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Journal of Veterinary Pharmacology and... Jun 2024Oclacitinib is a novel Janus kinase (JAK) inhibitor that potently inhibits JAK1-dependent cytokines involved in allergy, inflammation, and pruritus (IL-2, IL-4, IL-6,...
Oclacitinib is a novel Janus kinase (JAK) inhibitor that potently inhibits JAK1-dependent cytokines involved in allergy, inflammation, and pruritus (IL-2, IL-4, IL-6, IL-13, and IL-31). Oclacitinib (Apoquel®, Zoetis Inc, Parsippany, NJ) is approved for the treatment/control of pruritus associated with allergic dermatitis and treatment/control of clinical manifestations of atopic dermatitis in dogs at least 12 months of age. To evaluate the effectiveness of oclacitinib in dogs with flea allergy dermatitis, the JAK1 selective inhibitor was tested in a placebo-controlled, masked, single-dose (0.4 mg/kg) or repeat-dose (0.4 mg/kg, twice daily for 2 weeks) study. Pruritic behaviors were quantitated by video recording, and erythema and skin lesions were assessed using a 10-cm visual analog scale (VAS). Results showed that oclacitinib reduced pruritus by 61% as early as 1.5 h after a single oral dose compared to placebo, with an average reduction (compared to placebo) of 85% 1-5 h after dosing (0.4 mg/kg; p < .0001). Oclacitinib also significantly reduced erythema (p < .0001) and skin lesion (p < .0005) VAS scores on Day 14 compared to placebo in a repeat dose study. No adverse events were noted during the conduct of these studies. IL-31 concentrations were elevated in the majority of dogs after flea infestation, suggesting JAK1-dependent cytokines may drive clinical signs of flea allergy dermatitis. These findings show that oclacitinib, an inhibitor of JAK1-dependent cytokines involved in allergy and inflammation can rapidly reduce clinical signs associated with flea allergic dermatitis in dogs.
PubMed: 38926932
DOI: 10.1111/jvp.13462 -
Helicobacter 2024Helicobacter pylori (H. pylori) colonizes the stomach and leads to the secretion of a vast range of cytokines by infiltrated leukocytes directing immune/inflammatory... (Review)
Review
Helicobacter pylori (H. pylori) colonizes the stomach and leads to the secretion of a vast range of cytokines by infiltrated leukocytes directing immune/inflammatory response against the bacterium. To regulate immune/inflammatory responses, suppressors of cytokine signaling (SOCS) proteins bind to multiple signaling components located downstream of cytokine receptors, such as Janus kinase (JAK), signal transducers and activators of transcription (STAT). Dysfunctional SOCS proteins in immune cells may facilitate the immune evasion of H. pylori, allowing the bacteria to induce chronic inflammation. Dysregulation of SOCS expression and function can contribute to the sustained H. pylori-mediated gastric inflammation which can lead to gastric cancer (GC) development. Among SOCS molecules, dysregulated expression of SOCS1, SOCS2, SOCS3, and SOCS6 were indicated in H. pylori-infected individuals as well as in GC tissues and cells. H. pylori-induced SOCS1, SOCS2, SOCS3, and SOCS6 dysregulation can contribute to the GC development. The expression of SOCS molecules can be influenced by various factors, such as epigenetic DNA methylation, noncoding RNAs, and gene polymorphisms. Modulation of the expression of SOCS molecules in gastric epithelial cells and immune cells can be considered to control gastric carcinogenesis as well as regulate antitumor immune responses, respectively. This review aimed to explain the interplay between H. pylori and SOCS molecules in GC development and immune response induction as well as to provide insights regarding potential therapeutic strategies modulating SOCS molecules.
Topics: Humans; Stomach Neoplasms; Helicobacter pylori; Helicobacter Infections; Suppressor of Cytokine Signaling Proteins; Host-Pathogen Interactions; Signal Transduction
PubMed: 38924222
DOI: 10.1111/hel.13105 -
Arthritis & Rheumatology (Hoboken, N.J.) Jun 2024The 48-week, phase 2 SLEek study (NCT03978520) evaluated the efficacy and safety of upadacitinib (Janus kinase inhibitor) and elsubrutinib (Bruton's tyrosine kinase...
OBJECTIVE
The 48-week, phase 2 SLEek study (NCT03978520) evaluated the efficacy and safety of upadacitinib (Janus kinase inhibitor) and elsubrutinib (Bruton's tyrosine kinase inhibitor) alone or in combination (ABBV-599) in adults with moderately to severely active systemic lupus erythematosus (SLE).
METHODS
Patients were randomized 1:1:1:1:1 to once-daily (QD) ABBV-599 high dose (HD; elsubrutinib 60mg + upadacitinib 30mg), ABBV-599 low dose (LD; elsubrutinib 60mg + upadacitinib 15mg), elsubrutinib 60mg, upadacitinib 30mg, or placebo. The primary endpoint was the proportion of patients achieving both SLE Responder Index-4 (SRI-4) and glucocorticoid dose ≤10mg QD at week 24. Additional assessments through week 48 included British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) and Lupus Low Disease Activity State (LLDAS) responses, number of flares, time to first flare, and adverse events.
RESULTS
The study enrolled 341 patients. The ABBV-599LD and elsubrutinib arms were discontinued after a planned interim analysis showed lack of efficacy (no safety concerns). More patients achieved the primary endpoint with upadacitinib (54.8%; P=0.028) and ABBV-599HD (48.5%; P=0.081) versus placebo (37.3%). SRI-4, BICLA, and LLDAS response rates were higher for both upadacitinib and ABBV-599HD versus placebo at weeks 24 and 48. Flares were reduced and time to first flare through week 48 was substantially delayed with both upadacitinib and ABBV-599HD versus placebo. No new safety signals were observed beyond those previously reported for upadacitinib or elsubrutinib.
CONCLUSIONS
Upadacitinib 30mg alone or in combination with elsubrutinib (ABBV-599HD) demonstrated significant improvements in SLE disease activity, reduced flares and were well tolerated through 48 weeks.
PubMed: 38923871
DOI: 10.1002/art.42926 -
Current Opinion in Rheumatology Jun 2024This review provides an update on current management strategies for giant cell arteritis (GCA), emphasizing the need for alternative therapies to reduce disease relapses...
PURPOSE OF THE REVIEW
This review provides an update on current management strategies for giant cell arteritis (GCA), emphasizing the need for alternative therapies to reduce disease relapses and mitigate glucocorticoid (GC)-related morbidity.
RECENT FINDINGS
The standard of care for GCA has traditionally involved prolonged use of GC, and recent studies are exploring faster GC tapering regimens in an effort to reduce adverse effects while maintaining disease control. Randomized clinical trials have highlighted the efficacy of tocilizumab (TCZ), an interleukin-6 receptor inhibitor, in reducing disease flares and sparing GCs. However, the optimal treatment duration with TCZ is unknown and patients remain at risk of relapse after treatment discontinuation. An unmet therapeutic need persists for patients who are not candidates for TCZ, and for those who have inadequate response to this biologic. Therefore, investigations into alternative therapies such as targeting interleukin-17A, blocking T-cell activation or inhibiting the Janus kinase-signal transducer and activator of transcription pathway, showcase potential avenues for tailored treatments.
SUMMARY
While GCs remain the cornerstone of therapy, TCZ emerges as a promising GC-sparing agent. Ongoing research targeting different pathways implicated in GCA pathogenesis have led to encouraging results. However, the preliminary nature of these findings necessitates larger randomized controlled trials to establish their efficacy conclusively.
PubMed: 38920090
DOI: 10.1097/BOR.0000000000001029 -
Current Pharmaceutical Biotechnology Jun 2024Atopic Dermatitis (AD) is an inflammatory skin condition with a severe itch. The topical therapy using corticosteroids is not sufficient for the effective therapy of...
BACKGROUND
Atopic Dermatitis (AD) is an inflammatory skin condition with a severe itch. The topical therapy using corticosteroids is not sufficient for the effective therapy of moderate to severe cases of AD. The investigation and development of immunological targetspecific human monoclonal antibodies have changed the paradigm for the therapy of moderate to severe cases of AD.
OBJECTIVE
The establishment of target-specific, tolerable, and efficacious human monoclonal antibodies might lead to the better management of moderate to severe cases of AD.
METHODOLOGY
The scientific literature available in databases, such as Pubmed and Clinicaltrial.gov, was searched and discussed for available clinical therapeutic information.
DISCUSSION
The present review has discussed the potential immunological targets of specific monoclonal antibodies developed and approved or which are under investigation in clinical trials.
CONCLUSION
The development of targeted monoclonal antibodies can improve the understanding of the role of different immunological pathways and biomarkers in AD and become the future of AD treatment.
PubMed: 38919081
DOI: 10.2174/0113892010311098240530104530 -
Immunopharmacology and Immunotoxicology Jun 2024Autoimmune dermatosis (AID) occurs when the body's immune system attacks skin or tissue, leading to various types of skin disorders or injuries. Recent studies show that...
OBJECTIVE
Autoimmune dermatosis (AID) occurs when the body's immune system attacks skin or tissue, leading to various types of skin disorders or injuries. Recent studies show that Janus kinases (JAKs) play critical roles in autoimmune diseases including AID by regulating multiple cytokine signaling pathways. CS12192, a novel JAK3/JAK1/TBK1 inhibitor, has been reported to exert ameliorative effects in rheumatoid arthritis. However, the efficacy of CS12192 on AID is undetermined. This study aims to investigate the therapeutic efficacy of CS12192 on psoriasis (PSO), systemic lupus erythematosus (SLE) and atopic dermatitis (AD) in mouse models.
METHODS
Interleukin-23 (IL-23)-induced PSO model, spontaneous SLE model of MRL/MpJ-Faslpr/J (MRL/lpr) mice, and oxazolone (OXA) and dinitrochlorobenzene (DNCB) induced murine AD models were used for the evaluation of curative effects of CS12192, respectively. The skin lesion, biochemical parameters, ear thickness, ear weight and histopathology were assessed accordingly.
RESULTS
In PSO model, mice treated with CS12192 show reduced ear thickness and ear weight as compared with vehicle. In SLE model, CS12192 ameliorates cutaneous parameters such as lymphadenectasis and skin lesion but not systematic parameters such as proteinuria concentration and score, serum dsDNA and BUN concentration. In AD models, CS12192 dose-dependently improves ear swelling and reduces histological scores, exerting equivalent efficacy with baricitinib, a marketed JAK1/JAK2 inhibitor. Our findings suggest that the novel JAK3/JAK1/TBK1 inhibitor CS12192 is potentially to alleviate autoimmune dermatosis.
PubMed: 38918174
DOI: 10.1080/08923973.2024.2373223 -
Gene Jun 2024Renal cell carcinoma (RCC) represents a significant portion of genitourinary cancers, marked by challenging prognosis and high metastasis rates. Immunotherapy has been...
Renal cell carcinoma (RCC) represents a significant portion of genitourinary cancers, marked by challenging prognosis and high metastasis rates. Immunotherapy has been applied in managing advanced renal cell carcinoma, but the therapeutic outcomes are unsatisfactory. In this study, we order to construct a Janus kinase/signal transduction and activator transcriptional (JAK/STAT)-related signature linked to kidney patient outcomes for better predicting the efficacy to immune checkpoint inhibitors (ICIs) and to provide guidance for effective combination therapy. We screened 25 differentially expressed genes (DEGs) that exhibited high expression in RCC samples and were enriched in the JAK-STAT signaling pathway. Among these genes, 11 key genes were identified and correlated with the expectation of Kidney Clear Cell Carcinoma (KIRC) patients and all these genes was significantly elevated in RCC tumor tissues and cancer cells compared to para-cancer tissues and normal renal cells. Utilizing these 11 genes, we divided RCC patients into high-risk and low-risk groups. We found a clear correlation between the clinicopathologic factors of KIRC patients and the JAK-STAT-related risk score. And the IHC results shown that the JAK3 and STAT4 expression of tumor was significantly higher than normal tissue in RCC patients, the level of JAK3 and STAT4 was positively related to the T stage of RCC patients. In addition, high-risk patients had a poorer prognosis and greater protumor immune cell infiltration, and benefitted less from immunotherapy than did low-risk patients. Furthermore, the JAK-STAT-related risk score can predict disease-free survival (DFS) in RCC patients according to the nomogram, which constructed in combination with other clinical features such as age, TNM-staging and stage. Our study demonstrated the JAK-STAT signaling pathway's important regulatory function in RCC tumor immunity. This insight not only enhances our ability to accurately predict the survival rate of RCC patients, but also underscores a potential therapeutic alternative for RCC, involving the combined targeting of the JAK-STAT pathway and immune checkpoints.
PubMed: 38917875
DOI: 10.1016/j.gene.2024.148719 -
Blood Advances Jun 2024
Topics: Humans; Venous Thrombosis; Intracranial Thrombosis; Animals; Mice; Janus Kinases
PubMed: 38916898
DOI: 10.1182/bloodadvances.2024012977 -
Expert Opinion on Drug Metabolism &... Jun 2024In the realm of autoimmune rheumatic diseases, understanding JAK inhibitors (JAKi) nuances is vital. Baricitinib, tofacitinib, upaacitinib, filgotinib, and peficitinib... (Review)
Review
INTRODUCTION
In the realm of autoimmune rheumatic diseases, understanding JAK inhibitors (JAKi) nuances is vital. Baricitinib, tofacitinib, upaacitinib, filgotinib, and peficitinib exhibit subtle yet impactful pharmacokinetic (PK) and pharmacodynamic (PD) variations.
AREAS COVERED
This narrative review critically assesses PK and PD distinctions among globally approved JAKi for rheumatoid arthritis, which primarily guide clinical decisions in autoimmune diseases, particularly rheumatoid arthritis. It explores the intricate JAK-STAT signaling pathway, offering insights into JAKs' roles in inflammation, hematopoiesis, and immune homeostasis. Emphasis on PK parameters, including absorption, distribution, metabolism, and excretion, along with CYP3A4 drug interactions, is highlighted. The review underscores integrating PK and PD properties, considering patient-specific factors like hepatic and renal clearance, for judicious JAKi selection in RA and related autoimmune conditions. The literature has been collected from all available databases based on the review question.
EXPERT OPINION
Integrating PK and PD properties with patient-specific factors is pivotal for judicious JAKi selection. Recognizing disparities in PK and PD across diseases, ethnicities, and environmental factors is crucial for personalized JAKi choices. This expert opinion underscores the significance of a second compartment analysis, elucidating the interplay between PK and PD and its impact on JAKi efficacy.
PubMed: 38916236
DOI: 10.1080/17425255.2024.2373092 -
Reumatismo Jun 2024The safety profile of baricitinib (BARI), a Janus kinase inhibitor broadly used for the treatment of rheumatoid arthritis (RA), includes asymptomatic laboratory...
The safety profile of baricitinib (BARI), a Janus kinase inhibitor broadly used for the treatment of rheumatoid arthritis (RA), includes asymptomatic laboratory abnormalities, such as an increase in creatine kinase (CK). Data from randomized controlled trials suggest that concomitant myalgia is rare in RA and does not lead to drug discontinuation. We describe the case of a 68-year-old Caucasian female with longstanding, multi-failure RA who started BARI and achieved disease remission. However, she developed a symptomatic CK increase, as well as a parallel increase in total cholesterol, low-density lipoprotein, and triglycerides. Dechallenge-rechallenge demonstrated a plausible relationship between the clinical/laboratory abnormalities and BARI. In fact, when the drug was withdrawn, CK returned to normal and myalgia disappeared, whereas symptoms returned and CK levels increased when BARI was restarted. BARI may be rarely associated with symptomatic CK elevation, and this may pose clinical challenges, particularly for patients with multi-failure RA who achieved good disease control with BARI but required drug discontinuation due to intolerance.
Topics: Humans; Arthritis, Rheumatoid; Female; Purines; Aged; Azetidines; Pyrazoles; Sulfonamides; Creatine Kinase; Myalgia; Antirheumatic Agents; Janus Kinase Inhibitors
PubMed: 38916168
DOI: 10.4081/reumatismo.2024.1620