A Common Error In Using Combined Treatment With Rituximab And Plasmapheresis (Pp) To Prevent Or Treat Antibody Mediated Rejection (Amr)

Background: PP and rituximab are two major therapies commonly used in transplantation. They are often used in combination to prevent or treat AMR. Since PP can remove antibodies while rituximab is a B-cell depleting monoclonal antibody. The right sequence of using rituximab and PP is critical to achieve the best treatment efficacy. This meta-analysis analyzed the commonly used PP/rituximab protocols and pointed out a common error in current clinic practice. Methods: We did a PubMed title search for recent 5 years literature in major transplant journals and investigated treatment protocols with rituximab and PP. We tried to address the question whether rituximab treatment followed by multiple sessions of PP will compromise B-cell depleting effects of rituximab. Results: Among a total of 12 papers in which rituximab was used with concomitant PP, three papers did not describe detailed treatment sequence. Rituximab was given after multiple sessions of PP in three studies. In the rest 6 studies, one or two doses of rituximab were administered followed by multiple sessions of PP. The half-life of rituximab is approximately 2-4 weeks with a wide variability between subjects. The clearance rate of rituximab after one session of PP/PE is 47-54%. Multiple (4-5) sessions of PP/PE can clear it to undetectable level. Apparently, the B cell depletion effect of rituximab will be significantly compromised if PP treatment is performed right after the rituximab is given. Significantly, a single dose of rituximab without PP usually completely removed peripheral B cells within 1-2 days and sustained profound B cell suppression up to 2-3 years of observation period. However, when multiple cycles of PP were performed right after rituximab therapy, peripheral B cells were detectable within 1st week in 60-71% of patients. B cell counts started to increase from month 5-6, and recovered to baseline levels with 1-2 years. Conclusion: A combined treatment with rituximab therapy followed by multiple cycles of PP is a very common error in current clinic practice. These treatment protocols significantly diminished treatment efficacy of rituximab. People may argue that the maximum effect of rituximab in depleting circulating B cells was observed within 2 days with more than 90% depletion rate. However, this argument ignores the long-term effect of rituximab on CD20+ B cells in lymphoid tissues. Similar mistaken treatment sequence is commonly found in other protocols which also need to be paid attention to. Authors suggest that PP should be used either before or after 1-2 half-life of any given immune-suppressants, which will help maintain or maximize their effects. Certainly, it is a different issue if PP is used to remove rituximab or other drugs from peripheral blood in order to minimize their severe side effects.