Effective Suppression of Cerebrospinal Fluid B Cells by Rituximab and Cyclophosphamide in Progressive Multiple Sclerosis—Reply

In reply

Included in this issue of the ARCHIVES is a case report describing a patient with relapsing-remitting MS who responded favorably to rituximab treatment alone¹ and the preceding letter, which describes a patient with relapsing-remitting MS who responded favorably to rituximab combined with cyclophosphamide. In both instances, the authors also assessed CD19⁺ B cell frequencies in the peripheral blood and spinal fluid of their patients, as we had done in our previous report in the ARCHIVES.² However, in contrast to our data, both of these cases demonstrated complete depletion of CD19⁺ CSF B cells in response to rituximab. Several factors may contribute to the apparent discordance with our results. First, the CSF was sampled during the first few courses of treatment, which represent much earlier samplings than what we had previously reported. We had hypothesized that B cell depletion in the CSF of patients with MS would require a longer period of exposure because it has been reported that rituximab concentrations in the CSF are roughly 10% of what can be achieved in the peripheral blood.³ However, the data presented in the preceding letter and the case report by Stüve et al¹ suggest that CSF B cell depletion may occur at the same rate as in peripheral blood. Second, and perhaps even more importantly, the patients treated in these 2 cases had relapsing-remitting MS, rather than primary progressive MS, which further punctuates the possibility that these 2 distinct patient populations may respond to rituximab differently.

It is difficult to determine the relative impact of the rituximab/cyclophosphamide combination on CD19⁺ B cell depletion compared with rituximab alone. Nevertheless, rituximab therapy in both cases resulted in vast improvement of these patients’ MS symptoms, underlining that rituximab treatment is a legitimate treatment option for at least some MS patients, perhaps even as a primary treatment rather than a last alternative.

Finally, assessing the effect of rituximab mechanistically will likely require at least 3 additional pieces of information. First, what concentrations of rituximab in CSF are obtained during treatment? This will provide us with a clear indication of what concentration of rituximab is required to deplete CSF B cells. Second, does the oligoclonal banding pattern change in response to rituximab? If patients continue to improve on rituximab therapy, even if the oligoclonal banding pattern does not change, then perhaps depletion of long-lived plasma cells is not required to alleviate disease. Third, what types of CSF B cells are being depleted in response to rituximab, and what types of B cells repopulate the CSF after rituximab has been cleared? Understanding the population dynamics of CSF B cells in response to rituximab will help us determine whether short- or long-term rituximab treatment protocols need to be considered and may be clarified in the ongoing phase 2/3 multicenter trial sponsored by Genentech (South San Francisco, Calif). In any case, these reports substantiate the urgency in defining the effect of rituximab on CSF B cells and, ultimately, on our MS patient population.

Correspondence: Dr Monson, Department of Neurology and Center for Immunology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390 (nancy.monson@utsouthwestern.edu).