Update: B-Cells in Rheumatic Disease
Volume 8 | October 1, 2007 - December 31, 2007
Return to B-Cell Literature Review Index
Highest Rated Articles
Thurlings and colleagues have conducted an important and complex study giving us important insights into the mechanism of action of rituximab at the level of the joint. They studied 24 patients with active RA, treating them with rituximab. Serial synovial biopsies were performed at baseline and weeks 4 and 16, and they followed clinical activity and monitored peripheral B cells though week 24. The study reaffirmed that rituximab is an effective agent at reducing the signs and symptoms of RA and is accompanied by a rapid disappearance of B cells from peripheral blood in virtually all patients.
This study also revealed that the dynamics on joint histopathology are far more varied and, in some ways, sequential. Not surprisingly, B cells were quickly reduced in the joint at week 4 and further reduced at week 16, but total depletion was not seen in all patients. More intriguingly, other cells lines were more delayed in their reductions with macrophages, T cells, and plasma cells showing their greatest reductions at weeks 4 and 16. In accord with reductions noted in plasma cells were reductions in serum levels of rheumatoid factor (RF) and CCP-direct antibodies. Furthermore, these reductions at latter time points — weeks 4 through 16 — correlated with clinical response. This study asserts that an important mechanism of action of rituximab is not merely the reduction of B cells but a far more complex disruption of the integrated immune response that occurs over time.
Teng and colleagues have published an important study that for the first time explores the effects of rituximab on B cell subsets in the blood synovium and bone marrow in patients with active RA refractory to DMARD therapy, including anti-TNF inhibitors. The 25 study participants were assessed at baseline and week 12. As expected, rituximab rapidly and profoundly depleted peripheral blood in all patients. Furthermore most patients were depleted of CD20 cells in the synovium and bone marrow as well. What is novel in this study and adding insight into the issue of targeted B cell depletion was that persistence of B cell populations that while CD20 negative were residually CD19 + and CD 79+. While we largely assume that CD19 and CD 20 are found on the same cell population, there were clear subpopulations discordant for these markers likely representing early precursor populations. Another interesting observation was a correlation between positivity for IgM anti-CCP antibodies and high infiltration of CD79+ B cells and clinical response, adding further to the notion that some serologic subsets of RA patients may reflect an enhanced susceptibility to B cell depletion strategies.
In this article, Keystone and colleagues report the results of a large clinical study on the efficacy and safety of repeated courses of rituximab in patients with RA. A total of 1,039 patients received more than one course of rituximab, with 570 receiving two courses, 191 receiving three, and 40 patients receiving four. Total observation period was 1,669 patient years.
Recognizing that the follow-up period for those most frequently infused was inadequate, several overall trends are important to clinicians. First, the rate and severity of severe infusion reactions did not increase but rather decreased, suggesting that infusion reactions are unlikely to be on the basis of allergic sensitization to the molecule and more likely reflects the sequelae of B cell lysis. Second, there were trends for immunoglobulin reductions over time, although these were generally nonprogressive and did not correlate with the rates of serious infections per 100 patient years. However, one must be mindful of the limited follow-up for those most frequently infused. Last and consistent with previous studies, there was no consistent correlation between B cell depletion and clinical response. Human anti-chimeric antibodies were detected in about 9.2% of subjects and were only occasionally associated with adverse events. This study provides an important wealth of data as more patients are exposed to courses of rituximab.
