Efficacy and Safety of Multiple Dosages of Fostamatinib in Adult Patients With Rheumatoid Arthritis: A Systematic Review and Meta-Analysis

Kang, Yaqi; Jiang, Xinrui; Qin, Da-Lian; Wang, Long; Yang, Jing; Wu, Anguo; Huang, Feihong; Ye, Yun; Wu, Jianming

doi:10.3389/fphar.2019.00897

Cited by 33 publications

(26 citation statements)

References 26 publications

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“…To date, many clinical trials on R788 have been completed and some have already evaluated its safety and efficacy for the RA treatment. The trials denoted that fostamatinib is an effective therapeutic medicine administered to patients with over 24 weeks [82]. Our experiments showed a central role of Syk kinase in the T-cell response to redox stress indicating it has a key role upstream of the Tyr phosphorylation cascade.…”

Section: Discussionmentioning

confidence: 63%

Signaling Response to Transient Redox Stress in Human Isolated T Cells: Molecular Sensor Role of Syk Kinase and Functional Involvement of IL2 Receptor and L-Selectine

Secchi

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et al. 2020

Sensors

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Reactive oxygen species (ROS) are central effectors of inflammation and play a key role in cell signaling. Previous reports have described an association between oxidative events and the modulation of innate immunity. However, the role of redox signaling in adaptive immunity is still not well understood. This work is based on a novel investigation of diamide, a specific oxidant of sulfhydryl groups, and it is the first performed in purified T cell tyrosine phosphorylation signaling. Our data show that ex vivo T cells respond to –SH group oxidation with a distinctive tyrosine phosphorylation response and that these events elicit specific cellular responses. The expression of two essential T-cell receptors, CD25 and CD62L, and T-cell cytokine release is also affected in a specific way. Experiments with Syk inhibitors indicate a major contribution of this kinase in these phenomena. This pilot work confirms the presence of crosstalk between oxidation of cysteine residues and tyrosine phosphorylation changes, resulting in a series of functional events in freshly isolated T cells. Our experiments show a novel role of Syk inhibitors in applying their anti-inflammatory action through the inhibition of a ROS-generated reaction.

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Section: Discussionmentioning

confidence: 63%

Signaling Response to Transient Redox Stress in Human Isolated T Cells: Molecular Sensor Role of Syk Kinase and Functional Involvement of IL2 Receptor and L-Selectine

Secchi

Orecchioni

Carta

et al. 2020

Sensors

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“…The drug was proposed on its action on AAK1 which is a regulator of endocytosis, although how AAK1 was prioritized as target was not described in the study. Fostamatinib, which we prioritized in this study, also inhibits JAK1, JAK2 and AAK1 48 based on curations from DrugBank and was shown to be effective for RA 43 . Of note, two other JAK-STAT signaling inhibitors were recommended by Stebbing et al 45 , while in our analysis JAK-STAT signaling is among the top 10 pathways enriched for top proteins linked to ACE2 expression.…”

Section: On Ace2 Expression and Exploring Drug Candidatesmentioning

confidence: 99%

“…This drug has been approved for treating Immune Thrombocytopenic Purpura (ITP), and is a spleen tyrosine kinase inhibitor 42 . There has been trials on rheumatoid arthritis (RA) 43 and IgA nephropathy as well 42 .…”

Section: On Ace2 Expression and Exploring Drug Candidatesmentioning

confidence: 99%

Exploring diseases/traits and blood proteins causally related to expression of ACE2, the putative receptor of SARS-CoV-2: A Mendelian Randomization analysis highlights tentative relevance of diabetes-related traits

Rao

Lau

2020

Preprint

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The novel coronavirus 2019-nCoV has caused major outbreaks in many parts of the world. A better understanding of the pathophysiology of COVID-19 is urgently needed. Clinically, it is important to identify who may be susceptible to infection and identify treatments for the disease.There is good evidence that ACE2 is a receptor for 2019-nCoV, and studies also suggested that high expression of ACE2 may increase susceptibility to infection. Here we conducted a phenome-wide Mendelian randomization (MR) study to prioritize diseases/traits and blood proteins that may be causally linked to ACE2 expression in the lung. Expression data was based on GTEx. We also explored drug candidates whose targets overlapped with the top-ranked proteins in MR analysis, as these drugs could potentially alter ACE2 expression and may be clinically relevant. Notably, MR is much less vulnerable to confounding and reverse causality compared to observational studies.The most consistent finding was a tentative causal association between diabetes-related traits and increased ACE2 expression. Based on one of the largest GWAS on type II diabetes (T2DM) to date (N=898,130), we found that T2DM is causally linked to raised ACE2 expression (beta=0.1835, 95% CI 0.0853-0.2817; p=2.49E-4; GSMR method). Significant associations (at nominal level; p<0.05) was also observed across multiple datasets, with different analytic methods, and for both type I and II diabetes. Other diseases/traits having nominal significant associations with increased ACE2 included inflammatory bowel disease, (ER+) breast and lung cancers, asthma, smoking and elevated ALT, among others. We also uncovered a number of plasma/serum proteins potentially linked to altered ACE2 expression, and the top enriched pathways included cytokine-cytokine-receptor interaction, VEGF signaling, JAK-STAT signaling etc. We also explored drugs that target some of the top-ranked proteins in the MR analysis.

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“…Anomalous regulation of this kinase could lead to different allergic disorders and antibody-mediated autoimmune diseases. Thus, Syk may serve as a therapeutically relevant target for rheumatoid arthritis, asthma, psoriasis, and allergic rhinitis [8][9][10]. It has been believed for years that Syk function is solely linked to hematopoietic cell signalling.…”

Section: Introductionmentioning

confidence: 99%

Synergistic Anti-Tumour Effect of Syk Inhibitor and Olaparib in Squamous Cell Carcinoma: Roles of Syk in EGFR Signalling and PARP1 Activation

Huang

Chen

et al. 2020

Cancers

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Syk is a non-receptor tyrosine kinase involved in the signalling of immunoreceptors and growth factor receptors. Previously, we reported that Syk mediates epidermal growth factor receptor (EGFR) signalling and plays a negative role in the terminal differentiation of keratinocytes. To understand whether Syk is a potential therapeutic target of cancer cells, we further elucidated the role of Syk in disease progression of squamous cell carcinoma (SCC), which is highly associated with EGFR overactivation, and determined the combined effects of Syk and PARP1 inhibitors on SCC viability. We found that pharmacological inhibition of Syk could attenuate the EGF-induced phosphorylation of EGFR, JNK, p38 MAPK, STAT1, and STAT3 in A431, CAL27 and SAS cells. In addition, EGF could induce a Syk-dependent IL-8 gene and protein expression in SCC. Confocal microscopic data demonstrated the ability of the Syk inhibitor to change the subcellular distribution patterns of EGFR after EGF treatment in A431 and SAS cells. Moreover, according to Kaplan-Meier survival curve analysis, higher Syk expression is correlated with poorer patient survival rate and prognosis. Notably, both Syk and EGFR inhibitors could induce PARP activation, and synergistic cytotoxic actions were observed in SCC cells upon the combined treatment of the PARP1 inhibitor olaparib with Syk or the EGFR inhibitor. Collectively, we reported Syk as an important signalling molecule downstream of EGFR that plays crucial roles in SCC development. Combining Syk and PARP inhibition may represent an alternative therapeutic strategy for treating SCC.

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Efficacy and Safety of Multiple Dosages of Fostamatinib in Adult Patients With Rheumatoid Arthritis: A Systematic Review and Meta-Analysis

Cited by 33 publications

References 26 publications

Signaling Response to Transient Redox Stress in Human Isolated T Cells: Molecular Sensor Role of Syk Kinase and Functional Involvement of IL2 Receptor and L-Selectine

Signaling Response to Transient Redox Stress in Human Isolated T Cells: Molecular Sensor Role of Syk Kinase and Functional Involvement of IL2 Receptor and L-Selectine

Exploring diseases/traits and blood proteins causally related to expression of ACE2, the putative receptor of SARS-CoV-2: A Mendelian Randomization analysis highlights tentative relevance of diabetes-related traits

Synergistic Anti-Tumour Effect of Syk Inhibitor and Olaparib in Squamous Cell Carcinoma: Roles of Syk in EGFR Signalling and PARP1 Activation

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