Background Although B cell depletion therapy with rituximab is successful in the majority of rheumatoid arthritis (RA) patients, 30–40% of patients do not respond. The mechanism behind this is yet unknown, as B cell depletion generally takes place in all patients. This study aims to explore changes in serum cytokines during rituximab therapy in established RA patients.
Methods Serum was collected from 18 established RA patients before and after 1, 3, 6, 9 and 12 months of rituximab therapy. A panel of thirty-four cytokines was measured in a multiplex immunoassay. Patients with a change in disease activity score (∆DAS28) >1.2 after 6 months were considered responders.
Results During rituximab therapy, CXCL13 significantly decreased in all patients (median 1.9-fold decrease (IQR 1.4-3.3)), irrespective of responder status. This coincided with B cell depletion, suggesting that CXCL13 reflects B cell levels in the circulation.
No differences were observed between responders and non-responders after 1 and 3 months of therapy. However, at 6, 9 and 12 months, CXCL10 dynamics differed significantly between responders and non-responders (R vs. NR, T6/T0 p = 0.004, T9/T0 p = 0.003, T12/T0 p = 0.001). Non-responders showed an increase compared to baseline, whereas responders did not. The change in CXCL10 correlated to the ∆DAS28 at 6 months, indicating that this reflects disease activity rather than a mechanistic effect of rituximab. Most strikingly, IL-12 was undetectable in most non-responders until 6 months, but showed a substantial increase after 9 months of therapy, which did not occur in the responders (R vs. NR T9/T6 p = 0.030, Fisher’s exact p = 0.049). The change in IL-12 did not correlate to ∆DAS28.
Conclusions This study shows that during rituximab therapy, cytokine changes occur in the patient serum, both related and unrelated to the clinical response. CXCL13 seems to reflect B cells levels in the circulation, whereas the dynamics of CXCL10 and IL-12 during therapy are regulated differently between responders and non-responders during rituximab treatment. These findings indicate different pharmacological effects of rituximab between responders and non-responders.
This research was supported by the Center for Translational Molecular Medicine (CTMM) and the Dutch Arthritis Foundation (TRACER).