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Human Antibodies 23 (2014/2015) 31–36 DOI 10.3233/HAB-150281 IOS Press

Multiple sclerosis and immunological-related risk factors: Results from a case-control study Mohammad Mahdi Eftekhariana,b,c,∗, Mehrnoush Mousavid , Mona Bahmani Hormozd , Ghodratollah Roshanaeie and Mehrdokht Mazdehf a

Faculty of Paramedicine, Hamadan University of Medical Sciences, Hamadan, Iran Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran c Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran d Hamadan University of Medical Sciences, Hamadan, Iran e Modeling of Noncommunicable diseases Research Center, Department of Biostatistics and Epidemiology, School of Public Health, Hamadan University of Medical Sciences, Hamadan, Iran f Faculty of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran b

Abstract. AIM: Multiple sclerosis is a demyeliting autoimmune inflammatory disorder of central nervous system (CNS) with unknown etiology, which afflicts more than 2.5 millions of the world’s population. The aim of this study was to investigate the association between some immunological-related risk factors (tonsillectomy, appendectomy and hepatitis B vaccination) and multiple sclerosis in 2014 in Hamadan city, west of Iran. METHODS: As a case-control study, data of filled questionnaire with written consents from 250 patients and 250 age and sex matched controls, were collected and analyzed using SPSS version 16 software and Logistic regression test. RESULTS: In both groups, the case and the control, with average age of 33 years, 70% of the participants were women. Statistical analysis showed that there was no significant association between tonsillectomy and appendectomy with the multiple sclerosis (p > 0.05). Also hepatitis B vaccination did not increase the risk of MS significantly (p > 0.05), although there was a trend toward more vaccination rate in the patients. CONCLUSION: Considering previous global investigations on this topic with the result of our study, it seems more studies are needed to determine the definitive association between tonsillectomy, appendectomy and hepatitis B vaccination with multiple sclerosis. Keywords: Multiple sclerosis, tonsillectomy, appendectomy, hepatitis B vaccine, risk factors

1. Background Multiple sclerosis (MS) as a demyeliting inflammatory disorder of CNS with unknown etiology is considered to be a complex or multifactorial autoimmune disease that is not ascribable to a single genetic or environmental factor. Indeed scientists believe that some ∗ Corresponding author: M.M. Eftekharian, Faculty of Paramedicine, Hamadan University of Medical Sciences, Fahmideh Blvd., Hamadan, Iran. Tel.: +98 8138381037; Fax: +98 8138381017; E-mail: [email protected]

complicated interactions between genes function and environmental factors lead to tissue injury by autoimmune mechanisms, implicated by strong circumstantial evidences [1]. Based on valid reports, MS is the second leading cause of disability after trauma among young adults [2]. Initially, a T-cell–mediated autoimmunity originated from aberrant immune response to myelin antigens, with the classic paradigm of a shift toward Th1/17 vs. Th2 may be the inducing event [2,3]. In this condition, proinflammatory cytokines induced by Th1/17 axis and recruitment of inflammatory cells into the CNS through blood brain barrier have central

c 2014/2015 – IOS Press and the authors. All rights reserved ISSN 1093-2607/14/15/$35.00 

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M.M. Eftekharian et al. / Immunological-related risk factors and Multiple sclerosis

role in induction of pathological face of MS. Four main patterns of MS are recognized: relapsing remitting (as most common clinical pattern), primary progressive, secondary progressive and progressive relapsing [4]. It is evident that comprehensive knowledge about relative risk factors gives us new insights into the underlying definite causes of the disease. Furthermore this information may decrease the incidence of MS using programmed and useful instruction in preventive methods. According to the aforementioned, several studies about different risk factors and their relations with MS have been performed in different areas of the world. The controversial results related to different areas have demonstrate that some risk factors are geographically limited and we cannot generalize them to other parts of the world, because of the effectiveness of some known and unknown area-dependant factors. The risk factors which have often been considered include family history (genetic) [5–8], neuropsychological conditions [9–13], history of particular infections [14–17], vitamin D deficiency [18–23] and smoking [24–28]. Since MS as a autoimmune disease originates from dysregulation of immune responses, we decided to investigate any possible association between some immunological-related risk factors such as tonsillectomy, appendectomy and hepatitis B vaccination with multiple sclerosis in Hamadan, a city located in the west of the Iran in 2014.

2. Methods 2.1. Patients This study was designed based on a case-control study involving incident cases of MS that were from the population referring to Hamadan multiple sclerosis society in west of Iran. The recruitment period for the controls and cases was 2014 (January to May) and written consents were obtained from both patients and controls. As mentioned above, all Referring potential cases were introduced by Hamadan multiple sclerosis society under supervision of a neurologist. Primary statistical analysis was then conducted in order to calculate the average of sex and age in the case group. A total of 250 control populations were selected by our team among apparently healthy persons matched for age and sex with the case group.

2.2. Data collection Required data about tonsillectomy, appendectomy and hepatitis B vaccination were collected by standard questionnaire in the presence of trained persons of our team. 2.3. Statistical analysis Logistic regression test was used to compare the means of the examined groups. All comparisons were two-sided. P values lower than 0.05 considered as statistical significance. The statistical software used for this analysis was SPSS version 16. Results were analyzed and studied using cross-tabulation.

3. Results All results based on completed questionnaires were cross-tabulated including sex distribution in two groups. The case and control groups include 186 and 181females respectively (74.4% and 72.4%) and the rest (25.6% and 27.6%) were males (Table 1). Also the mean age among the both groups was 33 years. The data were analyzed using SPSS version 16 software and Logistic regression test. Tonsillectomy did not show a significant association with MS (odds ratio = 1, 95% confidence interval: 0.5, 1.8) (Table 2). Similar results were obtained in another part of our study. Based on these results, we found that there is not significant association between appendectomy and MS onset (odds ratio = 1.76, 95% confidence interval: 0.95, 3.2) (Table 3). In addition, hepatitis B vaccination did not increase the risk of MS significantly (p > 0.05), although there was a trend toward more vaccination rate in the patients (odds ratio = 1.29, 95% confidence interval: 0.89, 1.78) (Table 4).

4. Discussion We have previously investigated the association between several risk factors e.g. smoking [29], level of education [30], diabetes [31], family history [31], obesity [32], hematological factor of peripheral blood [33], tonsillectomy and appendectomy [30] with rheumatoid arthritis as a Th1/Th17 mediated autoimmune disease in Hamadan located in west of Iran. In the present project we studied the association between some immunological related risk factors with MS as

M.M. Eftekharian et al. / Immunological-related risk factors and Multiple sclerosis

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Table 1 Cross-Tabulation for sex distribution in case and control groups Case

Groups Sex Male Female Total

Number 64 186 250

Control Number Percent 69 27.6 181 72.4 250 100

Percent 25.6 74.4 100

Total Number 133 367 500

Percent 26.6 73.4 100

Table 2 Cross-Tabulation between tonsillectomy and MS Studied groups Case Control Total

Tonsil status

Without tonsillectomy

With tonsillectomy

Total

Number

Percent

Number

Percent

Number

226 226 452

90.4 90.4 90.4

24 24 48

9.6 9.6 9.6

250 250 500

Odds ratio

95% confidence

Percent

(OR)

interval (CI)

100 100 100

1

0.5, 1.8

Table 3 Cross-Tabulation between appendectomy and MS Studied groups Case Control Total

Appendix status

Without appendectomy

With appendectomy

Odds ratio

95% confidence

Number

Percent

Number

Percent

Number

Total Percent

(OR)

interval (CI)

220 233 453

88 93.2 90.6

30 17 47

12 6.8 9.4

250 250 500

100 100 100

1.76

0.95, 3.2

Table 4 Cross-Tabulation between hepatitis B vaccination and MS

Studied groups Case Control Total

Hepatitis B Vaccination done vaccination status Number Percent 101 103 204

40.4 41.2 40.8

No vaccination

No information

Total

Number Percent

Number Percent

Number Percent

108 142 250

43.2 56.8 50

a widespread Th1/Th17 mediated autoimmune disease of CNS. The first part of results showed that there was not significant (p > 0.05) association between tonsillectomy and appendectomy with risk for MS in Hamadan, although there was a trend toward appendectomy in the patients. It is likely that if more people were included in the study groups, the results might show significant differences. Since, it seems that appendectomy may have a role in increasing the risk of MS. As, numerous studies have been conducted by other researchers, Lunny et al. [34] used a metaanalysis of case-control studies to investigate and examine surgery as a risk factor for MS. The scientists searched for observational studies that evaluated the risk for developing multiple sclerosis after surgery in childhood ( 20 years of age) or “premorbid” (> 20 years of age). They showed that there was a small but statistically significant association between tonsillectomy and appendectomy in individual’s  20 years

41 5 46

16.4 2 9.2

250 250 500

Odds ratio 95% confidence

100 100 100

(OR)

interval (CI)

1.29

0.89, 1.78

of age and the subsequent risk for developing MS. There was no statistically significant association between risk for MS and tonsillectomy or appendectomy occurring after age 20 and in those with adenoidectomy at  20 years of age. They also could not find any convincing evidence to support the association of other surgeries and the risk for MS. Several theories linking tonsillectomy and appendectomy to risk of MS have been presented over the years. Meurman et al. [35] proposed that tonsillectomy may increase the risk of upper respiratory tract infections. Also it can cause locally deficiency of immune system which may facilitate the invasion of an etiologically relevant infectious agents followed by onset of MS in the future. Furthermore, tonsillectomy may leave sufficient lymphoid tissue adjacent to the CNS to provoke the immune response to exaggerate and in turn auto reactivate, the phenomenon seen in MS [35,36]. Lucas et al. [37] found that based on a meta-analysis

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M.M. Eftekharian et al. / Immunological-related risk factors and Multiple sclerosis

of case-control and cohort study there is a statistically significant combined relative risk for MS in those with a history of Epstein-Barr virus (EBV) infection called infectious mononucleosis. Similar association, particularly in humoral immunity and production of autoantibodies has also been reported in some other common infections [38–41]. It seems that infection may cause immune dysregulation which leads to the onset of MS during long time [42–44]. The literature review showed that previous studies about possible association between risk of MS and appendectomy have produced inconsistent results, perhaps because they did not examine the reason underlying appendectomy [45,46]. Roshanisefat et al. [45] based on a case-control study in Sweden showed that appendectomy eventuated from perforated appendix, was inversely associated with MS, although not statistically significant (odds ratio 0.86 with 95% confidence interval of (0.70–1.04). The odds ratios were 1.04 (0.94–1.16) for appendicitis without perforation and 1.14 (0.98–1.33) for appendectomy without appendicitis. On the other hand, since appendix contains white blood cells (WBC) and acts as a reservoir for helpful bacteria for the gut, scientists consider it as a part of the body’s immune system [47]. They believe that it has a reservoir role for normal flora. When intestine is purged from bacteria caused by dysentery, the helpful bacteria are replaced from the stores in the appendix. As a result, inflammation of the appendix called appendicitis may indicate inadequate immunological function leading to immune dysregulation [45, 46,48–51]. This process may result in activation of peripheral blood mononuclear cells (PBMCs) which cause inflammatory destruction of myelin [45,48] as a trigger of MS. To explain the reason for these discrepancies, it seems that the reason underlying appendectomy should be considered. Furthermore there are some similarities between MS and appendicitis. For example both of them are categorized among autoimmune diseases which are more prevalent in industrialized countries located in North America and Europe [52,53]. Based on the hygiene hypothesis it seems that increasing the allergic and autoimmune diseases incidence may be an unanticipated consequence of advances in public health and sanitation [54,55]. In another part of our study, we found that hepatitis B vaccination did not increase the risk of MS significantly (p > 0.05), although there was a trend toward more vaccination rate in the patients. It seems that reason is due to low number of samples. So it is likely that use of groups with more population

could obtain the significant expected results. Public concern about possible increases in the risk of multiple sclerosis associated with hepatitis B vaccination followed by low vaccination coverage during recent years motivated the scientists to investigate the veracity or falsity of this idea [56]. Autoimmune reactions against vaccinations in predisposed individuals may rarely be induced by molecular mimicry or bystander activation mechanisms. These reactions are seen in Guillain-Barré syndrome, immune thrombocytopenic purpura and myopericarditis after infection to swine influenza (in 1976), measles/mumps/rubella and smallpox vaccination respectively. They are attributed to post-vaccination events result in tissue damage [57]. In this context, scientists tried to understand the suspected association between hepatitis B vaccine and multiple sclerosis, but it has not been further confirmed [57]. Mikaeloff et al. [56] investigated whether hepatitis B vaccination after a first episode of Acute CNS Inflammatory Demyelination (ACID) increased the risk of conversion to multiple sclerosis in childhood. They studied the French Kid Scled’rose en Plaques (KIDSEP) neuropaediatric cohort of patients (1994 and 2003) from their first episode of ACID until the occurrence of a second episode, up to 2005. The results showed that there was not any significant relation between vaccination against hepatitis B (or tetanus) after a first episode of ACID in childhood with increasing the risk of conversion to MS, although the possibility of a small increase in risk cannot be excluded. Two years later based on a case-control study [58] which the cases were children with a first episode of acute CNS inflammatory demyelination in France (1994–2003) it was shown that although hepatitis B vaccination did not significantly increase the risk of CNS inflammatory demyelination in childhood, The “Engerix” type of B vaccine appears to increase this risk, particularly for confirmed MS. In 2003, DeStefano et al. [59] based on a case-control study showed that vaccination against hepatitis B was not associated with an increased risk of multiple sclerosis or optic neuritis. As conclusion, despite the multiplicity of studies and with regard to the frequent discrepancies in their results which may be attributed to the methodological and/or geographical differences, it seems that more studies are needed to determine the definitive association among tonsillectomy, appendectomy and hepatitis B vaccination with multiple sclerosis.

M.M. Eftekharian et al. / Immunological-related risk factors and Multiple sclerosis

Acknowledgments The authors wish to thank all the participants of the Hamadan Multiple Sclerosis Society, Dr. Mehrdad Afshari and Dr. M. Sabouri Ghannad for their valuable helps.

Conflict of interest The authors declare that they have no competing interests.

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Multiple sclerosis and immunological-related risk factors: results from a case-control study.

Multiple sclerosis is a demyeliting autoimmune inflammatory disorder of central nervous system (CNS) with unknown etiology, which afflicts more than 2...
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