RECURRENT APHTHOUS STOMATITIS – ETIOLOGY, SERUM AUTOANTIBODIES, ANEMIA, HEMATINIC DEFICIENCIES, AND MANAGEMENT

Kleinman et al.

2

reported a point prevalence

of 1.23% and a lifetime prevalence of 36.5% for RAS in 40,693 USA school children.

In Taiwan, the prevalence of RAS is 10.5% in the general population.

3

Classification of recurrent aphthous stomatitis

Three types of RAS, namely minor, major, and herpetiform types, are

recognized.

Minor RAS is the most common type that occurs in 80% of RAS

patients. The oral ulcerative lesions of minor RAS measure between 3 mm and 10 mm

in diameter. They usually arise from the nonkeratinized oral

mucosae

with the buccal

and labial mucosae being affected frequently. The lesion may be preceded by an

erythematous macule with the

prodromal symptoms

of burning or stinging for a few

hours to one or two days. Then, the

oral ulceration

appears and is subsequently

covered by a yellow-white fibrinopurulent pseudomembrane. The oral ulcers heal

without scarring in 7–14 days. Although the minor RAS lesion is small, the pain is

often out of proportion for the size of the

ulceration

.

The oral ulcerative lesions of major RAS measure from 1 cm to 3 cm in

diameter. They usually take 2–6 weeks to heal and may lead to scarring. The labial

mucosa,

soft palate

, and tonsillar fauces are most frequently involved. In severe cases,

the repeated scarring processes may result in a limitation of mouth opening.

Herpetiform RAS has the greatest number of

oral lesions

and the most

frequent recurrences. Their oral ulcerative lesions vary from 1 mm to 3 mm in

diameter and some of them may coalesce into larger irregular ulcerations. The oral

ulcerations heal between 7 and 10 days. The herpetiform RAS has a female

predilection and a typical onset in adulthood. Herpetiform RAS

oral lesions

may be

confused with those of herpes simplex virus (HSV) type 1 (HSV-1 or HHV-1)

infection. However, the herpetiform RAS lesions are commonly found on

nonkeratinized

oral mucosae

and the HSV-1 lesions are often present on keratinized

oral mucosae such as

and

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Etiology of recurrent aphthous stomatitis

RAS belongs to the group of chronic, inflammatory, ulcerative diseases of the

oral mucosa. Up to date, the etiopathogenesis of this disease remains unclear;

however, it is considered to be multifactorial.

The results of previous studies indicate

that genetically mediated disturbances of the innate and acquired immunity play an

important role in the

disease development

. Factors that modify the immunologic

responses in RAS include

genetic predisposition

, viral and bacterial infections,

food

allergies

, vitamin and microelement deficiencies,

systemic diseases

, hormonal

imbalance, mechanical

injuries

, and stress.

For the

genetic predisposition

, the positive family history of the RAS was

reported in 24%–46% of RAS cases.

5

6

The patients with a positive family history

of RAS suffer more frequent recurrences and more severe course of the disease

compared to those with a negative RAS family history.

Furthermore, in both

RAS and

Behcet's disease

, the risk of the disease development was higher

in

than in

The

that

modify the individual susceptibility to RAS include various

DNA polymorphisms

in

patients, especially those related with the alterations in the metabolism

of

interleukins

(IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12), interferon (IFN)-γ, and

tumor necrosis factor (TNF)-α, can modify the individual susceptibility to RAS.

Our

previous studies showed a strong association of HLA-DRw9 with RAS in Chinese

patients and a strong association of anti-epithelial

cell antibodies

with HLA-DR3 or

DR7 phenotype in RAS patients.

11

12

In addition, our previous study also demonstrated that the phenotype

frequencies of HLA-DR5, -DRw8 and -DQw1 as well as the haplotype frequencies

of HLA-DR5/DQw1 and HLA-DRw8/DQw1 in patients with the mucocutaneous

type of

Behcet's disease

are significantly higher than those in RAS patients.

Moreover, the relative risks of HLA-DR5/DQw1 and HLA-DRw8/DQw1 haplotypes

are greater than the relative risks of HLA-DR5, HLA-DRw8, and HLA-DQw1

antigens. These results suggest that some specific HLA-DR/DQ haplotypes may be

more important than the individual HLA-DR and HLA-DQ phenotypes in the disease

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shift from RAS to the mucocutaneous type of BD.

13

In RAS patients, higher

incidences of HLA-A33, HLA-B35 and HLA-B81,

14

HLA-B12,

15

HLA-B51,

16

HLA-

DR7 and HLA-DR5

17

18

are observed when compared to healthy control subjects.

Bacterial (

Streptococcus oralis

Helicobacter pylori

) and viral (HSV,

varicella-zoster virus,

cytomegalovirus

, and adenoviruses) antigens have been

reported to be potential factors that may modify the immunologic response and

subsequently induce recurrent aphthae in predisposed subjects. However, the results

of these studies are ambiguous and conflicting.

In addition, Greenspan

et al.

19

concluded that neither cell-mediated hypersensitivity to streptococcal or viral

antigens nor cross-reactivity between oral mucosal and

streptococcal antigens

is

likely to play a role in the pathogenesis of RAS.

Deficiencies of

hematinics

(iron, vitamin

B12

, and folic acid) and zinc have

been demonstrated in some RAS patients, but it has not been well explained why the

hematinic deficiencies may influence on the course of immune response in RAS.

We

tried to explain why

anemia

and hematinic deficiencies might cause the occurrence

of RAS.

Deficiencies of iron, vitamin

B12

, or

folic acid

may lead to anemia in RAS

patients. Because RAS patients with anemia have reduced capacity of the blood to

carry oxygen to oral mucosa, finally resulting in atrophy of oral mucosa.

Moreover,

iron is essential to the normal functioning of oral epithelial cells,

21

and both vitamin

B12

and

folic

acid

play

important

roles

in

DNA

synthesis

and

cell

division.

22

23

Oral epithelial cells have a high turnover rate. Therefore, deficiencies

of iron, vitamin B12, and folic acid may result in oral epithelial atrophy. Atrophic oral

epithelium in hematinic-deficient patients may explain why some patients with

deficiencies

of

hematinics

are

prone

to

have

RAS.

Furthermore,

high

blood

homocysteine

level (due to deficiencies of mainly

vitamins B6

and B12 and

folic acid) in some RAS patients may result in an elevated frequency of thrombosis

in the feeding

arterioles

that supply the oral epithelial cells.

This in

turn leads to a breakdown of oral epithelium and finally produces an

oral ulceration

.

Taken

these

together,

anemia,

hematinic

deficiencies,

and

a

high

blood

homocysteine

level can decrease oral epithelial barrier and thus increase the

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frequency of RAS occurrence.

In addition, Volkov et al.

29

found that oral vitamin

B12 supplementation can improve the

symptoms and signs

of RAS regardless of the

initial serum levels of vitamin B12. This finding also confirms the role of

vitamin B12

deficiency

in the development of RAS.

Some previous studies mentioned that exposure to some specific ingredients

(e.g., chocolate,

gluten

cow milk

, preservatives, nuts, and food coloring agents) may

induce RAS.

However, a previous double-blind study did not confirm the role of

specific food ingredient allergy in the development of RAS.

30

Some

patients

with

systemic

diseases

inflammatory bowel diseases

especially

the

Behcet's

disease,

(Crohn's disease, ulcerative colitis),

celiac

disease

, and immunodeficiency virus (HIV) disease, are prone to have

RAS.

Moreover, RAS is one of the criteria for the diagnosis of Behcet's

disease.

inflammatory bowel diseases

Patients with

or celiac disease are more likely

to have the complications of

nutrient deficiencies

due to the

malabsorption

of

nutrients. Moreover, these patients tend to have autoimmune reactions that result in

oral aphthous ulcerations.