Is a History of Type 1 Allergic Diseases Associated with the Risk of Developing Multiple Sclerosis?

Abdulrahman Alfawzan; Saeed Alshahrani; Ahmad Alswaidan; Ala Alkharaan; Hayyaf Aldossary; Awad Almuklass

doi:10.2991/dsahmj.k.210210.001

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Volume 3, Issue 2, June 2021, Pages 60 - 65

Is a History of Type 1 Allergic Diseases Associated with the Risk of Developing Multiple Sclerosis?

Authors

Abdulrahman Alfawzan¹^{, *}^,, Saeed Alshahrani¹, Ahmad Alswaidan¹, Ala Alkharaan¹, Hayyaf Aldossary², Awad Almuklass²

¹College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia

²College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia; King Abdullah International Medical Research Center (KAIMRC), Riyadh, Saudi Arabia

^*Corresponding author. Email: alfawzan.job@gmail.com

Corresponding Author

Abdulrahman Alfawzan

Received 25 October 2020, Accepted 31 January 2021, Available Online 19 February 2021.

DOI: 10.2991/dsahmj.k.210210.001 How to use a DOI?
Keywords: Multiple sclerosis; allergy type 1; hypersensitivity; atopy; allergic diseases
Abstract: Multiple Sclerosis (MS) is an autoimmune disorder affecting the central nervous system, characterized by demyelination of the neurons with limited remyelination. There has been a rising trend toward associating a history of allergy with MS. Both MS and type 1 allergies are developed by a hyper-reactive immune system. This is further reinforced by the similar environmental and genetic factors of both diseases. This review examines the association between a history of type 1 allergic diseases and the risk of MS, as well as the influence of study location on the association. A literature search was conducted through the Saudi Digital Library search engine, which includes many databases, such as PubMed and Web of Science; articles addressing the relationship between MS and type 1 allergies were retrieved. In this review, most studies show an inverse or no association between type 1 allergy history and MS. Most articles concluded that the relationship is not statistically significant. One study stated that asthma increases MS risk. Geographical location does not influence MS and allergy association.
Copyright: © 2021 Dr. Sulaiman Al Habib Medical Group. Publishing services by Atlantis Press International B.V.
Open Access: This is an open access article distributed under the CC BY-NC 4.0 license (http://creativecommons.org/licenses/by-nc/4.0/).

1. INTRODUCTION

Multiple Sclerosis (MS) is an autoimmune disorder affecting the central nervous system, characterized by demyelination of the neurons with limited remyelination [1]. MS occurs when the immune system loses one of its unique features, self-tolerance, leading it to mistakenly attack the body’s cells and tissues [1]. Development of tolerance arises in through the central and peripheral immune systems. In central tolerance, the thymus and bone marrow participate in the early differentiation of T and B cells, respectively. The cells then leave the central sites, and peripheral tolerance ensures that any remaining self-reactive cells do not cause autoimmune disease [2]. Unfortunately, autoimmune diseases reflect a loss of self-tolerance arising from molecular mimicry, especially after infection [3,4]. Another explanation is epitope spreading, which occurs when self-epitopes are hidden from the immune system, manifested clinically as a relapsing–remitting course like MS [5,6]. When naïve T helper cells lose their self-tolerance, they react to the myelin sheath to develop T Helper 1 (Th1) cells, which produce cytokines, such as tumor necrosis factor-alpha, Interleukin 1 (IL-1), and IL6, which trigger more T cells, macrophages, and Immunoglobulin E (IgE) antibodies from B cells, causing demyelination of the myelin sheath [7,8]. In hypersensitivity type 1, Th2 cells respond to an originally harmless substance, leading to the production of IgE antibodies, which bind to different antigens, such as dust, food, and pollen, promoting the release and production of proinflammatory mediators and causing the clinical signs and symptoms of allergies [9]. Along with genetic and environmental factors, both MS and allergies are developed by a hyperreactive immune system involving T helper cells.

The relationship between MS and allergies has been tested in many studies, which have concluded that the history of allergies is inversely related to MS risk, and that Th2 allergic cells are protective against MS [10]. Furthermore, low exposure to microbes in childhood increases the risk of developing a hyperreactive immune system for both MS and allergies later [11,12].

The prevalence of MS diagnoses has increased worldwide because of the growing awareness of the disease, its signs, and symptoms, as well as improving diagnostic capability, leading to increased life expectancy. Geographically, MS incidence is higher near the north and south latitudes, which could be attributed to more sophisticated healthcare systems in those areas [13,14]. The prevalence in Saudi Arabia is 25 out of 100,000, which is relatively low [14,15]. Other factors associated with increased risk of MS include smoking [16], vitamin D deficiency [17], and viral infections (e.g., Epstein–Barr virus) [18]. Interestingly, there is a 2–4% risk of developing MS among siblings, 5% risk among dizygotic twins, and 30% among monozygotic twins [19].

Although MS is a common, disabling disease, minimal data have been collected to study the association between type 1 allergies and MS. Therefore, a literature search was conducted through the Saudi Digital Library search engine, which includes many databases, such as PubMed and Web of Science; articles addressing the relationship between MS and type 1 allergies were retrieved. This short review assesses the association between the history of allergic diseases type 1 and the risk of MS. It will also determine the influence of the geographical locations of studies on the nature of the association.

2. MATERIALS AND METHODS

We collected all articles addressing the relationship between MS and type 1 allergies. Articles were retrieved from the Saudi Digital Library and the Google Scholar database. Keywords used in the search engines were Multiple Sclerosis, Allergy, Hypersensitivity, Atopy, and Allergic Diseases. All articles addressing the relationship between MS and type 1 allergies were included. Select articles from the bibliographies were added. Limitations included (1) studies not written in English, (2) conference articles, and (3) unpublished articles. Thirty-three articles were initially retrieved, but with the literature review exclusion criteria, only 15 articles were incorporated. We read each article thoroughly prior to summarizing its salient points in a Word document. Then, we extracted the data into a table. The table shows the journal’s impact factor and the study’s name, design, location, inclusion and exclusion criteria, sample size, statistical tests, severity of allergy, types of MS, conclusion, and limitations. No statistical program was used. We excluded articles published in nonindexed journals, articles addressing the association of type 1 allergies with other autoimmune diseases, and articles whose study design had no comparison groups.

3. RESULTS

Although one study suggested the possibility of a risk association, six concluded that allergies tend to be inversely associated with MS, and 11 studies indicated no association between allergies and MS. The Odds Ratios (ORs) are shown in Table 1. The asthma OR was associated with a higher risk of developing MS in Australia [20]. Four studies in the UK [21], the USA [22], a meta-analysis [23], and France [24] showed no risk of MS among asthma patients. Two studies in Italy [25,26] concluded that asthma tends to be protective against developing MS. Moreover, respiratory allergies, including asthma and allergic rhinitis, showed an inverse association with MS in USA, Iran, and Italy [26–28]. Whereas allergic rhinitis showed an inverse association in Iran [27] and Italy [25], no relationship was found in Australia [20], the UK [21], the USA [22], or in a meta-analysis [23]. In two US studies [22,29], a history of food and drug allergies [22] showed no MS risk relation, but in Iran [27], a food or drug allergy history showed an inverse association. Four studies [21,23,26,29] evaluated the risk of developing MS in patients with a history of skin allergies such as urticaria and eczema. None of the studies found a relation.

Study, year, site	Cases:controls	Types of allergy	OR (95% CI)
Ponsonby et al. [20], 2006, Australia	34:46	Asthma	1.67 (1.00–2.80)
	51:98	Allergic rhinitis	1.05 (0.68–1.62)
	22:34	All allergies	1.36 (0.75–2.47)
Ansari et al. [31], 1976, Iran	49:85	Asthma, allergic rhinitis	0.44 (0.28–0.70)
Ansari et al. [31], 1976, Iran	16:53	Food or drug allergy	0.23 (0.12–0.43)
Bergamaschi et al. [25], 2009, Italy	4:7	Asthma	0.41 (0.11–1.47)
Bergamaschi et al. [25], 2009, Italy	19:47	Allergic rhinitis	0.27 (0.14–0.50)
Strandgaard and Jørgensen [32], 1972, USA		Asthma, URTI, bronchitis	0.38 (0.19–0.77)
Strandgaard and Jørgensen [32], 1972, USA		All other allergies	0.29 (0.18–0.49)
Pedotti et al. [26], 2009, Italy	36:88	Atopic^a	0.58 (0.38–0.89)
Pedotti et al. [26], 2009, Italy	70:87	Nonatopic^b	1.13 (0.79–1.63)
Alonso et al. [21], 2006, UK	8:68	Allergic rhinitis	1.1 (0.5–2.3)
	5:38	Urticaria	1.2 (0.5–3.2)
	8:84	Asthma	0.9 (0.4–2.0)
	14:128	Eczema	1.1 (0.6–1.9)
	3:9	Other allergies	2.5 (0.6–11.3)
Alonso et al. [22], 2008, USA	91:409	Pollens	1.0 (0.7–1.3)
	53:237	House dust	1.0 (0.7–1.4)
	51:170	Animal dander	1.3 (0.9–1.9)
	34:173	Foods	0.9 (0.6–1.3)
	138:539	Drugs	1.1 (0.8–1.5)
	91:384	Other allergies	1.0 (0.7–1.4)
	52:216	Conjunctivitis	1.1 (0.7–1.6)
	93:410	Rhinitis	1.0 (0.7–1.4)
	27:109	Asthma	1.1 (0.7–1.8)
	99:404	Hives	1.1 (0.8–1.5)
Bourne et al. [29], 2017, USA	13:37	Foods	0.61 (0.31–1.22)
	14:13	Antibiotics	2.05 (0.91–4.6)
	32:80	Environmental	0.65 (0.4–1.06)
	43:84	Skin allergy	0.81 (0.53–1.26)
	23:53	Runny nose/puffy eyes	0.72 (0.41–1.28)
Monteiro et al. [23], 2011, meta-analysis		Allergic diseases	0.91 (0.68–1.23)
		Asthma	0.83 (0.48–1.44)
		Allergic rhinitis	0.81 (0.59–1.12)
		Eczema	0.93 (0.71–1.23)

a

Atopic: asthma, rhinitis, conjunctivitis, atopic eczema/dermatitis syndrome, or food allergy with respiratory allergies.

b

Nonatopic: contact dermatitis, insect bites, medications, or food allergy without respiratory allergies.

CI, confidence interval; URTI, upper respiratory tract infections.

Table 1

Odds ratio between multiple sclerosis and different types of allergy

Six studies in France [24], Italy [25], Northern Italy [26], Iran [27], and the USA [28,29] showed an inverse association between type 1 allergies and MS (Table 2). Respiratory allergy prevalence was significantly low in MS patients in Iran [27], Italy [25], the USA [28], and Northern Italy [26]. Females with respiratory allergies tend to have less risk of developing MS than do males in France (p = 0.001) [24]. However, a case–control study (including females only) in the USA [22] concluded that there was no relationship between MS and allergies such as allergic rhinitis and asthma.

Study, year, site	Sample size	Allergy type	Results	Notes
Sahraian et al. [27], 2013, Iran	195:195	(1) Respiratory tract allergy (RTA)	History of allergy and MS (p = 0.04)	80% female participants.
		(2) Cutaneous allergy (CA)	RTA (OR = 0.43; 95% CI, 0.28–0.66; p < 0.001)	Prevalence of asthma 1:9, allergic rhinitis 49:84
		(3) Food or drug allergy (FDA) and nonspecific agent (including dust, animal dander)	FDA (OR = 0.24; 95% CI, 0.13–0.43; p < 0.001)	No OR of other allergies
Neukirch et al. [24], 1997, Paris and Toulouse	Paris 302:3152	Asthma and nasal allergies	Paris results	Did not show Toulouse results
	Paris 302:3152		Nasal allergies, p = 0.006
	Toulouse 308:3774		Females only
			(1) Asthma, p = 0.05
			(2) Nasal allergy, p = 0.001
			In Toulouse, association not statistically significant
Ren et al. [28], 2017,^a USA	829:2441	Respiratory tract allergies: asthma, URTI, and bronchitis	p = 0.039 (OR = 0.38; 0.19, 0.77)
Bergamaschi et al. [25], 2009, Italy	200:200	(1) At least one allergic respiratory disease (ARD)	ARDs (OR = 0.33, p > 0.001)	Asthma cases = 4; control = 7
		(2) Asthma	Allergic rhinitis (OR = 0.27, p > 0.001)
		(3) Allergic rhinitis	Asthma (OR = 0.41, p < 0.169)
Pedotti et al. [26], 2009,^a Northern Italy	423:643	Asthma, rhinitis, conjunctivitis, atopic eczema/dermatitis syndrome, or (food allergy with respiratory allergies)	p = 0.017
Bourne et al. [29], 2017,^a USA	418:271	Skin reaction (include rash and eczema), nose or eyes reaction (include swollen eyes and stuffy nose), gastrointestinal reaction (including vomiting and diarrhea) and anaphylactic shock	MS relapse and food allergy, p = 0.01

a

These studies have results in Table 3.

CA = urticaria, angioedema, eczema; RTA = asthma, allergic rhinitis.

Table 2

Data of case–control studies finding an inverse relation between allergy and MS

Table 3 presents the data, method, results, and limitations of 11 studies that found no relationship between MS and allergies [21–23,26,28–34]. A large Canadian population-based cohort with 6638 MS participants and 2509 controls was conducted to investigate the relationship between MS and cow milk allergies [34]. No association was found between MS and cow milk allergies during the perinatal period (males, p = 0.83; females, p = 0.61), early childhood (males, p = 0.3; females, p = 0.82), or late childhood (males, p = 0.51; females, p = 0.32). The geographical distribution showed no trends relating allergies and MS.

Study, year, site	Design	Sample size	Allergy type	p + OR
Ansari et al. [31], 1976, USA	Cohort	36:40	Asthma, hay fever or eczema, or allergy to food, dust, dyes, contrast material, or drugs	No results in manuscript
Ren et al. [28], 2017,^a USA	Case–control	829:2441	Skin allergy, eye allergy, ear allergy, and other unspecified allergies that are not respiratory	p = 0.281
Ren et al. [28], 2017,^a USA	Case–control	829:2441		OR = 0.38; 0.19–0.77
Strandgaard and Jørgensen [32], 1972, Denmark	Cohort	12:12	Hypersensitivity reaction	No results in manuscript
Alonso et al. [21], 2006, UK	Case–control	163:1523	Allergic rhinitis, asthma, urticaria/angioedema, eczema, other allergic conditions prior to the index date (date of first Sx of MS)	OR 1.1; 0.8–1.6
Karimi et al. [33], 2013, Iran	Case–control	40:40	Any allergy manifested as rhinitis conjunctivitis eczema, urticaria, or asthma. Family history of allergy IgE testing	p = 1.00
				p = 0.392 higher EDSS and allergy in MS group
				p = 0.776 MS initial symptoms and allergy
Alonso et al. [22], 2008, USA	Case–control	Primary: 294:1248	(1) Allergy to pollens, house dust, animal dander, foods, drugs, and other	OR 1.0; 0.8–1.4
		Secondary 248:248	(2) Manifested as conjunctivitis, rhinitis, asthma, hives, and other manifestation
		All participants females
Ramagopalan et al. [34] 2010, Canada	Cohort	6638:2509	Cow milk allergy	Perinatal: males p = 0.83, females p = 0.61
			Perinatal	Perinatal: males p = 0.83, females p = 0.61
			Early childhood up to 3 years	Early childhood: males p = 0.3, females p = 0.82
			Late childhood up to 11 years	Late childhood: males p = 0.51, females p = 0.32
Bourne et al. [29], 2017, USA	Case–control	418:271	Skin reaction (include rash and eczema), Nose or eyes reaction (include swollen eyes and stuffy nose), Gastrointestinal reaction (include vomiting and diarrhea) and Anaphylactic shock	Age at onset of MS (p = 0.41)
				Sex (p = 0.30)
				Race (p = 0.06)
				Ethnicity (p = 0.54)
Monteiro et al. [23], 2011	Systematic review and meta-analysis	2764:262,620	Allergic disease	Allergic diseases (OR = 0.91; 95% CI, 0.68–1.23)
			Asthma	Asthma (OR = 0.83; 95% CI, 0.48–1.44)
			Allergic rhinitis	Allergic rhinitis (OR = 0.81; 95% CI, 0.59–1.12)
			Eczema	Eczema (OR = 0.93; 95% CI, 0.71–1.23)
Ashtari et al. [30], 2013, Iran	Case–control	48:48	Cow milk allergy
Pedotti et al. [26], 2009,^a Northern Italy	Population-based case–control	423:643	Contact dermatitis, insect bites, medications, or food allergy without respiratory allergies	p = 0.503

a

This study also has results in the inverse association table.

EDSS, Expanded Disability Status Scale.

Table 3

Data of studies finding no relation between allergy and MS

4. DISCUSSION

We aimed to investigate the association between MS and type 1 allergy histories. Most studies addressed an inverse or nonstatistically significant association between type 1 allergy histories and MS.

Hygiene theory has been linked to many autoimmune diseases and allergies, including MS and asthma, emphasizing that early childhood exposure to infections can protect against subsequent autoimmune illnesses [35]. The theory also explains the increased modern prevalence of both disorders, but it has never been proven. Also, one T cell lineage produces IL-17, which induces both allergic inflammation and MS [36–38]. The results of many studies that confirmed the risk association between allergies and MS may have been biased owing to less sophisticated healthcare systems in the past, underdiagnosed allergies in rural populations, and frequent diagnosis of MS patients because of frequent hospital visits with symptoms.

Six studies (Table 2) showed an inverse association between allergies and MS. Th2 cells, which are responsible for type 1 allergies, secrete IL-4, IL-5, and IL-10, which protect against the autoimmunity damage caused by the Th1 cells responsible for MS. With regard to asthma, there are two types, nonatopic (nonallergic) and atopic (allergic). Unfortunately, only one study distinguished between the two types and showed an inverse association [27]. Further studies, both longitudinal and experimental, should be conducted to investigate the relationship.

In this short review, the limitations are methodological or attributable to fundamental issues in the collected studies. Methodological limitations include publication bias and the exclusion of non-English papers. With regard to the collected studies themselves, the limitations include the lack of diagnostic criteria for MS and allergies, the low sample size, and the failure to classify allergy severity or types of MS. Cofactors were also not mentioned, such as vitamin D deficiency, family history, ethnicity, and residence.

All studies included a comparison group that could hide genetic susceptibility, resulting in biased results. Thus, we recommend a further longitudinal, cohort study conducted only on people with MS. Also, there is a lack of studies corresponding to the severity and timing of allergic reactions or diseases with the clinical manifestations, course, and severity of MS.

5. CONCLUSION

Most studies in this review showed an inverse or a statistically nonsignificant association between type 1 allergy histories and MS. One study reported that asthma increased MS risk. Furthermore, geographical location has no influence on the relationship between MS and allergies.

CONFLICTS OF INTEREST

The authors declare they have no conflicts of interest.

AUTHORS’ CONTRIBUTION

All authors have contributed to the manuscript and fulfilled the authorship criteria. A. Alfawzan, SA, A. Alswaidan and A. Alkharaan contributes effectively in data collection and writing the first and final draft of the study. HA and A. Almuklass were responsible for conception and design of the study, and provided critical revision of the article. All authors approved the final version to be submitted.

Footnotes

Peer review under responsibility of the Dr. Sulaiman Al Habib Medical Group

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Journal: Dr. Sulaiman Al Habib Medical Journal
Volume-Issue: 3 - 2
Pages: 60 - 65
Publication Date: 2021/02/19
ISSN (Online): 2590-3349
ISSN (Print): 2666-819X
DOI: 10.2991/dsahmj.k.210210.001 How to use a DOI?
Open Access: This is an open access article distributed under the CC BY-NC 4.0 license (http://creativecommons.org/licenses/by-nc/4.0/).

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ris enw bib

TY  - JOUR
AU  - Abdulrahman Alfawzan
AU  - Saeed Alshahrani
AU  - Ahmad Alswaidan
AU  - Ala Alkharaan
AU  - Hayyaf Aldossary
AU  - Awad Almuklass
PY  - 2021
DA  - 2021/02/19
TI  - Is a History of Type 1 Allergic Diseases Associated with the Risk of Developing Multiple Sclerosis?
JO  - Dr. Sulaiman Al Habib Medical Journal
SP  - 60
EP  - 65
VL  - 3
IS  - 2
SN  - 2590-3349
UR  - https://doi.org/10.2991/dsahmj.k.210210.001
DO  - 10.2991/dsahmj.k.210210.001
ID  - Alfawzan2021
ER  -

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