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Hong Kong Bull Rheum Dis 2009;9:40-44 Review Article

Update on Behet's Disease

Joyce Kit-Yu Young and Daniel Kam-Hung Ng

Abstract: Behet's disease was initially described a triad of symptoms including oral aphthous ulcers, genital ulcers
and uveitis. It was subsequently found to be a multisystem disease characterized by other manifestations
involving the articular, cutaneous, neurological, vascular, gastrointestinal and pulmonary systems. Over
past years, new information has added to our understanding of this disease. This article summarizes an
update in the classification criteria, pathophysiology, clinical manifestation and treatment options in Behet's
disease.

Keywords: Behet's disease, Pathophysiology, Treatment

Introduction extending from the Mediterranean to the Far East. Its


prevalence differs in different ethnic groups. It ranges from
Behet's disease (BD) is a chronic inflammatory disease first less than 1 per 100,000 in United Kingdom to around 400 per
described by Hulusi Behet in 1937 as a triad of symptoms, 100,000 in some part of Turkey.1 Some clinical manifestations
namely oral aphthous ulcers, genital ulcers and uveitis. The show regional difference. The gastrointestinal involvement is
disease is indeed recognized worldwide and its severity tends more common in the Far East but rare in Turkey. More positive
to correlate with its prevalence. Over the past years, there pathergy tests were observed in the Turkish and the Japanese
have been ongoing studies and research to help add to the than in the Northern European and Americans.1 BD is rare in
understanding of this disease. Improved recognition and Hong Kong. According to Mok et al, only 37 adult patients
reporting has contributed to physicians' awareness on some were classified as BD from four regional hospitals between
of the latest developments. This review highlights the recent the years 1978 to 2000. Local BD runs a more benign course.
update in the classification criteria, pathophysiology, neuro- The presenting features at the time of diagnosis were oral
manifestation as well as latest treatment options in Behet's ulceration (100%), genital ulcers (81%), skin lesions (73%),
disease. arthritis/arthralgia (54%) and ocular lesion (35%). Other major
organ involvement was rare.2

Epidemiology
Classification Criteria
BD is also known as the "Silk road disease" because it is most
commonly seen in the region along the ancient trading route There are no specific symptoms, signs nor laboratory findings
in BD. The diagnosis is made merely by recognizing a group
of clinical features. Hence various experts have developed
various clinical criteria. More than ten sets of classification
D EPARTMENT OF MEDICINE AND GERIATRICS , C ARITAS M EDICAL
criteria have been developed internationally since 1946. The
CENTRE, 111 WING HONG STREET, SHAMSHUIPO, KOWLOON, HONG
KONG SAR
Diagnostic Criteria defined by the 1990 International Study
Joyce Kit-Yu Young MBChB, MRCP(UK) Group (ISG) for BD is one of the more commonly cited ones.
Daniel Kam-Hung Ng MBBS, MRCP, FHKAM In the ISG criteria, recurrent oral ulceration is a pre-requisite,
plus any two of the following features include recurrent genital
Correspondence to: Joyce Kit-Yu Young ulceration, eye lesions, skin lesions or positive pathergy test.3
Young and Ng 41

However, Fereydoun Davatchi showed that this classification to be linked with disease susceptibility as well. 10 Small
criterion has good specificity, poor sensitivity and accuracy ubiquitin-like modifier 4 (SUMO4) gene is involved in
for the diagnosis of BD in the Iranian. 4 This led to the autoimmune and inflammatory responses through down
development of a new International Criteria of Behet's regulation of NF-B signal, leading to decrease transcription
Disease 2006 (Table 1).5 Validation studies showed that this of pro-inflammatory cytokines. Its' polymorphism has been
new criterion has a sensitivity of 96.1%, a specificity of shown to correlate with type I diabetes in several Asian
88.7% and an accuracy of 93.8%. populations. Hou et al found that SUMO4 +438C allele
associates with susceptibility to BD in HLA-51 negative
Chinese Han patients, while the AGAT haplotype is protective
Pathophysiology against BD in HLA-B51 negative patients.11 Polymorphism
in the natural resistance associated macrophage protein
Genetics (NRAMP1) gene, also named as solute carrier family 11
The exact pathophysiology of BD remains unknown. It is member A1 gene (SLC11A1) seems result in different BD
generally accepted as an intense inflammatory reaction in a susceptibility in different ethnic group. SLC11A1 exerts its'
genetically predisposed host. Among all the genes that have role by up-regulating TNF-, inducible nitric oxide syntase
been proposed to play a role, human leukocyte antigen-B51 (iNOS), and major histocompatibility complex (MHC) class
(HLA-B51) has the strongest association. 6,7 The genetic II genes expression. Kim et al concluded SLC11A1
association of HLA-B51 among different ethnic groups nearly polymorphism may offer a protective effect against BD in the
corresponds with global disease distribution of BD. Countries Korean population.12 while the others found another genetic
with high prevalence of HLA-B51, like Greece, Turkey, polymorphism in SLC11A1 may be one of the plausible
Middle East, Iran and Japan, were found to associate with candidate genes of BD in Turkish.13
high BD prevalence. While in those ethnic groups with low
HLA-B51 prevalence, like the European and the African, BD Immunopathogenesis
is similarly infrequent.6 Apart from HLA-B51, the associations Apart from underlying genetic predisposition, immune
with other HLA alleles may have prognostic significance in dysfunction plays a crucial role in BD. It has been shown that
BD patients. Bettencourt et al found that HLA-B27 allele was the pathergy test at 4 hours was mediated by neutrophils and
increased in the severe Portugal BD patients but absent in lymphocytes in the absence of vasculitis.14 At 48 hours, the
those with mild disease.8 dermis in the pathergy test was infiltrated by mononuclear
cells composed mainly of T lymphocytes.15 This suggested
Indeed, many other non-HLA genes may also correlate with the role of T lymphocytes in the disease progression of BD. It
BD. From whole genome screening of multi-case families, is postulated that T cells in BD are hypersensitive to a variety
BD was found to have genetic association with at least 16 of antigens, and this hypersensitivity triggers off the immune
different non-HLA susceptibility foci. 9 In the Turkish cascade in BD. The activated T cells recruit and activate
population, tumor necrosis factor- (TNF-) allele was found monocytes through CD40-CD154 interaction and other T cell
derived cytokines. The turned-on monocytes produce IL-12,
leading to the shift to Th1 response. And in consequence to
T cells activation and production of proinflammatory
Table 1. International Criteria of Behet's Disease cytokines such as TNF-, IFN-, IL-8 and IL-17, neutrophils
Criteria Point were primed and activated.16, 17

Oral aphthosis 1 A number of antigens induce T cells hypersensitivity. These


Skin lesion 1 include antigens from viruses, bacteria; heat shock proteins
Vascular lesion 1 and some autoantigens. For example, in BD uveitis,
autoimmunity to retinal antigens (like the S-antigen, a soluble
Positive pathergy test 1
protein in retina and pineal gland and -enolase, a glycolytic
Genital aphthosis 2 enzyme present in many tissues) is well known. Antibodies
Eye lesion 2 to the selenium binding protein have recently found to
3 points or more indicates Behet's disease associate with Behet's uveitis.18
42 Update on Behet's Disease

According to a study by Choi et al, antibodies against thrombosis. The manifestations are typical symptoms and
saccharomyces cerevisiae (ASCA), which is a species of signs of increased intracranial pressure.
budding yeast used in baking and brewing, are present in
44% of BD patients with active gastrointestinal (GI) Three case-control studies have reported more neurological
involvement, compared to only 3% in those without active manifestations in BD patients who have received cyclosporin
GI manifestation.19 A than in those who did not. In the study by Ktter and
colleagues,24 among 117 studied cases (all were adult, fulfilled
Vasculopathy in Behet's Disease the ISG criteria or the Dilsen criteria for the classification of
Vascular involvement is not uncommon in those high disease BD, 4 largest treatment groups identified were steroid,
prevalence ethnic groups. Venous thrombosis composes interferon, azathioprine and cyclosporine A, frequency of
majority of cases with vascular presentation. What gives rise ocular disease in the 4 groups were 61%, 96%, 76% and 71%
to such a 'prothrombotic state' in BD remains uncertain. respectively), 10 developed neurological manifestations and
Studies have been done to try looking into the pathogenic all presented with parenchymal involvement. Six of them were
mechanism behind. This prothrombotic phenomenon seems on maintenance cyclosporin A treatment and the other four
not related to the deficiency of protein C, protein S, were untreated at the onset of neurological symptoms. All 6
antithrombin III and factor V Leiden.16,20 Though there is cases came from 21 cyclosporine A treatments. In contrast,
increase in thrombin, thrombomodulin generation as well as those treated with other regimens had no new neurological
fibrinolysis, these were not related to thrombosis observed in manifestations. This difference was significant. Regarding the
BD. 16,20 In that case, coagulopathy may not explain the use of cyclosporine A in BD, the increased risk of neurological
thrombosis in BD. Study shown a higher prevalence of anti- complication raises caution amongst doctors. In the latest
endothelial cell antibodies in the sera of BD patients and their European League Against Rheumatism (EULAR)
presence correlated with the clinical activity.21 Whether or recommendations for the management of Behet's disease,25
not the presence of anti-endothelial antibodies predispose to it suggested that cyclosporin A should not be used in patients
thrombosis remains to be elucidated. with BD with central nervous system involvement unless
necessary for intraocular inflammation.
Concerning arterial involvement, it mainly manifests as arterial
occlusion and aneurysm formation. Histologically, the
inflammation involving the vessel wall is mainly confined to New Treatment Option for Behet's Disease
the adventitial layer.22 And the number of vasa vasorum with
infiltration of neutrophils and lymphocytes was significantly Generally, in patients with mild mucocutaneous and/or
increased in vasculo-Behet's disease compared with that arthritic symptoms, local steroid and oral colchicine are the
observed in other inflammatory aneurysms.23 This suggested drugs of choice. In case of moderate to severe mucocutaneous
BD arterial inflammation probably caused by a neutrophilic lesions, vascular, neurological and GI symptoms, systemic
vasculitis directed at the vasa vasorum, causing arterial wall steroid or other immunosuppressants should be considered.
degeneration and subsequent aneurysm formation. Azathioprine plus steroid are the core drug treatments for
uveitis. For patients with refractory eye involvement,
cyclosporin A is the drug of choice.
Cyclosporin A and Neuro-Behet's Disease
Anti-tumor necrosis factor (TNF) agents have recently
Though rare, neurological features occur in 5 to 10% of BD received considerable attention in BD. Amongst all anti-TNF
patients. The neurological features contribute significantly to agents, infliximab is the drug most studied. It was first
both morbidity and mortality.1 Among those with neurological described as a rapid and effective treatment for 5 patients with
manifestation, more than 70% of them affect the brain relapsing uveitis.26 After a single infusion at the dosage of
parenchyma, involve the brainstem, cerebral and/or cerebellar 5 mg/kg; it decreased the ocular inflammation by 50% on
hemispheres or spinal cord. It gives rise to sensorimotor day 1 and 90% by day 4. By day 7, the retinal infiltrates and
symptoms/signs, long tract signs, cranial nerves palsies and vasculitis had completely resolved in all patients. Subsequent
cerebellar dysfunction. The remaining 25% of patients present three open prospective studies have demonstrated that
with non-parenchymal features in the form of dural sinus infliximab was able to reduce the frequency of uveitis relapse
Young and Ng 43

significantly during treatment period. 27-29 In addition to B cell depletion therapy has also been reported to be effective
reducing frequency of relapse; infliximab improved visual in difficult cases of BD. A case of resistant retinal vasculitis,
acuity, reduced muco-cutaneous lesions and spared the use refractory to azathioprine, local and systemic steroid,
of other immunosuppressants. Among the three studies, only subsequent methylprednisolone and etanercept, was
one case of tuberculosis was reported. effectively treated with rituximab infusion. Remission was
sustained for up to 24 months.34
So far, there have been no controlled trials on the efficacy of
treatments for any sort of neurological involvement in BD. A randomized, single blind controlled study to evaluate the
For the use of infliximab in neuro-Behet, only case reports efficacy of rituximab in treating severe ocular manifestation of
available.30 Infliximab seems to have a role in patients who Behet's disease is completed and awaiting to be published.35
failed to response to other immunosuppressive agents.
Other novel treatments reported to reduce the number of oral
Naganuma et al looked into the efficacy of infliximab for ulcers include probiotic yogurts containing the bacteria
induction and maintenance of remission for fluminant Bifidobacterium lactis, topical tacrolimus, sublingual tablets
intestinal BD.31 Among 6 patients with steroid dependent of interferon-, zinc sulphate mouth wash and nigellar sativa
intestinal BD and were refractory to immunosuppressants, oil.5
4 of them achieved remission by infliximab and the remission
was maintained with scheduled treatment of infliximab, with In 2008, the European League Against Rheumatism (EULAR)
the longest remission for about 3 years. The other 2 required published a comprehensive recommendation for the
surgery and one of them has maintained remission by management of BD. Treatments suggested for ocular,
infliximab for 2 years after operation. It seemed that infliximab mucocutanoeus and arthritic symptoms are mostly evidence-
is a good choice as induction and maintain remission in severe based. However, recommendations for vascular, neurological
intestinal BD. and intestinal involvement were largely based on expert
opinion and uncontrolled evidence due to lack of controlled
Etanercept was showed to suppress most of the muco- studies for these rare and potentially fatal manifestations.25
cutaneous lesions when compared to placebo in a double-
blinded placebo controlled trial.32
Conclusion
For adlimumab, there is limited data to support its' use in BD
currently. Behet's disease like other chronic inflammatory disease is a
complicated disease entity with various clinical manifestations
Concerning the safety issue with the use of anti-TNF agents and severity of symptoms. With new advances and innovative
in BD, we have to always bear in mind the major side effects concepts, we are looking forward to further new studies and
include infection, demyelinating disease, malignancies and breakthrough management in this disease.
congestive heart failure. Either short-term or long-term
administration of infliximab was well tolerated in almost all
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