Belimumab in systemic lupus erythematosus (SLE): evidence-to-date and clinical usefulness

Castro, Sara Guerreiro; Isenberg, David

doi:10.1177/1759720x17690474

Cited by 32 publications

(17 citation statements)

References 32 publications

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“…The symptoms of SLE include facial red rash, painful and swollen joints, fever, chest pain, hair loss, mouth ulcers, swollen lymph nodes, and fatigue. The BAFF inhibitor belimumab has been accepted for clinical use in SLE [75], and type I IFN antagonist anifrolumab is currently in phase III trials [76]. The activated cytokine signaling implies that SLE as well as alopecia areata (AA), in which Th1, Th2, Th17 and/or Treg cells have been suggested to play roles in pathogenesis [77, 78], could benefit from certain biologics and JAK inhibitors but none has entered the clinics to date.…”

Section: Inflammatory and Autoimmune Diseases: Rationale For Janus Kimentioning

confidence: 99%

Selective JAKinibs: Prospects in Inflammatory and Autoimmune Diseases

et al. 2019

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Cytokines, many of which signal through the JAK-STAT (Janus kinase-Signal Transducers and Activators of Transcription) pathway, play a central role in the pathogenesis of inflammatory and autoimmune diseases. Currently three JAK inhibitors have been approved for clinical use in USA and/or Europe: tofacitinib for rheumatoid arthritis, psoriatic arthritis and ulcerative colitis, baricitinib for rheumatoid arthritis, and ruxolitinib for myeloproliferative neoplasms. The clinical JAK inhibitors target multiple JAKs at high potency and current research has focused on more selective JAK inhibitors, almost a dozen of which currently are being evaluated in clinical trials. In this narrative review, we summarize the status of the pan-JAK and selective JAK inhibitors approved or in clinical trials, and discuss the rationale for selective targeting of JAKs in inflammatory and autoimmune diseases.

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Section: Inflammatory and Autoimmune Diseases: Rationale For Janus Kimentioning

confidence: 99%

Selective JAKinibs: Prospects in Inflammatory and Autoimmune Diseases

et al. 2019

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“…Attempts to inhibit BAFF and APRIL have, to date, yielded mixed responses. Belimumab, an mAb against soluble BAFF, is marketed for the treatment of SLE, although there is little evidence to support efficacy outside of joint and skin involvement 92. Tabalumab—an mAb against both soluble and membrane-bound BAFF—and the anti-BAFF peptibody blisibimod both exhibited disappointing efficacy for SLE in recent phase III clinical trials 93–95.…”

Section: Targeting Specific Cellular Subsetsmentioning

confidence: 99%

Novel therapies for immune-mediated inflammatory diseases: What can we learn from their use in rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, psoriasis, Crohn’s disease and ulcerative colitis?

2017

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The past three decades have witnessed remarkable advances in our ability to target specific elements of the immune and inflammatory response, fuelled by advances in both biotechnology and disease knowledge. As well as providing superior treatments for immune-mediated inflammatory diseases (IMIDs), such therapies also offer unrivalled opportunities to study the underlying immunopathological basis of these conditions.In this review, we explore recent approaches to the treatment of IMIDs and the insights to pathobiology that they provide. We review novel biologic agents targeting the T-helper 17 axis, including therapies directed towards interleukin (IL)-17 (secukinumab, ixekizumab, bimekizumab), IL-17R (brodalumab), IL-12/23p40 (ustekinumab, briakinumab) and IL-23p19 (guselkumab, tildrakizumab, brazikumab, risankizumab, mirikizumab). We also present an overview of biologics active against type I and II interferons, including sifalumumab, rontalizumab, anifrolumab and fontolizumab. Emerging strategies to interfere with cellular adhesion processes involved in lymphocyte recruitment are discussed, including both integrin blockade (natalizumab, vedolizumab, etrolizumab) and sphingosine-1-phosphate receptor inhibition (fingolimod, ozanimod). We summarise the development and recent application of Janus kinase (JAK) inhibitors in the treatment of IMIDs, including first-generation pan-JAK inhibitors (tofacitinib, baricitinib, ruxolitinib, peficitinib) and second-generation selective JAK inhibitors (decernotinib, filgotinib, upadacitinib). New biologics targeting B-cells (including ocrelizumab, veltuzumab, tabalumab and atacicept) and the development of novel strategies for regulatory T-cell modulation (including low-dose IL-2 therapy and Tregitopes) are also discussed. Finally, we explore recent biotechnological advances such as the development of bispecific antibodies (ABT-122, COVA322), and their application to the treatment of IMIDs.

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“…Although the highly anticipated rituximab therapeutic effect in systemic lupus erythematosus (SLE) was not demonstrated in clinical trials, targeting BAFF was successful (belimumab) ( 231 ). IL-1 blocking agents decreased pro-inflammatory cytokines and leukocyte subsets in CSF of pediatric patients with neonatal-onset multisystem inflammatory disease ( 113 ), although there were differences in efficacy in the intrathecal compartment (anakinra vs canakinumab).…”

Section: Targeting Cks or Other Cytokinesmentioning

confidence: 99%

Advances in Biomarker-Guided Therapy for Pediatric- and Adult-Onset Neuroinflammatory Disorders: Targeting Chemokines/Cytokines

Pranzatelli

2018

Front. Immunol.

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The concept and recognized components of “neuroinflammation” are expanding at the intersection of neurobiology and immunobiology. Chemokines (CKs), no longer merely necessary for immune cell trafficking and positioning, have multiple physiologic, developmental, and modulatory functionalities in the central nervous system (CNS) through neuron–glia interactions and other mechanisms affecting neurotransmission. They issue the “help me” cry of neurons and astrocytes in response to CNS injury, engaging invading lymphoid cells (T cells and B cells) and myeloid cells (dendritic cells, monocytes, and neutrophils) (adaptive immunity), as well as microglia and macrophages (innate immunity), in a cascade of events, some beneficial (reparative), others destructive (excitotoxic). Human cerebrospinal fluid (CSF) studies have been instrumental in revealing soluble immunobiomarkers involved in immune dysregulation, their dichotomous effects, and the cells—often subtype specific—that produce them. CKs/cytokines continue to be attractive targets for the pharmaceutical industry with varying therapeutic success. This review summarizes the developing armamentarium, complexities of not compromising surveillance/physiologic functions, and insights on applicable strategies for neuroinflammatory disorders. The main approach has been using a designer monoclonal antibody to bind directly to the chemo/cytokine. Another approach is soluble receptors to bind the chemo/cytokine molecule (receptor ligand). Recombinant fusion proteins combine a key component of the receptor with IgG1. An additional approach is small molecule antagonists (protein therapeutics, binding proteins, and protein antagonists). CK neutralizing molecules (“neutraligands”) that are not receptor antagonists, high-affinity neuroligands (“decoy molecules”), as well as neutralizing “nanobodies” (single-domain camelid antibody fragment) are being developed. Simultaneous, more precise targeting of more than one cytokine is possible using bispecific agents (fusion antibodies). It is also possible to inhibit part of a signaling cascade to spare protective cytokine effects. “Fusokines” (fusion of two cytokines or a cytokine and CK) allow greater synergistic bioactivity than individual cytokines. Another promising approach is experimental targeting of the NLRP3 inflammasome, amply expressed in the CNS and a key contributor to neuroinflammation. Serendipitous discovery is not to be discounted. Filling in knowledge gaps between pediatric- and adult-onset neuroinflammation by systematic collection of CSF data on CKs/cytokines in temporal and clinical contexts and incorporating immunobiomarkers in clinical trials is a challenge hereby set forth for clinicians and researchers.

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Belimumab in systemic lupus erythematosus (SLE): evidence-to-date and clinical usefulness

Cited by 32 publications

References 32 publications

Selective JAKinibs: Prospects in Inflammatory and Autoimmune Diseases

Selective JAKinibs: Prospects in Inflammatory and Autoimmune Diseases

Novel therapies for immune-mediated inflammatory diseases: What can we learn from their use in rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, psoriasis, Crohn’s disease and ulcerative colitis?

Advances in Biomarker-Guided Therapy for Pediatric- and Adult-Onset Neuroinflammatory Disorders: Targeting Chemokines/Cytokines

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