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JAK-STAT signalling pathway was discovered more than quarter century ago. The JAK-STAT pathway protein is considered as one of the crucial hubs for cytokine secretion which mediates activation of different inflammatory, cellular responses and hence involved in different etiological factors. The various etiological factors involved are haematopoiesis, immune fitness, tissue repair, inflammation, apoptosis, and adipogenesis. The presence of the active mutation V617K plays a significant role in the progression of the JAK-STAT pathway-related disease. Consequently, targeting the JAK-STAT pathway could be a promising therapeutic approach for addressing a range of causative factors. In this current review, we provided a comprehensive discussion for the in-detail study of anatomy and physiology of the JAK-STAT pathway which contributes structural domain rearrangement, activation, and negative regulation associated with the downstream signaling pathway, relationship between different cytokines and diseases. This review also discussed the recent development of clinical trial entities. Additionally, this review also provides updates on FDA-approved drugs. In the current investigation, we have classified recently developed small molecule inhibitors of JAK-STAT pathway according to different chemical classes and we emphasized their synthetic routes, biological evaluation, selectivity, and structure-activity relationship.

Introduction: Tocilizumab and baricitinib are recommended treatment options for COVID-19 patients with hyperinflammatory response; however, there is a lack of systematic review directly evaluating their efficacy and safety. Objective: This review was conducted to evaluate the efficacy and safety of tocilizumab and baricitinib in the treatment of hospitalized patients with COVID-19. Methods: Relevant databases were searched for studies that compared the effect or safety of baricitinib or tocilizumab in hospitalized patients with COVID-19. The mortality was the main outcome. The hospital length of stay or adverse drug reactions were taken into consideration as secondary endpoints. The analyses were performed in Revman 5.3 or Stata 16.0. The protocol and analysis plan were pre-registered in PROSPERO, with the registration number CRD42023408219. Results: In total, 10 studies with 2,517 patients were included. The overall pooled data demonstrated that, there was no statistically significant difference in the 28-day mortality rate and the hospital length of stay between the tocilizumab and baricitinib (OR = 1.10, 95% CI = 0.80-1.51, p = 0.57; OR = -0.68, 95% CI = -2.24-0.87, p = 0.39). The adverse reactions including secondary infection rate, thrombotic and bleeding events, and acute liver injury of tocilizumab were significantly higher than that of baricitinib. (OR = 1.49, 95% CI = 1.18-1.88, p < 0.001,OR = 1.52, 95% CI = 1.11-2.08, p = 0.009; OR = 1.52, 95% CI = 1.11-2.08, p = 0.009; OR = 2.24, 95% CI = 1.49-3.35, p < 0.001). Conclusion: In patients hospitalized with COVID-19, no discernible difference in therapeutic efficacy was observed between tocilizumab and baricitinib; however, the group treated with baricitinib demonstrated a significantly lower incidence of adverse effects.

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The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway plays a critical role in orchestrating immune and inflammatory responses, and it is essential for a wide range of cellular processes, including differentiation, cell growth, and apoptosis. Over the years, this pathway has been heavily investigated due to its key role in the pathogeneses of several chronic inflammatory conditions, e.g., psoriasis, atopic dermatitis (AD), and inflammatory bowel diseases (IBDs). Nevertheless, the impact of this pathway on the pathogenesis of inflammatory conditions remains unclear. This review describes the role of the JAK/STAT signaling pathway in the pathogenesis of inflammatory diseases such as psoriasis (Pso), psoriatic arthritis (PsA), AD, and IBD with a focus on ulcerative colitis (UC) and briefly resumes the use of JAK inhibitors in their clinical management.

UNASSIGNED: Treatment of severe rheumatoid arthritis (RA) is currently based either on biological agents or Janus kinase/signal transducer and activator of transcription inhibitors, most often in combination with methotrexate (MTX).
UNASSIGNED: The aim of the study was to compare the effectiveness and side effects of bio- logic disease-modifying antirheumatic drugs (bDMARDs) and targeted synthetic (ts) DMARDs treatment.
UNASSIGNED: The analysis included 108 RA patients with active disease treated with MTX 25 mg per week. Eighty patients (group I) were treated with bDMARDs and 28 patients (group II) with JAK-STAT inhibitors. The duration of morning stiffness, pain on Visual Analogue Scale (VAS), 28-joints Disease Activity Score (DAS28) and Simplified Disease Activity Score (SDAI) were assessed. Classical radiographic images of patients\' hands and feet using the Larsen and Dale\'s criteria were evaluated. The effects of treatment with bDMARDs and tsDMARDs were analyzed.
UNASSIGNED: All studied patients presented at least Larsen and Dale\'s stage 3 of X-ray changes typical for RA. There were no statistically significant differences in disease duration, ESR, CRP, DAS28 and SDAI values between studied groups. Patients from group II previously used higher numbers of bDMARDs than group I treated with bDMARDs. Low disease activity after treatment was achieved by all patients; therefore patients from group II (treated with tsDMARDs) achieved lower values of patients\' global assessment on VAS.
UNASSIGNED: The results of the present observational study indicated that treatment with JAK inhibitors is very promising. These drugs are not inferior in effectiveness to bDMARDs. It is important to monitor patients for thromboembolic events before and during JAK treatment.

In spite of advances in vaccination, control of the COVID-19 pandemic will require the use of pharmacological treatments against SARS-CoV2. Their development needs to consider the existence of two phases in the disease, namely the viral infection and the inflammatory stages. The main targets for antiviral therapeutic intervention are: (a) viral proteins, including the spike (S) protein characteristic of the viral cover and the viral proteases in charge of processing the polyprotein arising from viral genome translation; (b) host proteins, such as those involved in the processes related to viral entry into the host cell and the release of the viral genome inside the cell, the elongation factor eEF1A and importins. The use of antivirals targeted at host proteins is less developed but it has the potential advantage of not being affected by mutations in the genome of the virus and therefore being active against all its variants. Regarding drugs that address the hyperinflammatory phase of the disease triggered by the so-called cytokine storm, the following strategies are particularly relevant: (a) drugs targeting JAK kinases; (b) sphingosine kinase 2 inhibitors; (c) antibodies against interleukin 6 or its receptor; (d) use of the traditional anti-inflammatory corticosteroids.

Atopic dermatitis (AD) is an inflammatory disorder centered around loss of epidermal barrier function, and T helper 2 (Th2) immune responses. The current understanding of disease heterogeneity and complexity, limits the rational use of existing topical, systemic therapeutic agents, but paves way for development of advanced therapeutic agents. Additionally, advanced nanocarriers that deliver therapeutics to target cells, seem to offer a promising strategy, to overcome intrinsic limitations and challenges of conventional, and traditional drug delivery systems. Ever-evolving understanding of molecular target sites and complex pathophysiology, adverse effects of current therapeutic options, inefficient disease recapitulation by existing animal models are some of the challenges that we face. Also, despite limited success in market translatibility, nanocarriers have demonstrated excellent preclinical results and have been extensively studied for AD. Detailed research on behavior of nanocarriers in different patients and tailored therapy to account for phenotypic variability of the disease are the new research avenues that we look forward to.

The risk of Coronavirus infection continues, and the fear of resurgence indicates the lack of a successful therapeutic strategy. In severe COVID-19 infection, many immune cells and their products are involved, making management difficult. The abundant release of cytokines and chemokines in severe COVID-19 patients leads to profound hyper inflammation and the mobilization of immune cells, triggering the cytokine storm. The complications associated with the cytokine storm include severe respiratory distress, intravascular coagulation, multi-organ failure, and death. The enormous formation of interleukin (IL)-6 and hemopoietic factors such as granulocyte-macrophage colony-stimulating factor (GM-CSF) are implicated in the severity of the infection. Moreover, these inflammatory cytokines and factors signal through the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway causing the activation of cytokine-related genes. The neutralization of these proteins could be of therapeutic help in COVID-19 patients and could mitigate the risk of mortality. IL-6 antagonist, IL-6 receptor antagonists, GM-CSF receptor inhibitors, and JAK-STAT inhibitors are being investigated to prevent intense lung injury in COVID-19 patients and increase the chances of survival. The review focuses the role of IL-6, GM-CSF, and JAK-STAT inhibitors in regulating the immune response in severely affected COVID-19 patients.

BACKGROUND: Alopecia areata (AA) and generalized form, universalis (AU) are common causes of noncicatricial alopecia, targeting anagen hair follicles. A dominant interferon-gamma transcriptional signaling and cytotoxic T lymphocytes were accused as the main drivers of disease pathogenesis. Tofacitinib is a Janus kinase inhibitor that has been proven to interfere with the positive feedback loop between the follicular cell and the cytotoxic T lymphocytes in AA. There is an increasing number of studies reporting success with tofacitinib in AA.
OBJECTIVE: We aimed to assess oral tofacitinib\'s safety and efficacy in 13 recalcitrant AA and AU patients.
METHODS: This is a retrospective pilot study performed between 2017 and 2020. The demographic features and the treatment responses were evaluated with Severity of Alopecia Tool score changes.
RESULTS: Thirteen recalcitrant alopecia areata patients (3 AA, 10 AU), aged between 17 and 49, were included in the study. The treatment duration was 3-15 months. All three AA patients responded well; however, the therapy was unsuccessful in five of ten AU patients. Relapse was observed in one of the AA and three of the AU responders. Acneiform lesions and elevation of transaminases were the major side effects.
CONCLUSIONS: Tofacitinib seems to be more promising and thriving in the treatment of AA than AU. Starting the therapy earlier can bring more successful results. Unfortunately, even in the cases that fully respond to treatment, relapse can be observed after discontinuation of the treatment. It is essential to inform patients about this situation in reducing the frustrations that may occur later.