The pipeline of targeted therapies under clinical development for primary Sjögren's syndrome: A systematic review of trials

Felten, Renaud; Scher, Florence; Sibilia, Jean; Gottenberg, Jacques-Éric; Arnaud, Laurent

doi:10.1016/j.autrev.2018.12.008

Cited by 36 publications

(23 citation statements)

References 39 publications

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“…A low dose therapy with IL-2, restored the Th17/Treg cells balance by augmenting CD4+ Treg cells numbers [ 77 ]. Nevertheless, there is a limited repertoire of T cell-targeted therapeutic agents evaluated in clinical trials; the existent ones display controversial results, coursing different phases, whose status are either finished, recruiting or with inability to meet objective protocols leading to premature termination (reviewed by Felten [ 11 ], Mavragani [ 90 ]).…”

Section: Molecular Therapeutic Targets In T Cellsmentioning

confidence: 99%

“…Additionally, recent evidence depicting molecular pathways in SS pathogenesis has allowed for the discovery of novel potential targets directed to T cells response. Hence, T cells immunobiology can be selectively inhibited either directly or indirectly by targeting activator and survival factors, as well as other molecules implicated in their pathological roles in SS [ 6 , 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

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T Cells Subsets in the Immunopathology and Treatment of Sjogren’s Syndrome

2020

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Sjogren’s syndrome (SS) is an autoimmune disease whose pathogenesis is characterized by an exacerbated T cell infiltration in exocrine glands, markedly associated to the inflammatory and detrimental features as well as the disease progression. Several helper T cell subsets sequentially converge at different stages of the ailment, becoming involved in specific pathologic roles. Initially, their activated phenotype endows them with high migratory properties and increased pro-inflammatory cytokine secretion in target tissues. Later, the accumulation of immunomodulatory T cells-derived factors, such as IL-17, IFN-γ, or IL-21, preserve the inflammatory environment. These effects favor strong B cell activation, instigating an extrafollicular antibody response in ectopic lymphoid structures mediated by T follicular helper cells (Tfh) and leading to disease progression. Additionally, the memory effector phenotype of CD8+ T cells present in SS patients suggests that the presence of auto-antigen restricted CD8+ T cells might trigger time-dependent and specific immune responses. Regarding the protective roles of traditional regulatory T cells (Treg), uncertain evidence shows decrease or invariable numbers of circulating and infiltrating cells. Nevertheless, an emerging Treg subset named follicular regulatory T cells (Tfr) seems to play a critical protective role owing to their deficiency that enhances SS development. In this review, the authors summarize the current knowledge of T cells subsets contribution to the SS immunopathology, focusing on the cellular and biomolecular properties allowing them to infiltrate and to harm target tissues, and that simultaneously make them key therapeutic targets for SS treatment.

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Section: Molecular Therapeutic Targets In T Cellsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

T Cells Subsets in the Immunopathology and Treatment of Sjogren’s Syndrome

2020

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“…32 In large studies, rituximab had no significant effects on improving dryness, fatigue or composite primary endpoints. 28,33 Epratuzumab targets B cell-specific protein CD22, interferes with the formation of B cell receptor (BCR) signal complex, enhances the inhibitory effect of CD22 on BCR, reduces the count and activity of peripheral blood B cells, and improves the level of clinical markers related to disease activity. In all patients treated with epratuzumab, the B cell count, the levels of IgM and anti-Ro/SSA antibodies continued to decline.…”

Section: Management Of Sicca Symptomsmentioning

confidence: 99%

Update on disease pathogenesis, diagnosis, and management of primary Sjögren’s syndrome

2020

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Primary Sjögren's syndrome (pSS) is a typical multisystem disease, characterized by lymphocytic infiltration of the exocrine glands leading to glandular dysfunction. Multiple systemic manifestations occur in those of serious conditions, with different courses and outcomes. Its pathogenesis is complex, and its diagnosis and management are being constantly updated and improved. We have failed to have much progress in targeted immunotherapy for pSS, and as yet this is still based on empirical treatment. Many studies have tried to define pSS more accurately, to study its pathogenesis, to find effective treatment strategies, opening up new avenues for early diagnosis and precise management of pSS.

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“…Two randomized phase II trials of anti-BAFF therapies for pSS are ongoing. In one study, belimumab has been combined with rituximab (ClinicalTrials.gov identifier: NCT02631538; Table 2) on the basis of the rationale that elevated BAFF following B-cell depletion results in selection of self-reactive B-cells during the reconstitution of the B-cell repertoire 54 . Also, patients in the TEARS study with high baseline BAFF levels had a less robust response to rituximab, raising the possibility that neutralization of BAFF improves the response to rituximab therapy 55, 56 .…”

Section: Identifying Mechanistically Based Therapeutic Targetsmentioning

confidence: 99%

“…Early support for this strategy was provided by a study of the JAK inhibitor filgotinib, which has been shown to modify messenger RNA expression of interferon-related genes and the BAFF gene in human salivary gland epithelial cells and salivary gland organoid cultures 63 . A phase II trial of filgotinib in pSS is ongoing (ClinicalTrials.gov identifier: NCT03100942; Table 2) 54 .…”

Section: Identifying Mechanistically Based Therapeutic Targetsmentioning

confidence: 99%

Recent advances in the search for a targeted immunomodulatory therapy for primary Sjögren’s syndrome

Leverenz

Clair

2019

F1000Res

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Primary Sjögren’s syndrome is a chronic autoimmune disease characterized by salivary and lacrimal gland dysfunction, leading to substantial morbidity and reduced quality of life. Many patients with primary Sjögren’s syndrome also have extraglandular systemic complications, some of which can be organ- or life-threatening. Over the last decade, numerous targeted immunomodulatory therapies for primary Sjögren’s syndrome have failed to show a benefit in clinical trials, and as yet no disease-modifying therapy has been approved for this disease. Herein, we provide an updated review of the clinical trial landscape for primary Sjögren’s syndrome and the numerous efforts to move the field forward, including the development of new classification criteria and outcome measures, the results of recent clinical trials in this field, the challenges faced in the search for effective therapies, and the expanding pipeline of novel therapies under development.

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The pipeline of targeted therapies under clinical development for primary Sjögren's syndrome: A systematic review of trials

Cited by 36 publications

References 39 publications

T Cells Subsets in the Immunopathology and Treatment of Sjogren’s Syndrome

T Cells Subsets in the Immunopathology and Treatment of Sjogren’s Syndrome

Update on disease pathogenesis, diagnosis, and management of primary Sjögren’s syndrome

Recent advances in the search for a targeted immunomodulatory therapy for primary Sjögren’s syndrome

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