Rheumatology criteria; LDA = low disease activity
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