Worsening demyelination, what can we learn from failed trials

Barreras P, Mealy MA, Pardo CA.TNF-alpha inhibitor associated myelopathies: A neurological complication in patients with rheumatologic disorders. J Neurol Sci. 2017;373:303-306.

OBJECTIVES:Tumor necrosis factor-alpha inhibitors (TNFα-I) are biological agents used in the treatment of rheumatologic disorders. TNFα-I have been associated with demyelinating disorders mimicking multiple sclerosis. The goal of this report is to illustrate cases of myelopathy which developed during the use of TNFα-I.
METHODS:We describe the clinical, neuroimaging and laboratory features of 4 cases of myelopathy associated with TNFα-I.
RESULTS:The mean period of TNFα-I exposure was 27 [12-36] months. Three of the four patients exhibited active inflammatory myelopathy as the spinal cord MRI lesions enhanced with gadolinium and CSF pleocytosis or oligoclonal bands were present. All patients had normal brain MRIs at the time of presentation.
CONCLUSIONS:TNFα-I may play a role in the development of myelopathies in absence of brain involvement or other features of demyelinating disease. TNFα-I associated myelopathy should be considered in patients with history of treatment with TNFα-I who exhibit symptoms of myelopathy.

Last week we heard of a basic scientist suggesting that blocking TNF would be good for MS to promote remyelination, but today shows a reason why basic scientitsts need to take their heads from the mechanistic sand to visit the real world. Becuase, we aim to treat a disease and not a mechanism.

In rheumatoid arthritis you block TNF and some individuals get demyelinating disease, which looks like MS. Furthermore, TNF blockade with antibodies and TNF blocking fusion proteins in MS were stopped because of disease worsening. Studies with rolipram a PDE4 inhibitor that blocks TNF was also stopped because of worsening. Do we learn? We are doing a trial (MS-SPRINT) with ibudilast, another PDE4 inhibitor that blocks TNF. What's going to happen there?

Effective treatment tells us something about MS, and likewise we can learn from things that make MS worse. The question is what is it? 

I suspect the answer will not be a simple one, and maybe that TNF has an immune modulating effect but also TNF influences nerve function. When alemtuzumab infusion causes a cytokine storm, including elevated TNF, as it is killing cells, the exisiting demyelinating lesions are reactivated. Is this in part got something to do with TNF? 

Blocking TNF may influence glial function, so the ultimate effect is a balance of good and bad and with anti-TNF the balance for some is bad. But if we can get an idea of why anti-TNF is worsening MS it will allow us to more to create a more effective treatment. 

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