Opponent's comments

The lack of efficacy of MMF- and cyclophosphamide-based regimens and their toxicity define the need for better treatments. Dr Mok well describes the evidence in support of tacrolimus as a component of induction regimens for lupus nephritis. In his background information he states that black patients do less well with cyclophosphamide, although this was reported from the Aspreva Lupus Management Study (ALMS), but these data are unreliable due to the open-label design; the recent Abatacept and Cyclophosphamide Combination Therapy for Lupus Nephritis (ACCESS) trial found similar rates of response to cyclophosphamide and steroid in all ethnic groups. He also states that cyclophosphamide is preferred for severe nephritis, while our post hoc analysis of those with a GFR <30 mL/min from ALMS found better recovery with MMF, although all groups did poorly.

The concept of a multitarget approach with tacrolimus, mycophenolate mofetil and glucocorticoids is gaining traction as achieving superior early response rates in lupus nephritis. A major gap in our understanding is to what extent this impacts long-term stability of renal function. Recent interventional studies in IgA nephropathy and diabetic nephropathy have found reductions in proteinuria that have not been reflected by later beneficial effects on GFR.

Specific to the multitarget regimen, there has been inconsistent dosing of tacrolimus and mycophenolate and inconsistent use of tacrolimus level monitoring and no mycophenolic acid level monitoring. This is of particular relevance in lupus nephritis, where treatment-related toxicity and infections are a major barrier to the delivery of effective dosing. Examination of serious adverse events (SAEs) and treatment withdrawals in the large multitarget trial by Liu et al. [1] reveals 13 (7.2%) versus 5 (2.8%) SAEs and 10 versus 5 withdrawals in the multitarget and control groups, respectively.

Another key outcome for lupus nephritis patients is renal relapse. We do not know the longer-term effects on relapse of multitarget therapy or whether all three drugs need to be continued or for how long. In the tacrolimus versus MMF trial by Mok et al. [2] there was an excess of relapse in the tacrolimus group on longer-term follow-up when both groups had been switched to azathioprine. A high relapse rate following tacrolimus withdrawal has also been noted in primary glomerulonephritis.

Despite similar efficacy to cyclophosphamide, MMF has not become the routine induction agent for lupus nephritis, and widespread cyclophosphamide use continues. Further data with the multitarget approach need to continue to show superiority and benefit on longer-term outcomes if this is to define a new standard of care.

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