Case study: IVIg as a treatment for MS

On the NHS, we don’t treat MS or MS relapses with IVIg. However we occasionally use plasma exchange to treat severe or catastrophic relapses that fail to respond to high-dose steroids.

Case study

I had a very simple set of bloodwork done from the week of the onset of my first MS symptoms and it showed both EBV IgG and IgM levels that were through the roof. I was 35 years old and never had EBV until my onset. The only real help during my summertime flares has been IVIg. Can you suggest why IVIg helps when no other FDA-approved MS meds work?

Chernobyl - a symbol of catastrophic damage. Photo by Artem Zhukov on Unsplash

Prof G’s opinion

EBV

The fact that you had very high anti-EBV antibody levels at the time of your MS onset is not unusual. What is unusual is the observation that you were anti-EBV IgM positive, which should indicate very recent EBV exposure, i.e. within the last few months. This is unusual. However, saying this a paediatric virologist recently informed me that anti-EBV IgM antibody responses can come and go with a condition called chronic EBV infection and its variants. There is even a subset of people diagnosed with chronic fatigue syndrome who have anti-EBV IgM antibodies. What I am saying is the fact that you were anti-EBV IgM positive doesn’t necessarily mean that you had been infected with EBV weeks to months before you developed your initial MS symptoms. You could have been infected with EBV years prior to your MS onset and the IgM antibodies would simply indicate you had a chronic EBV infection. I think there is mounting evidence that pwMS have a problem dealing with EBV infection, which may be a marker of immune dysregulation. Whether the latter is why some people get MS is a moot point.

IVIg

Now the question of why your flares respond to IVIg and not other therapies is difficult. To be honest, the only other treatments that have been shown to make a consistent difference in terms of relapse outcomes are ACTH and high-dose intravenous or oral methylprednisolone. Even with ACTH and high-dose methylprednisolone, the treatment effects are quite small, i.e. they simply speed up recovery from relapse by about 2 weeks and don’t impact the final outcome when assessed at 6 months. 

I am aware that despite initial positive studies of IVIg as a treatment for MS larger blinded studies showed no impact on disease outcome. This is why IVIg never got licensed as a disease-modifying therapy for MS. In terms of treating relapses, the data is more nuanced and there are many neurologists particularly in Germany, Eastern Europe and Israel who use IVIg and/or plasma exchange acutely to manage relapses. I suspect their anecdotal experiences may be correct.

IVIg and plasma exchange both work by clearing endogenous or self-made immunoglobulins. IVIg does this by saturating the so-called neonatal Fc-receptor, which leads to increased catabolism (breakdown) of immunoglobulins. Plasma exchange works by removing immunoglobulins from the blood. IVIg may also work by a so-called mechanism called idiotype anti-idiotype interactions; put simply some of the immunoglobulins in IVIg may neutralise pathogenic circulating immunoglobulins. 

It is clear in conditions such as NMO (neuromyelitis optica) that have pathogenic autoantibodies, i.e. anti-aquaporin-4 (anti-AQ4) antibodies, both IVIg and plasma exchange help treat acute relapses. There is good evidence that anti-AQ4 antibodies activate complement and cause damage to the CNS. There is a theory that autoantibodies may be doing the same thing in at least a subset of pwMS and this may explain why IVIg helps you get over relapses. You may have a type of MS with autoantibodies.

I would recommend that in terms of your MS management you should not only be reacting to and treating MS flares or relapses. You should explore treatments or DMTs that prevent relapses. With each flare or attack you have, you will be losing nerve fibres and neurons and this damage will accumulate over time. The current treatment target for MS is NEIDA (no evident inflammatory disease activity) in the hope that suppressing all new lesions development will prevent or reduce smouldering MS disease pathology and maintain your neurological reserve so that you don’t enter the progressive phase of the disease. I would therefore suggest asking your neurologist about potential DMTs you have not tried to achieve NEIDA.

Please note in the UK, i.e. on the NHS, we don’t have the ability to treat MS or MS relapses with IVIg. Saying this we occasionally use plasma exchange to treat severe or catastrophic relapses that fail to respond to high-dose steroids. 

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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust. The advice is intended as general advice and should not be interpreted as being personal clinical advice. If you have problems please tell your own healthcare professional who will be able to help you.