Smoking and multiple sclerosis: A systematic review and meta-analysis using the Bradford Hill criteria for causation

Highlights

• There is strong evidence that smoking plays a causal role in MS risk.

• There is moderate evidence that smoking plays a causal role in MS progression.

• More research is needed examining the link between second-hand smoking and MS.

• Anti-smoking policies and programs should consider MS as an additional outcome.

Abstract

Background

Despite being one of the most common neurological disorders globally, the cause(s) of multiple sclerosis (MS) remain unknown. Cigarette smoking has been studied with regards to both the development and progression of MS. The Bradford Hill criteria for causation can contribute to a more comprehensive evaluation of a potentially causal risk factor-disease outcome relationship. The objective of this systematic review and meta-analysis was to assess the relationship between smoking and both MS risk and MS progression, subsequently applying Hill's criteria to further evaluate the likelihood of causal associations.

Methods

The Medline, EMBASE, CINAHL, PsycInfo, and Cochrane Library databases were searched for relevant studies up until July 28, 2015. A random-effects meta-analysis was conducted for three outcomes: MS risk, conversion from clinically isolated syndrome (CIS) to clinically definite multiple sclerosis (CDMS), and progression from relapsing-remitting multiple sclerosis (RRMS) to secondary-progressive multiple sclerosis (SPMS). Dose-response relationships and risk factor interactions, and discussions of mechanisms and analogous associations were noted. Hill's criteria were applied to assess causality of the relationships between smoking and each outcome. The effect of second-hand smoke exposure was also briefly reviewed.

Results

Smoking had a statistically significant association with both MS risk (conservative: OR/RR 1.54, 95% CI [1.46–1.63]) and SPMS risk (HR 1.80, 95% CI [1.04–3.10]), but the association with progression from CIS to CDMS was non-significant (HR 1.13, 95% CI [0.73–1.76]). Using Hill's criteria, there was strong evidence of a causal role of smoking in MS risk, but only moderate evidence of a causal association between smoking and MS progression. Heterogeneity in study designs and target populations, inconsistent results, and an overall scarcity of studies point to the need for more research on second-hand smoke exposure in relation to MS prior to conducting a detailed meta-analysis.

Conclusion

This first review to supplement systematic review and meta-analytic methods with Hill's criteria to analyze the smoking-MS association provides evidence supporting the causal involvement of smoking in the development and progression of MS. Smoking prevention and cessation programs and policies should consider MS as an additional health risk when aiming to reduce smoking prevalence in the population.

Introduction

Multiple sclerosis (MS) is among the most common neurological diseases globally, affecting approximately 2.3 million people in 2013, with the highest prevalence reported in North America and Europe (Multiple Sclerosis International Federation, 2013). MS is characterized by damage to the myelin surrounding the nerves of the central nervous system (CNS), as well as damage to the nerve axons, contributing to disrupted impulse conduction ultimately leading to MS symptoms (Murray, 2005). The cause of MS remains unknown (World Health Organization, 2008), but likely involves an interaction between genetic and environmental factors (Jankosky et al., 2012). Human Leukocyte Antigen (HLA) (Abolfazli et al., 2014, Sawcer et al., 2014), Epstein-Barr virus (EBV) (Almohmeed et al., 2013, Pakpoor et al., 2013), Vitamin D deficiency (Harandi et al., 2014, Pandit et al., 2013), and cigarette smoking (O'Gorman et al., 2014, Salzer et al., 2013) may be involved.

The past decade witnessed an increase in research examining the association between smoking and MS, whereby many studies have demonstrated that smoking is associated with MS risk (O'Gorman et al., 2014; Asadollahi et al., 2013; Hedstrom et al., 2013; Hernan et al., 2001, Hernan et al., 2005; Maghzi et al., 2011; Mansouri et al., 2014). However, the relationship between smoking and MS progression is less clear. Some studies demonstrate an effect of smoking on the conversion from a first episode of CNS demyelination—clinically isolated syndrome (CIS)—to clinically definite multiple sclerosis (CDMS) (Correale and Farez, 2015, Di Pauli et al., 2008), as well as on the conversion from a relapsing-remitting multiple sclerosis (RRMS) course to a secondary-progressive multiple sclerosis (SPMS) course (Healy et al., 2009; Roudbari et al., 2013). Other studies show no effect (Arikanoglu et al., 2013; Koch et al., 2007; Kuhle et al., 2015). There have also been mixed results investigating associations between different forms of second-hand smoke exposure and MS, some studies demonstrating an increased MS risk in relation to passive (Hedstrom et al., 2014a, Hedstrom et al., 2011a) and maternal prenatal smoke exposure (Mueller et al., 2013), while others do not (Montgomery et al. ,2008; Ramagopalan et al., 2013).

Previous systematic reviews with meta-analyses examining the association between smoking and MS risk have demonstrated a statistically significant relationship with an effect estimate of approximately 1.5 (Handel et al., 2011; Hawkes, 2007; O'Gorman and Broadley, 2014; Poorolajal et al., 2016; Zhang et al., 2016). The two most recent reviews examined the effect of passive smoking on MS, and while one showed a statistically significant relationship (Zhang et al., 2016), the other did not (Poorolajal et al., 2016). Only one previous review examined the association between smoking and MS progression, showing no statistically significant association between smoking and SPMS risk (Handel et al., 2011).

These previous reviews have several limitations and research gaps remain. More recently published and previously missed studies providing direct and indirect evidence relevant to the smoking-MS risk association should be included. Review and meta-analysis of the smoking-MS progression association has previously been minimal, and studies investigating CIS to CDMS progression in relation to smoking have not previously been included in a systematic review and meta-analysis. While a couple of systematic reviews with meta-analyses examined the relationship between passive smoking and MS (Poorolajal et al., 2016, Zhang et al., 2016), studies investigating additional forms of second-hand smoke exposure should be collated and summarized, possibly representing MS risk factors requiring further examination. Finally, the Bradford Hill criteria for causation (Hill, 1965) provide a useful complimentary tool for evaluating research evidence for causal relationships; Hill's criteria have previously only been used in narrative reviews (Loken-Amsrud et al., 2015, Wingerchuk, 2012) on smoking and MS.

The primary objective of this research was to a) examine the association between smoking and both MS risk and MS progression (i.e., CIS to CDMS, and RRMS to SPMS) through a systematic review and meta-analysis, and b) use Hill's criteria to more comprehensively assess the causality of each association. A secondary objective was to summarize the literature on the relationship between second-hand smoke exposure (i.e., general passive, prenatal) and MS by systematic review.