Occurrence of Multiple Sclerosis After Drug Exposure: Insights From Evidence Mapping.
The role of drugs in the occurrence of multiple sclerosis (MS) is perceived to be insufficiently investigated.
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.
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.
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.
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!