Synovial tissue macrophages: a sensitive biomarker for response to treatment in patients with rheumatoid arthritis

Abstract

Background: Previous work identified synovial sublining macrophage numbers as a potential biomarker for clinical efficacy in rheumatoid arthritis.

Objective: To investigate the association between changes in infiltration of synovial macrophages and clinical improvement after antirheumatic treatment.

Methods: 88 patients who participated in various clinical trials were studied. All patients underwent serial arthroscopy before initiation of treatment and after different time intervals. Immunohistochemical and digital image analysis were performed according to standardised procedures to detect changes in CD68+ synovial sublining macrophages in relationship to changes in the 28 joint count Disease Activity Score (DAS28). Statistical analysis was performed using one way analysis of variance, the independent samples t test, linear regression, and the standardised response mean (SRM).

Results: For good, moderate, and non-responders, according to the DAS28 response criteria, there was a significant difference in the change in sublining macrophages (mean (SEM) cells/mm(2) -643 (124), -270 (64), and -95 (60), respectively; p<0.0003). There was a significant correlation between the change in the number of macrophages and the change in DAS28 (Pearson correlation 0.874, p<0.01). The change in sublining macrophages explained 76% of the variation in the change in DAS28 (p<0.02). The sensitivity to change of the biomarker was high in patients treated actively (SRM >0.8), whereas the ability to detect changes in placebo treated patients was weak (SRM <0.3).

Conclusion: The results suggest that changes in synovial sublining macrophages can be used to predict possible efficacy of antirheumatic treatment.

Figure 1

Mean values of the change compared with baseline in (A) the number of CD68+ macrophages in the intimal lining layer and (B) the synovial sublining for, respectively, non-responders, moderate responders, and good responders according to the DAS28 response criteria in the total study group.

Figure 2

Correlation between the mean change for each substudy in the number of CD68+ sublining macrophages and the mean change in DAS28 (p<0.01, Pearson correlation 0.874, weighted linear regression p<0.02, R² = 0.755, 95% confidence interval (95% CI) 0.001 to 0.005). t, interval between the first and second measurement, n, number of patients; TI, treatment initiation.

Figure 3

Standardised response mean (SRM) of the change in DAS28 (SRM DAS28) and the number of CD68+ macrophages in the sublining (SRM CD68sl) for the individual studies (t, interval between the first and second measurement; n, number of patients, TI, treatment initiation) and grouped for patients who received initiation of an active compound (n = 70) and placebo (n = 18). The solid line indicates the 0.5 SRM cut off point (moderate), the dotted line indicates the 0.8 SRM cut off point (high).