Journal Club

Mycophenolate mofetil (Cellcept) is superior to azathioprine (Imuran) in the maintenance phase of lupus nephritis

Published today in the New England Journal of Medicine, Dooley and co-workers report the results of a 36-month study of maintenance therapy with either mycophenolate mofetil (MMF) or azathioprine (AZA) in patients who had a specified response to treatment during the ALMS induction study.

The bottom line is that this is a very well designed study that convincingly points to MMF being superior to AZA in maintaining a renal response to treatment and in preventing relapse in patients with lupus nephritis who had a response to induction therapy. This study should put to rest the debate about whether MMF is superior to AZA in the maintenance phase of lupus nephritis. MMF clearly wins.

Background to Study

• Lupus nephritis is observed in 22% to 50% of patients with systemic lupus erythrmatosus and is an important determinant of morbidity and mortality. Renal disease also poses demanding therapeutic challenges.
• Most patients develop evidence of renal involvement soon after the diagnosis of SLE, commonly within the first 6 to 36 months. The incidence of ESRD due to SLE in the USA appears to be increasing: 1.3 cases/million in 1982 to 3.1 in 1995. Despite the success of steroids and powerful cytotoxic agents, such as cyclophosphamide or mycophenalate mofetil or azathioprine in the treatment of lupus nephritis, the proportion of patients’ that progress to end-stage renal disease has remained relatively unchanged over the past decade.
• It is widely accepted that cytotoxic agents have an important role in the treatment of lupus nephritis because of their ability to retard long-term renal deterioration and because cytotoxic agents have a steroid-sparing effect that reduce the potentially serious side-effects of long-term steroid therapy.
• The choice of immunosuppressive agent, cyclophosphamide versus azathioprine, and lately cyclophosphamide versus mycophenalate mofetil, or azathioprine versus mycophenalate mofetil has generated controversy over the past decades since the emergence of cytotoxic therapy.
• While mycophenolate mofetil is the most popular regimen for both the induction and the maintenance phase of the treatment of lupus nephritis, azathioprine continues to be used.
• The Aspreva Lupus Management Study (ALMS), which examined the efficacy and safety of induction therapy with MMF as compared with intravenous cyclophosphamide (plus standardized tapering of glucocorticoid therapy) in patients with active lupus nephritis (renal-biopsy active class III, IV, or V was published in JASN, and showed no significant difference between the two drugs.

Key aspects of the study

Overall Design: Randomly controlled double-blind double dummy intention-to-treat

1. Sample

• N=227 patients
• Age 12 to 75 years of age
• Active class III, IV, or V lupus nephritis who had had a clinical response to either oral mycophenolate mofetil or intravenous cyclophosphamide during the induction studywere randomly assigned (in a 1:1 ratio) to one of these two agents in the maintenance study.

227 patients randomized: 116 in MMF group, 43 withdrawn (29 for adverse effects); 111 in aza group, 57 withdrawn (43 for adverse effects)

2. Study duration

• 36 months, regardless of events.

3. Interventions

• Oral mycophenolate mofetil (1 g, twice daily) or oral azathioprine (2 mg per kilogram of body weight per day). 
• Plus up to 10 mg prednisone or its equivalent.

4. Outcome

a. Primary efficacy end point was the time to treatment failure, measured as the time until the first event and defined as death, end-stage renal disease, sustained doubling of the serum creatinine level, renal flare (proteinuric or nephritic), or the need for rescue therapy (glucocorticoids, plasmapheresis, intravenous immune globulin, or immunosuppressive drugs not specified in the protocol) in the event of exacerbation or deterioration of lupus nephritis.

b. Other end-points

• Proteinuric renal flare: doubling of the urinary protein:creatinine ratio and proteinuria (≥1 g of protein per 24 hours in patients with urinary protein clearance of ≤0.5 g per 24 hours at the end of induction, and ≥2 g per 24 hours in patients with urinary protein clearance of >0.5 g per 24 hours at the end of induction)
• Nephritic renal flare: increase of 25% or more in the lowest serum creatinine level during the period from screening to the end of induction, plus one or more of the following findings: simultaneous doubling of urinary protein clearance, reaching a minimum of 2 g per 24 hours (or the urinary protein:creatinine ratio equivalent); new or increased hematuria (≥5 red cells per high-power field or ≥2+ on a dipstick test for blood); or the appearance of cellular casts.

c. Key secondary end points 

• Time to the event for each component of treatment failure
• Time to treatment failure defined more broadly (i.e., the components of the primary end point
• Major extrarenal flare
• Withdrawal for any reason
• Suspected renal flare
• Complete renal remission (urinary protein clearance, <500 mg per 24 hours; absence of hematuria and cellular casts; and improved or stable serum creatinine ±25% of baseline)
• Combined renal and extrarenal remission (absence of a British Isles Lupus Assessment Group category A score [severe lupus flare] in one extrarenal system or lack of a concurrent category B score [moderate lupus flare] in three extrarenal systems), and immunologic variables (C3, C4, and anti–double-stranded DNA antibodies).

5. Results

• Mycophenolate mofetil was significantly superior to azathioprine with respect to the primary end point, time to treatment failure (hazard ratio for treatment failure, 0.44; 95% confidence interval [CI], 0.25 to 0.77; P=0.003). Overall observed rates of treatment failure were 16.4% (19 of 116 patients) in the mycophenolate mofetil group and 32.4% (36 of 111) in the azathioprine group. The superiority of mycophenolate mofetil was consistent, regardless of induction therapy, race, and geographic region.
• Mycophenolate mofetil was also superior to azathioprine with respect to individual components of treatment failure, including the time to renal flare (hazard ratio for flare, 0.50; 95% CI, 0.26 to 0.93; P=0.03).
• Renal flare occurred in 15 of 116 patients (12.9%) given mycophenolate mofetil versus 26 of 111 patients (23.4%) given azathioprine.
• The time to rescue therapy for lupus nephritis was also longer with mycophenolate mofetil than with azathioprine (hazard ratio, 0.39; 95% CI, 0.18 to 0.87; P=0.02); the rates of rescue were 7.8% (9 of 116 patients) and 17.1% (19 of 111), respectively.
• Mycophenolate mofetil was significantly superior to azathioprine for the key secondary end points of the broader definition of treatment failure (rate, 42.2% [49 of 116 patients] in the mycophenolate mofetil group vs. 56.8% [63 of 111] in the azathioprine group; hazard ratio, 0.66; 95% CI, 0.46 to 0.97; P=0.03), and the time to documented or suspected renal flare (rate, 21.6% [25 of 116 patients] vs. 36.0% [40 of 111], respectively; hazard ratio, 0.56; 95% CI, 0.35 to 0.89; P=0.01).
• All other components of the primary efficacy end point showed a numerical benefit in favor of mycophenolate mofetil, including the time to end-stage renal disease (rate, 0% [0 of 116 patients] in the mycophenolate mofetil group vs. 2.7% [3 of 111] in the azathioprine group; P=0.07), and the time to sustained doubling of the serum creatinine level (rate, 0.9% [1 of 116 patients] vs. 4.5% [5 of 111], respectively; P=0.07).
• Adverse events, most commonly minor infections and gastrointestinal disorders, occurred in more than 95% of the patients in both groups (P=0.68).
• Serious adverse events occurred in 33.3% of patients in the azathioprine group and in 23.5% of those in the mycophenolate mofetil group (P=0.11),
• The rate of withdrawal due to adverse events was higher with azathioprine than with mycophenolate mofetil (39.6% vs. 25.2%, P=0.02). 

Limitations

The paper doesn’t provide any limitations. Here are some:

• The withdrawal rate was high in both arms of the study, but higher in the AZA arm than the MMF arm. The analysis was using intention-to-treat but a per-protocol analysis should have also been provided (i.e., the patients who actually received the treatment).
• There were subtle differences between the patients in their baseline characteristics – for example, more class 3 disease in MMF treated patients and more class 4 disease in Aza treated patients. The renal function was a tad worse in the Aza treatment patients compared to those treated with MMF. This suggests that, perhaps, the AZA treated patients at the inception of the trial had a lower likelihood to respond to treatment. The authors state that: “The benefit of mycophenolate mofetil was maintained after adjustments were made for the serum creatinine level (P=0.004) and the estimated glomerular filtration rate at the end of induction therapy (P=0.004).”
• The manuscript was drafted initially by medical writers from Caudex Medical (Oxford, United Kingdom), with funding from Vifor Pharma. There is no information on who controls the data-base.