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ISSN 1439-7595 (print), 1439-7609 (online)
Correspondence to: Seyedeh Tahereh Faezi, Rheumatology Research
Center (RRC), Shariati Hospital, Tehran University of Medical Sciences
(TUMS), Kargar Avenue, Tehran, Iran. Tel: 98 2184902405. Fax: 9 8
2184902405. E-mail: s.t_faezi@yahoo.com
ORIGINAL ARTICLE
Clinical features of Behcet ’ s disease in patients without oral aphthosis
Seyedeh Tahereh Faezi 1 , Pedram Paragomi 1 , Farhad Shahram 1 , Hormoz Shams 2 , Cheida Shams-Davatchi 3 ,
Zahra Ghodsi 3 , Abdolhadi Nadji 1 , Maassoumeh Akhlaghi 1 , and Fereydoun Davatchi 1
1 Rheumatolology Research Center (RRC ), Shariati Hospital, Tehran University of Medical Sciences, (TUMS), Kargar Avenue, Tehran, Iran,
2 Department of Ophthalmology, Farabi Hospital, Tehran University of Medical Sciences (TUMS), Kargar Avenue, Qazvin Square, Tehran, Iran,
and
3 Department of Dermatology, Razi Hospital, Tehran University of Medical Sciences (TUMS), Vahdat-e-eslami Square, Tehran, Iran
Keywords
Behcet ’ s disease , Dermatology , Internal
medicine , Ophthalmology , Oral aphthosis
Materials and methods
Since 1975 patients diagnosed for BD, from all regions of
Iran, were referred to the BD Research Unit, Rheumatology
Research Center, Shariati Hospital, Tehran University of Medi-
cal Sciences, Tehran, Iran. The diagnosis of BD is based on
expert ’ s opinion confi rmed at least by two Rheumatologist
experts on BD. Various diagnostic criteria for BD are consid-
ered in order to establish BD diagnosis. Most notable applied
criteria are ICBD [16], Japan revised [17], Dilsen [18], and
classifi cation tree [19]. Meanwhile nearly all patients from this
cohort were classifi ed by at least two diagnostic criteria. A total
number of 6821 patients till December 2011 were registered in
an ongoing prospective cohort study. All demographic, clinical,
and paraclinical data have been registered in an electronic data-
base. Predesigned software facilitates analysis of data excerpted
from our database, including the proportion of BD patients
which fulfi ll each diagnostic criterion. The registry is based on
the work of a multidisciplinary team including rheumatologist,
ophthalmologist, and dermatologist. The BD patients were sub-
divided into two groups: NOA cases and patients with OA (OA
cases). The study was conducted in accordance with ethical
principles of the 1964 Declaration of Helsinki. The statistical
comparison was performed by chi square and Fischer ’ s exact
test. The Odds Ratio was computed by logistic regression.
A confi dence interval of 95% (95% CI) was calculated for means
and percentages. P-values lower than 0.05 were considered as
signifi cant.
Mod Rheumatol, 2013; Early Online: 1–3
© 2013 Japan College of Rheumatology
DOI: 10.3109/14397595.2013.844400
History
Received 29 May 2013
Accepted 17 July 2013
Published online 18 October 2013
Introduction
Behcet ’ s Disease (BD) is a vasculitic disease with relapsing
pattern and unpredictable remissions and exacerbations [1 – 2].
The pathogenesis of disease is not fully clarifi ed. Moreover
the clinical picture of BD highly varies according to diff erent
reports [3 – 6]. The clinical picture of BD includes mucocuta-
neous, ocular, articular, vascular, gastrointestinal, and nervous
system involvement [3,7 – 8]. Mucous lesions are expected to
appear at early stage of disease [5,7]. Oral aphthosis (OA) has
been reported as the presenting manifestation in majority of BD
cases and is the most constant fi nding in BD patients. However
studies in large series of BD patients indicated 1 – 8% patients
do not manifest oral aphthosis throughout the clinical course of
disease [3 – 5,9 – 13].
Even though OA is mandatory to fulfi ll International study
group (ISG) criteria [14], BD patients without OA (NOA cases)
constitute a minority subset of BD patients which should be cor-
rectly diagnosed by clinical judgement or other feasible criteria
such as International Criteria for BD (ICBD) [15].
This study was designed to address the prevalence, and demo-
graphic and clinical parameters of Behcet ’ s NOA cases.
Abstract
Objectives. In current study we evaluated clinical features of Behcet ’ s Disease (BD) in patients
without oral aphthosis (NOA cases).
Methods. In a cohort of BD, patients registered during a period of 36 years were collected.
We determined clinical features of BD NOA cases and compared them with patients with oral
aphthosis (OA cases). The comparison was performed by chi square and Fischer ’ s exact test.
Results. Among 6821 BD patients, 175 patients (2.56%) were NOA cases. Male/Female ratio was
less in NOA cases (p-value: 0.078). Mean age of disease onset was signifi cantly higher in NOA
cases (p-value: 0.001). Among NOA cases, the fi rst manifestations comprised uveitis (70.3%), joint
involvement (8.0%), retinal vasculitis (6.9%), and genital aphthosis (4.0%). During the course of
disease, the prevalence of ocular lesions and positive pathergy test were signifi cantly higher in
NOA cases. Conversely genital aphthosis (OR: 0.048), mucocutaneous (OR: 0.470), joint involve-
ment (OR: 0.478), and positive family history for BD (OR:0.138) were signifi cantly less frequent
in NOA cases. NOA cases fulfi lled diff erent criteria including International Criteria for BD (ICBD),
Japan Revised, Iran, Dilsen, and Classifi cation Tree.
Conclusions. These results addressed the distinct clinical features in NOA subset of BD Including
more prevalent eye involvement and positive pathergy.
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2 S. T. Faezi et al. Mod Rheumatol, 2013; Early Online: 1–3
Results
Demographic features
Among 6821 patients with BD, 175 patients (2.56%) were NOA
cases. Male to female ratio was lower in NOA cases (0.95:1.00
vs. 1.25:1.00) however the diff erence was not signifi cant (p-value:
0.290). Mean age of disease onset was signifi cantly higher in NOA
cases (29.0 11.7 vs. 25.9 11.3, p-value: 0.001). Mean dura-
tion of follow-up was longer in NOA patients but not statistically
signifi cant (4.9 6.7 vs. 4.6 6.0, p-value: 0.760). On the other
hand diagnosis delay was shorter in NOA cases but not statistically
signifi cant (4.6 7.3 vs. 6.7 6.4, p-value: 0.089). Furthermore
positive family history of BD was signifi cantly higher in OA cases
(4.0% vs. 0.6%, p-value: 0.01).
Despite the fact that diagnosis of our patients is bases on expert
opinion, this subset of NOA patients also fulfi lled some classifi ca-
tion criteria, most notably ICBD (97.1%), Japan Revised (95.4%),
Iran (94.9%), Dilsen (78.3%), and Classifi cation Tree (76.0%).
The complete list of criteria and sensitivity of each in detection of
NOA patients is demonstrated in Figure 1.
First manifestations
Among NOA cases, the fi rst manifestation comprised of uveitis
(70.3%), joint involvement (8.0%), retinal vasculitis (6.9%), and
genital aphthosis (4.0%). In OA subgroup presenting signs com-
prised of oral aphthosis (84.6%), Genital aphthosis (10.0%), uveitis
(6.7%), and retinal vasculitis (0.2%).
HLA-B5 and HLA-B51
HLA-B5 was examined in 167 NOA cases and in 90 cases
(53.9%) HLA-B5 was positive. In 6418 examined OA cases,
positive HLA-B5 was obtained in 3381 cases (52.7%). HLA-B51
was tested in 19 of NOA cases and positive results were obtained
in 10 patients (52.6%). Meanwhile in 1836 OA cases tested for
HLA-B51, 842 patients had positive results (45.8%). Neither
HLA-B5 (OR: 1.050, p-value: 0.183) nor HLA-B51 (OR: 1.312,
p-value: 0.096) in NOA and OA subsets, had signifi cant diff er-
ence between two subgroups.
Comparison: clinical course of BD in NOA and OA patients
We compared diff erent clinical manifestations in two subsets of BD
during course of disease (Table 1). Ocular involvements including
anterior and posterior uveitis and retinal vasculitis were signifi cantly
more common in NOA cases. Anterior uveitis was detected in 78.9%
of NOA subset while only 40.0% of OA subset had this lesion (OR:
5.75, 95% CI: 3.88 – 8.07). Posterior uveitis was detected in 85.7%
and 43.9% of NOA and OA patients, respectively (OR: 7.94, 95%CI:
4.99 – 11.70). Moreover, retinal vasculitis was detected in 57.1% of
NOA patients and in 32.3% of OA cases, which remarked more pro-
nounced tendency in NOA subset (OR: 2.76, 95%CI: 2.06 – 3.79).
Mucocutaneous lesions including pseudofolliculitis, erythema
nodosum, and genital aphthosis, were signifi cantly less common in
NOA cases, however positive pathergy test was signifi cantly more
common in NOA patients. Joint involvements were signifi cantly
less prevalent in NOA subset. Moreover neurologic manifesta-
tions, gastrointestinal involvement, and deep vein thrombosis were
less frequently detected in NOA group; however, the diff erence in
these features was not signifi cant (Table 1).
Discussion
Oral aphthosis is the most common presenting manifestation in BD
patients and is considered the most consistent clinical component in
whole clinical course of BD so that the presence of OA is manda-
tory in order to fulfi ll ISG classifi cation criteria [4 – 5,14]. However, a
number of previous studies have addressed a minority of BD patients
who does not develop oral aphthosis at any stage of disease [3 – 5,9].
Our data analysis revealed a number of distinguishable demo-
graphic and clinical features in NOA patients in comparison with
OA subgroup. NOA cases were signifi cantly older at the disease
onset and had lower rate of positive family history. However, posi-
tive HLA-B5 and HLA-B51 did not reveal signifi cant diff erence
between NOA and OA subpopulations.
Positive pathergy test was more frequently detected among NOA
patients. This might be partly related to obligatory fulfi llment of BD
diagnostic criteria in the absence of oral aphthosis. A previous study
has described the decreased sensitivity of pathergy test in Iranian
patients [20]. This point may partly justify the rather lower rate of
Figure 1. Sensitivity of BD criteria in
diagnosis of NOA subset.
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DOI 10.3109/14397595.2013.844400 Clinical features of Behcet’s disease 3
positive pathergy in OA subset. Eye involvements including uveitis
and retinal vasculitis were the most common presenting manifesta-
tions in NOA case. The higher rate of ocular lesions at this stage
may be partially due to obligatory fulfi llment of BD criteria in NOA
cases. It means that a few percent of BD patients may present with eye
involvement without any history of oral aphthosis during the course
of disease. Furthermore during the course of disease ocular involve-
ments were signifi cantly more common in NOA cases. However, the
NOA/OA ratio in patients with anterior uveitis, posterior uveitis, and
retinal vasculitis were relatively low which was due to limited quan-
tity of NOA cases in comparison with OA cases. Mucocutaneous
manifestations and joint involvement were signifi cantly less common
in NOA cases compare with OA cases. These distinct features further
may support the notion of NOA cases as a unique subset of BD.
According to our established therapeutic approach, BD patients
with ocular lesions receive immunosuppressive treatments [21].
Although immunosuppressive administration may be addressed
as the preventive factor in oral aphthosis occurrence, 46.3% of
NOA patients developed other mucocutaneous manifestations
(including genital aphthosis, eryhthema nodosum, and pseudo-
folliculitis). Therefore the absence of oral aphthosis may not be
totally related to immunosuppressive treatment in NOA cases.
Diagnosis of BD is an issue, which must be deliberately
addressed in NOA patients. Due to absence of oral aphthosis none
of these patients fulfi ll ISG criteria. Therefore other classifi cation
criteria are crucial in diagnosis of NOA cases. Among valid cri-
teria for BD, ICBD, Japan revised, and Iran criteria demonstrated
higher sensitivity in diagnosis of NOA subset.
One of t he limitations of current study was the unavailability of com-
plete drug history and time sequence of therapies they had received.
Therefore it was not possible to compare therapeutic responses
between OA and NOA patients. However, due to preponderance
of ocular lesions as the onset manifestations in NOA cases and the
established therapies administered in these patients [21], we investi-
gated the role of immunosuppressive treatment in prevention of OA.
Collectively the studied demographic and clinical features sup-
port the rationale to verify NOA patients as a unique subset of
BD. These patients constitute a minority of BD population with a
higher prevalence of eye involvement which demands more atten-
tion in clinical assessments.
Conclusions
Minority of patients with BD does not demonstrate oral aphthosis
in the whole course of disease. This subset of BD patients con-
stitutes a unique presentation, which is characterized by more
likelihood of eye involvement, and positive pathergy test but
less likelihood of mucocutaneous, joint involvement, and family
history of BD. Further studies of large series are warranted to
elaborate this specifi c category of BD patients.
Confl ict of interest
None.
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Table 1. Prevalence of various clinical parameters in NOA and OA subsets
of Behcet cohort during the course of disease.
Manifestations
NOA
(N 175)
%
OA cases
(N 6646)
% OR (95% CI)
Mucocutaneous 46.3 64.7 0.476 (0.35 – 0.64)
pseudofolliculitis 38.3 53.8 0.526 (0.35 – 0.64)
Erythema Nodosum 11.4 23.0 0.434 (0.27 – 0.69)
Genital Aphthosis 8.6 66.2 0.048 (0.03 – 0.08)
Ocular Lesions 97.1 56.5 27.03 (10.74 – 63.78)
Uveitis (ant.) 78.9 40.0 5.75 (3.88 – 8.07)
Uveitis (post.) 85.7 43.9 7.94 (4.99 – 11.70)
Retinal Vasculitis 57.1 32.3 2.76 (2.06 – 3.79)
Joint 22.8 38.2 0.48 (0.34 – 0.69)
Neurology 8.6 10.7 0.71 (0.46 – 1.34)
Gastrointestinal 3.4 7.4 0.43 (0.19 – 1.01)
Deep Vein Thrombosis 3.4 6.0 0.55 (0.20 – 1.02)
Large Vessel Involvements 0.6 1.8 0.32 (0.04 – 2.15)
Positive Pathergy Test 75.4 51.0 2.95 (2.08 – 4.18)
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