MD you are full of SH1!: Remyelination with a *****Nib

M

I know you all like to say “MD you are full of SH1” you write a paper

Baker D, Hadjicharalambous C, Gnanapavan S, Giovannoni G. Can rheumatologists stop causing demyelinating disease? Mult Scler Relat Disord. 2021 Aug;53:103057.

There you warn against using tofacitnib and here we have a paper showing remyelination with it….Shouldn’t we be taking toacitinib?

Günaydın C, Önger ME, Avcı B, Bozkurt A, Terzi M, Bilge SS. Tofacitinib enhances remyelination and improves myelin integrity in cuprizone-induced mice. Immunopharmacol Immunotoxicol. 2021 Oct 7:1-9. 

Aim: Demyelination and subsequent remyelination are well-known mechanisms in multiple sclerosis (MS) pathology. Current research mainly focused on preventing demyelination or regulating the peripheral immune system to protect further damage to the central nervous system. However, information about another essential mechanism, remyelination, and its balance of the immune response within the central nervous system’s boundaries is still limited.

Materials and methods: In this study, we tried to demonstrate the effect of the recently introduced Janus kinase (JAK)-signal transducer and activator of transcription (STAT) inhibitor, tofacitinib, on remyelination.Demyelination was induced by 6-week cuprizone administration, followed by 2-week tofacitinib (10, 30, and 100 mg/kg) treatment.

Results: At the functional level, tofacitinib improved cuprizone-induced decline in motor coordination and muscle strength, which were assessed by rotarod and hanging wire tests. Tofacitinib also showed anti-inflammatory effect by alleviating the cuprizone-induced increase in the central levels of interferon-γ (IFN-γ), interleukin (IL)-6, IL-1β, and tumor necrosis alpha (TNF-α). Furthermore, tofacitinib also suppressed the cuprizone-induced increase in matrix metalloproteinases (MMP)-9 and MMP-2 levels. Additionally, cuprizone-induced loss of myelin integrity and myelin basic protein expression was inhibited by tofacitinib. At the molecular level, we also assessed phosphorylation of STAT-3 and STAT-5, and our data indicates tofacitinib suppressed cuprizone-induced phosphorylation in those proteins.

Conclusion: Our study highlights JAK/STAT inhibition provides beneficial effects on remyelination via inhibition of inflammatory cascade.

So in Baker D, Hadjicharalambous C, Gnanapavan S, Giovannoni G. Can rheumatologists stop causing demyelinating disease? Mult Scler Relat Disord. 2021 Aug;53:103057. we wrote

“JAK kinases (JAK1, JAK2, JAK3 and TYK2 tyrosine kinase two) are a group of tyrosine kinases that transduce cytokine-mediated signals notably IL-4, IL-6, IL-7, IL-9, IL-15, IL-21, and interferon gamma (Harrington et al., 2020) and a number have been used in rheumatoid arthritis (Harrington et al., 2020Smolen et al., 2019). Tofacitinib citrate which inhibits JAK1/JAK3 is approved for treatment of adults with moderately to severely active rheumatoid arthritis who have had an inadequate response to, or who are intolerant of, methotrexate (Harrington et al., 2020). Tofacitinib has recently been reported to induce CNS demyelination (Massoud et al., 2020), again treatment can lead to a reduction in TNF production, although this effect is not probably direct (Harrington et al., 2020Krueger et al., 2016). Ruxolitinib, a JAK1/JAK2 inhibitor has been associated with a few case reports of peripheral neuropathy (Gonzalez Vicent et al., 2019Trantham et al., 2020). Baricitinib is an JAK1/JAK2 inhibitor is another DMARD that likewise can inhibit TNF but this does not seem to induce CNS demyelination (Harrington et al., 2020Bronte et al., 2020). Both tofacitinib and baricitinib are associated with increases in class switched memory B cells in some individuals (Rizzi et al., 2017Tanaka et al., 2018). However the notable difference between these agents are that there is CNS penetration of baricitinib, with a cerebrospinal fluid:plasma ratio of about 20%, compared with about 0.1% for tofacitinib and 3.5% for ruxolitinib (Richardson et al., 2020)”.

The thesis of that paper is

Now if you google Tofacitinib gets into the CNS and it must do to affect the cuprizone effect but remember it is all relative .

This paper (above) is behind a paywall and I don,t have access to it at the moment , so we have an experiment for any readers with access. What happened?

Did it work at 10mg/kg or 100mg/kg and what happened at 10mg/kg?

So the question of CNS penetration is relative, if you give enough of it it will get in. The human dose is 5mg/ twice a day so at best about 0.1mg/kg. So in the mouse experiments they use 1000-2000 times the human dose. Some will enter the CNS even if it is 0.1% penetrant.

I don’t know, but if I were to move this forward I would simply say try baricitinib first and I would want to see evidence for benefit before I took it.

General Disclaimer: Please note that the opinions expressed here are those of the author and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice.

About the author

MouseDoctor

Add comment

By MouseDoctor

Translate

Categories

Recent Posts

Recent Comments

Archives