Multiple Sclerosis and Related Disorders 1 (2012) 59–60

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Multiple sclerosis and risk behavior Christopher H. Hawkes Neuroscience Centre, Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, 4 Newark Street, London E1 2AT, United Kingdom

There are several aspects to the concept of risk behavior in MS patients. Foremost is their attitude to novel immunotherapies with the attendant short and long term hazards. Related to this, is their concern about everyday risks to health before disease onset. Finally, there is the behavior pattern of patients once they have the disease and its impact on lifestyle. These aspects of riskrelated behavior have been studied relatively little. An initial study by Prosser et al. (2002) addressed the attitude to medication risk in MS and explored why many patients who were eligible for beta-interferon or glatiramer acetate chose to forgo or discontinue treatment. Sixty-two patients with MS completed a survey on risk preference, and risk attitude was measured using an in-house standard gamble question on shortterm health outcomes. It was found that risk-taking patients were less likely to choose standard treatment compared to risk-averse patients. In other words the more risk-seeking an individual is, the more likely they would choose no treatment—a somewhat unexpected finding. Risk attitude did not appear to have an important effect on the decision to discontinue treatment. In their subsequent survey (Prosser and Wittenberg, 2007) 56 MS patients and 57 community members were assessed for risk attitude based again on standard gamble questions relating to money or health outcomes. Patients and community members were predominantly risk neutral with respect to health outcomes and risk averse with respect to money. In a further study (Johnson et al., 2009) evaluated by questionnaire the willingness of 651 MS patients to accept lifethreatening adverse event risks in exchange for improvements in their health outcome. Patients chose imaginary therapies from pairs of treatment alternatives that had varying levels of clinical efficacy and associated drawbacks. It was found that delay in years to disability progression was the most important factor in treatment preferences. In return for decreases in relapse rates from 4 to 1 and increases in delay in progression from 3 to 5 years, patients were willing to accept a 0.38 percent annual risk of death or disability from progressive multifocal leukoencephalopathy (PML) a 0.39 percent annual risk of death from liver failure or a 0.48 percent annual risk of death from leukemia. There are few publications that assess directly the willingness of the treating physician to offer newer immunotherapies but one would expect most doctors would be more cautious than their

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patients. Thus, a recent publication (Heesen et al., 2010) assessed risk perception in Natalizumab-treated MS patients and their neurologists. Sixty-nine patients and 66 neurologists received an information leaflet about Natalizumab-associated PML. Patients were significantly more likely than physicians to continue Natalizumab treatment and were willing to accept higher risks of PML. Forty-nine percent of physicians would stop treatment at a PML risk of 2:10,000 or lower, while only 17 percent of patients would do so. Overall, their MS patients were willing to accept a higher risk of PML than neurologists. An exception to this general rule that has not been studied in depth might be Mitoxantrone, which according to the most recent report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology (Marriott et al., 2010) is associated with systolic dysfunction (  12 percent) congestive heart failure (  0.4 percent) and leukemia (  0.8 percent). However, many neurologists prescribe Mitoxantrone for patients with medication-resistant secondary progressive or (off license) for primary progressive cases. One might question whether the patients are fully informed of its complications particularly leukemia which carries a 24 percent risk of death (Ellis and Boggild, 2009). Doubtless, there are regional and national variations in physicians’ approach. Furthermore, the chronic cerebro-spinal venous insufficiency story has shown that people will tolerate the risk of as yet unproven and potentially harmful treatment if they believe claims that the treatment offers new hope for improved function or even cure. Turning to another aspect, i.e. risk behavior, it was suggested that before disease onset, MS patients are more likely to indulge in health-adverse behavior patterns (Hawkes, 2005). Lifestyle exposures that were reviewed included smoking, alcohol, recreational drug use, oral contraception, cholesterol intake, risk attitude and behavior, ultraviolet light and vitamin D exposure, and viral infection. Relatively few articles have addressed these aspects and for controls many have employed rheumatoid arthritis (RA). Given the relatively close relationship between MS and RA some degree of overmatching will be unavoidable. In the above review (Hawkes, 2005) it was proposed that the best evidence related to prior smoking, not taking vitamin D supplements and Epstein-Barr viral infection. It was suggested that there may be a pattern of risk-associated behavior that characterizes patients with MS and brings them into contact with one or more causative agents. This principle was corroborated in a further study by Marrie et al. (2009) in a survey of 8983 MS patients


C.H. Hawkes / Multiple Sclerosis and Related Disorders 1 (2012) 59–60

derived from the North American Research Committee on Multiple Sclerosis (NARCOMS) Registry. A high prevalence of smoking, alcohol consumption, obesity and infrequent physical activity was noted. The main drawback of this study was the lack of a proper control group. A potential twist to this story came at ECTRIMS 2011 in a presentation by Riise et al. (2011) at present available only in abstract form. This was a multinational study of 2125 cases and 4455 controls. It was confirmed that individually, smoking and history of infectious mononucleosis (IM) were risk factors for MS. Unexpectedly, there was a significant negative interaction between smoking and history of IM. This finding was common across all centers and found separately for both males and females. Their observations did not support the notion that the risk of MS related to EBV was increased by smoking. Although the rate of IM in the MS group was perhaps lower than expected at around 14 percent, in essence, their findings imply that smoking might protect against IM. This uncomfortable finding is plausible given for example, the suspected protective effect of smoking on subsequent risk of idiopathic Parkinson’s Disease (Morens et al., 1995; 1996) and possibly Alzheimer’s disease. There are other plausible explanations however. Smoking might act as a nonspecific immune stimulant that protects against IM. It is possible that smokers are more likely to acquire EBV exposure younger (due to shared cigarettes for example) which in turn reduces the chances of IM. These preliminary counter-intuitive but intriguing findings may represent the play of chance and will need peer review and probable re-examination in other centers. Previous studies have addressed the concept of cumulative effects from several risk factors to define an ‘endophenotype’ for MS (Ramagopalan et al., 2010) but the findings of Riise and colleagues

should alert us to the possibility of both positive and negative interaction between risk factors and not simple additive effects. References Ellis R, Boggild M. Therapy-related acute leukaemia with Mitoxantrone: what is the risk and can we minimise it? Multiple Sclerosis 2009;15:505–8. Hawkes CH. Are multiple sclerosis patients risk-takers? QJM 2005;98:895–911. Heesen C, Kleiter I, Nguyen F, et al. Risk perception in natalizumab-treated multiple sclerosis patients and their neurologists. Multiple Sclerosis 2010;16:1507–12. Johnson FR, Van HG, Ozdemir S, et al. Multiple sclerosis patients’ benefit-risk preferences: serious adverse event risks versus treatment efficacy. Journal of Neurology 2009;256:554–62. Marrie R, Horwitz R, Cutter G, Tyry T, Campagnolo D, Vollmer T. High frequency of adverse health behaviors in multiple sclerosis. Multiple Sclerosis 2009;15: 105–13. Marriott JJ, Miyasaki JM, Gronseth G, O’Connor PW. Evidence report: the efficacy and safety of mitoxantrone (Novantrone) in the treatment of multiple sclerosis: Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2010;74:1463–70. Morens DM, Grandinetti A, Davis JW, Ross GW, White LR, Reed D. Evidence against the operation of selective mortality in explaining the association between cigarette smoking and reduced occurrence of idiopathic Parkinson disease. American Journal of Epidemiology 1996;144:400–4. Morens DM, Grandinetti A, Reed D, White LR, Ross GW. Cigarette smoking and protection from Parkinson’s disease: false association or etiologic clue? Neurology 1995;45:1041–51. Prosser LA, Kuntz KM, Bar-Or A, Weinstein MC. The relationship between risk attitude and treatment choice in patients with relapsing-remitting multiple sclerosis. Medical Decision Making 2002;22:506–13. Prosser LA, Wittenberg E. Do risk attitudes differ across domains and respondent types? Medical Decision Making 2007;27:281–7. Ramagopalan SV, Dobson R, Meier UC, Giovannoni G. Multiple sclerosis: risk factors, prodromes, and potential causal pathways. Lancet Neurology 2010;9:727–39. Riise T, Pugliatti M, Casetta J, et al. Negative interaction between smoking and infectious mononucleosis and the risk of MS. Multiple Sclerosis Journal 2011;17. Abstract 131.

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