Annals of the Rheumatic Diseases | A EULAR & BMJ ...



Appendix Table 3. Questions for the literature search and results from the systematic review of the literatureQ1. What are the indications and optimal timing for first renal biopsy in SLE patients and are they different compared to non-SLE patients?ItemExample(s) of outcome or effect sizeNo. studiesDesign 1ReferencesAbnormal SCr (≥130 μmol/L [1.4 mg/dL]) and/or GFR levels (<80 ml/min/1.73m2) correlate with adverse histological forms of LNSCr ≥130 μmol/L associated with OR 2.1 for class IV LN24IIIb3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPlJldHJvc3BlY3RpdmUg

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ADDIN EN.CITE.DATA 1-24Abnormal urinalysis (proteinuria >0.5 g/24-hr and/or haematuria and/or cellular casts) with normal SCr is associated with class III-IV LN Proteinuria >0.5 g/24-hr or haematuria or cellular casts: 70% class III-IV LN at biopsy; isolated haematuria (>5 RBC/hpf) with proteinuria <0.5 g/24-hr: 22% active class III-IV LN at biopsy26IIILyplcGlkZW1pb2xvZ3kvcGh5c2lvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tl

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ADDIN EN.CITE.DATA 1,3,6,7,9,11,13-20,23,25-35Clinically ‘silent’ LN (proteinuria <0.3-0.5 g/24-hr, inactive urinary sediment, normal GFR) is associated with class I-II LN and a favorable outcomePrevalence of histologic class III-V LN: 86% in ‘overt’ versus 36% in ‘silent’ cases (defined as proteinuria <0.3 g/24-hr with inactive urinary sediment and GFR >70 ml/min//1.73m2)10IIIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WYWxlbnRlIGRlIEFsbWVpZGE8L0F1dGhvcj48WWVhcj4x

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ADDIN EN.CITE.DATA 36-45Delay in kidney biopsy and diagnosis of LN is associated with progression of renal disease and histological lesions, reduced rates of renal remission after treatment, and increased risk for ESRDDelay >6 months is associated with adjusted HR 4.2–9.3 for ESRD9IIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Fc2RhaWxlPC9BdXRob3I+PFllYXI+MTk4OTwvWWVhcj48

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ADDIN EN.CITE.DATA 3,13,28,46-51Q2. Evaluation of the ISN/RPS 2003 classification system. What is the prognostic significance of renal biopsy findings?ItemExample(s) of outcome or effect sizeNo. studiesDesignReferencesImproved inter-observer reproducibility with the ISN/RPS 2003 classificationKappa coefficient for inter-observer reproducibility is 0.53 versus 0.44 with the WHO classification; cases re-classified from WHO class III into ISN/RPS class IV had lower rates of response to therapy and increased risk for progression to ESRD6IIIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XZWVuaW5nPC9BdXRob3I+PFllYXI+MjAwNDwvWWVhcj48

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ADDIN EN.CITE.DATA 5,16,52-55The histological class of nephritis (defined by the WHO or the ISN/RPS classification) correlates with patient and renal outcome (death, ESRD, doubling SCr, development of chronic renal insufficiency)Proliferative (class III-IV) versus non-proliferative LN is associated with RR 3.0 for death; class IV versus class III LN is associated with HR 4.3 for ESRD; class V LN has worse outcome than class I-II (abnormal renal function in 15% and ESRD in 5% during long-term follow-up); class V with superimposed proliferative lesions (class V+III-IV) has worse outcome than pure class V (ESRD rate 36% versus 12%) 52IId29yZD5NZWNobG9yZXRoYW1pbmUvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPlJl

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ADDIN EN.CITE.DATA 1,3-6,11,14,16,28,47,48,56-96ISN/RPS class IV-G versus IV-S is associated with more severe clinical disease and/or worse histological lesionsIncreased endo-capillary hyper-cellularity, interstitial inflammation, activity lesions; no definitive difference in renal outcome11IIIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db3V6aTwvQXV0aG9yPjxZZWFyPjIwMDc8L1llYXI+PFJl

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ADDIN EN.CITE.DATA 5,12,17,18,33,55,97-101Prognostic significance of kidney deposits detected by immunofluorescence or electron microscopyIntensity/extension of deposits correlates with clinical & histological severity of renal disease, and renal outcome; intra-membranous electron-dense deposits are associated (RR 4.8) with death19IIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbGV4b3BvdWxvczwvQXV0aG9yPjxZZWFyPjE5OTA8L1ll

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ADDIN EN.CITE.DATA 1,7,46,47,61,94,102-114Prognostic significance of activity lesions on kidney biopsy (hypercellularity, leukocyte exudation, karyorrhexis/fibrinoid necrosis, cellular crescents, hyaline deposits, interstitial inflammation)The composite AI correlates with poor renal outcome (increased relapse rates, doubling SCr, ESRD, death; HR 1.4 per 1-unit); cellular crescents >30% of glomeruli is associated with RR 7.2 for doubling SCr; ≥25% interstitial infiltration is associated with HR 1.9 for doubling SCr or ESRD44IIPjx0aXRsZT5GYWN0b3JzIGFzc29jaWF0ZWQgd2l0aCBjaHJvbmljIHJlbmFsIGZhaWx1cmUgaW4g

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ADDIN EN.CITE.DATA 50,94,110,111Prognostic significance of chronicity lesions on kidney biopsy (glomerular sclerosis, fibrous crescents, tubular atrophy, interstitial fibrosis)The composite CI correlates with poor response to immunosuppressive therapy, and poor long-term renal outcome (increased relapse rates, doubling SCr, ESRD, death; HR 1.18 per 1-unit for doubling Scr or death); glomerular sclerosis ≥25% glomeruli is associated (RR 3.3) with ESRD; interstitial fibrosis is associated (HR 2.0) with doubling SCr or ESRD; tubular atrophy ≥25% is associated (HR 2.4) with doubling SCr or ESRD60IIbnVtYmVyPjY8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWR1bHQ8L2tleXdvcmQ+PGtleXdv

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ADDIN EN.CITE.DATA 1,3,8,10,11,13,17,23,25,28,47,48,56,57,61,63,65,73,75,76,79,81,84,87,90,92,100-103,110,111,113,115,119-127,129-145Prognostic significance of tubulointerstitial lesions on kidney biopsyThe composite tubulo-interstitial index (interstitial infiltrates + tubulorrhexis + interstitial sclerosis) is associated with higher proteinuria and SCr levels, and increased risk for ESRD (HR 72 in patients with class V LN)15IIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbGV4b3BvdWxvczwvQXV0aG9yPjxZZWFyPjE5OTA8L1ll

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ADDIN EN.CITE.DATA 7-9,15,46,47,58,79,101,102,106,115-118Prognostic significance of renal vascular lesions (lupus vasculopathy, HUS/TTP/malignant hypertension-like lesions, vasculitis, arteriosclerosis)Association with higher SCr levels, increased rates of hypertension, lower 5- and 10-yr kidney survival rates (74% and 58% vs. 90% and 86% in patients without vascular lesions)3IIIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EZXNjb21iZXM8L0F1dGhvcj48WWVhcj4xOTk3PC9ZZWFy

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ADDIN EN.CITE.DATA 46,47,70Q3. How well do biochemistry tests, serological tests, urinalysis, biomarkers correlate with renal biopsy findings in lupus nephritis?ItemExample(s) of outcome or effect sizeNo. studiesDesignReferencesDiagnostic value of SCr and/or GFR (estimated or measured) levelsHigher SCr and/or lower GFR levels correlate with more advanced histological class (class IV>III>other; IV-G>IV-S), higher biopsy AI and CI (r = 0.27-0.46), tubulo-interstitial lesions, kidney deposits, and presence of cellular crescents; in patients with SCr ≤1.4 mg/dL, those with MDRD-GFR below 60 ml/min/1.73m2 had more chronic lesions in renal biopsy26IIIdXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9lbnRyZXovcXVlcnkuZmNnaT9jbWQ9UmV0

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ADDIN EN.CITE.DATA 1-24,30,103Diagnostic value of hemoglobin levelsLower hemoglobin levels correlate with more advanced histological class (Hb <9 g/dL is associated with OR 3.2 for class IV LN)6IIIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HdW88L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFyPjxSZWNO

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ADDIN EN.CITE.DATA 6,7,14,17,18,33Diagnostic value of serum complement levelsLower levels at the time of diagnosis correlate modestly with more advanced histology (proliferative < non-proliferative LN; class IV < III; IV-G < IV-S); correlation with karryorrhexis, endocapillary proliferation, and CI (r = -0.32 to -0.39); there is a single study reporting better predictive ability of serum C3 versus C413IIIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BYmQtRWxrYXJlZW08L0F1dGhvcj48WWVhcj4yMDEwPC9Z

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ADDIN EN.CITE.DATA 2,4,14,18,23,30,148-154Diagnostic value of serum anti-dsDNA antibodiesIncreased titers (ELISA, Crithidia, or Farr assay) at the time of diagnosis is associated with proliferative versus non-proliferative LN (OR 6.0), class IV > other; correlation with active / severe renal histology (biopsy AI, extra-capillary proliferation, karryorhexis, hyaline deposits, fibrinoid necrosis, electron-dense deposits; r coefficient ranging 0.35 to 0.81)18IIIcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlRyb24s

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ADDIN EN.CITE.DATA 1,2,7,23,103,148-150,152-161Diagnostic value of serum anti-C1q antibodies Increased titers (ELISA) are associated with active proliferative (class III-IV) LN (PPV 68%, NPV 98%); higher titers in class IV > other classes); correlation with biopsy AI and CI, glomerular infiltration, endo-capillary proliferation, fibrinoid necrosis, crescents (r coefficient ranging 0.32 to 0.56)10IIIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ba2h0ZXI8L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFyPjxS

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ADDIN EN.CITE.DATA 18,63,149,155,159,162-166Diagnostic value of other serological tests (anti-chromatin, anti-histone, anti-nucleosome, anti-ribosomal P, anti-RNP, anti-Sm, ANCA, anti-endothelial cell antibodies)Limited diagnostic value; higher titers of anti-endothelial cell IgG in class IV vs. other classes of LN19IIIbmcsIENoaW5hLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkF1dG9hbnRpYm9kaWVzIGFn

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ADDIN EN.CITE.DATA 17,18,149,151,156,159,160,167-178Diagnostic value of proteinuria (24-hr urine collection or random spot urine protein to creatinine ratio)Higher proteinuria levels correlate with more advanced histological lesions (class IV-V > III > II; IV-G > IV-S), higher biopsy AI and CI, increased glomerular and tubulo-interstitial lesions; proteinuria >0.2 g/24-hr is associated (OR 4.4) with class IV LN; nephrotic-range proteinuria is common in class IV or V (± III-IV) LN14IIIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BcHBlbDwvQXV0aG9yPjxZZWFyPjE5Nzg8L1llYXI+PFJl

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ADDIN EN.CITE.DATA 1,3,6,9,11,13-16,18,19,32-34Diagnostic value of active urine sediment (haematuria >5 RBC/hpf and/or pyuria >5 WBC/hpf and/or cellular casts); see also Q1More common in active class III-IV LN (OR 6.0), class IV-G versus IV-S, crescentic versus non-crescentic forms of LN; correlation with proteinuria levels and higher biopsy AI and CI; isolated abnormalities (in absence of proteinuria >0.5 g/24-hr) are less predictive for active class III-IV LN11IIIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BcHBlbDwvQXV0aG9yPjxZZWFyPjE5Nzg8L1llYXI+PFJl

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AG==

ADDIN EN.CITE.DATA 1,7,9,11,15,17,19,23,29,33,35Diagnostic value of serum biomarkers (ICAM-1, VCAM-1, fribrinolytic split products, IL-18, nitrate, IL-12p70, IFN-γ, IL-2-receptor, IFN-γ+/ΙL-4+ PBMCs [flow cytometry])Limited diagnostic value9IIIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ba2h0ZXI8L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFyPjxS

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ADDIN EN.CITE.DATA 149,179-186Diagnostic value of urine biomarkers (cytokines [IL-6, IL-12, IL-10, IL-2], TGFβ, ICAM-1, VCAM-1, T-bet, GATA-3, RANTES, MCP-1, proteomics)MCP-1 levels correlate with active class III-IV LN, biopsy AI and CI (n=4 studies); proteomic analysis demonstrates sensitivity 86-100% and specificity 50-100% for different histological classes of LN, and correlates with biopsy AI (r = 0.77) and CI (r = 0.87)12IIIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Jd2FubzwvQXV0aG9yPjxZZWFyPjE5OTM8L1llYXI+PFJl

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ADDIN EN.CITE.DATA 30,182,185,187-195Q4. What are the indications for initiating immunosuppressive therapy in lupus nephritis?ItemOutcome and example(s) of effect sizeNo. studiesDesignReferencesClass II LNTreatment with low-to-moderate doses of GC (0.25-0.5 mg/kg/day) if proteinuria exceeds 1 g/24-hr especially in presence of glomerular haematuria; immunosuppressive therapy (usually AZA; MPA and CY have also been used) is added in cases of inadequate response to GC (± HCQ), or when unable to taper their dose6VPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYWxkd2luPC9BdXRob3I+PFllYXI+MTk3NzwvWWVhcj48

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ADDIN EN.CITE.DATA 59,196-200Class III-IV LNCombination of immunosuppressive agents with GC are more effective than GC alone in prevention of ESRD or death; effect more pronounced in class IV versus III LN4IPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GZWxzb248L0F1dGhvcj48WWVhcj4xOTg0PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA 221-228Q5. What is the comparative evidence for the benefits and harms of therapeutic agents or interventions in patients with lupus nephritis and according to different histologic classes of kidney disease?ItemOutcome and example(s) of effect sizeNo. studiesDesignReferencesClass II LNLow-to-moderate doses of GC (0.25-0.5 mg/kg/day); immunosuppressive therapy can be added (usually AZA; also MPA, CY) if proteinuria exceeds 1 g/24-hr, especially in presence of glomerular haematuria 6VPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYWxkd2luPC9BdXRob3I+PFllYXI+MTk3NzwvWWVhcj48

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ADDIN EN.CITE.DATA 59,196-200Class III-IV LN: initial treatmentGlucocorticoidsGC-only regimens are less efficacious than the combination of GC and immunosuppressive agents in prevention of ESRD and/or death4IPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GZWxzb248L0F1dGhvcj48WWVhcj4xOTg0PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA 63,82,83,123,134,143,216,217Regimens used: high-dose GC (1 mg/kg/day ×4-6 wks, then tapered); or, pulses IV-MP (0.5-1 g ×3 days), followed by oral prednisone (0.5-0.7 mg/kg/day); both regimens have been used in RCTs───Benefit from the use of IV-MP pulses: may expedite the reduction of abnormal SCr and/or proteinuria levels; has been associated with improved renal outcome (increased remission rates, reduced relapse rates; extrapolation from two RCTs); has been used in severe crescentic LN2IIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Hb3VybGV5PC9BdXRob3I+PFllYXI+MTk5NjwvWWVhcj48

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ADDIN EN.CITE.DATA 208,2121III ADDIN EN.CITE <EndNote><Cite><Author>Harisdangkul</Author><Year>1989</Year><RecNum>827</RecNum><DisplayText><style face="superscript">230</style></DisplayText><record><rec-number>827</rec-number><foreign-keys><key app="EN" db-id="rfzsw2fw9w0rt5e92z5xwtw6dr20xrrxeedp">827</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Harisdangkul, V.</author><author>Rockhold, L.</author><author>Myers, A.</author></authors></contributors><auth-address>Department of Medicine, University of Mississippi Medical Center, Jackson 39216.</auth-address><titles><title>Lupus nephritis: efficacy of monthly pulse therapy with intravenous methylprednisolone</title><secondary-title>South Med J</secondary-title></titles><periodical><full-title>South Med J</full-title></periodical><pages>321-7</pages><volume>82</volume><number>3</number><keywords><keyword>Acute Disease</keyword><keyword>Adolescent</keyword><keyword>Adult</keyword><keyword>Child</keyword><keyword>Creatinine/blood</keyword><keyword>Drug Administration Schedule</keyword><keyword>Drug Evaluation</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Infusions, Intravenous</keyword><keyword>Lupus Nephritis/blood/complications/*drug therapy</keyword><keyword>Male</keyword><keyword>Methylprednisolone/*analogs &amp; derivatives</keyword><keyword>Methylprednisolone Hemisuccinate/*administration &amp; dosage/therapeutic use</keyword><keyword>Middle Aged</keyword><keyword>Random Allocation</keyword><keyword>Time Factors</keyword></keywords><dates><year>1989</year><pub-dates><date>Mar</date></pub-dates></dates><accession-num>2646729</accession-num><urls><related-urls><url> </url></related-urls></urls></record></Cite></EndNote>2303IVPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYWtpbm88L0F1dGhvcj48WWVhcj4xOTk1PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA 17,232-238CyclophosphamideCombination of CY (IV or oral) with GC is efficacious in stabilizing renal function (RR 0.63 for ESRD; RR 0.59 for doubling SCr); superiority over GC-only regimen becomes evident after 5 years of follow-up; long-term (≥10 years) follow-up data available4IPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GZWxzb248L0F1dGhvcj48WWVhcj4xOTg0PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA 87,119,140,198,199,239-244Benefit demonstrated in patients with high-risk features (high biopsy CI, impaired renal function, nephrotic syndrome, class V+IV LN, crescentic LN, rapidly progressive glomerulonephritis)3IIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BdXN0aW48L0F1dGhvcj48WWVhcj4xOTg2PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA 17,134,237,238,248-253Comparable efficacy of IV-CY versus oral CY; in the long-term (7 years) follow-up of a RCT comparing immunosuppressive agents versus GC alone, only the IV-CY regimen was statistically superior in individual group comparisons; in the meta-analyses of early RCTs, results were more robust for the IV-CY regimen; a single RCT comparing intermittent IV-CY versus oral CY followed by AZA found no difference in efficacy or adverse events (trial prematurely terminated); trend for more adverse reactions (herpes zoster infections, leukopenia) with oral CY; oral CY has demonstrated efficacy in class IV LN with rapidly progressive renal failure1I ADDIN EN.CITE <EndNote><Cite><Author>Bansal</Author><Year>1997</Year><RecNum>71</RecNum><DisplayText><style face="superscript">204</style></DisplayText><record><rec-number>71</rec-number><foreign-keys><key app="EN" db-id="rfzsw2fw9w0rt5e92z5xwtw6dr20xrrxeedp">71</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bansal, V. K.</author><author>Beto, J. A.</author></authors></contributors><auth-address>Division of Renal Disease and Hypertension, Loyola University Medical Center, Maywood, IL 60153, USA.</auth-address><titles><title>Treatment of lupus nephritis: a meta-analysis of clinical trials</title><secondary-title>Am J Kidney Dis</secondary-title></titles><periodical><full-title>Am J Kidney Dis</full-title></periodical><pages>193-9</pages><volume>29</volume><number>2</number><keywords><keyword>Adult</keyword><keyword>Azathioprine/administration &amp; dosage/therapeutic use</keyword><keyword>Child</keyword><keyword>Cyclophosphamide/administration &amp; dosage/therapeutic use</keyword><keyword>Drug Therapy, Combination</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Immunosuppressive Agents/administration &amp; dosage/therapeutic use</keyword><keyword>Lupus Nephritis/complications/*drug therapy</keyword><keyword>Male</keyword><keyword>Prednisone/administration &amp; dosage/therapeutic use</keyword></keywords><dates><year>1997</year><pub-dates><date>Feb</date></pub-dates></dates><accession-num>9016889</accession-num><urls><related-urls><url> </url></related-urls></urls></record></Cite></EndNote>2045IIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BdXN0aW48L0F1dGhvcj48WWVhcj4xOTgzPC9ZZWFyPjxS

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ADDIN EN.CITE.DATA 134,255Low-dose versus high-dose IV-CY. In White patients with moderate-risk features (class IV 70%; mean proteinuria 2.9-3.2 g/24-hr; mean biopsy CI 0.8-0.9), initial treatment with low-dose IV-CY (3g) has similar efficacy (prevention of ESRD; follow-up 10 years) and better toxicity profile (reduced infections) than high-dose IV-CY (NIH regimen; both regimens followed by AZA); in patients with high-risk features (class IV 85-90%; 35-50% Black; nephritic with GFR <80 ml/min or GFR >80 ml/min with crescents >25%; mean proteinuria 5.0 g/24-hr; mean biopsy CI 3.7-4.4), extended course (30 months) of IV-CY was associated with lower rates of doubling SCr and of renal relapse compared to short course (6 months) IV-CY1I ADDIN EN.CITE <EndNote><Cite><Author>Lee</Author><Year>2010</Year><RecNum>856</RecNum><DisplayText><style face="superscript">256</style></DisplayText><record><rec-number>856</rec-number><foreign-keys><key app="EN" db-id="rfzsw2fw9w0rt5e92z5xwtw6dr20xrrxeedp">856</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Lee, Y. H.</author><author>Woo, J. H.</author><author>Choi, S. J.</author><author>Ji, J. D.</author><author>Song, G. G.</author></authors></contributors><auth-address>Division of Rheumatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea. lyhcgh@korea.ac.kr</auth-address><titles><title>Induction and maintenance therapy for lupus nephritis: a systematic review and meta-analysis</title><secondary-title>Lupus</secondary-title></titles><periodical><full-title>Lupus</full-title></periodical><pages>703-10</pages><volume>19</volume><number>6</number><edition>2010/01/13</edition><keywords><keyword>Azathioprine/adverse effects/*therapeutic use</keyword><keyword>Bias (Epidemiology)</keyword><keyword>Cyclophosphamide/adverse effects/*therapeutic use</keyword><keyword>Humans</keyword><keyword>Immunosuppressive Agents/adverse effects/*therapeutic use</keyword><keyword>Lupus Nephritis/*drug therapy/prevention &amp; control</keyword><keyword>Mycophenolic Acid/adverse effects/*analogs &amp; derivatives/therapeutic use</keyword><keyword>Randomized Controlled Trials as Topic</keyword><keyword>Recurrence</keyword><keyword>Remission Induction</keyword><keyword>Sensitivity and Specificity</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>2010</year><pub-dates><date>May</date></pub-dates></dates><isbn>1477-0962 (Electronic)&#xD;0961-2033 (Linking)</isbn><accession-num>20064907</accession-num><urls><related-urls><url> [pii]&#xD;10.1177/0961203309357763</electronic-resource-num><language>eng</language></record></Cite></EndNote>2566IIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cb3VtcGFzPC9BdXRob3I+PFllYXI+MTk5MjwvWWVhcj48

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ADDIN EN.CITE.DATA 240,250,255,262-264Toxicity of CY-based regimens: amenorrhea (dose- and age-dependent risk: in women aged ≥32 years D50 has been calculated to 8 g/m2), infections (particularly herpes zoster), leukopenia3IVPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cb3VtcGFzPC9BdXRob3I+PFllYXI+MTk5MzwvWWVhcj48

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ADDIN EN.CITE.DATA 265-267AzathioprineEarly trials showed that the combination of AZA with GC is more efficacious than GC alone in preventing death (RR 0.6) but not ESRDIn patients with class III-IV (±V) LN and moderate-risk features (70% Whites; mean SCr 109 μmol/L, mean proteinuria 3.2 g/24-hr, mean biopsy CI 2.3), the AZA/IV-MP/GC regimen had comparable rates of renal response with the IV-CY/GC regimen during the first 2 years (after a median follow-up of 6.3 years more than 80% of AZA-treated patients remained free of CY; after a median follow-up of 9.6 years there were no significant differences between the two regimens in terms of doubling SCr, ESRD, or mortality, although AZA-treated patients had HR 4.5 for renal relapse)Weak evidence-base for efficacy of AZA (prevention of ESRD) in severe forms of class III-IV LN 3IPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GZWxzb248L0F1dGhvcj48WWVhcj4xOTg0PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA 50,119,197,277-282Mycophenolic acid (mycophenolate mofetil, mycophenolate sodium)Comparable efficacy with CY regimens in terms of induction of renal remission (rates 56-81% in MPA, 52-76% in CY), prevention of ESRD and death; characteristics of patients included in the RCTs: most (53-67%) had class IV LN, relatively preserved renal function (mean SCr 1.1-1.3 mg/dL), average proteinuria 4.1-6.2 g/24-hr (except for two trials: 1.8-2.0 g/24-hr), chronic lesions in kidney biopsies (mean biopsy CI 2.8-3.9), heterogeneous ethnic background; MMF dose: 2-3 g/dayA single RCT demonstrating superiority of MPA over CY included more Black patients, more patients with pure class V LN, and only 62% of patients in the CY arm received all 6 pulses of IV-CYSignificant variation in renal response rates according to race (lower response rates of IV-CY in Black/Hispanics) and region (better efficacy of MPA in regions outside Asia) More favorable toxicity profile of MPA versus CY (reduced amenorrhea, leukopenia, alopecia rates; trend for lower rates of infections; increased gastrointestinal events [diarrhea] with MPA versus CY)Open-label studies have also demonstrated efficacy and histological improvement with MPA in class III-IV LN8IPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LYW1hbmFtb29sPC9BdXRob3I+PFllYXI+MjAxMDwvWWVh

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ADDIN EN.CITE.DATA 49,88,199,298-302Efficacy of enteric-coated mycophenolate sodium (1440-2160 mg/day) in class III-IV LN 1II ADDIN EN.CITE <EndNote><Cite><Author>Zeher</Author><Year>2011</Year><RecNum>994</RecNum><DisplayText><style face="superscript">303</style></DisplayText><record><rec-number>994</rec-number><foreign-keys><key app="EN" db-id="rfzsw2fw9w0rt5e92z5xwtw6dr20xrrxeedp">994</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Zeher, M.</author><author>Doria, A.</author><author>Lan, J.</author><author>Aroca, G.</author><author>Jayne, D.</author><author>Boletis, I.</author><author>Hiepe, F.</author><author>Prestele, H.</author><author>Bernhardt, P.</author><author>Amoura, Z.</author></authors></contributors><auth-address>1Institute for Internal Medicine, Debrecen, Hungary.</auth-address><titles><title>Efficacy and safety of enteric-coated mycophenolate sodium in combination with two glucocorticoid regimens for the treatment of active lupus nephritis</title><secondary-title>Lupus</secondary-title></titles><periodical><full-title>Lupus</full-title></periodical><pages>1484-93</pages><volume>20</volume><number>14</number><edition>2011/10/07</edition><dates><year>2011</year></dates><isbn>1477-0962 (Electronic)&#xD;0961-2033 (Linking)</isbn><accession-num>21976398</accession-num><urls><related-urls><url> [pii]&#xD;10.1177/0961203311418269</electronic-resource-num><language>eng</language></record></Cite></EndNote>3031IIIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UcmFpdGFub248L0F1dGhvcj48WWVhcj4yMDA4PC9ZZWFy

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ADDIN EN.CITE.DATA 310-312TacrolimusComparable short-term efficacy of tacrolimus versus pulses IV-CY (both in combination with GC) in class III-IV LN with moderate-risk features (class IV 72%; normal SCr levels; mean proteinuria 2.2-3.0 g/24-hr; mean biopsy CI 1.0-1.2).In patients with mixed class V+IV LN (normal SCr levels; mean proteinuria 4.1-4.4 g/24-hr, mean biopsy CI 1.3-1.4; 65% had been previously treated with MPA or CY), combination therapy with tacrolimus/MMF/prednisone was associated with higher rates of complete response at 6 months compared to pulse IV-CY therapy (50% versus 5%)3IIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYW88L0F1dGhvcj48WWVhcj4yMDA4PC9ZZWFyPjxSZWNO

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ADDIN EN.CITE.DATA 315-320Plasma exchangeNo benefit of adding plasma exchange cycles to immunosuppressive therapy (AZA, IV-CY) in terms of renal remission or death rates (evidence from RCTs that included patients with class IV 40-100%; mean proteinuria 5.5-8.6 g/24-hr, impaired renal function)Plasma exchange / immunoadsorption cycles in combination with GC and/or cytotoxic therapy have been used in cases with rapidly progressive glomerulonephritis or crescentic class IV LN1IPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GbGFuYzwvQXV0aG9yPjxZZWFyPjIwMDQ8L1llYXI+PFJl

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ADDIN EN.CITE.DATA 321-3241III ADDIN EN.CITE <EndNote><Cite><Author>Danieli</Author><Year>2002</Year><RecNum>794</RecNum><DisplayText><style face="superscript">325</style></DisplayText><record><rec-number>794</rec-number><foreign-keys><key app="EN" db-id="rfzsw2fw9w0rt5e92z5xwtw6dr20xrrxeedp">794</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Danieli, M. G.</author><author>Palmieri, C.</author><author>Salvi, A.</author><author>Refe, M. C.</author><author>Strusi, A. S.</author><author>Danieli, G.</author></authors></contributors><auth-address>Istituto di Clinica Medica, Ematologia ed Immunologia Clinica, Torrette di Ancona, Italy. eleonora@popcsi.unian.it</auth-address><titles><title>Synchronised therapy and high-dose cyclophosphamide in proliferative lupus nephritis</title><secondary-title>J Clin Apher</secondary-title></titles><periodical><full-title>J Clin Apher</full-title></periodical><pages>72-7</pages><volume>17</volume><number>2</number><keywords><keyword>Adolescent</keyword><keyword>Adult</keyword><keyword>Combined Modality Therapy</keyword><keyword>Cyclophosphamide/*administration &amp; dosage/toxicity</keyword><keyword>Disease-Free Survival</keyword><keyword>Female</keyword><keyword>Follow-Up Studies</keyword><keyword>Humans</keyword><keyword>Lupus Erythematosus, Systemic/complications/therapy</keyword><keyword>Lupus Nephritis/complications/*therapy</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>*Plasmapheresis</keyword><keyword>Recurrence</keyword><keyword>Remission Induction</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>2002</year></dates><accession-num>12210709</accession-num><urls><related-urls><url> </url></related-urls></urls></record></Cite></EndNote>3252IVPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdWdpbW90bzwvQXV0aG9yPjxZZWFyPjIwMDY8L1llYXI+

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ADDIN EN.CITE.DATA 3311V ADDIN EN.CITE <EndNote><Cite><Author>Zhang</Author><Year>2009</Year><RecNum>1027</RecNum><DisplayText><style face="superscript">332</style></DisplayText><record><rec-number>1027</rec-number><foreign-keys><key app="EN" db-id="rfzsw2fw9w0rt5e92z5xwtw6dr20xrrxeedp">1027</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Zhang, F. S.</author><author>Nie, Y. K.</author><author>Jin, X. M.</author><author>Yu, H. M.</author><author>Li, Y. N.</author><author>Sun, Y.</author></authors></contributors><auth-address>Department of Rheumatology, The Second Hospital Affiliated Harbin Medical University, 150086 Harbin, People&apos;s Republic of China.</auth-address><titles><title>The efficacy and safety of leflunomide therapy in lupus nephritis by repeat kidney biopsy</title><secondary-title>Rheumatol Int</secondary-title></titles><periodical><full-title>Rheumatol Int</full-title></periodical><pages>1331-5</pages><volume>29</volume><number>11</number><edition>2009/01/27</edition><keywords><keyword>Adolescent</keyword><keyword>Adult</keyword><keyword>Biopsy</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Immunosuppressive Agents/*therapeutic use</keyword><keyword>Isoxazoles/adverse effects/*therapeutic use</keyword><keyword>Kidney/*pathology</keyword><keyword>Lupus Nephritis/*drug therapy/pathology</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword></keywords><dates><year>2009</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>1437-160X (Electronic)&#xD;0172-8172 (Linking)</isbn><accession-num>19169882</accession-num><urls><related-urls><url> chlorambucil in combination with GC has shown comparable efficacy with the combination of oral CY with GC in prevention of renal or patient death (active class III-IV ± V cases; histological improvements at follow-up renal biopsy)1III ADDIN EN.CITE <EndNote><Cite><Author>Sabbour</Author><Year>1979</Year><RecNum>980</RecNum><DisplayText><style face="superscript">274</style></DisplayText><record><rec-number>980</rec-number><foreign-keys><key app="EN" db-id="rfzsw2fw9w0rt5e92z5xwtw6dr20xrrxeedp">980</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sabbour, M. S.</author><author>Osman, L. M.</author></authors></contributors><titles><title>Comparison of chlorambucil, azathioprine or cyclophosphamide combined with corticosteroids in the treatment of lupus nephritis</title><secondary-title>Br J Dermatol</secondary-title></titles><periodical><full-title>Br J Dermatol</full-title></periodical><pages>113-25</pages><volume>100</volume><number>2</number><keywords><keyword>Adolescent</keyword><keyword>Adult</keyword><keyword>Azathioprine/*therapeutic use</keyword><keyword>Child</keyword><keyword>Chlorambucil/*therapeutic use</keyword><keyword>Clinical Trials</keyword><keyword>Comparative Study</keyword><keyword>Cyclophosphamide/*therapeutic use</keyword><keyword>Drug Therapy, Combination</keyword><keyword>Female</keyword><keyword>Follow-Up Studies</keyword><keyword>Glomerulonephritis/complications/*drug therapy</keyword><keyword>Glucocorticoids/*therapeutic use</keyword><keyword>Humans</keyword><keyword>Lupus Erythematosus, Systemic/complications/*drug therapy</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Mortality</keyword></keywords><dates><year>1979</year><pub-dates><date>Feb</date></pub-dates></dates><accession-num>85455</accession-num><urls><related-urls><url> </url></related-urls></urls></record></Cite></EndNote>2741V ADDIN EN.CITE <EndNote><Cite><Author>Snaith</Author><Year>1973</Year><RecNum>1105</RecNum><DisplayText><style face="superscript">333</style></DisplayText><record><rec-number>1105</rec-number><foreign-keys><key app="EN" db-id="rfzsw2fw9w0rt5e92z5xwtw6dr20xrrxeedp">1105</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Snaith, M. L.</author><author>Holt, J. M.</author><author>Oliver, D. O.</author><author>Stephenson, A.</author></authors></contributors><titles><title>Successful treatment of patients with systemic lupus erythematosus, including nephritis, using chlorambucil</title><secondary-title>Ann Rheum Dis</secondary-title></titles><periodical><full-title>Ann Rheum Dis</full-title></periodical><pages>279-80</pages><volume>32</volume><number>3</number><keywords><keyword>Chlorambucil/*therapeutic use</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Lupus Erythematosus, Systemic/*drug therapy</keyword><keyword>Nephritis/*drug therapy</keyword><keyword>Proteinuria/drug therapy</keyword></keywords><dates><year>1973</year><pub-dates><date>May</date></pub-dates></dates><accession-num>4715550</accession-num><urls><related-urls><url> </url></related-urls></urls></record></Cite></EndNote>333RituximabCombination therapy with rituximab/MMF/GC was no superior than MMF/GC in terms of renal response rates (57% versus 46% at 1 year); n=8 placebo patients versus no rituximab-treated patients required CY rescue therapy (cases with moderate-risk features: White 31%; class IV 66%; mean SCr 1.0 mg/dL; mean proteinuria 4.0 g/24-hr)2IIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaTwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+PFJlY051

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ADDIN EN.CITE.DATA 336-338BelimumabPost-hoc analysis of RCT: reduced rates of renal flares in the high-dose drug arm versus placebo1III ADDIN EN.CITE <EndNote><Cite><Author>Petri</Author><Year>2011</Year><RecNum>1036</RecNum><DisplayText><style face="superscript">339</style></DisplayText><record><rec-number>1036</rec-number><foreign-keys><key app="EN" db-id="rfzsw2fw9w0rt5e92z5xwtw6dr20xrrxeedp">1036</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Petri, M.</author></authors></contributors><titles><title>Author&apos;s reply</title><secondary-title>Lancet</secondary-title></titles><periodical><full-title>Lancet</full-title></periodical><pages>2080-2081</pages><volume>377</volume><dates><year>2011</year><pub-dates><date>June 18, 2011</date></pub-dates></dates><urls></urls></record></Cite></EndNote>339Class III-IV LN: subsequent treatmentIn class III-IV LN patients responding to initial immunosuppressive therapy (‘induction therapy’), absence or shorter duration of subsequent immunosuppressive therapy (‘maintenance therapy’) is associated with increased risk for renal relapse4IVPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb2s8L0F1dGhvcj48WWVhcj4yMDA2PC9ZZWFyPjxSZWNO

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ADDIN EN.CITE.DATA 134,199,340,341CyclophosphamideLower dose and/or less frequently administered intermittent IV-CY (quarterly pulses) or oral CY, sequentially administered after remission induction for another 12-24 months is associated with lower rates of renal relapse, doubling SCr or ESRD; experience in patients with high-risk features (nephrotic syndrome and/or impaired renal function) with remission rates up to 72% 15IIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cb2xldGlzPC9BdXRob3I+PFllYXI+MTk5OTwvWWVhcj48

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L0VuZE5vdGU+

ADDIN EN.CITE.DATA 87,136,198,239,240,243,252,263,264,341AzathioprineUsed for maintenance of renal remission following successful initial treatment with CY (evidence from RCTs and uncontrolled case series); also, sequentially after initial treatment with AZA (in milder LN cases)A single retrospective controlled study in class IV LN (mean proteinuria 5.9-6.8 g/24-hr, mean SCr 122-135 μmol/L) comparing pulse IV-CY versus oral CY followed by AZA found no difference in renal relapse or doubling SCr rates11IIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGFuPC9BdXRob3I+PFllYXI+MjAwMDwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA 50,140,197,242,244,249,250,263,264,278,280,281,305Mycophenolic acidUsed after initial treatment with CY or MPA (sequential therapy)RCT comparing quarterly pulses IV-CY (0.5-1 g/m2) versus MMF (0.5-3 g/day) versus AZA (1-3 mg/kg/day) after initial treatment with pulse IV-CY in patients with high-risk features (Hispanics 50%; class IV 68-85%; mean SCr 1.5-1.7 mg/dL; mean proteinuria 4.7-5.7 g/24-hr; mean biopsy CI 1.9-3.8): during follow-up (mean 5.5 years) there were reduced renal and patient survival rates and more relapses in the IV-CY group (40% versus 32% in AZA, 15% in MMF)ALMS trial (42% Whites, class IV ± V 72%, composite endpoint, responders after initial treatment with either IV-CY or MMF were re-randomized to study arms): reduced renal flares with MMF versus AZA (13% versus 23% during 3-year period); MAINTAIN trial (79% Whites, class IV 59%, time to flare used as endpoint, randomization upon enrollment regardless of response to initial low-dose IV-CY regimen): comparable rates of renal flares with MMF versus AZA (19% versus 25% during 3-year period)2IPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5aaHU8L0F1dGhvcj48WWVhcj4yMDA3PC9ZZWFyPjxSZWNO

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ADDIN EN.CITE.DATA 309,3481V ADDIN EN.CITE <EndNote><Cite><Author>Tam</Author><Year>1998</Year><RecNum>920</RecNum><DisplayText><style face="superscript">312</style></DisplayText><record><rec-number>920</rec-number><foreign-keys><key app="EN" db-id="rfzsw2fw9w0rt5e92z5xwtw6dr20xrrxeedp">920</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Tam, L. S.</author><author>Li, E. K.</author><author>Leung, C. B.</author><author>Wong, K. C.</author><author>Lai, F. M.</author><author>Wang, A.</author><author>Szeto, C. C.</author><author>Lui, S. F.</author></authors></contributors><auth-address>Department of Medicine and Clinical Therapeutics, Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong.</auth-address><titles><title>Long-term treatment of lupus nephritis with cyclosporin A</title><secondary-title>Qjm</secondary-title></titles><periodical><full-title>Qjm</full-title></periodical><pages>573-80</pages><volume>91</volume><number>8</number><keywords><keyword>Adult</keyword><keyword>Anti-Inflammatory Agents/therapeutic use</keyword><keyword>Cyclosporine/*therapeutic use</keyword><keyword>Drug Therapy, Combination</keyword><keyword>Female</keyword><keyword>Follow-Up Studies</keyword><keyword>Glucocorticoids/therapeutic use</keyword><keyword>Hemoglobins/metabolism</keyword><keyword>Humans</keyword><keyword>Immunosuppressive Agents/*therapeutic use</keyword><keyword>Lupus Nephritis/blood/*drug therapy/pathology</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Prednisolone/therapeutic use</keyword><keyword>Prospective Studies</keyword><keyword>Proteinuria/drug therapy</keyword><keyword>Serum Albumin/metabolism</keyword></keywords><dates><year>1998</year><pub-dates><date>Aug</date></pub-dates></dates><accession-num>9893761</accession-num><urls><related-urls><url> </url></related-urls></urls></record></Cite></EndNote>312TacrolimusLimited experience with prolonged (sequential) treatment of class III-IV LN2VPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Bc2FtaXlhPC9BdXRob3I+PFllYXI+MjAwOTwvWWVhcj48

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ADDIN EN.CITE.DATA 349Plasma exchange / immunoadsorptionWeak evidence-base; benefit has been demonstrated for prolonged versus short duration treatment cycles 1II ADDIN EN.CITE <EndNote><Cite><Author>Loo</Author><Year>2010</Year><RecNum>864</RecNum><DisplayText><style face="superscript">350</style></DisplayText><record><rec-number>864</rec-number><foreign-keys><key app="EN" db-id="rfzsw2fw9w0rt5e92z5xwtw6dr20xrrxeedp">864</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Loo, C. Y.</author><author>Mohamed Said, M. S.</author><author>Mohd, R.</author><author>Abdul Gafor, A. H.</author><author>Saidin, R.</author><author>Halim, N. A.</author><author>Chua, M. K.</author><author>Kong, N. C.</author></authors></contributors><auth-address>Universiti Kebangsaan Malaysia Medical Center, Kuala Lumpur, Malaysia. cyloo@</auth-address><titles><title>Immunoadsorption and plasmapheresis are equally efficacious as adjunctive therapies for severe lupus nephritis</title><secondary-title>Transfus Apher Sci</secondary-title></titles><periodical><full-title>Transfus Apher Sci</full-title></periodical><pages>335-40</pages><volume>43</volume><number>3</number><edition>2010/11/06</edition><keywords><keyword>Adult</keyword><keyword>Creatinine/blood</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>*Immunosorbent Techniques</keyword><keyword>Lupus Nephritis/*therapy</keyword><keyword>Male</keyword><keyword>*Plasmapheresis</keyword><keyword>Platelet Count</keyword><keyword>Serum Albumin</keyword><keyword>Treatment Outcome</keyword><keyword>Young Adult</keyword></keywords><dates><year>2010</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>1473-0502 (Print)&#xD;1473-0502 (Linking)</isbn><accession-num>21051293</accession-num><urls><related-urls><url>(10)00186-2 [pii]&#xD;10.1016/j.transci.2010.10.003</electronic-resource-num><language>eng</language></record></Cite></EndNote>3501IIIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5ZYW1hamk8L0F1dGhvcj48WWVhcj4yMDA4PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA 87,130,140,198,249,263Switch to or add another immunosuppressive agentCY. Non-responders to MPA may respond to CY (but not to AZA) 2V ADDIN EN.CITE <EndNote><Cite><Author>Kasitanon</Author><Year>2006</Year><RecNum>247</RecNum><DisplayText><style face="superscript">298</style></DisplayText><record><rec-number>247</rec-number><foreign-keys><key app="EN" db-id="rfzsw2fw9w0rt5e92z5xwtw6dr20xrrxeedp">247</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kasitanon, N.</author><author>Fine, D. M.</author><author>Haas, M.</author><author>Magder, L. S.</author><author>Petri, M.</author></authors></contributors><auth-address>Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, USA.</auth-address><titles><title>Hydroxychloroquine use predicts complete renal remission within 12 months among patients treated with mycophenolate mofetil therapy for membranous lupus nephritis</title><secondary-title>Lupus</secondary-title></titles><periodical><full-title>Lupus</full-title></periodical><pages>366-70</pages><volume>15</volume><number>6</number><dates><year>2006</year></dates><accession-num>16830883</accession-num><urls><related-urls><url> </url></related-urls></urls></record></Cite></EndNote>298MPA has demonstrated efficacy in class III-IV LN patients who relapsed or were refractory to CY or AZA (mean proteinuria ranging 3.3 to 5.5 g/24-hr; complete and partial renal response rates 50-60%)5VPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Eb29sZXk8L0F1dGhvcj48WWVhcj4xOTk5PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA 351-355CsA in combination with moderate doses of GC (prednisone 0.5 mg/kg/day) is efficacious in class III-IV LN cases with incomplete response or proteinuric relapse while on immunosuppressive treatment with CY or AZA (response rates 50-60%; stabilization of SCr levels); maintenance CsA therapy is needed to prevent relapses; histological improvements have been shown in follow-up renal biopsies (class down-transformation, reduced biopsy AI) 5VPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Eb3N0YWw8L0F1dGhvcj48WWVhcj4xOTk4PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA 310,312,356-358Tacrolimus in combination with GC is efficacious in refractory class III-IV LN or in cases with persistent proteinuria despite immunosuppressive treatment with MMF or CY: reduction in proteinuria, stabilization of SCr levels, steroid-sparring effect; has been used as add-on therapy to MMF in cases with incomplete or no response or flare (renal response rates up to 70% after an average 11 months therapy; increased risk for infections and neurotoxicity)6VPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Bc2FtaXlhPC9BdXRob3I+PFllYXI+MjAwOTwvWWVhcj48

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ADDIN EN.CITE.DATA 315,317,318,359-361IVIG. Rapid (within 1 month) anti-proteinuric effect in severe LN cases (nephrotic syndrome, impaired renal function) refractory to immunosuppressive treatment (CY); paucity of long-term data2VPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MZXZ5PC9BdXRob3I+PFllYXI+MjAwMDwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA 364-366Rituximab (anti-CD20 mAb)Regimen: IV RTX (375 mg/m2 on days 1,9,16,23 or 1000 mg ×2 times 3 weeks apart) + IV-MP 250 mg + IV-CY 0.5 g/m2 (on days 1, 23); concomitant immunosuppressive treatment can be continued Efficacious in refractory or relapsing class III-IV cases (majority previously treated with CY; mean proteinuria 4.3 g/24-hr; mean serum albumin 2.4 g/dL; mean GFR 80 ml/min; mean biopsy AI 8, CI 3) with renal response rates 60% (class III), 39% (class IV), 26% (mixed V+III-IV); steroid-sparring effect; mostly used in White patients but also efficacious in case series with Black/Asian patientsPredictors for poor response: baseline GFR <30 ml/min; rapidly progressive glomerulonephritis; nephrotic syndrome; Black race; no B-cell depletion after 1 monthRelapses are common (27% after mean 12 months); 80% are successfully re-treated with RTXWell tolerated; mild infections18VLXJlc291cmNlLW51bT48bGFuZ3VhZ2U+ZW5nPC9sYW5ndWFnZT48L3JlY29yZD48L0NpdGU+PENp

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ADDIN EN.CITE.DATA 381-387Immunoablative IV-CY1V ADDIN EN.CITE <EndNote><Cite><Author>Petri</Author><Year>2003</Year><RecNum>1075</RecNum><DisplayText><style face="superscript">388</style></DisplayText><record><rec-number>1075</rec-number><foreign-keys><key app="EN" db-id="rfzsw2fw9w0rt5e92z5xwtw6dr20xrrxeedp">1075</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Petri, M.</author><author>Jones, R. J.</author><author>Brodsky, R. A.</author></authors></contributors><auth-address>Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.</auth-address><titles><title>High-dose cyclophosphamide without stem cell transplantation in systemic lupus erythematosus</title><secondary-title>Arthritis Rheum</secondary-title></titles><periodical><full-title>Arthritis Rheum</full-title></periodical><pages>166-73</pages><volume>48</volume><number>1</number><keywords><keyword>Adult</keyword><keyword>Cyclophosphamide/*administration &amp; dosage</keyword><keyword>Female</keyword><keyword>Follow-Up Studies</keyword><keyword>Hematopoiesis</keyword><keyword>Humans</keyword><keyword>Immunosuppressive Agents/*administration &amp; dosage</keyword><keyword>Lupus Erythematosus, Cutaneous/drug therapy</keyword><keyword>Lupus Erythematosus, Systemic/*drug therapy</keyword><keyword>Lupus Nephritis/drug therapy</keyword><keyword>Lupus Vasculitis, Central Nervous System/drug therapy</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Research Support, Non-U.S. Gov&apos;t</keyword><keyword>Research Support, U.S. Gov&apos;t, P.H.S.</keyword><keyword>Severity of Illness Index</keyword><keyword>Stem Cell Transplantation</keyword></keywords><dates><year>2003</year><pub-dates><date>Jan</date></pub-dates></dates><accession-num>12528116</accession-num><urls><related-urls><url> </url></related-urls></urls></record></Cite></EndNote>388Leflunomide1V ADDIN EN.CITE <EndNote><Cite><Author>Tam</Author><Year>2006</Year><RecNum>1079</RecNum><DisplayText><style face="superscript">389</style></DisplayText><record><rec-number>1079</rec-number><foreign-keys><key app="EN" db-id="rfzsw2fw9w0rt5e92z5xwtw6dr20xrrxeedp">1079</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Tam, L. S.</author><author>Li, E. K.</author><author>Wong, C. K.</author><author>Lam, C. W.</author><author>Li, W. C.</author><author>Szeto, C. C.</author></authors></contributors><titles><title>Safety and efficacy of leflunomide in the treatment of lupus nephritis refractory or intolerant to traditional immunosuppressive therapy: an open label trial</title><secondary-title>Ann Rheum Dis</secondary-title></titles><periodical><full-title>Ann Rheum Dis</full-title></periodical><pages>417-8</pages><volume>65</volume><number>3</number><keywords><keyword>Adult</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Immunosuppressive Agents/*therapeutic use</keyword><keyword>Isoxazoles/*therapeutic use</keyword><keyword>Lupus Nephritis/*drug therapy</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Prospective Studies</keyword><keyword>Severity of Illness Index</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>2006</year><pub-dates><date>Mar</date></pub-dates></dates><accession-num>16474039</accession-num><urls><related-urls><url> </url></related-urls></urls></record></Cite></EndNote>389Total lymphoid irradiation4VPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HZW5vdmVzZTwvQXV0aG9yPjxZZWFyPjIwMDI8L1llYXI+

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ADDIN EN.CITE.DATA 220ChlorambucilOral chlorambucil (0.2 mg/kg) alternating monthly with IV-MP is more efficacious (higher renal response rate; fewer relapses) than GC alone (WHO class Va/b/c; preserved renal function at baseline; mean SCr 1.6 mg/dL at last follow-up) 1III ADDIN EN.CITE <EndNote><Cite><Author>Moroni</Author><Year>1998</Year><RecNum>1091</RecNum><DisplayText><style face="superscript">219</style></DisplayText><record><rec-number>1091</rec-number><foreign-keys><key app="EN" db-id="rfzsw2fw9w0rt5e92z5xwtw6dr20xrrxeedp">1091</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Moroni, G.</author><author>Maccario, M.</author><author>Banfi, G.</author><author>Quaglini, S.</author><author>Ponticelli, C.</author></authors></contributors><auth-address>Division of Nephrology and Dialysis, IRCCS, Ospedale Maggiore, Milano, Italy.</auth-address><titles><title>Treatment of membranous lupus nephritis</title><secondary-title>Am J Kidney Dis</secondary-title></titles><periodical><full-title>Am J Kidney Dis</full-title></periodical><pages>681-6</pages><volume>31</volume><number>4</number><keywords><keyword>Adolescent</keyword><keyword>Adrenal Cortex Hormones/administration &amp; dosage</keyword><keyword>Adult</keyword><keyword>Chlorambucil/administration &amp; dosage</keyword><keyword>Comparative Study</keyword><keyword>Drug Evaluation</keyword><keyword>Drug Therapy, Combination</keyword><keyword>Female</keyword><keyword>Glucocorticoids/administration &amp; dosage</keyword><keyword>Humans</keyword><keyword>Lupus Nephritis/*drug therapy</keyword><keyword>Methylprednisolone/administration &amp; dosage</keyword><keyword>Middle Aged</keyword><keyword>Nephrotic Syndrome/drug therapy</keyword><keyword>Proteinuria/drug therapy</keyword><keyword>Retrospective Studies</keyword><keyword>Time Factors</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>1998</year><pub-dates><date>Apr</date></pub-dates></dates><accession-num>9531186</accession-num><urls><related-urls><url> </url></related-urls></urls></record></Cite></EndNote>219AzathioprineProlonged (for at least 1 year) treatment with AZA in combination with GC is efficacious in class V LN with moderate-risk features (mean proteinuria 3.9 g/24-hr; mean GFR 80 ml/min)1IIIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CaXRlbmNvdXJ0IERpYXM8L0F1dGhvcj48WWVhcj4yMDEx

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ADDIN EN.CITE.DATA 221,223CyclophosphamideThe combination of GC with IV-CY (0.5-1 g/m2 bimonthly ×6 pulses) is more efficacious than GC alone (complete response rates at 1 year 40% versus 13%), and is associated with fewer relapses than the combination of GC with CsA (baseline clinical characteristics: 71% non-White; GFR 80-89 ml/min; proteinuria 5.0-5.8 g/24-hr); oral CY regimen also efficacious2IIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BdXN0aW48L0F1dGhvcj48WWVhcj4yMDA5PC9ZZWFyPjxS

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PgB=

ADDIN EN.CITE.DATA 198,222Mycophenolic acidIn a pooled analysis of two RCTs comparing MMF (2-3 g/day) versus IV-CY (pulses 0.5-1 g/m2), both in combination with GC, the two groups had comparable improvements in proteinuria at 24 wks; there was no difference within the subset of nephrotic patients (clinical characteristics of patients: 30% Blacks; mean proteinuria 5.0-5.8 g/24-hr; mean SCr 61-72 μmol/L); leukopenia and alopecia were more common with IV-CY1IIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SYWRoYWtyaXNobmFuPC9BdXRob3I+PFllYXI+MjAxMDwv

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ADDIN EN.CITE.DATA 224,225,298,347,397,398Ciclosporin AThe combination of GC with IV-CY (0.5-1 g/m2 bimonthly ×6 pulses) is more efficacious than GC alone (complete response rates at 1 year 40% versus 13%), and is associated with fewer relapses than the combination of GC with CsA (baseline clinical characteristics: 71% non-White; GFR 80-89 ml/min; proteinuria 5.0-5.8 g/24-hr)1IIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BdXN0aW48L0F1dGhvcj48WWVhcj4yMDA5PC9ZZWFyPjxS

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ZT5=

ADDIN EN.CITE.DATA 218Efficacious in nephrotic patients with preserved renal function; dose adjustments may be needed based on SCr levels; toxicity: hypertension, metabolic adverse effects 3VPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYWxsZWd1YTwvQXV0aG9yPjxZZWFyPjIwMDA8L1llYXI+

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ADDIN EN.CITE.DATA 319RituximabEfficacious in small case series in class V LN (used as first-line treatment)3VPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SYW1vcy1DYXNhbHM8L0F1dGhvcj48WWVhcj4yMDA5PC9Z

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ADDIN EN.CITE.DATA 336-338Class V LN: subsequent treatmentLow-dose GC1III ADDIN EN.CITE <EndNote><Cite><Author>Moroni</Author><Year>1998</Year><RecNum>1091</RecNum><DisplayText><style face="superscript">219</style></DisplayText><record><rec-number>1091</rec-number><foreign-keys><key app="EN" db-id="rfzsw2fw9w0rt5e92z5xwtw6dr20xrrxeedp">1091</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Moroni, G.</author><author>Maccario, M.</author><author>Banfi, G.</author><author>Quaglini, S.</author><author>Ponticelli, C.</author></authors></contributors><auth-address>Division of Nephrology and Dialysis, IRCCS, Ospedale Maggiore, Milano, Italy.</auth-address><titles><title>Treatment of membranous lupus nephritis</title><secondary-title>Am J Kidney Dis</secondary-title></titles><periodical><full-title>Am J Kidney Dis</full-title></periodical><pages>681-6</pages><volume>31</volume><number>4</number><keywords><keyword>Adolescent</keyword><keyword>Adrenal Cortex Hormones/administration &amp; dosage</keyword><keyword>Adult</keyword><keyword>Chlorambucil/administration &amp; dosage</keyword><keyword>Comparative Study</keyword><keyword>Drug Evaluation</keyword><keyword>Drug Therapy, Combination</keyword><keyword>Female</keyword><keyword>Glucocorticoids/administration &amp; dosage</keyword><keyword>Humans</keyword><keyword>Lupus Nephritis/*drug therapy</keyword><keyword>Methylprednisolone/administration &amp; dosage</keyword><keyword>Middle Aged</keyword><keyword>Nephrotic Syndrome/drug therapy</keyword><keyword>Proteinuria/drug therapy</keyword><keyword>Retrospective Studies</keyword><keyword>Time Factors</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>1998</year><pub-dates><date>Apr</date></pub-dates></dates><accession-num>9531186</accession-num><urls><related-urls><url> </url></related-urls></urls></record></Cite></EndNote>219Pulses IV-CY (quarterly) in combination with low-dose GC1IIIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SaXZlcmE8L0F1dGhvcj48WWVhcj4yMDA5PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA 224,225,242,298,347,397,398AZA in combination with low-dose GC (after initial treatment with CY)3VPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NY0tpbmxleTwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+

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ADDIN EN.CITE.DATA 221,353-358Tacrolimus1V ADDIN EN.CITE <EndNote><Cite><Author>Mok</Author><Year>2009</Year><RecNum>326</RecNum><DisplayText><style face="superscript">221</style></DisplayText><record><rec-number>326</rec-number><foreign-keys><key app="EN" db-id="rfzsw2fw9w0rt5e92z5xwtw6dr20xrrxeedp">326</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mok, C. C.</author><author>Ying, K. Y.</author><author>Yim, C. W.</author><author>Ng, W. L.</author><author>Wong, W. S.</author></authors></contributors><auth-address>Department of Medicine, Tuen Mun Hospital, Hong Kong, SAR China. ccmok2005@</auth-address><titles><title>Very long-term outcome of pure lupus membranous nephropathy treated with glucocorticoid and azathioprine</title><secondary-title>Lupus</secondary-title></titles><periodical><full-title>Lupus</full-title></periodical><pages>1091-5</pages><volume>18</volume><number>12</number><edition>2009/09/19</edition><keywords><keyword>Adult</keyword><keyword>Azathioprine/*therapeutic use</keyword><keyword>Creatinine/blood</keyword><keyword>Female</keyword><keyword>*Glomerulonephritis, Membranous/drug therapy/etiology</keyword><keyword>Glucocorticoids/*therapeutic use</keyword><keyword>Humans</keyword><keyword>Immunosuppressive Agents/*therapeutic use</keyword><keyword>Lupus Erythematosus, Systemic/*complications/*drug therapy/physiopathology</keyword><keyword>Middle Aged</keyword><keyword>Prednisolone/therapeutic use</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>2009</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>1477-0962 (Electronic)&#xD;0961-2033 (Linking)</isbn><accession-num>19762384</accession-num><urls><related-urls><url> [pii]&#xD;10.1177/0961203309106602</electronic-resource-num><language>eng</language></record></Cite></EndNote>221RTX (± other concomitant immunosuppressive agent)13VPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SYW1vcy1DYXNhbHM8L0F1dGhvcj48WWVhcj4yMDA5PC9Z

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ADDIN EN.CITE.DATA 364-366Leflunomide1V ADDIN EN.CITE <EndNote><Cite><Author>Tam</Author><Year>2006</Year><RecNum>1079</RecNum><DisplayText><style face="superscript">389</style></DisplayText><record><rec-number>1079</rec-number><foreign-keys><key app="EN" db-id="rfzsw2fw9w0rt5e92z5xwtw6dr20xrrxeedp">1079</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Tam, L. S.</author><author>Li, E. K.</author><author>Wong, C. K.</author><author>Lam, C. W.</author><author>Li, W. C.</author><author>Szeto, C. C.</author></authors></contributors><titles><title>Safety and efficacy of leflunomide in the treatment of lupus nephritis refractory or intolerant to traditional immunosuppressive therapy: an open label trial</title><secondary-title>Ann Rheum Dis</secondary-title></titles><periodical><full-title>Ann Rheum Dis</full-title></periodical><pages>417-8</pages><volume>65</volume><number>3</number><keywords><keyword>Adult</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Immunosuppressive Agents/*therapeutic use</keyword><keyword>Isoxazoles/*therapeutic use</keyword><keyword>Lupus Nephritis/*drug therapy</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Prospective Studies</keyword><keyword>Severity of Illness Index</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>2006</year><pub-dates><date>Mar</date></pub-dates></dates><accession-num>16474039</accession-num><urls><related-urls><url> </url></related-urls></urls></record></Cite></EndNote>389Other options (immunoablative dose of IV-CY; mesenchymal stem cell transplantation)3VPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QZXRyaTwvQXV0aG9yPjxZZWFyPjIwMDM8L1llYXI+PFJl

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ADDIN EN.CITE.DATA 383,386,388Q6. What are the best validated definitions of therapeutic goals in lupus nephritis?ItemOutcome and example(s) of effect sizeNo. studiesDesignReferencesRenal responseFailure to achieve complete renal response/remission is associated with poor long-term renal outcome (most patients with class IV LN)Heterogeneity in definitions of renal response; usually it includes normal (or improved) SCr / GFR, proteinuria below 0.3 to 1 g/24-hr, and inactive urinary sediment; lack of complete response after immunosuppressive treatment is associated with increased risk (HR 4.5 – 9.9) for ESRD 16IIIL2RydWcgZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5QcmVkbmlzb2xvbmUvdGhlcmFwZXV0aWMg

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ADDIN EN.CITE.DATA 17,58,59,78,135,136,196,404-406Complete response of the nephrotic syndrome (class V LN; usually defined as proteinuria below 0.25-0.4 g/24-hr with normal GFR, inactive urinary sediment, and normal serum albumin) is associated with favourable long-term outcome (lack of complete response is associated with HR 9.3 for ESRD)1III ADDIN EN.CITE <EndNote><Cite><Author>Appel</Author><Year>1987</Year><RecNum>43</RecNum><DisplayText><style face="superscript">56</style></DisplayText><record><rec-number>43</rec-number><foreign-keys><key app="EN" db-id="rfzsw2fw9w0rt5e92z5xwtw6dr20xrrxeedp">43</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Appel, G. B.</author><author>Cohen, D. J.</author><author>Pirani, C. L.</author><author>Meltzer, J. I.</author><author>Estes, D.</author></authors></contributors><auth-address>Department of Medicine, College of Physicians and Surgeons, Columbia University, Presbyterian Hospital, New York, New York 10032.</auth-address><titles><title>Long-term follow-up of patients with lupus nephritis. A study based on the classification of the World Health Organization</title><secondary-title>Am J Med</secondary-title></titles><periodical><full-title>Am J Med</full-title></periodical><pages>877-85</pages><volume>83</volume><number>5</number><keywords><keyword>Actuarial Analysis</keyword><keyword>Biopsy</keyword><keyword>Follow-Up Studies</keyword><keyword>Humans</keyword><keyword>Kidney/pathology</keyword><keyword>Kidney Failure, Chronic/etiology</keyword><keyword>Lupus Nephritis/*mortality/pathology</keyword><keyword>Nephrotic Syndrome/etiology</keyword><keyword>Prognosis</keyword><keyword>Research Support, U.S. Gov&apos;t, P.H.S.</keyword><keyword>Time Factors</keyword><keyword>World Health Organization</keyword></keywords><dates><year>1987</year><pub-dates><date>Nov</date></pub-dates></dates><accession-num>3674094</accession-num><urls><related-urls><url> </url></related-urls></urls></record></Cite></EndNote>561IVPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdW48L0F1dGhvcj48WWVhcj4yMDA4PC9ZZWFyPjxSZWNO

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ADDIN EN.CITE.DATA 126,129,140,141,4011IV ADDIN EN.CITE <EndNote><Cite><Author>So</Author><Year>2011</Year><RecNum>414</RecNum><DisplayText><style face="superscript">405</style></DisplayText><record><rec-number>414</rec-number><foreign-keys><key app="EN" db-id="rfzsw2fw9w0rt5e92z5xwtw6dr20xrrxeedp">414</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>So, M. W.</author><author>Koo, B. S.</author><author>Kim, Y. G.</author><author>Lee, C. K.</author><author>Yoo, B.</author></authors></contributors><auth-address>Division of Rheumatology, Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, 388-1 Pungnap-dong, Songpa-gu, Seoul, South Korea.</auth-address><titles><title>Predictive value of remission status after 6 months induction therapy in patients with proliferative lupus nephritis: a retrospective analysis</title><secondary-title>Clin Rheumatol</secondary-title></titles><periodical><full-title>Clin Rheumatol</full-title></periodical><pages>1399-405</pages><volume>30</volume><number>11</number><edition>2011/05/20</edition><dates><year>2011</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1434-9949 (Electronic)&#xD;0770-3198 (Linking)</isbn><accession-num>21594768</accession-num><urls><related-urls><url> flareFlares ( ‘proteinuric’ or ‘nephritic’) are associated with adverse renal outcome (both in class III-IV and class V LN)Severe nephritic flares accompanied by deterioration of renal function demonstrate the strongest association with adverse renal outcome (LR 11.8 for ESRD)Proteinuric flares also associated with worse renal outcome (increase in proteinuria by ≥2 g/24-hr or doubling if initial proteinuria was >3.5 g/24-hr is associated with OR 9.3 for doubling SCr)8IIIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Lb3JiZXQ8L0F1dGhvcj48WWVhcj4yMDAwPC9ZZWFyPjxS

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ADDIN EN.CITE.DATA 17,117,124,135,136Q7. What is the evidence for the benefits and harms of adjunct therapies in lupus nephritis?ItemOutcome and example(s) of effect sizeNo. studiesDesignReferencesACE-inhibitors (ACEi) / angiotensin receptor blockers (ARBs)Class II LN: use of ACEi (in addition to steroids) is associated with increased rates of renal response 1IV ADDIN EN.CITE <EndNote><Cite><Author>Tam</Author><Year>2003</Year><RecNum>424</RecNum><DisplayText><style face="superscript">196</style></DisplayText><record><rec-number>424</rec-number><foreign-keys><key app="EN" db-id="rfzsw2fw9w0rt5e92z5xwtw6dr20xrrxeedp">424</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Tam, L. S.</author><author>Li, E. K.</author><author>Lai, F. M.</author><author>Chan, Y. K.</author><author>Szeto, C. C.</author></authors></contributors><auth-address>Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong. tamls_813@</auth-address><titles><title>Mesangial lupus nephritis in Chinese is associated with a high rate of transformation to higher grade nephritis</title><secondary-title>Lupus</secondary-title></titles><periodical><full-title>Lupus</full-title></periodical><pages>665-71</pages><volume>12</volume><number>9</number><keywords><keyword>Adolescent</keyword><keyword>Adult</keyword><keyword>*Asian Continental Ancestry Group</keyword><keyword>Disease Progression</keyword><keyword>Enzyme Inhibitors/therapeutic use</keyword><keyword>Female</keyword><keyword>Follow-Up Studies</keyword><keyword>Glomerular Mesangium/*pathology</keyword><keyword>Glucocorticoids/*therapeutic use</keyword><keyword>Humans</keyword><keyword>Immunosuppressive Agents/*therapeutic use</keyword><keyword>Lupus Nephritis/*drug therapy/*ethnology/pathology</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Predictive Value of Tests</keyword><keyword>Prognosis</keyword><keyword>Retrospective Studies</keyword><keyword>Severity of Illness Index</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>2003</year></dates><accession-num>14514128</accession-num><urls><related-urls><url> </url></related-urls></urls></record></Cite></EndNote>196Class III–V LN: in stable renal disease with persistent proteinuria >1 g/24-hr despite steroids and immunosuppressive therapy, addition of ACEi/ARB results in reduction of proteinuria and blood pressure levels5IIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EYXphPC9BdXRob3I+PFllYXI+MjAwNTwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA 413HydroxychloroquineUse of HCQ is associated with higher rates of renal remission, fewer renal relapses during maintenance therapy, lower risk for major renal flare (HR 0.26), and lower accrual of renal damage (HR 0.19)8IIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYXJiZXI8L0F1dGhvcj48WWVhcj4yMDA2PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA 49,80,298,406,414-417Omega-3 fatty acidLipid-lowering effect; no significant impact on renal function4IIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DbGFyazwvQXV0aG9yPjxZZWFyPjE5ODk8L1llYXI+PFJl

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ADDIN EN.CITE.DATA 418-421Lipid-lowering therapies[See Q10]Q8. How do blood tests, serological tests, urinalysis/proteinuria, biomarkers, kidney histology (repeat biopsy) compare with regard to their ability to monitor lupus nephritis?ItemOutcome and example(s) of effect sizeNo. studiesDesignReferencesReproducible increases in SCr levels (≥20-30% above baseline value) and/or reduction in GFR (≥10% from baseline)Included in the definitions of active or flare of LN; specificity >80% but low sensitivity for proteinuric renal activity; 24-hr creatinine clearance is considered the ‘gold standard’ in assessing renal function (not validated in LN; single study showing unpredictable variability in serial measurements); The Cockcroft-Gault equation tends to overestimate, the MDRD equation tends to underestimate GFR; in Caucasians the accuracy for classifying patients with GFR 60-89 ml/min/1.73m2 was 82% with the Cockcroft-Gault vs. 59% with the MDRD equation 6IIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb3NsZXk8L0F1dGhvcj48WWVhcj4yMDA2PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA 422-427Monitoring ability of other blood tests (hemoglobin, serum albumin)Improvements during inactive versus active LN3IIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj50ZXIgQm9yZzwvQXV0aG9yPjxZZWFyPjE5OTE8L1llYXI+

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ADDIN EN.CITE.DATA 163,212,428; data also from RCTsMonitoring ability of serum anti-dsDNA antibodiesIncreased titers during active/flare state versus lower titers during inactive/remission of LN; most useful in class III-V LN (lower predictive value for proteinuric flares of class V LN); have been evaluated in the context of RCTs (reductions correlating with response to therapy); sensitivity 46-89% (typically ~70%), specificity 52-98%, PPV 11-52%, high NPV (typically 86-90%); the Farr method has been most extensively studied, yielding higher sensitivity/specificity rates than ELISA48IIa2V5d29yZD5BbnRpcGhvc3Bob2xpcGlkIFN5bmRyb21lL2NvbXBsaWNhdGlvbnMvbW9ydGFsaXR5

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ADDIN EN.CITE.DATA 69,129,130,149,150,152,158-160,162,164,212,359,422,429-462Rise in titers ≥25% (within 6 months prior to flare) are 65-91% sensitive for impending renal flare (poor specificity as it may also antedate non-renal SLE flare)6IIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CaWpsPC9BdXRob3I+PFllYXI+MjAwMjwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA 130,162,434,449,455,459Monitoring ability of serum complement (C3, C4)Reduced levels during active/flare state versus normal titers during inactive/remission of LN; serial measurements are useful to identify active proliferative renal disease (insensitive for proteinuric flares of class V LN); studied in the context of RCTs (normalization correlating with response to therapy); low C3 (e.g. ≤ 81) has sensitivity 72-85%, specificity 51-93% (typically 70%), PPV 22-28%, and NPV 93-97% for active renal disease; low C4 (e.g. ≤ 11) has sensitivity 28-74%, specificity 50-71%, PPV 17-31%, NPV 92-95%; two studies have reported superior performance of C3 versus C4, whereas data from a single RCT show that increases in C4 (not in C3) correlate with induction of LN remission25IIb3JkPjxrZXl3b3JkPkNvbXBsZW1lbnQgQzQvYW5hbHlzaXM8L2tleXdvcmQ+PGtleXdvcmQ+Q3Jl

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RW5kTm90ZT5=

ADDIN EN.CITE.DATA 129,130,149,150,163,212,409,422,440,442,443,450,452,458,459,463-472Persistently low levels (within 3-6 months prior to flare) are 75-90% sensitive for future renal flare4IIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CaXJtaW5naGFtPC9BdXRob3I+PFllYXI+MjAxMDwvWWVh

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ADDIN EN.CITE.DATA 130,459,463,467Monitoring ability of serum anti-C1q antibodiesIncreased titres are found at active versus inactive stage of proliferative LN; sensitivity 74-88%, specificity 70-92%, PPV 37-68%, NPV 91-100%; outperforms serum anti-dsDNA and C3/C4 (including in detecting class V proteinuric flares); combination with anti-dsDNA (Farr) further enhances sensitivity (91%) and specificity (100%) for active nephritis; have been validated against biopsy-proven active proliferative LN (PPV 68%, NPV 98%); less well studied than other serological markers in prospective controlled trials26IId29yZHM+PGRhdGVzPjx5ZWFyPjIwMDY8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5BcHI8L2RhdGU+

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ADDIN EN.CITE.DATA 130,149,152,159,162-164,166,431,435,439-441,453,455,457,473-482Appearance or increase in titres ≥50% (within 6 months prior to flare) have sensitivity 71-76%, specificity 84-92%, PPV 50-56%, NPV 70-97% for future renal flare3IIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db3JlbWFuczwvQXV0aG9yPjxZZWFyPjE5OTU8L1llYXI+

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ADDIN EN.CITE.DATA 162,164,455Monitoring ability of serum anti-nucleosome antibodiesIncreased titres are found at active stage of proliferative LN; sensitivity (32-89%), specificity (22-67%), PPV (16-40%), NPV (77-88%)9IIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CaWdsZXI8L0F1dGhvcj48WWVhcj4yMDA4PC9ZZWFyPjxS

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dGU+

ADDIN EN.CITE.DATA 158,431,432,436,439,449,454,483,484Monitoring ability of other serological tests (anti-chromatin, anti-histone, anti-ribosomal P, anti-CRP, anti-heparan sulfate, anti-α-actinin, anti-endothelial cell antibodies)Changes in titres correlate with LN activity; less extensively studied or validated19IIOTkzPC9ZZWFyPjxSZWNOdW0+OTA2PC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj45MDY8L3Jl

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ADDIN EN.CITE.DATA 130,149,151,159,160,176-178,436,437,448,451,456,460,484-488Monitoring ability of urine sediment‘Active sediment’ ([re-]appearance of haematuria, pyuria, casts) included in definition of active LN; also in the context of therapeutic (controlled) trials to define remission and flare of LN; cellular casts have sensitivity 81% for flares (defined according to increases in SCr and/or proteinuria; 96% for flares with proteinuria >1 g/24-hr), and may precede other flare signs by 10-13 weeks; haematuria (>5 RBC/hpf) has sensitivity 42% and specificity 84% for active versus inactive LN; urine cytology (lymphoblasts, plasma cells, monocytes) abnormal during renal flare7IIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IZWJlcnQ8L0F1dGhvcj48WWVhcj4xOTk1PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA 129,422,444,448,473,489,490Monitoring ability of proteinuriaShould be quantified as part of monitoring lupus renal disease; urine dipstick has suboptimal performance in detecting/excluding significant proteinuria (62-86% specificity to correctly exclude proteinuria ≥0.5 g/24-hr); spot urine measurements of urine protein to creatinine ratio show very good correlation with ratios determined by 24-hr urine collection over the entire range of proteinuria (r = 0.81-0.91) but poor concordance over the range of 0.5-3.0 (r = 0.48); first morning void urine sample performs better than random spot urine sample22IIaCBsdXB1cyBuZXBocml0aXM8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+SiBSaGV1bWF0b2w8L3Nl

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PC9FbmROb3RlPn==

ADDIN EN.CITE.DATA 23,129,422,443,444,448,464,465,473,491-502Monitoring ability of serum biomarkers (ICAM-1, VCAM-1, MCP-1, IL-2-receptor, IL-17, CXCL13, β2-microglobulin, nitrate, MMP-3, flow cytometry for various subsets of peripheral blood mononuclear cells)Limited diagnostic value17IIIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ba2h0ZXI8L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFyPjxS

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ADDIN EN.CITE.DATA 149,160,179,183,186,461,503-513Monitoring ability of urine biomarkers (cytokines, lipocalin-2, slit diaphragm proteins, FoxP3, ICAM-1, VCAM-1, TGFβ, OPG, MCP-1, TWEAK, NGAL, proteomics)MCP-1 mRNA correlates with proteinuria, haematuria, renal SLEDAI (levels >7.5 has PPV 98% and NPV 100% for renal SLEDAI >3); TWEAK mRNA shows modest correlation with renal SLEDAI (r = 0.39-0.41; values >9.1 has PPV 93% and NPV 67% for active nephritis); NGAL (ELISA) >13.6 ng/mL has 89% sensitivity and 72% specificity for biopsy-proven active LN; Proteomics: hepcidin-20/25 (changes in levels 4 months before and at the time of renal flare)22IIIPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5MdXB1cyBFcnl0aGVtYXRvc3VzLCBTeXN0ZW1pYy91

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ADDIN EN.CITE.DATA 30,187,188,190,192,193,422,438,443,444,465,490,500,514-522Monitoring ability of repeat kidney biopsyIn patients with proliferative LN who have responded to immunosuppressive treatment repeat biopsy shows histological class down-transformation (from III-IV to II / V), reduced AI (stable / mildly increased CI), improved immunofluorescence findings, reduced deposits; in treatment failure or severe flare there is often transformation from class II-III to class IV and from class V to mixed V+III-IV (no change in histological class in patients with class IV at initial biopsy), increased CI, scarring, glomerular sclerosis, and deposits; repeat biopsy can assist therapeutic decisions in patients with persistent non-nephrotic proteinuria (despite improved renal function) or with worsening of renal function27IIdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5T

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ADDIN EN.CITE.DATA 7,10,23,59,61,66,72,88,90,107,115,117,118,129,196,211,255,312,403,523-530Q9. What is the prognostic performance of biochemistry tests, serological tests, urinalysis, and biomarkers in lupus nephritis?ItemExample(s) of outcome or effect sizeNo. studiesDesignReferencesPrognostic value of SCr and/or GFR levelsHigher baseline (and follow-up) SCr correlates with higher follow-up SCr values, higher rates of doubling of SCr or ESRD (HR 1.26 per 1-mg/dL), lower odds for response to immunosuppressive treatment, and increased risk for death (HR 5.9); reduction of initially abnormal SCr at 6 months after treatment has OR 14.9 for good long-term renal outcome; in the ALMS trial patients with baseline GFR <30 ml/min/1.73m2 had OR 0.2 for response to therapy at 24 wks 65IILXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvZW50cmV6L3F1ZXJ5LmZjZ2k/

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ADDIN EN.CITE.DATA 3,4,13,19,22-24,46-48,57,58,60,65,68,71-73,76-79,83,84,86,88,91,101,105,115-117,120-124,126,127,134-136,140,141,143,145,255,258,401,402,404,405,464,500,531-541Prognostic value of haemoglobin (haematocrit) levelsHaematocrit <26-36% or haemoglobin <11 g/dL at LN onset is associated with increased rates of chronic renal failure, doubling SCr or ESRD (OR 0.6 for renal survival per 1-g/dL decrement); persistent anaemia (haematocrit <33%) at the time of response is associated with LR 4.6 for ESRD14IIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BdXN0aW48L0F1dGhvcj48WWVhcj4xOTk0PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA 65,68,115,120,121,126,135,136,452,531,532,542,543Prognostic value of platelet countLower numbers correlate with increased rates of deterioration of renal function (thrombocytopenia <20,000/μL is associated with HR 14.2 for ESRD)3IIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaHJ5c29jaG91PC9BdXRob3I+PFllYXI+MjAwODwvWWVh

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ZT4A

ADDIN EN.CITE.DATA 47,91,531Prognostic value of serum albumin levelsLower values associated with adverse renal outcome in class III-V LN (HR 0.9 per 1-g/dL increment for doubling SCr/ESRD; persistently levels <3.5 g/dL after immunosuppressive therapy is associated with RR 3.3 for doubling SCr)10IIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGFuPC9BdXRob3I+PFllYXI+MjAwMDwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA 47,115,133,134,144,258,290,359,539,542Prognostic value of serum lipidsHigh serum total cholesterol levels correlates with ESRD (HR 1.02) and death (HR 1.20); persistent dyslipidaemia after treatment of class III-IV LN is associated with future decline in GFR4IIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Gb250PC9BdXRob3I+PFllYXI+MjAwMTwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA 69,401,538,539Prognostic value of serum anti-dsDNA antibodiesPersistently high titres despite treatment is associated with increased risk for renal flare (RR 2.3 in class IV LN; LR 4.9 in complete responders); most associations are with anti-dsDNA measured by the Farr method15IIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BcHBlbDwvQXV0aG9yPjxZZWFyPjE5Nzg8L1llYXI+PFJl

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ADDIN EN.CITE.DATA 1,46,126,133,261,525,544-551Prognostic value of serum C3 levelsLow C3 (<76 mg/dL) levels is associated with lower rates of complete remission, persistent proteinuria (>1 g/24-hr), increased rates of chronic renal failure and ESRD; persistently low C3 after immunosuppressive treatment is associated with renal flares (RR 2.2) and adverse outcome (HR 2.3 for doubling SCr or ESRD or death)15IIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BdXN0aW48L0F1dGhvcj48WWVhcj4xOTk0PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA 19,46,103,120,121,130,133,134,464,468,525,547,548,552,553Prognostic value of serum C4 levelsLow C4 (<10-11 mg/dL) levels at baseline is associated with increased risk for future relapses, deterioration of renal function; low C4 at the time of response to treatment has LR 14.2 for future renal flare (follow-up of RCTs)8IIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EYWxsJmFwb3M7ZXJhPC9BdXRob3I+PFllYXI+MjAxMTwv

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ADDIN EN.CITE.DATA 19,73,126,255,409,464,548,554Prognostic value of other serological tests (anti-ribosomal P, anti-nucleosome, anti-Sm, anti-C1q, ANCA, anti-endothelial cell antibodies)Limited prognostic value 15IIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5kZSBNYWNlZG88L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFy

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ADDIN EN.CITE.DATA 63,73,78,151,168,173,534,544,546,549,551,555-557Prognostic value of urine sediment (haematuria , pyuria, cellular casts)Active urine sediment at the time of diagnosis is associated with worse renal outcome (HR 2.6 for SCr >130 μmol/L at last follow-up visit; RR 4.0 for patient death); disappearance of sediment abnormalities following therapy is associated with favourable long-term patient prognosis5IIIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BcHBlbDwvQXV0aG9yPjxZZWFyPjE5Nzg8L1llYXI+PFJl

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ADDIN EN.CITE.DATA 1,28,69,76,539Prognostic value of proteinuria levelNephrotic-range proteinuria at LN onset is associated with increased risk for ESRD (OR 6.5) or death (HR 4.0); associations confirmed in both proliferative and membranous LN; there is a dose effect (in LN cases with normal GFR and proteinuria in the range of 0.25-3.5 g/24-hr, baseline proteinuria >0.5 g/24-hr [vs. <0.5 g/24-hr] is associated with HR 2.3 for future decline in GFR); persistent proteinuria >0.5 g/24-hr despite immunosuppressive treatment is associated with future deterioration of renal function (HR 2.4 for doubling SCr; LR 5.9 for ESRD); reduction in proteinuria to less than 1 g/24-hr at 6 months after treatment has PPV 87% for good long-term renal outcome37IIPEF1dGhvcj5Jb2FubmlkaXM8L0F1dGhvcj48WWVhcj4yMDAwPC9ZZWFyPjxSZWNOdW0+ODM2PC9S

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ADDIN EN.CITE.DATA 16,23,46,47,56,60,68,73,77,82,87,115,117,126,127,130,133,134,218,221,257,258,359,401,404,405,464,537-542,554,558-560HypertensionHypertension (at baseline and/or persistent following treatment) is associated with doubling SCr (RR 6.7) and development of ESRD (HR 5.0)27IIPC9hdXRob3I+PGF1dGhvcj5RdWFnbGluaSwgUy48L2F1dGhvcj48YXV0aG9yPkdhbGxlbGxpLCBC

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ADDIN EN.CITE.DATA 19,47,48,58,60,65,68,69,72,77,79,83,86,123,130,133-136,532,539,561-566Q10. Are effective management options for chronic kidney disease and end-stage renal disease (including renal replacement therapies) different in SLE compared to non-SLE patients?ItemOutcome and example(s) of effect sizeNo. studiesDesignReferencesDialysis in SLE patients: outcome and predictorsSLE patients on HD are at increased risk for death (HR 1.17) and thrombotic microangiopathy (OR 3.7); majority of deaths are due to infections and cardiovascular disease events; high disease activity and need for immunosuppressives are predictors of adverse outcome (OR 7.3 for death); PD: increased rates of infections / peritonitis / hospitalizations due to infections (OR 6.0 versus non-diabetic controls), need for higher doses of erythropoietin to maintain similar haemoglobin levels; HD: increased rates of vascular access thrombosis (OR 3.1; risk factors are female gender, Black race, arterio-venous graft versus fistula, aPL positivity)21IIIYXBwPSJFTiIgZGItaWQ9InJmenN3MmZ3OXcwcnQ1ZTkyejV4d3R3NmRyMjB4cnJ4ZWVkcCI+NTEw

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ADDIN EN.CITE.DATA 86,567-586Renal activity during dialysis in SLEOften (>50%) there is clinical and to lesser extent, serological remission16IIIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGVpZ2g8L0F1dGhvcj48WWVhcj4xOTgzPC9ZZWFyPjxS

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ADDIN EN.CITE.DATA 570,571,577,579,580,583,587-596Renal transplantation in SLE: outcome Overall comparable renal graft and patient outcomes with other disease controls (data from single centres); increased risk for allograft loss (HR 1.09) and death (HR 1.18 versus diabetes controls) (data from registries); Renal transplantation in SLE: predictors of allograft lossStronger evidence for recipient age, recurrent LN (HR 4.1), graft rejection (HR 2.7), ethnicity of the recipient (Black ethnicity has HR 1.6-1.7), living vs. cadaveric donor (HR 0.64), HLA mismatch (HR 1.8), delayed graft function (HR 1.7), previous renal transplantation (HR 2.3), aPL positivity; less strong evidence for recipient gender, recipient body mass index, panel-reactive antibodies, smoking, donor ethnicity, donor age, pregnancy history, pre-transplantation dialysis mode25IIIeXdvcmQ+VGhyb21ib3Npcy9lcGlkZW1pb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+VHJhbnNwbGFu

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ADDIN EN.CITE.DATA 589,597-620Post-renal transplantation immunosuppressive therapySimilar regimens with those used in non-SLE patients; calcineurin inhibitor-based triple immunosuppression is associated with improved outcomes13IIIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BemV2ZWRvPC9BdXRob3I+PFllYXI+MTk5ODwvWWVhcj48

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ADDIN EN.CITE.DATA 589,598,602,603,608,611,615,621-626Recurrent lupus nephritis after renal transplantationWide range of reported frequencies (from 1.9% to 30-39% in studies performing protocol kidney biopsies; typically 4.5%)18IVeXdvcmRzPjxrZXl3b3JkPkFkdWx0PC9rZXl3b3JkPjxrZXl3b3JkPkNyZWF0aW5pbmUvYmxvb2Q8

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ADDIN EN.CITE.DATA 589,590,605-609,612-615,624-630Renal transplantation in SLE: adjunct therapyLipid-lowering therapy. Fluvastatin (40-80 mg/day) in patients with dyslipidaemia resulted in reductions in serum LDL-cholesterol by 29% and in major cardiac events by 73% (p=0.064; follow-up 7.3 years)1II ADDIN EN.CITE <EndNote><Cite><Author>Norby</Author><Year>2009</Year><RecNum>536</RecNum><DisplayText><style face="superscript">631</style></DisplayText><record><rec-number>536</rec-number><foreign-keys><key app="EN" db-id="rfzsw2fw9w0rt5e92z5xwtw6dr20xrrxeedp">536</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Norby, G. E.</author><author>Holme, I.</author><author>Fellstrom, B.</author><author>Jardine, A.</author><author>Cole, E.</author><author>Abedini, S.</author><author>Holdaas, H.</author></authors></contributors><auth-address>National Hospital, Oslo, Norway.</auth-address><titles><title>Effect of fluvastatin on cardiac outcomes in kidney transplant patients with systemic lupus erythematosus: A randomized placebo-controlled study</title><secondary-title>Arthritis Rheum</secondary-title></titles><periodical><full-title>Arthritis Rheum</full-title></periodical><pages>1060-4</pages><volume>60</volume><number>4</number><edition>2009/04/01</edition><dates><year>2009</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0004-3591 (Print)</isbn><accession-num>19333947</accession-num><urls><related-urls><url>. What are the prognostic and therapeutic implications of the presence of anti-phospholipid antibody serology / anti-phospholipid syndrome or histological lesions of anti-phospholipid syndrome-associated nephropathy (APSN) in patients with lupus nephritis?ItemOutcome and example(s) of effect sizeNo. studiesDesignReferencesPrognostic significance of aPL antibodies in renal outcome in SLENo significant association with renal outcome (single study reporting association with chronic renal insufficiency)8IIIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BYnUtU2hha3JhPC9BdXRob3I+PFllYXI+MTk5NTwvWWVh

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ADDIN EN.CITE.DATA 632-640Prevalence of APSN in SLEPrevalence of thrombotic microangiopathy: 6-46%; full-spectrum (thrombotic microangiopathy and chronic vascular lesions) of APSN lesions: 11-43%6IVPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGV1bnN1Y2hvbjwvQXV0aG9yPjxZZWFyPjIwMDc8L1ll

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ADDIN EN.CITE.DATA 641-646Association of aPL with APSNAPSN lesions are more frequent in aPL positive (lupus anticoagulant is associated with OR 11.5, anti-cardiolipin antibodies are associated with OR 5.7) and in APS patients (ca. 66% versus 20-30% in SLE/aPL/non-APS patients)18IIIZWNvbmRhcnktdGl0bGU+QW0gSiBUcmFuc3BsYW50PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+

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ADDIN EN.CITE.DATA 632-634,638,641,642,644-655Impact of APSN on renal outcome in SLEAssociation of APSN lesions with hypertension, higher SCr / lower GFR (OR 5.8) and proteinuria levels, and increased interstitial fibrosis at renal biopsy); no association with rates of renal remission, doubling SCr, or ESRD (follow-up 2-10 years)9IIIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CaGFuZGFyaTwvQXV0aG9yPjxZZWFyPjE5OTg8L1llYXI+

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Pn==

ADDIN EN.CITE.DATA 633,641-648Q12. What is the optimal management of lupus nephritis in stable pregnant patients and in case of flare during pregnancy?ItemOutcome and example(s) of effect sizeNo. studiesDesignReferencesRisk factors for adverse pregnancy outcomes in LNRisk factors are: a) high renal disease activity or renal flare at the time of conception (risk for miscarriage, stillbirth, pre-term delivery, IUGR, hypertension; first trimester proteinuria >0.5 g/24-hr has OR 4.1 for miscarriage; LN at remission for at least 6 months prior to and at pregnancy onset is associated with increased live birth rate [88% versus 64%]); b) high extra-renal SLE activity; c) thrombocytopenia (miscarriage, stillbirth; first trimester platelet count below 150,000/μL is associated with RR 3.3); d) hypertension (miscarriage, stillbirth, preterm delivery, IUGR); e) low serum C3/C4 (miscarriage, stillbirth, IUGR, neonatal death); f) anti-dsDNA (fetal loss); g) anti-SSA/Ro (pre-term delivery; CHB); h) anti-SSB/La (OR 11.5 for IUGR); i) aPL antibodies (miscarriage, stillbirth, preterm delivery, maternal hypertension, pre-eclampsia); j) hypo-albuminaemia (foetal loss [OR 19.1], IUGR [OR 7.0]); k) GC ≥10 mg/d prednisone (preterm delivery)36IPHJlYy1udW1iZXI+NTc4PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBk

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ADDIN EN.CITE.DATA 656-691Risk factors for exacerbation of renal disease during pregnancy Renal flares occur in 16-24% of LN pregnancies (often proteinuric); predictors for flares are: a) active renal disease at pregnancy onset (partial renal remission [proteinuria >0.2 but <1 g/24-hr] is associated with RR 3.0 for renal flare during pregnancy and 12 moths post-partum), b) high extra-renal disease activity at pregnancy onset (OR 1.6), c) use of glucocorticoids (OR 1.6) and azathioprine (HR 9.1) at pregnancy onset, d) no use of HCQ (association with higher rates of renal relapse; discontinuation of HCQ is associated with constitutional or arthritis flares), e) aPL positivity (OR 12.4), f) uncontrolled hypertension (OR 6.3)30IPGZ1bGwtdGl0bGU+QW0gSiBLaWRuZXkgRGlzPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFn

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ADDIN EN.CITE.DATA 656,659,661,663,665-667,670,671,676,678-684,686,690,692-702Management of stable renal disease during pregnancyTherapeutic agents include HCQ, GC (non-fluorinated, avoid >7.5 mg/d prednisone for more than 2 weeks), AZA, calcineurin inhibitors, aspirin; control hypertension with calcium-channel blockers, methyldopa, labetalol4IIIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EZXJrc2VuPC9BdXRob3I+PFllYXI+MTk5NDwvWWVhcj48

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ADDIN EN.CITE.DATA 668,682,683,691Management of renal flare during pregnancyGC (up to 1 mg/kg/day and/or IV-MP pulses); AZA (≤2.5 mg/kg/day); IVIG 10IVPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DbG93c2U8L0F1dGhvcj48WWVhcj4yMDA1PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA 658,663,665,666,671,679,680,699,703,704Monitoring of renal disease activity during pregnancySimilar to adult non-pregnant LN patients; serial measurement of serum C3 and C4 can help differentiate between SLE flare and pre-eclampsia1II ADDIN EN.CITE <EndNote><Cite><Author>Buyon</Author><Year>1986</Year><RecNum>575</RecNum><DisplayText><style face="superscript">705</style></DisplayText><record><rec-number>575</rec-number><foreign-keys><key app="EN" db-id="rfzsw2fw9w0rt5e92z5xwtw6dr20xrrxeedp">575</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Buyon, J. P.</author><author>Cronstein, B. N.</author><author>Morris, M.</author><author>Tanner, M.</author><author>Weissmann, G.</author></authors></contributors><titles><title>Serum complement values (C3 and C4) to differentiate between systemic lupus activity and pre-eclampsia</title><secondary-title>Am J Med</secondary-title></titles><periodical><full-title>Am J Med</full-title></periodical><pages>194-200</pages><volume>81</volume><number>2</number><keywords><keyword>Adult</keyword><keyword>Comparative Study</keyword><keyword>Complement C3/*analysis</keyword><keyword>Complement C4/*analysis</keyword><keyword>Diagnosis, Differential</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Lupus Erythematosus, Systemic/blood/*diagnosis</keyword><keyword>Pre-Eclampsia/blood/*diagnosis</keyword><keyword>Pregnancy</keyword><keyword>Pregnancy Trimester, Third</keyword><keyword>Research Support, Non-U.S. Gov&apos;t</keyword><keyword>Research Support, U.S. Gov&apos;t, P.H.S.</keyword></keywords><dates><year>1986</year><pub-dates><date>Aug</date></pub-dates></dates><accession-num>3740078</accession-num><urls><related-urls><url> </url></related-urls></urls></record></Cite></EndNote>705Q13. Is the management of paediatric lupus nephritis different from that in adult patients? Diagnosis, monitoring, and prognosisItemOutcome and example(s) of effect sizeNo. studiesDesignReferencesPrevalence of paediatric LNChildhood/juvenile-onset SLE patients are at increased risk for renal involvement compared to adult-onset SLE (>60-70% prevalence; OR 1.5-2.4 for proteinuria and/or casts); nephritis is often presenting feature of paediatric SLE; accompanying manifestations at onset are fever (OR 2.6), lymphadenopathy (OR 12.3), malar rash (OR 6.1), and arthritis; paediatric- vs. adult-onset LN: more severe disease (increased renal damage, increased progression to chronic renal insufficiency or ESRD, increased use of immunosuppressive agents)33IcmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5IZXJzaCwgQS4gTy48L2F1dGhvcj48YXV0aG9yPnZv

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ADDIN EN.CITE.DATA 706-738Kidney biopsy for the diagnosis of paediatric LNISN/RPS 2003 classification (no difference in distribution of histological classes compared to adult patients); histological class correlates with clinical severity of LN (proteinuria level, haematuria, serum albumin, hypertension and need for anti-hypertensive medication)[as above]Prognostic value of kidney biopsy findings in paediatric LNProliferative LN is associated with worse renal outcome than non-proliferative LN; class IV LN is associated with worse outcomes compared to other classes (lower rates of response to therapy, increased damage accrual, higher rates [HR 1.8] of progression to ESRD, reduced patient survival; classes IV-G and mixed V+IV have worse prognosis; fibrinoid necrosis is associated with progression to CRF; biopsy CI correlates with progression to ESRD; tubulo-interstitial lesions correlate with the level of proteinuria, GFR, blood pressure, and progression to CRF; vascular lesions (vasculitis) are associated with increased rates of progression to CRF 21IIIdXRob3I+RGVtaXJjaW48L0F1dGhvcj48WWVhcj4yMDA4PC9ZZWFyPjxSZWNOdW0+NzMzPC9SZWNO

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ADDIN EN.CITE.DATA 707,718,721,731,736,739-754Monitoring LN: blood, serological tests, and urinalysisRenal function tests (SCr, GFR), proteinuria, urine sediment, serum C3/C4, serum anti-dsDNA antibodies, serum anti-C1q antibodies, haemoglobin, platelet count, and serum albumin levels have monitoring ability comparable with that in adult SLE patients14IIIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BcmFnb248L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFyPjxS

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ADDIN EN.CITE.DATA 732,748,750,754-764Monitoring LN: biomarkers Urine NGAL levels show good correlation with the level of proteinuria, renal disease activity indices, kidney biopsy AI and CI (r = 0.39-0.73); urinary proteomics identify biomarkers with very good correlation with renal disease activity; weak evidence for other serum or urine biomarkers 11IIIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ib2Z0bWFuPC9BdXRob3I+PFllYXI+MjAwODwvWWVhcj48

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ADDIN EN.CITE.DATA 757,758,761,762,764-770Monitoring LN: diagnostic and prognostic value of repeat kidney biopsyHistological class transformation into milder forms (if response to therapy) or severe forms (class IV; if no response or severe flare); response to therapy correlates with improvement in pathology findings (particularly reduction in AI); persistent class IV after immunosuppressive treatment is associated with future renal flares 6IIIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BcGVudGVuZzwvQXV0aG9yPjxZZWFyPjIwMDY8L1llYXI+

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ADDIN EN.CITE.DATA 707,719,731,750,754,771Prognosis of paediatric LNIncreased mortality (~2-fold) (n=2 studies), damage accrual, and comorbidities (infections, cataract, avascular necrosis) compared to adult-onset LN; recently (years 2000-2011) published cohorts: 5-yr patient survival 77-98%, 10-yr rates: 65-92%; renal survival rates: 5-yr 75-94% (median 85%); 10-yr 54-90% (median 80%)36IIIZXl3b3JkPkN5Y2xvcGhvc3BoYW1pZGUvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3Jk

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ADDIN EN.CITE.DATA 707,710,713,717-719,721,722,727,732,733,736,739,740,742-745,747,751,771-786Prognostic factors in paediatric LNPredictors of adverse outcome: younger onset of LN; male gender (HR 2.6 for patient death); non-White ethnicity (OR 3.3 for ESRD in black patients); renal histological class (worse outcome in class IV; favourable outcome in class II LN); level of proteinuria (urine protein-to-creatinine ratio >1.0 at onset is associated with OR 3.6 for ESRD); low GFR (<80 ml/min/1.73m2); hypertension (at onset or persistent; HR 1.67 for ESRD); anaemia (haemoglobin <10 g/dL)27IIIMDIyWCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjE1MDA5ODY8L2FjY2Vzc2lvbi1u

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ADDIN EN.CITE.DATA 707,718,721,727,736,739-748,751,752,754,772,777,779,780,782,785,787-789Q13. Is the management of paediatric lupus nephritis different from that in adult patients? ESRDItemOutcome and example(s) of effect sizeNo. studiesDesignReferencesHD in paediatric LNIncreased risk for death in SLE vs. non-SLE paediatric patients on HD (HR 3.1; major causes of mortality are infections, cardiovascular events) (single study); increased risk for complications: less likely to reach target serum albumin levels (OR 0.18), and increased risk for permanent vascular catheter access (OR 2.5; instead of A-V fistulas or grafts)4IIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IaXJha2k8L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFyPjxS

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ADDIN EN.CITE.DATA 582,790-792Renal transplantation in paediatric LNComparable renal outcomes versus disease controls (5-yr allograft survival 71% versus 77%); increased mortality in SLE (HR 1.8; 5-yr recipient survival 91% versus 98%); predictors of allograft loss are recipient age (HR 1.05 per 1-yr), female gender (HR 1.2), Black ethnicity (HR 2.0), cadaveric versus living donor transplant (HR 1.3), HLA mismatch, previous rejection (HR 3.1); predictors of recipient mortality are Black ethnicity (HR 1.6) and cadaveric versus living donor transplant (HR 1.9)2IIIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYXJ0b3NoPC9BdXRob3I+PFllYXI+MjAwMTwvWWVhcj48

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ADDIN EN.CITE.DATA 793,794Q13. Is the management of paediatric lupus nephritis different from that in adult patients? TreatmentItemOutcome and example(s) of effect sizeNo. studiesDesignReferencesClass II LNOral prednisone (starting dose up to 1-2 mg/kg); addition of AZA (2-3 mg/kg/d) or MPA (MMF 300-600 mg/m2) if proteinuria exceeds 1 g/24-hr or SCr exceeds 1.0 mg/dL1III ADDIN EN.CITE <EndNote><Cite><Author>Garin</Author><Year>1986</Year><RecNum>946</RecNum><DisplayText><style face="superscript">795</style></DisplayText><record><rec-number>946</rec-number><foreign-keys><key app="EN" db-id="rfzsw2fw9w0rt5e92z5xwtw6dr20xrrxeedp">946</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Garin, E. H.</author><author>Sleasman, J. W.</author><author>Richard, G. A.</author><author>Iravani, A. A.</author><author>Fennell, R. S.</author></authors></contributors><titles><title>Pulsed methylprednisolone therapy compared to high dose prednisone in systemic lupus erythematosus nephritis</title><secondary-title>Eur J Pediatr</secondary-title></titles><periodical><full-title>Eur J Pediatr</full-title></periodical><pages>380-3</pages><volume>145</volume><number>5</number><keywords><keyword>Adolescent</keyword><keyword>Adult</keyword><keyword>Blood Pressure/drug effects</keyword><keyword>Child</keyword><keyword>Comparative Study</keyword><keyword>Complement C3/analysis</keyword><keyword>Complement C4/analysis</keyword><keyword>Creatinine/blood</keyword><keyword>Drug Administration Schedule</keyword><keyword>Drug Therapy, Combination</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Lupus Nephritis/*drug therapy/physiopathology</keyword><keyword>Male</keyword><keyword>Methylprednisolone/*administration &amp; dosage/adverse effects</keyword><keyword>Prednisone/*administration &amp; dosage/adverse effects</keyword></keywords><dates><year>1986</year><pub-dates><date>Oct</date></pub-dates></dates><accession-num>3792382</accession-num><urls><related-urls><url> </url></related-urls></urls></record></Cite></EndNote>7952IVPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cb2dkYW5vdmljPC9BdXRob3I+PFllYXI+MjAwNDwvWWVh

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ADDIN EN.CITE.DATA 797,802,803Combination of GC and CY (IV 0.5-1 g/m2 ×7 monthly pulses or oral 2 mg/kg/day) is the treatment of choice in most studies with complete response rates 50-70%; benefit over AZA in long-term (8 years) preservation of renal function and patient survival; the regimen is efficacious in steroid-refractory LN, in cases with nephrotic syndrome, abnormal GFR and/or adverse histology (crescents)1II ADDIN EN.CITE <EndNote><Cite><Author>Fu</Author><Year>1998</Year><RecNum>736</RecNum><DisplayText><style face="superscript">804</style></DisplayText><record><rec-number>736</rec-number><foreign-keys><key app="EN" db-id="rfzsw2fw9w0rt5e92z5xwtw6dr20xrrxeedp">736</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Fu, L. W.</author><author>Yang, L. Y.</author><author>Chen, W. P.</author><author>Lin, C. Y.</author></authors></contributors><auth-address>Department of Pediatrics, Veterans General Hospital-Taipei, Taiwan, ROC.</auth-address><titles><title>Clinical efficacy of cyclosporin a neoral in the treatment of paediatric lupus nephritis with heavy proteinuria</title><secondary-title>Br J Rheumatol</secondary-title></titles><periodical><full-title>Br J Rheumatol</full-title></periodical><pages>217-21</pages><volume>37</volume><number>2</number><keywords><keyword>Adolescent</keyword><keyword>Antibodies, Antinuclear/metabolism</keyword><keyword>Antirheumatic Agents/adverse effects/*therapeutic use</keyword><keyword>Child</keyword><keyword>Complement C3/metabolism</keyword><keyword>Cyclophosphamide/therapeutic use</keyword><keyword>Cyclosporine/adverse effects/*therapeutic use</keyword><keyword>DNA/immunology</keyword><keyword>Drug Therapy, Combination</keyword><keyword>Emulsions</keyword><keyword>Humans</keyword><keyword>Lupus Nephritis/complications/*drug therapy/metabolism</keyword><keyword>Prednisolone/therapeutic use</keyword><keyword>Proteinuria/complications/*drug therapy/metabolism</keyword><keyword>Safety</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>1998</year><pub-dates><date>Feb</date></pub-dates></dates><accession-num>9569080</accession-num><urls><related-urls><url> </url></related-urls></urls></record></Cite></EndNote>8042IIIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MYXU8L0F1dGhvcj48WWVhcj4yMDA4PC9ZZWFyPjxSZWNO

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Tm90ZT4A

ADDIN EN.CITE.DATA 710,718,740,743,752,754,785,796,805-813Combination of GC and MPA (MMF 300-900 mg/m2) is efficacious in class III-IV LN cases with preserved renal function; comparable short-term (6 months) efficacy with pulses IV-CY in class III LN; results from epidemiological studies suggest survival benefit since its introduction in the management of paediatric class III-IV LN1IIPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MYXU8L0F1dGhvcj48WWVhcj4yMDA4PC9ZZWFyPjxSZWNO

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ADDIN EN.CITE.DATA 740,743Combination of GC and calcineurin inhibitors (CsA, tacrolimus). Comparable efficacy of CsA (5 mg/kg/day) with the combination of high-dose steroids (2 mg/kg) plus oral CY (2 mg/kg) in reducing proteinuria in steroid-refractory class III-IV LN; ‘triple regimen’ (GC/MMF/CsA) has been used in severe LN cases 1II ADDIN EN.CITE <EndNote><Cite><Author>Fu</Author><Year>1998</Year><RecNum>736</RecNum><DisplayText><style face="superscript">804</style></DisplayText><record><rec-number>736</rec-number><foreign-keys><key app="EN" db-id="rfzsw2fw9w0rt5e92z5xwtw6dr20xrrxeedp">736</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Fu, L. W.</author><author>Yang, L. Y.</author><author>Chen, W. P.</author><author>Lin, C. Y.</author></authors></contributors><auth-address>Department of Pediatrics, Veterans General Hospital-Taipei, Taiwan, ROC.</auth-address><titles><title>Clinical efficacy of cyclosporin a neoral in the treatment of paediatric lupus nephritis with heavy proteinuria</title><secondary-title>Br J Rheumatol</secondary-title></titles><periodical><full-title>Br J Rheumatol</full-title></periodical><pages>217-21</pages><volume>37</volume><number>2</number><keywords><keyword>Adolescent</keyword><keyword>Antibodies, Antinuclear/metabolism</keyword><keyword>Antirheumatic Agents/adverse effects/*therapeutic use</keyword><keyword>Child</keyword><keyword>Complement C3/metabolism</keyword><keyword>Cyclophosphamide/therapeutic use</keyword><keyword>Cyclosporine/adverse effects/*therapeutic use</keyword><keyword>DNA/immunology</keyword><keyword>Drug Therapy, Combination</keyword><keyword>Emulsions</keyword><keyword>Humans</keyword><keyword>Lupus Nephritis/complications/*drug therapy/metabolism</keyword><keyword>Prednisolone/therapeutic use</keyword><keyword>Proteinuria/complications/*drug therapy/metabolism</keyword><keyword>Safety</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>1998</year><pub-dates><date>Feb</date></pub-dates></dates><accession-num>9569080</accession-num><urls><related-urls><url> </url></related-urls></urls></record></Cite></EndNote>8043VPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BcmFnb248L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFyPjxS

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ADDIN EN.CITE.DATA 806,808,811,814,815Other agents: calcineurin inhibitors, mizoribine1II ADDIN EN.CITE <EndNote><Cite><Author>Fu</Author><Year>1998</Year><RecNum>736</RecNum><DisplayText><style face="superscript">804</style></DisplayText><record><rec-number>736</rec-number><foreign-keys><key app="EN" db-id="rfzsw2fw9w0rt5e92z5xwtw6dr20xrrxeedp">736</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Fu, L. W.</author><author>Yang, L. Y.</author><author>Chen, W. P.</author><author>Lin, C. Y.</author></authors></contributors><auth-address>Department of Pediatrics, Veterans General Hospital-Taipei, Taiwan, ROC.</auth-address><titles><title>Clinical efficacy of cyclosporin a neoral in the treatment of paediatric lupus nephritis with heavy proteinuria</title><secondary-title>Br J Rheumatol</secondary-title></titles><periodical><full-title>Br J Rheumatol</full-title></periodical><pages>217-21</pages><volume>37</volume><number>2</number><keywords><keyword>Adolescent</keyword><keyword>Antibodies, Antinuclear/metabolism</keyword><keyword>Antirheumatic Agents/adverse effects/*therapeutic use</keyword><keyword>Child</keyword><keyword>Complement C3/metabolism</keyword><keyword>Cyclophosphamide/therapeutic use</keyword><keyword>Cyclosporine/adverse effects/*therapeutic use</keyword><keyword>DNA/immunology</keyword><keyword>Drug Therapy, Combination</keyword><keyword>Emulsions</keyword><keyword>Humans</keyword><keyword>Lupus Nephritis/complications/*drug therapy/metabolism</keyword><keyword>Prednisolone/therapeutic use</keyword><keyword>Proteinuria/complications/*drug therapy/metabolism</keyword><keyword>Safety</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>1998</year><pub-dates><date>Feb</date></pub-dates></dates><accession-num>9569080</accession-num><urls><related-urls><url> </url></related-urls></urls></record></Cite></EndNote>8045VPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UYW5ha2E8L0F1dGhvcj48WWVhcj4yMDA0PC9ZZWFyPjxS

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bmROb3RlPgB=

ADDIN EN.CITE.DATA 755,798,816-818Class V LNOral GC (0.5-2 mg/kg/day) alone or in combination with immunosuppressive agent (usually AZA; also IV-CY, calcineurin inhibitors, MPA)4VPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5OYXRoYW5zb248L0F1dGhvcj48WWVhcj4yMDA2PC9ZZWFy

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ADDIN EN.CITE.DATA 822,823IVIG (400 mg/kg/d for 5 days): induction of sustained renal response; improved histology1V ADDIN EN.CITE <EndNote><Cite><Author>Lin</Author><Year>1989</Year><RecNum>945</RecNum><DisplayText><style face="superscript">824</style></DisplayText><record><rec-number>945</rec-number><foreign-keys><key app="EN" db-id="rfzsw2fw9w0rt5e92z5xwtw6dr20xrrxeedp">945</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Lin, C. Y.</author><author>Hsu, H. C.</author><author>Chiang, H.</author></authors></contributors><auth-address>Department of Medical Research, Veterans General Hospital, Taipei, Taiwan.</auth-address><titles><title>Improvement of histological and immunological change in steroid and immunosuppressive drug-resistant lupus nephritis by high-dose intravenous gamma globulin</title><secondary-title>Nephron</secondary-title></titles><periodical><full-title>Nephron</full-title></periodical><pages>303-10</pages><volume>53</volume><number>4</number><keywords><keyword>Antigen-Antibody Complex/analysis</keyword><keyword>Biopsy</keyword><keyword>Child</keyword><keyword>Complement C3/analysis</keyword><keyword>Complement C4/analysis</keyword><keyword>Cyclophosphamide/therapeutic use</keyword><keyword>Drug Resistance</keyword><keyword>Female</keyword><keyword>Fluorescent Antibody Technique</keyword><keyword>Humans</keyword><keyword>Injections, Intravenous</keyword><keyword>Kidney/pathology</keyword><keyword>Lupus Nephritis/immunology/pathology/*therapy</keyword><keyword>Male</keyword><keyword>Methylprednisolone/therapeutic use</keyword><keyword>gamma-Globulins/*administration &amp; dosage</keyword></keywords><dates><year>1989</year></dates><accession-num>2481240</accession-num><urls><related-urls><url> </url></related-urls></urls></record></Cite></EndNote>824Mizoribine: improvements in proteinuria and serology 3VPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UYW5ha2E8L0F1dGhvcj48WWVhcj4yMDA2PC9ZZWFyPjxS

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aXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA 818,825,826RTX (miscellaneous regimens; 750 mg/m2 on days 1 and 15) alone or with concurrent/subsequent immunosuppression (MPA, AZA, or IV-CY): improvements in proteinuria, serum albumin levels, serology, and general SLE activity; steroid-sparring effect; complete renal remission 25-50%; partial renal remission rates 50% 3VPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Od29iaTwvQXV0aG9yPjxZZWFyPjIwMDg8L1llYXI+PFJl

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ADDIN EN.CITE.DATA 740,830,831Abbreviations: ACEi, ACE-inhibitor; AI, activity index; aPL, antiphospholipid antibody; APS, antiphospholipid syndrome; APSN, APS-associated nephropathy; ARB, angiotensin receptor blocker; AZA, azathioprine; CI, chronicity index; CRF, chronic renal failure; CsA, ciclosporin A; CY, cyclophosphamide; ESRD, end-stage renal disease; GC, glucocorticoids; GFR, glomerular filtration rate; HCQ, hydroxychloroquine; HD, haemodialysis; HR, hazard ratio; HUS, haemolytic-uremic syndrome; ISN/RPS, International Society of Nephrology / Renal Pathology Society; IUGR, intra-uterine growth restriction; IV-CY, intravenous cyclophosphamide; IVIG, intravenous immunoglobulin; IV-MP, intravenous methyl-prednisolone; LN, lupus nephritis; LR, likelihood ratio; MDRD, Modification of Diet in Renal Disease; MPA, mycophenolic acid; NIH, National Institutes of Health; OR, odds ratio; PD, peritoneal dialysis; RBC, red blood cells; RCT, randomized controlled trial; RR, relative risk; RTX, rituximab; SCr, serum creatinine; TTP, thrombocytopenic thrombotic purpura; WBC, white blood cells; WHO, World Health Organization1 The study design is assigned as follows: I, meta-analysis of RCTs; II, RCT (including long-term follow-up of original RCT using the same randomisation allocation); III, prospective controlled (non-randomized) study or epidemiological studies with prospective collection of data; IV, retrospective controlled or cross-sectional study, V, uncontrolled study (case series)References ADDIN EN.REFLIST 1.Appel GB, Silva FG, Pirani CL, Meltzer JI, Estes D. 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