Remission from lupus nephritis resistant to cyclophosphamide after additional treatment with cyclosporin A

L. Ferrario, M. Bellone, E. Bozzolo, E. Baldissera and M. G. Sabbadini1

Divisione di Medicina II, Istituto Scientifico H San Raffaele, and Università egli Studi, Milan, Italy

Sir, The renal involvement in systemic lupus erythematosus (SLE) exhibits considerable variability in terms of clinical severity, course and response to the common immunosuppressive and cytotoxic drugs [1]. The most aggressive cases often require the combination of methylprednisolone (MPD) and cytotoxic drugs [2].

The cytotoxic drug cyclophosphamide (CTX), given as intermittent pulse doses, has been used widely to treat severe lupus nephritis diseases [i.e. diffuse proliferative nephritis (WHO class IV) and extensive or necrotizing focal proliferative lupus nephritis (WHO class III; [2] and citations therein)]. The long-term follow-up of this treatment demonstrated a significantly reduced probability of progressing to renal failure [3]. The classic protocol, proposed by the National Institutes of Health group in Bethesda [3], consists of CTX given as six monthly boluses followed by quarterly boluses for an additional 2 yr, or for at least 2 yr after renal remission. Unfortunately, several patients do not achieve renal remission after the first cycle of therapy with intermittent boluses of CTX and need to be treated with additional cycles of the drug. Gourley et al. [2] reported that 38% of 21 patients treated with such a regimen did not gain renal remission, even after additional cycles of monthly boluses of CTX.

Cyclosporin A (CsA), an immunosuppressive drug initially used in organ transplantation, has been used increasingly in autoimmune diseases and in immune-related diseases of the kidney, such as proliferative glomerulonephritis, idiopathic nephrotic syndrome, vasculitis, and lupus nephritis [4]. The reports on the use of CsA in the treatment of lupus nephritis are scattered. Moreover, the risk of nephrotoxicity and hypertension increase concern on the use of CsA in renal diseases.

To our knowledge, the association between CTX and CsA for the treatment of lupus nephritis has not been reported so far.

In the period 1992–1998, 16 Caucasian patients (age range 16–67 yr; mean age 33 yr) affected by SLE (all patients fulfilled at least four of the criteria of the American Rheumatism Association for the diagnosis of SLE [5]) and lupus nephritis (WHO class III or IV) were followed in our institution and treated with intermittent pulse doses (mean monthly boluses: 8.4) followed by quarterly boluses of CTX for 2–3 yr.

We report on three of those patients whose nephritis was resistant to CTX therapy, and were successfully treated with the addition of CsA.

Case 1. A female was diagnosed as having SLE [photosensitivity, piastrinopenia, arthritis, and positive antinuclear (ANA), anti-DNA and anti-Sm antibodies] in 1992 at the age of 26 yr. In 1995, when she was in hydroxychloroquine and azathioprine (AZA) treatment, she developed proteinuria (>2 g/day) and microhaematuria (>20 dysmorphic red blood cells/high power field (hpf). The erythrocyte sedimentation rate was 75 mm, the ANA and anti-dsDNA antibody titres were >1/640 and 1/320, respectively, and the C3 level was reduced (35 mg/dl). A renal biopsy was not performed because of a blood coagulation defect (vonWillebrand disease). The patient received three pulse doses of MPD (1 g/bolus) followed by six monthly boluses of CTX (1 g/m2) and oral prednisone (0.8 mg/kg/day progressively tapered to a dose maintenance regimen of 10–15 mg/day). Because of the persistent proteinuria and the reduced C4 level, the patient received an additional three boluses of MPD (1 g/bolus) before starting quarterly boluses of CTX. After two quarterly boluses of CTX, proteinuria and haematuria increased (4–6 g/day, and >50 urine red blood cells/hpf, respectively). CsA (4 mg/kg) was added to the CTX therapeutic regimen. Within 2 months the patient gained renal remission (proteinuria <0.5 g/day and normal sediment). CTX was discontinued after 2 yr of quarterly boluses, CsA was maintained at 2–3 mg/day. At the latest control (March 1999) she was still in renal remission.

Case 2. A female presented in 1995, at the age of 26 yr, with a nephrotic syndrome (proteinuria 9–14 g/day), urine sediment abnormalities (>50 urine red blood cells/hpf), impaired renal function (creatinine 1.36 mg/dl), associated with sierositis, malar rash, leucopenia, high titres of ANA and anti-dsDNA antibodies and reduced levels of C3 and C4. A renal biopsy showed a diffuse proliferative glomerulonephritis (WHO class IV). The patient received three pulse doses of MPD (1 g/bolus) followed by oral prednisone (0.8 mg/kg/day progressively tapered to a dose maintenance regimen of 10–15 mg/day), and eight monthly boluses of CTX (1 g/m2) without complete renal remission (proteinuria >1.5 g/day). Two attempts to modify the CTX therapy to a quarterly regimen (the latter lasting 9 months) were rapidly followed by renal flare (proteinuria 5–6 g/day). In January 1998, CsA (3.5 mg/kg/day) was added to CTX (quarterly boluses) therapy. A complete renal remission was achieved in 4 months (proteinuria <0.5 g/day). At the latest control (November 1999), the patient was still in remission.

Case 3. A female was diagnosed as being affected by SLE (photosensitivity, arthritis, malar rash, and positive ANA and anti-DNA antibodies) in 1989 at the age of 33 yr. She was treated with prednisone and hydroxychloroquine with good control of the disease until April 1997, when she developed proteinuria (2–2.5 g/day) and microhaematuria (20–40 red blood cells/hpf) without impairment of renal function (creatinine 0.67 mg/dl). ANA and anti-dsDNA antibody titres were >1/640 and 1/160, respectively, and C3 and C4 levels were reduced (78 and 8 mg/dl, respectively). The patient was treated with AZA (150 mg/day) for the following 6 months without renal remission. A renal biopsy taken at that time showed an extensive focal proliferative glomerulonephritis (WHO class III). Treatment with three pulse doses of MPD (1 g/bolus) followed by nine monthly boluses of CTX (1 g/m2) did not modify the renal disease (proteinuria >2 g/day). CsA (3.5 mg/kg/day) was added to quarterly boluses of CTX. A complete resolution of proteinuria was achieved in 4 months (proteinuria <0.5 g/day). At the latest control (October 1999), the patient was still in remission.

In general the combined drug regimen was well tolerated in all three patients without relevant adverse events. In particular no impairment of the renal function (i.e. increase >30% over baseline value of the serum creatinine level) or hypertension occurred.

A complete renal remission was achieved within 2 months in case 1. In the other two cases, proteinuria significantly decreased in the first 2 months of CsA–CTX combined therapy and a complete renal remission was achieved in 4 months. Since the addition of CsA, the patients have been in continuous renal remission for 36, 18 and 13 months, respectively.

CTX remains the treatment of first choice in life-threatening manifestations of SLE like severe lupus nephritis. Intermittent pulse doses of CTX allow the reduction of associated adverse events. Nonetheless, among the patients treated for long periods with such a regimen, more than 50% develop sustained amenorrhoea, and approximately 25% develop one or more infections [2].

In our series, three of 16 patients treated with intermittent pulse doses of CTX did not gain renal remission, after six, eight and nine monthly boluses of CTX, respectively. The introduction of CsA determined a rapid reduction of proteinuria and renal remission. This allowed us to shift to a quarterly pulse regimen, and reduce the total amount of CTX administered without significant adverse events.

Our experience suggests that the addition of CsA to the CTX treatment may rescue SLE patients not reaching renal remission with cytotoxic therapy only. The effect of CsA treatment may be either due to a direct action on the glomerule, or mediated by the immunosuppressive action of the drug.

Our results may represent a rationale for a pilot study of combined therapy with CsA and CTX in severe lupus nephritis resistant to CTX.

Notes

1 Correspondence to: M. G. Sabbadini. Back

References

  1. Ponticelli C. Current treatment recommendations for lupus nephritis. Drugs 1990;40:19–30.
  2. Gourley MF, Austin III HA, Scott D, Yarboro CH, Vaughan EM, Muir J et al. Methylprednisolone and cyclophosphamide, alone or in combination, in patients with lupus nephritis. A randomised, controlled trial. Ann Int Med 1996;125:549–57.[Abstract/Free Full Text]
  3. Steinberg AD, Steinberg SC. Long-term preservation of renal function in patients with lupus nephritis receiving treatment that includes cyclophosphamide versus those treated with prednisone only. Arthritis Rheum 1991;34:945–50.[ISI][Medline]
  4. Klein M, Radhakrishnan J, Appel G. Cyclosporine treatment of glomerular diseases. Annu Rev Med 1999;50:1–15.[ISI][Medline]
  5. Tan EM, Choen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982;25:1271–7.[ISI][Medline]
Accepted 8 September 1999





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