Interferon β almost doubles the risk of stroke and migraine in MS. Why?

An important observational study on long term use of interferon β and increased risk of stroke and migraine in MS was just published by one of my favorite MS researchers, Professor Helen Tremlett at the University of British Columbia.  Current interferon beta drugs prescribed for MS are Avonex, Betaseron, and Rebif.  

The complete paper is available here:
Evaluating the Safety of B Interferons in MS

Dr. Tremlett does not represent any drug company or MS treatment.  Dr. Tremlett simply studies people with MS, to understand disease progression and environmental factors, like gut microbia, vascular commorbidities, liver enzymes, Vitamin D, sun exposure, fatigue and pregnancy.  link

She has been studying the adverse affects of MS drugs and documenting many things pharmaceutical trials marginalize, or completely ignore.  In her publications, she highlights MS DMDs' modest efficacy, and the fact that clinical trials are of short duration and in a highly selected patient group, and do not give us a complete picture of long-term adverse events.

The IFN-βs are modestly effective, reducing relapse rates by about one-third and having a beneficial effect on imaging outcomes,² but findings regarding longer-term effects on disability have been mixed.^3,4The IFN-βs are generally considered safe, especially compared to newer agents for MS.⁵ However, few studies have systematically assessed their safety in real-world clinical practice (appendix e-1 at Neurology.org).⁵ A meta-analysis of 9 clinical trials estimated that patients treated with IFN-β had a 2.8-fold increased risk of discontinuing drug because of an adverse event compared to the placebo group. The most common adverse events were flu-like symptoms, injection-site reactions, leukopenia, lymphopenia, and elevated liver enzymes.⁶ However, because of their short duration and relatively small sample sizes, clinical trials cannot identify all potential adverse effects of a drug treatment or predict the safety of the drug in clinical practice. Furthermore, participants in clinical trials are highly selected in terms of comorbidities and concomitant medications and often differ substantially from patients who use the drug once it reaches the market. We identified signals of potential adverse events related to IFN-β treatment in a large population-based cohort of patients with RRMS.

This new study looked at patients with RRMS, registered at the UBC MS Clinic from 1995-2004, who were treated with interferons.  2,485 eligible patients were followed up until death, until they left BC, or until they stopped taking interferons.  After compiling the data, the study showed that patients who had taken interferons, there was a 1.8 fold increase (almost double risk at 180%) of stroke or migraine.  There was also a 1.3 fold increase in depression and hematologic abnormalities.

I realize this might be an obvious observation to many of my readers, but I feel like it will be overlooked by neurologists.  All of these adverse affects are vascular.  Stroke, migraine, blood issues --and yes, even depression---are related to blood flow, cerebral perfusion, coagulation and endothelial health.  Interferon B changes platelet adhesion to the endothelium and appears to raise blood pressure.

Here's more on this from the paper:

Our study is a comprehensive assessment of the potential risks for a broad range of adverse events related to IFN-β in the real-world clinical setting. Several of the adverse events that we observed to be associated with IFN-β exposure such as migraine, hematologic abnormalities, and depression are included in the known safety profile of the IFN-βs. Stroke, on the other hand, is not well recognized as a potential adverse event, being limited to a few case reports.^19,20 Nonetheless, it is biologically plausible that this event is associated with IFN-β because this drug may alter wall competence or enhance the major histocompatibility complex-1 molecule expression of platelets and other cells,^21,22 resulting in enhanced platelet adhesion to the endothelium.^22,23 
Hypertension can also increase the risk of both migraine³⁵ and stroke, and we observed a higher risk for hypertension among current users of IFN-β, which might point to a common pathway.


Other researchers are also studying the long term vascular side effects caused by interferons---
including thrombotic microangiopathy, which is a disease of endothelial injury resulting in thrombosis.  These clots can cause stroke, chronic kidney disease and renal failure.  
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Also being studied is how interferons affect blood clotting and cause hypertension
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There have been case studies where people with MS who were treated with interferon B had subsequent strokes.
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Previous studies have shown that people with MS already have a two fold increase in risk of venous clots, independent of drug treatment.
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Perhaps long-term use of Interferon β-- which further increases the risks of clotting, hypertension,  stroke and endothelial dysfunction, while only reducing relapse risk by 1/3-- isn't the best approach for people with MS.

The vascular connection to MS is real.
Endothelial health is essential.

Joan