Tuesday, 13 June 2017

Can drugs cause MS?

Drug Saf. 2017 Jun 9. doi: 10.1007/s40264-017-0551-0. [Epub ahead of print]

Occurrence of Multiple Sclerosis After Drug Exposure: Insights From Evidence Mapping.


Antonazzo IC, Raschi E, Vignatelli L, Baldin E, Riise T, D'Alessandro R, De Ponti F, Poluzzi E.


Abstract

INTRODUCTION:

The role of drugs in the occurrence of multiple sclerosis (MS) is perceived to be insufficiently investigated.
 

OBJECTIVE:

The aim of this study was to map and assess the evidence on MS occurrence after drug exposure, in order to identify possible signals of causal association.
 

METHODS:

A search strategy was performed in MEDLINE and Embase as of July 2016; references consistent with the aim of the study were analysed to extract relevant measures of causal association between drugs and MS. The Newcastle-Ottawa Scale and appropriate guidelines from the International Society for Pharmacoepidemiology (ISPE) and the International Society of Pharmacovigilance (ISoP) were used to assess the quality of included studies.
 

RESULTS:

After screening 832 articles, 58 were selected (of which 14 were found by checking the reference lists of reviews): 30 case reports and case series, 24 longitudinal studies and four randomized controlled trials. Seven longitudinal studies had good (at least 7 out of 9) quality scores, whereas case reports/case series presented several limitations. Half of included articles focused on immunomodulatory drugs (etanercept, infliximab and adalimumab), especially in case reports/series, suggesting an association with MS occurrence. Contraceptives and antibacterials were investigated in some population-based studies, without definite results.
 

CONCLUSION:

A heterogeneous pharmacological profile of identified classes emerged. Low strength of evidence and conflicting results highlighted the difficulties in addressing the possible contribution of drugs in MS occurrence. Methodological advances are needed, especially to control the confounding role of underlying disease for specific drug classes.



More than an year ago I was appointed as the Neurologist for St Bartholomew's Hospital in London (referring teams have taken to calling me the 'Barts Neurologist'; which, as labels go isn't a bad one!). When my predecessor informed me a few years back that Barts needed a neuroimmunologist, he wasn't kidding. The hospital is a quaternary centre for a number of specialties, including arthritis (Barts Arthritis Centre), endocrinology (Barts Endocrinology Service), cardiovascular medicine (The Heart Centre for London), solid tumours and haemoncology (Barts Cancer Institute, Cancer Research UK). A paraphernalia of new drugs get used, some of them still sporting their pharmaceutical label

On the occasions I have been asked to review cases, the neurology has been inventive to say the least, but equally the potential for learning about the dynamics of disease - cause/treatment/effect, has been phenomenal. For instance, have you heard of ustekinumab? This targets IL-12 and IL-23 cytokines, which have a central role in modulating T cell inflammation. Or heard that Imatinib (or Gleevec), a breakthrough in cancer treatment and most commonly used agent for chronic myeloid leukemia (CML) can cause MS and anti-phosholipid antibody syndrome (an autoimmune state which increases clotting in blood vessels) at the same time? The MS field is two steps behind in its uptake of newer agents, which on certain days I think is a good thing.

Here the authors searched the published databases for reports focused on the onset of MS or on MS worsening. They identified 80 drugs for onset of MS and 14 drugs for MS worsening. Not surprisingly, immunomodulatory drugs are at the top of the list: adalimumab (anti-TNF), etanercept (anti-TNF), infliximab (anti-TNF), and interferon alfa (enhances proliferation of B cells and activates NK cells). Their association is an interesting concept, as de novo MS is multifactorial with a long latency, which differs from these as the time lag can be as short as a few months. However, this isn't to say that we cannot hypothesize a similar biological plausibility in MS itself. 

Hormonal therapies, oral contraceptives (which I've reviewed in this blog before) produce conflicting results with a possible association with MS onset as well as a protective effect on onset/worsening, or simply no association. Naturally, there is a significant remission in MS in the third trimester of pregnancy, and the relationship between sex hormones and MS would be important to understand. The authors also note a possible association with anaesthetics, although their significance is uncertain.

My approach has been to use mild efficacy immunomodulatory agents when faced with drug-induced MS. I rationalize this as not shifting the new established status quo in the immune system dramatically again in another direction. Of course, I would be the first to admit that there is no evidence base for this approach!

12 comments:

  1. There are some studies linking *unsuccessful* IVF with onset of symptoms. The downregulation in IVF cycles usually involves a drug like Lupron. If no pregnancy results, there isn't a "surge" of hormones after suppression with Lupron.

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    1. The modulation of hypothalamus pituitary axis is a feedback loop. Gonadotropin releasing hormone analogues (there is a variety of them) first initiate then suppress hormonal release because of this. What the intermediate-longterm effects of modulating HPA axis on the immune system isn't fully understood.

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  2. TNF blockers massively exacerbate MS, to the extent that someone with MS who has not yet had symptoms can have symptoms brought on by an anti-TNF therapy. This doesn't mean they cause the disease.

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    1. They promote the generation of memory B cells in some people...it is interesting that the B cell markers are receptors within the TNF-super family

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  3. Neuro Doc Gnanapavan it seems as if you are being drowned out by the hyperactivity of the MouseDoctor. Did he miss a few doses of Seroquel?

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    1. I'll make it up to to NGD, but our papers all coming out at the same time, which reminds me to contact journal.

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    2. Maybe MouseDoctor has an overactive gonadotropin axis and needs his testosterone levels checked ;)

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  4. Did someone on here say interferon beta may make MS worse? Or was I distracted by the latest news on the current political quagmire?

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  5. Some of our cases have a normal MRI head done for reasons to ensure that there is no CNS involvement. When typical looking lesions develop after a treatment on a follow up scan I pretty much call it.

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  6. I have chosen not to go back yet to oral contraceptives because I still find a conflicting "ground" with respect to the studies that involve them.
    It was the only "drug" I used when I had my first symptoms, plus I had a few months before a horrible relapse of IM.

    They could now go deeper into studies involving gender/sex hormone differences to try to understand why MS is much more common in women, especially after the sexual revolution of the 1960s with the advent of oral contraceptives.

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