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Open accessJournal ArticleDOI: 10.1093/RHEUMATOLOGY/KEAA410

A phase 2 randomized, double-blind, placebo-controlled, proof-of-concept study of oral seletalisib in primary Sjögren’s syndrome

02 Mar 2021-Rheumatology (Oxford Academic)-Vol. 60, Iss: 3, pp 1364-1375
Abstract: Objectives This phase 2 proof-of-concept study (NCT02610543) assessed efficacy, safety and effects on salivary gland inflammation of seletalisib, a potent and selective PI3Kδ inhibitor, in patients with moderate-to-severe primary Sjogren's syndrome (PSS). Methods Adults with PSS were randomized 1:1 to seletalisib 45 mg/day or placebo, in addition to current PSS therapy. Primary end points were safety and tolerability and change from baseline in EULAR Sjogren's Syndrome Disease Activity Index (ESSDAI) score at week 12. Secondary end points included change from baseline at week 12 in EULAR Sjogren's Syndrome Patient Reported Index (ESSPRI) score and histological features in salivary gland biopsies. Results Twenty-seven patients were randomized (seletalisib n = 13, placebo n = 14); 20 completed the study. Enrolment challenges led to early study termination with loss of statistical power (36% vs 80% planned). Nonetheless, a trend for improvement in ESSDAI and ESSPRI [difference vs placebo: -2.59 (95% CI: -7.30, 2.11; P=0.266) and -1.55 (95% CI: -3.39, 0.28), respectively] was observed at week 12. No significant changes were seen in saliva and tear flow. Serious adverse events (AEs) were reported in 3/13 of patients receiving seletalisib vs 1/14 for placebo and 5/13 vs 1/14 discontinued due to AEs, respectively. Serum IgM and IgG concentrations decreased in the seletalisib group vs placebo. Seletalisib demonstrated efficacy in reducing size and organisation of salivary gland inflammatory foci and in target engagement, thus reducing PI3K-mTOR signalling compared with placebo. Conclusion Despite enrolment challenges, seletalisib demonstrated a trend towards clinical improvement in patients with PSS. Histological analyses demonstrated encouraging effects of seletalisib on salivary gland inflammation and organisation. Trial registration https://clinicaltrials.gov, NCT02610543.

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Topics: Placebo (54%), Tolerability (50%)
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7 results found


Journal ArticleDOI: 10.1038/S41573-021-00209-1
Abstract: Overactive phosphoinositide 3-kinase (PI3K) in cancer and immune dysregulation has spurred extensive efforts to develop therapeutic PI3K inhibitors. Although progress has been hampered by issues such as poor drug tolerance and drug resistance, several PI3K inhibitors have now received regulatory approval — the PI3Kα isoform-selective inhibitor alpelisib for the treatment of breast cancer and inhibitors mainly aimed at the leukocyte-enriched PI3Kδ in B cell malignancies. In addition to targeting cancer cell-intrinsic PI3K activity, emerging evidence highlights the potential of PI3K inhibitors in cancer immunotherapy. This Review summarizes key discoveries that aid the clinical translation of PI3Kα and PI3Kδ inhibitors, highlighting lessons learnt and future opportunities PI3K signalling is one of the most frequently aberrantly activated pathways in cancer. However, the development of therapeutic PI3K pathway inhibitors has faced challenges including poor drug tolerance and drug resistance. Here, Vanhaesebroeck et al. review efforts to understand and therapeutically exploit the biology of PI3Kα and PI3Kδ — the key targets of currently approved PI3K inhibitors, highlighting lessons learned and future opportunities.

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14 Citations


Open accessJournal ArticleDOI: 10.1136/ANNRHEUMDIS-2021-220220
Abstract: We read with interest the correspondence related to our article, ‘Interleukin 6 receptor inhibition in primary Sjogren syndrome: a multicentre double-blind randomised placebo-controlled trial’, by Wang et al 1 who discuss the disappointing results of recent trials of primary Sjogren syndrome (pSS) To explain recent negative results of tocilizumab and abatacept, apart from the inefficacy of these biologicals in pSS, Wang et al discuss the contribution of the design of the study First, they discuss the choice of a primary endpoint based on the EULAR Sjogren’s Syndrome Disease Activity Index (ESSDAI) As mentioned by the authors, this score captures only the systemic complications of the disease, observed in 30%–50% …

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Topics: Clinical endpoint (52%), Tocilizumab (52%), Abatacept (51%)

7 Citations


Open accessJournal ArticleDOI: 10.1136/ANNRHEUMDIS-2020-219666
Bin Wang1, Shiju Chen1, Jingxiu Xuan1, Yan Li1  +4 moreInstitutions (1)
Abstract: We read with interest the article by Felten et al which assessed the efficacy of interleukin 6 receptor inhibition (tocilizumab) in Sjogren’s syndrome (SjS)1 SjS is a chronic rheumatic disease characterised by immune infiltrates into exocrine glands such as salivary and lacrimal glands, which can impair glandular function and result in profound dryness2 Despite the substantially expanded knowledge on its pathogenesis, the management of SjS has not been improved substantially in recent decades, and there are still some unmet needs in both the diagnosis and management of SjS3 4 Currently available therapies for SjS are limited, and most clinical trials of targeted therapies in SjS including another recent trial of cytotoxic T lymphocyte-associated antigen-4-Ig (abatacept) have reported disappointing findings1 5 6 There are some possible explanations for those negative findings, and the inefficacy of those evaluated biological drugs is undoubtedly a major possible reason3 6 Apart from the inefficacy of those drugs, the adopted clinical trial design such as the outcome measures has been regarded as a possible contributor …

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Topics: Placebo-controlled study (52%), Tocilizumab (51%), Abatacept (51%) ... show more

3 Citations


Journal ArticleDOI: 10.1038/S41584-021-00634-X
Abstract: Primary Sjogren syndrome (pSS) is a systemic autoimmune disease that is characterized by a triad of symptoms that affect all patients (dryness, pain and fatigue). In addition, systemic involvement can affect between one-third and one-half of patients. The management of patients with pSS has been negatively affected by a lack of effective treatments; however, knowledge of the epidemiology of pSS has increased, and advances in developing classification criteria, systemic disease activity scoring and patient-reported outcomes have been made during the past decade. Progress has also been made in understanding the mechanisms that underlie the pathogenesis of pSS, which has enabled a more targeted therapeutic approach to be taken. At present, therapeutic decisions rely on the evaluation of symptoms and systemic manifestations and are mostly formed on the basis of experience rather than evidence, and on similarities with other autoimmune diseases, although the 2019 management recommendations from EULAR are now being used to inform clinical management of pSS. This Review summarizes the available evidence for systemic treatments for pSS and includes discussions of advances in outcome assessment, the current evidence for DMARD use and an overview of promising future therapeutics. Advances in understanding the pathogenic mechanisms of primary Sjogren syndrome (pSS) and the development of new outcome measures are aiding drug development for this disease. This Review describes current treatments and highlights promising candidates for future therapies for pSS.

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2 Citations


Open accessJournal ArticleDOI: 10.1007/S40259-021-00505-7
Bin Wang1, Shiju Chen1, Yan Li1, Jingxiu Xuan1  +2 moreInstitutions (1)
03 Nov 2021-BioDrugs
Abstract: Primary Sjogren's syndrome (pSS) is an autoimmune exocrinopathy characterized by dryness symptoms. This review briefly describes recent advances in the targeted therapies for pSS. Biologics evaluated for pSS treatment mainly include B cell-depleting agents, inhibitors of B cell activation, and agents that target co-signaling molecules or proinflammatory cytokines. Small molecule inhibitors that target signaling pathways have also been evaluated. However, current evidence for the efficacy of targeted therapies in pSS is still sparse. Although ianalumab (an anti-B cell-activating factor [BAFF]-receptor antibody) and iscalimab (an anti-CD40 antibody) are promising biologics for pSS, their efficacy still needs to be evaluated in larger clinical trials. For other biologics, clinical trials have found no differences versus placebo in the change from baseline in European League Against Rheumatism Sjogren's Syndrome Disease Activity Index (ESSDAI) score and fatigue score. Possible causes of the disappointing outcomes mainly include the inefficacy of those evaluated biologics in treating pSS, the high heterogeneous nature of pSS, irreversible exocrine glandular failure at advanced disease stages, inappropriate recruitment strategy in clinical trials, and outcome measures. Early diagnosis and glandular function-centered outcome measures may help to improve the current situation in the systemic therapy of pSS.

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Topics: Targeted therapy (51%), Clinical trial (50%)

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25 results found


Open accessJournal ArticleDOI: 10.1136/ARD.61.6.554
Abstract: Classification criteria for Sjogren's syndrome (SS) were developed and validated between 1989 and 1996 by the European Study Group on Classification Criteria for SS, and broadly accepted. These have been re-examined by consensus group members, who have introduced some modifications, more clearly defined the rules for classifying patients with primary or secondary SS, and provided more precise exclusion criteria.

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Topics: Sicca syndrome (51%)

4,563 Citations


Open accessJournal ArticleDOI: 10.1073/PNAS.94.9.4330
Abstract: Phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases that have been implicated in signal transduction through tyrosine kinase- and heterotrimeric G-protein-linked receptors. We report herein the cloning and characterization of p110delta, a novel class I PI3K. Like p110alpha and p110beta, other class I PI3Ks, p110delta displays a broad phosphoinositide lipid substrate specificity and interacts with SH2/SH3 domain-containing p85 adaptor proteins and with GTP-bound Ras. In contrast to the widely distributed p110alpha and beta, p110delta is exclusively found in leukocytes. In these cells, p110alpha and delta both associate with the p85alpha and beta adaptor subunits and are similarly recruited to activated signaling complexes after treatment with the cytokines interleukin 3 and 4 and stem cell factor. Thus, these class I PI3Ks appear not to be distinguishable at the level of p85 adaptor selection or recruitment to activated receptor complexes. However, distinct biochemical and structural features of p110delta suggest divergent functional/regulatory capacities for this PI3K. Unlike p110alpha, p110delta does not phosphorylate p85 but instead harbors an intrinsic autophosphorylation capacity. In addition, the p110delta catalytic domain contains unique potential protein-protein interaction modules such as a Pro-rich region and a basic-region leucine-zipper (bZIP)-like domain. Possible selective functions of p110delta in white blood cells are discussed.

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Topics: Signal transducing adaptor protein (63%), P110δ (58%), Phosphoinositide 3-kinase (57%) ... show more

392 Citations


Open accessJournal ArticleDOI: 10.1146/ANNUREV-IMMUNOL-032712-095946
Klaus Okkenhaug1Institutions (1)
Abstract: Phosphoinositide 3-kinases (PI3Ks) control many important aspects of immune cell development, differentiation, and function. Mammals have eight PI3K catalytic subunits that are divided into three classes based on similarities in structure and function. Specific roles for the class I PI3Ks have been broadly investigated and are relatively well understood, as is the function of their corresponding phosphatases. More recently, specific roles for the class II and class III PI3Ks have emerged. Through vertebrate evolution and in parallel with the evolution of adaptive immunity, there has been a dramatic increase not only in the genes for PI3K subunits but also in genes for phosphatases that act on 3-phosphoinositides and in 3-phosphoinositide-binding proteins. Our understanding of the PI3Ks in immunity is guided by fundamental discoveries made in simpler model organisms as well as by appreciating new adaptations of this signaling module in mammals in general and in immune cells in particular.

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302 Citations


Journal ArticleDOI: 10.7326/M13-1085
Abstract: BACKGROUND: Primary Sjogren syndrome (pSS) is an autoimmune disorder characterized by ocular and oral dryness or systemic manifestations. OBJECTIVE: To evaluate efficacy and harms of rituximab in adults with recent-onset or systemic pSS. DESIGN: Randomized, placebo-controlled, parallel-group trial conducted between March 2008 and January 2011. Study personnel (except pharmacists), investigators, and patients were blinded to treatment group. (ClinicalTrials.gov: NCT00740948). SETTING: 14 university hospitals in France. PATIENTS: 120 patients with scores of 50 mm or greater on at least 2 of 4 visual analogue scales (VASs) (global disease, pain, fatigue, and dryness) and recent-onset (< 10 years) biologically active or systemic pSS. INTERVENTION: Randomization (1:1 ratio) to rituximab (1 g at weeks 0 and 2) or placebo. MEASUREMENTS: Primary end point was improvement of at least 30 mm in 2 of 4 VASs by week 24. RESULTS: No significant difference between groups in the primary end point was found (difference, 1.0% [95% CI, -16.7% to 18.7%]). The proportion of patients with at least 30-mm decreases in at least two of the four VAS scores was higher in the rituximab group at week 6 (22.4% vs. 9.1%; P = 0.036). An improvement of at least 30 mm in VAS fatigue score was more common with rituximab at weeks 6 (P < 0.001) and 16 (P = 0.012), and improvement in fatigue from baseline to week 24 was greater with rituximab. Adverse events were similar between groups except for a higher rate of infusion reactions with rituximab. LIMITATION: Low disease activity at baseline and a primary outcome that may have been insensitive to detect clinically important changes. CONCLUSION: Rituximab did not alleviate symptoms or disease activity in patients with pSS at week 24, although it alleviated some symptoms at earlier time points.

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Topics: Rituximab (56%), Randomized controlled trial (51%), Placebo (50%)

249 Citations


Open accessJournal ArticleDOI: 10.1002/ART.21062
Abstract: Objective Ectopic lymphoneogenesis can occur in the salivary glands of Sjogren's syndrome (SS) patients and is associated with local antigen-driven B cell responses, autoantibody formation, and potential lymphomatous transformation. CXCL13 and CCL21 have been identified in salivary glands, but their role in ectopic lymphoneogenesis in SS remains unclear. This study aimed to evaluate the microanatomic association between CXCL13 and CCL21 expression and the acquisition of lymphoid features in periductal foci. Methods Salivary glands from 37 SS patients and 9 chronic sialadenitis patients were analyzed by immunohistochemistry for T cell/B cell segregation, CD21+ follicular dendritic cell networks, and peripheral lymph node addressin (PNAd)–positive high endothelial venules (HEVs) in relationship to the size of the aggregates and the expression of CXCL13 and CCL21 within infiltrating cells, epithelium, and endothelium. Results Grade 1 aggregates (10–50 lymphocytes) demonstrated predominance of nonorganized CD3+ cells, while grade 2 (>50 lymphocytes) and grade 3 (>50 with germinal centers) showed a progressive increase in CD20+ B cells and T cell/B cell segregation. This higher degree of lymphoid organization was significantly related to an increased expression of CXCL13 within infiltrating cells and PNAd+ HEV–associated CCL21-producing cells. Conversely, no association between lymphoid organization and lymphoid chemokine expression by epithelial cells was observed. Conclusion The acquisition of lymphoid features by inflammatory foci in SS is critically associated with the enlargement of the inflammatory foci and with the expression of CXCL13 and CCL21 within the infiltrate, but is not associated with their expression by epithelial cells. These data strongly support an active participation of CXCL13 and CCL21 in regulating the progressive organization and maintenance of periductal foci.

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Topics: Follicular dendritic cells (59%), High endothelial venules (59%), Germinal center (57%) ... show more

213 Citations


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