Moving Forward With Biologics in Lupus Nephritis

Hobeika, Liliane; Ng, Lauren; Lee, Iris J.

doi:10.1053/j.ackd.2019.08.008

Cited by 7 publications

(4 citation statements)

References 103 publications

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“…In recent years, there have been an increasing number of reports on the treatment of LN with biological agents, and more favorable outcomes have been achieved with less toxicity (27,28). Compared with traditional therapeutic drugs, new biological agents target the pathogenesis of LN, offer rapid effects and few side effects, have gained increasing recognition, and have become a research hotspot (29). Of the eligible trials in this study, onethird of trials investigated the safety and efficacy of biologics in the treatment of LN.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Analysis of Clinical Trials Registration for Lupus Nephritis Therapy on ClinicalTrials.gov

Gao

Wang

et al. 2021

Front. Med.

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Objective: Clinical trials are the most effective method for evaluating therapeutic strategies. The purpose of this study was to comprehensively assess the characteristics of trials on lupus nephritis (LN) and provide a reference for LN treatment and research.Methods: Registered therapeutic trials on drug interventions for LN were obtained from ClinicalTrials.gov up to December 3, 2020. The general characteristics, methodological characteristics, detailed characteristics, investigated drugs, eligibility criteria, and outcome measures of these trials were analyzed.Results: A total of 126 eligible trials were evaluated, and these trials mainly investigated the initial treatment of adult proliferative LN. Half of the trials enrolled <50 participants, and 70.7% of the trials lasted for 6–24 months. In total, 95.2% of trials adopted an interventional study design. Of intervention trials, 56.6% were in phase 2 or phase 3, 76.7% were randomized, 77.5% employed a parallel assignment, and 41.7% were masked. The eligibility criteria and outcome measures of the included trials varied and involved a variety of indicators. Chemical agents and biologics are the most widely studied immunotherapies, of which mycophenolate mofetil, tacrolimus, and rituximab are the most studied. In addition, some trials studied cell transplantation treatment.Conclusions: The majority of clinical trials for LN therapy registered on ClinicalTrials.gov investigated the initial treatment of adult proliferative LN, and most of these trials were randomized, parallel assigned, and insufficiently masked interventional trials with small scale, short duration, various eligibility criteria, and outcome measures. We hope that more large-scale, long-term multicenter, and high-quality RCT trials with standardized inclusion criteria/exclusion criteria and treatment effect evaluation systems will be conducted and that more energy and funding will be put into exploring biological products and stem cell therapies. In addition, trials for membranous LN, childhood-onset LN, and maintenance phase LN are needed to establish optimal treatment strategies.

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Section: Discussionmentioning

confidence: 99%

Comprehensive Analysis of Clinical Trials Registration for Lupus Nephritis Therapy on ClinicalTrials.gov

Gao

Wang

et al. 2021

Front. Med.

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“…Since there is no cure for lupus, it is managed in the clinic through a variety of prescribed pharmaceuticals, such as glucocorticoids, immunosuppressants, and monoclonal antibodies ( 26 , 27 ). Despite the efficacy of these therapeutics against chronic inflammation and autoreactive immunity, patients still incur drug-related adverse side effects and steep financial costs ( 28 ). In addition, these therapeutics might need to be taken indefinitely because lupus symptoms can flare spontaneously over a lifetime.…”

Section: Introductionmentioning

confidence: 99%

Lipidome modulation by dietary omega-3 polyunsaturated fatty acid supplementation or selective soluble epoxide hydrolase inhibition suppresses rough LPS-accelerated glomerulonephritis in lupus-prone mice

et al. 2023

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IntroductionLipopolysaccharide (LPS)-accelerated autoimmune glomerulonephritis (GN) in NZBWF1 mice is a preclinical model potentially applicable for investigating lipidome-modulating interventions against lupus. LPS can be expressed as one of two chemotypes: smooth LPS (S-LPS) or rough LPS (R-LPS) which is devoid of O-antigen polysaccharide sidechain. Since these chemotypes differentially affect toll-like receptor 4 (TLR4)-mediated immune cell responses, these differences may influence GN induction.MethodsWe initially compared the effects of subchronic intraperitoneal (i.p.) injection for 5 wk with 1) Salmonella S-LPS, 2) Salmonella R-LPS, or 3) saline vehicle (VEH) (Study 1) in female NZBWF1 mice. Based on the efficacy of R-LPS in inducing GN, we next used it to compare the impact of two lipidome-modulating interventions, ω-3 polyunsaturated fatty acid (PUFA) supplementation and soluble epoxide hydrolase (sEH) inhibition, on GN (Study 2). Specifically, effects of consuming ω-3 docosahexaenoic acid (DHA) (10 g/kg diet) and/or the sEH inhibitor 1-(4-trifluoro-methoxy-phenyl)-3-(1-propionylpiperidin-4-yl) urea (TPPU) (22.5 mg/kg diet ≈ 3 mg/kg/day) on R-LPS triggering were compared.ResultsIn Study 1, R-LPS induced robust elevations in blood urea nitrogen, proteinuria, and hematuria that were not evident in VEH- or S-LPS-treated mice. R-LPS-treated mice further exhibited kidney histopathology including robust hypertrophy, hyperplasia, thickened membranes, lymphocytic accumulation containing B and T cells, and glomerular IgG deposition consistent with GN that was not evident in VEH- or SLPS-treated groups. R-LPS but not S-LPS induced spleen enlargement with lymphoid hyperplasia and inflammatory cell recruitment in the liver. In Study 2, resultant blood fatty acid profiles and epoxy fatty acid concentrations reflected the anticipated DHA- and TPPU-mediated lipidome changes, respectively. The relative rank order of R-LPS-induced GN severity among groups fed experimental diets based on proteinuria, hematuria, histopathologic scoring, and glomerular IgG deposition was: VEH/CON< R-LPS/DHA ≈ R-LPS/TPPU<<< R-LPS/TPPU+DHA ≈ R-LPS/CON. In contrast, these interventions had modest-to- negligible effects on R-LPS-induced splenomegaly, plasma antibody responses, liver inflammation, and inflammation-associated kidney gene expression.DiscussionWe show for the first time that absence of O-antigenic polysaccharide in R-LPS is critical to accelerated GN in lupus-prone mice. Furthermore, intervention by lipidome modulation through DHA feeding or sEH inhibition suppressed R-LPS-induced GN; however, these ameliorative effects were greatly diminished upon combining the treatments.

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“…In SLE, lupus nephritis (LN) is considered as the major pathogenic and fatal risk contributors ( Maria and Davidson, 2020 ), affecting almost 40% of adults with SLE, with 10% of LN patients having to face the torment of end-stage renal disease ultimately ( Bastian et al, 2002 ; Jakes et al, 2012 ; Almaani et al, 2017 ). Recently, the efficacy of corticosteroids, cyclophosphamide, mofetil/mycophenolate, and calcineurin inhibitors in LN was identified ( Fanouriakis et al, 2019 ), yet low complete response rates, risk of flares, side effects and adverse outcome events of these treatments still remain major concerns to physicians ( Hobeika et al, 2019 ). Hence, finding effective and safe alternative medicines to fight against LN is an urgent global issue to be addressed.…”

Section: Introductionmentioning

confidence: 99%

Molecular mechanism of Hedyotis Diffusae Herba in the treatment of lupus nephritis based on network pharmacology

Yang

2023

Front. Pharmacol.

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Aims: To determine the bioactive components of Hedyotis Diffusae Herba (HDH) and the targets in treating lupus nephritis (LN), and so as to elucidate the protective mechanism of HDH against LN.Methods and results: An aggregate of 147 drug targets and 162 LN targets were obtained from online databases, with 23 overlapped targets being determined as potential therapeutic targets of HDH against LN. Through centrality analysis, TNF, VEGFA and JUN were screened as core targets. And the bindings of TNF with stigmasterol, TNF with quercetin, and VEGFA with quercetin were further validated by molecular docking. By conducting Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses for drug targets, disease targets and the shared targets, TNF signaling pathway, Toll-like receptor signaling pathway, NF-kappa B signaling pathway and HIF-1 signaling pathway, etc., were found in all these three lists, indicating the potential mechanism of HDH in the treatment of LN.Conclusion: HDH may ameliorate the renal injury in LN by targeting multi-targets and multi-pathways, including TNF signaling pathway, NF-kappa B signaling pathway, HIF-1 signaling pathway and so on, which provided novel insights into further researches of the drug discovery in LN.

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Moving Forward With Biologics in Lupus Nephritis

Cited by 7 publications

References 103 publications

Comprehensive Analysis of Clinical Trials Registration for Lupus Nephritis Therapy on ClinicalTrials.gov

Comprehensive Analysis of Clinical Trials Registration for Lupus Nephritis Therapy on ClinicalTrials.gov

Lipidome modulation by dietary omega-3 polyunsaturated fatty acid supplementation or selective soluble epoxide hydrolase inhibition suppresses rough LPS-accelerated glomerulonephritis in lupus-prone mice

Molecular mechanism of Hedyotis Diffusae Herba in the treatment of lupus nephritis based on network pharmacology

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