Controlled trial of pulse methylprednisolone versus two regimens of pulse CYC in severe lupus nephritis

Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland 20892.
The Lancet (Impact Factor: 45.22). 10/1992; 340(8822):741-5. DOI: 10.1016/0140-6736(92)92292-N
Source: PubMed


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.

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    • "The eligibility criteria included treatment-refractory and active disease, as well as a Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score of more than 8 or at least one British Isles Lupus Assessment Group (BILAG) grade A or at least two BILAG grade B manifestations. Refractory to treatment was defined as lack of response to treatment with monthly intravenous pulse CYC (500 to 750 mg/m2) for at least 6 months [22,23], or lack of response to treatment with oral MMF (≥ 1,000 mg/day) [24] or leflunomide (20 mg/day) for at least 3 months, or continued daily doses of at least 20 mg of prednisone (Pred) or its equivalent. Patients were excluded from the study if they had uncontrolled infection, New York Heart Association functional classification III or IV, failure of one of the vital organs or were pregnant or lactating. "
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    ABSTRACT: Umbilical cord (UC)-derived mesenchymal stem cells (MSCs) have shown a good safety profile and therapeutic effect in severe and refractory systemic lupus erythematosus (SLE) in our single-center pilot study. The present multicenter clinical trial was undertaken to assess the safety and efficacy of allogenic UC MSC transplantation (MSCT) in active and refractory SLE patients. Forty patients with active SLE were enrolled from 4 clinical centers in China. Allogenic UC MSCs were infused intravenously on days 0 and 7. Primary endpoints were safety profiles. Second endpoints included major clinical response (MCR), partial clinical response (PCR) and relapse. Clinical index including SLEDAI score, BILAG score, renal functional indices were also determined. The overall survival rate was 92.5% (37/40). UC-MSCT was well tolerated, and no transplantation-related adverse event was observed. Thirteen and eleven patients achieved MCR (13/40, 32.5%) and PCR (11/40, 27.5%) during 12 months follow-up, respectively. Then three and four patients experienced disease relapse at 9 (12.5%) and 12 (16.7%) months follow-up, after a prior clinical response. SLEDAI score significantly decreased at 3, 6, 9 and 12 months follow-up. Total BILAG score markedly decreased at 3 months and continued to decrease at subsequent follow-up visits. BILAG scores for renal, hematopoietic and cutaneous systems significantly improved. For those with lupus nephritis, 24-hour proteinuria declined after transplantation, with statistical differences at 9 and 12 months. Serum creatinine and urea nitrogen decreased to the lowest level at 6 months, while these values slightly increased at 9 and 12 months as a result of 7 relapsed cases. In addition, serum levels of albumin and complement 3 increased after MSCT, peaked at 6 months and then slightly declined at 9 and 12 months follow-up. Serum antinuclear antibody and anti-double-strand DNA antibody decreased after MSCT, with statistical differences at 3 months follow-up. UC-MSCT results in satisfactory clinical response in SLE patients. However, several cases experienced disease relapse after 6 months, indicating the necessity to repeat MSCT after 6 months.Registration number: NCT01741857.
    Arthritis research & therapy 03/2014; 16(2):R79. DOI:10.1186/ar4520 · 3.75 Impact Factor
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    • "In parallel, it is important to include the biomarkers that predict disease activity and outcomes in SLE. For example, there are a few validated outcome measures that predict end-stage renal disease; it has been shown that doubling of serum creatinine [57,58] and persistently elevated serum creatinine at 48 weeks [58] is predictive of end-stage renal disease. Another routinely available biomarker in clinical practice is urinary protein and an improvement in proteinuria at 1 year [59] and a decrease in serum creatinine or proteinuria at 6 months [60], whilst it may also be reasonably expected that renal response may continue to improve beyond the first year of treatment and may be relevant to consider when identifying the maximal treatment difference for a clinical trial. "
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    ABSTRACT: B cells are believed to be central to the disease process in systemic lupus erythematosus (SLE), making them a target for new therapeutic intervention. In recent years there have been many publications regarding the experience in SLE of B-cell depletion utilising rituximab, an anti-CD20 mAb that temporarily depletes B cells,reporting promising results in uncontrolled open studies and in routine clinical use. However, the two large randomised controlled trials in extra-renal lupus (EXPLORER study) and lupus nephritis (LUNAR study) failed to achieve their primary endpoints. Based on the clinical experience with rituximab this failure was somewhat unexpected and raised a number of questions and concerns, not only into the true level of benefit of B-cell depletion in a broad population but also how to test the true level of effectiveness of an investigational agent as we seek to improve the design of therapeutic trials in SLE. A better understanding of what went wrong in these trials is essential to elucidate the underlying reasons for the disparate observations noted in open studies and controlled trials. In this review, we focus on various factors that may affect the ability to accurately and confidently establish the level of treatment effect of the investigational agent, in this case rituximab, in the tw studies and explore hurdles faced in the randomised controlled trials investigating the efficacy of ocrelizumab, the humanised anti-CD20 mAb, in SLE. Further, based on the lessons learned from the clinical trials, we make suggestions that could be implemented in future clinical trial design to overcome the hurdles faced.
    Arthritis research & therapy 02/2013; 15 Suppl 1(Suppl 1):S2. DOI:10.1186/ar3910 · 3.75 Impact Factor
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    • "The existing literature on lupus nephritis treated with intermittent iv CYC pulses reveals similar concussions. Approximately 15 to 38% of patients did not respond to treatment with CYC in previous studies, while renal relapse occurred in 37% and 40% of patients in two studies and at a lower percentage (14%) in another one [2,5,6,14,15,30-32]. Taking into consideration that renal flares have been previously shown to be strong predictors of poor long-term renal outcome due to their potential for cumulative damage [33], the combination CYC-MMF emphasizes a potentially better long-term efficacy of MMF vs. CYC as maintenance therapy. "
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    ABSTRACT: While the role of mycophenolate mofetil (MMF) in the management of lupus nephritis has been increasingly recognized, limited information is available regarding its efficacy and safety as a long-term maintenance treatment. The aim of the present study was to evaluate the efficacy and safety profile of MMF as maintenance therapy for proliferative lupus nephritis. Thirty-three consecutive patients with proliferative lupus nephritis received induction therapy with five to seven monthly intravenous (iv) pulses of cyclophosphamide (CYC) plus iv steroids followed by oral MMF 2 g/day as maintenance therapy for a median time of 29 months (range 9 to 71 months). Primary end points were the achievement of renal remission, complete renal remission, disease remission - renal and extrarenal -, the occurrence of renal relapse, chronic renal failure and death. Secondary end points were the extrarenal disease activity and drug adverse events. The clinical and laboratory parameters were compared during follow-up by means of nonparametric statistical tests. Time to event analysis was performed according to the Kaplan-Meier method. A significant improvement of all renal parameters was observed at the end of the induction treatment and at the latest follow-up compared to baseline. The rate of patients achieving renal remission until the end of follow-up was 73%, whereas that of complete renal remission was 58%. The median survival times in the Kaplan-Meier analyses were 7 and 16 months, respectively. Remission was maintained in all but four (12%) patients who relapsed within 19 to 39 months after initial response. At the end of follow-up, 51% of the patients had reached disease remission. The median survival time of disease remission was 18 months. Extrarenal manifestations were well controlled in most of the patients. In one patient receiving MMF, extrarenal activity led to treatment discontinuation. Non life-threatening drug adverse events developed in 18 patients (58%) and included infections, amenorrhea, myelotoxicity, gastrointestinal complications, hypercholesterolemia, alopecia and drug intolerance. None of the patients developed chronic renal insufficiency or died from any cause. MMF appeared to be efficacious and safe as maintenance treatment for proliferative lupus nephritis.
    Arthritis research & therapy 11/2010; 12(6):R208. DOI:10.1186/ar3184 · 3.75 Impact Factor
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