doi: 10.1111/1346-8138.

13381 Journal of Dermatology 2016; 43: 620–632

REVIEW ARTICLE
Behcß et’s disease: A comprehensive review with a focus on
epidemiology, etiology and clinical features, and management
of mucocutaneous lesions
Erkan ALPSOY
Department of Dermatology and Venereology, Akdeniz University School of Medicine, Antalya, Turkey

ABSTRACT
Behc ß et’s disease (BD) is a chronic, relapsing, inflammatory multisystem disease of unknown etiology. Oral ulcers,
genital ulcers, cutaneous lesions, and ocular and articular involvement are the most frequent features of the dis-
ease. Mucocutaneous lesions are considered hallmarks of the disease, and often precede other manifestations.
Therefore, their recognition may permit earlier diagnosis and treatment with beneficial results for prognosis. BD
is particularly prevalent in “Silk Route” populations but has a global distribution. The disease usually starts
around the third or fourth decade of life. Sex distribution is roughly equal. The diagnosis is based on clinical crite-
ria, as there is no pathognomonic test. Genetic factors have been investigated extensively, and association with
human leukocyte antigen (HLA)-B51 is still known as the strongest genetic susceptibility factor. The T-helper 17
and interleukin (IL)-17 pathways are active, and play an important role, particularly in acute attacks of BD. Neu-
trophil activity is increased in BD, and the affected organs show a significant neutrophil and lymphocyte infiltra-
tion. HLA-B51 association and increased IL-17 response are thought to play a role in neutrophil activation.
Treatment is mainly based on the suppression of inflammatory attacks of the disease using immunomodulatory
and immunosuppressive agents. Although treatment has become much more effective in recent years with the
introduction of newer drugs, BD is still associated with considerable morbidity and increased mortality. Male sex,
younger age of onset and increased number of organs involved at the diagnosis are associated with a more sev-
ere disease and, therefore, require more aggressive treatment.

Key words: Behcßet’s disease, clinical course, epidemiology, etiology, treatment.

DEFINITION Eastern and the Mediterranean countries. The prevalence of

Behcß et’s disease (BD) is an inflammatory multisystem disease
of unknown etiology with unpredictable exacerbations and
remissions. The disease was first described in 1937 by the
Turkish dermatologist Hulusi Behc ß et as a trisymptom complex,
characterized by recurrent oral ulcers (OU), genital ulcers (GU)
and uveitis.1 Later studies have shown that BD is a multisys-
temic disease with vascular, articular, gastrointestinal, neuro-
logic, urogenital, pulmonary and cardiac involvement.2
EPIDEMIOLOGY
Behcß et’s disease usually starts around the third or fourth dec-
ade of life.3 Epidemiological surveys suggest that sex distribu-
tion is roughly equal. However, there are some exceptions. BD
shows male predominance in some Middle Eastern and the
Mediterranean countries, and female predominance in Japan
and Korea.4 The disease is particularly prevalent in regions
along the “Silk Route”, extending from Japan to the Middle
the disease is 14–20/100 000 along the Silk Route.3 Turkey
has the highest prevalence. Azizlerli et al.5 from Istanbul
reported the prevalence of the disease to be nearly 1/250 of
the population aged 12 years or older. The disease is rarely
seen in Western countries; the prevalence of BD has been
found to be 0.64/100 000 in the UK and 0.12–0.33/100 000 in
the USA.6
Regional variability in disease expression is a well-known
epidemiological feature of BD. Besides genetic factors, envi-
ronmental factors may have an influence in the frequency of
the disease and/or individual symptoms. There is a close rela-
tionship between the geographic distribution of human leuko-
cyte antigen (HLA)-B51 and the prevalence of BD. HLA-B51
frequency among inhabitants along the Silk Route population
ranges 20–25% in the general population and 50–80% among
BD patients. On the contrary, HLA-B51 frequency is approxi-
mately 2–8% in Northern Europe and the USA in the general
population and 15% among BD patients.7 BD has been
reported to be less frequent among Japanese immigrants in

Correspondence: Erkan Alpsoy, M.D., Department of Dermatology and Venereology, Akdeniz University School of Medicine, 07059 Antalya,
Turkey. Email: ealpsoy@akdeniz.edu.tr
Received 20 December 2015; accepted 18 February 2016.

620 © 2016 Japanese Dermatological Association


the US mainland or Hawaii, and Turkish immigrants in Ger-
many. In earlier studies, BD has been reported to be extremely
rare among Japanese immigrants in California or Hawaii.8 In
the city of Berlin, risk of developing BD was found to be sub-
stantially higher in Turkish immigrants (77.3%/100 000) than
Germans (1.47%/100 000) and non-Germans (excluding Turks)
(26.6%/100 000), although it was still below the reported risk in
Turkey.9 In contrast to the previous two studies, Mahr et al.10
suggested that genetic factors may be more effective than
environmental factors on the incidence of the disease. In a
cross-sectional prevalence study in the suburbs of Paris, Mahr
et al. reported the frequency of BD as 7.1/100 000. BD among
immigrants of North African (34.6/100 000) or Asian ancestry
(17.5/100 000) is significantly higher than that in the European-
origin population (2.4/100 000), and comparable with rates
reported from North Africa and Asia. Within the migrant popu-
lation of either North African or Asian ancestry, BD prevalences
were similar for residents born in France. Therefore, authors
concluded that BD risk is not related to age at immigration and
the disease has a primarily hereditary basis.9
Gastrointestinal involvement is more common among the
patients from Japan and Korea compared with other countries
such as Turkey. Gastrointestinal involvement is between 1.4
and 3 in Turkey and up to 58% in Japan and 15% in Korea.11–14
It is of particular importance especially in Japan and Korea
because it is still associated with significant morbidity and mor-
tality in this region.
The skin pathergy test (SPT) positivity varies between geo-
graphic areas, and it is considered highly sensitive and specific
for BD in patients from Turkey, some Mediterranean, the Mid-
dle Eastern countries and Japan. Interestingly, a number of
studies from Japan and Turkey have reported a decline in the
positive rate of SPT. Sakane et al.6 reported positivity rate of
75% in 1972. The same rate was found to be at approximately
50% in the studies of Nishiyama et al.15 in 2003 and Ideguchi
et al.13 in 2011. Similar trend have also been recognized in
studies performed in Turkey. In the earlier studies, SPT positiv-
ity has been reported as 74% by Yazici et al.16 and 67% by
Dilsßen et al.17 In our multicenter study,11 we found this rate to
be 37.8%. Recent surveys in Iran also revealed a remarkable
decrease in the positivity of SPT.18 Differences in the method-
ology used to perform SPT and racial differences may be the
main reasons in the low prevalence of positive SPT. The more
important reason seems to be the widespread use of dispos-
able needles instead of blunt, reusable, sterilized needles.
Recently Togashi et al.19 have proposed a new diagnostic
pathergy test to overcome this problem. They performed a skin
prick test with neat and filter-sterilized saliva on the forearm
skin. Ninety percent of BD patients showed an indurative ery-
thema at the skin site pricked with self-saliva, whereas 60% of
recurrent aphthous stomatitis (RAS) patients demonstrated a
relatively weak reaction. Pricking with filter-sterilized saliva
failed to produce any of the positive skin reactions. They sug-
gested that skin prick test using self-saliva can be a simple
and valuable in vivo diagnostic approach for differentiating BD
and RAS from other mimicking mucocutaneous diseases. The
positive skin prick may be triggered by resident intraoral micro-
© 2016 Japanese Dermatological Association
Behcßet’s disease: an update
flora, particularly streptococci, and may in part address the
underlying immunopathology in BD.
ETIOLOGY
Although several immunological abnormalities have been
demonstrated, the exact mechanism of the inflammatory
changes occurring remains to be elucidated. The most proba-
ble hypothesis is that of an inflammatory reaction set off by
infectious agents such as herpes simplex virus (HSV)-1 or
Streptococcus species such as Streptococcus sanguinis or by
an autoantigen such as heat shock proteins (HSP) in geneti-
cally predisposed individuals.20
Infectious agents have been suspected to play a role in the
pathogenesis. Professor Hulusi Behc ß et was one of the first
physicians asserting the role of an infectious agent, HSV-1, in
the development of BD.1 In particular, a possible association
between HSV-1 with BD has been the subject of several inves-
tigations. Hybridization between HSV-1 DNA and complemen-
tary RNA in mononuclear cells was found to be higher in BD
patients than the control patients. Results indicated the pres-
ence of at least a part of the HSV-1 genome in mononuclear
cells of patients with BD.21
In recent years, several streptococcal strains has gained
increasing importance in infectious etiology. In this regard, the
emergence of some clinical manifestations of the disease fol-
lowing hypersensitivity tests applied with streptococcal anti-
gens in patients with BD was an important evidence. In
addition, antibodies directed against Streptococcus pyogenes
and S. sanguinis are obtained significantly more often in sera
of BD patients than the control group.22 Streptococcal 65-kDa
HSP from an uncommon serotype (KTH-1, strain BD113-20) of
oral S. sanguinis have been noted to be important extrinsic
factors in the pathogenesis of BD.4
Oral microbial flora have long been implicated in the patho-
genesis, as BD starts mostly from the oral mucosal surfaces.23
Dental interventions or tonsillitis have been indicated to result
in disease attacks such as OU as well as activation of other
manifestations.24,25 Antimicrobial agents including antibiotics
and antiseptic agents have been used to control disease acti-
vation.26 Previous and our studies demonstrated that oral
health was impaired in patients with BD as compared with
healthy controls.20,23,27 Additionally, Mumcu et al.23 observed
elevated plaque index score to be a significant risk factor for
increased severity score in patients with BD. Our study showed
that periodontal scores were higher in BD patients compared
with healthy controls and RAS. Moreover, increased periodon-
tal scores were correlated with the severity of the disease.20
Cß elenligil-Nazlıel et al.27 demonstrated that poor oral hygiene
leads to rapid bacterial plaque accumulation. They suggested
that the bacterial plaque ecology and/or immune responses to
these microorganisms may be affected in BD which could lead
to changes in the expression of periodontal disease. Improve-
ment of the oral health of BD patients may affect their disease
course, leading to a better prognosis. Karac ß aylı et al.28 showed
that, in BD patients, dental and periodontal therapies could be
associated with a flare-up of OU in the short term, but may
621
E. Alpsoy
decrease their number in longer follow up. They also lead to a
better oral health. Interestingly, several atypical streptococcal
species were significantly high in the oral flora of patients with
BD and a particular strain, S. sanguinis, has been shown to
enable the KTH-1 cells to secrete the pro-inflammatory media-
tors of interleukin (IL)-6, IL-8 and tumor necrosis factor (TNF)-a
in these patients. Therefore, it is entirely possible that in geneti-
cally predisposed individuals an inflammatory reaction set off
by infectious agents, such as streptococcus species, could
lead to development of BD.29,30
Genetic factors that predispose individuals to BD are con-
sidered to play important roles in the development of the dis-
ease. Familial aggregation studies in patients with BD indicate
a strong genetic background and a complex inheritance
model.31 The association of BD and HLA-B5(51) was first
defined by Ohno et al. in 1973.32 Several studies in different
ethnic groups confirmed the HLA-B51 association with BD.
Still, association with HLA-B51 is known as the strongest
genetic susceptibility factor for BD, and it is thought to play a
role in neutrophil activation. In this regard, a recent meta-ana-
lysis showed that subjects carrying HLA-B51/B5 have an
increased risk of developing BD with an odds ratio of 5.78
compared with non-carriers of this antigen.33 However, the
presence of HLA-B51 alone is not sufficient to explain all of
the symptoms observed in BD and, in agreement with this,
recent studies suggest the involvement of other genes. In a
recent multicenter study, including our department, Hughes
et al.34 tried to localize the genetic association between HLA-
B*51 and BD and explored additional susceptibility loci in the
HLA region. In the extended HLA locus, 8572 variants were
genotyped, and imputation and meta-analysis of 24 834 vari-
ants were carried out in two independent BD cohorts. The
most significant association was with rs116799036. To deter-
mine whether the genetic effect of this single nucleotide poly-
morphisms (SNP) can be explained by the repeatedly reported
genetic association between BD and HLA-B51, we performed
pairwise conditional analysis to control for HLA-B-5101. The
genetic association at rs116799036 remained significant, inde-
pendent of HLA-B-5101, in Turkish and Italian cohorts. Nota-
bly, the genetic association with HLA-B51 completely
disappeared when controlling for the genetic association with
this SNP. Our data strongly suggest that the association
between HLA-B51 and BD can be explained by this SNP,
which is located in the promoter region of HLA-B, between the
HLA-B and MICA genes. Therefore, we speculated that the risk
previously ascribed to HLA-B51 is likely not causal with
respect to BD. However, further functional studies are required
to confirm the consequences of our findings.
Besides our study, a recent six genome-wide association
studies,35–40 with the exception of the study by Fei et al.,35
have confirmed the association of BD with HLA-B51, and
reported new susceptibility genes in the remaining part of the
HLA class I region and several non-HLA genes for the disease.
Two of them, conducted in Turkey36 and Japan,37 reported
association between SNP of IL-10 and IL-23R/IL-12RB2 genes
and BD. The disease-associated variants were located in the
IL-23R side of the hot spot, suggesting that the association
622
with BD is more likely to be with IL-23R rather than IL-12RB2.
IL-23 which shares the p40 subunit with IL-12, acts to induce
T-cell activation to produce IL-17 and therefore is one of the
main T-helper (Th)17 pathway activators.
Overexpression of pro-inflammatory cytokines, mainly Th1
and Th17 from various cellular sources, appears to be respon-
sible for the enhanced inflammatory reaction in BD and may
be associated with genetic susceptibility. Affected organs
show significant neutrophil and lymphocyte infiltration. It is
believed that the stimulated lymphocytes contribute to neu-
trophil and endothelial cell activation in these patients.41 HSP
have been speculated to trigger both innate and adaptive
immunological reactions in patients with BD. Streptococcal 65-
kDa HSP of oral S. sanguinis have been claimed to play impor-
tant roles as an environmental factor in the pathogenesis. BD
patients are thought to acquire the hypersensitivity against oral
S. sanguinis through the innate immune system. Microbial load
and associated stress proteins found in OU and periodontal
tissues of patients with BD may cause a cross-reactivity with
host tissues and stimulate the expression of autoreactive T-cell
clones. HSP are considered to transfer antigenic peptides to
antigen-presenting cells and they can be recognized by pattern
recognition receptors (Toll-like receptors) to be an endogenous
“danger” signal leading to activation of innate and adaptive
immune responses. They may also, directly or indirectly,
increase the expression of vascular endothelial growth factor
by T cells, causing endothelial cell damage and vasculitis.29
Current data suggest that Th17 cells and IL-17 may have a
part in the development and/or activity of the disease. Hamzaoui
et al.42 reported increased serum levels of IL-17. Chi et al.43 have
shown elevated production of IL-17, IL-23 and interferon (IFN)-c
by peripheral blood mononuclear cells besides increased fre-
quencies of IL-17- and IFN-c-producing T cells in BD patients
with active uveitis. We investigated the role of IL-17 in the activity
and different organ involvements of BD in 45 patients and 33
age- and sex-matched healthy controls. Serum IL-17 levels of
BD patients were significantly higher than healthy controls. This
difference is more pronounced in active BD patients compared
with inactive BD patients and healthy controls. IL-17 levels of BD
patients with active stages of uveitis, OU, GU and articular symp-
toms were significantly higher than patients with inactive stages
of these symptoms. Compared with healthy controls, a signifi-
cant increase was observed in the number of IL-17-producing
cells obtained from BD patients after stimulation with S. san-
guinis, Escherichia coli and phytohemagglutinin (PHA) in
enzyme-linked immunospot. When we evaluated the proportion
of IL-17-secreting cells in patients with active organ involvement,
a significant increase in the percentage of IL-17, CD4+ IL-17+ and
CD4– IL-17+ T cells after E. coli and PHA stimulation was
observed. Taken together, our results indicate that Th17 and IL-
17 pathways are active in BD patients, and play an important role,
particularly in acute attacks of the disease. Increased neutrophil
activity and neutrophil infiltration in the affected organs may be
caused by increased IL-17 response in patients with BD.44
Possible regulation mechanisms based on basic experi-
mental evidence in the etiology of BD are summarized in
Figure. 1.
© 2016 Japanese Dermatological Association
 Behcßet’s disease: an update

Figure 1. Possible regulation mechanisms based on basic experimental evidence in the etiology of Behc ß et’s disease (BD). Genetic
factors are considered to play important roles in the development of BD. Association with human leukocyte antigen (HLA)-B51 is known
as the strongest genetic susceptibility factor. Recent genome-wide association studies have confirmed this association and reported
new susceptibility genes on the remaining part of HLA class I region and several non-HLA genes for the disease. Streptococcal 65-kDa
heat shock protein (HSP) of oral Streptococcus sanguinis has been noted to be an important extrinsic factor in the pathogenesis. Micro-
bial load and associated stress proteins found in oral ulcers and periodontal tissues of patients with BD may cause a cross-reactivity
with host tissues and stimulate the expression of autoreactive T-cell clones. HSP can be recognized by pattern recognition receptors to
be an endogenous “danger” signal leading to activation of innate and adaptive immune responses. They also increase the expression
of adhesion molecules on endothelial cells. Overexpression of pro-inflammatory cytokines, mainly T-helper (Th)1 and Th17 cells appear
to be responsible for the enhanced inflammatory reaction. Increased neutrophil activity and neutrophil infiltration in the affected organs
may be caused by increased interleukin (IL)-17 response. The immune system activated at the end of all these complex processes is
thought to eventually induce tissue damage and vasculitis. IFN, interferon; TNF, tumor necrosis factor.

MUCOCUTANEOUS LESIONS round ulcer within 2–3 days with rolled borders and a grayish
yellow necrotic base. An erythematous halo surrounds the
Mucocutaneous lesions constitute the hallmark of the disease.
ulcers (Fig. 2a). They are identical to conventional aphthae or
The high frequency of OU and GU and cutaneous lesions at
RAS in appearance. However, Main and Chamberlain45
any time in the course of the disease, or as onset signs, con-
reported that increased number of ulcers, concurrent variation
firm the importance of these clinical features for diagnosis. OU
in size from herpetiform to major aphthous, diffuse erythema-
(92–100%), GU (57–93%) and cutaneous lesions (38–99%)
tous surrounds and involvement of soft palate and oropharynx
together with ocular (29–100%) and articular (16–84%) involve-
may be useful to differentiate OU of BD from the conventional
ments, are the most frequent features of the disease in all
RAS. OU often subside spontaneously within 1–4 weeks and
countries. Erythema nodosum (EN)-like lesions (15–78%) and
recur at intervals from days to months. Local trauma can
papulopustular lesions (PPL) (28–96%) are the most commonly
induce new mucosal lesions (mucosal pathergy equivalent). OU
observed cutaneous lesions.3
can cause considerable pain and may result in difficulty when
eating, drinking, speaking, swallowing and performing routine
Oral ulcers oral hygiene.3
Oral ulcers are characterized by recurrent and painful ulcera-
tions of the oral mucosa. The most common sites are the
mucous membranes of the lips, buccal mucosa, tongue and Genital ulcers
soft palate. The lesions start as an erythematous, slightly Genital ulcers are similar in appearance and course to OU, but
raised area with vesiculopustular lesion evolving into an oval or may not recur as often. They are usually deeper than the OU

© 2016 Japanese Dermatological Association 623

E. Alpsoy
(a) (b)
(c) (d)
(e)
(f)
Figure 2. Mucocutaneous lesions of Behc ß et’s disease. (a) Oral
ulcers on the uvula with rolled borders and a grayish yellow
necrotic base, and numerous scars on the soft palate from the
previous ulcers. (b) Genital ulcers are similar in appearance and
course to oral ulcers; the scrotum is the most commonly involved
site in males. (c) Erythema nodosum-like lesions; pretibial, pain-
ful and hot, erythematous nodules. (d) Papulopustular lesions are
sterile, folliculitis- or acne-like lesions on an erythematous base
which appear as a papule and in the course of 24–48 h become
a pustule. (e) Superficial thrombophlebitis erythematous, tender
subcutaneous nodules arranged in a linear fashion. (f) Skin
pathergy test; positivity is defined as the development of a
papule or pustule at the needle-prick site after 24–48 h.
and heal within 10–30 days with a tendency to scar. The labia
major is the most frequently involved site in females but the
labia minor, vaginal mucosa and rarely cervix can also be
affected. The scrotum is the most commonly involved site in
males (Fig. 2b). Ulcers can also be observed on the shaft and
glans penis. Ulcers in the urethral orifice have also been
reported. GU may occur in both sexes in the groin, perineal
and perianal area.3 GU may cause severe pain, difficulty with
micturition, dyspareunia and marked difficulty in physical activ-
ity. Deep ulcers may scar and those in the vagina may be
complicated by bladder or urethral fistulae.3,41
Cutaneous lesions
Various cutaneous lesions have been described during the
course of BD. The cutaneous lesions include mainly, EN-like
624
lesions, PPL, superficial thrombophlebitis (TFB) and SPT. Other
cutaneous vasculitic lesions are rarely seen. Extragenital ulcer-
ation and Sweet’s syndrome-like lesions are relatively common
and better known cutaneous lesions; others (pyoderma gan-
grenosum-like lesions, erythema multiforme-like lesions, per-
nio-like cutaneous lesions, palpable purpura, Henoch–
Scho € nlein purpura, bullous necrotizing vasculitis, subungual
infarctions, hemorrhagic bullae, furuncles, abscesses and acral
purpuric papulonodular lesions) are limited to case reports.
Erythema nodosum-like lesions
Erythema nodosum-like lesions is mostly seen in females and
occur in approximately one-third of all patients. They have a
typical clinical presentation with bilateral, pretibial, painful and
hot, erythematous nodules (Fig. 2c). EN-like lesions can also
be localized to the face, neck, forearms and buttocks. The
lesions do not ulcerate and resolve spontaneously within 2–
3 weeks in pigmented ethnic groups with residual pigmenta-
tion; however, recurrence is common.41 Although they are clini-
cally similar to those of classical EN secondary to other
systemic causes, they differ from that condition with regard to
their microscopic features. Vasculitis or vascular reaction –
unlike classical EN lesions – are the main features of these
lesions, as they are in other cutaneous lesions of BD.3,46
Papulopustular lesions
Papulopustular lesions are sterile, folliculitis- or acne-like
lesions on an erythematous base which appear as a papule
and in the course of a 24–48 h become a pustule. Trunk, but-
tocks (Fig. 2d) and the lower limbs are the most common loca-
tions.47 PPL were reported to be more frequent in patients with
positive SPT47 and arthritis.48
Superficial thrombophlebitis
Behc ß et’s disease has been classified as variable vessel vas-
culitis which means the disease can affect vessels of any size
and type.49 The venous system is the major affected site, and
superficial TFB is, indeed, the most frequent type of venous
involvement. It is more common in males and frequently con-
fused with EN-like lesions. Patients usually present with erythe-
matous, tender, subcutaneous nodules arranged in a linear
fashion (Fig. 2e). The vein can be palpated as a string-like
hardening because of thrombosis leading to vessel sclerosis
with reddening of the overlying skin. The location of nodules
shows a tendency to change from day to day because multiple
segments of the vein may be involved. Superficial TFB is clini-
cally important because it could frequently be associated with
other forms of vascular disease in BD. Sarica-Kucukoglu
et al.50 evaluated the prevalence and types of vascular involve-
ment in BD. Among 2319 patients, prevalence of vascular
involvement was 14.3%, and superficial TFB was the most
common vascular symptom (53.3%).
Other cutaneous lesions
Extragenital ulcers resemble other aphthous lesions of the dis-
ease. They are recurrent and usually heal with scarring. Extra-
genital ulcers, although not frequently seen, are among the
© 2016 Japanese Dermatological Association

most characteristic and specific cutaneous findings of the dis-
ease. The lesions can be seen on various locations such as
the legs, axillae, breast, interdigital skin of the foot and
neck.3,51 Sweet’s syndrome-like lesions are rarely associated
with BD. They are characterized by painful erythematous nod-
ules and plaques associated with fever and leukocytosis.
Sweet’s syndrome-like lesions are usually fewer in number and
localized to the face, neck and extremities.51 Clinical and histo-
logical overlap exists between Sweet’s syndrome and BD.
Both conditions are considered within the neutrophilic der-
matosis group. Differential diagnosis may be extremely difficult.
Sweet’s syndrome presents with predominant skin involvement
and shows a distinctive clinical course. OU and GU are rarely
seen. On the other hand, among the overlapping extracuta-
neous manifestations of Sweet’s syndrome, asymmetrical pol-
yarthralgia and conjunctivitis and episcleritis can be seen. This
pattern of articular and ocular involvement is also different from
BD. Arthritis which often presents with monoarticular or
oligoarticular pattern is typically seen in BD. Panuveitis is the
most frequent ocular lesion in BD. Anterior uveitis, posterior
uveitis and retinal vasculitis are the other main ocular manifes-
tations. Fever, a diagnostic criterion of Sweet’s syndrome, is
not frequent in BD.
Skin pathergy test
The SPT is a non-specific skin hyperreactivity induced by nee-
dle prick. The test positivity is defined as the development of a
papule or pustule at the needle-prick site after 24–48 h
(Fig. 2f). It is similar to the spontaneously occurring PPL of the
disease, and more strongly positive among males. Bacterial
cultures of the SPT are negative.3
CLINICAL COURSE
Mucocutaneous lesions figure prominently in the presentation
and diagnosis, and may be considered the hallmarks of the
disease. Therefore, their recognition may permit earlier diagno-
sis and treatment. BD runs a chronic course with unpredictable
exacerbations and remissions. The natural course of the dis-
ease is not fully known. Our previous multicenter11 and recent
single center52 studies showed that OU are the most common
manifestation followed by GU, PPL, EN-like lesions and articu-
lar and ocular involvement. OU were also the most common
onset manifestation which was followed by GU, EN-like lesions
and ocular involvement. In approximately 15% of the patients,
more than one symptom appeared at the same time as the
onset manifestation. OU and GU were the most common com-
bination among the simultaneous occurrence of symptoms.
Each or any combination of mucocutaneous, articular and
ocular symptoms of the disease may have significant pain or
loss in function, or both. Besides considerable morbidity, the
disease confers an increased mortality, mainly because of pul-
monary as well as large vessel involvement, neurological
involvement and bowel perforation. Mortality ratios as well as
mucocutaneous and articular manifestations usually tend to
decrease significantly with the passage of time. Kural-Seyahi
et al. in a two-decade outcome survey of 387 patients with BD
© 2016 Japanese Dermatological Association
Behcßet’s disease: an update
noted a significant decrease in the proportion of all mucocuta-
neous disease manifestations (OU, GU, EN-like lesions and
PPL) and arthritis at the end of the study.53 Both the onset and
the greatest damage of ocular involvement are usually within
the first few years of the disease onset. However, recent stud-
ies and our studies demonstrated that neurological, gastroin-
testinal and large vessel involvements are exceptions, and can
have their onsets later (5–10 years) during the course of the
disease.11,13,52,53
Higher frequency of serious manifestations, such as ocu-
lar,11,52,54–57 vascular11,52,56,57 and neurological involve-
ment,11,56,57 have been reported in male patients, as detected
in our studies. Association of male sex with heart56 and renal58
involvement has also been reported. On the other hand, EN-
like lesions and articular involvement are more common in
female patients.11,55–57
Current published work and our experience indicate that BD
usually starts with relatively milder manifestations, and severe
involvements, in general, appear later. Mucocutaneous lesions,
especially OU and/or GU usually precede possible serious
involvements. Therefore, careful follow up is mandatory
because the disease shows a continuous activity. Male sex,
younger age of onset and increased number of organs involved
at the diagnosis are associated with a more severe disease,
and therefore, require more aggressive treatment.
DIAGNOSIS
Because of the lack of a universally recognized pathognomonic
laboratory test, the diagnosis of BD is primarily based on clini-
cal criteria following the exclusion of an alternative diagnosis.
Various criteria have been used, and most of them rely heavily
on mucocutaneous manifestations, particularly OU, GU, cuta-
neous vasculitic lesions and the SPT. International Study
Group for Behc ß et’s Disease criteria,59 briefly “ISG” criteria,
which depend on the presence of recurrent OU, plus any two
of recurrent GU, typical ocular lesions, typical cutaneous
lesions or a positive SPT, remain the most widely used and
well-accepted criteria among experts. An international team
developed new criteria under the name International Criteria for
Behc ß et’s Disease, briefly “ICBD” criteria, which were published
in 2006. These new criteria were revised in 2013, becoming
the 17th set of classification/diagnosis criteria for BD. In this
criteria, OU, GU and ocular manifestations get each 2 points,
and others (skin lesions, neurological manifestations, vascular
manifestations and positive SPT) get 1 point. If a patient gets
4 points or more, the patient is diagnosed as having BD.60 The
performance of ISG criteria versus ICBD revised criteria were
checked in different cohorts. These studies indicate that ICBD
revised criteria are more sensitive, and therefore diagnosis may
become easier using these criteria. However, they are less
specific than the ISG criteria, which means that the new ICBD
revised criteria may cause overdiagnosis, Therefore, they
should be interpreted cautiously.61
The Japanese Diagnostic Criteria,62 one of the most sensi-
tive and specific, and the most commonly used criteria espe-
cially in the Far East countries, include four major symptoms
625
E. Alpsoy

ß et’s disease and recurrent aphthous stomatitis in

Table 1. Main topical therapeutic agents used in the treatment of Behc
randomized controlled studies

Topical treatment Comment References

Effectiveness of topical therapeutic agents used in the treatment of Behc ß et’s disease
76
Triamcinolone acetonide Shown to be more effective than
versus Phenytoin phenytoin on OU
75
Sucralfate versus placebo Decreases the frequency, healing time
and pain of OU, and the healing
time and pain of GU
Pimecrolimus + colchicine Decrease the pain severity of GU 82

versus colchicine
83
Pimecrolimus versus placebo Accelerates the healing process of GU
Effectiveness of topical therapeutic agents used in the treatment of recurrent aphthous stomatitis
69
Listerine versus hydroalcoholic Accelerates the healing process and
control rinse reduces the severity of pain
70
Chlorhexidine versus placebo Effective on the pain severity and
healing duration
71
Penicillin G versus placebo Earlier ulcer healing and pain relief
77
Dexamethasone versus Faster healing with dexamethasone
Triamcinolone acetonide
78–80
Amlexanox versus placebo Decrease in the pain severity and
healing duration
81
5-aminosalicylic acid versus placebo Decreases the healing duration
72,73
Tetracycline versus placebo Reductions in ulcer duration, size and pain
74
Triclosan versus placebo Reduces the number of aphthous ulcers
86
Camel thorn distillate versus placebo Reductions in ulcer size and the pain severity
87
Diclofenac in hyaluronan versus Less pain with diclofenac in hyaluronan
hyaluronan versus lidocaine
88
Silver nitrate pencil versus placebo pencil Decreases the pain severity
89
CO2 laser versus inactive laser Reduction of pain after treatment
90
ND:YAG laser versus Triamcinolone Immediate relief of pain and faster
acetonide healing with ND:YAG laser
84
Minocycline versus Tetracycline Less pain with minocycline
85
Minocycline versus placebo Decreases the pain severity

GU, genital ulcers; ND:YAG, neodymium:yttrium–aluminum–garnet; OU, oral ulcers.

(OU, skin lesions, eye lesions and GU) besides the minor ones
(arthritis, intestinal ulcers, vascular disease, neuropsychiatric
disorders and epididymitis). Patients with four major symptoms
during the clinical course are defined as having complete BD;
and those patients with three major symptoms, with two major
and two minor symptoms, with typical recurrent ocular inflam-
mation and one or more major symptom, or with typical recur-
rent ocular inflammation and two minor symptoms, as having
incomplete BD.
HISTOPATHOLOGY
The histopathological features of BD are characterized by
mainly vasculitis and thrombosis. As a general rule, larger ves-
sel involvement tends to be vasculitic with often thrombosis or
aneurysm, and mucocutaneous lesions often have features of a
leukocytoclastic vasculitis or a neutrophilic vascular reaction.
Mucocutaneous lesions, for example, OU, GU, EN-like lesions,
superficial TFB, PPL and SPT, do not regularly present as vas-
culitis. Histopathological assessment of early cutaneous lesions
often have features of a leukocytoclastic vasculitis. On the other
hand, histopathological assessment of late lesions describe pri-
marily a lymphocytic perivasculitis. Neutrophil activity is
increased in BD, and the affected organs show a significant
neutrophil and lymphocyte infiltration. Therefore, vasculitis is
not the case for all patients, and a neutrophilic vascular reaction
without vasculitis can be seen in many cases.63–65
TREATMENT
Treatment of BD depends on a number of factors such as
involved organ/s and severity of this involvement/s, frequency
of recurrences, disease duration, age at disease onset and
sex. However, the main aim of the treatment should be the
prevention of irreversible organ damage, especially during the
early, active phase of the disease. Therefore, close monitoring,
and early and appropriate treatment is mandatory to reduce
morbidity and mortality. The treatment is mainly based on the
suppression of inflammatory attacks of the disease using
immunomodulatory and immunosuppressive agents. Based on
the mainly controlled studies and personal experience in clini-
cal practice and basic research in this field, a stepwise,

626 © 2016 Japanese Dermatological Association


Table 2. Activity spectrum of systemic therapeutic agents on Behc
Treatment
Colchicine versus placebo
Colchicine versus colchicine + benzathine penicillin
Colchicine versus benzathine penicillin
versus Colchicine + benzathine penicillin
Corticosteroids versus placebo
Dapsone versus placebo
Azathioprine versus placebo
Thalidomide versus placebo
Zinc sulfate versus placebo
Rebamipide versus placebo
CyA versus conventional treatments
(prednisolone, azathioprine)
CyA versus colchicine
CyA versus conventional treatments
(prednisolone, chlorambucil)
CyA versus CCP
CyA versus conventional treatments
(prednisolone, chlorambucil)
CCP + corticosteroids versus corticosteroids
IFN- versus placebo
Etanercept versus placebo
Rituximab versus cytotoxic combination therapy
© 2016 Japanese Dermatological Association
Behcßet’s disease: an update
ß et’s disease in randomized controlled studies
Dose Indication and reference
1–2 mg/d Decreases the frequency of EN, and
effective on arthralgia91
Reduces the occurrence of GU, EN and
arthritis in women, and the occurrence
of arthritis in men92
Significant improvement in disease activity
index, and OU, GU, EN and PPL in
both sexes93
1–2 mg/d; 1.2 MU/3 w Combined treatment more effective in
reducing frequency of arthritic episodes,
duration of OU and EN, and the
frequency of GU94
1 mg/d; 1.2 MU/mo Combined use of colchicine and
benzathine penicillin treatment more
effective than colchicine or
penicillin alone95
40 mg/every 3 w Decrease the frequency of EN in women96
100 mg/d Effective on the number, healing time and
frequency OU, number of GU, and
frequency of EN and PPL. Suppresses
arthritis and epididymitis97
2.5 mg/kg per d Reduces the occurrence of OU, GU,
arthritis and ocular symptoms. Prevents
the development of new eye disease98
100–300 mg/d Sustained remission of OU and GU
and PPL99
300 mg/d Significant improvement in the clinical
manifestations index of mucocutaneous
lesions100
300 mg/d Reduces the number of OU and pain101
5 mg/kg per d CyA more effective than conventional
therapy in OU, GU, cutaneous lesions,
TFB as well as articular and neurologic
symptoms102
10 mg/kg per d CyA more effective on the severity and
frequency of OU, GU and PPL. Superior
to colchicine in decreasing the frequency
and severity of ocular attacks103
10 mg/kg per d CsA more effective than conventional
therapy in ocular disease, however,
conventional therapy superior to CyA in
controlling OU, GU and arthritis108
5 mg/kg per d A significant improvement in VA during
the first 6 mo in CyA group compared
with CCP110
10 mg/kg per d Improvement of hearing loss in 25% of
patients receiving CyA treatment109
1 g/m2 per mo Combined treatment of CCP and
corticosteroids more effective in eye
disease than corticosteroids alone111
6 MU/d–39/w Effective on pain and healing time of OU,
and frequency of GU and PPL105
25 mg/d–29/w Reduces the occurrence of OU, nodular
skin lesions and PPL106
2 1000-mg courses (15-d interval) A significant improvement in total adjusted
disease activity index in rituximab
group112
627
E. Alpsoy

Table 2. (continued)

Treatment Dose Indication and reference

Apremilast 30 mg/twice daily Reduces the numbers of OU and GU, and
pain of OU104
Isotretinoin versus placebo 20 mg/d Significant improvement in the clinical
manifestations index, and OU and
skin manifestations parameters107
Secukinumab versus placebo 300 mg/2 w or 300 mg/mo No statistically significant differences in
uveitis recurrence; beneficial effect in
reducing the use of concomitant
immunosuppressive medication113
Daclizumab versus placebo 1 mg/kg/2 w for 6 w No beneficial effect in comparison with
placebo114

CCP, cyclophosphamide; CyA, cyclosporin A; d, day; EN, erythema nodosum-like lesions; GU, genital ulcers; IFN, interferon; mo, month; OU, oral
ulcers; PPL, papulopustular lesions, TFB; thrombophlebitis, VA, visual acuity; w, week.

symptom-based, algorithmic approach for the management of

mucocutaneous BD was proposed. This approach may enable
clinicians to rationalize and further increase the selection of the
most appropriate therapy among numerous treatment
options.66–68

Topical treatment
The number of controlled studies is still limited. The majority of
experience in the treatment of OU in patients with BD comes
from the studies performed in patients with RAS. OU of BD are
identical to RAS in appearance. Therefore, therapeutic reme-
dies related with RAS, to some extent, can be applied to OU
of BD.26 The main topical therapeutic agents used in the treat-
ment of BD and RAS in randomized controlled studies are
summarized in Table 1.
Antimicrobial agents (Listerineâ [Johnson & Johnson, New
Brunswick, NJ, USA] mouth rinse,69 chlorhexidine gel,70 peni-
cillin G potassium troches,71 tetracycline suspension,72,73 tri-
closan mouth rinse),74 sucralfate,75 corticosteroids,76,77
amlexanox78–80 and 5-aminosalicylic81 in OU, and pime- Figure 3. Treatment algorithm of mucocutaneous Behc ß et’s
crolimus82,83 in GU can be selected as first-line topical treat- disease; In these flow charts, all treatments were placed one
ment choices. Although controlled studies are still lacking, under the other in the right column. Algorithm began from the
potent corticosteroid ointments alone or in conjunction with box located in the upper left corner. Green arrow means simply
antiseptics are also used successfully in the clinical practice “yes”, and the red one “no”.
for the treatment of GU.66 Minocycline,84,85 camel thorn distil-
late,86 diclofenac,87 silver nitrate88 and lasers89,90 are other
alternatives for topical treatment of OU. In addition to the Systemic treatment
above-mentioned treatment approaches to OU, patients should Activity spectrum of systemic therapeutic agents on BD in ran-
be advised to maintain good daily oral hygiene. These patients domized controlled studies is summarized in Table 2. The
should avoid irritating agents such as acid, crusty, hard, spicy treatment algorithm for mucocutaneous BD summarized below
or salty nutrients and alcoholic beverages. EN-like lesions are are mainly based on controlled studies.66,67 In Figure 3, I have
treated topically like those of classic EN. Wet dressings such tried to recommend the most appropriate treatment we have
as aluminum acetate 3–5% (Burow’s solution) can be applied already used in our clinical practice.
in the early stage of these lesions. This approach is also helpful In the treatment of OU, GU, EN-like lesions and PPL, colchi-
for the treatment of superficial TFB. All therapy should be com- cine should be the first choice.91–93 If this is not effective, col-
bined with bedrest.26,66 However, it is very important for clini- chicine can be combined with benzathine penicillin.94,95 Short-
cians to be aware that topical treatment has a great possibility term corticosteroids in combination with other drugs such as
of having only local effects and should almost always be asso- colchicine can be used as an alternative in the treatment of
ciated with systemic therapy. acute attacks of OU, GU, EN-like lesions and superficial

628 © 2016 Japanese Dermatological Association


TFB.66,67,96 Dapsone97 can also be used at this stage as an
effective compound. Patients with severe mucocutaneous dis-
ease or those who are unresponsive to the respected treat-
ments can be treated with azathioprine.98 Thalidomide99 is also
an effective choice. However, because of potential side-
effects, it should be used cautiously in selected patients. It is
wise to keep in mind that EN-like lesions worsen during
thalidomide treatment. Zinc sulfate100 and rebamipide101 can
be other choices, however, there is still a need for well-orga-
nized newer studies of these agents. Cyclosporin,102,103
apremilast,104 IFN-a,105 anti-TNF- agents106 and isotretinoin107
are other alternatives to control the disease in unresponsive
cases.
New biological treatments
There is a general agreement that wider use of biologics such
as anti-TNF-a agents, yielded clinically significant improve-
ments in the majority of patients. Almost all trials with anti-
TNF-a agents, infliximab, adalimumab and etanercept reported
encouraging results for recalcitrant mucocutaneous lesions
besides ocular and gastrointestinal symptoms, arthritis and
cerebral vasculitis.66,115 Other biologics such as IL-1, -2, -6, -
12, -17 and -23-blocking agents and monoclonal antibody
against CD20 have been increasingly used in recent years in
patients with BD refractory to other treatments. Most of the
studies related to the respected biologics concentrated on the
eye disease or other major organ involvements. Only a few of
them evaluated the responses of individual mucocutaneous
manifestations. Vitale et al.116 used canakinumab, an IL-1b
inhibitor, in three patients and reported prompt and sustained
clinical efficacy in OU and GU besides ocular and gastrointesti-
nal symptoms. Cantarini et al.117 used anakinra, a recombinant
human IL-1 receptor antagonist, in nine refractory BD patients.
Eight of them showed a prompt improvement after starting
anakinra, supporting the concept that IL-1 plays a pathological
role in this disease. However, OU, GU and skin lesions were
the most frequent manifestations refractory to anakinra, with a
poor response in seven out of nine patients. On the other
hand, tocilizumab, an IL-6 receptor antibody, seems to be inef-
fective in the treatment of mucocutaneous BD while it was
reported to be effective on neurological involvement.118 Ustek-
inumab, a human monoclonal antibody against the common
p40 subunit of IL-12 and IL-23, was used in a patient with BD,
psoriasis and hidradenitis suppurativa. Baerveldt et al.119
reported a complete response within 3 months without adjunc-
tive immunosuppressive treatment in all three diseases. Zhao
et al.120 presented a challenging case of BD with OU, GU, EN-
like lesions and arthritis. Rituximab treatment, a chimeric mon-
oclonal antibody against CD20, resulted in marked clinical
improvement by allowing for reduction in steroid requirements.
In conclusion, as a high incidence of vital organ involve-
ment, as well as the increased mortality has been recorded in
patients with BD, continuous surveillance and good manage-
ment of the disease is warranted. Working in collaboration with
other specialties to improve patient outcomes in the manage-
ment of BD is mandatory. In this respect, patient-based organi-
zations that now are allied with cognizant physicians should be
© 2016 Japanese Dermatological Association
Behcßet’s disease: an update
encouraged. Treatment has become much more effective in
recent years because of advances in understanding the patho-
genesis of the disease, and introduction of more effective and
specific newer drugs. New treatments may help improve BD
patients’ outcomes. Alleviation of most symptoms, control of
the disease or even modification of the course of the disease
are now possible.
CONFLICT OF INTEREST: None declared.
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