JAK Inhibitors Research Articles

Differences in disease characteristics and treatment exposures between paediatric and adult-onset inflammatory bowel disease using a registry-based cohort.

Previous studies highlighted a more extensive phenotype for paediatric-onset than adult-onset inflammatory bowel disease (IBD). However, most lacked long-term follow-up, and some were conducted before the era of biologics. The aim of this study is to compare disease characteristics and treatment exposures between paediatric-onset and adult-onset IBD. From a registry that periodically and uniformly retrieves demographics, disease characteristics/phenotype, and treatments, we compared the characteristics of paediatric-onset (diagnosed at ≥6 and <18 years) and adult-onset IBD, diagnosed during 2000-2022 and with ≥12 months follow-up. Of the 2837 patients with Crohn's disease and 1332 with ulcerative colitis, 3316 had adult-onset and 853 paediatric-onset IBD. The median follow-up was 6 years. Patients with paediatric-onset presented with more extensive disease and received more intensified therapies, including biologics and JAK inhibitors than those with adult-onset IBD. Paediatric-onset ulcerative colitis showed a higher prevalence of E3 extensive colitis including pancolitis and a greater requirement for systemic steroids, immunomodulators, and biologics than adult-onset ulcerative colitis. Paediatric-onset versus adult-onset Crohn's disease exhibited greater L3 ileocolonic involvement and perianal disease phenotype, and higher exposure to immunomodulators and biologics. Kaplan-Meier curve and Cox proportional hazards analyses showed significantly lower 15-year biologic-free survival from diagnosis among those with paediatric-onset IBD than with adult-onset IBD (p = <0.001), indicating greater and earlier use of biologics in the former. Paediatric-onset presents with more extensive disease with higher exposures to immunomodulators and biologic therapies than adult-onset IBD.

A Practical Guide to Using Oral JAK Inhibitors for Atopic Dermatitis from the International Eczema Council.

Janus kinase inhibitors (JAKinibs) have the potential to dramatically alter the landscape of atopic dermatitis (AD) management due to their promising efficacy results from phase 3 trials and rapid onset of action. However, JAKinibs are not without risk, and their use is not appropriate for all AD patients, making this a medication class that dermatologists should understand and consider when treating patients with moderate-to-severe AD. This consensus expert opinion statement from the International Eczema Council (IEC) provides a pragmatic approach to prescribing JAKinibs, including choosing appropriate patients, dosing, clinical and lab monitoring, as well as long-term use. An international cohort of authors from the IEC with expertise in JAKinibs selected topics of interest and were formed into authorship groups covering 10 subsections. The groups performed topic-specific literature reviews, consulted up-to-date adverse event (AE) data, referred to product labels and provided analysis and expert opinion. The manuscript guidance and recommendations were reviewed by all authors as well as the IEC Research Committee. We recommend JAKinibs be considered for patients with moderate to severe AD seeking the benefits of rapid reduction in disease burden and itch, oral administration, and the potential for flexible dosing. Baseline risk factors should be assessed prior to prescribing JAKinibs, including increasing age, venous thromboembolisms, malignancy, cardiovascular health, kidney/liver function, pregnancy and lactation, and immunocompetence. Patients being considered for JAKinib therapy should be current on vaccinations and we provide a generalized framework for laboratory monitoring, though clinicians should consult individual product labels for recommendations as there are variations among the JAKinib class. Patients who achieve disease control should be maintained on the lowest possible dose, as many of the observed AEs occurred in a dose-dependent manner. Future studies are needed in AD patients to assess the durability and safety of continuous long-term use of JAKinibs, combination medication regimens, and the effects of flexible, episodic treatment over time. The decision to initiate a JAKinib should be shared among patient and provider, accounting for AD severity and personal risk/benefit assessment, including consideration of baseline health risk factors, monitoring requirements and treatment costs.

Risk factors that limit use of oral JAK inhibitors in chronic hand eczema: Findings from the Danish Skin Cohort

BackgroundOral Janus kinase inhibitors (JAKi) have black-box warnings of infections, cancer risk, cardiovascular and venous thromboembolic events. They may be used off-label for chronic hand eczema (CHE). ObjectivesAssess prevalence of risk factors potentially impacting oral JAKi safety in CHE patients. MethodsIn the Danish Skin Cohort, CHE patients were examined for risk factors affecting oral JAKi use at baseline and followed for 12 months. Data were collected through register linkage (e.g., cancer history) and through patient interviews (e.g., smoking habits). ResultsOf 941 adults with CHE (66.2% women; mean age 55.5 [standard deviation 13.3] years), 768 (81.6%) patients had at least one risk factor potentially impacting oral JAKi use, of which 682 (72.5%) had non-modifiable risk factors. Most common risk factors were current or former heavy smoking (62.8%, n=591), obesity (28.1%, n=264), hypercholesterolemia (21.5%, n=202), and hypertension (18.8%, n=177). Among patients without any risk factors at baseline (n=173), 20.2% (n=35) developed ≥1 risk factor during the following 12 months. LimitationsCertain risk factors may be underreported. ConclusionMost CHE patients have risk factors limiting appropriateness of oral JAKi use. Health care providers should assess risk factors in their patients when choosing treatment for CHE.

Relationship Between Janus Kinase Inhibitor Use and Development of Retinal Vein Occlusion

Background and Objective: Janus kinase (Jak) inhibitors may have increased risk of thromboembolism compared to tumor necrosis factor (TNF) inhibitors. This study investigates the association between Jak inhibitor use and retinal vein occlusion. Patients and Methods: This retrospective, non-randomized cohort study used a federated health research network. Propensity-score matched risk ratios with 95% CI were calculated for central and branch retinal vein occlusion (CRVO, BRVO) in patients with immune-mediated inflammatory diseases (IMIDs) treated with Jak inhibitors versus TNF inhibitors. Results: Jak and TNF inhibitor cohorts each had 5,249 patients. Risk ratio for CRVO with Jak inhibitors ( n = 11) versus TNF inhibitors ( n = 18) was 0.61 [CI (0.29,1.29)]. Risk ratio for BRVO with Jak inhibitors ( n = 17) compared to TNF inhibitors ( n = 19) was 0.89 [CI (0.47,1.72)]. Conclusion: This study did not find evidence of increased risk of RVO with the use of Jak inhibitors compared to TNF inhibitors among patients with IMIDs, contributing to literature on Jak inhibitor safety. [ Ophthalmic Surg Lasers Imaging Retina 2024;55:xx–xx.]

Increased risk of Pneumocystis jirovecii colonization in rheumatoid arthritis patients on biologics and Janus kinase inhibitor

BackgroundThe prevalence of Pneumocystis jirovecii (PJ) pneumonia among rheumatic patients is rising. PJ colonization serves as a reservoir for transmission and precedes the development of PJ pneumonia. We aim to clarify the association of PJ colonization in patients of rheumatoid arthritis (RA) treated with biologics or Janus kinase inhibitors (JAKi). MethodsA prospective cohort study was performed from March 2021 to July 2022 in the rheumatology outpatient department of National Cheng Kung University Hospital. We obtained oral-wash samples from asymptomatic RA patients treated with biologic disease-modifying antirheumatic drugs (bDMARDs) and JAKi. A real-time quantitative polymerase chain reaction assay focusing on the mitochondrial large subunit ribosomal ribonucleic acid gene of PJ was applied to detect colonization. ResultsOne hundred and ten RA patients were enrolled. Adjusted odds ratios (ORs) of PJ colonization were 6.40 (95% CI 1.34-30.57, p-value =0.02) in patients receiving bDMARDs or JAKi. Specifically, in patients treated with bDMARDs the adjusted OR was 8.08 (95% CI 1.57-41.51, p-value=0.012), and a trend toward developing PJ colonization was further identified in patients receiving JAKi (adjusted OR: 4.79, 95% CI 0.89-25.91, p=0.069). Among patients treated with bDMARDs or JAKi, medication duration >3 years and age >60 y/o are risk factors for PJ colonization. ConclusionRA patients on bDMARDs or JAK inhibitors have an approximately 6-fold higher risk of developing P. jirovecii colonization. Patients treated with bDMARDs had an 8-fold higher risk of P. jirovecii colonization. Risk factors of PJ colonization are medication duration >3 years and age > 60 y/o.

Bioactive Natural Leads and Traditional Herbal Plants in the Management of Inflammatory Bowel Diseases: A Brief Review

: Inflammatory bowel disease is a chronic relapsing disorder that causes chronic inflammation and ulcers in the GIT. Depending upon the location, ulcerative colitis and Crohn's disease come under IBD. The exact etiology of IBD is still unknown. Over 8 lakhs of people were affected by inflammatory disease yearly, and the death rate increased daily. Depending upon the severity of the disease, JAK inhibitors, anti-TNF agents, and immunosuppressants can be used to manage ulcerative colitis and Crohn's disease. However, these treatments have been associated with harmful adverse effects, which cannot be ignored. To treat inflammatory diseases safely, various herbal medicines and their bioactive are preferred as game changers. Recently, the effectiveness of herbal plants has been recommended as the treatment against IBD, as shown by various in vivo models and clinical trials. The various herbal plants reported in the literature include gallic acid, lupeol, and curcumin aloe vera. This review focused on medicinal plants' anti-inflammatory, antioxidant, and anti-ulcer properties. Over 1.2 million healthcare practitioners are using herbal bioactive and have the advantages of lower side effects. Therefore, it is estimated that in Europe, the demand for plant-based products/formulations has risen by millions in 2020, showing the current position of herbal-based products in consumer health awareness.

Design of a potent and selective dual JAK1/TYK2 inhibitor

Janus kinase (JAK) inhibitors have gathered interest as treatments for several inflammatory and autoimmune diseases. The four first marketed inhibitors target JAK1, with varying selectivity towards other JAK family members, but none inhibit tyrosine kinase-2 (TYK2) at clinically relevant doses. TYK2 is required for the signaling of the interleukin (IL)-12 and IL-23 cytokines, which are key to the polarization of TH1 and TH17 cells, respectively; two cell subtypes that play major roles in inflammatory diseases. Herein, we report our effort towards the optimization of a potent and selective dual JAK1/TYK2 inhibitor series starting from a HTS hit. Structural information revealed vectors required to improve both JAK1 and TYK2 potency as well as selectivity towards JAK2. The potent inhibition of both JAK1 (3.5 nM) and TYK2 (5.7 nM) in biochemical assays by our optimized lead compound, as well as its notable selectivity against JAK2, were confirmed in cellular and whole blood assays. Inhibition of TYK2 by the lead compound was demonstrated by dose-dependent efficacy in an IL-23 induced psoriasis-like inflammation mouse model.

52143 Post-Market Surveillance of the Safety of Systemic JAK Inhibitors for Dermatologic Diseases in Children

52143 Post-Market Surveillance of the Safety of Systemic JAK Inhibitors for Dermatologic Diseases in Children

Practical Recommendations on Laboratory Monitoring in Patients with Atopic Dermatitis on Oral JAK Inhibitors.

Oral Janus kinase inhibitors (JAKi), a class of advanced targeted systemic therapy, have demonstrated efficacy and safety in the treatment of moderate-to-severe atopic dermatitis (AD). Like other small molecules, oral JAKi have the potential for off-target effects including laboratory-related adverse events (AEs). Product labels for oral JAKi recommend an initial laboratory assessment and follow-up 4-12weeks later to monitor for potential changes, based on evidence from clinical trials across therapeutic indications for oral JAKi, which may not reflect a population of moderate-to-severe AD patients typically seen in routine clinical practice. To address this gap, a panel of eight dermatologists with clinical and research experience with oral JAKi for the management of AD conducted a targeted review of the literature focused on key laboratory-related AEs associated with oral JAKi in the moderate-to-severe AD population. Based on the synthesis of evidence and informed opinion, a set of best practice statements related to fundamental standards of care and consensus recommendations on laboratory monitoring were suggested, and level of agreement was ascertained using a Likert scale from 0 to 100. There was a high level of agreement on three of the four suggested recommendations related to assessment and monitoring of key laboratory parameters and to dose reduction or switching in response to laboratory changes; there was a lower level of agreement related to the frequency of ongoing laboratory monitoring. Appropriate patient selection and laboratory assessment is an important strategy to mitigate the potential risks associated with oral JAKi when treating AD.

52720 Comparing real-world effectiveness and adverse effects of oral JAK inhibitors versus dupilumab in patients with atopic dermatitis: A population-based cohort study

52720 Comparing real-world effectiveness and adverse effects of oral JAK inhibitors versus dupilumab in patients with atopic dermatitis: A population-based cohort study

53617 Current recommendations, risks, and use of JAK inhibitors across specialties for females of childbearing age

53617 Current recommendations, risks, and use of JAK inhibitors across specialties for females of childbearing age

High extracellular matrix stiffness promotes the metastasis of nasopharyngeal carcinoma through STAT3/FGF1 positive feedback regulation activated by JAK2

The stiffness of the extracellular matrix (EM) is known to be associated with tumor metastasis. This study aims to clarify the function and mechanisms of EM stiffness in nasopharyngeal carcinoma (NPC) and to provide a potential therapeutic target for patients with NPC. The NPC cell lines were cultured under varying stiffnesses. Plate cloning, Transwell assays and scratch tests were conducted to compare the phenotypes. Transcriptome sequencing and enrichment analysis were performed to explore the key molecules and the downstream signaling pathways, which were verified via in vitro and in vivo experiments. Our study showed that the NPC cells cultured on a stiff substrate (50 ​kPa) had greater colony formation, invasion and migration abilities than those cultured on a soft substrate. Transcriptome sequencing showed that a stiff environment induced high expression of fibroblast growth factor 1 (FGF1), which suggested a poor prognosis in various malignancies. The phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway played an important role in NPC metastasis activated by the FGF1 autocrine pathway in a stiff environment. The increased FGF1 expression was regulated by the transcription factor STAT3, and a positive feedback regulation between them was observed. The use of the JAK inhibitor Ruxolitinib and JAK2 interference inhibited the activation of STAT3. In conclusion, JAK2 activates STAT3/FGF1 positive feedback regulation and promotes NPC metastasis via the PI3K/Akt signaling pathway in a high-stiffness environment. Hence, FGF1 can be used as a potential therapeutic target for patients with NPC.

53950 Risk of thromboembolic events for JAK inhibitors in dermatology: pharmacovigilance analysis of real-world evidence in the Food and Drug Administration Adverse Event Reporting System (FAERS) from the RADAR (Research on Adverse Drug events And Reports) Prog

53950 Risk of thromboembolic events for JAK inhibitors in dermatology: pharmacovigilance analysis of real-world evidence in the Food and Drug Administration Adverse Event Reporting System (FAERS) from the RADAR (Research on Adverse Drug events And Reports) Prog

The interplay between aging and inflammation and its role in chronic disease development

This paper explores the complex relationship between aging and inflammation and its impact on the development of chronic diseases. Aging is an important contributor to elevated levels of inflammation, with mechanisms including changes in immune regulatory function, chronic low-grade inflammation, cellular aging and tissue damage, changes in gene expression, and increased oxidative stress. These inflammatory processes not only accelerate aging itself, but also promote the development of chronic diseases such as cardiovascular disease (CVD) and Alzheimers disease (AD). The article goes on to address other modern anti-inflammatory treatment approaches, such as biologics, JAK inhibitors, and nonsteroidal anti-inflammatory medications. These treatments help manage and mitigate aging-related pathologies by targeting key molecules and pathways of inflammation. A better comprehension of the relationship between inflammation and aging may serve as the foundation for the creation of novel therapeutic approaches that, in addition to reducing inflammatory reactions, may also prevent or slow the advancement of illnesses associated with age. This article aims to improve medical and scientific understanding of the relationship between inflammation and aging and to encourage the development and use of more potent therapies to lessen the burden of chronic illnesses and enhance the quality of life for the aged.

Design, synthesis and activity screening of cedrol derivatives as small molecule JAK3 inhibitors

The JAK-STAT signalling pathway is considered to be a significant role involved in the regulation of inflammatory diseases and immune responses, which indicate that specific inhibition of JAK-STAT pathway would be a potential key strategy for RA (Rheumatoid arthritis) treatment. Cedrol (CE), found from ginger by our group earlier, has been proven to play an excellent role in ameliorating RA via acting on JAK3. In this study, 27 new (1, 3–28), along with one known (2) derivatives of CE were synthesized by using chloroacetic acid and acryloyl chloride as intermediate ligands. In vitro, the inhibition effect on JAK kinases were performed using HTRF (Homogenous Time-Resolved Fluorescence) detection technology, which is more convenient and stable than traditional methods. The results compared with the secretion of LPS-induced p-JAK3 can better reflect the true kinase-selective effect of the compounds. Compound 22 was identified as a potent inhibitor to reduce the secretion of LPS-induced p-JAK3 with a dose-dependent manner. Given these results, compound 22 could serve as a favourable inhibitor of JAK3 for further research.

Kinases Inhibitors as New Therapeutic Opportunities in Cutaneous T-Cell Lymphoma

Cutaneous T-cell lymphomas (CTCLs) are a heterogeneous group of T-cell lymphomas characterised by high relapse rates and no curative treatments unless the allogeneic stem cell transplantation. The main complication in the management of this kind of malignancy is the variability that characterises the genetic and clinical features among the CTCL subtypes. JAK/STAT, MAPK/ERK, PI3K/Akt, and NF-kB are those signalling pathways that are found altered in CTCL and that are responsible for promoting both T-cell malignancy and the pro-tumorigenic microenvironment. Thus, targeting key players of these pathways can be an advantageous therapeutic option for CTCL. In this review, we aim to summarise the different approaches that precisely inhibit the kinases of each cited signalling. JAK inhibitors seem to be the most promising kinase inhibitors for CTCL. However, adverse events have been reported especially in patients with immunosuppression or an underlying autoimmune disease. More studies are needed, especially clinical trials, to investigate the benefits of these drugs for the treatment of cutaneous T-cell lymphomas.

Upadacitinib - New Janus Kinase Inhibitor - Literature Review

Atopic dermatitis (AD) is a chronic, recurrent dermatosis that affects an increasing percentage of the population. It usually affects children and resolves spontaneously, however, symptoms can persist into adulthood and even appear de novo later in life. The skin lesions that appear in this disease significantly reduce patients quality of life. Visual skin symptoms are exacerbated during stress, and pruritus leads to sleep problems. The effect of an inadequately controlled disease can even be a reduction in social activities and a reluctance to leave the house. The basis of treatment is skin care using emollients and avoiding triggers and aggravating factors. In the next stage, the doctor may prescribe topical or systemic treatment for the patient, depending on the severity of the disease. Such measures may not be enough, so more and more new drugs are being registered for the treatment of atopic dermatitis. One of them is upadacitinib, which appears to be extremely effective compared to other medications used to treat moderate to severe ad. It is a selective JAK inhibitor that reduces the inflammatory response by inhibiting migration, proliferation and cytokine secretion by granulocytes. It brings rapid and sustained effects in reducing skin lesions and reducing one of the most bothersome symptoms, pruritus.It may serve as a good alternative to the existing methods for treating moderate to severe atopic dermatitis The purpose of our study is to describe this new drug, its mechanism of action and discuss its possible benefits versus side effects.

Type I interferon signaling induces melanoma cell-intrinsic PD-1 and its inhibition antagonizes immune checkpoint blockade

Programmed cell death 1 (PD-1) is a premier cancer drug target for immune checkpoint blockade (ICB). Because PD-1 receptor inhibition activates tumor-specific T-cell immunity, research has predominantly focused on T-cell-PD-1 expression and its immunobiology. In contrast, cancer cell-intrinsic PD-1 functional regulation is not well understood. Here, we demonstrate induction of PD-1 in melanoma cells via type I interferon receptor (IFNAR) signaling and reversal of ICB efficacy through IFNAR pathway inhibition. Treatment of melanoma cells with IFN-α or IFN-β triggers IFNAR-mediated Janus kinase-signal transducer and activator of transcription (JAK/STAT) signaling, increases chromatin accessibility and resultant STAT1/2 and IFN regulatory factor 9 (IRF9) binding within a PD-1 gene enhancer, and leads to PD-1 induction. IFNAR1 or JAK/STAT inhibition suppresses melanoma-PD-1 expression and disrupts ICB efficacy in preclinical models. Our results uncover type I IFN-dependent regulation of cancer cell-PD-1 and provide mechanistic insight into the potential unintended ICB-neutralizing effects of widely used IFNAR1 and JAK inhibitors.

MPN-652 Long-Term Response to Selinexor in Patients With Myelofibrosis and Refractory or Intolerant to JAK Inhibitors: Follow-Up Results of a Single-Center, Phase II, Investigator-Initiated Trial (IIT)

MPN-652 Long-Term Response to Selinexor in Patients With Myelofibrosis and Refractory or Intolerant to JAK Inhibitors: Follow-Up Results of a Single-Center, Phase II, Investigator-Initiated Trial (IIT)

Long-Term Response to Selinexor in Patients With Myelofibrosis and Refractory or Intolerant to JAK Inhibitors: Follow-Up Results of a Single-Center, Phase II, Investigator-Initiated Trial (IIT)

Long-Term Response to Selinexor in Patients With Myelofibrosis and Refractory or Intolerant to JAK Inhibitors: Follow-Up Results of a Single-Center, Phase II, Investigator-Initiated Trial (IIT)