Prednisone and azathioprine compared to prednisone plus low-dose azathioprine and cyclophosphamide in the treatment of diffuse lupus nephritis. Prospective multicentre trial on the short-term effects of plasma exchange versus cytotoxic drugs in steroid-resistant lupus nephritis. Azathioprine/methylprednisolone versus cyclophosphamide in proliferative lupus nephritis. A randomized controlled trial. Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis. Successful treatment of class V+IV lupus nephritis with multitarget therapy. Immunosuppressive therapy in lupus nephritis: the Euro-Lupus Nephritis Trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide. Controlled trial of pulse methylprednisolone versus two regimens of pulse cyclophosphamide in severe lupus nephritis. Comparison of high and low dose of cyclophosphamide in lupus nephritis patients: a long-term randomized controlled trial. Is combination rituximab with cyclophosphamide better than rituximab alone in the treatment of lupus nephritis? Intravenous immunoglobulin compared with cyclophosphamide for proliferative lupus nephritis. Cyclosporine A or intravenous cyclophosphamide for lupus nephritis: the Cyclofa-Lune study. Monthly plasmapheresis for systemic lupus erythematosus with diffuse proliferative glomerulonephritis: a pilot study. Pulse methylprednisolone therapy in diffuse proliferative lupus nephritis. Is mycophenolate mofetil superior to pulse intravenous cyclophosphamide for induction therapy of proliferative lupus nephritis in Egyptian patients? Methylprednisolone and cyclophosphamide, alone or in combination, in patients with lupus nephritis. A randomized, controlled trial. Randomized controlled trial of pulse intravenous cyclophosphamide versus mycophenolate mofetil in the induction therapy of proliferative lupus nephritis. A controlled trial of pulse cyclophosphamide versus pulse methylprednisolone in severe lupus nephritis. Comparative effects of plasmapheresis and intravenous cyclophosphamide on urinary podocyte excretion in patients with proliferative Lupus nephritis. Therapy of lupus nephritis. Controlled trial of prednisone and cytotoxic drugs. Comparison of azathioprine, prednisone, and heparin alone or combined in treating lupus nephritis. Azathioprine versus mycophenolate mofetil for long-term immunosuppression in lupus nephritis: results from the MAINTAIN Nephritis Trial. EULAR randomised controlled trial of pulse cyclophosphamide and methylprednisolone versus continuous cyclophosphamide and prednisolone followed by azathioprine and prednisolone in lupus nephritis. Randomized controlled trial of pulse/synchronization cyclophosphamide/apheresis for proliferative lupus nephritis. Azathioprine plus prednisone compared with prednisone alone in the treatment of systemic lupus erythematosus. Report of a prospective controlled trial in 24 patients. Ciclosporin plus steroids versus steroids alone in the treatment of lupus nephritis. Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. Hong Kong-Guangzhou Nephrology Study Group. Short-term outcomes of induction therapy with tacrolimus versus cyclophosphamide for active lupus nephritis: A multicenter randomized clinical trial. Treatment of diffuse proliferative lupus nephritis with prednisone and combined prednisone and cyclophosphamide. Therapy of lupus nephritis. A two-year prospective study. Clinical efficacy of cyclosporin a neoral in the treatment of paediatric lupus nephritis with heavy proteinuria. Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis. Misoprostol and Prednisone Treatment of Lupus Nephritis.
A 1-year double-blind crossover study comparing prednisone and azathioprine to prednisone plus low-dose azathioprine and cyclophosphamide was carried out in 14 patients with diffuse lupus nephritis. Low-dose triple therapy had no apparent therapeutic advantage over prednisone plus azathioprine. Cyclophosphamide-induced ovarian failure and hematuria were not avoided by its use in low dose. nan Until recently, intravenous cyclophosphamide pulses with oral corticosteroids were regarded standard therapy for proliferative lupus nephritis (LN). Azathioprine, a less toxic alternative, was never proven to be inferior. In the first Dutch lupus nephritis study (enrollment between 1995 and 2001), we randomized 87 proliferative LN patients to either cyclophosphamide pulses (750 mg/m(2), 13 pulses in 2 years) combined with oral prednisone (CY) or to azathioprine (2 mg/kg/day in 2 years) combined with intravenous pulses of methylprednisolone (3 x 3 pulses of 1000 mg) and oral prednisone (AZA). After a median follow-up of 5.7 years (interquartile range 4.1-7.2 years), doubling of serum creatinine was more frequent in the AZA group, although not statistically significant (relative risk (RR): 4.1, with 95% confidence interval (95% CI): 0.8-20.4). Relapses occurred more often in the AZA group (RR: 8.8, 95% CI: 1.5-31.8). Creatinine and proteinuria at last visit did not differ between the two treatment arms. Moreover, 88.4% of the patients in the AZA arm were still free of cyclophosphamide treatment. During the first 2 years, the frequency of remission was not different, but infections, especially herpes zoster virus infections (HZV) were more frequent in the AZA group. Parameters for ovarian function did not differ between the two groups. In conclusion, in this open-label randomized controlled trial, cyclophosphamide was superior to azathioprine with regard to renal relapses and HZV. At last follow-up, there were no differences in serum creatinine or proteinuria between the two groups. However, since our study lacked sufficient power, longer follow-up is needed to reveal putative differences. Since anecdotal series and small, prospective, controlled trials suggest that mycophenolate mofetil may be effective for treating lupus nephritis, larger trials are desirable.
                We conducted a 24-week randomized, open-label, noninferiority trial comparing oral mycophenolate mofetil (initial dose, 1000 mg per day, increased to 3000 mg per day) with monthly intravenous cyclophosphamide (0.5 g per square meter of body-surface area, increased to 1.0 g per square meter) as induction therapy for active lupus nephritis. A change to the alternative regimen was allowed at 12 weeks in patients who did not have an early response. The study protocol specified adjunctive care and the use and tapering of corticosteroids. The primary end point was complete remission at 24 weeks (normalization of abnormal renal measurements and maintenance of baseline normal measurements). A secondary end point was partial remission at 24 weeks.
                Of 140 patients recruited, 71 were randomly assigned to receive mycophenolate mofetil and 69 were randomly assigned to receive cyclophosphamide. At 12 weeks, 56 patients receiving mycophenolate mofetil and 42 receiving cyclophosphamide had satisfactory early responses. In the intention-to-treat analysis, 16 of the 71 patients (22.5 percent) receiving mycophenolate mofetil and 4 of the 69 patients receiving cyclophosphamide (5.8 percent) had complete remission, for an absolute difference of 16.7 percentage points (95 percent confidence interval, 5.6 to 27.9 percentage points; P=0.005), meeting the prespecified criteria for noninferiority and demonstrating the superiority of mycophenolate mofetil to cyclophosphamide. Partial remission occurred in 21 of the 71 patients (29.6 percent) and 17 of the 69 patients (24.6 percent), respectively (P=0.51). Three patients assigned to cyclophosphamide died, two during protocol therapy. Fewer severe infections and hospitalizations but more diarrhea occurred among those receiving mycophenolate.
                In this 24-week trial, mycophenolate mofetil was more effective than intravenous cyclophosphamide in inducing remission of lupus nephritis and had a more favorable safety profile.
                Copyright 2005 Massachusetts Medical Society. Treatment of class V+IV lupus nephritis remains unsatisfactory despite the progress made in the treatment of diffuse proliferative lupus nephritis. In this prospective study, 40 patients with class V+IV lupus nephritis were randomly assigned to induction therapy with mycophenolate mofetil, tacrolimus, and steroids (multitarget therapy) or intravenous cyclophosphamide (IVCY). Patients were treated for 6 mo unless complete remission was not achieved, in which case treatment was extended to 9 mo. An intention-to-treat analysis revealed a higher rate of complete remission with multitarget therapy at both 6 and 9 mo (50 and 65%, respectively) than with IVCY (5 and 15%, respectively). At 6 mo, eight (40%) patients in each group experienced partial remission, and at 9 mo, six (30%) patients receiving multitarget therapy and eight (40%) patients receiving IVCY experienced partial remission. There were no deaths during this study. Most adverse events were less frequent in the multitarget therapy group. Calcineurin inhibitor nephrotoxicity was not observed, but three patients developed new-onset hypertension with multitarget therapy. In conclusion, multitarget therapy is superior to IVCY for inducing complete remission of class V+IV lupus nephritis and is well tolerated. Glomerulonephritis is a severe manifestation of systemic lupus erythematosus (SLE) that is usually treated with an extended course of intravenous (IV) cyclophosphamide (CYC). Given the side effects of this regimen, we evaluated the efficacy and the toxicity of a course of low-dose IV CYC prescribed as a remission-inducing treatment, followed by azathioprine (AZA) as a remission-maintaining treatment.
                In this multicenter, prospective clinical trial (the Euro-Lupus Nephritis Trial [ELNT]), we randomly assigned 90 SLE patients with proliferative glomerulonephritis to a high-dose IV CYC regimen (6 monthly pulses and 2 quarterly pulses; doses increased according to the white blood cell count nadir) or a low-dose IV CYC regimen (6 fortnightly pulses at a fixed dose of 500 mg), each of which was followed by AZA. Intent-to-treat analyses were performed.
                Followup continued for a median of 41.3 months in the low-dose group and 41 months in the high-dose group. Sixteen percent of those in the low-dose group and 20% of those in the high-dose group experienced treatment failure (not statistically significant by Kaplan-Meier analysis). Levels of serum creatinine, albumin, C3, 24-hour urinary protein, and the disease activity scores significantly improved in both groups during the first year of followup. Renal remission was achieved in 71% of the low-dose group and 54% of the high-dose group (not statistically significant). Renal flares were noted in 27% of the low-dose group and 29% of the high-dose group. Although episodes of severe infection were more than twice as frequent in the high-dose group, the difference was not statistically significant.
                The data from the ELNT indicate that in European SLE patients with proliferative lupus nephritis, a remission-inducing regimen of low-dose IV CYC (cumulative dose 3 gm) followed by AZA achieves clinical results comparable to those obtained with a high-dose regimen. Pulse cyclophosphamide is more effective than prednisone alone in preventing renal failure in lupus nephritis. We undertook a randomised, controlled trial to find out whether pulse methylprednisolone could equal pulse cyclophosphamide in preserving renal function in patients with lupus nephritis, and whether there was a difference between long and short courses of pulse cyclophosphamide in preventing exacerbations. 65 patients (60 female, 5 male; median [range] age 29 [10-48] years) with severe lupus nephritis were assigned randomly to monthly pulse methylprednisolone for 6 months (25 patients), monthly pulse cyclophosphamide for 6 months (20), or monthly cyclophosphamide for 6 months followed by quarterly pulse cyclophosphamide for 2 additional years (20). Patients treated with pulse methylprednisolone had a higher probability of doubling serum creatinine than those treated with long-course cyclophosphamide (p less than 0.04). Risk of doubling creatinine was not significantly different between short and long course cyclophosphamide. However, patients treated with short-course cyclophosphamide had a higher probability of exacerbations than those treated with long-course cyclophosphamide (p less than 0.01). An extended course of pulse cyclophosphamide is more effective than 6 months of pulse methylprednisolone in preserving renal function in patients with severe lupus nephritis. Addition of a quarterly maintenance regimen to monthly pulse cyclophosphamide reduces the rate of exacerbations. To evaluate the outcome of low doses of cyclophosphamide (Cyclo) therapy in lupus nephritis (LN) patients, we studied 117 biopsy-proven, de novo LN WHO class IV patients double-blinded and randomized in December 1997 to receive Cyclo in different doses; Group I (n=73) received Cyclo 10 mg/kg monthly for six months then every two months for 12 months. Group II (n=44) received Cyclo 5 mg/kg monthly for six months then every two months for 36 months. The patients were followed-up till January 2007. Six months post-induction values for creatinine clearance were significantly higher in Group I (67.7 ± 28.6 mL/min) compared with Group II (55.1 ± 30.1 mL/min), P = 0.026. Serum C4 and ANA were not significantly different between the groups (P > 0.05). At the mean follow-up of 6.77 ± 3.3 years, the mean creatinine clearance was 44.74 ± 31.7 mL/min in Group I vs. 49.3 ± 38.8 in Group II. Urinary protein was 1.65 ± 1.8 g/dL in Group I vs. 1.02 ± 1.01 in Group II (P = 0.03). The survival curve showed that kidney survival overtime was comparable in both groups (P = 0.2). Complete remission was observed in 25 (34.2%) patients in Group I vs. 11 (25%) in Group II (P = 0.288), while partial remission was similar in both groups; 43 (58.9%) patients in Group I vs. 26 (59%) patients in Group II. End-stage renal disease was observed in 10 (13.7%) patients in Group I vs. 9 (20.4%) patients in Group II (P = 0.359). Side-effects were more frequent in Group I patients than in Group II patients; gonadal toxicity and malignancy were lower in Group II patients (P = 0.0000). Moreover, different infections occurred in 23 (31.3%) patients vs. six (13.6%), digital infarcts occurred in 1.35% vs. 0%, diabetes in 4.1% vs. 2.27%, and vasculitis in 4.1% vs. 2.27% in Group I vs. Group II, respectively. Sustained amenorrhea without pregnancy was observed in both groups; however, significantly more in Group I patients, P ≤ 0.05. We conclude that low-dose Cyclo therapy is sufficiently effective for WHO class IV LN patients with lower side-effects compared with standard dose. To assess if combination rituximab and cyclophosphamide is more effective than rituximab monotherapy as an induction therapy for proliferative lupus nephritis.
                A randomized open-label pilot study in which 9 patients received rituximab alone and 10 patients received two doses rituximab + intravenous cyclophosphamide. The clinical, laboratory and renal histological changes were assessed after 48 weeks of treatment.
                At week 48, four patients had a complete response, 11 patients achieved partial response, 2 patients remained the same or stable and 2 worsened. There were no statistical differences in the proportion of patients with complete or partial response between the two groups. None of the variables was an independent predictor of response at week 48. Nine patients had significant improvement in activity indices in renal biopsies, but there were no significant differences between the two groups. Overall, 18 out of 19 patients were found to have effective B-cell depletion. The median duration of complete B-cell depletion in all patients was 22 weeks. There were no statistically significant differences in the proportion of patients with complete depletion at weeks 4, 8, 24 and 48 between the two groups except at week 2.
                Rituximab monotherapy appears to be effective as induction therapy in lupus nephritis. The addition of cyclophosphamide offers no additional improvement in clinical, laboratory and renal histological assessment or the duration of B-cell depletion at 48 weeks. Large-scale studies with longer duration are needed to confirm these findings. Among 14 randomised patients with proliferative lupus nephritis, monthly intravenous immunoglobulin maintained remission over 18 months, similar to standard intravenous cyclophosphamide treatment. Pulsed immunoglobulin may be a useful alternative therapy in lupus nephritis. Intravenous cyclophosphamide is considered to be the standard of care for the treatment of proliferative lupus nephritis. However, its use is limited by potentially severe toxic effects. Cyclosporine A has been suggested to be an efficient and safe treatment alternative to cyclophosphamide. Forty patients with clinically active proliferative lupus nephritis were randomly assigned to one of two sequential induction and maintenance treatment regimens based either on cyclophosphamide or Cyclosporine A. The primary outcomes were remission (defined as normal urinary sediment, proteinuria <0.3 g/24 h, and stable s-creatinine) and response to therapy (defined as stable s-creatinine, 50% reduction in proteinuria, and either normalization of urinary sediment or significant improvement in C3) at the end of induction and maintenance phase. Secondary outcomes were incidence of adverse events, and relapse-free survival. At the end of the induction phase, 24% of the 21 patients treated by cyclophosphamide achieved remission, and 52% achieved response, as compared with 26% and 43%, respectively of the 19 patients treated by the Cyclosporine A. At the end of the maintenance phase, 14% of patients in cyclophosphamide group, and 37% in Cyclosporine A group had remission, and 38% and 58% respectively response. Treatment with Cyclosporine A was associated with transient increase in blood pressure and reversible decrease in glomerular filtration rate. There was no significant difference in median relapse-free survival. In conclusion, Cyclosporine A was as effective as cyclophosphamide in the trial of sequential induction and maintenance treatment in patients with proliferative lupus nephritis and preserved renal function.(ClinicalTrials.gov identifier: NCT00976300) Twelve patients with systemic lupus erythematosus and biopsy-proved diffuse proliferative glomerulonephritis were randomly allocated to a control group (to continue receiving conventional therapy only) or to a plasmapheresis group (to receive conventional therapy along with one 4-I plasma exchange a month). The six patients treated with plasmapheresis had better preservation of renal function, reduced disease activity, fewer admissions to hospital and less need for steroid and immunosuppressive therapy than the six control patients. The patients treated with plasmapheresis also showed evidence of reduced immunologic activity and had no side effects attributable to the plasma exchange. These results suggest that monthly plasma exchange should be assessed in a controlled randomized trial as a possible therapeutic adjunct in patients with systemic lupus erythematosus and diffuse proliferative glomerulonephritis. The prognosis of patients with diffuse proliferative lupus nephritis is generally poor, and the majority of patients with this lesion develop progressive deterioration in renal function. Intravenous "pulses" of methylprednisolone have been advocated for the treatment of severe nephritis. In this study, 15 patients with biopsy-proven diffuse proliferative lupus nephritis were treated with oral high-dose prednisone therapy, initially 2 mg/kg/day. They were compared with seven patients with similar renal pathology treated with six daily pulses of methylprednisolone (30 mg/kg/day, not to exceed 1 gm/day), followed by prednisone orally, initially 2 mg/kg/day. There were no deaths in either group and the side effects of therapy were similar in the two groups. Pretreatment GFRs for the pulse and high-dose groups were similar. There was a more rapid improvement in GFR following pulse therapy, but the long-term effects on renal function for the two modes of therapy were the same. Recent studies have suggested that mycophenolate mofetil (MMF) may offer advantages over intravenous cyclophosphamide (IVC) for the treatment of lupus nephritis. The aim of this study was to evaluate the efficacy of MMF compared with IVC in the induction therapy of proliferative lupus nephritis.
                We randomly assigned 47 patients with newly diagnosed active proliferative lupus nephritis class III or IV to open-label oral MMF 2 g/day for 6 months or intravenous cyclophosphamide 0.5-1 g/m(2) monthly for 6 months in addition to corticosteroids.
                In the intention-to-treat analysis, 14 of the 24 patients (58.33%) receiving MMF and 12 of the 23 patients receiving cyclophosphamide (52.17%) had remission (P = 0.48); complete remission occurred in 6 of the 24 patients (25%) and 5 of the 23 patients (21.74%), respectively (P = 0.53). Improvements in packed cell volume, the erythrocyte sedimentation rate, anti-double-stranded DNA antibodies titer (anti-dsDNA), serum complement, proteinuria, urinary activity, renal function, serum soluble interleukin-2 receptor alpha concentration and the systemic lupus activity measure score were similar in both groups. Two patients assigned to MMF and another patient assigned to IVC developed end-stage renal failure with commencement of dialysis. Adverse events were similar. Major infections occurred in two patients in each group. There was no difference in gastrointestinal side effects, but more diarrhea occurred in those receiving MMF.
                In this 24-week trial, MMF or IVC combined with corticosteroids demonstrated equal efficacy in inducing remission of proliferative lupus nephritis. Uncertainty exists about the efficacy and toxicity of bolus therapy with methylprednisolone or of the combination of methylprednisolone and cyclophosphamide in the treatment of lupus nephritis.
                To determine 1) whether intensive bolus therapy with methylprednisolone is an adequate substitute for bolus therapy with cyclophosphamide and 2) whether the combination of methylprednisolone and cyclophosphamide is superior to bolus therapy with methylprednisolone or cyclophosphamide alone.
                Randomized, controlled trial with at least 5 years of follow-up.
                Government referral-based research hospital.
                82 patients with lupus nephritis who had 10 or more erythrocytes per high-power field, cellular casts, proteinuria (> 1 g of protein per day), and a renal biopsy specimen that showed proliferative nephritis.
                Bolus therapy with methylprednisolone (1 g/m2 body surface area), given monthly for at least 1 year; bolus therapy with cyclophosphamide (0.5 to 1.0 g/m2 body surface area), given monthly for 6 months and then quarterly; or bolus therapy with both methylprednisolone and cyclophosphamide.
                1) Renal remission (defined as < 10 dysmorphic erythrocytes per high-power field, the absence of cellular casts, and excretion of < 1 g of protein per day without doubling of the serum creatinine level), 2) prevention of doubling of the serum creatinine level, and 3) prevention of renal failure requiring dialysis.
                Renal remission occurred in 17 of 20 patients in the combination therapy group (85%), 13 of 21 patients in the cyclophosphamide group (62%), and 7 of 24 patients in the methylprednisolone group (29%) (P < 0.001). Twenty-eight patients (43%) did not achieve renal remission. By life-table analysis, the likelihood of remission during the study period was greater in the combination therapy group than in the methylprednisolone group (P = 0.028). Combination therapy and cyclophosphamide therapy were not statistically different. Adverse events were amenorrhea (seen in 41% of the cyclophosphamide group, 43% of the combination therapy group, and 7.4% of the methylprednisolone group), cervical dysplasia (seen in 11% of the cyclophosphamide group. 7.1% of the combination therapy group, and 0% of the methylprednisolone group), avascular necrosis (seen in 11% of the cyclophosphamide group, 18% of the combination therapy group, and 22% of the methylprednisolone group), herpes zoster (seen in 15% of the cyclophosphamide group, 21% of the combination therapy group, and 3.7% of the methylprednisolone group) and at least one infection (seen in 26% of the cyclophosphamide group. 32% of the combination therapy group, and 7.4% of the methylprednisolone group).
                Monthly bolus therapy with methylprednisolone was less effective than monthly bolus therapy with cyclophosphamide. A trend toward greater efficacy with combination therapy was seen. The aim of the present study was to evaluate the efficacy of mycophenolate mofetil in the induction therapy of proliferative lupus nephritis.
                Forty-four patients from eight centres with newly diagnosed lupus nephritis World Health Organization class III or IV were randomly assigned to either mycophenolate mofetil (MMF) 2 g/day for 6 months or intravenous cyclophosphamide (IVC) 0.75-1 g/m(2) monthly for 6 months in addition to corticosteroids.
                Remission occurred in 13 out of 25 patients (52%) in the IVC group and 11 out of 19 patients (58%) in the MMF group (P = 0.70). There were 12% in the IVC group and 26% in the MMF group that achieved complete remission (P = 0.22). Improvements in haemoglobin, the erythrocyte sedimentation rate, serum albumin, serum complement, proteinuria, urinary activity, renal function and the Systemic Lupus Erythematosus Disease Activity Index score were similar in both groups. Twenty-four follow-up renal biopsies at the end of therapy showed a significant reduction in the activity score in both groups. The chronicity index increased in both groups but was only significant in the IVC group. Adverse events were similar. Major infections occurred in three patients in each group. There was no difference in gastrointestinal side-effects.
                MMF in combination with corticosteroids is an effective induction therapy for moderately severe proliferative lupus nephritis. We carried out a prospective randomized trial comparing pulse cyclophosphamide and pulse methylprednisolone in 29 patients with severe lupus nephritis in activity. Patients were assigned to one of two regimens: monthly pulse cyclophosphamide (0.5-1.0 g/m2 body surface area) for 4 months, followed by bimonthly doses for 4 months and quarterly doses for 6 months (14 patients) or pulse methylprednisolone (10-20 mg/kg weight) initially for 3 consecutive days and thereafter in the same intervals as the alternative regimen (15 patients). The mean follow-up was 15 months. Two patients in the cyclophosphamide group and three in the methylprednisolone group died. Renal failure (doubling of serum creatinine) developed in four patients in the cyclophosphamide group compared with five patients in the methylprednisolone group. Cumulative probability of not doubling serum creatinine was similar for cyclophosphamide and methylprednisolone groups (0.66 vs 0.69, respectively, P > 0.20, after 18 months). Cumulative probability of survival without renal failure was also not significantly different (0.61 and 0.63, respectively, P > 0.20, after 18 months). These results suggest that pulse cyclophosphamide is as effective as pulse methylprednisolone in preserving renal function in patients with severe lupus nephritis. Intravenous cyclophosphamide (IVC) in combination with steroids is standard therapy for Lupus nephritis. Reduction of autoantibodies and circulating immune complexes can be used in the treatment of autoimmune diseases. The aim of the present study was to compare the effects of IVC pulse therapy and double-filtration plasmapheresis (DFPP) on proteinuria and urinary excretion of podocytes in adult patients with diffuse proliferative Lupus nephritis (DPLN). Twenty patients were randomly assigned to two groups. Group A (n = 10) was treated with IVC (0.75 - 1.0 g/m2 body surface area) pulse therapy, given as boluses once a month for 6 consecutive months, combined with oral corticosteroid (up to 1 mg/kg/day) administration. Group B (n = 10) was treated with a combination of DFPP (performed 1-2 times weekly) and corticosteroid (up to I mg/kg/ day). The total average number of treatments was 8.4 and the therapeutic efficacies were evaluated after 6 months. Twenty healthy individuals participated as a control group. Urinary podocytes were examined by immunofluorescence with monoclonal antibodies against podocalyxin. Both Group A and Group B reduced proteinuria (p < 0.001) as well as the number of urinary podocytes (p < 0.001). Differences between the 2 treatment outcomes were not statistically significant. Cyclophosphamide pulse therapy and DFPP may be similarly effective in the treatment of podocyte injury in patients with DPLN. We evaluated renal function in 107 patients with active lupus nephritis who participated in long-term randomized therapeutic trials (median follow-up, seven years). For patients taking oral prednisone alone, the probability of renal failure began to increase substantially after five years of observation. Renal function was better preserved in patients who received various cytotoxic-drug therapies, but the difference was statistically significant only for intravenous cyclophosphamide plus low-dose prednisone as compared with high-dose prednisone alone (P = 0.027). The advantage of treatment with intravenous cyclophosphamide over oral prednisone alone was particularly apparent in the high-risk subgroup of patients who had chronic histologic changes on renal biopsy at study entry. Patients treated with intravenous cyclophosphamide have not experienced hemorrhagic cystitis, cancer, or a disproportionate number of major infections. We conclude that, as compared with high-dose oral prednisone alone, treatment of lupus glomerulonephritis with intravenous cyclophosphamide reduces the risk of end-stage renal failure with few serious complications. nan Long-term immunosuppressive treatment does not efficiently prevent relapses of lupus nephritis (LN). This investigator-initiated randomised trial tested whether mycophenolate mofetil (MMF) was superior to azathioprine (AZA) as maintenance treatment.
                A total of 105 patients with lupus with proliferative LN were included. All received three daily intravenous pulses of 750 mg methylprednisolone, followed by oral glucocorticoids and six fortnightly cyclophosphamide intravenous pulses of 500 mg. Based on randomisation performed at baseline, AZA (target dose: 2 mg/kg/day) or MMF (target dose: 2 g/day) was given at week 12. Analyses were by intent to treat. Time to renal flare was the primary end point. Mean (SD) follow-up of the intent-to-treat population was 48 (14) months.
                The baseline clinical, biological and pathological characteristics of patients allocated to AZA or MMF did not differ. Renal flares were observed in 13 (25%) AZA-treated and 10 (19%) MMF-treated patients. Time to renal flare, to severe systemic flare, to benign flare and to renal remission did not statistically differ. Over a 3-year period, 24 h proteinuria, serum creatinine, serum albumin, serum C3, haemoglobin and global disease activity scores improved similarly in both groups. Doubling of serum creatinine occurred in four AZA-treated and three MMF-treated patients. Adverse events did not differ between the groups except for haematological cytopenias, which were statistically more frequent in the AZA group (p=0.03) but led only one patient to drop out.
                Fewer renal flares were observed in patients receiving MMF but the difference did not reach statistical significance. To compare the efficacy and side effects of intermittent pulse cyclophosphamide plus methylprednisolone with continuous oral cyclophosphamide plus prednisolone, followed by azathioprine, in patients with proliferative glomerulonephritis caused by systemic lupus erythematosus (SLE).
                A multicentre randomised controlled trial was conducted between June 1992 and May 1996 involving eight European centres. All patients satisfied the American College of Rheumatology criteria for SLE and had biopsy proven proliferative lupus nephritis. All received corticosteroids in addition to cytotoxic drugs, as defined in the protocol, for two years. The trial was terminated after four years as recruitment was disappointing.
                32 SLE patients with lupus nephritis were recruited: 16 were randomised to intermittent pulse cyclophosphamide and 16 to continuous cyclophosphamide plus azathioprine. Mean duration of follow up was 3.7 years in the continuous group (range 0 to 5.6) and 3.3 years in the pulse group (range 0.25 to 6). Three patients were excluded from the pulse therapy group as they were later found to have pure mesangial glomerulonephritis. Two patients in the continuous therapy group developed end stage renal failure requiring dialysis, but none in the intermittent pulse therapy (p = 0.488; NS). There were similar numbers of side effects and withdrawals from treatment in both groups. There were three deaths: two in the intermittent pulse therapy group and one in the continuous therapy group.
                There was no statistically significant difference in efficacy and side effects between the two regimens. Infectious complications occurred commonly, so careful monitoring is required during treatment. To assess the efficacy of pulse/synchronization cyclophosphamide/apheresis in patients with proliferative lupus nephritis.
                Eighteen patients with Class III or IV renal biopsies and chronicity indices <6 were prospectively randomized to receive 6 courses of parenteral cyclophosphamide over 8 months along with prednisone. Nine of these patients also received 3 daily plasmaphereses prior to each of the 6 courses of cyclophosphamide. Assessments compiled at 6 and 24 months included serum creatinine, albumin, anti DNA, 24-hour urine protein, and C3 complement along with SLAM scores.
                Two out of nine patients in each group evolved end stage renal disease and 3/9 patients in each group went into a renal remission at 24 months. Serum albumin, C3 complement, and SLAM scores improved in both groups, and anti-DNA improved in the pulse/synchronization patients (P < 0.025). No intergroup comparisons were significant.
                The addition of pulse/synchronization apheresis to cyclophosphamide therapy does not improve the course of patients with proliferative lupus nephritis. A prospective, randomized drug trial compared prednisone (60 mg per day initially) to azathioprine (3 to 4 mg/kg of body weight - day initially) plus prednisone in 24 patients with life-threatening systemic lupus erythematosus. Each group contained patients matched for age, sex, disease duration, previous therapy, and clinical and laboratory features of lupus erythematosus. During a mean follow-up period of 18 to 24 months, there were no significant differences between the two groups in number of deaths, renal or extrarenal manifestations of disease, serum complement levels, DNA antibodies, antinuclear antibody titers, lupus erythematosus cells, or Coombs' antibodies. There was no convincing evidence of a steroid-sparing effect of azathioprine. Side effects attributable to steroids were equally common in both groups; infections were not increased in the combination therapy group. Azathioprine was hepatotoxic in doses of 200 mg daily or more. Azathioprine was not a useful adjunct to corticosterolds in short-term therapy of a small number of patients with severe systemic lupus. nan The combination of cyclophosphamide and prednisolone is effective for the treatment of severe lupus nephritis but has serious adverse effects. Whether mycophenolate mofetil can be substituted for cyclophosphamide is not known.
                In 42 patients with diffuse proliferative lupus nephritis we compared the efficacy and side effects of a regimen of prednisolone and mycophenolate mofetil given for 12 months with those of a regimen of prednisolone and cyclophosphamide given for 6 months, followed by prednisolone and azathioprine for 6 months. Complete remission was defined as a value for urinary protein excretion that was less than 0.3 g per 24 hours, with normal urinary sediment, a normal serum albumin concentration, and values for serum creatinine and creatinine clearance that were no more than 15 percent above the base-line values. Partial remission was defined as a value for urinary protein excretion that was between 0.3 and 2.9 g per 24 hours, with a serum albumin concentration of at least 30 g per liter.
                Eighty-one percent of the 21 patients treated with mycophenolate mofetil and prednisolone (group 1) had a complete remission, and 14 percent had a partial remission, as compared with 76 percent and 14 percent, respectively, of the 21 patients treated with cyclophosphamide and prednisolone followed by azathioprine and prednisolone (group 2). The improvements in the degree of proteinuria and the serum albumin and creatinine concentrations were similar in the two groups. One patient in each group discontinued treatment because of side effects. Infections were noted in 19 percent of the patients in group 1 and in 33 percent of those in group 2 (P = 0.29). Other adverse effects occurred only in group 2; they included amenorrhea (in 23 percent of the patients), hair loss (19 percent), leukopenia (10 percent), and death (10 percent). The rates of relapse were 15 percent and 11 percent, respectively.
                For the treatment of diffuse proliferative lupus nephritis, the combination of mycophenolate mofetil and prednisolone is as effective as a regimen of cyclophosphamide and prednisolone followed by azathioprine and prednisolone but is less toxic. Intravenous cyclophosphamide with prednisone is an effective treatment for lupus nephritis, but with significant toxicities. We compared the efficacy and safety of tacrolimus versus intravenous cyclophosphamide as induction therapy.
                Multicenter noninferiority randomized controlled trial.
                81 patients with biopsy-proven lupus nephritis from 9 nephrology centers in China from 2006-2008.
                Prednisone and either tacrolimus (n = 42) or intravenous cyclophosphamide (n = 39) for 6 months. Tacrolimus was started at 0.05 mg/kg/d and titrated to achieve a trough blood concentration of 5-10 ng/mL. Intravenous cyclophosphamide was initiated at 750 mg/m² of body surface area, then adjusted to 500-1,000 mg/m² every 4 weeks for a total of 6 pulse treatments.
                The primary outcome was complete remission (proteinuria with protein excretion <0.3 g/24 h, serum albumin ≥3.5 g/dL, normal urinary sediment, and normal or stable serum creatinine level) at 6 months. Response (complete or partial remission), clinical parameters, and adverse effects were secondary end points.
                After the 6-month induction therapy, the tacrolimus group achieved higher cumulative probabilities of complete remission and response (52.4% vs 38.5% and 90.5% vs 82.1%, respectively) than the intravenous cyclophosphamide group, but differences were not statistically significant (log-rank test, P = 0.2 and P = 0.7, respectively). Proteinuria [corrected] was significantly decreased in tacrolimus- versus intravenous cyclophosphamide-treated patients after the first month of treatment, even with adjustment for baseline proteinuria (protein excretion, 1.76 vs 2.40 g/d; P = 0.02 for the log-transformed analysis). [corrected] After treatment, serum creatinine levels and estimated glomerular filtration rates were not significantly different between treatment groups. Adverse effects, such as leukopenia and gastrointestinal symptoms, were less frequent in the tacrolimus group.
                Nonblinded, small sample size, and short duration of follow-up.
                In conjunction with prednisone, induction therapy with tacrolimus is at least as efficacious as intravenous cyclophosphamide and prednisone in producing complete remission of lupus nephritis and has a more favorable safety profile.
                Copyright Â© 2011 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved. To evaluate the effectiveness of cyclophosphamide in the treatment of lupus nephritis, we designed a prospective study of patients with diffuse proliferative lupus nephritis. Twenty-six patients received prednisone (average dose, 40 mg per day) and 24 combined prednisone (average dose, 29 mg per day) and cyclophosphamide (average dose, 107 mg per day) for six months. Thereafter, all patients received maintenance doses of prednisone. Most of the patients improved (84 per cent) after six months of initial treatment with either program. Early progression of disease, ending mainly in end-stage renal disease, was equally frequent in the two treatment groups in patients with already advanced disease. In a four-year follow-up study there was a higher incidence (P approximately 0.04) and average rate (P approximately 0.02) of clinical recurrence of nephritis in the group initially given only steroid than in the group initially given both drugs. However, the proportion of patients alive after four years with stable or improved renal function was similar in the two treatment groups. The aim of our study was to compare the efficacy of 3 different therapeutic protocols in the treatment of patients with WHO class IV lupus nephritis and normal renal function. We carried out a randomized prospective trial. The treatment programs consisted of a standard therapy regimen alone (protocol A), plus plasmapheresis (protocol B) or pulse methylprednisolone (protocol C), followed by a slow (protocols A and B) or fast (protocol C) prednisone tapering schedule. Statistical analysis was performed, using univariate survival analysis according to Kaplan Meier and Breslow's test to compare survival curves. Eighteen patients entered the study: 6 protocol A, 5 protocol B and 7 protocol C. No patients developed renal insufficiency. Moreover, no statistical differences in the probability of inducing partial or complete disease remission and in reducing 24-hour urinary protein excretion to < or = 2 g per day were observed among the groups. Protocols A and B were more effective in comparison with protocol C in decreasing 24-hour urinary protein excretion to < or = 0.5 g and < or = 0.2 g per day. In conclusion, a slow prednisone tapering schedule is more effective in reducing 24-hour urinary protein excretion to < or = 0.5 and < or = 0.2 g per day as compared with a fast prednisone tapering schedule, even if it is preceded by methylprednisolone pulse therapy. Cyclosporin A (CsA) was introduced in recent years for the treatment of lupus nephritis in patients with steroid resistance or in those with severe corticosteroid toxicity. Our previous study on paediatric patients showed that Neoral (a new microemulsion formulation) had better bioavailability than CsA capsules. To evaluate the clinical efficacy of Neoral in children with lupus nephritis compared with conventional therapy, we performed an open randomized study on 40 children, ranging from 9 to 14 yr old, with class III-V lupus nephritis and heavy proteinuria. They were randomly assigned to either Neoral (5 mg/kg/day), administered q.12.h, or prednisolone (2 mg/kg/day) plus cyclophosphamide (2 mg/kg/day) for 1 yr. Both groups showed a significant decrease in proteinuria (Neoral: 4.62 +/- 1.93 to 0.35 +/- 0.29 g/day, P < 0.05; prednisolone plus cyclophosphamide: 4.52 +/- 1.86 to 0.62 +/- 0.21 g/day, P < 0.01). The CH50 haemolytic assay titre decreased after 1 yr of Neoral treatment (26.5 +/- 0.9 to 21.4 +/- 2.2 U/ml, P < 0.05). Serum C3 and anti-double-stranded (ds) DNA antibody levels also fell with Neoral (C3: 86.2 +/- 6.8 to 76.3 +/- 4.5 mg/dl; anti-ds DNA antibodies: 14.1 +/- 3.2 to 8.2 +/- 1.4 IU/ml, P < 0.05). The Neoral group had a significant increase in growth rate over the prednisolone plus cyclophosphamide group (8.2 +/- 1.1 cm/yr vs 2.7 +/- 0.6 cm/yr, P < 0.01) with improvement of growth status. During the study period, patients tolerated Neoral well with no significant changes in renal function, liver function or lipid profile. Our study implies that Neoral appears to be effective in suppressing proteinuria. Neoral should be regarded as being adjunctive therapy, perhaps with a steroid-sparing effect, in paediatric lupus nephritis. However, its long-term use awaits further studies. Recent studies have suggested that mycophenolate mofetil (MMF) may offer advantages over intravenous cyclophosphamide (IVC) for the treatment of lupus nephritis, but these therapies have not been compared in an international randomized, controlled trial. Here, we report the comparison of MMF and IVC as induction treatment for active lupus nephritis in a multinational, two-phase (induction and maintenance) study. We randomly assigned 370 patients with classes III through V lupus nephritis to open-label MMF (target dosage 3 g/d) or IVC (0.5 to 1.0 g/m(2) in monthly pulses) in a 24-wk induction study. Both groups received prednisone, tapered from a maximum starting dosage of 60 mg/d. The primary end point was a prespecified decrease in urine protein/creatinine ratio and stabilization or improvement in serum creatinine. Secondary end points included complete renal remission, systemic disease activity and damage, and safety. Overall, we did not detect a significantly different response rate between the two groups: 104 (56.2%) of 185 patients responded to MMF compared with 98 (53.0%) of 185 to IVC. Secondary end points were also similar between treatment groups. There were nine deaths in the MMF group and five in the IVC group. We did not detect significant differences between the MMF and IVC groups with regard to rates of adverse events, serious adverse events, or infections. Although most patients in both treatment groups experienced clinical improvement, the study did not meet its primary objective of showing that MMF was superior to IVC as induction treatment for lupus nephritis. Fourteen patients were enrolled in a placebo-controlled double-blind randomized trial of 8 weeks of treatment for active lupus nephritis. Seven patients received prednisone at a dose of 1 mg kg(minus sign1) day(minus sign1) plus misoprostol at a dose of 200 &mgr;g P.O. Q.I.D.; 7 patients received prednisone plus placebo. The patients included 12 females, 2 males; 3 African-Americans, 3 Asians, 5 Hispanics, and 3 Caucasians. There were no serious side effects associated with prednisone or misoprostol treatment during the 8-week study period. Laboratory measures obtained at baseline, 4, 8, and 12 weeks included complete blood count (CBC), ESR, C reactive protein (CRP), serum creatinine, creatinine clearance, 24-h urine protein excretion, C3, C4, and anti-double stranded DNA (anti-dsDNA). Statistical analysis was conducted assessing change in measures over time in the entire study group by paired t-tests. The effect of treatment on change over time was examined by analysis of covariance. Log transformation of the variables was performed prior to statistical analysis. For the entire study group, the mean levels of ESR, CRP, 24-h protein excretion, C3, C4, and anti-dsDNA were improved at 4, 8, and 12 weeks. The mean ESR at baseline was 70 plus minus 8 compared to 42 plus minus 8 at 12 weeks (p < 0.01). The mean CRP at baseline was 0.6 plus minus 0.2 compared to 0.2 plus minus 0.1 at 12 weeks (p < 0.01). The 24-h protein excretion was 4367 plus minus 769 mg at baseline compared to 2512 plus minus 709 mg at 12 weeks (p = 0.02). The mean C3 at baseline was 40 plus minus 4 mg dl(minus sign1) compared to 60 plus minus 4 mg dl(minus sign1) at 12 weeks (p < 0.01). The mean C4 at baseline was 14 plus minus 1 mg dl(minus sign1) compared to 23 plus minus 2 mg dl(minus sign1) at 12 weeks (p < 0.01). The mean anti-dsDNA at baseline was 4268 plus minus 1780 compared to 316 plus minus 111 at 12 weeks (p < 0.001). The baseline serum creatinine (1.12 plus minus.15 mg dl(minus sign1)) and creatinine clearance (82 plus minus 15 ml min(minus sign1)) were not significantly changed at 12 weeks (1.10 plus minus 0.2 mg dl(minus sign1) and 80 plus minus 17 ml min(minus sign1), respectively). Comparing the misoprostol treatment group to the placebo group, there were no statistically significant differences for ESR, CRP, creatinine, creatinine clearance, 24-h protein excretion, C3, C4, or anti-dsDNA at any time points. However, comparing the misoprostol treatment group at 4 weeks to the placebo group, a more rapid decrease in anti-dsDNA (reduction of 3297 plus minus 2374) was observed in the misoprostol treatment group versus 304 plus minus 409 in the placebo group), as well as lower mean anti-dsDNA levels (464 plus minus 140) in the misoprostol treatment group versus 4118 plus minus 3834 in the placebo group). Also, the C3 and C4 levels at 12 weeks in the misoprostol treatment group (67 plus minus 5 and 27 plus minus 3 mg dl(minus sign1), respectively) were greater than levels in the placebo group (52 plus minus 4 and 19 plus minus 3 mg dl(minus sign1), respectively). The data demonstrate that oral prednisone is effective in reducing proteinuria and improving the biological markers of disease activity (i.e., ESR, CRP, C3, C4, and anti-dsDNA) following short-term treatment of active lupus nephritis. Additionally, the more rapid change in anti-dsDNA levels and superior normalization of complement levels in the treatment group, although not statistically significant, are consistent with a biologic effect of misoprostol on lymphocyte function and the production of a pathogenic autoantibodies.
MMF is as effective as cyclophosphamide in inducing remission in lupus nephritis, but is safer with a lower risk of ovarian failure. MMF is more effective than azathioprine in maintenance therapy for preventing relapse with no increase in clinically important side effects. Adequately powered trials with long term follow-up are required to more accurately define the risks and eventual harms of specific treatment regimens.