Abstract

Background. Mycophenolate mofetil (MMF) is an immunosuppressive drug widely used in solid organ transplantation, and it may play an increasing role in autoimmune disease. MMF has been introduced as a novel immunosuppressive agent in systemic lupus erythematosus (SLE), often in patients intolerant of or resistant to conventional immunosuppressive regimens.

Methods. We studied 21 patients with SLE, most of whom had previously received courses of cyclophosphamide therapy and had also received courses of azathioprine or methotrexate. Indications for treatment included uncontrolled disease activity and worsening renal involvement.

Results. MMF treatment resulted in reduced disease activity, as assessed by the SLEDAI (SLE disease activity index) (P=0.0001) and decreased proteinuria (P=0.027) while allowing a significant reduction in oral corticosteroid dose (P=0.0001). Levels of complement factors C3 and C4 and anti‐double‐stranded DNA antibodies were not significantly affected.

Conclusion. MMF appears to be a safe and effective alternative immunosuppressant for extra‐renal and renal disease in SLE not responding to conventional immunosuppressive treatment.

Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease characterized by a plethora of autoantibodies directed at autoantigens that include double‐stranded DNA (dsDNA). Several organ systems can be affected, including the joints, the skin, the cardiorespiratory and nervous systems and the kidneys. Renal and cerebral diseases represent the more severe manifestations and may require immunosuppression, including corticosteroids, cyclophosphamide, azathioprine, cyclosporin or methotrexate.

Standard immunosuppressive regimens for SLE can be associated with substantial side‐effects and in some patients may not be effective. Therapeutic inefficacy may arise in various ways: intolerance of the standard regimen due to side‐effects; inability to induce remission; or relapse of disease during therapy or following withdrawal of therapy.

Renal disease is a frequent manifestation of SLE and has varying clinical and histopathological manifestations. Progression to end‐stage renal failure may occur in the absence of, and sometimes in spite of, treatment. Standard treatment protocols for lupus nephritis involve intravenous pulses of corticosteroids and cyclophosphamide, with oral corticosteroids and azathioprine as longer‐term maintenance treatment. Although pulsed intravenous cyclophosphamide is effective in improving renal survival, it is associated with a substantial side‐effect profile [1].

Mycophenolate mofetil (MMF) is an immunosuppressive drug used in renal transplantation that reduces the incidence of acute rejection episodes when compared with azathioprine‐containing regimens [2]. MMF has been used in autoimmune diseases, including rheumatoid arthritis, systemic vasculitis and autoimmune haemolytic anaemia [35]. In the NZB/W mouse, which develops an immune complex disease with nephritis that is similar to human SLE, MMF has a beneficial effect on both renal and overall survival [6].

MMF has been introduced as a novel immunosuppressive agent in SLE, often in patients intolerant of or resistant to conventional immunosuppressive regimens [7, 8]. Studies reported to date have been encouraging, and here we report our experience with MMF for extra‐renal and renal disease in a group of patients with SLE.

Patients and methods

We prospectively studied 21 patients with SLE who had at least four of the American College of Rheumatology criteria for the classification of SLE [9]. Most of the patients had previously received one or more courses of cyclophosphamide therapy and had also received previous courses of azathioprine or methotrexate (Table 1). The indications for treatment with MMF were uncontrolled disease activity in eight patients and worsening renal involvement in 13 patients.

Data were collected at entry to the study and at 6‐month intervals thereafter. Measurements included the SLE disease activity index (SLEDAI) [10], the concomitant oral steroid dose, serum creatinine, chromium 51 ethylenediamine tetraacetic acid glomerular filtration rate (EDTA‐GFR) [11] and 24‐h urine protein. Levels of serum complement C3 and C4 were measured by nephelometry and anti‐dsDNA antibodies were measured by radioimmunoassay. At each clinic visit, the patients were specifically questioned about possible side‐effects.

Renal biopsies were studied by light, electron and immunofluorescence microscopy. The histopathological observations were classified according to the WHO classification [12].

The starting dose for MMF was 0.5 g per day. The MMF dose was increased up to a maximum of 2 g per day with the aim of suppressing renal or overall disease activity, unless gastrointestinal or haematological toxicity developed.

Some patients also received other treatments. These included antihypertensive medication (diuretics, angiotensin‐converting enzyme inhibitors, calcium channel blockers); oral anticoagulation for previous thrombotic events; corticosteroids; and antimalarials. Antihypertensive medication remained largely unchanged throughout the study.

Statistical analysis

A non‐parametric test (Mann–Whitney) was used for comparison between baseline and post‐treatment values of the different variables. A P value <0.05 was considered statistically significant.

Table 1. 

Baseline clinical parameters

 Organs involved Previous treatment
 

 

 
Renal biopsy
 

 
Patient
 

 
Cyp
 
Aza
 
Mtx
 
WHO class
 
Date
 
 1 K, J Vd 98 
 2 K, J IVc 98 
 3 – – 
 4 K, J Vc 98 
 5 CNS, J, S – – 
 6 S, J – – 
 7 S, J, K IIIa 94 
 8 S, J, K II 97 
 9 S, J – – 
10 S, J, K IIIb 00 
11 S, J, K III 00 
12 S, J, K IVa 00 
13 CNS, J – – 
14 S, J, K III 00 
15 S, J, K IV 97 
16 S, J – – 
17 J, K IV 97 
18 S, J, K IV 97 
19 H, S, J – – 
20 K, J IV 00 
21 J, S, O – – 
 Organs involved Previous treatment
 

 

 
Renal biopsy
 

 
Patient
 

 
Cyp
 
Aza
 
Mtx
 
WHO class
 
Date
 
 1 K, J Vd 98 
 2 K, J IVc 98 
 3 – – 
 4 K, J Vc 98 
 5 CNS, J, S – – 
 6 S, J – – 
 7 S, J, K IIIa 94 
 8 S, J, K II 97 
 9 S, J – – 
10 S, J, K IIIb 00 
11 S, J, K III 00 
12 S, J, K IVa 00 
13 CNS, J – – 
14 S, J, K III 00 
15 S, J, K IV 97 
16 S, J – – 
17 J, K IV 97 
18 S, J, K IV 97 
19 H, S, J – – 
20 K, J IV 00 
21 J, S, O – – 

K, kidneys; S, skin; J, joints; H, blood; CNS, central nervous system; O, eyes; Cyp, cyclophosphamide; Aza, azathioprine; Mtx, methotrexate.

Results

Baseline clinical parameters

The patients included 20 women and one man, their median age was 33.6 (range 21–47) yr and the median follow‐up period was 14 (range 0.5–33) months. The racial distribution included 12 white and eight black patients and one patient of Chinese origin. The median duration of SLE was 8.44 (range 3–25) yr. On entry into the study, 13 patients had active renal disease. Renal biopsies showed WHO class IV nephritis in six patients, class III in four patients, class V in two and class II in one patient (Table 1).

Therapy

Table 2 shows the doses of MMF and prednisolone therapy used during the study. In general, we aimed to reach an MMF dose of 2 g daily, though this target was variable dependent on when control of disease activity or side‐effects occurred. The prednisolone dose per day was significantly reduced from 19.5±6.9 to 9.75±3.6 mg (P=0.0001). In one patient the dose of MMF was decreased because of herpes zoster infection, and in another because of viral warts. One patient required a dose reduction because of migrainous headaches. Two patients needed an increase in MMF dose because of a flare and they also each received three intravenous pulses of 500 mg methylprednisolone.

Table 2. 

Therapy and disease activity

 Duration Last dose Initial Last Basal Last 
 of MMF of MMF prednisolone prednisolone SLEDAI SLEDAI 
Patient
 
(months)
 
(g/day)
 
dose (mg/day)
 
dose (mg/day)
 
score
 
score
 
 1 33 15  8 12 
 2 30 15  7.5 12 
 3 24 30 10 20 
 4 29 0.75 15  7 
 5 14 25 14 16 
 6 24 15 12 12 
 7 0.5 0.5 10 Withdrawal 12 Withdrawal 
 8 12 1.5 15 10 12 
 9 14 40 12.5 10 
10 15 Withdrawal 12 Withdrawal 
11 10 1.5 20  5 12 
12 13 1.5 15  7.5 14 
13 14 20  7.5 20 
14 1.25 15  7.5 15 
15 12 15 Pregnancy 14 Pregnancy 
16 0.5 15 Pregnancy Pregnancy 
17 0.5 30 Withdrawal Withdrawal 
18 20 20 20 
19 20  7.5 10 
20 15 10 12 
21 18 17.5 10 10 
 Duration Last dose Initial Last Basal Last 
 of MMF of MMF prednisolone prednisolone SLEDAI SLEDAI 
Patient
 
(months)
 
(g/day)
 
dose (mg/day)
 
dose (mg/day)
 
score
 
score
 
 1 33 15  8 12 
 2 30 15  7.5 12 
 3 24 30 10 20 
 4 29 0.75 15  7 
 5 14 25 14 16 
 6 24 15 12 12 
 7 0.5 0.5 10 Withdrawal 12 Withdrawal 
 8 12 1.5 15 10 12 
 9 14 40 12.5 10 
10 15 Withdrawal 12 Withdrawal 
11 10 1.5 20  5 12 
12 13 1.5 15  7.5 14 
13 14 20  7.5 20 
14 1.25 15  7.5 15 
15 12 15 Pregnancy 14 Pregnancy 
16 0.5 15 Pregnancy Pregnancy 
17 0.5 30 Withdrawal Withdrawal 
18 20 20 20 
19 20  7.5 10 
20 15 10 12 
21 18 17.5 10 10 

Disease activity

The SLEDAI (Table 2) score was 12.6±3.6 at baseline and 3.56±1.5 at the last visit. This represented a significant reduction (P=0.0001). Three patients were excluded because they discontinued MMF as a result of side‐effects, and two patients were excluded because they discontinued MMF as they wished to conceive.

Renal outcome

Table 3 shows the renal parameters at baseline and at the most recent out‐patient attendance. Protein excretion in 24 h decreased significantly, from 3.7±2 to 1.14±1 g at the last visit (P=0.027). There were no significant changes in serum creatinine (P=0.67), which remained stable or improved in all patients. The EDTA‐GFR showed a tendency to improvement (70.6±21.8 to 77.2±26.7 ml/min) but the difference did not reach significance (P=0.20). Three patients in whom MMF was commenced for renal disease were excluded from analysis as MMF was discontinued because of adverse reactions. One patient with renal disease was excluded because she discontinued MMF prior to conception.

Table 3. 

Renal outcomes

   Last Basal Last Basal Last 
 Follow‐up Basal creatinine 24 h urine 24 h urine EDTA‐GFR EDTA‐GFR 
Patient
 
(months)
 
creatinine
 
(μmol/l)
 
protein (g)
 
protein (g)
 
(ml/min)
 
(ml/min)
 
 1 33 103  91 5.76 3.3 52  51.2 
 2 30 67  75 3.4 0.35 63 102.1 
 4 29 50  56 4.62 0.12 122 130 
 7 0.5 86 Withdrawal 1.19 Withdrawal 44 Withdrawal 
 8 12 105 100 5.73 1.3 69.2  54.8 
10 72 Withdrawal 0.83 Withdrawal 80 Withdrawal 
11 10 127 139 1.8 46  43.9 
12 13 69  65 2.34 0.54 80  82.9 
14 69  87 0.18 2.10 68.4  77.5 
15 12 73 Pregnancy Pregnancy n/a Pregnancy 
17 247 Withdrawal 0.5 Withdrawal n/a Withdrawal 
18 20 103  89 2.3 0.50 72.6  78.8 
20 121  91 6.79 0.41 62.8  74.3 
   Last Basal Last Basal Last 
 Follow‐up Basal creatinine 24 h urine 24 h urine EDTA‐GFR EDTA‐GFR 
Patient
 
(months)
 
creatinine
 
(μmol/l)
 
protein (g)
 
protein (g)
 
(ml/min)
 
(ml/min)
 
 1 33 103  91 5.76 3.3 52  51.2 
 2 30 67  75 3.4 0.35 63 102.1 
 4 29 50  56 4.62 0.12 122 130 
 7 0.5 86 Withdrawal 1.19 Withdrawal 44 Withdrawal 
 8 12 105 100 5.73 1.3 69.2  54.8 
10 72 Withdrawal 0.83 Withdrawal 80 Withdrawal 
11 10 127 139 1.8 46  43.9 
12 13 69  65 2.34 0.54 80  82.9 
14 69  87 0.18 2.10 68.4  77.5 
15 12 73 Pregnancy Pregnancy n/a Pregnancy 
17 247 Withdrawal 0.5 Withdrawal n/a Withdrawal 
18 20 103  89 2.3 0.50 72.6  78.8 
20 121  91 6.79 0.41 62.8  74.3 

n/a, data not available.

Immunological parameters

Table 4 shows the results of anti‐dsDNA and complement testing. Seven patients had negative anti‐dsDNA antibody test results at the start of the study and remained negative at the last visit. In the other patients, anti‐dsDNA antibody levels were 96.5±55.2 IU/ml at the initial visit and 57±65.5 IU/ml at the last visit (P=0.11). Levels of complement factors C3 and C4 did not change significantly (C3, 0.51±0.24 vs 0.71±0.30 g/l, P=0.06; C4, 0.16±0.09 vs 0.15±0.08 g/l, P=1.0).

Table 4. 

Complement and anti‐dsDNA antibody levels

  Anti‐dsDNA Anti‐dsDNA C3
 

 
C4
 

 
 Follow‐up baseline last visit Baseline Last visit Baseline Last visit 
Patient
 
(months)
 
(IU/ml)
 
(IU/ml)
 
(g/l)
 
(g/l)
 
(g/l)
 
(g/l)
 
 1 33 Negative Negative 0.29 0.48 0.15 0.17 
 2 30 100 160 0.35 0.73 0.09 0.12 
 3 24  39   5 0.51 0.62 0.18 0.10 
 4 29  21  10 0.56 0.73 0.15 0.11 
 5 14 100  20 0.61 0.29 0.21 
 6 24 Negative Negative 0.90 0.83 0.21 0.23 
 7 0.5  70 Withdrawal 0.29 Withdrawal 0.10 Withdrawal 
 8 12  89  40 0.02 0.03 0.09 0.17 
 9 14 Negative Negative 0.23 0.34 0.05 0.05 
10  94 Withdrawal 0.41 Withdrawal 0.06 Withdrawal 
11 10 Negative Negative 0.82 1.26 0.17 0.21 
12 13 Negative Negative 0.31 0.73 0.19 0.22 
13 14 Negative Negative 0.53 0.88 0.17 0.17 
14 160 100 0.32 0.46 0.10 0.07 
15 12 Negative Pregnancy 0.40 Pregnancy 0.10 Pregnancy 
16 Negative Pregnancy 0.32 Pregnancy 0.11 Pregnancy 
17  19 Withdrawal 0.48 Withdrawal 0.6 Withdrawal 
18 20  40   0 0.56 0.49 0.15 0.14 
19 Negative Negative 0.88 1.00 0.16 0.14 
20 160  18 0.75 0.88 0.42 0.37 
21 18 160 160 0.55 0.93 0.05 0.05 
  Anti‐dsDNA Anti‐dsDNA C3
 

 
C4
 

 
 Follow‐up baseline last visit Baseline Last visit Baseline Last visit 
Patient
 
(months)
 
(IU/ml)
 
(IU/ml)
 
(g/l)
 
(g/l)
 
(g/l)
 
(g/l)
 
 1 33 Negative Negative 0.29 0.48 0.15 0.17 
 2 30 100 160 0.35 0.73 0.09 0.12 
 3 24  39   5 0.51 0.62 0.18 0.10 
 4 29  21  10 0.56 0.73 0.15 0.11 
 5 14 100  20 0.61 0.29 0.21 
 6 24 Negative Negative 0.90 0.83 0.21 0.23 
 7 0.5  70 Withdrawal 0.29 Withdrawal 0.10 Withdrawal 
 8 12  89  40 0.02 0.03 0.09 0.17 
 9 14 Negative Negative 0.23 0.34 0.05 0.05 
10  94 Withdrawal 0.41 Withdrawal 0.06 Withdrawal 
11 10 Negative Negative 0.82 1.26 0.17 0.21 
12 13 Negative Negative 0.31 0.73 0.19 0.22 
13 14 Negative Negative 0.53 0.88 0.17 0.17 
14 160 100 0.32 0.46 0.10 0.07 
15 12 Negative Pregnancy 0.40 Pregnancy 0.10 Pregnancy 
16 Negative Pregnancy 0.32 Pregnancy 0.11 Pregnancy 
17  19 Withdrawal 0.48 Withdrawal 0.6 Withdrawal 
18 20  40   0 0.56 0.49 0.15 0.14 
19 Negative Negative 0.88 1.00 0.16 0.14 
20 160  18 0.75 0.88 0.42 0.37 
21 18 160 160 0.55 0.93 0.05 0.05 

Toxicity

Leucocyte counts were taken at each visit. One patient became leucopenic; this was associated with herpes zoster infection and responded to a decrease in dose. Two patients stopped MMF at 2 months because of gastrointestinal side‐effects (nausea and diarrhoea) and one patient at 2 weeks because of severe skin lesions. Two patients in clinical remission discontinued MMF therapy because they were trying to conceive. They did not report any side‐effects over 1 yr of treatment.

Figure 1 summarizes the results of the effect of MMF therapy on concomitant oral prednisolone dose, disease activity (SLEDAI) and proteinuria.

Fig. 1. 

Oral corticosteroid dose, disease activity index (SLEDAI) and 24‐h urinary protein at baseline and last clinic visits.

Fig. 1. 

Oral corticosteroid dose, disease activity index (SLEDAI) and 24‐h urinary protein at baseline and last clinic visits.

Discussion

The results that we have observed and those of others indicate that MMF is an effective treatment in the management of SLE, and in particular lupus nephritis [7, 8, 13]. In our patients, indications for treatment included refractory disease activity despite immunosuppression, and lupus nephritis. We assessed efficacy by the measurement of a number of different parameters, both non‐renal and renal. The degree of disease activity (SLEDAI score) was significantly reduced over the course of follow‐up, while the concomitant oral corticosteroid dose was also significantly reduced. MMF was thus an effective steroid‐sparing agent.

MMF is an ester prodrug of the active agent mycophenolic acid (MPA), compared with which it has higher oral bioavailability. MPA non‐competitively and reversibly inhibits inosine monophosphate dehydrogenase (IMP‐DH), which catalyses a rate‐limiting step in the de novo synthesis pathway of purine nucleotides. Unlike other eukaryotic cells, lymphocytes are dependent on the de novo pathway and hence MMF has a relatively specific effect on lymphocytes. In addition, MMF inhibits five times more potently the type II isoform of IMP‐DH expressed in stimulated (rather than resting) lymphocytes. MMF inhibits the proliferation of both B and T lymphocytes and decreases antibody production [14].

Despite this, the literature reports mixed findings in relation to the effect of MMF on anti‐dsDNA antibody production. Kingdon et al. [15] recently demonstrated decreases in anti‐dsDNA antibodies in only four out of 11 lupus nephritis patients treated with MMF. Chan et al. [13] reported significant changes in anti‐dsDNA antibodies and complement C3 over a 12‐month period of study. In contrast, Gaubitz et al. [7] did not report significant changes, corresponding to our own findings of trends to a reduction in dsDNA antibodies and an increase in complement C3, without reaching significance. Changes in complement C4 levels in patients with SLE are often inconsistent because of the presence in many patients of a varying number of C4 null alleles.

This variability in the effect of MMF on anti‐dsDNA antibodies is also reflected in the MRL/lpr mouse model of SLE: Jonsson et al. [16] reported a significant reduction in anti‐dsDNA antibodies while Van Bruggen et al. [17] found no change, despite both studies reporting a reduction in proteinuria. It has been shown that MMF has effects beyond the inhibition of lymphocyte proliferation, and these other effects may also contribute to the beneficial influence of MMF on parameters of renal outcome as well as on overall disease activity.

MMF interferes with the glycosylation of adhesion molecules such as VLA‐4 on activated lymphocytes, and in vitro MMF inhibits the cytokine‐induced expression of adhesion molecules on endothelial cells. Hence MMF may inhibit lymphocyte–endothelial interactions. Effects of MMF in animal models have been reviewed by Adu et al. [18].

Other mechanisms involved in lupus nephritis may include the overexpression of inducible nitric oxide synthase (iNOS). MMF reduces renal cortical expression of iNOS in MRL/lpr mice via a mechanism independent of the nuclear factor‐κB pathway [19]. MPA suppresses in vitro endothelial cell nitric oxide (NO) production induced by interferon γ and tumour necrosis factor α, while MMF reduces renal inflammation in a rat model of chronic NO inhibition associated with high salt intake [19, 20].

MMF inhibits both human and rat mesangial cell proliferation by guanosine depletion in vitro and ameliorates experimental mesangial proliferative glomerulonephritis in the anti‐Thy1.1 rat nephritis model [21, 22]. In the latter model, improvement in glomerular cellularity and extracellular matrix deposition is accompanied by a decrease in proteinuria [22].

In the remnant kidney or 5/6 nephrectomy model of progressive renal failure, MMF causes a reduction in glomerular, tubular and interstitial cellular proliferation, associated with stabilization or normalization of proteinuria and normalization or slowing of the increase in serum creatinine. Interstitial myofibroblast infiltration and type III collagen deposition are both reduced. The differentiation of myofibroblasts, a critical step in fibrosis, has been noted to be impaired by MMF in vitro [18, 23].

These varied actions of MMF may be implicated in the clinical results that we have observed, particularly with respect to renal involvement. Evidence of its efficacy in improving renal disease is provided by the significant reduction in proteinuria and the tendency to improvement of GFR. Such a reduction in proteinuria is unlikely to represent the natural progression of SLE renal disease—this would be more likely to result in the maintenance of proteinuria or an increase in it. This reduction could not be ascribed to changes in antihypertensive treatment, which remained largely unchanged over the follow‐up period.

It should be noted that the group in whom MMF was used consisted of patients whose disease had failed to respond to conventional immunosuppressive regimens. Thus, this group should be considered to be at the severe end of the disease spectrum. That MMF was effective in this group of patients suggests that it will also be effective in patients with less severe disease.

In our study, MMF was effective in treating patients with non‐renal and renal manifestations of SLE. Gaubitz et al. [7] studied 10 patients treated with MMF for uncontrolled disease activity for up to 16 months. They noted a significant decrease in the SLAM (Systemic Lupus Activity Measure) score, with reduction in prednisolone dosage. Dooley et al. [8] reported 13 patients treated with MMF for severe lupus nephritis. They found a significant decrease in levels of serum creatinine and proteinuria. A recent controlled study of 42 patients with diffuse proliferative lupus nephritis demonstrated that the combination of prednisolone and MMF was as effective as a regimen of prednisolone and initially oral cyclophosphamide replaced later by azathioprine [13].

The other immunosuppressive agents in common use for SLE include corticosteroids, cyclophosphamide, azathioprine and cyclosporin. These agents have a high incidence of serious side‐effects. Amongst such side‐effects, of particular note are cytopenias, effects on fertility and increased risks of infection and malignancy with cyclophosphamide; hypertension and nephrotoxicity with cyclosporin; and hypertension, impaired glucose tolerance, obesity and osteoporosis with corticosteroids. These side‐effects demonstrate the need for effective immunosuppressive agents with more favourable side‐effect profiles. In our study, therapy with MMF was discontinued in two out of 20 patients because of gastrointestinal side‐effects and in one patient because of severe skin lesions. Gastrointestinal side‐effects are the most frequently reported side‐effect in studies using MMF, both in transplantation and lupus nephritis [2, 7]. Out of 13 patients, Dooley et al. [8] noted two patients with nausea/diarrhoea, two patients with asymptomatic leucopenia, and one patient each with pancreatitis, thinning of scalp hair and herpes simplex stomatitis associated with leucopenia. Other than pancreatitis, they noted that all other side‐effects resolved with a reduction in MMF dose. The most frequent side‐effect observed by Gaubitz et al. [7] was mild or moderate diarrhoea in four out of 10 patients. No patient in their study required reduction or cessation of treatment. Chan et al. [13] reported that one patient out of 21 had to discontinue MMF, because of diarrhoea. They noted infections (four respiratory and two herpes zoster) occurring in four patients, with a similar incidence to that in the oral cyclophosphamide group. The low incidence of side‐effects observed in these studies suggests that MMF is in general well tolerated by SLE patients. Whilst diarrhoea is the most frequent side‐effect, it is only infrequently severe enough to necessitate discontinuation of treatment. A reduction in dose of MMF should be tried prior to stopping the drug.

The low incidence of side‐effects compared with that seen in trials of MMF for transplantation should not necessarily be ascribed to the dose range. The dose at the end of our study varied from 1–2 g per day, similar to other studies of MMF in SLE [7, 8]. The dose typically used in renal transplantation is 1 g twice daily (though some groups use 1.5 g twice daily). The main differences are in a lower incidence of opportunistic infection, for example tissue‐invasive cytomegalovirus disease, and lymphomas and lymphoproliferative disease, compared with renal transplantation [24]. Possible explanations include the shorter duration of follow‐up in the lupus nephritis trials, the slightly lower MMF doses used, and the absence of a third agent (typically cyclosporin). Although we did not see any cancers in our patients on MMF, the study numbers and period of follow‐up were insufficient to allow a significant assessment of cancer risk from MMF in SLE.

An important point is illustrated by the two patients who discontinued MMF because they were trying to conceive. Clearly, patients with SLE, particularly those with severe disease or with renal involvement, should not be encouraged to consider pregnancy until their disease is well controlled or in a period of remission. Patients should not become pregnant while taking MMF because of the potential risk of teratogenicity [25]. Toxicity has been demonstrated in animal studies [26, 27]. Pregnancy should be excluded before commencing MMF. Birth control measures are necessary both during treatment and for 6 weeks after stopping MMF. Patients may continue azathioprine in pregnancy, as there is little evidence to suggest teratogenicity from the extensive clinical use of azathioprine in transplantation [28]. In patients in whom future fertility is a particular concern, MMF may be considered as an alternative where cyclophosphamide would otherwise be required.

The efficacy of MMF in SLE including lupus nephritis should be evaluated in large‐scale, prospective, randomized controlled trials conducted over longer periods of follow‐up. The results that we and others have shown provide the premise for such trials. An example is the MAINTAIN trial coordinated by the Eurolupus study group, which aims to compare MMF with azathioprine for the maintenance of remission in lupus nephritis. The recent study by Chan et al. [13] compared MMF with oral cyclophosphamide. However, Isenberg and Karassa commented that intravenous cyclophosphamide therapy is the standard treatment for diffuse proliferative lupus nephritis [29, 30]. The duration of follow‐up reported was 12 months, which may not have allowed sufficient time for differences to develop between the two groups.

Further details should be sought regarding therapeutic efficacy, including perhaps the relationship between the WHO class of nephritis and the response to treatment, information regarding the side‐effect profile specific to SLE and lupus nephritis, and dosage requirements.

In conclusion, MMF appears to be a safe and effective alternative immunosuppressant for renal and extra‐renal disease in SLE that does not respond to conventional immunosuppressive treatment.

Correspondence to: M. Y. Karim, Department of Immunology, 2nd floor, North Wing, St Thomas' Hospital, Lambeth Palace Road, London SE1 7EH, UK.

References

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