Can rheumatologists stop causing demyelinating disease?

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Hello, I am Charalambos Hadjicharalambous, a medical student at Barts and the London School of Medicine and Dentistry working with Dr Gnanapavan (aka NDG) and Prof Baker (aka Mouse Doctor). In my spare time during the COVID-19 pandemic, I have been helping the BartsMS team with their COVID-19 studies. I am writing here to discuss an article that we’ve written detailing a potential rare link between drugs used to treat rheumatoid arthritis (anti-rheumatic drugs) and demyelination.

The review focuses on current scientific evidence regarding the effects of anti-rhematic drugs on memory B cells and other immunological processes in the central nervous system, suspected to cause MS. Rheumatoid arthritis (RA) is an autoimmune disorder with similar pathways of disease to MS. This means that various drugs can treat both diseases. In rheumatology, they are called DMARDs, (Disease modifying anti-rheumatic drugs, which are like the disease modyfying treatments (DMT) used in MS). There are a large group of potent anti-rheumatic drugs acting on B-cells and other immune processes. Some are similar to those used in MS, but others are different. Tumour necrosis factor (TNF) inhibitors is a large class of agents included under DMARDs. Even though these drugs are potent medications against RA, they have recently been associated with the future development of demyelinating disease and made MS worse when it was used in some trials.

There are a number of other DMARDS that are also associated with the development of MS or other demyelinating conditions and we wondered why this may be. I started searching through the literature to see if there was anything in common with the ant-TNF drugs.

Biological DMARDs, such as antibodies, are relatively large molecules, making them unable to cross the barrier between blood and the central nervous system (the blood-brain barrier, or BBB). Indeed many DMARDs given for RA do not enter the central nervous system. So use of TNF-blocking drugs characteristically leads to TNF inhibition and B-cell alteration in the body, excluding the central nervous system, which seems to have the potential to induce demyelinating disease in the brain (Figure 1)

Figure 1: This describes the action of DMARDS that are unable to cross the Blood-brain barrier. As shown in the figure, B-cells and TNF are inactivated in the blood and other tissues but not in the central nervous system, which can lead to demyelinating disease. Created in BioRender.com.

On the other hand, Baricitinib, a Janus Kinase (JAK) inhibitor that inhibits TNF and crosses through the BBB, doesn’t. However, most other JAK inhibitors are associated with central nervous system demyelination, Baricitinib is not. This example supports the theory that TNF inhibition in the body, with no corresponding inhibition in the central nervous system, may induce demyelination and MS. This support the hypothesis that exclusion of a TNF inhibitor from the central nervous system may lead to demyelination.

Figure 2. This shows different types of DMARDS that can cross the blood-brain barrier. In this case, B-cells and TNF are also inactivated in the central nervous system. Created in BioRender.com.

Similarly, phosphodiesterase four inhibitors which are potent TNF inhibitors were suggested as possible agents in MS management. Specifically, Ibudilast and Pentoxifylline are two agents that can penetrate the central nervous system barrier and have a central effect, with Ibudilast showing some neuroprotective effects in MS. Even though a lot of the data collected supports our hypothesis, it is worth mentioning that there is evidence showing that one of the DMARDs, Apremilast, that is not associated with demyelination does not enter the central nervous system. We are not sure if this specific drug is an exception to the rule or if another pathway is involved. Our study is not conclusive and requests further research around the topic but it suggests a way that arthrtis drugs may be designed not to cause MS. We believe that this can be the ground for new research that can help understand the effect of DMARDs and TNF inhibitors on the central nervous system. Understanding the pathway can help prevent demyelination from anti-rheumatic drugs and possibly find a way to use TNF inhibitors to benefit people with MS (Figure 2).

You can now read my paper (here)
https://authors.elsevier.com/a/1dDfV7skof5uVg

This is a more complicated figure that we drew. Created with BioRender.com

Baker D, Hadjicharalambous C, Gnanapavan S, Giovannoni G. Can rheumatologists stop causing demyelinating disease? Multi Scler Rel Disord. 2021. DOI:https://doi.org/10.1016/j.msard.2021.103057

Background: Perhaps the most informative experiments in human disease are clinical trials and notably, responses to specific therapies can be highly-informative to help understand disease pathogenesis. There are reagents that inhibit a variety of different autoimmune conditions, such as CD20 memory B cell depleters that are active in both multiple sclerosis (MS), rheumatoid arthritis (RA) and other conditions, suggesting influences on common immune mechanisms in different diseases. However, a notable exception seemed to be the use of tumour necrosis factor (TNF) inhibitors that limits RA, yet seem to, rarely, trigger demyelination and induce MS. This was first seen with TNF-inhibiting monoclonal antibodies and TNF-receptor-immunoglobulin fusion proteins. However, this is also seen with tyrosine and Janus kinase inhibitors that inhibit RA, yet induce demyelinating disease in some individuals.

Purpose: To provide an overview, from a B cell centric perspective, that may underpin the biology that links arthritis treatments to the development of demyelinating disease.

Conclusions: It is apparent that the disease modifying anti-rheumatoid drugs that cause demyelination share a number of common features. These agents tend to inhibit TNF-receptor signalling, augment or exhibit limited inhibitor activity on class-switched memory B cells and importantly appear to be relatively excluded from the central nervous system (CNS). They will thus not target ectopic B cell follicles in the CNS, unlike that occurring in peripheral autoimmunity as seen with anti-TNF treatments in RA. Agents such as ibudilast and some Janus kinase inhibitors that inhibit TNF and clearly penetrate the CNS do not appear to induce demyelination and may even be neuroprotective. It remains to be established whether selection or development of CNS penetrant agents may avoid CNS-complications of treatments for RA. Clearly, further studies are warranted

CoI: None

COI: ProfB Ad-hoc consultant with InMUNeBio, who had no involvement in the descision to write or content of the manuscript. ProfB has an out of date (worthless) patent for treatment of MS with anti-TNF notably with CNS delivery with Sir Marc Feldmann, who filed the first patent for anti-TNF treatment of rheumatoid arthritis.

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.

About the author

The MS Bloggger

13 comments

  • Nice post

    Question Tnf belong to a superfamily so its possible that when you have a large family you have manny people doing manny things

    One off those things is promoting inflamation ,one other would be dampem inflamation

    So inhibition of the tnf would also lead to inhibition of the regulatory component of Tnf creating off target efects

    Did you look at this?

    Regulation of T cell homeostasis by induction of apoptosis

    Regulation of B cell activation and T cell homeostasi

    Induction of apoptosis of T cells and B cells, prevention of autoimmunity

    Regulation of B cell development and plasma cell survival

    Stimulation of B cell proliferation and differentiation

    etc

    https://en.wikipedia.org/wiki/Tumor_necrosis_factor_superfamily

    Look luck

      • When we looked at anti-TNF many years ago, we delivered anti-TNF into the brain and it worked very well in EAE…However the biology has moved on and you could use differnt agents to target differnt elements of the TNF pathway..

        As for the superfamily you are correct and an important one is TNFS7 (CD70), this binds to TNFRSF7, which is also known as CD27 with is the memory B cell marker survival growth factor. BAFF and APRIL bind to TNF superfamily members and so is very important.

  • It’s Friday, so please excuse the pun, but PDE-*5* inhibitors definitely have a place in MS management (for males anyway) 🙂

    • Yes but PDE5 inhibitors that reach the parts that other blue pills cant are not PDE-4 inhibitorsthat block TNF

  • My Mom suffered severely with RA. As DRs put her many different meds & as she got older, I noticed many neurological symptoms come about. Upon looking at trusty Google with her symptoms, MS came up a multitude of times. A Dr even got pissy at me when I suggested they do an MRI on her brain and cervical. Now I know why she resembled an MS patient so closely.

  • I was diagnosed with RA and put on an anti TNF Benepali, within months I developed tinnitus and had a CIS. I’ve now been diagnosed with RRMS. Interestingly prior to Benepali I had my vitamin D checked and it was fine. It was checked again about a year later after the neurological symptoms and it was in my boots. No change to lifestyle or diet.

    • Often people ask which came first the drug or the MS. I think you have to fall back on one of the criteria of causality, which is the temporal relationship between the two factors that tells you the direction of the momentum.

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