Tacrolimus in refractory lupus nephritis?

One of my patients has recently presented a treatment conundrum.  She is a young woman with lupus that has required chronic low-dose steroids and mycofenolate mofetil at maximum dose to prevent relapse, a regimen she has been taking for the past two years. She was referred to us last year after developing increasing proteinuria (now at about 3 g/d), and after developing an active sediment with hematuria and occasional granular casts this fall, she was biopsied. The pathology showed chronic-appearing membranous nephropathy with more recent focal proliferative changes.  Her creatinine has remained in the normal range, but her proteinuria has gradually increased. She has not been able tolerate an ACE inhibitor due to symptomatic low blood pressure.

Because she is of childbearing age, we would prefer to avoid cyclophosphamide therapy; but we have struggled to decide on an alternative regimen that is effective and safe.   Rituximab is one possibility, which was discussed comprehensively by Jeremy Duffield in a post from August of this year. The other choice we have been weighing is adding tacrolimus to her regimen. There is some evidence that tacrolimus in addition to MMF and prednisone may improve clinical response. Bao et al performed a randomized trial of prednisone + MMF + tacrolimus versus cyclophosphamide alone as treatment for class IV + V lupus, in which a majority of patients had been previously treated with cyclophosphamide or MMF. In an intention-to-treat analysis, the multi-agent therapy was superior to cyclophosphamide at achieving complete remission at 6 and 9 months. More recently, Cortes-Hernandes et al administered tacrolimus .075 mg/kg/d in addition to MMF in 17 patients with biopsy-proven class IV or V lupus who either responded, then relapsed on induction therapy with prednisone + MMF during 65 months of follow-up, or failed to respond at all to treatment. Twelve of seventeen had achieved either a partial or complete response to tacrolimus therapy at two years’ followup.

Neither one of these trials fits our patient’s clinical scenario of class III nephritis developing while on steroids and MMF, but they do give reason to hope that treatment with tacrolimus might be efficacious. So it seems we are staring down rituximab or tacrolimus as possible next agents—any alternative suggestions or advice welcome.