| Targeted therapies have proven successful in the treatment of chronic inflammatory diseases and hold great promise for the future. However, due to the complex patho-physiological mechanisms at play the frequency of response and benefit is not optimal. In order to increase the success rate for targeted therapies we have to change the treatment regime from a group average to an individualized treatment regime. Therefore, it is important to identify biomarkers to select patients with a high likelihood of benefit. In this project we study the response of rheumatoid arthritis (RA) patients to treatment with neutralizing antibodies to TNFα (infliximab) and B-cell depletion therapy (rituximab, anti-CD20), which is highly variable. The underlying mechanism for therapy responsiveness is currently unknown. In search for biomarkers that could predict the response to TNF blockade, we discovered that treatment induced changes in type I IFN response genes appeared clinically relevant since patients with an anti-TNF induced increased IFN response gene activity had a poor clinical outcome, measured at 16 weeks after the start of treatment. We also studied the pharmacodynamics of rituximab in RA. As anticipated, rituximab resulted in depletion of B cell-expressed genes. We observed that patients with a low baseline IFN response gene activity had a significantly stronger reduction in DAS28 and more often achieved a EULAR response at week 12 and 24 compared to patients with an increased IFN-response activity. These data indicate that the type I IFN signature negatively predicts the clinical response to rituximab treatment in RA, supporting the notion that IFN signalling plays a role in RA immunopathology. Pharmacogenomic analyses demonstrated marked inter-individual differences in the pharmacological responses at 3 and 6 months after the start of therapy with rituximab. Interestingly, only differences in the regulation of the type I IFN-response genes at 3 months after therapy correlated with the ΔDAS28 response. We observed that a good clinical response to rituximab in RA is associated with a selective drug-induced increase in type I IFN-response activity in RA patients. This finding may provide insight in the biological mechanism underlying the therapeutic response to rituximab. Current studies are aimed to further validate these findings in independent cohorts and to understand the biomolecular basis of the differential responsiveness. |
