Serum S100A8/A9 and S100A12 Levels in Children With Polyarticular Forms of Juvenile Idiopathic Arthritis: Relationship to Maintenance of Clinically Inactive Disease During Anti-Tumor Necrosis Factor Therapy and Occurrence of Disease Flare After Discontinuation of Therapy

Abstract

Objective: To determine the relationship between serum levels of S100A8/A9 and S100A12 and the maintenance of clinically inactive disease during anti-tumor necrosis factor (anti-TNF) therapy and the occurrence of disease flare following withdrawal of anti-TNF therapy in patients with polyarticular forms of juvenile idiopathic arthritis (JIA).

Methods: In this prospective, multicenter study, 137 patients with polyarticular-course JIA whose disease was clinically inactive while receiving anti-TNF therapy were enrolled. Patients were observed for an initial 6-month phase during which anti-TNF treatment was continued. For those patients who maintained clinically inactive disease over the 6 months, anti-TNF was withdrawn and they were followed up for 8 months to assess for the occurrence of flare. Serum S100 levels were measured at baseline and at the time of anti-TNF withdrawal. Spearman's rank correlation test, Mann-Whitney U test, Kruskal-Wallis test, receiver operating characteristic (ROC) curve, and Kaplan-Meier survival analyses were used to assess the relationship between serum S100 levels and maintenance of clinically inactive disease and occurrence of disease flare after anti-TNF withdrawal.

Results: Over the 6-month initial phase with anti-TNF therapy, the disease state reverted from clinically inactive to clinically active in 24 (18%) of the 130 evaluable patients with polyarticular-course JIA; following anti-TNF withdrawal, 39 (37%) of the 106 evaluable patients experienced a flare. Serum levels of S100A8/A9 and S100A12 were elevated in up to 45% of patients. Results of the ROC analysis revealed that serum S100 levels did not predict maintenance of clinically inactive disease during anti-TNF therapy nor did they predict disease flare after treatment withdrawal. Elevated levels of S100A8/A9 were not predictive of the occurrence of a disease flare within 30 days, 60 days, 90 days, or 8 months following anti-TNF withdrawal, and elevated S100A12 levels had a modest predictive ability for determining the risk of flare within 30, 60, and 90 days after treatment withdrawal. Serum S100A12 levels at the time of anti-TNF withdrawal were inversely correlated with the time to disease flare (r = -0.36).

Conclusion: Serum S100 levels did not predict maintenance of clinically inactive disease or occurrence of disease flare in patients with polyarticular-course JIA, and S100A12 levels were only moderately, and inversely, correlated with the time to disease flare.

Trial registration: ClinicalTrials.gov NCT00792233.

© 2018, American College of Rheumatology.

Figures

Figure 1:

Correlation between individual subject’s S100A8/A9 and S100A12 levels both at baseline and at the end of the first phase (Spearman correlation coefficient 0.82).

Figure 2:

Receiver operating curve (ROC) curve characteristics of serum S100 levels: (A) S100A8/A9 at baseline and the occurrence of loss of clinically inactive disease during six months of anti-TNF continuation (area-under the curve [AUC] 0.52, 95% confidence interval [CI] 0.38–0.65), (B) S100A8/A9 at the time of anti-TNF agent withdrawal and the occurrence of disease flare within eight months following anti-TNF withdrawal (AUC 0.56, CI 0.44–0.67), (C)) S100A12 at baseline and the occurrence of loss of clinically inactive disease during six months of anti-TNF continuation (AUC 0.53, CI 0.38–0.67), (B) S100A12 at the time of anti-TNF agent withdrawal and the occurrence of disease flare within eight months following anti-TNF withdrawal (AUC 0.51, CI 0.39–0.62).

Figure 3:

Kaplan-Meier survival analysis comparing flare-free survival throughout the eight-month phase following anti-TNF withdrawal according to elevated vs. normal (A) serum S100A8/A9 and (B) serum S100A12 levels at the time of anti-TNF withdrawal (Hazard ratio per logrank test for S100A8/A9 >690 ng/ml 0.72 (95% CI 0.36–1.42) and for S100A12 >120 ng/ml 1.13 [95% CI 0.55–2.33])