ORIGINAL RESEARCH ARTICLE
Occurrence of Multiple Sclerosis After Drug Exposure: Insights
From Evidence Mapping
Ippazio Cosimo Antonazzo
Fabrizio De Ponti
Published online: 9 June 2017
Ó Springer International Publishing Switzerland 2017
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 New-
castle-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 longitu-
dinal 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. Method-
ological advances are needed, especially to control the con-
founding role of underlying disease for speciﬁc drug classes.
Different risk factors have been associated with
multiple sclerosis (MS); however, the role of drugs
in its pathogenesis is still a matter of debate and is
perceived to be incompletely investigated.
Immunomodulatory drugs, contraceptives and
antibacterials represented the most frequently
investigated classes, especially in case reports. For
each class, residual confounders can be identiﬁed:
common mechanisms of underlying diseases,
masking of MS symptoms and proxy of actual cause.
Correlation between drug exposure and MS requires
development of new data analysis approaches
through improvement in data collection such as
better reporting of cases, and controlling for main
biases in large database analyses.
Electronic supplementary material The online version of this
article (doi:10.1007/s40264-017-0551-0) contains supplementary
material, which is available to authorized users.
& Elisabetta Poluzzi
Pharmacology Unit, Department of Medical and Surgical
Sciences, Alma Mater Studiorum, University of Bologna, Via
Irnerio 48, 40126 Bologna, BO, Italy
IRCCS—Institute of Neurological Sciences of Bologna,
Epidemiology and Biostatistics Service, Via Altura 3, 40139
Bologna, BO, Italy
Gertrude H. Sergievsky Center, Columbia University,
New York, NY, USA
Department of Global Public Health and Primary Care,
University of Bergen, Kalfarveien 31, 5020 Bergen, Norway
The Norwegian Multiple Sclerosis Competence Center,
Haukeland University Hospital, Jonas Lies vei 65, 5021
Drug Saf (2017) 40:823–834