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Cladribine in the treatment of systemic lupus erythematosus nephritis
  1. VLASSIS KONTOGIANNIS,
  2. PETER C LANYON,
  3. RICHARD J POWELL
  1. Clinical Immunology Unit, University Hospital, Queens Medical Centre
  2. Nottingham NG7 2UH
  1. Dr V Kontogiannis.

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Systemic lupus erythematosus (SLE) nephritis often requires treatment with cyclophosphamide, which carries the risk of major side effects including infection, ovarian failure and bladder malignancy. Therapeutic strategies that would specifically target lymphocytes are appealing. Following the first report of the use of the purine nucleoside analogue cladribine (2-chloro-2’-deoxyadenosine), a selective lymphocyte depleting agent, in the treatment of lupus nephritis,1 we report our experience in two patients with severe renal involvement.

CASE 1

A 32 year old woman was diagnosed with SLE at age 28, with polyarthritis, photosensitive rash, subcutaneous nodules, fatigue and lymphopenia. ANA, anti-dsDNA, anti-Sm and anti-RNP antibodies were present. Various immunosuppressants and corticosteroids failed to maintain a sustained remission. Two and a half years after presentation, she developed haematuria and proteinuria and renal biopsy revealed WHO Class III lupus nephritis. Treatment with pulsed intravenous cyclophosphamide and methylprednisolone had to be stopped after four months and a total cyclophosphamide dose of 9 g because of an anaphylactic reaction during an infusion. Despite azathioprine, 150 mg/day, and prednisolone, up to 20 mg/day, she developed severe hypertension (210/120 mm Hg) and biopsy confirmed lymphocytic cutaneous vasculitis. Cladribine (0.05 mg/kg/day for seven days as continuous intravenous infusion) and prednisolone 60 mg/day were started. Cutaneous vasculitis resolved within five days and serum creatinine fell from 190 to 120 μmol/l in five weeks. Cladribine was well tolerated apart from a herpes simplex infection in the natal cleft that responded to acyclovir. She relapsed three months later, with a new rise in creatinine (154 μmol/l) and recurrence of cutaneous vasculitis.

A further infusion of cladribine was given, keeping prednisolone at 5 mg/day. Although the vasculitic rash again resolved, renal function and proteinuria continued to deteriorate.

She has subsequently been maintained with mycophenolate mofetil 1 g twice daily and oral prednisolone. Serum creatinine has returned to 98 μmol/l and proteinuria to 5.3 g/24 h and remained stable despite gradual reduction of prednisolone dose to 15 mg daily.

CASE 2

A 35 year old woman was diagnosed with SLE at age 31, with fever, pancytopenia, and nephrotic syndrome (proteinuria 6.65 g/24 h). ANA and anti-dsDNA antibodies were present. Renal biopsy revealed WHO Class III lupus nephritis. In the next four years she required three treatment cycles of intravenous cyclophosphamide (total dose per six month cycle: 9–10 g). Azathioprine, methotrexate, cyclosporin A and prednisolone 5–40 mg/day in the interim had failed to control her disease. Cyclophosphamide, additionally, had resulted in premature ovarian failure. Repeat renal biopsy showed progression to Class IV nephritis with focal necrosis and crescents. Cladribine (continuous IV infusion of 0.05 mg/kg/day for seven days) and prednisolone 40 mg/day proved ineffective as creatinine rose from 149 to 243 μmol/l in two months. She also developed a perineal herpes simplex infection but drug was otherwise well tolerated. Pulse intravenous cyclophosphamide and methylprednisolone were subsequently reintroduced and creatinine has again fallen to 118 μmol/l.

Table 1 shows the results of investigations before and after cladribine infusions for both cases.

Table 1

Results of investigations before and after cladribine infusions

In the initial study by Davis et al,1 three of seven patients treated with continuous cladribine infusion for a week responded completely and renal function did not deteriorate in any of the seven patients. Our limited experience suggests that cladribine may be effective in other manifestations of SLE (that is, cutaneous vasculitis), but it does not seem to have a consistent effect in severe nephritis. Good tolerability of the drug was confirmed and although herpes simplex infections occurred in both patients the role of corticosteroids cannot be ignored.

Further studies are required to establish the position of cladribine in the treatment of SLE especially in the presence of other lymphocyte depleting agents such as mycophenolate mofetil, which is reported to be effective in lupus nephritis,2-4 even in cases refractory to cyclophosphamide.5

References

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