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Rituximab (RTX) is used for the treatment of lymphomas and rheumatoid arthritis (RA), achieving its beneficial effect through B cell depletion.1 2 Recently it has been suggested that the effect of RTX may be inhibited by the concomitant use of statins.3,–,5 B cell depletion is achieved through apoptosis of B cells induced by hypercrosslinking of CD20 molecules with RTX. This process depends on the presence and integrity of lipid rafts in the cell membrane.3 6 7 In vitro, Winiarska et al showed that cholesterol depletion reduces apoptosis by RTX, inhibiting B cell depletion.3 However, two clinical studies that investigated concomitant statin use in patients with lymphoma reported no diminished effect on patient survival.8 9 These patients received chemotherapy, cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) or CHOP-like, containing several other medications apart from RTX, making it difficult to study the isolated effect of statins on RTX. In RA the question remains whether statins can inhibit the effect of RTX. To our knowledge, this has not been studied to date. The objective of this study was to investigate whether the concomitant use of statins and RTX leads to an inhibited effect of RTX on RA disease activity compared with RTX alone.
All patients with RA who started RTX in the Dutch Rheumatoid Arthritis Monitoring (DREAM) registry (N=187) were included in this prospective cohort study; 23 patients were exposed to the combination of statins and RTX. With the first RTX infusion all patients received 50 mg prednisone. The primary outcome was change in disease activity score using 28 joint counts (DAS28) from 0 to 6 months, analysed by analysis of covariance including potential confounders in the model. Power was calculated in advance and exceeded 0.80, α=0.05. The secondary outcome was effective period of the first RTX course which was analysed using Kaplan–Meier plots and Cox proportional hazards regression including confounder correction. The effective period was determined by the length of time between the initial course of RTX and the point where the patient was in need of RTX or another disease-modifying antirheumatic drug because of an increase or an insufficient decrease in disease activity (failure event).
Patients exposed to statins (n=23) were older and more frequently male than unexposed patients (n=164). DAS28 scores of both groups were similar at baseline (p=0.999). Other variables did not differ significantly at baseline (table 1). The course of disease activity over time is shown in figure 1A, the common 3-month effects probably induced by the standard prednisone therapy. At 6 months the mean±SD reduction in DAS28 differed between patients exposed to statins and controls (0.5±1.9 vs 0.1±1.3), a difference of borderline significance (p=0.049) when corrected for age, gender, baseline DAS28 and rheumatoid factor positivity. Patients exposed to statins experienced a shorter effective period than those not exposed (median 7 months vs 9 months, p<0.001, figure 1B). Exposed patients were more likely to experience a failure event than non-exposed patients (p=0.002, HR 2.3, 95% CI 1.4 to 3.9) corrected for the same confounders.
Some study limitations need to be addressed. A relatively small sample size was included although the power was sufficient and a clinically relevant difference in change in DAS28 0–6 months and effective period of RTX was demonstrated. No randomisation was performed, although this should not be a problem because confounding by indication is unlikely. B cell depletion could not be measured. Keeping in mind these limitations, our findings suggest that statins can inhibit the effect of RTX in RA. More information is required regarding the repeatability of these findings and the magnitude of this effect. Particularly interesting is the influence of different cholesterol levels and statin dosages on B cell depletion rates. Significant interactions of statins with RTX in RA have not previously been shown. A critical review of common practice regarding concomitant use of statins in RTX-treated patients with RA is needed.
Funding Funding of the Dutch affiliations of Wyeth Pharmaceuticals, Abbott Pharmaceuticals, Schering-Plough Corporation, Roche Pharmaceuticals, UCB Pharma and Bristol-Myers Squibb enabled the data collection for the DREAM cohort.
Competing interests The DREAM registry is funded by several pharmaceutical industries including Roche Pharmaceuticals.
Ethics approval The protocol of the DREAM registry has been approved by the responsible medical ethical committee.
Provenance and peer review Not commissioned; externally peer reviewed.
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