MMF recommended for lupus nephritis, refractory SLE

London, UK - Mycophenolate mofetil (MMF) (CellCept, Roche Pharmaceuticals) allowed patients with lupus nephritis or treatment-resistant systemic lupus erythematosus (SLE) to significantly reduce their steroid dosage, was as good as cyclophosphamide (CYC) for maintaining remissions, and is a candidate to become first-line therapy for lupus nephritis, according to data reported by Dr Cecilia N Pisoni (St Thomas's Hospital, London, UK) and colleagues in the June 2005 issue of the Journal of Rheumatology
"MMF appears to be a safe and successful treatment to maintain remission in patients with lupus nephritis and to control overall disease activity," writes Pisoni.
In an editorial commenting on this paper [ 2 ], Drs W Joseph McClune and Mona M Riskalla (University of Michigan, Ann Arbor) conclude that this study "adds support to the use of MMF in patients with both renal and nonrenal SLE." The editorial also reviews several recent trials of MMF in lupus nephritis and, on the basis of all available data, raises a number of points concerning the use of MMF in the treatment of lupus.
Retrospective study of MMF-treated patients
The Pisoni paper is a retrospective study of 93 patients with SLE treated with MMF because of renal involvement (68.6%), uncontrolled disease activity (16.3%), or other SLE-related manifestations. Two patients were excluded because they did not fulfill American College of Rheumatology (ACR) criteria for SLE, and five patients were excluded because of missing data. All patients had taken MMF for at least three months. The average duration of SLE was more than 10 years. Fifty percent of patients had previously received CYC, 87.2% azathioprine, and 11.6% methotrexate treatment.
Over the course of MMF treatment, steroid dose, erythrocyte sedimentation rate (ESR), anti-dsDNA, and European Consensus Lupus Activity Measure (ECLAM) significantly decreased, and complement C3 significantly increased.
Effects of MMF treatment in patients with SLE
Patients with mesangial proliferation (WHO class II) typically present with proteinuria and haematuria. Such patients are usually treated with steroids in the hope of preventing progression to more severe disease although there have been no controlled trials of treatment. Similarly, there have been no controlled trials of treatment of lupus membranous nephropathy, which is found in between 12 and 26% of patients with lupus nephritis. Using the old WHO classification the 10‐year survival free of end‐stage renal failure or death was 72–90% for class Va and Vb (membranous nephropathy with mild mesangial hypercellularity and scattered deposits) [2,3] and 48–81% for WHO class Vc and Vd (membranous nephropathy with focal or diffuse proliferative glomerulonephritis) [2,3]. These patients had been treated with prednisolone and cyclophosphamide or azathioprine. In the revised WHO classification patients with WHO class Vc and Vd (membranous nephropathy with focal or diffuse proliferative glomerulonephritis, respectively) were reclassified as WHO classes III and IV [4]. Our practice is to treat patients with WHO class Va and Vb with prednisolone and to use azathioprine as a steroid sparing agent and to treat patients with WHO class Vc and Vd as for a proliferative lupus nephritis
In the 1960s the 3‐year patient survival in patients with a proliferative lupus nephritis who were treated with steroids was 50–60% [5,6] and patients with these lesions became the focus of the controlled trials of treatment comparing prednisolone alone versus prednisolone and azathioprine or cyclophosphamide. In a narrative review, Donadio and Glassock argued that the addition of immunosuppressants to steroids could not convincingly be shown to confer benefit in terms of preventing end‐stage renal failure or deaths as compared with steroids alone [7]. In a pooled analysis, Felsom and Anderson [8] came to the opposite view and reported that patients receiving immunosuppressive drugs were less likely to develop end‐stage renal failure or to die from this than patients receiving steroids alone. The meta‐analysis carried out by Bansal and Beto [9] concluded that the addition of immunosuppressants (cyclophosphamide or azathioprine) to steroids reduced the risk of dying or of developing end‐stage renal failure as compared with prednisolone alone.
New treatment
The age‐ and dose‐related toxicity of cyclophosphamide with oligospermia in men and premature ovarian failure in women [21,22] together with its oncogenicity has prompted a search for equally effective but less toxic treatment for lupus nephritis. One such drug might be mycophenolate mofetil (MMF), which inhibits the de novo pathway of purine synthesis and therefore lymphocyte proliferation [23]. MMF is an immunosuppressive drug that is of established efficacy in renal transplantation [24].
MMF and lupus nephritis
We have recently reviewed the role of MMF in the treatment of lupus nephritis [25]. There have been several case reports and case series of the use of MMF together with steroids in treating patients with lupus nephritis whose disease was relapsing or was resistant to cyclophosphamide and steroids. In addition, open pilot studies suggested that MMF might have a beneficial role in lupus nephritis. This was confirmed by preliminary analysis of the ongoing pilot study of MMF in the treatment of lupus nephritis organized by the UK Renal Association Clinical Trials Committee [DRW Jayne, personal communication].
Randomized controlled trials of MMF
Chan et al. reported a randomized controlled trial of 42 patients with WHO Class IV lupus nephritis that compared the effect of MMF (1 g twice daily for 6 months, then 0.5 g twice daily for 6 months), and prednisolone with oral cyclophosphamide (2.5 mg/kg daily for 6 months followed by azathioprine (1.5 mg/kg daily) and prednisolone [26]. Both drugs led to comparable rates of complete remission (MMF 81%: cyclophosphamide 76%), partial remission (MMF 14%: cyclophosphamide 14%), deaths (MMF 0%: cyclophosphamide (10%) and relapse (MMF 15%: cyclophosphamide 11%). Infections were more common in the patients treated with cyclophosphamide (33 vs 19%) and amenorrhoea (23%), hair loss (19%) and leukopenia (10%) only occurred in the patients treated with cyclophosphamide. The numbers of patients studied was small and the patients had mild renal impairment. There is, therefore, a requirement for a larger appropriately powered study in patients with proliferative lupus nephritis to study the efficacy and toxicity of prednisolone with MMF as compared with prednisolone and cyclophosphamide.