Finally, some TAC response occurs via immediate vasomotor mechanisms occurring before T cell or immunosuppression effects take hold. Would these non-immunologic, non-remission inducing effects of TAC lack durability? One would think so, but the overall benefit of TAC effect does seem durable at two to five years in the Chinese cohort.8,10 This feature of durability, however, may not be generalizable for the same reason that the apparent equivalence of TAC to MMF might not hold in all groups, namely unanticipated differences between populations as implied by the Medicaid survival data showing differences between ethnic groups.9
Proposals for New Studies Comparing TAC with Rituximab
What should the study design be to test the null hypothesis that rituximab and TAC are equivalent in either induction or maintenance? Ideally, half the patients would be African American, for example.
For TAC, the most definitive study would come in the subset for which TAC is most likely to work, that with a strong membranous component on biopsy. This test would also come in the subset with the least chance of suffering TAC nephrotoxicity, that with close-to-normal GFR to start. This means a limited subset of lupus nephritis with class V and histologically mixed classes (IV/V and III/V). It might also mean creatinine less than 1.2 mg/dL for example.
Would a more applicable study of TAC be after failure of MMF alone? But would this study of TAC after failure of MMF need to recruit only the subset of patients with failure of MMF defined as unresponsive or increasing proteinuria without increased creatinine?
Rituximab may need to be included in the control arm because continuing MMF alone would not be ethical if it had already been judged to have failed. Also required would be two types of studies with arms for both drugs: one study to test initial induction and one for salvage after initial failure, MMF plus rituximab vs. MMF plus TAC.
Therefore, we are looking at a narrow window of time for patients with ominous biopsies with membranous component, but good current GFR, in several and different trials to account for both induction and salvage scenarios. These will be hard studies to fill.
Conclusions
Despite newer data suggesting some value in the use of TAC to augment treatment of lupus nephritis, TAC remains salvage therapy for the moment. It remains a particularly good alternative for those concerned about pregnancy and fertility. Despite the well-known negative results of the LUNAR study of 2012, rituximab has gained prominence in competing salvage or steroid-sparing strategy for treatment of lupus nephritis based in part upon recent reports. Given the loss of renal clearance still associated with the calcineurin inhibition and related mechanisms, a hypothetical TAC plus MMF induction strategy for lupus nephritis with membranous component might need to beat or match not only MMF alone, but also the emerging steroid-sparing regimens based on MMF plus rituximab, in order to enter the mainstream.
