Treatment of Active Lupus Nephritis With 15-deoxyspergualin
Treatment of Active Lupus Nephritis With 15-deoxyspergualin
Introduction: As the immunosuppressive potency of 15-deoxyspergualin (DSG) has been shown in the therapy of renal transplant rejection and Wegener's granulomatosis, the intention of this study was to evaluate the safety of DSG in the therapy of lupus nephritis (LN).
Methods: Patients with histologically proven active LN after prior treatment with at least one immunosuppressant were treated with 0.5 mg/kg normal body weight/day DSG, injected subcutaneously for 14 days, followed by a break of one week. These cycles were repeated to a maximum of nine times. Doses of oral corticosteroids were gradually reduced to 7.5 mg/day or lower by cycle 4. Response was measured according to a predefined decision pattern. The dose of DSG was adjusted depending on the efficacy and side effects.
Results: A total of 21 patients were included in this phase-I/II study. After the first DSG injection, one patient was excluded from the study due to renal failure. Five patients dropped out due to adverse events or serious adverse events including fever, leukopenia, oral candidiasis, herpes zoster or pneumonia. Eleven out of 20 patients achieved partial (4) or complete responses (7), 8 were judged as treatment failures and 1 patient was not assessable. Twelve patients completed all nine cycles; in those patients, proteinuria decreased from 5.88 g/day to 3.37 g/day (P = 0.028), Selena-SLEDAI (Safety of Estrogens in Lupus Erythematosus - National Assessment - systemic lupus erythematosus disease activity index) decreased from 17.6 to 11.7. In 13 out of 20 patients, proteinuria decreased by at least 50%; in 7 patients to less than 1 g/day.
Conclusions: Although the number of patients was small, we could demonstrate that DSG provides a tolerably safe treatment for LN. The improvement in proteinuria encourages larger controlled trials.
Systemic lupus erythematosus (SLE) is an aggressive autoimmune disease. Lupus nephritis (LN) is a major complication of SLE and a strong determinant of morbidity and mortality. Standard treatment protocols for lupus nephritis involve intravenous (IV) pulses of corticosteroids and cyclophosphamide (CYC) or mycophenolate mofetil (MMF) for induction therapy, with oral corticosteroids (OCS) and azathioprine (AZA) or mycophenolic acid as long-term maintenance treatment. Although pulsed IV CYC is effective in improving renal survival, a significant proportion of patients demonstrate poor renal response or relapses. The optimal therapy for such patients with CYC-resistant or relapsing LN remains unclear. Moreover, CYC is associated with a substantial side-effect profile. The risk of these side effects remains higher for more than 10 years after termination of CYC treatment, and is especially high if the patients received a cumulative dosage of >36 g.
15-deoxyspergualin (DSG; Gusperimus) shows immunosuppressive activity both in vitro and in vivo, affecting B-lymphocyte, T-lymphocyte and macrophage/monocyte function. In rodents and human cell systems, DSG shows a dose-dependent inhibition of primary and secondary responses to T-, B- and antigen-presenting cell dependent reactions. It has been demonstrated that DSG binds with high affinity to heat shock protein c (hsc) 73. DSG also blocks nuclear translocation of NF-κB in a pre-B-cell line, thereby affecting NF-κB-driven transcription of the kappa light chain. Finally, Nishimura et al. reported that DSG inhibits desoxyhypusine synthase, the first enzyme in the formation of active eukaryotic translation initiation factor 5A. This factor is important for the stabilization of certain mRNA transcripts (TNF-α and others).
The immunosuppressive properties of DSG have been demonstrated in preclinical animal studies including SLE models. In humans with glucocorticoid-resistant kidney transplant rejection, DSG shows the same efficacy rate as the strongly T-cell depleting anti-CD3 monoclonal antibody. DSG has been licensed in Japan for acute renal allograft rejection since 1994. In 2003, an open clinical trial successfully tested DSG in patients with persistent ANCA-associated vasculitis. Adverse events (AE) were common but rarely led to treatment discontinuation. Against this background, DSG was granted an orphan drug status for the treatment of Wegener's granulomatosis by the European Medicines Agency (EMA).
As DSG induces a reversible maturation block of granulocytes, it needs to be administered in cycles with intermittent wash-out periods. In the previous studies, it was concluded that the degree of the clinical response does not correlate to the severity or duration of leukopenia elicited in the individual patient. This was an important influence on the protocol for our current SLE study: for safety reasons, we shortened the treatment intervals and started with lower dosages, as SLE patients are more prone to leuko- and lymphocytopenia than patients with Wegener's granulomatosis. In human studies on cancer treatment, in contrast, DSG was applied intravenously at much higher dosages and was still generally well tolerated. The study presented here was also encouraged by beneficial results achieved when three patients with active LN were treated with DSG using the same protocol as used here. All three patients had been treated with various immunosuppressives including cyclophosphamide; after informed consent, we started treating with DSG along with corticosteroids, which could be gradually reduced within the first cycles. Indicators of response were a decrease of proteinuria, hematuria and an improvement in the serological parameters of lupus activity.
Thus, based on the favourable toxicity profile of DSG, the limited number of immunosuppressants available for the treatment of aggressive SLE, the sometimes considerable side effects of cyclophosphamide as the best evaluated immunosuppressant for treatment of aggressive SLE, the good efficacy and safety data for DSG in the treatment of Wegener's granulomatosis, and the favourable data from the three previously mentioned patients with LN, we initiated this multicenter open phase I/II trial of DSG in the treatment of refractory LN.
Abstract and Introduction
Abstract
Introduction: As the immunosuppressive potency of 15-deoxyspergualin (DSG) has been shown in the therapy of renal transplant rejection and Wegener's granulomatosis, the intention of this study was to evaluate the safety of DSG in the therapy of lupus nephritis (LN).
Methods: Patients with histologically proven active LN after prior treatment with at least one immunosuppressant were treated with 0.5 mg/kg normal body weight/day DSG, injected subcutaneously for 14 days, followed by a break of one week. These cycles were repeated to a maximum of nine times. Doses of oral corticosteroids were gradually reduced to 7.5 mg/day or lower by cycle 4. Response was measured according to a predefined decision pattern. The dose of DSG was adjusted depending on the efficacy and side effects.
Results: A total of 21 patients were included in this phase-I/II study. After the first DSG injection, one patient was excluded from the study due to renal failure. Five patients dropped out due to adverse events or serious adverse events including fever, leukopenia, oral candidiasis, herpes zoster or pneumonia. Eleven out of 20 patients achieved partial (4) or complete responses (7), 8 were judged as treatment failures and 1 patient was not assessable. Twelve patients completed all nine cycles; in those patients, proteinuria decreased from 5.88 g/day to 3.37 g/day (P = 0.028), Selena-SLEDAI (Safety of Estrogens in Lupus Erythematosus - National Assessment - systemic lupus erythematosus disease activity index) decreased from 17.6 to 11.7. In 13 out of 20 patients, proteinuria decreased by at least 50%; in 7 patients to less than 1 g/day.
Conclusions: Although the number of patients was small, we could demonstrate that DSG provides a tolerably safe treatment for LN. The improvement in proteinuria encourages larger controlled trials.
Introduction
Systemic lupus erythematosus (SLE) is an aggressive autoimmune disease. Lupus nephritis (LN) is a major complication of SLE and a strong determinant of morbidity and mortality. Standard treatment protocols for lupus nephritis involve intravenous (IV) pulses of corticosteroids and cyclophosphamide (CYC) or mycophenolate mofetil (MMF) for induction therapy, with oral corticosteroids (OCS) and azathioprine (AZA) or mycophenolic acid as long-term maintenance treatment. Although pulsed IV CYC is effective in improving renal survival, a significant proportion of patients demonstrate poor renal response or relapses. The optimal therapy for such patients with CYC-resistant or relapsing LN remains unclear. Moreover, CYC is associated with a substantial side-effect profile. The risk of these side effects remains higher for more than 10 years after termination of CYC treatment, and is especially high if the patients received a cumulative dosage of >36 g.
15-deoxyspergualin (DSG; Gusperimus) shows immunosuppressive activity both in vitro and in vivo, affecting B-lymphocyte, T-lymphocyte and macrophage/monocyte function. In rodents and human cell systems, DSG shows a dose-dependent inhibition of primary and secondary responses to T-, B- and antigen-presenting cell dependent reactions. It has been demonstrated that DSG binds with high affinity to heat shock protein c (hsc) 73. DSG also blocks nuclear translocation of NF-κB in a pre-B-cell line, thereby affecting NF-κB-driven transcription of the kappa light chain. Finally, Nishimura et al. reported that DSG inhibits desoxyhypusine synthase, the first enzyme in the formation of active eukaryotic translation initiation factor 5A. This factor is important for the stabilization of certain mRNA transcripts (TNF-α and others).
The immunosuppressive properties of DSG have been demonstrated in preclinical animal studies including SLE models. In humans with glucocorticoid-resistant kidney transplant rejection, DSG shows the same efficacy rate as the strongly T-cell depleting anti-CD3 monoclonal antibody. DSG has been licensed in Japan for acute renal allograft rejection since 1994. In 2003, an open clinical trial successfully tested DSG in patients with persistent ANCA-associated vasculitis. Adverse events (AE) were common but rarely led to treatment discontinuation. Against this background, DSG was granted an orphan drug status for the treatment of Wegener's granulomatosis by the European Medicines Agency (EMA).
As DSG induces a reversible maturation block of granulocytes, it needs to be administered in cycles with intermittent wash-out periods. In the previous studies, it was concluded that the degree of the clinical response does not correlate to the severity or duration of leukopenia elicited in the individual patient. This was an important influence on the protocol for our current SLE study: for safety reasons, we shortened the treatment intervals and started with lower dosages, as SLE patients are more prone to leuko- and lymphocytopenia than patients with Wegener's granulomatosis. In human studies on cancer treatment, in contrast, DSG was applied intravenously at much higher dosages and was still generally well tolerated. The study presented here was also encouraged by beneficial results achieved when three patients with active LN were treated with DSG using the same protocol as used here. All three patients had been treated with various immunosuppressives including cyclophosphamide; after informed consent, we started treating with DSG along with corticosteroids, which could be gradually reduced within the first cycles. Indicators of response were a decrease of proteinuria, hematuria and an improvement in the serological parameters of lupus activity.
Thus, based on the favourable toxicity profile of DSG, the limited number of immunosuppressants available for the treatment of aggressive SLE, the sometimes considerable side effects of cyclophosphamide as the best evaluated immunosuppressant for treatment of aggressive SLE, the good efficacy and safety data for DSG in the treatment of Wegener's granulomatosis, and the favourable data from the three previously mentioned patients with LN, we initiated this multicenter open phase I/II trial of DSG in the treatment of refractory LN.
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