The safety population comprised all 21 patients, the ITT population 20 patients as one patient dropped out after the first injection in cycle 1, due to an increase in serum creatinine (rated as SAE). One patient was taken off the study after cycle 4, three patients after the fifth cycle, and four patients after the sixth cycle. Twelve patients were treated for all nine cycles.
DSG dose remained unchanged in one patient over nine cycles; in three patients, DSG was reduced to 0.35 mg/kg/day (all patients were excluded from the study after five to six cycles). Fifteen patients received 0.7 mg/kg/day of DSG starting at cycle 5; in five patients DSG could be increased to 1.0 mg/kg/day in cycles 7 to 9.
Intermittent leukopenia (a known side effect of DSG) of grade 3 according to WHO classification (< 1.0 to 1.9 × 109/L) was observed in seven patients during the course of the trial; however, it was observed in two cycles in only one patient. Importantly, neither the severity of leukopenia nor the DSG dosage correlated to the frequency and severity of side effects.
Overall, 329 AEs were reported in the 21 patients (Table , , ). The most frequently reported AEs were infections and infestations (59 reports in 18 patients; Table ), followed by gastrointestinal disorders (52 reports in 16 patients) and general disorders/injection site reaction (39 reports in 17 patients). A total of 218 of 329 AEs were of mild intensity. A relationship with the administration of DSG was assessed as possible in 86 AEs (18 patients), as probable in 37 AEs (13 patients), and definite in 6 AEs (4 patients). In most of the AEs (299), the patients remained in the trial. Sixteen patients received additional therapy due to 81 AEs. Eight patients experienced 18 SAEs (Table ), seven patients were hospitalized and five patients terminated the study due to SAEs including fever, leukopenia, oral candidiasis, herpes zoster or pneumonia with a consecutive SLE-flare (Table ). No deaths occurred during the study and the follow-up period. Again, DSG dosage and number or severity of side effects did not correlate.
Summary of AEs and their relation to DSG treatment, outcome
Listing of infections and infestations
Overview of the SAEs during the study or the post-study observation period
Based on the predefined response criteria, 11 of 20 (55%) patients achieved PR (four) or CR (seven) on their final visits (one patient with PR after cycle 5, all other patients after cycle 9), eight (40%) were judged as TF on their final visit. Importantly, of these eight patients, two first responded well and achieved PR or CR, but consequently experienced a flare of their LN. Both patients had incompliantly stopped application of DSG, thus they had to be rated as TF. In one patient, response was not assessable due to missing data. Figure shows the responses at cycles 4, 6 and 9. Sixteen patients completed cycle 6 (four in CR, five in PR, four as TF; for three patients, data were missing for the definition of response). Twelve patients were treated for the full nine cycles, with seven patients finishing DSG therapy in CR, three in PR. Six patients never improved, however, 14 of 20 (70%) patients improved to at least PR at some point during the study.
Response rate during DSG treatment. Response rate (CR in black, PR in dark grey, SD in bright grey, TF in white) at cycles (CYC) 4, 6 and 9 (ITT population). *In both cycles 4 and 6, three patients were not assessable.
Proteinuria decreased significantly: at screening, the patients in the study population had a mean protein excretion of 5.124+/-4,379 g/day (range 0.248 to 20.880; n = 20; missing entry data on proteinuria for one patient), this decreased to 3.374+/-4,787 g/day in those 12 patients who were treated for all nine cycles. Table summarizes the average proteinuria at entry and at cycles 4, 6 and 9 for the overall study population. In the 12 patients who were treated through all cycles, proteinuria fell from 5.883+/-5,503 g/day to 3.374+/-4,787 g/day (P = 0.028). The increase from cycle 6 to cycle 9 is mainly due to a 6- to 10-fold increase in proteinuria in the two patients who had incompliantly stopped application of DSG (patients with CRF 10 and 31 in Table ). In 13 of 20 patients, proteinuria decreased by 50% (Table ); in 7 patients, to less than 1 g/day (levels on entry: 1.13 to 20.88 g/day); and in 9 patients, proteinuria fell below the baseline values before onset of the recent LN flare. Only one of four patients with WHO type V LN responded (partially) to DSG; the patient with WHO type III did not improve.
Proteinuria during DSG treatment: proteinuria (g/day) in the study population (n = patient number)
Proteinuria over the study period in patients with a 50% decrease of proteinuria (mg/day)
The analysis of urinary erythrocyte and granular casts revealed casts at screening and study entry for eight patients. In all but one patient, casts disappeared at the latest by cycle 9. At screening, patients of the ITT population had a mean EGFR of 83.75 ml/minute (range 34 to 179 ml/minute). By the end of cycle 2, mean EGFR increased to 91.57 ml/minute. During the subsequent treatment cycles, EGFR was generally stable with mean values ranging between 88.45 ml/minute (cycle 5) and 107.81 ml/minute (cycle 9). Due to the high variability and the low number of patients in this trial this did not reach statistical significance.
Interestingly, SLE-associated rashes improved in six out of eight of the affected patients (completely in four patients, partially in two). Selena-SLEDAI scores were calculated at entry, on the last day of cycles 4, 6 and 9 and at each follow-up visit. The overall scores decreased from a mean of 16.9 (12 to 32; n = 20) at screening to 12.9 (4 to 21; n = 20), 13.7 (4 to 22; n = 15) and 11.7 (6 to 21; n = 12) at the end of cycles 4, 6 or 9, respectively (again, due to the high variability and the low number of patients in this trial this did not reach statistical significance). In the 12 patients who were treated through all nine cycles, Selena-SLEDAI score decreased from 17.6 at entry to 11.7 at the end of cycle 9. The most frequent parameters scoring for the Selena-SLEDAI at the end of the study were low complements, positive dsDNA Ab titers, pyuria, hematuria, rash and arthritis, The response was maintained: at follow-up visits 1, 2 and 3, the average scores were 11.7 (n = 16), 12.2 (15) and 12.0 (13), respectively.
Steroid dosage, an indirect measure of treatment efficacy, could be decreased throughout the cycles as shown in Figure . The number of days on which the predniso(lo)ne dose was lower than 7.5 mg/day increased continuously with treatment cycle, from an average of 2.8 days during cycle 1 to 18 days during cycle 9. Complement C3 (screening: 0.70 +/- 0.23 g/L, cycle 9: 0.76 +/- 0.25 g/L) and C4 (screening: 0.08 +/- 0.05 g/L, cycle 9: 0.15 +/- 0.20 g/L) concentrations tended to increase, C-reactive protein (CRP) (screening: 4.59 +/- 6.88 g/L; cycle 9: 2.58 +/- 3.21 g/L) and dsDNA antibody levels decreased (screening: 287.6 +/- 277 U/ml, cycle 9: 160.15 +/- 134 U/ml) (P > 0.05 for CRP and dsDNA Ab titers).
Daily OCS dosage over DSG cycles. Each line represents one patient.
In the follow-up period after DSG therapy, two patients (both TF during DSG therapy) received CYC and four patients received MMF (two patients with CR during DSG therapy for maintenance, two patients with TF despite DSG therapy for induction therapy); data on three of those patients are available and indicate stable disease. Five patients were treated with rituximab (1 CR, 1 PR, 3 TF during DSG therapy); one of those patients still flared and three patients experienced a complete response. Five patients were treated with AZA and another with Cyclosporine A (CSA) (for maintenance therapy; all PR or CR with DSG therapy).