Appeal type: Formulary Exception
Decision: Upheld

Diagnosis: Nephrotic Syndrome with Diffuse Membranous Glomerulonephritis
Treatment: Formulary exception for Rituxan
The insurer denied the formulary exception for Rituxan.
The denial is upheld.

The patient is a male with nephrotic syndrome due to diffuse membranous glomerulonephritis.  Rituxan was prescribed.

No, the health plan should not cover the propose treatment.

Standard therapy for membranous glomerulonephritis for which extensive data have been published over several decades includes the Ponticelli protocol (steroids and chlorambucil), Cytoxan, mycophenolate, and calcineurin inhibitor therapy (cyclosporine, tacrolimus) and are not documented to have been tried or to be contraindicated in this patient.

In a ten-year follow-up of one of the original studies in membranous glomerulonephritis by Claudio Ponticelli (6), treated patients (using steroids and chlorambucil or Cytoxan) had a higher likelihood of complete or partial remission (88 versus 47% in the placebo group) and a greater likelihood of surviving without renal failure (92 versus 60%).  

A prospective randomized trial (11) evaluated the efficacy of cyclosporine in 51 patients unresponsive to a six-month course of daily corticosteroid therapy.  All patients received prednisone and were randomly assigned to either placebo or cyclosporine.  The administration of cyclosporine was associated with a higher proteinuria remission rate at both 26 weeks (68 versus 22% for placebo) and 78 weeks (43 versus 19%).  

Cyclosporine plus low dose prednisone has been shown in several studies to be effective in inducing remission of proteinuria and in preventing progression to end-stage renal disease.  The best data are from a randomized trial (12) of 51 patients (mean protein excretion 9.3 grams [g]/day and mean serum creatinine 1.2 milligrams per deciliter [mg/dL]) who were unresponsive to at least an eight-week course of daily glucocorticoid therapy.  The patients were assigned to prednisone plus either placebo or cyclosporine for 26 weeks.  The cyclosporine-treated group had a significantly higher rate of complete (300 mg/day) or partial remission of proteinuria, which was defined as less than 3.5 g/day plus at least a 50% reduction from baseline (75 versus 22% with placebo).  Renal function was the same in both groups.  One year after the cessation of therapy, relapse of proteinuria was common, but 39% of treated patients were still in remission, compared to 13% with placebo.  

A randomized trial (14) of 20 patients with membranous glomerulonephritis (with mean proteinuria 5.7 g/day) compared the effect of mycophenolate (2.0 g/day) plus prednisolone, to that of daily chlorambucil given for three months and alternating monthly with prednisolone.  There was no difference between the percentages of patients who achieved complete or partial remission; (64% of the group that received mycophenolate and 67% of the group that received chlorambucil).  At the end of follow-up (nine months after end of therapy), there were no differences in patients with treatment resistance (four versus three) or relapse (two versus one).  

In a second randomized, open label trial (15) including 21 patients with membranous glomerulonephritis, mycophenolate was found to be as effective as cyclophosphamide, with both therapies provided for six months.  The remission rate was similar (64 versus 80%), and there were no relapses during a follow-up of 17 months.  A nonrandomized study (16) of 64 patients with membranous nephropathy with a median baseline serum creatinine of 1.8 mg/dL included 32 treated with mycophenolate, compared to 32 historic control patients who had received cyclophosphamide at a dose of 1.5 mg per kilogram per day.  Both groups also received glucocorticoids. The remission rate at 12 months was not significantly different (66 versus 72%).  

There is no documentation of a contraindication to any of these drugs.  In summary, other agents including mycophenolate, Ponticelli protocol, Cytoxan, and calcineurin inhibitors are supported as efficacious in membranous glomerulonephritis by a greater body of data than is present for rituximab.  

In addition, rituximab does not have Food and Drug Administration (FDA) indication for treatment of membranous glomerulonephritis.  The published data showing efficacy of rituximab in treating membranous glomerulonephritis include very small numbers.  In fact, the largest report includes only 20 patients and was not randomized or controlled.  Several reports include only a single patient.  

In summary, based on medical literature, rituximab is not medically appropriate and the health plan should not cover the proposed treatment.