Abstracts
Potential environmental modifiable factors involved in multiple sclerosis (MS) include low adherence to treatment, smoking, obesity, low levels of liposoluble vitamins A and D, high consumption of salt, and a sedentary lifestyle. Chronic tobacco use, obesity, sedentarism and insufficient levels of these vitamins all contribute to maintenance of a proinflammatory state. It is unlikely that there will be noticeable improvement in the inflammatory condition of MS if stopping smoking, reducing weight, exercising, increasing vitamin levels are done in an isolated and erratic manner. Modification of each and every one of these environmental risk factors is likely to be an important approach in the management of MS. The present review presents the arguments for an association between these hazardous modifiable factors and the chronic inflammatory state observed in MS.
multiple sclerosis; smoking; obesity; vitamin D; vitamin A; exercise
Potenciais fatores ambientais modificáveis envolvidos na esclerose múltipla (EM) incluem baixa adesão ao tratamento, tabagismo, obesidade, baixos níveis das vitaminas lipossolúveis A e D, e um estilo de vida sedentário. O uso crônico de tabaco, obesidade, sedentarismo e níveis insuficientes destas vitaminas podem todos contribuir para a manutenção de um estado pró-inflamatório. É pouco provável que haja melhora notável na condição inflamatória da EM se a cessação do tabagismo, a redução de peso, exercícios e maiores níveis de vitaminas forem obtidos isoladamente e de maneira errática. A modificação de cada um destes fatores de risco ambientais poderá ser importante parte do manejo eficaz da EM. A presente revisão apresenta argumentos para uma associação entre os fatores modificáveis nocivos e o estado inflamatório crônico observado na EM.
esclerose múltipla; tabagismo; obesidade, vitamina D; vitamina A; exercícios
Evidence for the inflammatory pathogenic basis of multiple sclerosis (MS) is
overwhelming. This chronic neurological disease is characterized by demyelination,
multifocal inflammation, reactive gliosis and axonal/neuron loss11 . Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG.
Multiple sclerosis. N Engl J Med. 2000;343(13):938-52.
http://dx.doi.org/10.1056/nejm200009283431307
https://doi.org/10.1056/nejm200009283431...
.
The most effective treatments for MS are immunosuppressive in nature and may, for
example, include monoclonal antibodies such as natalizumab [NTZ], daclizumab
[DCL], and alemtuzumab [ATZ]. Patients with MS who do not respond to
immunomodulatory drugs (first-line therapy) receive immunosuppressive drugs (second-line
therapy), which have the risk of potentially fatal adverse events. The monoclonal
antibodies recommended for MS treatment may have to be withdrawn after a certain period
of use, due to intolerance of side effects. At this time, MS may reactivate with severe
inflammatory reactions22 . Fragoso YD, Arruda NM, Arruda WO, Brooks JBB, Correa EC, Damasceno
A et al. We know how to prescribe natalizumab for multiple sclerosis, but do we
know how to withdraw it? Expert Rev Neurother. 2014;14(2):127-30.
http://dx.doi.org/10.1586/14737175.2014.874947
https://doi.org/10.1586/14737175.2014.87...
.
It is possible that, with a specific approach to modifiable factors, the use of more
aggressive treatment may not be necessary and the patient might thrive on
immunomodulatory drugs that have less severe side effects. However, when the patient
presents an aggressive form of MS and/or does not respond to immunomodulatory drugs33 . McGraw CA, Lublin FD. Interferon beta and glatiramer acetate
therapy. Neurotherapeutics. 2013;10(1):2-18.
http://dx.doi.org/10.1007/s13311-012-0163-4
https://doi.org/10.1007/s13311-012-0163-...
, the immediate reaction is to progress
to immunosuppression44 . Rieckmann P. Concepts of induction and escalation therapy in
multiple sclerosis. J Neurol Sci. 2009;277 Suppl 1:S42-5.
http://dx.doi.org/10.1007/s13311-012-0163-4
https://doi.org/10.1007/s13311-012-0163-...
.
Perhaps it is time to consider the modifiable factors in MS when treating a patient. It goes without saying that adequate adherence to treatment needs to have been confirmed before the patient is given second-line therapy with potentially more serious, and even fatal, side effects. Through quitting smoking, losing weight, exercising and maintaining proper serum levels of vitamins A and D, the patient may respond better to all pharmacological treatments. It is, after all, the environmental factors that perpetuate the inflammatory state in MS and, for unknown reasons, these factors are frequently ignored. A summary of the potentially modifiable factors in presented in Table.
Summary of the effects of modifiable environmental factors in multiple sclerosis (MS). Simple changes in lifestyle are capable of altering the pro-inflammatory state of MS, inducing favorable shifts towards homeostasis and an anti-inflammatory state.
Smoking
Cigarette smoking increases the risk of developing autoimmune diseases and leads to
worse disease evolution for patients suffering from immunological diseases55 . Costenbader KH, Karlson EW. Cigarette smoking and autoimmune
disease: what can we learn from epidemiology? Lupus. 2006;15(11):737-45.
http://dx.doi.org/10.1177/0961203306069344
https://doi.org/10.1177/0961203306069344...
. The relative risk of developing MS
among smokers is almost twice that of never-smokers55 . Costenbader KH, Karlson EW. Cigarette smoking and autoimmune
disease: what can we learn from epidemiology? Lupus. 2006;15(11):737-45.
http://dx.doi.org/10.1177/0961203306069344
https://doi.org/10.1177/0961203306069344...
,66 . Maghzi AH, Etemadifar M, Heshmat-Ghahdarijani K, Moradi V, Nonhal
S, Ghorbani A et al. Cigarette smoking and the risk of multiple sclerosis: a
sibling case-control study in Isfahan, Iran. Neuroepidemiology.
2011;37(3-4):238-42. http://dx.doi.org/10.1159/000332765
https://doi.org/10.1159/000332765...
. Cigarette smoke is capable of increasing the expression of
Fas on B and CD4 T lymphocyte cell surfaces77 . Bijl M, Horst G, Limburg PC, Kallenberg CG. Effects of smoking on
activation markers, Fas expression and apoptosis of peripheral blood
lymphocytes. Eur J Clin Invest. 2001;31(6):550-3.
http://dx.doi.org/10.1046/j.1365-2362.2001.00842.x
https://doi.org/10.1046/j.1365-2362.2001...
. Fas (CD95) is a pro-apoptotic transmembrane protein
that also induces release of inflammatory cytokines by macrophages88 . Wang F, Lu Z, Hawkes M, Yang H, Kain KC, Liles WC. Fas (CD95)
induces rapid, TLR4/IRAK4-dependent release of pro-inflammatory HMGB1 from
macrophages. J Inflamm (Lond). 2010;7(1):30.
http://dx.doi.org/10.1186/1476-9255-7-30
https://doi.org/10.1186/1476-9255-7-30...
. In addition, cigarette smoking
leads to release of matrix metalloproteinases99 . Seagrave J, Barr EB, March TH, Nikula KJ. Effects of cigarette
smoke exposure and cessation on inflammatory cells and matrix metalloproteinase
activity in mice. Exp Lung Res. 2004;30(1):1-15.
http://dx.doi.org/10.1080/01902140490252858
https://doi.org/10.1080/0190214049025285...
and affects immunological homeostasis1010 . Moszczyński P, Żabiński Z, Moszczyński P
Jr, Rutowski J, Słowińskia S, Tabarowski Z. Immunological findings
in cigarette smokers. Toxicol Lett. 2001;118(3):121-7.
http://dx.doi.org/10.1016/s0378-4274(00)00270-8
https://doi.org/10.1016/s0378-4274(00)00...
,1111 . Robbins CS, Dawe DE, Goncharova SI, Pouladi MA, Drannik AG,
Swirski FK et al. Cigarette smoke decreases pulmonary dendritic cells and
impacts antiviral immune responsiveness. Am J Respir Cell Mol Biol.
2004;30(2):202-11. http://dx.doi.org/10.1165/rcmb.2003-0259oc
https://doi.org/10.1165/rcmb.2003-0259oc...
.
Patients with MS who smoke have a more severe disease course and a faster disability
progression rate1212 . Manouchehrinia A, Tench CR, Maxted J, Bibani RH, Britton J,
Constantinescu CS. Tobacco smoking and disability progression in multiple
sclerosis: United Kingdom cohort study. Brain. 2013;136(Pt 7):2298-304.
http://dx.doi.org/10.1093/brain/awt139
https://doi.org/10.1093/brain/awt139...
,1313 . Roudbari SA, Ansar MM, Yousefzad A. Smoking as a risk factor for
development of secondary progressive multiple sclerosis: A study in IRAN,
Guilan. J Neurol Sci. 2013;330(1-2):52-5.
http://dx.doi.org/10.1016/j.jns.2013.04.003
https://doi.org/10.1016/j.jns.2013.04.00...
. Furthermore, smokers run a risk of developing antibodies
against natalizumab that is almost three times higher than that of non-smokers1414 . Hedström A, Alfredsson L, Lundkvist Ryner M, Fogdell-Hahn A,
Hillert J, Olsson T. Smokers run increased risk of developing anti-natalizumab
antibodies. Mult Scler. 2013;20(8):1081-5.
http://dx.doi.org/10.1177/1352458513515086
https://doi.org/10.1177/1352458513515086...
. A recent meta-analysis has shown
that, independently of the type of study, smoking is associated to MS1515 . O'Gorman C, Broadley SA. Smoking and multiple sclerosis:
evidence for latitudinal and temporal variation. J Neurol. 2014;261(9)1677-83.
http://dx.doi.org/10.1007/s00415-014-7397-5
https://doi.org/10.1007/s00415-014-7397-...
. An interesting and recent study
points out that smoking is associated to MS only for certain genotypes,
characterizing a situation where environmental and genetic factors interact1616 . Briggs FB, Acuna B, Shen L, Ramsay P, Quach H, Bernstein A et al.
Smoking and risk of multiple sclerosis: evidence of modification by NAT1
variants. Epidemiology. 2014;25(4):605-14.
http://dx.doi.org/10.1097/ede.0000000000000089
https://doi.org/10.1097/ede.000000000000...
.
Passive smoking also increases the risk of developing MS1717 . Hedström AK, Bäärnhielm M, Olsson T, Alfredsson L.
Exposure to environmental tobacco smoke is associated with increased risk for
multiple sclerosis. Mult Scler. 2011;17(7):788-93.
http://dx.doi.org/10.1177/1352458511399610
https://doi.org/10.1177/1352458511399610...
and it is advisable that patients with MS should
not be exposed to environments with tobacco smoke.
Obesity
Individuals who were overweight or obese during childhood or adolescence have twice
the risk of developing MS in adulthood1818 . Munger KL, Chitnis T, Ascherio A. Body size and risk of MS in two
cohorts of US women. Neurology. 2009;73(19):1543-50.
http://dx.doi.org/10.1212/wnl.0b013e3181c0d6e0
https://doi.org/10.1212/wnl.0b013e3181c0...
,1919 . Munger K, Bentzen J, Laursen B, Stenager E, Koch-Henrisken N,
Sørensen TI et al. Childhood body mass index and multiple sclerosis risk: a
long-term cohort study. Mult Scler, 2013;19(10):1323-9.
http://dx.doi.org/10.1177/1352458513483889
https://doi.org/10.1177/1352458513483889...
,2020 . Hedström AK, Olsson T, Alfredsson L. High body mass index
before age 20 is associated with increased risk for multiple sclerosis in both
men and women. Mult Scler. 2012;18(9):1334-6.
http://dx.doi.org/10.1177/1352458512436596
https://doi.org/10.1177/1352458512436596...
. In fact, other autoimmune diseases are also more common
in individuals who are above the proper weight2121 . Harpsøe MC, Basit S, Andersson M, Nielsen NM, Frisch M,
Wohlfahrt J et al. Body mass index and risk of autoimmune diseases: a study
within the Danish National Birth Cohort. Int J Epidemiol. 2014;43(3):843-55.
http://dx.doi.org/10.1093/ije/dyu045
https://doi.org/10.1093/ije/dyu045...
. Exposure to the so-called "Western diet", which
includes high fat and cholesterol, high protein, high sugar, and excess salt intake,
promotes obesity, metabolic syndrome, cardiovascular disease and autoimmune
diseases2222 . Manzel A, Muller DN, Hafler DA, Erdman SE, Linker RA,
Kleinewietfeld M. Role of "western diet" in inflammatory autoimmune diseases.
Curr Allergy Asthma Rep. 2014;14(1):404.
http://dx.doi.org/10.1007/s11882-013-0404-6
https://doi.org/10.1007/s11882-013-0404-...
.
White adipose tissue is not an inert tissue devoted solely to energy storage. Adipocytes can be regarded as part of an endocrine organ that releases several proinflammatory mediators, such as tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), leptin and C-reactive protein2323 . Fietta P, Delsante G. Focus on adipokines. Theor Biol Forum. 2013;106(1-2):103-29.. A small number of adipocytes have anti-inflammatory properties and release the beneficial protein adiponectin2424 . Ouchi N, Ohashi K, Shibata R, Murohara T. Adipocytokines and obesity -linked disorders. Nagoya J Med Sci. 2012;74(1-2):19-30.. In the presence of obesity, production and/or secretion of these factors may be dysfunctional, leading to obesity-related disorders, including autoimmune diseases.
One key player in the immunological tolerance response that can be affected by
obesity is regulatory T cells (Tregs). These are forkhead box P3 (FOXP3)+
T cells that have pivotal importance in the mechanisms controlling immunological
homeostasis and function2525 . Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and
immune tolerance. Cell. 2008;133(5):775-87.
http://dx.doi.org/10.1016/j.cell.2008.05.009
https://doi.org/10.1016/j.cell.2008.05.0...
.
Leptin, one of the inflammatory cytokines released by adipocytes, can affect the
function of Tregs2626 . Zeng H, Chi H. The interplay between regulatory T cells and
metabolism in immune regulation. Oncoimmunology. 2013;2(11):e26586.
http://dx.doi.org/10.4161/onci.26586
https://doi.org/10.4161/onci.26586...
.
Administration of an anti-leptin antibody has been found to succeed in reversing the
anergic status of Tregs in vitro, enabling them to proliferate in
response to anti-CD3 and anti-CD28 stimulation2727 . De Rosa V, Procaccini C, Calì G, Pirozzi G, Fontana S,
Zappacosta S et al. A key role of leptin in the control of regulatory T cell
proliferation. Immunity. 2007;26(2):241-55.
http://dx.doi.org/10.1016/j.immuni.2007.01.011
https://doi.org/10.1016/j.immuni.2007.01...
. In vivo, a significant inverse
correlation is observed between the number of Foxp3 Treg cells and body weight and
plasma leptin levels2828 . Wagner NM, Brandhorst G, Czepluch F, Lankeit M, Eberl C, Herzberg
S et al. Circulating regulatory T cells are reduced in obesity and may identify
subjects at increased metabolic and cardiovascular risk. Obesity (Silver
Spring). 2013;21(3):461-8. http://dx.doi.org/10.1002/oby.20087
https://doi.org/10.1002/oby.20087...
. Leptin has
also been found to promote Th17 inflammatory responses in normal human CD4(+) T
cells and in mice, both in vitro and in vivo2929 . Deng J, Liu Y, Yang M, Wang Z, Zhang M, Wang X et al. Leptin
exacerbates collagen-induced arthritis via enhancement of Th17 cell response.
Arthritis Rheum. 2012;64(11):3564-73.
http://dx.doi.org/10.1002/art.34637
https://doi.org/10.1002/art.34637...
,3030 . Yu Y, Liu Y, Shi FD, Zou H, Matarese G, La Cava A. Cutting edge:
Leptin-induced RORγt expression in CD4+ T cells promotes Th17 responses in
systemic lupus erythematosus. J Immunol. 2013;190(7):3054-8.
http://dx.doi.org/10.4049/jimmunol.1203275
https://doi.org/10.4049/jimmunol.1203275...
. Leptin is also a major contributor to vascular
damage in obesity-related cardiovascular diseases, which are not the subject of the
present review3131 . Pucino V, De Rosa V, Procaccini C, Matarese G. Regulatory T cells,
leptin and angiogenesis. Chem Immunol Allergy. 2014;99:155-69.
http://dx.doi.org/10.1159/000353557
https://doi.org/10.1159/000353557...
. However, it is
clear that cardio and cerebrovascular complications in a patient with MS represent
an extra burden on the patient, the family and society.
Vitamin A
Retinoic acid (RA), the active metabolite of vitamin A, modulates the functional
balance between Th1, Th2, Th17, Tregs, B cells and dendritic cells3232 . Fragoso YD, Stoney PN, McCaffery PJ. The evidence for a beneficial
role of vitamin A in multiple sclerosis. CNS Drugs. 2014;28(4):291-9.
http://dx.doi.org/10.1007/s40263-014-0148-4
https://doi.org/10.1007/s40263-014-0148-...
. RA plays a major role both in
increasing tolerance and in decreasing inflammation, and RA synthesis may be
manipulated by the complex cross-talk among cells during infection and
inflammation3333 . Hall JA, Grainger JR, Spencer SP, Belkaid Y. The role of retinoic
acid in tolerance and immunity. Immunity. 2011;35(1):13-22.
http://dx.doi.org/10.1016/j.immuni.2011.07.002
https://doi.org/10.1016/j.immuni.2011.07...
.
Specific receptors for RA, namely RXRγ, can promote remyelination by acting on
oligodendrocytic precursor cells3434 . Huang JK, Jarjour AA, Nait Oumesmar B, Kerninon C, Williams A,
Krezel W, et al. Retinoid X receptor gamma signaling accelerates CNS
remyelination. Nat Neurosci. 2011;14(1):45-53.
http://dx.doi.org/10.1038/nn.2702
https://doi.org/10.1038/nn.2702...
. It has long been known that RA suppresses development of
autoimmune experimental encephalitis (EAE) in rats3535 . Massacesi L, Castigli E, Vergelli M, Olivotto J, Abbamondi AL,
Sarlo F et al. Immunosuppressive activity of 13-cis-retinoic acid and prevention
of experimental autoimmune encephalomyelitis in rats. J Clin Invest.
1991;88(4):1331-7. http://dx.doi.org/10.1172/JCI115438
https://doi.org/10.1172/JCI115438...
in association with increased IL-4 levels in the
animal3434 . Huang JK, Jarjour AA, Nait Oumesmar B, Kerninon C, Williams A,
Krezel W, et al. Retinoid X receptor gamma signaling accelerates CNS
remyelination. Nat Neurosci. 2011;14(1):45-53.
http://dx.doi.org/10.1038/nn.2702
https://doi.org/10.1038/nn.2702...
.
Although studies on vitamin A supplementation are at a nascent stage, it is reasonable to maintain normal retinol values in the plasma of patients with MS. Intake of foods that are rich in carotenoids and retinyl esters, which are both precursors of retinol, must be encouraged. Serum levels of retinol should be assessed in the same manner in which vitamin D metabolites are now regularly assessed in patients with MS. It is important to highlight that no supplementation with vitamin A has ever been tested or proven effective for the treatment of MS and excess vitamin A can be fatal.
Vitamin D
Over the last decades, studies on vitamin D, immune-mediated diseases, cancer and bone metabolism have shown that homeostasis of vitamin D is crucial.
Vitamin D is almost immediately hydrolyzed in the liver by 25-hydroxylase to 25-hydroxyvitamin D (25(OH)D). This circulating metabolite of vitamin D best reflects the vitamin D status of the patient, but 25(OH)D can be further hydrolyzed to 1,25-dihydroxyvitamin D (1,25(OH)2D) or calcitriol. This is the biologically active metabolite of vitamin D3636 . Racke MK, Burnett D, Pak SH, Albert PS, Cannella B, Raine CS et al. Retinoid treatment of experimental allergic encephalomyelitis. IL-4 production correlates with improved disease course. J Immunol. 1995;154(1):450-8..
Vitamin D is a hormone with important immunological roles. IL-10 expression is
induced by 1,25(OH)2D in different cells of the immune system. Vitamin D
has a direct effect on naive CD4(+) T cells, leading to development of Th2
cells3737 . Smolders J, Damoiseaux J, Menheere P, Hupperts R. Vitamin D as an
immune modulator in multiple sclerosis, a review. J Neuroimmunol.
2008;194(1-2):7-17.
http://dx.doi.org/10.1016/j.jneuroim.2007.11.014
https://doi.org/10.1016/j.jneuroim.2007....
. Macrophages
conditioned with 1,25(OH)2D3 potently suppressed the
expression of pro-inflammatory parameters such as TNFα, IL-12 and inducible NO
synthase (iNOS)3838 . Boonstra A, Barrat FJ, Crain C, Heath VL, Savelkoul HF,
O’Garra A. 1α, 25-dihydroxyvitamin d3 has a direct effect on naive
CD4(+) T cells to enhance the development of Th2 cells. J. Immunol.
2001;167(9):4974-80.
http://dx.doi.org/10.4049/jimmunol.167.9.4974
https://doi.org/10.4049/jimmunol.167.9.4...
,3939 . Korf H, Wenes M, Stijelmans B, Takiishi T, Robert S, Miani M et
al. 1,25-Dihydroxyvitamin D3 curtails the inflammatory and T cell stimulatory
capacity of macrophages through an IL-10-dependent mechanism. Immunobiology.
2012;217(12):1292-300.
http://dx.doi.org/10.1016/j.imbio.2012.07.018
https://doi.org/10.1016/j.imbio.2012.07....
.
Low serum levels of 25-hydroxyvitamin D (25[OH]-D) were found to correlate
with MS activation and progression over five years in a large population of
individuals presenting a first demyelinating episode4040 . Ascherio A, Munger KL, White R, Köchert K, Simon KC, Polman
CH, et al. Vitamin D as an early predictor of multiple sclerosis activity and
progression. JAMA Neurol. 2014;71(3):306-14.
http://dx.doi.org/10.1001/jamaneurol.2013.5993
https://doi.org/10.1001/jamaneurol.2013....
. This finding was independent of treatment with
interferon beta. Vitamin D3 add-on treatment to interferon beta reduced the activity
of MS in relation to patients treated only with interferon beta, as assessed by
magnetic resonance imaging4040 . Ascherio A, Munger KL, White R, Köchert K, Simon KC, Polman
CH, et al. Vitamin D as an early predictor of multiple sclerosis activity and
progression. JAMA Neurol. 2014;71(3):306-14.
http://dx.doi.org/10.1001/jamaneurol.2013.5993
https://doi.org/10.1001/jamaneurol.2013....
,4141 . Soilu-Hänninen M, Aivo J, Lindström BM, Elovaara I,
Sumelahti ML, Färkkilä M et al. A randomised, double blind, placebo
controlled trial with vitamin D3 as an add-on treatment to interferon β-1b
in patients with multiple sclerosis. J Neurol Neurosurg Psychiatr.
2012;83(5):565-71. http://dx.doi.org/10.1136/jnnp-2011-301876
https://doi.org/10.1136/jnnp-2011-301876...
. On the other hand, there are also very sound studies
showing that vitamin D has a disputable relation to MS4242 . Antico A, Tampoia M, Tozzoli R, Bizzaro N. Can supplementation
with vitamin D reduce the risk or modify the course of autoimmune diseases? A
systematic review of the literature. Autoimmun Rev. 2012;12(2):127-36.
http://dx.doi.org/10.1016/j.autrev.2012.07.007
https://doi.org/10.1016/j.autrev.2012.07...
,4343 . Theodoratou E, Tzoulaki I, Zgaga L, Ioannidis JP. Vitamin D and
multiple health outcomes: umbrella review of systematic reviews and
meta-analyses of observational studies and randomised trials. BMJ.
2014;348:g2035. http://dx.doi.org/10.1136/bmj.g2035
https://doi.org/10.1136/bmj.g2035...
.
Even if an association between MS and vitamin D is considered to exist, the correct
manner in which to proceed with supplementation, if necessary, remains a matter to
be clarified in the future4444 . Simon KC, Munger KL, Ascherio A. Vitamin D and multiple sclerosis:
epidemiology, immunology, and genetics. Curr Opin Neurol. 2012;25(3):246-51.
http://dx.doi.org/10.1097/WCO.0b013e3283533a7e
https://doi.org/10.1097/WCO.0b013e328353...
.
However, it is advisable that patients with MS should maintain normal serum levels
of vitamin D, and be encouraged to eat foods that are sources of this vitamin.
Moderate sun exposure at early hours of the day is also essential if vitamin D
levels are to be corrected.
It is important to observe that 1,25(OH)2D and RA have synergistic effects
on the regulation of T cells, in particular Th174545 . Ikeda U, Wakita D, Ohkuri T, Chamoto K, Kitamura H, Iwakura Y et
al. 1alpha,25-Dihydroxyvitamin D3 and all-trans retinoic acid synergistically
inhibit the differentiation and expansion of Th17 cells. Immunol Lett.
2010;134(1):7-16. http://dx.doi.org/10.1016/j.imlet.2010.07.002
https://doi.org/10.1016/j.imlet.2010.07....
. To give supplements of one vitamin and not the other
may negatively influence their effects on Th17 cell-related immune diseases3232 . Fragoso YD, Stoney PN, McCaffery PJ. The evidence for a beneficial
role of vitamin A in multiple sclerosis. CNS Drugs. 2014;28(4):291-9.
http://dx.doi.org/10.1007/s40263-014-0148-4
https://doi.org/10.1007/s40263-014-0148-...
,3333 . Hall JA, Grainger JR, Spencer SP, Belkaid Y. The role of retinoic
acid in tolerance and immunity. Immunity. 2011;35(1):13-22.
http://dx.doi.org/10.1016/j.immuni.2011.07.002
https://doi.org/10.1016/j.immuni.2011.07...
. It is, therefore, likely that vitamin D
supplementation will be less effective in patients with MS whose levels of vitamin A
are insufficient. In fact, dietary intake of all vitamins should be encouraged
rather than supplementation with pills.
It is also of importance to emphasize that high doses of vitamin D are hazardous and should not be used, especially because there is no scientific evidence of its efficacy.
Exercise
Exercise in MS is more than rehabilitation. It is a form of treatment that does not
lead to adverse events and can be quite inexpensive. Several types of exercises have
been studied, and aerobic training, endurance exercises, exercise classes, aquatic
exercises and yoga have all been shown to be beneficial in relation to several
aspects of the disease, including fatigue, depression and disability4646 . Sá MJ. Exercise therapy and multiple sclerosis : a systematic
review. J Neurol. 2013;261(9)1651-61.
http://dx.doi.org/10.1007/s00415-013-7183-9
https://doi.org/10.1007/s00415-013-7183-...
. Exercise induces favorable
changes in T cells by reducing plasma levels of interferon gamma and IL-174747 . Golzari Z, Shabkhiz F, Soudi S, Kordi MR, Hashemi SM. Combined
exercise training reduces IFN-γ and IL-17 levels in the plasma and the
supernatant of peripheral blood mononuclear cells in women with multiple
sclerosis. Int Immunopharmacol. 2010;10(11):1415-9.
http://dx.doi.org/10.1016/j.intimp.2010.08.008
https://doi.org/10.1016/j.intimp.2010.08...
. Secondary benefits from regular
physical activities include somatic-affective improvement in mood4848 . Swank C, Thompson M, Medley A. Aerobic exercise in people with
multiple sclerosis: its feasibility and secondary benefits. Int J MS Care.
2013;15(3):138-45. http://dx.doi.org/10.7224/1537-2073.2012-037
https://doi.org/10.7224/1537-2073.2012-0...
. In fact, exercise and physical
activity may have beneficial effects on depression symptoms that are comparable to
those of antidepressant treatments4949 . Dinas PC, Koutedakis Y, Flouris AD. Effects of exercise and
physical activity on depression. Ir J Med Sci. 2011;180(2):319-25.
http://dx.doi.org/10.1007/s11845-010-0633-9
https://doi.org/10.1007/s11845-010-0633-...
.
Low salt diet, omega-3 and probiotics
High salt (sodium chloride) diet has been shown to boost the induction of Th17
lymphocytes both in animal models and in humans5050 . Kleinewietfeld M, Manzel A, Titze J, Kvazan H, Yosef N, Linker RA
et al. Sodium chloride drives autoimmune disease by the induction of pathogenic
TH17 cells. Nature. 2013;496(7446):518-22.
http://dx.doi.org/10.1038/nature11868
https://doi.org/10.1038/nature11868...
,5151 . Wu C, Yosef N, Thalhamer T, Zhu C, Xiao S, Kishi Y et al.
Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1.
Nature. 2013;496(7446):513-7.
http://dx.doi.org/10.1038/nature11984
https://doi.org/10.1038/nature11984...
. The Th17 cells generated under high-salt diet appear
to be highly pathogenic and related to pro-inflammatory cytokines. Although still an
experimental observation that needs epidemiological confirmation, it is important to
alert the patients about this potentially hazardous factor.
A diet rich in omega-3 unsaturated fatty acids, polyphenols and probiotics has been
described to influence the development and character of regulatory T lymphocytes, or
T regs5252 . Issazadeh-Navikas S, Teimer R, Bockermann R. Influence of dietary
components on regulatory T cells. Mol Med. 2012;18(1):95-110.
http://dx.doi.org/10.2119/molmed.2011.00311
https://doi.org/10.2119/molmed.2011.0031...
,5353 . Kim W, Lee H. Advances in nutritional research on regulatory
T-cells. Nutrients. 2013;5(11):4305-15.
http://dx.doi.org/10.3390/nu5114305
https://doi.org/10.3390/nu5114305...
.
Alcohol
A dose-dependent association between alcohol consumption and the risk of developing
MS has been shown recently5454 . Hedström AK, Hillert J, Olsson T, Alfredsson L. Alcohol as a
modifiable lifestyle factor affecting multiple sclerosis risk. JAMA Neurol.
2014;71(3):300-5.
http://dx.doi.org/10.1001/jamaneurol.2013.5858
https://doi.org/10.1001/jamaneurol.2013....
.
Patients with MS seem to have a tendency to misuse alcohol, but only very few
studies have been carried out on the subject5555 . Beier M, D'Orio V, Spat J, Shuman M, Foley FW. Alcohol and
substance use in multiple sclerosis. J Neurol Sci. 2014;338(1-2):122-7.
http://dx.doi.org/10.1016/j.jns.2013.12.029
https://doi.org/10.1016/j.jns.2013.12.02...
. At least in vitro, ethanol can
induce a cytokine profile consistent with a Th17 regulatory phenotype5656 . Freysdottir J, Sigurpalsson MB, Omarsdottir S, Olafsdottir ES,
Vikingsson A, Hardardottir I. Ethanol extract from birch bark (Betula pubescens)
suppresses human dendritic cell mediated Th1 responses and directs it towards a
Th17 regulatory response in vitro. Immunol Lett. 2011;136(1):90-6.
http://dx.doi.org/10.1016/j.imlet.2010.12.009
https://doi.org/10.1016/j.imlet.2010.12....
. A further complication of the
long-term alcohol consumption in patients is, obviously, the cognitive alterations
induce both by ethanol and MS.
DISCUSSION
The pathogenic inflammatory aspects of MS are of major importance regarding
treatment. The presently approved treatments are all anti-inflammatory and have
variable efficacy, which generally speaking, is positively associated with the
severity of side effects. To declare that a patient is not responsive to a
particular treatment implies that all possible ways of controlling the inflammation
have been taken into consideration. Modifiable factors could be specifically
discussed with the patient during routine consultations. Although most patients seem
to be willing to receive high doses of vitamin D (even megadoses, without any
scientific evidence for their use), not too many patients seem to be willing to stop
smoking, drinking, starting with exercise and weight loss programs. In fact, there
are reports clearly showing that patients are willing to run the risk of
life-endangering side effects from immunosuppressive drugs for MS in order to
continue with the treatment5757 . Kachuck NJ. When neurologist and patient disagree on reasonable
risk: new challenges in prescribing for patients with multiple sclerosis.
Neuropsychiatr Dis Treat. 2011;7:197-208.
http://dx.doi.org/10.2147/NDT.S17522
https://doi.org/10.2147/NDT.S17522...
,5858 . Heesen C, Kleiter I, Nguyen F, Schäffler N, Kwasper J,
Köpke S, et al. Risk perception in natalizumab-treated multiple sclerosis
patients and their neurologists. Mult Scler. 2010;16(12):1507-12.
http://dx.doi.org/10.1177/1352458510379819
https://doi.org/10.1177/1352458510379819...
. Furthermore, thousands of patients with MS worldwide were
found to be willing to submit themselves to a vascular surgical procedure to treat
their MS for which there was no scientific basis5959 . Valdueza JM, Doepp F, Schreiber SJ, Oosten BW, Schmierer K, Paul F
et al. What went wrong? The flawed concept of cerebrospinal venous
insufficiency. J Cereb Blood Flow Metab. 2013;33(5):657-68.
http://dx.doi.org/10.1038/jcbfm.2013.31
https://doi.org/10.1038/jcbfm.2013.31...
. The evidence arising from these events therefore begs
the following questions: Should modifiable factors be so difficult to modify, given
that the methods are inexpensive and safe? Are we doing enough to resist the
introduction of immunosuppressive treatment for patients with MS?
Introduction of a diet rich in vitamins A and D can contribute towards weight loss.
Exercise will be beneficial both for the disease and for weight management. With a
healthier lifestyle, better nutrient intake and regular exercise, the patient is
likely to be less resistant to stopping smoking and drinking. It is perhaps time to
consider more than just supplementation of vitamin D for patients with MS6060 . Pekmezovic T, Drulovic J, Milenkovic M, Jarebinski M,
Stojsavljevic N, Mesaros S et al. Lifestyle factors and multiple sclerosis: a
case-control study in Belgrade. Neuroepidemiology. 2006;27(4):212-6.
http://dx.doi.org/10.1159/000096853
https://doi.org/10.1159/000096853...
,6161 . Salzer J, Biström M, Sundström P. Vitamin D and multiple
sclerosis: where do we go from here? Expert Rev Neurother. 2014;14(1):9-18.
http://dx.doi.org/10.1586/14737175.2014.864952
https://doi.org/10.1586/14737175.2014.86...
. In fact, single supplementation of vitamin D
(often at high doses or even megadoses) may alter the delicate immunological
homeostasis that occurs between vitamin D and vitamin A3333 . Hall JA, Grainger JR, Spencer SP, Belkaid Y. The role of retinoic
acid in tolerance and immunity. Immunity. 2011;35(1):13-22.
http://dx.doi.org/10.1016/j.immuni.2011.07.002
https://doi.org/10.1016/j.immuni.2011.07...
. Other life style habits, such as chronic
caffeine ingestion, may also be related to the development of MS and further
research into other modifiable factors is urgently needed. The criteria for
therapeutic failure of a treatment are clearly related to inflammation and its lack
of control, e.g., relapses and lesions in the brain and spinal cord6262 . Graber JJ, Dhib-Jalbut S. Biomarkers of disease activity in
multiple sclerosis. J Neurol Sci. 2011;305(1-2):1-10.
http://dx.doi.org/10.1016/j.jns.2011.03.026
https://doi.org/10.1016/j.jns.2011.03.02...
. Thus, if a patient does not
respond well to a given treatment, perhaps we should ask ourselves whether
everything that could be done to decrease inflammation has indeed been done. At the
same time, in our daily practice, we should encourage all patients to modify the
factors that prolong their exposure to inflammatory cytokines since the very
beginning of the disease. In time, perhaps we will see that our future rate of
non-responders may not the same we have now.
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Publication Dates
-
Publication in this collection
Nov 2014
History
-
Received
18 June 2014 -
Reviewed
16 Aug 2014 -
Accepted
04 Sept 2014