Advertisement

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.

      Abbreviations:

      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)

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Multiple Sclerosis and Related Disorders
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Abolfazli R.
        • Samadzadeh S.
        • Sabokbar T.
        • et al.
        Relationship between HLA-DRB1* 11/15 genotype and susceptibility to multiple sclerosis in Iran.
        J. Neurol. Sci. 2014; 345: 92-96
        • Al-Afasy H.H.
        • Al-Obaidan M.A.
        • Al-Ansari Y.A.
        • et al.
        Risk factors for multiple sclerosis in Kuwait: a population-based case-control study.
        Neuroepidemiology. 2013; 40: 30-35
        • Almohmeed Y.H.
        • Avenell A.
        • Aucott L.
        • Vickers M.A.
        Systematic review and meta-analysis of the sero-epidemiological association between Epstein Barr virus and multiple sclerosis.
        PLoS One. 2013; 8: e61110
        • Anzures-Cabrera J.
        • Higgins J.P.
        Graphical displays for meta-analysis: an overview with suggestions for practice.
        Res. Synth. Methods. 2010; 1: 66-80
        • Arikanoglu A.
        • Shugaiv E.
        • Tuzun E.
        • Eraksoy M.
        Impact of cigarette smoking on conversion from clinically isolated syndrome to clinically definite multiple sclerosis.
        Int. J. Neurosci. 2013; 123: 476-479
        • Asadollahi S.
        • Fakhri M.
        • Heidari K.
        • Zandieh A.
        • Vafaee R.
        • Mansouri B.
        Cigarette smoking and associated risk of multiple sclerosis in the Iranian population.
        J. Clin. Neurosci. 2013; 20: 1747-1750
        • Bjornevik K.
        • Riise T.
        • Cortese M.
        • et al.
        Level of education and multiple sclerosis risk after adjustment for known risk factors: the EnvIMS study.
        Mult. Scler. 2016; 22: 104-111
        • Briggs F.B.
        • Acuna B.
        • Shen L.
        • et al.
        Smoking and risk of multiple sclerosis: evidence of modification by NAT1 variants.
        Epidemiology. 2014; 25: 605-614
        • Carlens C.
        • Hergens M.P.
        • Grunewald J.
        • et al.
        Smoking, use of moist snuff, and risk of chronic inflammatory diseases.
        Am. J. Respir. Crit. Care Med. 2010; 181: 1217-1222
        • Chen J.L.
        • Wei L.
        • Bereczki D.
        • et al.
        Nicotine raises the influx of permeable solutes across the rat blood-brain barrier with little or no capillary recruitment.
        J. Cereb. Blood Flow. Metab. 1995; 15: 687-698
        • Clayton D.
        • Hills M.
        Statistical Models in Epidemiology.
        Oxford University Press, 1993
        • Coles A.J.
        • Wing M.G.
        • Molyneux P.
        • et al.
        Monoclonal antibody treatment exposes three mechanisms underlying the clinical course of multiple sclerosis.
        Ann. Neurol. 1999; 46: 296-304
        • Connor Gorber S.
        • Schofield-Hurwitz S.
        • Hardt J.
        • Levasseur G.
        • Tremblay M.
        The accuracy of self-reported smoking: a systematic review of the relationship between self-reported and cotinine-assessed smoking status.
        Nicotine Tob. Res. 2009; 11: 12-24
        • Correale J.
        • Farez M.F.
        Smoking worsens multiple sclerosis prognosis: two different pathways are involved.
        J. Neuroimmunol. 2015; 281: 23-34
        • Costenbader K.H.
        • Kim D.J.
        • Peerzada J.
        • et al.
        Cigarette smoking and the risk of systemic lupus erythematosus: a meta-analysis.
        Arthritis Rheum. 2004; 50: 849-857
        • DerSimonian R.
        • Laird N.
        Meta-analysis in clinical trials.
        Control Clin. Trials. 1986; 7: 177-188
        • Di Pauli F.
        • Reindl M.
        • Ehling R.
        • et al.
        Smoking is a risk factor for early conversion to clinically definite multiple sclerosis.
        Mult. Scler. 2008; 14: 1026-1030
        • Egger M.
        • Davey Smith G.
        • Schneider M.
        • Minder C.
        Bias in meta-analysis detected by a simple, graphical test.
        BMJ. 1997; 315: 629-634
        • Fagerstrom K.
        The epidemiology of smoking: health consequences and benefits of cessation.
        Drugs. 2002; 62: 1-9
        • Gardener H.
        • Munger K.L.
        • Chitnis T.
        • Michels K.B.
        • Spiegelman D.
        • Ascherio A.
        Prenatal and perinatal factors and risk of multiple sclerosis.
        Epidemiology. 2009; 20: 611-618
        • George J.
        • Levy Y.
        • Shoenfeld Y.
        Smoking and immunity: an additional player in the mosaic of autoimmunity.
        Scand. J. Immunol. 1997; 45: 1-6
        • Ghadirian P.
        • Dadgostar B.
        • Azani R.
        • Maisonneuve P.
        A case-control study of the association between socio-demographic, lifestyle and medical history factors and multiple sclerosis.
        Can. J. Public Health. 2001; 92: 281-285
        • Gustavsen M.W.
        • Page C.M.
        • Moen S.M.
        • et al.
        Environmental exposures and the risk of multiple sclerosis investigated in a Norwegian case-control study.
        BMC Neurol. 2014; 14: 196
        • Guyatt G.H.
        • Oxman A.D.
        • Kunz R.
        • Vist G.E.
        • Falck-Ytter Y.
        • Schunemann H.J.
        What is "quality of evidence" and why is it important to clinicians?.
        BMJ. 2008; 336: 995-998
        • Handel A.E.
        • Williamson A.J.
        • Disanto G.
        • Dobson R.
        • Giovannoni G.
        • Ramagopalan S.V.
        Smoking and multiple sclerosis: an updated meta-analysis.
        PLoS One. 2011; 6: e16149
        • Harandi A.A.
        • Pakdaman H.
        • Sahraian M.A.
        Vitamin D and multiple sclerosis.
        Iran. J. Neurol. 2014; 13: 1-6
        • Hawkes C.H.
        Smoking is a risk factor for multiple sclerosis: a metanalysis.
        Mult. Scler. 2007; 13: 610-615
        • Healy B.C.
        • Ali E.N.
        • Guttmann C.R.
        • et al.
        Smoking and disease progression in multiple sclerosis.
        Arch. Neurol. 2009; 66: 858-864
        • Hedstrom A.K.
        • Baarnhielm M.
        • Olsson T.
        • Alfredsson L.
        Tobacco smoking, but not Swedish snuff use, increases the risk of multiple sclerosis.
        Neurology. 2009; 73: 696-701
        • Hedstrom A.K.
        • Baarnhielm M.
        • Olsson T.
        • Alfredsson L.
        Exposure to environmental tobacco smoke is associated with increased risk for multiple sclerosis.
        Mult. Scler. 2011; 17: 788-793
        • Hedstrom A.K.
        • Sundqvist E.
        • Baarnhielm M.
        • et al.
        Smoking and two human leukocyte antigen genes interact to increase the risk for multiple sclerosis.
        Brain. 2011; 134: 653-664
        • Hedstrom A.K.
        • Hillert J.
        • Olsson T.
        • Alfredsson L.
        Smoking and multiple sclerosis susceptibility.
        Eur. J. Epidemiol. 2013; 28: 867-874
        • Hedstrom A.K.
        • Bomfim I.L.
        • Barcellos L.F.
        • et al.
        Interaction between passive smoking and two HLA genes with regard to multiple sclerosis risk.
        Int. J. Epidemiol. 2014; 43: 1791-1798
        • Hedstrom A.K.
        • Hillert J.
        • Olsson T.
        • Alfredsson L.
        Alcohol as a modifiable lifestyle factor affecting multiple sclerosis risk.
        JAMA Neurol. 2014; 71: 300-305
        • Henriksen M.
        • Creaby M.W.
        • Lund H.
        • Juhl C.
        • Christensen R.
        Is there a causal link between knee loading and knee osteoarthritis progression? A systematic review and meta-analysis of cohort studies and randomised trials.
        BMJ Open. 2014; 4: e005368
        • Hernan M.A.
        • Olek M.J.
        • Ascherio A.
        Cigarette smoking and incidence of multiple sclerosis.
        Am. J. Epidemiol. 2001; 154: 69-74
        • Hernan M.A.
        • Jick S.S.
        • Logroscino G.
        • Olek M.J.
        • Ascherio A.
        • Jick H.
        Cigarette smoking and the progression of multiple sclerosis.
        Brain. 2005; 128: 1461-1465
        • Higgins J.P.
        • Thompson S.G.
        Quantifying heterogeneity in a meta-analysis.
        Stat. Med. 2002; 21: 1539-1558
        • Higgins J.P.
        • Thompson S.G.
        • Deeks J.J.
        • Altman D.G.
        Measuring inconsistency in meta-analyses.
        BMJ. 2003; 327: 557-560
      1. Higgins J.P.T., Green S., 2011a. (editors). Section 9.4.3: A generic inverse-variance approach to meta-analysis. In: Cochrane handbook for systematic reviews of interventions (version 5.1.0)[updated March 2011]. Cochrane Collaboration. Available at: 〈www.handbook.cochrane.org〉.

      2. Higgins J.P.T., Green S., 2011b. (editors). Section 7.7.7.2: Obtaining standard errors from confidence intervals and P values: Absolute (difference) measures; Section 7.7.7.3: Obtaining standard errors from confidence intervals and P values: Ratio measures. In: Cochrane handbook for systematic reviews of interventions (version 5.1.0)[updated March 2011]. Cochrane Collaboration. Available at: 〈www.handbook.cochrane.org〉.

      3. Higgins J.P.T., Green S. , 2011c. (editors). Section 9.5.2: Identifying and measuring heterogeneity. In: Cochrane handbook for systematic reviews of interventions (version 5.1.0)[updated March 2011]. Cochrane Collaboration. Available at: 〈www.handbook.cochrane.org〉.

        • Hill A.B.
        The environment and disease: association or causation?.
        Proc. R. Soc. Med. 1965; 58: 295-300
        • Horakova D.
        • Zivadinov R.
        • Weinstock-Guttman B.
        • et al.
        Environmental factors associated with disease progression after the first demyelinating event: results from the multi-center SET study.
        PLoS One. 2013; 8: e53996
        • Jafari N.
        • Hoppenbrouwers I.A.
        • Hop W.C.
        • Breteler M.M.
        • Hintzen R.Q.
        Cigarette smoking and risk of MS in multiplex families.
        Mult. Scler. 2009; 15: 1363-1367
        • Jankosky C.
        • Deussing E.
        • Gibson R.L.
        • Haverkos H.W.
        Viruses and vitamin D in the etiology of type 1 diabetes mellitus and multiple sclerosis.
        Virus Res. 2012; 163: 424-430
        • Kappus N.
        • Weinstock-Guttman B.
        • Hagemeier J.
        • et al.
        Cardiovascular risk factors are associated with increased lesion burden and brain atrophy in multiple sclerosis.
        J. Neurol. Neurosurg. Psychiatry. 2016; 87: 181-187
        • Koch M.
        • van Harten A.
        • Uyttenboogaart M.
        • De Keyser J.
        Cigarette smoking and progression in multiple sclerosis.
        Neurology. 2007; 69: 1515-1520
        • Kuhle J.
        • Disanto G.
        • Dobson R.
        • et al.
        Conversion from clinically isolated syndrome to multiple sclerosis: a large multicentre study.
        Mult. Scler. 2015; 21: 1013-1024
        • Loken-Amsrud K.I.
        • Lossius A.
        • Torkildsen O.
        • Holmoy T.
        Impact of the environment on multiple sclerosis.
        Tidsskr. Nor. Laege. 2015; 135: 856-860
        • Maghzi A.H.
        • Etemadifar M.
        • Heshmat-Ghahdarijani K.
        • et al.
        Cigarette smoking and the risk of multiple sclerosis: a sibling case-control study in Isfahan, Iran.
        Neuroepidemiology. 2011; 37: 238-242
        • Majka D.S.
        • Holers V.M.
        Cigarette smoking and the risk of systemic lupus erythematosus and rheumatoid arthritis.
        Ann. Rheum. Dis. 2006; 65: 561-563
        • Mansouri B.
        • Asadollahi S.
        • Heidari K.
        • et al.
        Risk factors for increased multiple sclerosis susceptibility in the Iranian population.
        J. Clin. Neurosci. 2014; 21: 2207-2211
        • Mente A.
        • de Koning L.
        • Shannon H.S.
        • Anand S.S.
        A systematic review of the evidence supporting a causal link between dietary factors and coronary heart disease.
        Arch. Intern. Med. 2009; 169: 659-669
        • Mikaeloff Y.
        • Caridade G.
        • Tardieu M.
        • Suissa S.
        Parental smoking at home and the risk of childhood-onset multiple sclerosis in children.
        Brain. 2007; 130: 2589-2595
        • Miller D.
        • Barkhof F.
        • Montalban X.
        • Thompson A.
        • Filippi M.
        Clinically isolated syndromes suggestive of multiple sclerosis, part I: natural history, pathogenesis, diagnosis, and prognosis.
        Lancet Neurol. 2005; 4: 281-288
        • Minagar A.
        • Alexander J.S.
        Blood-brain barrier disruption in multiple sclerosis.
        Mult. Scler. 2003; 9: 540-549
        • Moher D.
        • Liberati A.
        • Tetzlaff J.
        • Altman D.G.
        Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
        PLoS Med. 2009; 6: e1000097
        • Montgomery S.M.
        • Bahmanyar S.
        • Hillert J.
        • Ekbom A.
        • Olsson T.
        Maternal smoking during pregnancy and multiple sclerosis amongst offspring.
        Eur. J. Neurol. 2008; 15: 1395-1399
        • Mouhieddine T.H.
        • Darwish H.
        • Fawaz L.
        • Yamout B.
        • Tamim H.
        • Khoury S.J.
        Risk factors for multiple sclerosis and associations with anti-EBV antibody titers.
        Clin. Immunol. 2015; 158: 59-66
        • Mueller B.A.
        • Nelson J.L.
        • Newcomb P.A.
        Intrauterine environment and multiple sclerosis: a population-based case-control study.
        Mult. Scler. 2013; 19: 106-111
      4. Multiple Sclerosis International Federation, 2013. Atlas of MS. London, UK: Multiple Sclerosis International Federation, 2013.

        • Murray T.J.
        Multiple Sclerosis: the History of a Disease.
        Demos Medical Publishing, New York, NY2005
        • O'Gorman C.
        • Broadley S.A.
        Smoking and multiple sclerosis: evidence for latitudinal and temporal variation.
        J. Neurol. 2014; 261: 1677-1683
        • O'Gorman C.
        • Bukhari W.
        • Todd A.
        • Freeman S.
        • Broadley S.A.
        Smoking increases the risk of multiple sclerosis in Queensland, Australia.
        J. Clin. Neurosci. 2014; 21: 1730-1733
        • Pakpoor J.
        • Giovannoni G.
        • Ramagopalan S.V.
        Epstein-Barr virus and multiple sclerosis: association or causation?.
        Expert Rev. Neurother. 2013; 13: 287-297
        • Pandit L.
        • Ramagopalan S.V.
        • Malli C.
        • D'Cunha A.
        • Kunder R.
        • Shetty R.
        Association of vitamin D and multiple sclerosis in India.
        Mult. Scler. 2013; 19: 1592-1596
        • Philbrick D.J.
        • Hopkins J.B.
        • Hill D.C.
        • Alexander J.C.
        • Thomson R.G.
        Effects of prolonged cyanide and thiocyanate feeding in rats.
        J. Toxicol. Environ. Health. 1979; 5: 579-592
        • Pittas F.
        • Ponsonby A.L.
        • van der Mei I.A.
        • et al.
        Smoking is associated with progressive disease course and increased progression in clinical disability in a prospective cohort of people with multiple sclerosis.
        J. Neurol. 2009; 256: 577-585
        • Ploughman M.
        • Beaulieu S.
        • Harris C.
        • et al.
        The Canadian survey of health, lifestyle and ageing with multiple sclerosis: methodology and initial results.
        BMJ Open. 2014; 4: e005718
        • Poorolajal J.
        • Bahrami M.
        • Karami M.
        • Hooshmand E.
        Effect of smoking on multiple sclerosis: a meta-analysis.
        J. Public Health (Oxf.). 2016; 39: 312-320
        • Prummel M.F.
        • Wiersinga W.M.
        Smoking and risk of Graves' disease.
        JAMA. 1993; 269: 479-482
        • Ramagopalan S.V.
        • Lee J.D.
        • Yee I.M.
        • et al.
        Association of smoking with risk of multiple sclerosis: a population-based study.
        J. Neurol. 2013; 260: 1778-1781
        • Riise T.
        • Nortvedt M.W.
        • Ascherio A.
        Smoking is a risk factor for multiple sclerosis.
        Neurology. 2003; 61: 1122-1124
        • Rothman K.J.
        • Greenland S.
        Causation and causal inference in epidemiology.
        Am. J. Public Health. 2005; 95: S144-S150
        • Roudbari S.A.
        • Ansar M.M.
        • Yousefzad A.
        Smoking as a risk factor for development of secondary progressive multiple sclerosis: a study in Iran, Guilan.
        J. Neurol. Sci. 2013; 330: 52-55
        • Salzer J.
        • Hallmans G.
        • Nystrom M.
        • Stenlund H.
        • Wadell G.
        • Sundstrom P.
        Smoking as a risk factor for multiple sclerosis.
        Mult. Scler. 2013; 19: 1022-1027
        • Salzer J.
        • Stenlund H.
        • Sundstrom P.
        The interaction between smoking and Epstein-Barr virus as multiple sclerosis risk factors may depend on age.
        Mult. Scler. 2014; 20: 747-750
        • Sawcer S.
        • Franklin R.J.
        • Ban M.
        Multiple sclerosis genetics.
        Lancet Neurol. 2014; 13: 700-709
      5. Schoenbach, V. J., Rosamund, W. D., 2000. Relating risk factors to health outcomes. In: Understanding the fundamentals of epidemiology--An evolving text. Chapel Hill, NC: Department of Epidemiology, School of Public Health, University of North Carolina, pp. 161–207.

        • Simon K.C.
        • van der Mei I.A.
        • Munger K.L.
        • et al.
        Combined effects of smoking, anti-EBNA antibodies, and HLA-DRB1*1501 on multiple sclerosis risk.
        Neurology. 2010; 74: 1365-1371
        • Simon K.C.
        • Schmidt H.
        • Loud S.
        • Ascherio A.
        Risk factors for multiple sclerosis, neuromyelitis optica and transverse myelitis.
        Mult. Scler. 2015; 21: 703-709
        • Smith K.J.
        • Kapoor R.
        • Hall S.M.
        • Davies M.
        Electrically active axons degenerate when exposed to nitric oxide.
        Ann. Neurol. 2001; 49: 470-476
        • Sundqvist E.
        • Sundstrom P.
        • Linden M.
        • et al.
        Lack of replication of interaction between EBNA1 IgG and smoking in risk for multiple sclerosis.
        Neurology. 2012; 79: 1363-1368
        • Sundstrom P.
        • Nystrom L.
        Smoking worsens the prognosis in multiple sclerosis.
        Mult. Scler. 2008; 14: 1031-1035
        • Sundstrom P.
        • Nystrom L.
        • Hallmans G.
        Smoke exposure increases the risk for multiple sclerosis.
        Eur. J. Neurol. 2008; 15: 579-583
        • Thorogood M.
        • Hannaford P.C.
        The influence of oral contraceptives on the risk of multiple sclerosis.
        Br. J. Obstet. Gynaecol. 1998; 105: 1296-1299
        • Tierney J.F.
        • Stewart L.A.
        • Ghersi D.
        • Burdett S.
        • Sydes M.R.
        Practical methods for incorporating summary time-to-event data into meta-analysis.
        Trials. 2007; 8: 16
      6. U.S. Department of Health and Human Services, 2006. The health consequences of involuntary exposure to tobacco smoke: A report of the Surgeon General. Atlanta, GA: Centers for Disease Control and Prevention.

        • Villard-Mackintosh L.
        • Vessey M.P.
        Oral contraceptives and reproductive factors in multiple sclerosis incidence.
        Contraception. 1993; 47: 161-168
        • Wingerchuk D.M.
        Smoking: effects on multiple sclerosis susceptibility and disease progression.
        Ther. Adv. Neurol. Disord. 2012; 5: 13-22
      7. World Health Organization, 2008. Atlas: Multiple sclerosis resources in the world. Geneva, CH: WHO Press.

        • Zhang P.
        • Wang R.
        • Li Z.
        • et al.
        The risk of smoking on multiple sclerosis: a meta-analysis based on 20,626 cases from case-control and cohort studies.
        PeerJ. 2016; 4: e1797