JAK Inhibitors for Treatment of Psoriasis: Focus on Selective TYK2 Inhibitors

Nogueira, Miguel; Puig, L.; Torres, Tiago

doi:10.1007/s40265-020-01261-8

Cited by 107 publications

(128 citation statements)

References 106 publications

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“…Some of these candidate JAK inhibitors also have potential in addressing the concern underlying the use of JAK inhibitors on host antiviral and antibacterial immunity responses. For example, BMS-986165 and PF-06826647, TYK2 selective inhibitors currently in Phase II clinical trials for psoriasis [70] (Clinical Trial Numbers ii : NCT03881059 and NCT03895372) (Figure 1), can be tested in COVID-19. These inhibitors would potentially not interact with the Type II IFN response (IFNγ) necessary in antibacterial immunity but still inhibit other cytokines in COVID-19.…”

Section: Outstanding Questionsmentioning

confidence: 99%

Targeting JAK-STAT Signaling to Control Cytokine Release Syndrome in COVID-19

Luo

Jiang

et al. 2020

Trends in Pharmacological Sciences

236

246

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Recent advances in the pathophysiologic understanding of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has indicated that patients with severe coronavirus disease 2019 (COVID-19) might experience cytokine release syndrome (CRS), characterized by increased interleukin (IL)-6, IL-2, IL-7, IL-10, etc. Therefore, the treatment of cytokine storm has been proposed as a critical part of rescuing severe COVID-19. Several of the cytokines involved in COVID-19 employ a distinct intracellular signaling pathway mediated by Janus kinases (JAKs). JAK inhibition, therefore, presents an attractive therapeutic strategy for CRS, which is a common cause of adverse clinical outcomes in COVID-19. Below, we review the possibilities and challenges of targeting the pathway in COVID-19. COVID-19 and Cytokine Release StormIn December 2019, cases with a new type of viral pneumonia with unknown etiology occurred in Wuhan, China. A novel coronavirus SARS-CoV-2 was found to be a causal agent and the disease was named COVID-19 [1]. With the number of confirmed cases and deaths rapidly expanding, the COVID-19 pandemic is currently the focus of global attention.Accumulating evidence indicate that patients with severe COVID-19 infection may present with CRS [2] where, similar to the pathogenesis of severe acute respiratory syndrome (SARS) and the Middle East respiratory syndrome (MERS), higher plasma levels of cytokines, including IL-2, IL-6, IL-7, IL-10, granulocyte-colony stimulating factor (G-CSF), interferon-γ (IFNγ), macrophage inflammatory protein 1α (MIP1A), and tumor necrosis factor-α (TNF-α) were found in patients with severe COVID-19 [3,4]. Extensive changes in these cytokines are related to the severity and prognosis of the disease [5]. Moreover, pathological findings from a patient who died of severe SARS-CoV-2 infection revealed bilateral diffuse alveolar damage with cellular fibromyxoid exudates, indicating acute respiratory distress syndrome (ARDS) [6]. These findings suggested that CRS was involved in the progression of COVID-19.COVID-19 induces a cytokine storm resembling the secondary hemophagocytic lymphohistiocytosis (sHLH), which had previously been reported in patients with SARS [7]. sHLH is a potentially life-threatening complication of the hyperinflammatory syndrome, commonly triggered by severe viral infections [8] and characterized by CRS, cytopenias, and multiorgan dysfunction [9]. Apart from the elevated serum cytokines, aberrantly activated macrophages are also a hallmark of sHLH and implicated as the source of the observed increased ferritin. Therefore, sHLH is also known as macrophage activation syndrome (MAS) [10]. Zhou et al. retrospectively found that serum ferritin was also elevated in COVID-19 fatalities [11]. Giamarellos-Bourboulis et al. investigated the immune responses in COVID-19 patients with Highlights Recent advances in the pathophysiologic understanding of COVID-19 infection have suggested a critical role of cytokine release syndrome (CRS) in severe COVID-19 patients.Sever...

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Section: Outstanding Questionsmentioning

confidence: 99%

Targeting JAK-STAT Signaling to Control Cytokine Release Syndrome in COVID-19

Luo

Jiang

et al. 2020

Trends in Pharmacological Sciences

236

246

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“…Many of the key pathogenic cytokines in psoriasis (eg, IFNs, IL-6, IL-22, IL-23) bind to their receptor and transmit the intracellular signaling through the JAK/STAT signaling pathway. 82 The janus kinases family includes four different intracellular tyrosine kinases (JAK1, JAK2, JAK3 and TYK2), and the STAT family includes seven different STAT proteins (STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, STAT6). 83 Upon cytokine binding, the JAKs become activated, autophosphorylated and phosphorylate the receptor leading to binding of STAT proteins ( Figure 2 ).…”

Section: Treatmentmentioning

confidence: 99%

“…15 , 86 Also, STAT3 is implicated in the pathological response of keratinocytes to cytokines, including keratinocyte proliferation and production of antimicrobial peptides secondary to activation of JAK1/TYK2 and STAT3 induced by IL-22 signaling. 82 , 87 Although TNF-α and IL-17A do not directly activate the JAK-STAT pathway, the inhibition of JAK-STAT may indirectly suppress the effects of these cytokines by inhibition of other JAK/STAT dependent cytokines involved in the vicious cytokine circuits known to drive the disease pathogenesis in psoriasis (eg, inhibition of IL-23 acting upstream to IL-17). 88 …”

Section: Treatmentmentioning

confidence: 99%

Key Signaling Pathways in Psoriasis: Recent Insights from Antipsoriatic Therapeutics

Abdallah

Johansen

Iversen

2021

PTT

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Psoriasis is a common chronic inflammatory skin disease associated with several comorbidities and reduced quality of life. In the past decades, highly effective targeted therapies have led to breakthroughs in the management of psoriasis, providing important insights into the pathogenesis. This article reviews the current concepts of the pathophysiological pathways and the recent progress in antipsoriatic therapeutics, highlighting key targets, signaling pathways and clinical effects in psoriasis.

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“…In this view, also tyrosine kinase (TYK) 2 inhibitors -currently in their approval phasehave been presented. 10…”

Section: Introductionmentioning

confidence: 99%

Experimental Pharmacological Management of Psoriasis

Campione¹,

Cosio²,

Prete³

et al. 2021

JEP

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Psoriasis is a chronic, relapsing, immune-mediated systemic disease. Its pathogenesis is complex and not fully understood yet. Genetic and epigenetic factors interact with molecular pathways involving TNF-α, IL-23/IL-17 axis, and peculiar cytokines, as IL-36 or phosphodiesterase 4. This review discusses the mechanisms involved in the development of the disease, as well as the therapeutic options proposed following the investigation of the inflammatory psoriatic pathways. We performed a comprehensive search using the words "psoriasis" and the newest molecules currently under investigation and approval. From these data, a new scenario in psoriasis is occurring to personalize the therapies -especially systemic ones and those using small molecules -and avoid topical and injectable drugs. We reported the newest therapeutic opportunities, including the inhibitors of Janus kinase/ tyrosine kinase 2, phosphodiesterase-4 and IL-36 receptor. Today, more than 20 molecules are under investigation for the treatment of cutaneous psoriasis. Most of them are constituted by small molecules or biologic therapies. This underlines how psoriasis needs systemic therapies, due to its complex pathogenesis and multisystemic involvement.

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JAK Inhibitors for Treatment of Psoriasis: Focus on Selective TYK2 Inhibitors

Cited by 107 publications

References 106 publications

Targeting JAK-STAT Signaling to Control Cytokine Release Syndrome in COVID-19

Targeting JAK-STAT Signaling to Control Cytokine Release Syndrome in COVID-19

Key Signaling Pathways in Psoriasis: Recent Insights from Antipsoriatic Therapeutics

Experimental Pharmacological Management of Psoriasis

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