Mechanisms of action of radon therapy on cytokine levels in normal mice and rheumatoid arthritis mouse model

Background:Long-term observational data on the real-life use of JAK inhibitors (JAKis) for rheumatoid arthritis (RA) and their comparison with biological drugs are still very limited. Large population-based registries have been increasingly used to investigate the performance of targeted drugs in a real-life setting.Objectives:The aim of this study is to evaluate and compare the 3-year retention rate of JAKis, TNF inhibitors (TNFis) and biologic drugs with other mechanisms of action (OMAs) in the large cohort of RA patients included in the Italian national GISEA registry.Methods:Data of all RA patients treated with targeted synthetic or biologic drugs were prospectively collected in the Italian multicentric GISEA registry. The analysis was limited to patients who started a first- or second-line targeted drug in the period after the first JAKi was marketed in Italy (1st December 2017). The 3-year retention rate was calculated by the Kaplan-Meier method and compared between different drug classes by a log-rank test. A descriptive analysis of reasons for discontinuation was performed.Results:The study population included 1027 RA patients (79.8% females, mean age [±SD] 56.9 [±13.5] years, mean disease duration 9.8 [±9] years, mean baseline SDAI 17.5 [±11.9], ACPA positive 67.4%, RF positive 62.7%) who received JAKis (baricitinib or tofacitinib, n=297), TNFis (n=365), or OMAs (n=365) as first or second targeted drug. Main baseline characteristics of study population were overall well balanced between treatment groups. Retention rate was numerically but not statistically higher (p=0.18) in patients treated with JAKis compared with TNFis or OMAs (80.6, 78.9 and 76.4% at 1 year and 73, 56.8 and 63.8% at 3 years, respectively) (Figure 1). Drug survival was significantly higher in patients receiving concomitant methotrexate (MTX) compared with monotherapy only in TNFis (66.8 vs 47.1%, p=0.04) but not in JAKis (76.1 vs 70.1%, p=0.54) and OMAs (66.1 vs 61.9%, p=0.41) group. Therapy was discontinued in a total of 211 patients because of ineffectiveness (n=107), adverse events (n=88), or compliance/other reasons (n=16). The most frequent reason for treatment withdrawal was ineffectiveness in both JAKis (n=30 out of 56) and TNFis (n=45 out of 74) groups, whereas OMAs were discontinued more frequently because of adverse events (n=41 out of 81).Conclusion:Our data confirmed in a real-life setting a favorable 3-year retention rate of all available targeted mechanisms of action for RA therapy. As expected, concomitant MTX significantly impacted persistence on therapy of TNFis only. Discontinuations of JAKis for adverse events were infrequent overall, confirming the safety profile observed in randomized clinical trials.Figure 1.Three-year retention rate by treatment groupDisclosure of Interests:None declared

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Neuroimaging, Urinary, and Plasma Biomarkers of Treatment Response in Huntington’s Disease: Preclinical Evidence with the p75NTR Ligand LM11A-31

Neurotherapeutics ◽

10.1007/s13311-021-01023-8 ◽

2021 ◽

Author(s):

Danielle A. Simmons ◽

Brian D. Mills ◽

Robert R. Butler III ◽

Jason Kuan ◽

Tyne L. M. McHugh ◽

...

Keyword(s):

Mouse Model ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Treatment Response ◽

Diffusion Tensor ◽

Disease Onset ◽

Therapeutic Effects ◽

Plasma Cytokine ◽

Cytokine Levels ◽

Pharmacodynamic Biomarkers

AbstractHuntington’s disease (HD) is caused by an expansion of the CAG repeat in the huntingtin gene leading to preferential neurodegeneration of the striatum. Disease-modifying treatments are not yet available to HD patients and their development would be facilitated by translatable pharmacodynamic biomarkers. Multi-modal magnetic resonance imaging (MRI) and plasma cytokines have been suggested as disease onset/progression biomarkers, but their ability to detect treatment efficacy is understudied. This study used the R6/2 mouse model of HD to assess if structural neuroimaging and biofluid assays can detect treatment response using as a prototype the small molecule p75NTR ligand LM11A-31, shown previously to reduce HD phenotypes in these mice. LM11A-31 alleviated volume reductions in multiple brain regions, including striatum, of vehicle-treated R6/2 mice relative to wild-types (WTs), as assessed with in vivo MRI. LM11A-31 also normalized changes in diffusion tensor imaging (DTI) metrics and diminished increases in certain plasma cytokine levels, including tumor necrosis factor-alpha and interleukin-6, in R6/2 mice. Finally, R6/2-vehicle mice had increased urinary levels of the p75NTR extracellular domain (ecd), a cleavage product released with pro-apoptotic ligand binding that detects the progression of other neurodegenerative diseases; LM11A-31 reduced this increase. These results are the first to show that urinary p75NTR-ecd levels are elevated in an HD mouse model and can be used to detect therapeutic effects. These data also indicate that multi-modal MRI and plasma cytokine levels may be effective pharmacodynamic biomarkers and that using combinations of these markers would be a viable and powerful option for clinical trials.

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Polyherbal formula SC-E3 inhibits rheumatoid arthritis activity in a mouse model of type-II collagen-induced arthritis

Journal of Integrative Medicine ◽

10.1016/j.joim.2020.12.001 ◽

2020 ◽

Author(s):

Ju-Yeon Park ◽

Young-Won Kwon ◽

Sun-Ah Kim ◽

Sun-Dong Park ◽

Chang-Hyun Kim ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Mouse Model ◽

Type Ii Collagen ◽

Type Ii ◽

Collagen Induced Arthritis ◽

Rheumatoid Arthritis Activity

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THU0074 Vitamin e uncouples joint inflammation and articular destruction, in a transgenic mouse model of rheumatoid arthritis

10.1136/annrheumdis-2001.951 ◽

2001 ◽

Author(s):

MJ De Bandt ◽

F Driss ◽

M Grossin ◽

J Pincemail ◽

C Babin-Chevaye ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Vitamin E ◽

Mouse Model ◽

Transgenic Mouse ◽

Joint Inflammation ◽

Transgenic Mouse Model

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PK/PD Modeling of the PDE7 Inhibitor—GRMS-55 in a Mouse Model of Autoimmune Hepatitis

Pharmaceutics ◽

10.3390/pharmaceutics13050597 ◽

2021 ◽

Vol 13 (5) ◽

pp. 597

Author(s):

Artur Świerczek ◽

Hanna Plutecka ◽

Marietta Ślusarczyk ◽

Grażyna Chłoń-Rzepa ◽

Elżbieta Wyska

Keyword(s):

Mouse Model ◽

Autoimmune Hepatitis ◽

Disease Progression ◽

Hepatoprotective Activity ◽

Mechanisms Of Action ◽

Progression Model ◽

Adrenoceptor Agonist ◽

Tnf Α ◽

Disease Progression Model ◽

Time Courses

This study aimed to assess the efficacy and explore the mechanisms of action of a potent phosphodiesterase (PDE)7A and a moderate PDE4B inhibitor GRMS-55 in a mouse model of autoimmune hepatitis (AIH). The concentrations of GRMS-55 and relevant biomarkers were measured in the serum of BALB/c mice with concanavalin A (ConA)-induced hepatitis administered with GRMS-55 at two dose levels. A semi-mechanistic PK/PD/disease progression model describing the time courses of measured biomarkers was developed. The emetogenicity as a potential side effect of the studied compound was evaluated in the α2-adrenoceptor agonist-induced anesthesia model. The results indicate that liver damage observed in mice challenged with ConA was mainly mediated by TNF-α and IFN-γ. GRMS-55 decreased the levels of pro-inflammatory mediators and the transaminase activities in the serum of mice with AIH. The anti-inflammatory properties of GRMS-55, resulting mainly from PDE7A inhibition, led to a high hepatoprotective activity in mice with AIH, which was mediated by an inhibition of pro-inflammatory signaling. GRMS-55 did not induce the emetic-like behavior. The developed PK/PD/disease progression model may be used in future studies to assess the potency and explore the mechanisms of action of new investigational compounds for the treatment of AIH.

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