Long-term treatment of rheumatoid arthritis with rituximab and the influence on the immunoglobulin concentration

Objective Biologicals are drugs composed of proteins directed against specific cells or cytokines. Biologicals are making a change in the treatment of rheumatic and immunological conditions. Apart from TNF-blockers currently other targets like CD20 positive B-cells are used for the treatment of Rheumatoid Arthritis (RA). Rituximab is such a monoclonal antibody directed against B-cells. Because of the B-cell depleting properties of rituximab, the influence of this drug on B-cells and their products (immunoglobulins) is interesting. In line with the immunological mechanism, a state of hypogammaglobulinemia might occur after multiple infusions of rituximab that can cause recurrent infections. Long-term follow-up data of pivotal trial patients revealed persistence of B-cell depletion and low immunoglobulin concentration in 25% of patients. However, the accompanying rise in infection rate was not reported. That is why we investigated the influence of multiple rituximab infusions on immunoglobulin levels. Patients and methods Data were collected by using the DREAM (Dutch Rheumatoid Arthritis Monitoring Coalition) registry about RA patients using biologicals. Within this DREAM registry, a sufficient amount of rituximab using patients was available. We retrieved data from hospitals and we used paired univariant analysis as well as repeated measurement analysis. Results We collected immunoglobulin levels of 55 patients, of which 37 could be used for statistical analysis until 4 infusion courses of IgM and IgA levels and 12 for IgG levels. For IgM, a significant difference in concentration could be demonstrated for all baseline comparisons and there was also a significant decrease for course 1 compared to course 2,3 and 4. A further non-significant decrease after 4 courses was also seen. For IgA, there is a significant decrease in concentration when baseline values were compared to course 2,3 and 4. IgA levels also show a further decrease after 4 courses. IgG levels do not yet decrease significantly within 4 infusion courses of rituximab. Conclusion There is a significant decrease in IgM and IgA concentration when patients receive as much as 4 infusions of rituximab. In line with the immunological mechanism, IgG levels do not yet decrease after 4 courses. Our data suggest that depleting B-cells result in decreased immunological response on novel antigens (IgM and IgG). It might be hypothised if continued exposure to rituximab will result in decreased IgG levels as well affecting the immunological defense.