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Optimal treatment for patients with relapsing lupus nephritis remains unclear. The ability of 15-deoxyspergualin (gusperimus; 15-DSG) to suppress systemic lupus erythematosus (SLE)-like diseases has been demonstrated in animals and humans.1–4 15-DSG exerted no nephrotoxicity or hepatotoxicity but reversibly induced leucocytopenia.5,6
In this study we aimed at evaluating the safety of 15-DSG in the treatment of glomerulonephritis associated with SLE.
Table 1 shows the patient characteristics.
15-DSG was provided by Nippon Kayaku Co Ltd, Tokyo, Japan. Patients gave their informed consent, and 15-DSG 0.5 mg/kg normal body weight (height in cm minus 100)/day was self administered subcutaneously for 14 days, followed by a break of 7 days ( = 1 cycle). The dose was adjusted (dependent on efficacy or safety, or both) after cycles 4 and 6 to 0.35 mg/kg and 0.25 mg/kg, or 0.7 mg/kg and 1.0 mg/kg.
After a bolus, daily corticosteroids could be decreased to 5 mg after 9 weeks. The patient received six cycles of 15-DSG without major problems. Leucocyte counts were always >4×109 cells/l, no infection was seen, no (serious) adverse events and occurred with the exception of parageusia. GN resolved and her SLE associated activity measures improved (table 1, fig 1). After the sixth cycle the patient was switched from 15-DSG to a combination of ciclosporin A (CSA) and azathioprine, and later azathioprine alone. Renal function was normal at the end of the trial, SELENA-SLEDAI (Safety of Oestrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index) decreased from 12 to 0, and the corticosteroid dosage was reduced to 5 mg/day.
Oral corticosteroids were increased to 40 mg/day and tapered to 5 mg/day within 9 weeks. Proteinuria decreased to 700–750 mg/day (fig 1; table 1). During the second cycle, she had herpes zoster exanthema (which completely disappeared after treatment with antiviral agents). The white blood cell count was always >5×109 cells/l. Because dsDNA antibody titres remained high, the 15-DSG dosage was increased to 0.75 mg/kg/day for cycles 5 and 6, to 1.0 mg/kg/day for cycles 7–9. During cycle 5 she experienced bacterial bronchitis without fever. At the end of cycle 6 her anaemia worsened (possibly 15-DSG-related?).7 Within the ninth cycle, for the first time during treatment with 15-DSG, the urine sediment indicated a flare of GN. At this time, proteinuria was 890 mg/day (fig 1); creatinine was always normal. SELENA-SLEDAI decreased from 12 to 4 (end of cycle 8). The corticosteroid dosage was 5 mg/day at the end of the study.
Treatment was switched to 150 mg oral cyclophosphamide. During her last visit to our clinic the anaemia had improved (115 g/l), proteinuria was stable (1100 mg/day), and erythrocyturia was present without signs of active GN.
After a bolus, corticosteroids could be tapered to 5 mg/day (end of cycle 3). Maximum proteinuria was 10 300 mg/day at entry into 15-DSG treatment (fig 1; table 1). By the end of cycle 3, proteinuria had decreased to <1000 mg/day (fig 1). Within cycles 3 and 4 she had a prolonged urogenital infection, possibly related to leucocytopenia (3.9×109 cells/l at the end of cycle 3, 1.7×109 cells/l at the end of cycle 4). She now experienced a flare of her GN (increased proteinuria up to 7100 mg/day at the end of cycle 5; fig 1). We increased the corticosteroids to 60 mg/day, continued 15-DSG as previous success was excellent, but decreased the dosage to 0.35 mg/kg/day because of (possibly 15-DSG-related?) leucocytopenia and the infectious episodes. In addition, we prescribed low dose CSA (2.5 mg/kg/day) as 15-DSG had been successfully used together with CSA.8 Subsequently, corticosteroids could be tapered to 5 mg/day within 7 weeks. Proteinuria decreased to 780 mg/day (cycle 9; fig 1); creatinine was always normal. No infections were reported during the 15-DSG + CSA treatment. She is now receiving CSA alone. SELENA-SLEDAI decreased from 14 to 6; the corticosteroid dosage was reduced to 5 mg/day at the end of the study.
As far as we know, this is the first report on safety of 15-DSG in the treatment of active SLE-GN. Two of the three patients had non-severe infectious episodes, but otherwise 15-DSG was well tolerated. We are currently conducting a phase I/II trial with 15-DSG in patients with SLE and active GN which will also focus on efficacy measurement.
We thank our patients for their collaboration and help in performing this trial.
PAH is an employee of Euro Nippon Kayaku, a branch of the mother company Nippon Kayaku, Tokyo, Japan, which provided the drug for this trial free of charge.
Treatment of SLE-GN with 15-DSG was approved by the local ethics committee.
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