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Mycophenolate mofetil treatment in children and adolescents with lupus
  1. Ina Kazyra1,
  2. Clarissa Pilkington2,
  3. Stephen D Marks3,
  4. Kjell Tullus3
  1. 1Department of Paediatrics, Belarus State Medical University, Minsk, Belarus
  2. 2Department of Paediatric Rheumatology, Great Ormond Street Hospital for Children NHS Trust, London, UK
  3. 3Department of Paediatric Nephrology, Great Ormond Street Hospital for Children NHS Trust, London, UK
  1. Correspondence to Kjell Tullus, Department of Paediatric Nephrology, Nephrology Unit, Great Ormond Street Hospital for Children, Great Ormond Street, London WC1N 3JH, UK; tulluk{at}gosh.nhs.uk

Abstract

Safety and efficacy data are presented on the use of mycophenolate mofetil (MMF) in 26 children and adolescents with lupus. Data include therapy before and 12 months after starting MMF. 18 of 26 patients had biopsy-proved lupus nephritis. Group 1 were commenced on MMF induction and/or maintenance therapy (n=14), group 2 converted from azathioprine because of inadequate disease control (n=12). 73% of all (10 (71%) group 1 and 10 (83%) group 2) patients experienced a significant improvement in British Isles Lupus Assessment Group score (from median 9.0 to 3.0). Children with hypocomplementaemia increased their C3 significantly in both groups (0.53–1.15 for group 1 and 0.63–1.2 g/l for group 2, p=0.001), and C4 level only in group 1 (0.08–0.17, p=0.01). Renal function and albuminuria improved in those with active nephritis (p≤0.01). Significant improvements were seen in both groups in haemoglobin, erythrocyte sedimentation rate and lymphocyte counts. Prednisolone dose was weaned in both groups, p<0.05. Side-effects were seen in four patients, but none was judged to be severe enough to discontinue treatment. MMF treatment in this cohort of children with lupus seemed to be safe, well tolerated and effective.

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Introduction

Treatment of children with systemic lupus erythematosus (SLE) is based on corticosteroids as first-line therapy in combination with steroid-sparing agents including cyclophosphamide (CYC) and azathioprine (AZA). The prognosis is still poor and there are substantial side-effects with treatment. The optimal maintenance immunosuppressive treatment and the duration of therapy for patients are not entirely clear.

Several studies in adults have shown that mycophenolate mofetil (MMF) is a good therapeutic option both for induction and maintenance treatment. The published experience of MMF in the paediatric population is limited and only a few studies have been reported to date.1,,4 MMF seems to be equivalent to AZA for remission maintenance.

The aim of the present study was to report the effectiveness and safety of MMF treatment in 26 children and adolescents with SLE.

Patients and methods

The medical records of 26 children and adolescents (23 females) aged 5–18 (median 15) years with SLE who had been treated with MMF at the paediatric nephrology and rheumatology departments of Great Ormond Street Hospital for Children NHS Trust and University College Hospital, London, UK, were retrospectively analysed. The median age of the patients when treatment with MMF was commenced was 15.5 years. Patient data including immunosuppressive therapy before and 12 months after starting MMF were collected. Eighteen children had biopsy-proved lupus nephritis (LN). The biopsies were done between 3 months and 2.6 years before the MMF treatment.

Patients were divided into two groups

  1. Started on MMF as planned treatment either as (A) maintenance after induction with intravenous CYC and steroids (n=8) or intravenous rituximab, intravenous CYC induction pulses and steroids (n=4) or (B) treated with MMF as induction and maintenance therapy, together with oral prednisolone after intravenous methylprednisolone pulses (n=2).

  2. Converted from AZA (n=12) owing to inadequate control of their disease.

Treatment

MMF was prescribed in combination with prednisolone in group 1 at an initial dose of 5–60 mg/day (median 25) weaned to 0–10 mg/day (median 6.5), p<0.05, and in group 2 from 0–60 mg/day (median 15) to 0–10 mg/day (median 5), p<0.05, and hydroxychloroquine (16 patients with 100–400 mg/day). An MMF dose of 20–25 mg/kg/day was aimed for: median starting dose was 500 mg/day (range 250–1500) and after 12 months 1500 mg/day (range 1000–2000).

Evaluation

The disease activity was assessed using the British Isles Lupus Assessment Group (BILAG) index and by blood and urine investigations. Data for BILAG, antinuclear antibody (ANA) and anti-dsDNA are reported for the all patients while for the other studied parameters we report findings in children with pathological results at onset.

Statistical analysis

All values described in the text and figures are expressed as median and range. Statistical analyses were carried out using Graph Pad Prism 4 (Graph Pad Software, San Diego, California, USA). Non-parametric tests (two-tailed Mann-Whitney U test, Fisher's exact test and one-tailed Spearman rank correlation test) were applied throughout with differences being considered significant for p values <0.05.

Results

British Isles Lupus Assessment Group

Ten of 14 (71%) and 10 of 12 (83%) children in groups 1 and 2, respectively, experienced an improvement in BILAG score: in group 1 before MMF treatment from median 9.0 (2.0–23.0) to 3.0 (1.0–8.0) after 12 months (p<0.05) (figure 1A) and in group 2 from 9.0 (4.0–21.0) to 3.0 (1.0–8.0) (p<0.05 figure 1B).

Figure 1

British Isles Lupus Assessment Group (BILAG) scores in (A) group 1 and (B) group 2.

Immunological parameters

Median ANA and anti-dsDNA titres (IU/ml, ELISA) decreased in group 1 from 1:2560 to 1:160 and from 27 to 25 and in group 2 from 1:1280 to 1:160 and 36 to 10, respectively, but this did not reach statistical significance.

Group 1 increased their low C3 and C4 levels from 0.53 g/l to 1.15 g/l (p=0.001) and 0.08 g/l to 0.17 g/l, p=0.01, respectively (table 1). Group 2 children showed increased C3 from 0.63 g/l to 1.2 g/l, p=0.001, and C4 levels from 0.07 g/l to 0.11 g/l (NS) (table 1).

Table 1

Main parameters in children with initially abnormal levels in groups 1 and 2 (medians)

Renal involvement

According to the ISN/RRP classification, two patients (one from each group) had Class II LN; six had Class III (four from group 2) and 10 had Class IV (six from group 1).

Five children who at the start of MMF treatment had an active LN with impaired kidney function improved their median serum creatinine concentration from 100 μmol/l to 53 μmol/l (p=0.01) (table 1), one of those belonged to group 2. Children in group 1 (n=9) who had increased urine albumin/creatinine ratio showed significant reduction from 190.0 mg/mmol to 5 mg/mmol, but this change did not reach significance in group 2 (n=6) (table 1).

Haematological involvement

The haemoglobin concentration significantly improved from 9.7 g/dl to 12.6 g/dl, (p<0.05) in group 1 and in group 2 from 9.5 g/dl to 13.1 g/dl p<0.05 (table 1). A significant reduction of erythrocyte sedimentation rate was achieved in group 1 from 63 mm to 16 mm in the first hour (p<0.05) and in group 2 from 43 mm to 13.5 mm in the first hour after 12 months (NS) (table 1).

The number of leucocytes, neutrophils and platelets did not change significantly after starting treatment with MMF, while the number of lymphocytes in group 1 increased significantly from 0.57 × 109/l to 1.71 × 109/l (p<0.05) and in group 2 from 0.83 × 109/l to 1.75 × 109/l, (p=0.001) (table 1).

It was possible to reduce the prednisolone dose in both groups of patients (table 1).

MMF as induction therapy was used together with prednisolone after intravenous methylprednisolone pulses in two patients (group 1). Both of them showed improved in BILAG (20 to 2), anti-dsDNA became negative and C3 and C4 normalised. Median urine albumin/creatinine ratios improved from 190 mg/mmol to 13.3 mg/mmol. Haematological parameters also improved: leucocytes, neutrophils, lymphocytes and haemoglobin after 12 months of MMF therapy. The daily prednisolone dose was reduced from 50 mg to 5.5 mg.

Adverse effects were seen in four patients: nausea, diarrhoea and leucopenia with viral acute respiratory tract infections. None of them was judged serious enough to stop treatment and no child needed to be hospitalised for side-effects.

Discussion

MMF proved to be safe and effective in our series of 26 children and adolescents with lupus. There was marked improvement in BILAG score, laboratory parameters and in the prednisolone dose that was needed. MMF was also very well tolerated without any severe side-effects.

Controlled data in children do not exist and published experience in paediatric populations is also very limited. Buratti et al1 reported on 11 children with LN: indications for MMF included treatment refractory LN despite on high dose oral or intravenous prednisolone, AZA and/or CYC. These difficult to treat children did not respond to MMF if they had Class IV nephritis while the four with Class V did respond. In contrast, Fu and Liu2 described promising effects of MMF in two children who were refractory not only to CYC but also to ciclosporin.

A multicentre study from Italy studied the efficacy of MMF in controlling the disease activity in 26 children and adolescents with juvenile onset SLE3: 14 showed improvement in disease activity, only two stopped the drug because of severe diarrhoea and abdominal pain. Two further studies involving 14 children also suggested that MMF is an effective drug with few side-effects.4

Our data on the efficacy and safety of MMF are encouraging. They confirm results obtained in previous studies in adults. As childhood lupus is a more aggressive disease than the adult form our findings should prompt the initiation of randomised controlled trials in children.

References

Footnotes

  • Competing interests None.

  • Patient consent Obtained.

  • Provenance and peer review Not commissioned; externally peer reviewed.