Baricitinib for the treatment of rheumatoid arthritis

Urits, Ivan; Israel, Jacob; Hakobyan, Hayk; Yusin, George; Lassiter, Grace; Fackler, Nathan; Berger, Amnon A; Kassem, Hisham; Kaye, Alan D.; Viswanath, Omar

doi:10.5114/reum.2020.102006

Cited by 20 publications

(16 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Several JAK inhibitors (JAKi), including tofacitinib, baricitinib, and ruxolitinib, are already being investigated for the treatment of various autoimmune diseases ( 17 ). JAK inhibitors have been approved to treat rheumatoid arthritis (RA) ( 18 – 20 ) for many years, whereas the efficacy of JAK inhibitors in SSc remains unclear. Tofacitinib, an oral pan-JAK inhibitor, has improved cutaneous stiffness and the healing of DU in a 27-year-old SSc male patient ( 21 ).…”

Section: Introductionmentioning

confidence: 99%

JAK1/2 Inhibitor Baricitinib Improves Skin Fibrosis and Digital Ulcers in Systemic Sclerosis

Hou

Han

et al. 2022

Front. Med.

View full text Add to dashboard Cite

BackgroundSystemic sclerosis (SSc) is a rare disabling connective tissue disease with few available treatment options. Diffuse cutaneous systemic sclerosis (dcSSc) is associated with high mortality. A previous experiment has shown that JAK2 inhibitor can significantly improve skin fibrosis in bleomycin (BLM)-induced murine model, including reducing dermal thickening and collagen accumulation. We aimed to describe the efficacy of oral JAK1/2 inhibitor baricitinib in SSc patients, especially focusing on skin fibrosis and microvascular manifestations.MethodsWe described the different effects of oral selective JAK1, JAK2, or JAK3 inhibitor treatment in a BLM-induced skin fibrosis mouse model. Furthermore, 10 adult patients with dcSSc were treated with baricitinib. We assessed the changes in modified rodman skin score (mRSS) and digital ulcer net burden at week 12 and 24 from baseline. We also compared the absolute changes in scores on the Scleroderma Health Assessment Questionnaire (SHAQ) and a total score on the St. George's Respiratory Questionnaire (SGRQ) over a 24-week period.ResultsIn the experimental mouse model of skin fibrosis, a JAK1 and JAK2 inhibitor ameliorated skin fibrosis, and a JAK2 inhibitor had the most obvious effect. Treatment with the JAK2 inhibitor also blunted the capillary rarefaction. We demonstrated that skin fibrosis and digital ulcers were significantly relieved in 10 SSc patients treated with baricitinib. The mRSS significantly improved at week 12 from baseline, with a mean change in mRSS of −8.3 [95% confidence interval (CI), −12.03 to −4.574; p = 0.0007] and improved greater at week 24 to −11.67 (95% CI, −16.84 to −6.496; p = 0.0008). Among the four patients with digital ulcers (DU), three were completely healed at week 24, the number of ulcers in another patient was significantly reduced, and there was no patient with new ulcers. Only one adverse event (AE) of herpes zoster was observed.ConclusionsOur results indicate that selective JAK1 and JAK2 inhibitor alleviates skin fibrosis, and oral JAK1/2 inhibitor baricitinib is a potentially effective treatment for dcSSc patients with skin fibrosis and DU. Baricitinib was well-tolerated by most patients in this study. Additional large clinical trials are needed to confirm our pilot findings.Chinese Clinical Trial Registry NumberChiCTR2000030995.

show abstract

Section: Introductionmentioning

confidence: 99%

JAK1/2 Inhibitor Baricitinib Improves Skin Fibrosis and Digital Ulcers in Systemic Sclerosis

Hou

Han

et al. 2022

Front. Med.

View full text Add to dashboard Cite

show abstract

“…Baricitinib is an immunosuppressive oral selective Jak1 and Jak2 inhibitor and reactivation of HBV replication is a well-recognised complication of patients receiving Baricitinib, especially those with rheumatoid arthritis. 46 Baricitinib treatment of HBV infected organoids resulted in an increase (approximately 1 log) in HBV RNA suggesting suppression of the tyrosine kinases Jak1 and Jak2 can increase HBV genome replication. The mechanism of this HBV increase is unclear in our organoid model, however given that the JAK-STAT signalling pathway plays a role in signal transduction for several key cytokines, a number of mechanisms are possible.…”

Section: Discussionmentioning

confidence: 99%

Human Liver Organoids as a Patient-derived Model for HBV Infection and Cellular Response

Lim

Romeo

Chilver

et al. 2022

Preprint

View full text Add to dashboard Cite

Background & AimsCurrent HBVin vitromodel systems suffer from many physiological limitations that restrict understanding of complex viral-host interactions and thus prohibit prediction of diseasein vivo. We developed and assessed adult stem cell (AdSC) derived liver organoids as a novel model system for characterisation of the HBV lifecycle, the cellular response to infection and demonstrate their utility in assessing antiviral and immunomodulator response. This model system has the potential to be used in predicting individual HBV responses to antivirals and viral reactivation in the setting of immunosuppressive agents.MethodsDuctal stem cells were isolated from healthy tissue acquired from liver resections or biopsy (n=12). Wnt3a & RSPO-1 containing medium was used to stimulate ductal stem cell expansion into organoids which were subsequently differentiated into hepatocyte-like cells. Mature hepatocyte metabolic markers (albumin, CYP3A4) and HBV entry receptor (Na-taurocholate co-transporting polypeptide, NTCP) expression were evaluated throughout differentiation using qRT-PCR and confocal microscopy. We assessed the organoids culture conditions required for HBV infection and HBV life cycle using HepAD38 (genotype D) and plasma derived HBV (genotype B & C). HBV infection was confirmed using immunofluorescence staining (HBcAg), qRT-PCR (RNA, cccDNA, extracellular DNA) and ELISA (HBsAg and HBeAg). We also assessed drug responsiveness using antivirals and an immunosuppressive agent, and cellular responses (interferon-stimulated genes) using interferon-α and viral mimic (PolyI:C).ResultsFollowing differentiation, organoids underwent structural remodelling and changes in cellular polarity, accompanied with an increase in albumin, CYP3A4 and NTCP mRNA expression. Optimal HBV infection was achieved in well-differentiated organoids using spinoculation of at least 200 copies/cell of AD38 derived HBV. Infected organoids demonstrate time and donor dependent increase in HBV RNA, cccDNA, extracellular DNA, HBe and HBsAg consistent with viral replication and antigen secretion. Using these markers we assessed drug-responsiveness to the HBV entry inhibitor, Myrcludex B and the JAK inhibitor, Baricitinib. Despite having a very robust interferon stimulated gene response to interferon-α and PolyI:C stimulation, HBV infection in liver organoids did not reveal innate immune activation.ConclusionsAdSC derived liver organoids support the full life cycle of HBV with significant donor dependent variation in viral replication and cellular responses. These features can be utilised for development of personalised drug testing platform for antivirals.Lay SummaryHuman liver organoid culture provides a personalised assessment of HBV infection, replication and responsiveness to antiviral therapy. This model system has a robust innate immune response and could be used to assess novel immune-modulating curative therapy.

show abstract

“…The JAK/STAT signaling pathway is an emergent player in metabolism and has been shown to be dysregulated in obesity and T2D [ 124 ]. Recently, baricitinib, a selective JAK1/2 inhibitor used to treat rheumatoid arthritis [ 125 ], has been investigated for the treatment of T2D and its complications. Barcitinib decreased inflammatory biomarkers and restored insulin signaling in the liver and skeletal muscle of HFD-fed mice by targeting JAK/STAT-mediated PI3K/AKT signaling [ 126 , 127 ].…”

Section: Discussionmentioning

confidence: 99%

The PI3K/Akt Pathway in Meta-Inflammation

Acosta-Martínez

Cabail

2022

IJMS

View full text Add to dashboard Cite

Obesity is a global epidemic representing a serious public health burden as it is a major risk factor for the development of cardiovascular disease, stroke and all-cause mortality. Chronic low-grade systemic inflammation, also known as meta-inflammation, is thought to underly obesity’s negative health consequences, which include insulin resistance and the development of type 2 diabetes. Meta-inflammation is characterized by the accumulation of immune cells in adipose tissue, a deregulation in the synthesis and release of adipokines and a pronounced increase in the production of proinflammatory factors. In this state, the infiltration of macrophages and their metabolic activation contributes to complex paracrine and autocrine signaling, which sustains a proinflammatory microenvironment. A key signaling pathway mediating the response of macrophages and adipocytes to a microenvironment of excessive nutrients is the phosphoinositide 3-kinase (PI3K)/Akt pathway. This multifaceted network not only transduces metabolic information but also regulates macrophages’ intracellular changes, which are responsible for their phenotypic switch towards a more proinflammatory state. In the present review, we discuss how the crosstalk between macrophages and adipocytes contributes to meta-inflammation and provide an overview on the involvement of the PI3K/Akt signaling pathway, and how its impairment contributes to the development of insulin resistance.

show abstract

Baricitinib for the treatment of rheumatoid arthritis

Cited by 20 publications

References 48 publications

JAK1/2 Inhibitor Baricitinib Improves Skin Fibrosis and Digital Ulcers in Systemic Sclerosis

JAK1/2 Inhibitor Baricitinib Improves Skin Fibrosis and Digital Ulcers in Systemic Sclerosis

Human Liver Organoids as a Patient-derived Model for HBV Infection and Cellular Response

The PI3K/Akt Pathway in Meta-Inflammation

Contact Info

Product

Resources

About