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RMD Open May 2024To compare the effectiveness of a strategy administering baricitinib versus one using TNF-inhibitors (TNFi) in patients with rheumatoid arthritis (RA) after conventional... (Randomized Controlled Trial)
Randomized Controlled Trial Comparative Study
PERFECTRA: a pragmatic, multicentre, real-life study comparing treat-to-target strategies with baricitinib versus TNF inhibitors in patients with active rheumatoid arthritis after failure on csDMARDs.
OBJECTIVE
To compare the effectiveness of a strategy administering baricitinib versus one using TNF-inhibitors (TNFi) in patients with rheumatoid arthritis (RA) after conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) failure in a real-life treat-to-target (T2T) setting.
METHODS
Patients with biological and targeted synthetic DMARD (b/tsDMARD) naïve RA with disease duration ≤5 years without contraindications to b/tsDMARD were randomised to either TNFi or baricitinib when csDMARD failed to achieve disease control in a T2T setting. Changes in clinical and patient-reported outcome measures (PROMs) were assessed at 12-week intervals for 48 weeks. The primary endpoint was non-inferiority, with testing for superiority if non-inferiority is demonstrated, of baricitinib strategy in the number of patients achieving American College of Rheumatology 50 (ACR50) response at 12 weeks. Secondary endpoints included 28-joint count Disease Activity Score with C reactive protein (DAS28-CRP) <2.6, changes in PROMs and radiographic progression.
RESULTS
A total of 199 patients (TNFi, n=102; baricitinib, n=97) were studied. Both study groups were similar. Baricitinib was both non-inferior and superior in achieving ACR50 response at week 12 (42% vs 20%). Moreover, 75% of baricitinib patients achieved DAS28-CRP <2.6 at week 12 compared with 46% of TNFi patients. On secondary outcomes throughout the duration of the study, the baricitinib strategy demonstrated comparable or better outcomes than TNFi strategy. Although not powered for safety, no unexpected safety signals were seen in this relatively small group of patients.
CONCLUSION
Up to present, in a T2T setting, patients with RA failing csDMARDs have two main strategies to consider, Janus Kinases inhibitor versus bDMARDs (in clinical practice, predominantly TNFi). The PERFECTRA study suggested that starting with baricitinib was superior over TNFi in achieving response at 12 weeks and resulted in improved outcomes across all studied clinical measures and PROMs throughout the study duration in these patients.
Topics: Humans; Purines; Sulfonamides; Arthritis, Rheumatoid; Pyrazoles; Azetidines; Male; Female; Middle Aged; Antirheumatic Agents; Aged; Treatment Outcome; Tumor Necrosis Factor Inhibitors; Treatment Failure; Adult; Patient Reported Outcome Measures; Severity of Illness Index
PubMed: 38816210
DOI: 10.1136/rmdopen-2024-004291 -
PNAS Nexus May 2024C-type lectins (CTLs) are a family of carbohydrate-binding proteins and an important component of mosquito saliva. Although CTLs play key roles in immune activation and...
C-type lectins (CTLs) are a family of carbohydrate-binding proteins and an important component of mosquito saliva. Although CTLs play key roles in immune activation and viral pathogenesis, little is known about their role in regulating dengue virus (DENV) infection and transmission. In this study, we established a homozygous knockout mutant line using CRISPR/Cas9 to study the interaction between and viruses in mosquito vectors. Furthermore, mouse experiments were conducted to confirm the transmission of DENV by mutants. We found that was mainly expressed in the medial lobe of the salivary glands (SGs) in female . knockout increased DENV replication and accumulation in the SGs of female , suggesting that plays an important role in DENV transmission. We also found a reduced expression of immunodeficiency and Janus kinase/signal transducer and activator of transcription pathway components correlated with increased DENV viral titer, infection rate, and transmission efficiency in the mutant strain. The findings of this study provide insights not only for guiding future investigations on the influence of CTLs on immune responses in mosquitoes but also for developing novel mutants that can be used as vector control tools.
PubMed: 38813522
DOI: 10.1093/pnasnexus/pgae188 -
JAAD Case Reports Jun 2024
PubMed: 38813063
DOI: 10.1016/j.jdcr.2024.04.017 -
Dermatology Practical & Conceptual Apr 2024The introduction of Janus Kinase inhibitors (JAKi) seems to revolutionize the field of alopecia areata (AA) therapeutics. However, real-world data are still missing.
INTRODUCTION
The introduction of Janus Kinase inhibitors (JAKi) seems to revolutionize the field of alopecia areata (AA) therapeutics. However, real-world data are still missing.
OBJECTIVES
To provide evidence about effectiveness and safety of tofacitinib and baricitinib in AA in real-world settings and describe baseline disease characteristics and patients profiles that are considered good candidates for JAKi in the daily practice. Furthermore, we intended to investigate potential correlations between baseline characteristics and treatment outcomes.
METHODS
We retrospectively reviewed the databases of two tertiary Hospitals in Greece, to identify individuals of any age currently being treated with systemic JAKi for severe AA.
RESULTS
We identified 42 individuals, including 3 adolescents. In our cohort, 52.3% (22/42) were under tofacitinib and 47.6% (20/42) under baricitinib treatment. Efficacy analysis was performed on the subgroup of 30 patients that had completed at least a 3-month follow-up on treatment. In the latter group, mean time on treatment was 10 months. Mean Severity of Alopecia Tool and mean Dermatology Life Quality Index scores decreased from 84.46% and 12.86 at baseline, to 43.26% and 6.63, respectively. Complete response (CR) was recorded in 4 (13.33%), partial in 12 (40%) and no response in 14 patients (46.66%), correspondingly. Seventeen out of 42 (40.5%) individuals in total, reported at least 1 adverse event. No patient required hospitalization. Among 15 patients (35.7%) who got COVID-19, one suffered from serious infection. The 3 adolescents achieved CR with no significant adverse events.
CONCLUSIONS
Real-world data suggest efficacy and safety of JAKi in severe forms of AA. Tolerability is optimal in younger individuals.
PubMed: 38810065
DOI: 10.5826/dpc.1402a73 -
Journal of Biomedical Research Mar 2024Ferroptosis is an iron-mediated regulatory cell death pattern characterized by oxidative damage. The molecular regulating mechanisms are related to iron metabolism,...
Ferroptosis is an iron-mediated regulatory cell death pattern characterized by oxidative damage. The molecular regulating mechanisms are related to iron metabolism, lipid peroxidation, and glutathione metabolism. Additionally, some immunological signaling pathways, such as the cyclic GMP-AMP synthase-stimulator ofinterferon genes axis, Janus kinase-signal transducer and activator of transcription 1 axis, and transforming growth factor beta 1-Smad3 axis may also participate in the regulation of ferroptosis. Studies have shown that ferroptosis is closely related to many diseases such as cancer, neurodegenerative diseases, inflammatory diseases, and autoimmune diseases. Considering the pivotal role of ferroptosis-regulating signaling in the pathogenesis of diverse diseases, the development of ferroptosis inducers or inhibitors may have significant clinical potential for the treatment of the aforementioned conditions.
PubMed: 38808552
DOI: 10.7555/JBR.37.20230224 -
Frontiers in Pharmacology 2024Hepatocellular carcinoma (HCC) has a high morbidity and mortality rate, and the survival rate of HCC patients remains low. Animal medicines have been used as potential... (Review)
Review
Hepatocellular carcinoma (HCC) has a high morbidity and mortality rate, and the survival rate of HCC patients remains low. Animal medicines have been used as potential therapeutic tools throughout the long history due to their different structures of biologically active substances with high affinity to the human body. Here, we focus on the effects and the mechanism of action of animal-derived natural products against HCC, which were searched in databases encompassing Web of Science, PubMed, Embase, Science Direct, Springer Link, and EBSCO. A total of 24 natural products from 12 animals were summarized. Our study found that these natural products have potent anti-hepatocellular carcinoma effects. The mechanism of action involving apoptosis induction, autophagy induction, anti-proliferation, anti-migration, and anti-drug resistance via phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR), Ras/extracellular signal regulated kinases (ERK)/mitogen-activated protein kinase (MAPK), Wnt/β-catenin, and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways. Huachansu injection and sodium cantharidate have been used in clinical applications with good efficacy. We review the potential of animal-derived natural products and their derivatives in the treatment of HCC to date and summarize their application prospect and toxic side effects, hoping to provide a reference for drug development for HCC.
PubMed: 38803433
DOI: 10.3389/fphar.2024.1399882 -
Tofacitinib for the treatment of refractory immune checkpoint inhibitor-associated immune nephritis.Clinical Kidney Journal May 2024Immune checkpoint inhibitor (ICI)-associated immune nephritis or acute interstitial nephritis (AIN) is one of the rare but known complication of ICI therapy. Guidelines...
Immune checkpoint inhibitor (ICI)-associated immune nephritis or acute interstitial nephritis (AIN) is one of the rare but known complication of ICI therapy. Guidelines recommend treatment of ICI-associated AIN with steroids, then TNF-alpha inhibitor infliximab. However, some cases are refractory to these therapies, potentially due to insufficient cytokine blockade. This is the first case where a 65-year-old female with metastatic lung adenocarcinoma, requiring high maintenance doses of steroids for immune nephritis was treated with tofacitinib, an oral Janus kinase (JAK) inhibitor. Tofacitinib enabled successful steroid tapering and might be a therapy option for refractory immune nephritis.
PubMed: 38803394
DOI: 10.1093/ckj/sfae127 -
Nature Communications May 2024Deciphering the intricate dynamic events governing type I interferon (IFN) signaling is critical to unravel key regulatory mechanisms in host antiviral defense. Here, we...
Deciphering the intricate dynamic events governing type I interferon (IFN) signaling is critical to unravel key regulatory mechanisms in host antiviral defense. Here, we leverage TurboID-based proximity labeling coupled with affinity purification-mass spectrometry to comprehensively map the proximal human proteomes of all seven canonical type I IFN signaling cascade members under basal and IFN-stimulated conditions. This uncovers a network of 103 high-confidence proteins in close proximity to the core members IFNAR1, IFNAR2, JAK1, TYK2, STAT1, STAT2, and IRF9, and validates several known constitutive protein assemblies, while also revealing novel stimulus-dependent and -independent associations between key signaling molecules. Functional screening further identifies PJA2 as a negative regulator of IFN signaling via its E3 ubiquitin ligase activity. Mechanistically, PJA2 interacts with TYK2 and JAK1, promotes their non-degradative ubiquitination, and limits the activating phosphorylation of TYK2 thereby restraining downstream STAT signaling. Our high-resolution proximal protein landscapes provide global insights into the type I IFN signaling network, and serve as a valuable resource for future exploration of its functional complexities.
Topics: Humans; Interferon Type I; Signal Transduction; TYK2 Kinase; Receptor, Interferon alpha-beta; Janus Kinase 1; Ubiquitination; Phosphorylation; STAT2 Transcription Factor; HEK293 Cells; STAT1 Transcription Factor; Interferon-Stimulated Gene Factor 3, gamma Subunit; Proteome; Ubiquitin-Protein Ligases
PubMed: 38802340
DOI: 10.1038/s41467-024-48800-5 -
Clinical Case Reports Jun 2024Generalized lichen planus pigmentosus significantly improved with the daily administration of Tofacitinib at a dosage of 15 mg.
Generalized lichen planus pigmentosus significantly improved with the daily administration of Tofacitinib at a dosage of 15 mg.
PubMed: 38799517
DOI: 10.1002/ccr3.8829 -
Frontiers in Pharmacology 2024Acute myeloid leukemia (AML) is a malignancy in the myeloid lineage that is characterized by symptoms like fatigue, bleeding, infections, or anemia, and it can be fatal...
Acute myeloid leukemia (AML) is a malignancy in the myeloid lineage that is characterized by symptoms like fatigue, bleeding, infections, or anemia, and it can be fatal if untreated. In AML, mutations in tyrosine kinases (TKs) lead to enhanced tumor cell survival. The most frequent mutations in TKs are reported in -like tyrosine kinase 3 (FLT3), Janus kinase 2 (JAK2), and KIT (tyrosine-protein kinase KIT), making these TKs potential targets for TK inhibitor (TKI) therapies in AML. With 30% of the mutations in TKs, mutated FLT3 is associated with poor overall survival and an increased chance of resistance to therapy. FLT3 inhibitors are used in FLT3-mutant AML, and the combination with hypomethylating agents displayed promising results. Midostaurin (MDS) is the first targeted therapy in FLT3-mutant AML, and its combination with chemotherapy showed good results. However, chemotherapies induce several side effects, and an alternative to chemotherapy might be the use of nanoparticles for better drug delivery, improved bioavailability, reduced drug resistance and induced toxicity. The herein study presents MDS-loaded gold nanoparticles and compares its efficacy with MDS alone, on both and models, using the FLT3-ITD-mutated AML cell line transfected to express luciferin. Our preclinical study suggests that MDS-loaded nanoparticles have a better tumor inhibitory effect than free drugs on models by controlling tumor growth in the first half of the treatment, while in the second part of the therapy, the tumor size was comparable to the cohort that was treatment-free.
PubMed: 38799169
DOI: 10.3389/fphar.2024.1382399