A secondary analysis of the Belimumab International Study in Lupus Nephritis trial examined effects of belimumab on kidney outcomes and preservation of kidney function in patients with lupus nephritis

We performed a post hoc analysis of the Belimumab International Study in Lupus Nephritis (BLISS-LN), a Phase 3, multinational, double-blind, 104-week trial, in which 448 patients with lupus nephritis were randomized to receive intravenous belimumab 10 mg/kg or placebo with standard therapy (cyclophosphamide/azathioprine or mycophenolate mofetil). Add-on belimumab was found to be most effective in improving the primary efficacy kidney response and complete kidney response in patients with proliferative lupus nephritis and a baseline urine protein/creatinine ratio under 3 g/g. However, there was no observed improvement in the kidney response with belimumab treatment in patients with lupus nephritis and sub-epithelial deposits or with a baseline protein/creatinine ratio of 3 g/g or more. Belimumab significantly reduced the risk of kidney-related events or death and lupus nephritis flare in the overall population. Belimumab reduced the risk of a sustained 30% or 40% decline in estimated glomerular filtration rate (eGFR) versus standard treatment alone and attenuated the annual rate of eGFR decline in patients who remained on-study. Thus, our data suggest that the addition of belimumab to standard therapy could attenuate the risk of lupus nephritis flare and eGFR decline in a broad spectrum of patients with lupus nephritis.Nephrolog

Management and treatment of glomerular diseases (part 2): conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference

Contains fulltext : 203024.pdf (publisher's version ) (Open Access)In November 2017, the Kidney Disease: Improving Global Outcomes (KDIGO) initiative brought a diverse panel of experts in glomerular diseases together to discuss the 2012 KDIGO glomerulonephritis guideline in the context of new developments and insights that had occurred over the years since its publication. During this KDIGO Controversies Conference on Glomerular Diseases, the group examined data on disease pathogenesis, biomarkers, and treatments to identify areas of consensus and areas of controversy. This report summarizes the discussions on primary podocytopathies, lupus nephritis, anti-neutrophil cytoplasmic antibody-associated nephritis, complement-mediated kidney diseases, and monoclonal gammopathies of renal significance

KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases

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Safety and Efficacy of Belimumab in Patients with Lupus Nephritis Open-Label Extension of BLISS-LN Study

Background and objectives In the BLISS-LN study, belimumab improved kidney outcomes in adult patients with active lupus nephritis. This 28-week open-label extension of BLISS-LN assessed belimumab's safety and efficacy. Design, setting, participants, & measurements Eligible patients completing BLISS-LN received monthly intravenous belimumab 10 mg/kg plus standard therapy. End points included safety, open-label week 28 primary efficacy renal response (urine protein-creatinine ratio [UPCR] _60 ml/min per 1.73 m2, no prohibited medications) and complete renal response (UPCR _90 ml/min per 1.73 m2, no prohibited medications), and UPCR and eGFR by visit. Responses were also analyzed post hoc using the double-blind phase criteria. Results Of 257 enrolled patients, 255 were treated (safety population: n=123 switched from placebo-tobelimumab; n=132 remained on belimumab); 245 (97%) patients completed the study. Adverse events and serious adverse events were experienced by 62% and 4% of placebo-to-belimumab patients, respectively, and by 70% and 8% of belimumab-to-belimumab patients, respectively. One death occurred in the placebo-to-belimumab group. From open-label baseline to week 28, increases occurred in the proportions of patients achieving primary efficacy renal response (placebo-to-belimumab: from 60% to 67%; belimumab-to-belimumab: from 70% to 75%) and complete renal response (placebo-to-belimumab: from 36% to 48%; belimumab-to-belimumab: from 48% to 62%). Based on double-blind phase criteria, changes also occurred in the proportions achieving primary efficacy renal response (placebo-to-belimumab: from 54% to 53%; belimumab-to-belimumab: from 66% to 52%) and complete renal response (placebo-to-belimumab: from 34% to 35%; belimumab-to-belimumab: from 46% to 41%). The seeming decrease in response rates in the belimumab-to-belimumab groups was attributed to discontinuations/administration of glucocorticoids for non-SLE reasons as opposed to nephritis. Median UPCR and eGFR values were similar at open-label baseline and week 28. Conclusions No new safety signals were identified, and efficacy was generally maintained throughout the open label phase. contributing the affiliations listed at the article. Correspondence: Dr. Richard Division of Rheumatology, Northwell Donald and Zucker School Medicine, Northwell Suite 302, NY 11021. [email protected]

Safety and Efficacy of Belimumab in Patients with Lupus Nephritis Open-Label Extension of BLISS-LN Study

Background and objectives In the BLISS-LN study, belimumab improved kidney outcomes in adult patients with active lupus nephritis. This 28-week open-label extension of BLISS-LN assessed belimumab's safety and efficacy. Design, setting, participants, & measurements Eligible patients completing BLISS-LN received monthly intravenous belimumab 10 mg/kg plus standard therapy. End points included safety, open-label week 28 primary efficacy renal response (urine protein-creatinine ratio [UPCR] _60 ml/min per 1.73 m2, no prohibited medications) and complete renal response (UPCR _90 ml/min per 1.73 m2, no prohibited medications), and UPCR and eGFR by visit. Responses were also analyzed post hoc using the double-blind phase criteria. Results Of 257 enrolled patients, 255 were treated (safety population: n=123 switched from placebo-tobelimumab; n=132 remained on belimumab); 245 (97%) patients completed the study. Adverse events and serious adverse events were experienced by 62% and 4% of placebo-to-belimumab patients, respectively, and by 70% and 8% of belimumab-to-belimumab patients, respectively. One death occurred in the placebo-to-belimumab group. From open-label baseline to week 28, increases occurred in the proportions of patients achieving primary efficacy renal response (placebo-to-belimumab: from 60% to 67%; belimumab-to-belimumab: from 70% to 75%) and complete renal response (placebo-to-belimumab: from 36% to 48%; belimumab-to-belimumab: from 48% to 62%). Based on double-blind phase criteria, changes also occurred in the proportions achieving primary efficacy renal response (placebo-to-belimumab: from 54% to 53%; belimumab-to-belimumab: from 66% to 52%) and complete renal response (placebo-to-belimumab: from 34% to 35%; belimumab-to-belimumab: from 46% to 41%). The seeming decrease in response rates in the belimumab-to-belimumab groups was attributed to discontinuations/administration of glucocorticoids for non-SLE reasons as opposed to nephritis. Median UPCR and eGFR values were similar at open-label baseline and week 28. Conclusions No new safety signals were identified, and efficacy was generally maintained throughout the open label phase. contributing the affiliations listed at the article. Correspondence: Dr. Richard Division of Rheumatology, Northwell Donald and Zucker School Medicine, Northwell Suite 302, NY 11021. [email protected]

Tolérance et efficacité du belimumab intraveineux dans une étude d’extension en ouvert de 6 mois chez des patients atteints de glomérulonéphrite lupique

Une étude précédente dans la glomérulonéphrite lupique (GNL) a montré que le belimumab (BEL) par voie intraveineuse (IV)+traitement standard (TS) améliorait les résultats par rapport au TS seul chez des patients (pts) avec une GNL active à 24 mois. Évaluer les données de tolérance et d’efficacité de BEL+TS dans une phase d’extension en ouvert (OL) de 6 mois, après les 2 ans de traitement en double aveugle (DB). Dans cette phase OL, tous les patients ayant terminé la phase DB ont reçu mensuellement BEL 10mg/kg IV+TS pendant 6 mois. Critères d’évaluation : – tolérance ; – réponse rénale primaire d’efficacité (PERR : uPCR≤0,7 ; baisse du DFGe<20 % de la valeur à baseline OL ou≥60mL/min/1,73m2 ; aucun médicament interdit) ; – réponse rénale complète (CRR ; uPCR<0,5 ; baisse du DFGe<10 % de la valeur à baseline OL ou≥90mL/min/1,73m2 ; aucun médicament interdit) à la semaine (S) 28 de l’OL ; – proportion de pts avec un score SLEDAI<4 ; – utilisation de corticoïdes ; – biomarqueurs. Les analyses étaient basées sur les données observées et résumées par rapport à la baseline OL (dernière valeur mesurée avant la première dose de traitement en OL). Au total, 257 pts (57,4 % des pts dans BEL114054) ont été inclus et 255 ont été traités. Tous les pts traités ont été inclus dans l’étude de tolérance (123 pts sont passés du placebo [PBO] à BEL ; 132 sont restés sous BEL). L’efficacité a été évaluée sur la population de l’étude de tolérance, sauf 1 pt exclus pour non-conformité (population mITT ; PBO-BEL : 122 pts ; BEL-BEL : 132 pts). Parmi les pts, 96,5 % ont terminé la phase d’OL ; 3,5 % se sont retirés, principalement pour des événements indésirables (EI : 2,0 %). Tolérance globale : 168/255 (65,9 %) pts avaient≥1 EI (76/123 [61,8 %] pts PBO-BEL et 92/132 [69,7 %] pts BEL-BEL) ; 15/255 (5,9 %) pts avaient≥1 EI grave (5/123 [4,1 %] pts PBO-BEL et 10/132 [7,6 %] pts BEL-BEL) ; 1 (0,8 %) pt est décédé dans le groupe PBO-BEL. Dans les deux groupes, la proportion de répondeurs PERR et CRR a augmenté de la baseline OL à S28. La proportion de répondeurs PERR est passée de 73/122 (59,8 %) à 79/118 (66,9 %) dans le groupe PBO-BEL et de 93/132 (70,5 %) à 91/122 (74,6 %) dans le groupe BEL-BEL. La proportion de répondeurs CRR est passée de 44/122 (36,1 %) à 57/118 (48,3 %) dans le groupe PBO-BEL et de 63/132 (47,7 %) à 76/122 (62,3 %) dans le groupe BEL-BEL. La proportion de pts avec un score SLEDAI<4 est passée de 64/132 (48,5 %) à baseline OL à 64/122 (52,5 %) à la S28 dans le groupe BEL-BEL et a diminué de 44/122 (36,1 %) à 40/118 (33,3 %) dans le groupe PBO-BEL. Parmi les pts recevant des doses quotidiennes moyennes≤5mg ou≤7,5mg d’équivalent prednisone, la dose a été maintenue de la baseline OL (≤5mg : 59/122 [48,4 %] PBO-BEL ; 78/132 [59,1 %] BEL-BEL ; ≤7,5mg : 62/122 [50,8 %] PBO-BEL ; 85/132 [64,4 %] BEL-BEL) à S28 (≤5mg : 60/118 [49,6 %] PBO-BEL ; 75/122 [58,6 %] BEL-BEL ; ≤7,5mg : 66/122 [54,5 %] PBO-BEL ; 83/122 [64,8 %] BEL-BEL). Chez les pts présentant des auto-anticorps à baseline OL, les taux d’anti-ADNdb et d’anti-C1q ont diminué entre la baseline OL et S28 dans les deux groupes. Dans le groupe PBO-BEL, la diminution médiane exprimée en pourcentage par rapport à la baseline OL était de −30,2 % (intervalle interquartile [IQR] : −43,6 ; −6,8) et −23,0 % (IQR : −41,5 ; 0,5) pour les anti-ADNdb et anti-C1q, respectivement. Dans le groupe BEL-BEL, cette diminution était de −10,7 % (IQR : −27,2 ; 9,1) pour les anti-ADNdb et de −16,5 % (IQR : −33,0 ; 6,1) pour les anti-C1q. Chez les pts avec une consommation du complément à baseline OL, l’augmentation médiane exprimée en pourcentage était de 6,2 % (IQR : −4,2 ; 14,6) pour le C3 et 23,6 % (IQR : 11,1 ; 37,5) pour le C4 dans le groupe PBO-BEL et de 4,7 % (IQR : −4,8 ; 16,9) et 11,1 % (IQR : 0,0 ; 57,1) respectivement, dans le groupe BEL-BEL à S28. Dans cette phase OL, la proportion de répondeurs PERR et CRR a augmenté dans les 2 groupes PBO-BEL-et BEL-BEL et aucun nouveau signal de sécurité n’a été observé. Les taux de biomarqueurs se sont améliorés, en particulier chez les patients qui sont passés du PBO au BEL. Présentation antérieure : Abstract repris du congrès annuel EULAR, 2–5 juin 2021. EULAR ne garantit ni n’approuve aucun produit ou service commercial. Reprise par GSK

Phenotypes, genotypes and disease susceptibility associated with gene copy number variations: complement C4 CNVs in European American healthy subjects and those with systemic lupus erythematosus

A new paradigm in human genetics is high frequencies of inter-individual variations in copy numbers of specific genomic DNA segments. Such common copy number variation (CNV) loci often contain genes engaged in host-environment interaction including those involved in immune effector functions. DNA sequences within a CNV locus often share a high degree of identity but beneficial or deleterious polymorphic variants are present among different individuals. Thus, common gene CNVs can contribute, both qualitatively and quantitatively, to a spectrum of phenotypic variants. In this review we describe the phenotypic and genotypic diversities of complement C4 created by copy number variations of RCCX modules (RP-C4-CYP21-TNX) and size dichotomy of C4 genes. A direct outcome of C4 CNV is the generation of two classes of polymorphic proteins, C4A and C4B, with differential chemical reactivities towards peptide or carbohydrate antigens, and a range of C4 plasma protein concentrations (from 15 to 70 mg/dl) among healthy subjects. Deliberate molecular genetic studies enabled development of definitive techniques to determine exact patterns of RCCX modular variations, copy numbers of long and short C4A and C4B genes by Southern blot analyses or by real-time quantitative PCR. It is found that in healthy European Americans, the total C4 gene copy number per diploid genome ranges from 2 to 6: 60.8% of people with four copies of C4 genes, 27.2% with less than four copies, and 12% with more than four copies. Such a distribution is skewed towards the low copy number side in patients with systemic lupus erythematosus (SLE), a prototypic autoimmune disease with complex etiology. In SLE, the frequency of individuals with less than four copies of C4 is significantly increased (42.2%), while the frequency of those with more than four copies is decreased (6%). This decrease in total C4 gene copy number in SLE is due to increases in homozygous and heterozygous deficiencies of C4A but not C4B. Therefore, it is concluded that lower copy number of C4 is a risk factor for and higher gene copy number of C4 is a protective factor against SLE disease susceptibility