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Gemma D Banham, Shaun M Flint, Nicholas Torpey, Paul A Lyons, Don N Shanahan, Adele Gibson, Christopher J E Watson, Ann-Marie O'Sullivan, Joseph A Chadwick, Katie E Foster, Rachel B Jones, Luke R Devey, Anna Richards, Lars-Peter Erwig, Caroline O Savage, Kenneth G C Smith, Robert B Henderson, Menna R Clatworthy
BACKGROUND: B cells produce alloantibodies and activate alloreactive T cells, negatively affecting kidney transplant survival. By contrast, regulatory B cells are associated with transplant tolerance. Immunotherapies are needed that inhibit B-cell effector function, including antibody secretion, while sparing regulators and minimising infection risk. B lymphocyte stimulator (BLyS) is a cytokine that promotes B-cell activation and has not previously been targeted in kidney transplant recipients...
June 14, 2018: Lancet
Renaud Felten, Elida Dervovic, François Chasset, Jacques-Eric Gottenberg, Jean Sibilia, Florence Scher, Laurent Arnaud
Currently, Systemic Lupus Erythematosus (SLE) therapies range from antimalarials to glucocorticoids, in addition to immunosupressive agents or biologics such as rituximab or belimumab, when needed. Several unmet needs remain in the treatment SLE and more targeted drugs with improved safety profiles are expected. Based on recent advances in the understanding of the complex pathogenesis of SLE, several targeted treatments are currently assessed in clinical trials. In this study, we performed a systematic review of all targeted therapies under clinical development in SLE in 17 online registries of clinical trials...
June 6, 2018: Autoimmunity Reviews
Damir Bojadzic, Peter Buchwald
Protein-protein interactions (PPIs) that are part of the costimulatory and coinhibitory (immune checkpoint) signaling are critical for adequate T cell response and are important therapeutic targets for immunomodulation. Biologics targeting them have already achieved considerable clinical success in the treatment of autoimmune diseases or transplant recipients (e.g., abatacept, belatacept, and belimumab) as well as cancer (e.g., ipilimumab, nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab). In view of such progress, there have been only relatively limited efforts toward developing small-molecule PPI inhibitors (SMPPIIs) targeting these cosignaling interactions, possibly because they, as all other PPIs, are difficult to target by small molecules and were not considered druggable...
May 30, 2018: Current Topics in Medicinal Chemistry
A Doria, D Bass, A Schwarting, A Hammer, D Gordon, M Scheinberg, N L Fox, J Groark, W Stohl, C Kleoudis, D Roth
Objective To evaluate the safety, tolerability and efficacy of subcutaneous (SC) belimumab in patients with systemic lupus erythematosus (SLE) beyond 1 year. Methods This was a 24-week, open-label extension following a 52-week, double-blind, placebo-controlled trial of belimumab SC. Patients who completed the double-blind phase were eligible to enter the open-label phase. All patients received weekly belimumab 200 mg SC plus standard SLE therapy. Outcome measures included safety and efficacy (SLE Response Index (SRI) and SLE Flare Index (SFI) rates), and changes in biomarker and B cell levels...
January 1, 2018: Lupus
Martin Aringer, Thomas Dörner
The work on new classification criteria for SLE supported by both EULAR and ACR has led to the reconfirmation that almost all SLE patients are ANA positive. The criteria developed now rely on ANA as an entry criterion and weighted additive criteria. Remission criteria have reached international consensus, which combine the absence of inflammatory activity with glucocorticoids of not higher than 5 mg prednisolone/prednisone q. d. This is also meant to reduce the excessive risk of atherosclerosis, where ASS and moderate alcohol consumption appear to be helpful...
June 2018: Deutsche Medizinische Wochenschrift
Yoshiya Tanaka, Damon Bass, Myron Chu, Sally Egginton, Beulah Ji, Herbert Struemper, David Roth
OBJECTIVES: To assess the efficacy and safety of intravenous belimumab plus standard systemic lupus erythematosus (SLE) therapy (SoC) in Japanese patients with SLE. METHODS: A Phase 3, multicenter, double-blind, placebo-controlled, 52-week study (BEL 113750; NCT01345253) in patients with SLE, randomized 2:1 to belimumab 10 mg/kg plus SoC or placebo plus SoC to Week 48. RESULTS: Sixty of 707 randomized patients were enrolled from study centers in Japan (belimumab, n = 39; placebo, n = 21)...
May 24, 2018: Modern Rheumatology
Amanda L Hulbert, Elizabeth N Pavlisko, Scott M Palmer
PURPOSE OF REVIEW: There is increasing recognition of the importance of antibody-mediated rejection (AMR) after lung transplantation. The development of donor-specific antibodies, a key feature of AMR, occurs in approximately 30% of lung transplant recipients and is associated with poor posttransplant outcomes. This review highlights recently developed AMR diagnostic criteria in lung transplantation, potential mechanisms that mediate the development of AMR, and discusses current and emerging treatment strategies for this significant, graft-limiting complication...
June 2018: Current Opinion in Organ Transplantation
Francesca Trentin, Mariele Gatto, Margherita Zen, Maddalena Larosa, Linda Nalotto, Francesca Saccon, Elisabetta Zanatta, Luca Iaccarino, Andrea Doria
The original version of this article unfortunately contained a mistake. Maddalena Larosa's given name and surname were inadvertently interchanged.
April 16, 2018: Clinical Reviews in Allergy & Immunology
Sulabha Ramachandran, Daniel Parks, Milena Kurtinecz, David A Roth, Rafael Alfonso-Cristancho
AIM: To compare the efficacy of intravenous (IV) and subcutaneous (SC) belimumab plus standard therapy in patients with active, autoantibody-positive systemic lupus erythematosus and high disease activity (HDA). PATIENTS & METHODS: An indirect treatment comparison using patient-level data of patients with HDA from three belimumab IV Phase III randomized controlled trials (BLISS-52 [BEL110751]; BLISS-76 [BEL110752]; Northeast Asia study [BEL113750]) and one belimumab SC randomized controlled trial (BLISS-SC [BEL112341])...
June 2018: Journal of Comparative Effectiveness Research
A Doria, W Stohl, A Schwarting, M Okada, M Scheinberg, R van Vollenhoven, A E Hammer, J Groark, D Bass, N L Fox, D Roth, D Gordon
OBJECTIVE: To investigate the efficacy and safety of belimumab, a human immunoglobulin monoclonal antibody against B lymphocyte stimulator, in a subset of patients with systemic lupus erythematosus (SLE) who were hypocomplementemic (C3 [<90 mg/dL] and/or C4 [<10 mg/dL]) and anti-double-stranded(ds)DNA-positive (≥30 IU/mL) at baseline. METHODS: This Phase III, double-blind, placebo-controlled study (BEL112341; NCT01484496) randomized patients (2:1) with moderate-to-severe SLE (Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index ≥8) to weekly subcutaneous (SC) belimumab 200 mg or placebo, plus standard SLE therapy, for 52 weeks...
April 18, 2018: Arthritis & Rheumatology
Karen Hewett, Donald B Sanders, Richard A Grove, Christine L Broderick, Todd J Rudo, Ashlyn Bassiri, Marina Zvartau-Hind, Vera Bril
OBJECTIVE: To investigate the efficacy and safety of belimumab, a fully human immunoglobulin G1λ monoclonal antibody against B-lymphocyte stimulator, in participants with generalized myasthenia gravis (MG) who remained symptomatic despite standard of care (SoC) therapy. METHODS: Eligible participants with MG were randomized 1:1 to receive IV belimumab 10 mg/kg or placebo in this phase II, placebo-controlled, multicenter, double-blind study (NCT01480596; BEL115123)...
April 17, 2018: Neurology
Pedro L Carreira, David A Isenberg
SLE has a complex pathogenesis, and multiple therapeutic targets have been discovered in recent years. In spite of belimumab being approved by the US Food and Drug Administration and the widespread use of rituximab, there have been many failed attempts to treat SLE successfully using biologic agents. In this review, we consider newer biologic approaches that might offer the hope of improving the outcome of SLE patients. These include the fully humanized anti-CD20 mAbs, PEGylated anti-CD40L, IFNα inhibitors, rigerimod and immune complexes blockade...
April 5, 2018: Rheumatology
Michal Abrahamowicz, John M Esdaile, Rosalind Ramsey-Goldman, Lee S Simon, Vibeke Strand, Peter E Lipsky
BACKGROUND: Trials of new SLE treatments are hampered by the lack of effective outcome measures. To address this, we developed a new Lupus Multivariable Lupus Outcome Score (LuMOS). METHOD: The LuMOS formula was developed by analyzing raw data of two pivotal trials: BLISS-52 and BLISS-76, the basis for approval of belimumab (Bel). Using data from BLISS-76 as the learning dataset, we optimized discrimination between outcomes for patients treated with 10mg/kg Bel versus placebo over the first 52 weeks of follow-up using multivariable logistic regression analyses...
April 12, 2018: Arthritis & Rheumatology
Radim Bečvář
Vasculitides with positivity of autoantibodies to neutrophil leukocytes cytoplasm (ANCA, AAV) belong to primary vasculitides involving small and less commonly medium size blood vessels. Three different clinical types of AAV can be distinguished: granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis and microscopic polyangiitis. Since these autoantibodies seem to be weak activity biomarkers of AAV new molecules and factors start to come up, e.g. neutrophil extracellular traps NET, several T-lymphocyte subpopulations and different immunoglobulins classes of ANCA...
2018: Vnitr̆ní Lékar̆ství
Woori Shin, Hyun Tae Lee, Heejin Lim, Sang Hyung Lee, Ji Young Son, Jee Un Lee, Ki-Young Yoo, Seong Eon Ryu, Jaejun Rhie, Ju Yeon Lee, Yong-Seok Heo
BAFF, a member of the TNF superfamily, has been recognized as a good target for autoimmune diseases. Belimumab, an anti-BAFF monoclonal antibody, was approved by the FDA for use in treating systemic lupus erythematosus. However, the molecular basis of BAFF neutralization by belimumab remains unclear. Here our crystal structure of the BAFF-belimumab Fab complex shows the precise epitope and the BAFF-neutralizing mechanism of belimumab, and demonstrates that the therapeutic activity of belimumab involves not only antagonizing the BAFF-receptor interaction, but also disrupting the formation of the more active BAFF 60-mer to favor the induction of the less active BAFF trimer through interaction with the flap region of BAFF...
March 23, 2018: Nature Communications
Michele Vigolo, Melissa G Chambers, Laure Willen, Dehlia Chevalley, Klaus Maskos, Alfred Lammens, Aubry Tardivel, Dolon Das, Christine Kowalczyk-Quintas, Sonia Schuepbach-Mallepell, Cristian R Smulski, Mahya Eslami, Antonius Rolink, Edith Hummler, Eileen Samy, Yves Fomekong Nanfack, Fabienne Mackay, Maofu Liao, Henry Hess, Xuliang Jiang, Pascal Schneider
The B cell survival factor (TNFSF13B/BAFF) is often elevated in autoimmune diseases and is targeted in the clinic for the treatment of systemic lupus erythematosus. BAFF contains a loop region designated the flap, which is dispensable for receptor binding. Here we show that the flap of BAFF has two functions. In addition to facilitating the formation of a highly active BAFF 60-mer as shown previously, it also converts binding of BAFF to TNFRSF13C (BAFFR) into a signaling event via oligomerization of individual BAFF-BAFFR complexes...
March 23, 2018: Nature Communications
Antonis Fanouriakis, Christina Adamichou, Sofia Koutsoviti, Stylianos Panopoulos, Chrysanthi Staveri, Anastasia Klagou, Christina Tsalapaki, Lamprini Pantazi, Styliani Konsta, Clio P Mavragani, Despoina Dimopoulou, Styliani Ntali, Georgios Katsikas, Kyriaki A Boki, Dimitrios Vassilopoulos, Pinelopi Konstantopoulou, Stamatis-Nick Liossis, Antonia Elezoglou, Maria Tektonidou, Prodromos Sidiropoulos, Abdulsamet Erden, Petros P Sfikakis, George Bertsias, Dimitrios T Boumpas
BACKGROUND: Low disease activity is a validated target of current systemic lupus erythematosus (SLE) therapy. The aim of this study was to assess the ability of belimumab to achieve low disease activity states in real-life settings. METHODS: Multicentre prospective observational study of consecutive SLE patients receiving belimumab for at least 3 months, due to active disease refractory to at least one conventional immunosuppressant. Disease activity, including the recently defined lupus low disease activity state (LLDAS) and remission (clinical SLEDAI-2K = 0), accrual of organ damage, flares and side effects were documented...
February 23, 2018: Seminars in Arthritis and Rheumatism
Daniel Geh, Caroline Gordon
Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease. There are three drugs licensed for the treatment of lupus: corticosteroids, hydroxychloroquine and belimumab. Immunosuppressants such as azathioprine, methotrexate and mycophenolate are also used. Despite these treatments there is still considerable morbidity. New treatments are needed for the management of active lupus. Epratuzumab a humanized IgG1 monoclonal antibody that targets CD22 resulting in selective B cell modulation that has been considered a potential treatment for SLE...
April 2018: Expert Review of Clinical Immunology
Roberta Gualtierotti, Maria Orietta Borghi, Maria Gerosa, Tommaso Schioppo, Paola Larghi, Jens Geginat, Pier Luigi Meroni
OBJECTIVES: B cells play an important role in the initiation and progression of systemic lupus erythematosus (SLE). Accordingly, B cell-targeted therapy has been suggested as a new rational approach for treating lupus. Belimumab, a human monoclonal antibody directed against B lymphocyte stimulator (BLyS), was reported as the first biological treatment effective in reducing mild-to-moderate SLE disease activity by using different scoring systems and endpoints. Conversely clinical trials with rituximab, a chimeric monoclonal antibody directed against the CD20 expressed by B cells, have failed to achieve primary endpoints in spite of a number of reports showing its beneficial effects...
February 27, 2018: Clinical and Experimental Rheumatology
Surabhi S Vinod, Annelle B Reed, Jamelle Maxwell, Randy Q Cron, Matthew L Stoll
BACKGROUND: Children with chronic rheumatic disease often require intravenous (IV) therapy. Our center has instituted standardized protocols for use of IV medications in rheumatology patients. Herein, we introduce the therapeutic protocols and report on their short-term safety. METHODS: This was an institutional review board (IRB) approved retrospective chart review of all patients who had received IV infusions between the years 2012 and 2015 at a single center, prescribed by a pediatric rheumatologist...
March 9, 2018: Pediatric Rheumatology Online Journal
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