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High-dose cyclophosphamide versus monthly intravenous cyclophosphamide for systemic lupus erythematosus: a prospective randomized trial.

ABSTRACT: OBJECTIVE:Monthly intravenous (IV) cyclophosphamide for 6 months has been the standard induction regimen for lupus nephritis, followed by a maintenance regimen of quarterly infusions for 2 years. We undertook this study to compare the efficacy and safety of the standard regimen versus a high-dose IV cyclophosphamide regimen. METHODS:We performed a prospective randomized trial comparing monthly IV cyclophosphamide at 750 mg/m(2) body surface area for 6 months followed by quarterly IV cyclophosphamide for 2 years (traditional treatment) against high-dose IV cyclophosphamide (50 mg/kg daily for 4 days) (high-dose treatment). Entry criteria included renal lupus, neurologic lupus, or other organ system involvement with moderate-to-severe activity. RESULTS:Fifty-one patients were randomized; 3 withdrew before treatment and 1 committed suicide after 2 months of high-dose treatment. Twenty-two had renal lupus, 14 had neurologic lupus, and 11 had other organ involvement. The outcome measure was the Responder Index for Lupus Erythematosus (complete response, partial response, no change, or worsening). At 6 months (the end of induction), 11 of 21 patients (52%) in the high-dose treatment group had a complete response compared with 9 of 26 patients (35%) in the traditional treatment group (P = 0.13). At the final visit (30 months), 10 of 21 patients (48%) in the high-dose treatment group had a complete response compared with 13 of 20 patients (65%) who continued with traditional treatment (P = 0.13). Six patients crossed over from traditional treatment to high-dose treatment because of lack of response, and 3 of those patients became complete responders. CONCLUSION:There was not strong evidence that monthly IV cyclophosphamide and high-dose IV cyclophosphamide differed in complete or in any (complete or partial) response to induction or maintenance therapy. However, nonresponders to monthly IV cyclophosphamide can sometimes be rescued with high-dose IV cyclophosphamide.

SUBMITTER: Petri M

PROVIDER: S-EPMC2911961 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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High-dose cyclophosphamide versus monthly intravenous cyclophosphamide for systemic lupus erythematosus: a prospective randomized trial.

Petri Michelle M Brodsky Robert A RA Jones Richard J RJ Gladstone Douglas D Fillius Michael M Magder Laurence S LS

Arthritis and rheumatism 20100501 5

<h4>Objective</h4>Monthly intravenous (IV) cyclophosphamide for 6 months has been the standard induction regimen for lupus nephritis, followed by a maintenance regimen of quarterly infusions for 2 years. We undertook this study to compare the efficacy and safety of the standard regimen versus a high-dose IV cyclophosphamide regimen.<h4>Methods</h4>We performed a prospective randomized trial comparing monthly IV cyclophosphamide at 750 mg/m(2) body surface area for 6 months followed by quarterly ...[more]

PMID: 20131296

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Project description:Background Belimumab is a recombinant, human, IgG1λ monoclonal antibody that targets B-lymphocyte stimulator. The intravenous formulation is indicated for the treatment of active, autoantibody-positive systemic lupus erythematosus (SLE). Belimumab has been formulated for subcutaneous (SC) administration to improve patient convenience. This post-hoc modeling and simulation analysis characterizes the population pharmacokinetics (PK) of SC belimumab, and compares the exposure profiles of the approved belimumab IV dose-10 mg/kg every four weeks-to the 200 mg SC weekly dose in SLE patients, highlighting key pharmacological differences relevant for clinicians. Methods Data from two Phase 1 studies in US American and Japanese healthy subjects were analyzed with a non-linear mixed effects modeling approach. The resulting SC population PK model and a previously developed IV population PK model were used to conduct simulation trials in a Phase 3 IV belimumab SLE patient population, comparing chronic exposure profiles and exposure ranges stratified by body weight tertiles for IV vs SC dosing. Results The PK of belimumab following SC administration was best described by a linear two-comment model. The estimates for clearance, steady-state volume of distribution, and bioavailability were 208 mL/day, 5250 mL, and 76%, respectively. After four weeks of SC dosing, simulated belimumab concentrations exceeded the steady-state trough concentrations of the IV dosing regimen. At steady state simulated serum profiles demonstrated comparable average belimumab concentrations (Cavg,ss) after IV and SC dosing. Simulated belimumab exposures demonstrated largely overlapping concentration ranges following 200 mg SC weekly and 10 mg/kg IV every four weeks dosing. Discussion The predicted Cavg,ss of belimumab in SLE patients was comparable following 200 mg SC weekly and 10 mg/kg IV every four weeks dosing. The simulated belimumab accumulation following SC weekly dosing indicated that administration of a loading dose was not required. Similar Cavg,ss ranges were predicted for fixed dose SC and weight-proportional IV regimens in the simulated SLE population, albeit with a reversed body-size-to-exposure relationship for the SC regimen. These findings provide rheumatologists with a better understanding of expected differences in belimumab exposure when comparing IV and SC dosing regimens.

Project description:BackgroundInfection is a major cause of mortality in patients with systemic lupus erythematosus (SLE). Therefore, minimizing the risk of infection is an important clinical goal to improve the long-term prognosis of SLE patients. Treatment with ≥7.5 mg prednisolone (PSL) or equivalent has been reported to increase the risk of infections. However, it remains unclear whether <7.5 mg PSL or equivalent dose affects the risk of infection in SLE patients. This study evaluated the association between the occurrence of infection in patients with SLE and low-dose glucocorticoid (GC) usage, especially <7.5 mg PSL or equivalent, to explore the GC dose that could reduce infection occurrence.MethodsThis prospective cohort study included patients from the Japanese multicenter registry of patients with SLE (defined as ≥4 American College of Rheumatology 1997 revised criteria) over 20 years of age. The PSL dose was categorized as PSL 0-2.5, 2.6-5.0, 5.1-7.5, and 7.6-15.0 mg. The primary outcome was infection requiring hospitalization. We conducted a multivariable analysis using time-dependent Cox regression analysis to assess the hazard ratio of infection occurrence compared with a dose of 0-2.5 mg PSL or equivalent in the other three PSL dose groups. Based on previous reports and clinical importance, the covariates selected were age, sex, and concurrent use of immunosuppressants with GC. In addition, two sensitivity analyses were conducted.ResultsThe mean age of the 509 SLE patients was 46.7 years; 89.0% were female, and 77.2% used multiple immunosuppressants concomitantly. During the observation period, 52 infections requiring hospitalization occurred. The incidence of infection with a PSL dose of 5.0-7.5 mg was significantly higher than that in the PSL 0-2.5 mg group (adjusted hazard ratio: 6.80, 95% confidence interval: 2.17-21.27). The results of the two sensitivity analyses were similar.ConclusionsOur results suggested that the use of 5.0-7.5 mg PSL or equivalent could pose an infection risk in SLE patients. This finding indicates that PSL dose should be reduced to as low as possible in SLE patients to avoid infection.

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High-dose cyclophosphamide versus monthly intravenous cyclophosphamide for systemic lupus erythematosus: a prospective randomized trial.

Publications

High-dose cyclophosphamide versus monthly intravenous cyclophosphamide for systemic lupus erythematosus: a prospective randomized trial.

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