Investigational IRAK-4 inhibitors for the treatment of rheumatoid arthritis

Wiese, Michael; Manning-Bennett, Arkady T.; Abuhelwa, Ahmad Y.

doi:10.1080/13543784.2020.1752660

Cited by 43 publications

(34 citation statements)

References 58 publications

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“…Consistent with this notion, the IRAK4 inhibitor PF-06650833 was reported to be well tolerated with no dose-limiting adverse events observed in two phase I clinical trials 177 . In a phase II trial, only 6% of the 187 participants stopped treatment owing to an adverse effect occurring during treatment 178 . Further information about the efficacy of these and other IRAK4 inhibitors in chronic inflammatory diseases is awaited with interest.…”

Section: Kinase Inhibitors In Diseases Other Than Cancermentioning

confidence: 99%

Kinase drug discovery 20 years after imatinib: progress and future directions

Cohen

Cross

Jänne

2021

Nat Rev Drug Discov

693

465

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Section: Kinase Inhibitors In Diseases Other Than Cancermentioning

confidence: 99%

Kinase drug discovery 20 years after imatinib: progress and future directions

Cohen

Cross

Jänne

2021

Nat Rev Drug Discov

693

465

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“…Although developed recently, IRAK4 inhibitors are under assessment in psoriasis, whilst in rheumatoid arthritis a completed phase II clinical trial has demonstrated clinical improvement (142). Interestingly, dimethyl fumarate, already of proven clinical efficacy in treating both multiple sclerosis and psoriasis, is not only a direct inhibitor of IRAK4 but also suppresses innate proinflammatory cytokines in pDCs, providing a strong mechanistic rationale for its recently proposed repurposing for COVID-19 "cytokine storm" (143,144).…”

Section: Discussionmentioning

confidence: 99%

Involvement of Interleukin-1 Receptor-Associated Kinase 4 and Interferon Regulatory Factor 5 in the Immunopathogenesis of SARS-CoV-2 Infection: Implications for the Treatment of COVID-19

Stoy

2021

Front. Immunol.

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Interleukin-1 receptor-associated kinase 4 (IRAK4) and interferon regulatory factor 5 (IRF5) lie sequentially on a signaling pathway activated by ligands of the IL-1 receptor and/or multiple TLRs located either on plasma or endosomal membranes. Activated IRF5, in conjunction with other synergistic transcription factors, notably NF-κB, is crucially required for the production of proinflammatory cytokines in the innate immune response to microbial infection. The IRAK4-IRF5 axis could therefore have a major role in the induction of the signature cytokines and chemokines of the hyperinflammatory state associated with severe morbidity and mortality in COVID-19. Here a case is made for considering IRAK4 or IRF5 inhibitors as potential therapies for the “cytokine storm” of COVID-19.

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“…Other phosphorylated signaling molecules, such as JAK2 and 3, STAT1, 3, and 6 in different leukocyte subsets, have been examined as markers of treatment response in smaller RA collectives by ( 20 – 22 ). However, trials to establish IRAK-4 inhibitors as a new therapy in rheumatoid arthritis are underway ( 23 ), which underlines the possible value of this target. Analysis of phosphorylated signaling proteins by flow cytometry has been reported in various conditions, like cancer and HIV infection ( 24 ), in multiple sclerosis ( 25 ) and for the immunopathological characterization of primary immunodeficiency diseases ( 26 , 27 ).…”

Section: Discussionmentioning

confidence: 99%

Case Report: Extensive Phosphorylation of Interleukin-1 Receptor-Associated Kinase 4 in a Patient With Schnitzler Syndrome

et al. 2020

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Schnitzler syndrome (SchS) is a rare autoinflammatory disease, characterized by urticarial rash, recurrent fever, osteo-articular pain/arthritis with bone condensation, and monoclonal gammopathy. Diagnosis may be difficult due to overlapping signs with other diseases. Here, we describe the case of a 62-year-old man with SchS, who was initially misdiagnosed with multicentric Castleman disease (MCD). As excessive release of IL-6 is characteristic of MCD, in contrast to IL-1 in SchS, we measured the phosphorylation of intracellular signaling proteins of the respective pathways by flow cytometry. We found a distinct increase of phosphorylated IRAK-4 in our patient’s B cells and monocytes while phosphorylation of STAT-3 was low, suggesting predominant IL-1 signaling. In accordance with these results and the classification criteria, we established the diagnosis of SchS instead of MCD and commenced therapy with the IL-1 receptor antagonist anakinra. We observed a rapid remission of signs accompanied by a reduction of phosphorylated IRAK-4 to normal levels. In conclusion, we propose phosphorylated IRAK-4 in B cells and monocytes as a potential marker for diagnosis of SchS and for treatment response to IL-1 blockade.

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Investigational IRAK-4 inhibitors for the treatment of rheumatoid arthritis

Cited by 43 publications

References 58 publications

Kinase drug discovery 20 years after imatinib: progress and future directions

Kinase drug discovery 20 years after imatinib: progress and future directions

Involvement of Interleukin-1 Receptor-Associated Kinase 4 and Interferon Regulatory Factor 5 in the Immunopathogenesis of SARS-CoV-2 Infection: Implications for the Treatment of COVID-19

Case Report: Extensive Phosphorylation of Interleukin-1 Receptor-Associated Kinase 4 in a Patient With Schnitzler Syndrome

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