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


      • 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.



      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.


      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.


      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.


      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.


      CDMS (Clinically Definite Multiple Sclerosis), CI (Confidence Interval), CIS (Clinically Isolated Syndrome), CNS (Central Nervous System), EBV (Epstein-Barr Virus), GRADE (Grading of Recommendations Assessment, Development, and Evaluation), HLA (Human Leukocyte Antigen), HR (Hazard Ratio), IV (Inverse Variance), MS (Multiple Sclerosis), OR (Odds Ratio), PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses), RR (Risk Ratio), RRMS (Relapsing-Remitting Multiple Sclerosis), SE (Standard Error), SPMS (Secondary-Progressive Multiple Sclerosis)


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