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B cell depletion by rituximab requires cross linking of CD20, which induces redistribution of CD20 to lipid rafts. This redistribution is correlated with efficiency of complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC) in previous studies. The integrity of the lipid rafts may also be important in induction of apoptosis. In vitro, statins interfere with the formation of cholesterol-rich micro domains within the plasma membrane- the lipid rafts, which impairs lymphoma cell killing by ADCC and CDC by rituximab.1 We previously demonstrated that pre- and post-treatment numbers of plasmablasts were associated with clinical response to rituximab.2 Statins were recently reported to inhibit rituximab's clinical efficacy in rheumatoid arthritis (RA).3 We therefore tested for an association of statin use and both plasmablast number and clinical response and in our cohort.
One hundred and nineteen patients pooled from three clinical trials were treated with 2×1000 mg of rituximab. All were positive for rheumatoid factor and/or anti-cyclic citrullinated protein antibodies. Disease activity score 28 and European League Against Rheumatism (EULAR) response were calculated at baseline and 6 months. B cell naïve, memory and plasmablast subsets were measured by flow cytometry, using a protocol optimised for the detection of low numbers of plasmablasts as previously described,2 defining complete B cell depletion as numbers of naïve, memory and plasmablasts below 0.0001 cells×109/l at 2 weeks.
Among 119 patients, 26 patients received a statin. Baseline characteristics are summarised in table 1. Age was clearly significantly higher in patients receiving a statin, and there were trends to lower IgM, IgG and naïve B cells close to significance at the 5% level.
After therapy with 2×1 g rituximab, we found no evidence of less complete B cell or plasmablast depletion in patients receiving a statin (p=0.650, χ2 test) and no evidence of inferior clinical responses in this group (p=0.590, t test for independent groups for change in DAS) (table 2).
Higher age in patients receiving statins was expected and is a potential confounder in many similar studies. Lower immunoglobulin titres and naïve B cell numbers were not necessarily expected. These results may relate to age, although an effect of statins on humoral immunity cannot be excluded.
We have not replicated the results of the previous study. There is no clear difference between our cohorts to explain this discrepancy, although in the previous report there was a trend to lower rate of RF positivity in the statin group and cyclic citrullinated protein status was not reported. An effect of statins on the binding of monoclonal antibodies to cell surface proteins would be of significance to numerous biological therapies. We have not demonstrated any such effect in the case of rituximab for RA using a cellular biomarker.
MFM was sponsored by Valencia Society of Rheumatology & Spanish Society of Rheumatology.
Contributors All authors contributed to the planning, conduct and reporting of the work.
Funding This work was funded by the Leeds Musculoskeletal Biomedical Research Unit. EMV, SD, MHB and PE have received honoraria from Roche. MFM was sponsored by the Valencian Society of Rheumatology & Spanish Society of Rheumatology.
Competing interests PE has received consultancy fees from Pfizer, MSD, Abbott, UCB BMS, Roche and Novartis, and lecture fees from Pfizer, MSD, Abbott and UCB. SD has received funding from Roche, Pfizer. MFM has received a funding grant from Valencia Society of Rheumatology and Spanish Society of Rheumatology. EV has received a funding grant and lecture fees from Roche. SDass has received consultancy and lecture fees from Roche. MB has received consultancy fees from Abbot, BMS, Roche; lecture fees from Abbott, BMS, Roche, Pfizer and a pending grant from Pfizer.
Provenance and peer review Not commissioned; externally peer reviewed.
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