Clinical efficacy of new JAK inhibitors under development. Just more of the same?

Westhovens, René

doi:10.1093/rheumatology/key256

Cited by 48 publications

(37 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A recent study has indicated that the new pathogenesis of hyperuricemia is mainly intestinal microbiota (Pascart & Lioté, 2019), but the specific pathogenesis of gut microbiota is unclear. Some studies have reported altered gut microbiome in gout patients (Shao et al, 2017), with gut bacteria expressing the gene of allantoinase significantly reduced (Crane, 2013), suggesting that altered gut microbiota may associate with gout, and therefore, may help distinguish gout patients from healthy patients and serve as new targets for disease treatment (Guo et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

The altered gut microbiota of high-purine-induced hyperuricemia rats and its correlation with hyperuricemia

Liu

Ren³

et al. 2020

PeerJ

View full text Add to dashboard Cite

Some studies on the hyperuricemia (HUA) have focused on intestinal bacteria. To better understand the correlation between gut microbiota and HUA, we established a HUA rat model with high-purine diet, and used 16S rRNA genes sequencing to analyze gut microbiota changes in HUA rats. To analyze the potential role played by gut microbiota in HUA, we altered the gut microbiota of HUA rats with antibiotics, and compared the degree of uric acid elevation between HUA and antibiotic-fed HUA rats (Ab+HUA). Finally, we established a recipient rat model, in which we transplanted fecal microbiota of HUA and normal rats into recipient rats. Three weeks later, we compared the uric acid content of recipient rats. As a result, the diversity and abundance of the gut microbiota had changed in HUA rats. The Ab-fed HUA rats had significantly lower uric acid content compared to the HUA rats, and gut microbiota from HUA rats increased uric acid content of recipient rats. The genera Vallitalea, Christensenella and Insolitispirillum may associate with HUA. Our findings highlight the association between gut microbiota and HUA, and the potential role played by gut microbiota in HUA. We hope that this finding will promote the isolation and culture of HUA-related bacteria and orient HUA-related studies from being correlational to mechanistic. These steps will therefore make it possible for us to treat HUA using gut microbiota as the target.

show abstract

Section: Discussionmentioning

confidence: 99%

The altered gut microbiota of high-purine-induced hyperuricemia rats and its correlation with hyperuricemia

Liu

Ren³

et al. 2020

PeerJ

View full text Add to dashboard Cite

show abstract

“…Baricitinib was recently approved in Europe for the treatment of RA following the completion of a large phase III clinical trial programme in which it was administered in a once daily dosing regimen [17–20]. A number of other investigational oral jakinibs with varying selectivity for the four JAK enzymes have been evaluated in phase II trials in patients with RA and these studies will be discussed in the article by Dr Westhovens [21].…”

Section: Introductionmentioning

confidence: 99%

Clinical efficacy of launched JAK inhibitors in rheumatoid arthritis

2019

View full text Add to dashboard Cite

Tofacitinib and baricitinib are the first orally available, small-molecule inhibitors of Janus kinase (JAK) enzymes to be approved for the treatment of RA. Tofacitinib is a selective JAK1, 3 inhibitor with less activity against JAK2 and TYK2 and baricitinib is a selective, oral JAK1, 2 inhibitor with moderate activity against TYK2 and significantly less activity against JAK3. Both drugs have undergone extensive phase III clinical trials in RA and demonstrated rapid improvements in disease activity, function and patient-reported outcomes as well as disease modification. Tofacitinib 5 mg bd, was approved by the Federal Drug Administration in 2012 for the treatment of RA in patients who are intolerant or unresponsive to MTX. An extended release formulation for the treatment of RA was approved by Federal Drug Administration in 2016. In 2017 the European Medicines Agency approved tofacitinib 5 mg bd in combination with MTX and baricitinib 4 mg and 2 mg once daily for the treatment of moderate to severe active RA in adult patients who are intolerant or unresponsive to one or more conventional synthetic DMARDs.

show abstract

“…Variances in the clinical performance of both JAK inhibitors have been observed [ 22 ]. However, the reason for these differences are unknown given that they both TKIs target Janus Kinases resulting in a reduced STAT3 phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

Tofacitinib and Baricitinib Are Taken up by Different Uptake Mechanisms Determining the Efficacy of Both Drugs in RA

Amrhein

Drynda

Schlatt

et al. 2020

IJMS

View full text Add to dashboard Cite

Background: Rheumatoid arthritis (RA) is a systemic autoimmune disease in which synovial fibroblasts (SF) play a key role. Baricitinib and Tofacitinib both act intracellularly, blocking the ATP-binding side of JAK proteins and thereby the downstream signalling pathway via STAT-3. Therefore, we investigated the role of organic cation transporters (OCTs) in Baricitinib and Tofacitinib cellular transport. Methods: OCT expression was analysed in SF isolated from RA and osteoarthritis (OA) patients, as well as peripheral blood mononuclear cells. The interaction of Baricitinib and Tofacitinib with OCTs was investigated using quenching experiments. The intracellular accumulation of both drugs was quantified using LC/MS. Target inhibition for both drugs was tested using Western blot for phosphorylated JAK1 and STAT3 upon stimulation with IL-6. Results: MATE-1 expression increased in OASF compared to RASF. The other OCTs were not differentially expressed. The transport of Baricitinib was not OCT dependent. Tofacitinib; however, was exported from RASF in a MATE-1 dependent way. Tofacitinib and Baricitinib showed comparable inhibition of downstream signalling pathways. Conclusion: We observed different cellular uptake strategies for Baricitinib and Tofacitinib. Tofacitinib was exported out of healthy cells due to the increased expression of MATE1. This might make Tofacitinib the favourable drug.

show abstract

Clinical efficacy of new JAK inhibitors under development. Just more of the same?

Cited by 48 publications

References 40 publications

The altered gut microbiota of high-purine-induced hyperuricemia rats and its correlation with hyperuricemia

The altered gut microbiota of high-purine-induced hyperuricemia rats and its correlation with hyperuricemia

Clinical efficacy of launched JAK inhibitors in rheumatoid arthritis

Tofacitinib and Baricitinib Are Taken up by Different Uptake Mechanisms Determining the Efficacy of Both Drugs in RA

Contact Info

Product

Resources

About