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Close Association of HLA-B52 and HLA-B44 Antigens in Israeli Arab Adolescents With Recurrent Aphthous Stomatitis
Lutfi Jaber, MD;
Abraham Weinberger, MD;
Tirza Klein, PhD;
Isaac Yaniv, MD;
Masza Mukamel, MD
Arch Otolaryngol Head Neck Surg. 2001;127:184-187.
ABSTRACT
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Objectives To investigate the incidence and clinical features of recurrent aphthous
stomatitis (RAS) among Israeli Arab adolescents and to determine the HLA typing
profile in affected subjects.
Study Design Cross-sectional study.
Setting Junior high school in the largest Arab town in Israel.
Participants Four hundred seventy-seven Israeli Arab junior high school students
filled out a questionnaire. Students who reported more than 4 episodes of
RAS during the previous year were interviewed by telephone. Those whose responses
were confirmed were invited to the clinic. Of these, 22 were chosen at random
for HLA typing. Findings were compared with those in 117 healthy Israeli Arabs
who were candidate donors of bone marrow to patients at the Institute of Hematology–Oncology,
Schneider Children's Medical Center of Israel, Petah Tiqva.
Results Recurrent aphthous stomatitis was confirmed in 80 subjects (16.7%).
Of the 22 patients who underwent HLA typing, 7 (31.4%) had HLA-B52 antigens
and 8 (36.4%) had HLA-B44 antigens; corresponding figures for the control
group were 10 subjects (8.5%) (P = .007) and 9 subjects
(7.7%) (P = .001), respectively.
Conclusions There is a close association of HLA-B52 and HLA-B44 in Israeli Arab
youths with RAS. Long-term follow-up is needed to determine the relationship
between RAS and Behçet disease.
INTRODUCTION
RECURRENT aphthous stomatitis (RAS) is a common disorder in the general
population.1 It is characterized by intermittent
episodes (ranging from days to months) of 1 or more painful ulcers in areas
of nonkeratinized mucosa, such as the buccal mucosa, floor of the mouth, and
ventral surface of the tongue. The lesions are categorized as minor, major,
and herpetiform.2 The minor form, which is
the most prevalent, is preceded by a prodromal burning sensation in the mucosa
followed within 24 to 48 hours by the appearance of shallow round or oval
ulcers less than 5 mm in diameter surrounded by an erythematous halo. Complete
healing occurs within 7 to 10 days. In the major form, which usually begins
after puberty, the ulcers are larger, deeper, last longer, and heal with scarring.
Herpetiform lesions appear in 1- to 3-mm-diameter clusters, tend to be more
common among women, and have a later onset than the other 2 forms.1
The origin of RAS is unknown, although various systemic, environmental,
immunological, and genetic factors may be implicated.1
Recently, a strong association of RAS with Behçet syndrome was observed
in Japan and the Mediterranean region including Israel.3, 4, 5, 6, 7
A high frequency of RAS has also been observed in families with Behçet
syndrome.5 Shohat-Zabarski et al5
reported a close association of HLA-B51 and RAS in the Israeli Jewish population.
The aims of this study were to investigate the incidence and clinical
features of RAS among Israeli Arab adolescents and to determine the HLA typing
profile in affected subjects.
SUBJECTS, MATERIALS, AND METHODS
The study was conducted from March 1, 1998, through December 31, 1998.
A brief questionnaire on the occurrence and frequency of aphthae was distributed
to 477 students at 1 of the 2 junior high schools in Taibe, the largest Arab
town in Israel (population, 30 000), located 40 km (25 miles) northeast
of Tel Aviv. Students who reported having more than 4 episodes of RAS during
the last year, with each episode lasting longer than 7 days, were contacted
by telephone and interviewed together with their parents to confirm their
response. Those who answered affirmatively were invited to attend the clinic,
accompanied by a parent, during an attack of aphthae for a detailed medical
history and physical examination. Only those subjects examined by one of us
(L.J.) and in whom the existence of lesions were confirmed as RAS were included
in the study. A blood sample was drawn from a random sample for HLA typing.
One hundred seventeen healthy unrelated Israeli Arabs who were candidate donors
of bone marrow to patients at the Institute of Hematology–Oncology,
Schneider Children's Medical Center of Israel, Petah Tiqva, underwent complete
HLA studies and served as control subjects.
HLA TYPING
Peripheral blood lymphocytes were separated on a Ficoll-Hypaque density
gradient. HLA-A, -B, and -C tissue typing was performed with the standard
2-stage National Institutes of Health microlymphocytotoxicity technique.8
STATISTICAL ANALYSIS
The frequency of HLA antigens in the RAS-affected and control groups
was compared using the  2 test. Odd ratios (ORs) and 95% confidence
intervals (95% CIs) were calculated from Table 1. P .05 was considered statistically
significant.
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Table 1. HLA Typing of Subjects With Recurrent Aphthous Stomatitis
(RAS) and Control Subjects
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RESULTS
Of the 477 students (98% of the school population) who completed the
brief questionnaire, 220 (46%) initially reported having RAS; this number
was reduced to 80 (16.7%) after the telephone interview. Of these, 73 (91%)
were of unrelated parents and they visited the clinic with a parent while
they had an episode. Their clinical data are given in Table 2.
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Table 2. Clinical Data of 73 Adolescents With Recurrent Aphthous Stomatitis
(RAS)
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A blood sample was drawn for HLA typing from 22 subjects, 10 male and
12 female (Table 1). The HLA-B52
antigen was found in 7 subjects (31.8%) and the HLA-B51 in 3 subjects (13.6%).
Corresponding rates in the control group were 10 subjects (8.5%) for HLA-B52
antigen and 13 subjects (11.1%) for HLA-B51 antigen; this difference was statistically
significant for HLA-B52 antigens. Subjects with HLA-B52–positive antigen
are almost 5 times at risk of developing RAS, P =
.007, OR = 4.99, 95% CI, 1.77 to 14.06. The 3 subjects with HLA-B51–positive
antigen had 1 or more relatives with Behçet syndrome. HLA-B44 antigen
was found in 8 subjects (36.4%) compared with 9 controls (7.7%). Subjects
with HLA-B44–positive antigen are almost 7 times at risk of developing
RAS, P = .001, OR = 6.86, 95% CI, 2.51 to 18.75.
Only 1 subject with HLA-B44–positive antigen also had HLA-B51–positive
antigen; the remainder had HLA-B51– and HLA-B52–negative antigen.
COMMENT
The findings of our study show a high frequency of RAS in the Arab adolescent
population in Israel. An almost equal number of male and female subjects were
affected. The mean age at first onset was 9.8 years. Our data represent a
range of 1 to 5 lesions (mean number of lesions, 2.9) per episode and the
duration of symptoms ranged from 7 to 30 days (mean number of days, 9.9),
which is higher than the 7 to 14 days described by Antoon and Miller.2 Many of the affected subjects (72%) had a family history
of RAS, and a high percentage of these subjects were positive for HLA-B52
and HLA-B44 antigens.
Our finding of a 16.7% incidence of RAS was based on strict inclusion
criteria: 4 or more yearly RAS episodes of more than 7 days' duration each.
We also examined the subjects and personally interviewed them with 1 of their
parents. Studies of RAS in different populations have reported rates of 2%
in Sweden to 60% in other countries1; the wide
range was probably because of the differences in the methods used. One work9 spanning 30 countries on 6 continents reported a prevalence
rate of 38.7% in male subjects and 49.2% in female subjects. The frequency
and severity were directly related to socioeconomic status.10
Most cases of RAS are primary or idiopathic. Many factors are suspected
to contribute to the disorder, such as systemic disease, trauma, smoking,
and stress9; the exact origin is unknown. The
pathogenesis is immunologically mediated, but no convincing theory of immunopathogenesis
has as yet been suggested.
The high rate (73%) of a positive family history in our study raises
the possibility of a genetic basis for RAS transmission. Previous studies
have suggested that RAS susceptibility may involve a complex interaction between
host and environment.11 This theory is supported
by the sudden increase in disease after the age of 5 years and the significant
association between the prevalence of disease in children and its presence
in none, 1, or both parents.11
We are aware that the best control group would have been children from
the same population who did not have aphthous ulcers. However, for that purpose,
informed consent must be obtained from the parent(s) according to the Helsinki
Declaration and the regulations of the Israeli Ministry of Health. Thus, the
probability of subjects from the Arab community agreeing to participate in
the study is very low, owing in part to the Arabic tradition that is opposed
to the drawing of blood. Therefore, HLA-typing data were obtained from healthy
Israeli Arabs who were candidates as donors for bone marrow transplantation.
Data were processed in our Tissue Typing Laboratory, Rabin Medical Center,
Beilinson Campus, Petah Tiqva.
We noted a high frequency of HLA-B52 and HLA-B44 antigens in the subjects
with RAS. Our finding of a high frequency of HLA-B44 antigen is interesting,
as all 8 of the HLA-B44–positive subjects were negative for HLA-B52
antigen, and only 1 was positive for HLA-B51 antigen. This may indicate that
1 subgroup of RAS is associated with the HLA-B52 antigen and another subgroup
with the HLA-B44 antigen. There is a possibility that the notable relationship
among HLA-B44, HLA-B52, and RAS may be due to the significance with multiple
comparisons. However, HLA-B52 and HLA-B44 antigens were found to be more frequent
in subjects with RAS with highly significant P values
(P = .007 and P = .001,
respectively). Thus, it is unlikely that these findings were coincidental.
Furthermore, 4 family members of the 3 subjects who had HLA-B51–positive
antigens also had Behçet syndrome, 3 with the complete syndrome (1
of whom died), and 1 still being studied. The latter individual also has RAS
and recurrent genital ulcers, and is testing HLA-B51 positive. These findings
support the hypothesis that some patients with RAS may actually have Behçet
syndrome that manifests initially as RAS.5, 12
Behçet syndrome is a complex, multisystem disease characterized
by RAS, recurrent genital ulcers, and uveitis or chorioretinitis. It may affect
the skin, blood vessels, joints, central nervous system, and other organs.
It is rare in adults and rarer in children.13, 14
It usually occurs in subjects between the ages of 15 and 45 years (mean age,
30 years)1, 15 and is common in
the Mediterranean area, Middle East, and Japan.1
The origin is unclear, but some evidence supports viral involvement.1 A genetic predisposition has been proposed because
of an established association with major histocompatibility complex.5, 12 However, previous studies of HLA typing
have not mentioned an association between RAS and HLA-B52 or HLA-B44 antigen,
and its association with other HLA antigens is controversial (Table 3).15, 16 More
recent investigations have found a nonsignificant rise in the frequencies
of HLA-A2 and -Aw29 in subjects with RAS and an association with HLA-B,12, 17 but this was not confirmed.18 Some authors19, 20
have reported an association between RAS and HLA-DR2 and HLA-DR7 antigens.
In 1 study, HLA-B51 antigen was found in 23% of Jewish subjects with RAS.5 Long-term follow-up studies of affected adolescents
with RAS are needed to determine the association of RAS with Behçet
syndrome, and if the presence of either HLA-B52, HLA-B51, or HLA-B44 antigen
can be useful as a determinant for those subjects at risk to develop Behçet
syndrome.
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Table 3. Recurrent Aphthous Stomatitis (RAS) and HLA Typing in the
Literature
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AUTHOR INFORMATION
Accepted for publication November 10, 2000.
We thank Jaqueline Sulkes, PhD, for her statistical assistance and Gloria
Ginzach and Hanni Penn for editing and typing the manuscript.
From The Bridge to Peace Community Pediatric Center, Taibe (Dr Jaber),
the Emergency Department and Day Care (Dr Jaber) and the Pediatric Rheumatology
Unit (Drs Jaber and Mukamel), Institute of Hematology– Oncology (Dr
Yaniv), Schneider Children's Medical Center of Israel, Petah Tiqva, and the
Department of Medicine B and the Felsenstein Medical Research Center (Dr Weinberger),
and Tissue Typing Laboratory (Dr Klein), Rabin Medical Center, Beilinson Campus,
Petah Tiqva, and the Sackler Faculty of Medicine, Tel Aviv University, Tel
Aviv, Israel (Drs Jaber, Weinberger, Klein, Yaniv, and Mukamel).
Corresponding author: Lutfi Jaber, MD, Box 27, Taibe 40400, Israel.
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