Small Molecule Therapy for Inflammatory Bowel Disease: JAK Inhibitors and S1PR Modulators DOI Creative Commons
Yu Kyung Jun, Hyuk Yoon

Korean Journal of Gastroenterology, Journal Year: 2024, Volume and Issue: 84(2), P. 51 - 64

Published: Aug. 23, 2024

Small molecules, including Janus kinase (JAK) inhibitors and sphingosine-1-phosphate receptor modulators (S1PRMs), are promising new treatments for inflammatory bowel disease (IBD). molecules exhibit more predictable pharmacokinetics than biologics, less likely to induce immune responses, can be administered orally. JAK function by blocking the activity of enzymes, which prevents subsequent phosphorylation activation signal transducer activator transcription (STAT) proteins. Tofacitinib filgotinib approved treating ulcerative colitis (UC), while upadacitinib is UC Crohn's disease. Nevertheless, increase risk herpes zoster, cancer, major adverse cardiovascular events, venous thromboembolism. S1PRMs bind S1PRs, particularly S1PR1, on lymphocytes. This interaction inhibits lymphocytes from exiting lymph nodes migrating gut, thereby reducing inflammation response in intestinal mucosa. Ozanimod etrasimod treatment UC, but they cause side effects such as bradycardia, conduction disorder, macular edema. Overall, offer significant benefits managing IBD, although their potential require careful monitoring.

Language: Английский

Inhibition of the JAK-STAT Pathway in the Treatment of Psoriasis: A Review of the Literature DOI Open Access

Andreea Roxana Furtunescu,

Simona Roxana Georgescu, Mircea Tampa

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(9), P. 4681 - 4681

Published: April 25, 2024

Psoriasis is a highly prevalent dermatological disease associated with an increased systemic inflammatory response. In addition, joint involvement also present in around 20% of patients. Therefore, treatment modalities used this condition should be simultaneously effective at improving skin manifestations, reducing inflammation, and addressing psoriatic arthritis when present. Twenty years ago, the introduction biologic treatments for psoriasis was turning point management condition, offering reasonably safe option patients whose could not adequately controlled conventional therapies. At moment, Janus Kinase inhibitors (JAKis) are new class promising molecules psoriasis. They orally administered can show benefits who failed therapy. We conducted scoping review order to identify randomized-controlled trials that investigated different JAKis plaque arthritis, emphasis on have been approved by European Medicines Agency Food Drug Administration. The added value study it collected information about two indications, provide integrated understanding range effects whole spectrum manifestations.

Language: Английский

Citations

10
A Phase 3 Trial of Upadacitinib for Giant-Cell Arteritis DOI
Daniël Blockmans,

Sara K. Penn,

Arathi Setty

et al.

New England Journal of Medicine, Journal Year: 2025, Volume and Issue: unknown

Published: April 2, 2025

Giant-cell arteritis is a systemic vasculitis with limited treatment options. The efficacy and safety of upadacitinib - selective Janus kinase (JAK) inhibitor that blocks the signaling several cytokines, including interleukin-6 interferon-γ are unknown in patients giant-cell arteritis. We randomly assigned new-onset or relapsing arteritis, 2:1:1 ratio, to receive at dose 15 mg 7.5 orally once daily plus 26-week glucocorticoid taper placebo 52-week taper. primary end point was sustained remission week 52, defined by absence signs symptoms from 12 through 52 adherence protocol-specified A total 209 received mg, 107 112 placebo; 70% had Upadacitinib showed superiority over respect (46.4% [95% confidence interval {CI}, 39.6 53.2] vs. 29.0% CI, 20.6 37.5]; P = 0.002). superior analysis hierarchically prespecified multiplicity-controlled key secondary points complete remission, time disease flare, cumulative exposure, patient-reported outcomes. not (41.1% 31.8 50.4]). Safety outcomes during period weeks were similar groups. Although cardiovascular risk potential concern JAK inhibitor, no major adverse events occurred In but (Funded AbbVie; SELECT-GCA ClinicalTrials.gov number, NCT03725202.).

Language: Английский

Citations

1
Pregnancy Outcomes in Patients Treated with Upadacitinib: Analysis of Data from Clinical Trials and Postmarketing Reports DOI Creative Commons
Uma Mahadevan,

Gweneth Levy,

Lianne S. Gensler

et al.

Drug Safety, Journal Year: 2024, Volume and Issue: 47(10), P. 1039 - 1049

Published: July 15, 2024

Upadacitinib is indicated for diseases affecting persons of childbearing potential including rheumatoid arthritis, psoriatic axial spondyloarthritis, atopic dermatitis, Crohn's disease, and ulcerative colitis; however, teratogenicity was observed in animal studies. Given the human fetal risk, pregnancy avoidance measures were required during clinical trials. This analysis describes outcomes patients exposed to upadacitinib pregnancy. Clinical trial postmarketing cases utero exposure identified AbbVie's safety database through 25 April, 2023. Analysis reports are presented separately; prospective retrospectively reported integrated each. Descriptive rates summarize outcomes. There 128 maternal upadacitinib-exposed pregnancies with known identified; 80 48 trials setting, respectively. In (mean 5 weeks, 3 days), live births (54%), spontaneous abortions (24%), elective terminations (21%), ectopic (1%) reported. one report a congenital malformation: 35-week infant an atrial septal defect. cases, (46%), (38%), (15%), (2%) As data limited upadacitinib, definitive conclusions cannot be drawn regarding effect on Rates adverse comparable general population or autoimmune inflammatory diseases. To date, no apparent evidence exists analyses first trimester.

Language: Английский

Citations

7
Neutrophil diversity and function in health and disease DOI Creative Commons

F Zhang,

Yidan Xia,

Jiayang Su

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Dec. 5, 2024

Abstract Neutrophils, the most abundant type of granulocyte, are widely recognized as one pivotal contributors to acute inflammatory response. Initially, neutrophils were considered mobile infantry innate immune system, tasked with immediate response invading pathogens. However, recent studies have demonstrated that versatile cells, capable regulating various biological processes and impacting both human health disease. Cytokines other active mediators regulate functional activity by activating multiple receptors on these thereby initiating downstream signal transduction pathways. Dysfunctions in disruptions neutrophil homeostasis been implicated pathogenesis numerous diseases, including cancer disorders, often due aberrant intracellular signaling. This review provides a comprehensive synthesis functions, integrating advancements this field. Moreover, it examines roles signaling pathways involved regulation activity. The pathophysiology diseases emerging therapeutic approaches targeting them also elaborated. addresses current limitations within field research, highlighting critical gaps knowledge warrant further investigation. In summary, seeks establish multidimensional model regulation, providing new perspectives for potential clinical applications research.

Language: Английский

Citations

6
Varicella-Zoster Meningitis and Myelitis After Herpes Zoster Dermatitis Treatment With Amenamevir: A Case Series and Literature Review DOI Open Access
Satoru Tada,

Yuta Kaito,

Akihiro Watanabe

et al.

Cureus, Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 23, 2024

Varicella-zoster virus (VZV), known for causing chickenpox, establishes latent infections in neural tissues. Reactivation of VZV can lead to herpes zoster (HZ) and various neurological complications. In this report, we present four cases meningitis myelitis following amenamevir treatment HZ dermatitis with positive DNA cerebrospinal fluid (CSF) revealed by polymerase chain reaction (PCR). Three them were considered immunocompromised hosts given the fact that two these patients taking immunosuppressive drugs rheumatoid arthritis, one patient had a history sigmoid colon cancer (four months after resection). After onset, amenamevir, which has poor CSF transfer, was prescribed all patients, developed central nervous complications (meningitis three case) confirmed PCR. All treated acyclovir, higher fully recovered. We speculate might have failed prevent infection system (CNS) think consideration should be administering acyclovir preference ΗΖ at high risk CNS infection, such as hosts.

Language: Английский

Citations

5
Effectiveness of Dose Increase in Upadacitinib from 15 mg to 30 mg for Patients with Moderate-to-Severe Atopic Dermatitis: A Real-World Clinical Practice in Japan DOI
Teppei Hagino,

Risa Hamada,

Mai Yoshida

et al.

Clinical Drug Investigation, Journal Year: 2024, Volume and Issue: 44(4), P. 261 - 269

Published: March 6, 2024

Language: Английский

Citations

5
SOCS1 and SOCS3 as key checkpoint molecules in the immune responses associated to skin inflammation and malignant transformation DOI Creative Commons
Martina Morelli, Stefania Madonna, Cristina Albanesi

et al.

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: June 21, 2024

SOCS are a family of negative inhibitors the molecular cascades induced by cytokines, growth factors and hormones. At level, proteins inhibit kinase activity specific sets receptor-associated Janus Activated Kinases (JAKs), thereby suppressing propagation intracellular signals. Of eight known members, SOCS1 SOCS3 JAKs mainly cytokines can play key roles in regulation inflammatory immune responses. most well-characterized members skin diseases, where their inhibitory on cytokine activated consequent anti-inflammatory action has been widely investigated epidermal keratinocytes. Structurally, share presence N-terminal domain containing region (KIR) motif able to act as pseudo-substrate for JAK its activity. During last decades, design employment SOCS3-derived peptides mimicking KIR domains experimental models dermatoses definitively established strong ameliorative impact inhibition Herein, we discuss importance findings collected past function responses associated immune-mediated diseases malignancies, development inhibitor drugs. Among them, different have introduced clinical practice treatment atopic dermatitis psoriasis, others being like alopecia areata vitiligo.

Language: Английский

Citations

4
JAK inhibitors: a new choice for diabetes mellitus? DOI Creative Commons

Mengjun Zhou,

Qi Shen,

Bo Li

et al.

Diabetology & Metabolic Syndrome, Journal Year: 2025, Volume and Issue: 17(1)

Published: Jan. 23, 2025

Altered tyrosine kinase signaling is associated with a variety of diseases. Tyrosine kinases can be classified into two groups: receptor type and nonreceptor type. Nonreceptor-type are subdivided Janus (JAKs), focal adhesion (FAKs) tec protein (TECs). The beneficial effects receptor-type inhibitors (TKIs) for the treatment diabetes mellitus (DM) mechanisms involved have been previously described. Recently, several clinical cases involving reversal 1 (T1DM) during JAK reported, studies described improvement 2 (T2DM) inhibitors. In vivo in vitro experimental elucidated some behind this effect, which seem to based mainly on reduction β-cell disruption insulin resistance. review, we briefly describe among DM attempt analyze involved.

Language: Английский

Citations

0
Targeting Janus kinase 1 in refractory Behçet’s disease: a case report on the clinical efficacy of upadacitinib DOI

Claudia Ammoscato,

Francesca Gatti, Florenzo Iannone

et al.

Internal and Emergency Medicine, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 27, 2025

Language: Английский

Citations

0
Real-world effectiveness and retention rate of upadacitinib in patients with rheumatoid arthritis: results from a multicentre study DOI Creative Commons
Caterina Baldi, Stefano Gentileschi, Francesca Li Gobbi

et al.

Clinical and Experimental Medicine, Journal Year: 2025, Volume and Issue: 25(1)

Published: Feb. 5, 2025

Abstract This study evaluates upadacitinib (UPA) effectiveness and drug retention rate (DRR) in patients with rheumatoid arthritis (RA). Multicentre prospective observational study. Consecutive RA receiving UPA were evaluated at 0, 3, 6, 12, 18, 24 months of treatment. Key outcomes included DRR changes clinical serological measures over time. The 215 (72.6% female sex, mean age 60.1 ± 11.7 years). was 91.6% (95% CI 88.0–95.4%) 6 months, 84.6% 79.8–89.7%) 12 80.3% 75.0–86.0%) 18 80% months. similar between monotherapy methotrexate combination (p = 0.47), across different treatment lines 0.58). A statistically significant improvement from baseline observed considering erythrocyte sedimentation rate, C-reactive protein (CRP), Health Assessment Questionnaire (HAQ), Disease Activity Score (DAS)28-CRP, Physician’s (Ph) Patient’s (Pt) Global (GA), Visual Analogue Scale (VAS) Pain, Simplified Clinical Index (SDAI CDAI) < 0.00 for all them). Patients discontinuing more likely to be male 0.02), a longer disease duration 0.03), higher values VAS Pain 0.00), PtGA PhGA CDAI SDAI 0.00) corticosteroid dosage 0.04). confirms managing the real-world practice, demonstrating sustained improvements laboratory Also, could valuable option multi-refractory when is preferred.

Language: Английский

Citations

0