Can rheumatologists stop causing demyelinating disease?

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.

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.