Background Tocilizumab (TCZ) is a humanized anti-IL-6R monoclonal antibody approved for the treatment of active rheumatoid arthritis (RA). Response to treatment may depend on the dose and dose interval as well as on the achieved trough serum levels.
Objectives To analyze serum trough levels of TCZ in two cohorts of RA patients on chronic treatment with TCZ and their relationship with disease activity and clinical remission. To establish a cut-off point of TCZ serum levels with high discriminative capacity for clinical remission state.
Methods Cross-sectional study of two cohorts (Barcelona, Spain and Lausanne, Switzerland) including all RA patients on chronic treatment with IV TCZ. Demographic data, disease activity measured by DAS28, acute phase reactants, TCZ trough levels (detectable levels ≥1μg/ml) (LISA TRACKER Tocilizumab Theradiaag, France) and IL6 serum levels (ELISA) were analyzed. All samples were collected just before treatment infusion. TCZ levels were correlated with different clinical and serological parameters. Multivariate logistic regression was used to determine the variables associated with remission (DAS28≤2.6). Receiver operating characteristic (ROC) curve analysis was used to determine the discriminatory capacity of the area under the curve (AUC) of TCZ levels in predicting remission.
Results 82 RA patients were included (40 Barcelona Cohort, 42 Lausanne Cohort) (90% were women, mean age 55.5±13 years, disease duration of 13.7±8 years, 60.3% anti-CCP+, 22.2% on monotherapy, 37.2% received low dose glucocorticoids and 26.8% were on reduced dose of TCZ). The mean DAS28 was of 2.5±1.1 and 44 patients (54.3%) were in remission. Swiss patients had a lower disease activity and were more frequently in remission, had less glucocorticoids use and were less frequently on a reduced dose. 25 patients (30.5%) had undetectable levels of TCZ (<1 μg/ml), and this was associated in both cohorts with significantly higher levels of CRP and lower levels of IL-6. DAS28 was higher in patients with undetectable levels of TCZ, but the difference was significant only in Swiss patients (Barcelona cohort DAS28 3.25±1.2 vs 2.82±0.9, Lausanne cohort DAS28 2.79±1.02 vs 1.75±0.9, p=0.017 in patients with undetectable and detectable trough levels of TCZ respectively). The proportion or patients on clinical remission or low disease activity was higher on the group of patients with detectable trough levels of TCZ. There were no differences between groups in the use of combination therapy with glucocorticoids or DMARDs. In the multivariate analysis, detectable levels of TCZ and glucocorticoids use were independently associated with clinical remission. The TCZ trough level with the greatest discriminative capacity for remission was 3.48 μg/ml (AUC 0.724; 95% CI: 0.607-0.840; p=0.001) with a sensitivity of 79.5% and a specificity of 67%.
Conclusions Detectable levels of TCZ (≥1 μg/ml) in RA patients on chronic treatment with TCZ were associated with lower disease activity and, especially, with lower CRP levels in the unvaried analysis, and with clinical remission in the multivariate analysis. The cut-off point with the greatest discriminative capacity for clinical remission was of 3.48 μg/ml.
Disclosure of Interest None declared