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

Article · October 1992with52 Reads
DOI: 10.1016/0140-6736(92)92292-N · Source: PubMed
Abstract
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.
    • Nincs egyértelmű irányelv a szteroid dózisára vonatkozóan, de a legtöbb vizsgálat NIH-protokoll alapján indukciós terápia során iv. 50–1000 mg methylprednisolont ír elő 3 napig, per os folytatva 0,5–1 mg/ kg dózisról indulva napi 5–10 mg-ra csökkentve [31]. A tacrolimus alternatív szer lehet, ha a beteg nem tolerálja a standard terápiát.
    [Show abstract] [Hide abstract] ABSTRACT: The authors present the latest guideline for the treatment of lupus nephritis and their own single-centre results with mycofenolate mofetil treated lupus nephritis. Lupus nephritis and mainly its proliferative form is a frequent and potentially life-threatening manifestation of systemic lupus erythematosus that can lead to end-stage renal disease. The treatment of lupus nephritis greatly improved in the last decades; mycofenolate mofetil has become an alternative of cyclophosphamide both in remission induction and as a maintenance regimen as well in the treatment of Class III and IV glomerulonephritis. The authors ordered mycofenolate mofetil for 25 patients with lupus nephritis so far. Histologically most of them had Class III (A/C) or IV (A) glomerulonephritis (30-30%), and only 16% of the patients had renal impairment at that time. Mycofenolate mofetil given after glucocorticoid and cyclophosphamide induction therapy reduced the daily proteinuria from 3.18 grs to 1.06 grs. Complete remission could be achieved in 24% and partial remission in 48% of the patients. The authors conclude that mycofenolate mofetil is effective in the therapy of lupus nephritis.
    Article · Aug 2016
    • Clinical trials have shown that intravenous (IV) CYC, an alkylating agent with a low therapeutic index, is effective in achieving remission and preserving renal function in proliferative LN [6,7]. However, between 30–40% of patients treated with CYC fail to achieve renal remission and response to CYC treatment is difficult to predict [6,7]. The pharmacokinetics and metabolism of CYC have been much studied [8].
    [Show abstract] [Hide abstract] ABSTRACT: Objective To investigate association between genetic polymorphisms of GST, CYP and renal outcome or occurrence of adverse drug reactions (ADRs) in lupus nephritis (LN) treated with cyclophosphamide (CYC). CYC, as a pro-drug, requires bioactivation through multiple hepatic cytochrome P450s and glutathione S transferases (GST). Methods We carried out a multicentric retrospective study including 70 patients with proliferative LN treated with CYC. Patients were genotyped for polymorphisms of the CYP2B6, CYP2C19, GSTP1, GSTM1 and GSTT1 genes. Complete remission (CR) was defined as proteinuria ≤0.33g/day and serum creatinine ≤124 µmol/l. Partial remission (PR) was defined as proteinuria ≤1.5g/day with a 50% decrease of the baseline proteinuria value and serum creatinine no greater than 25% above baseline. Results Most patients were women (84%) and 77% were Caucasian. The mean age at LN diagnosis was 41 ± 10 years. The frequency of patients carrying the GST null genotype GSTT1-, GSTM1-, and the Ile→105Val GSTP1 genotype were respectively 38%, 60% and 44%. In multivariate analysis, the Ile→105Val GSTP1 genotype was an independent factor of poor renal outcome (achievement of CR or PR) (OR = 5.01 95% CI [1.02–24.51]) and the sole factor that influenced occurrence of ADRs was the GSTM1 null genotype (OR = 3.34 95% CI [1.064–10.58]). No association between polymorphisms of cytochrome P450s gene and efficacy or ADRs was observed. Conclusion This study suggests that GST polymorphisms highly impact renal outcome and occurrence of ADRs related to CYC in LN patients.
    Full-text · Article · Mar 2016
    • A meta-analysis found that cyclophosphamide plus glucocorticoids compared to glucocorticoids alone reduced the risk of renal progression as measured by creatinine doubling , but also increased the risk of ovarian failure in some trials [58]. There are no set guidelines on oral dosing of steroids but most studies used the following regimen for induction: in severe disease, intravenous methylprednisolone 500–1000 mg given over 30 min daily for 3 days was used, then transitioned to oral prednisone tapered from an initial dose of 0.5–1 mg/kg to a maintenance level of 5–10 mg/day, as per NIH protocol [59]. Cyclophosphamide may be given as a high-dose regimen (NIH protocol) or lower-dose (Euro-lupus protocol).
    [Show abstract] [Hide abstract] ABSTRACT: Lupus nephritis (LN) is an inflammatory condition of the kidneys that encompasses various patterns of renal disease including glomerular and tubulointerstitial pathology. It is a major predictor of poor prognosis in patients with systemic lupus erythematosus (SLE). Genetic factors, including several predisposing loci, and environmental factors, such as EBV and ultraviolet light, have been implicated in the pathogenesis. It carries a high morbidity and mortality if left untreated. Renal biopsy findings are utilized to guide treatment. Optimizing risk factors such as proteinuria and hypertension with renin-angiotensin receptor blockade is crucial. Immunosuppressive therapy is recommended for patients with focal or diffuse proliferative lupus nephritis (Class III or IV) disease, and certain patients with membranous LN (Class V) disease. Over the past decade, immunosuppressive therapies have significantly improved long-term outcomes, but the optimal therapy for LN remains to be elucidated. Cyclophosphamide-based regimens, given concomitantly with corticosteroids, have improved survival significantly. Even though many patients achieve remission, the risk of relapse remains considerably high. Other treatments include hydroxychloroquine, mycofenolate mofetil, and biologic therapies such as Belimumab, Rituximab, and Abatacept. In this paper, we provide a review of LN, including pathogenesis, classification, and clinical manifestations. We will focus, though, on discussion of the established as well as emerging therapies for patients with proliferative and membranous lupus nephritis.
    Article · Oct 2015
    • Cyclophosphamide is an alkylating agent that is toxic to all human cells to differing degrees, with hematopoetic cells forming a particularly sensitive target (104). Primary toxicities, such as bladder toxicity, gonadal toxicity, and later malignancy, have led to attempts to minimize exposure (,250-300 mg/kg cumulative dose to avoid gonadal toxicity and ,360 mg/kg cumulative dose to minimize the risk of malignancy), attempts to use intermittent intravenous rather than daily oral therapy to minimize exposure, and search for alternative agents (for example, mycophenolate mofetil in lupus nephritis and rituxan in ANCA-related vasculitis) (105)(106)(107).
    [Show abstract] [Hide abstract] ABSTRACT: Immunosuppressive agents are commonly used in the nephrologist's practice in the treatment of autoimmune and immune-mediated diseases and transplantation, and they are investigational in the treatment of AKI and ESRD. Drug development has been rapid over the past decades as mechanisms of the immune response have been better defined both by serendipity (the discovery of agents with immunosuppressive activity that led to greater understanding of the immune response) and through mechanistic study (the study of immune deficiencies and autoimmune diseases and the critical pathways or mutations that contribute to disease). Toxicities of early immunosuppressive agents, such as corticosteroids, azathioprine, and cyclophosphamide, stimulated intense investigation for agents with more specificity and less harmful effects. Because the mechanisms of the immune response were better delineated over the past 30 years, this specialty is now bestowed with a multitude of therapeutic options that have reduced rejection rates and improved graft survival in kidney transplantation, provided alternatives to cytotoxic therapy in immune-mediated diseases, and opened new opportunities for intervention in diseases both common (AKI) and rare (atypical hemolytic syndrome). Rather than summarizing clinical indications and clinical trials for all currently available immunosuppressive medications, the purpose of this review is to place these agents into mechanistic context together with a brief discussion of unique features of development and use that are of interest to the nephrologist. Copyright © 2015 by the American Society of Nephrology.
    Article · Jul 2015
    • The pioneering studies by investigators at the National Institute of Health (NIH) have demonstrated the importance of intravenous cyclophosphamide in the management of lupus nephritis [9,10].The so-called "NIH-regimen", consisting of monthly, intravenous pulses of 0.5-1 g/m 2 of cyclophosphamide (CYC) and steroids , became the standard of care for three decades, despite its high toxicity. The Eurolupus Nephritis Trial (ELNT) showed that equal efficacy could be achieved with lower doses (a total of 3 g) and shorter duration (3 months) of cyclophosphamide [11].
    [Show abstract] [Hide abstract] ABSTRACT: The treatment of lupus nephritis still represents a therapeutic challenge for the clinician. Besides early recognition, appropriate guiding by the histologic classification at presentation as well as at relapsing disease, is essential. The most severe proliferative and mixed forms require aggressive induction therapy. Nevertheless, recent but established by RCTs advances, as low dose iv cyclophosphamide, lower doses of cor-ticosteroids and mychophenolate acid (MPA) allow us to achieve remission induction with lower toxicity without any cost in terms of efficacy. For maintenance, azathioprine and mycophenolate acid with concomitant low dose steroids have shown both good results with a slight superiority of mycophenolate acid. Emerging therapies as B cell targeting-either by depleting agents as the anti-CD 20 mAb Rituximab, or by modulating agents as the anti-Bliss Belimumab, further contribute to the effort to minimize toxicity. This review mainly focuses on the recent efforts to treat the most aggressive form of lupus nephritis effectively with the minimal possible toxicity.
    Full-text · Article · Jan 2015
    • Though high-dose IV CYC in combination with glucocorticoids viewed as the most effective immunosuppressive medication for LN, no final conclusion has yet been reached on this matter so far. With development of further research into this issue, several investigators have raised concerns about the high-dose CYC regimen for the treatment of SLE, especially the risks of infection and ovarian failure [9, 10]. Meanwhile, other researchers put forward a question on whether the patients with mild damage should use this regimen or not.
    [Show abstract] [Hide abstract] ABSTRACT: Cyclophosphamide (CYC) has long been considered a gold standard in inducing renal remission and preventing renal flares for patients with systemic lupus erythematosus (SLE). However, the rational use of CYC has not reached a consensus, such as the timing and length of treatment, the route of administration, and the ideal dosage. The objective of this study was to assess the efficacy and safety of short-interval lower-dose (SILD) intravenous (IV) CYC in the treatment of SLE. A total of 225 patients with lupus nephritis were randomly assigned to a 1-year trial, either the SILD group (12 fortnightly pulses at a fixed dose of 400 mg followed by 6 monthly pulses) or high-dose (HD) group (6 monthly pulses followed by two quarterly pulses at a dose of 0.5~1.0 g/m(2)). At 6 months of treatment, 28 % (30/107) of patients in the SILD group reached a complete remission (CR), and 51.4 % (55/107) were in partial remission (PR), as compared with 32.7 % (35/107) and 45.8 % (49/107) in the HD group, respectively. Serum albumin, 24-h urinary protein, and the scores of disease activity were significantly improved in both groups at 6 months and maintained at the end of clinical trial. However, the SILD group showed much less menstrual disturbances (11.5 %), gastrointestinal adverse effects (5.3 %), and leukopenia (9.7 %) than the HD group (28.6, 26.8, and 19.8 %, respectively) at the end of clinical trial. The efficacy of the short-interval lower-dose (SILD) IV CYC regimen in the treatment of lupus nephritis is equivalent to that of the high-dose (HD) regimen, whereas the incidence of adverse events is much lower in the SILD group.
    Article · Apr 2014
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