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Joint European League Against Rheumatism and European Renal Association–European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis

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      Abstract

      Objectives

      To develop recommendations for the management of adult and paediatric lupus nephritis (LN).

      Methods

      The available evidence was systematically reviewed using the PubMed database. A modified Delphi method was used to compile questions, elicit expert opinions and reach consensus.

      Results

      Immunosuppressive treatment should be guided by renal biopsy, and aiming for complete renal response (proteinuria <0.5 g/24 h with normal or near-normal renal function). Hydroxychloroquine is recommended for all patients with LN. Because of a more favourable efficacy/toxicity ratio, as initial treatment for patients with class III–IV A or A/C (±V) LN according to the International Society of Nephrology/Renal Pathology Society 2003 classification, mycophenolic acid (MPA) or low-dose intravenous cyclophosphamide (CY) in combination with glucocorticoids is recommended. In patients with adverse clinical or histological features, CY can be prescribed at higher doses, while azathioprine is an alternative for milder cases. For pure class V LN with nephrotic-range proteinuria, MPA in combination with oral glucocorticoids is recommended as initial treatment. In patients improving after initial treatment, subsequent immunosuppression with MPA or azathioprine is recommended for at least 3 years; in such cases, initial treatment with MPA should be followed by MPA. For MPA or CY failures, switching to the other agent, or to rituximab, is the suggested course of action. In anticipation of pregnancy, patients should be switched to appropriate medications without reducing the intensity of treatment. There is no evidence to suggest that management of LN should differ in children versus adults.

      Conclusions

      Recommendations for the management of LN were developed using an evidence-based approach followed by expert consensus.

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      Most cited references 171

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      The classification of glomerulonephritis in systemic lupus erythematosus revisited.

      The currently used classification reflects our understanding of the pathogenesis of the various forms of lupus nephritis, but clinicopathologic studies have revealed the need for improved categorization and terminology. Based on the 1982 classification published under the auspices of the World Health Organization (WHO) and subsequent clinicopathologic data, we propose that class I and II be used for purely mesangial involvement (I, mesangial immune deposits without mesangial hypercellularity; II, mesangial immune deposits with mesangial hypercellularity); class III for focal glomerulonephritis (involving or = 50% of total number of glomeruli) either with segmental (class IV-S) or global (class IV-G) involvement, and also with subdivisions for active and sclerotic lesions; class V for membranous lupus nephritis; and class VI for advanced sclerosing lesions]. Combinations of membranous and proliferative glomerulonephritis (i.e., class III and V or class IV and V) should be reported individually in the diagnostic line. The diagnosis should also include entries for any concomitant vascular or tubulointerstitial lesions. One of the main advantages of the current revised classification is that it provides a clear and unequivocal description of the various lesions and classes of lupus nephritis, allowing a better standardization and lending a basis for further clinicopathologic studies. We hope that this revision, which evolved under the auspices of the International Society of Nephrology and the Renal Pathology Society, will contribute to further advancement of the WHO classification.
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        Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis.

        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.
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          Immunosuppressive therapy in lupus nephritis: the Euro-Lupus Nephritis Trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide.

          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.
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            Author and article information

            Affiliations
            [1 ]Department of Medicine, Rheumatology, Clinical Immunology and Allergy, University of Crete, Iraklion, Greece
            [2 ]First Department of Internal Medicine, Rheumatology, University of Athens, Athens, Greece
            [3 ]Department of Internal Medicine, French National Reference Center for SLE, Université Paris VI Pierre et Marie Curie, Hôpital Pitié-Salpêtrière, Paris, France
            [4 ]Division of Rheumatology, Department of Medicine III, University Medical Center Carl Gustav Carus, Dresden, Germany
            [5 ]Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
            [6 ]Department of Nephrology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
            [7 ]Department of Nephrology and Transplantation Center, Laiko General Hospital, Athens, Greece
            [8 ]Department of Autoimmune Diseases, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain
            [9 ]Department of Medicine, Rheumatology and Clinical Immunology, Charité—University Medicine Berlin, Berlin, Germany
            [10 ]Division of Rheumatology, Department of Medicine, University of Padova, Padova, Italy
            [11 ]Nephropathology Center, San Gerardo Hospital, Monza and Milan Bicocca University, Monza, Italy
            [12 ]Division of Nephrology and Clinical Immunology, RWTH University of Aachen, Aachen, Germany
            [13 ]Department of Rheumatology, Cliniques Universitaires Saint-Luc, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Bruxelles, Belgium
            [14 ]Stanford Prevention Research Center, Department of Medicine, and Department of Health Research and Policy, Stanford University School of Medicine, Stanford, California, USA
            [15 ]Centre for Rheumatology Research, Division of Medicine, University College London, London, UK
            [16 ]Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
            [17 ]Section of Renal Medicine, Division of Immunology and Inflammation, Department of Medicine, Imperial College London, London, UK
            [18 ]Department of Paediatric Nephrology, Great Ormond Street Hospital for Children NHS Trust, London, UK
            [19 ]Pediatria II, Reumatologia, IRCCS Istituto G Gaslini, Università di Genova, Genova, Italy
            [20 ]Divisione di Nefrologia e Dialisi Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy
            [21 ]Division of Nephrology, Internal Medicine, Wilhelminenspital, Vienna, Austria
            [22 ]Nephrology Division, Hospital Universitario 12 de Octubre, Universidad Complutense de Madrid, Madrid, Spain
            [23 ]Department of Medicine, Rheumatology, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany
            [24 ] Patient representative (Iraklio), Rethymnon, Greece
            [25 ]Department of Nephrology, First School of Medicine, Charles University, Prague, Czech Republic
            [26 ]Unidade de Imunologia Clinica, Hospital Santo Antonio, Centro Hospitalar do Porto, UMIB-ICBAS, Universidade do Porto, Porto, Portugal
            [27 ]Rheumatology Unit, Department of Medicine, Karolinska University Hospital in Solna, Stockholm, Sweden
            [28 ]Nephrology Unit, Moscow City Hospital n.a. S.P. Botkin, Moscow State Medicine and Dentistry University, Moscow, Russian Federation
            [29 ]Department of Nephrology and Hypertension, Hannover Medical School, Hannover and Klinikum Fulda, Fulda, Germany
            [30 ]Rheumatology Research Group, School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham, West Midlands, UK
            [31 ]Vasculitis and Lupus Clinic, Addenbrooke's Hospital, Cambridge, UK
            Author notes
            [Correspondence to ] Dr Dimitrios T Boumpas, Department of Rheumatology, Clinical Immunology, and Allergy, University of Crete, Faculty of Medicine, Iraklio, Greece; boumpasd@ 123456med.uoc.gr
            Journal
            Ann Rheum Dis
            Ann. Rheum. Dis
            annrheumdis
            ard
            Annals of the Rheumatic Diseases
            BMJ Group (BMA House, Tavistock Square, London, WC1H 9JR )
            0003-4967
            1468-2060
            November 2012
            31 July 2012
            : 71
            : 11
            : 1771-1782
            3465859
            22851469
            annrheumdis-2012-201940
            10.1136/annrheumdis-2012-201940
            Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions

            This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/3.0/ and http://creativecommons.org/licenses/by-nc/3.0/legalcode

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