Behcet Disease

Background

Behcet disease is a rare disorder characterized by recurrent oral and genital ulceration, eye lesions, and multiple skin lesions. The first modern description was in the 1930s by a Turkish dermatologist, Hulusi Behcet, who noted the triad of aphthous oral ulcers, genital lesions, and recurrent eye inflammation. A recent consensus conference identified several criteria to establish the diagnosis. Some of these parameters include:

Mucocutaneous lesions (oral ulcers-recurrent, at least three times per year)

Patients must also meet two of the following four criteria:
Recurrent genital ulcerations
Eye lesions (uveitis or retinal vasculitis)
Positive pathergy test (trauma induced lesions)
Skin lesions as diagnostic of Behcet's disease

The skin lesions range from leukocytoclastic vasculitis, pustular dermatitis, and clinical lesions resembling Sweet's syndrome, pyoderma gangrenosum, and erythema nodosum. Some investigators believe only cutaneous lesions containing infiltrates of neutrophils around blood vessels is diagnostic.

This disease is characterized by recurrence and relapse. Like many vasculitides, this disease may affect multiple organs. See the outline below for a detailed discussion.

OUTLINE

Epidemiology

Disease Associations

Pathogenesis

Laboratory/Radiologic/Other Diagnostic Testing

Gross Appearance and Clinical Variants

Histopathological Features and Variants

Special Stains/
Immunohistochemistry/
Electron Microscopy

Differential Diagnosis

Prognosis

Treatment

Commonly Used Terms

Internet Links

EPIDEMIOLOGY CHARACTERIZATION

INCIDENCE Behcet syndrome

GEOGRAPHY
Japan and China
Mediterranean Sea, including countries such as Turkey and Iran. Rare in the United States

SWITZERLAND

Behcet's disease in Western Switzerland: epidemiology and analysis of ocular involvement.

Ambresin A, Tran T, Spertini F, Herbort C.

Department of Ophthalmology, Hopital Ophtalmique Jules Gonin, Switzerland.

Ocul Immunol Inflamm 2002 Mar;10(1):53-63 Abstract quote
PURPOSE: To determine the epidemiology of Behcet's disease in Western Switzerland and to study the characteristics of ocular disease.

METHODS: Patients newly diagnosed with Behcet's disease, seen from January 1990 to December 1998 at Hopital Jules Gonin, La Source Eye Center, and the Division of Immunology and Allergy, University of Lausanne, were analyzed. The Japanese diagnostic criteria for Behcet's disease were used and both complete and incomplete forms were included. Incidence, proportion of cases with ocular involvement, and the characteristics of ocular disease were determined.

RESULTS: During the follow-up period, a total of 35 Behcet's patients were seen in the three study centers. Twenty-five of these patients had ocular involvement. The incidences of Behcet's disease and Behcet's ocular disease in the western part of Switzerland, with a referral population of roughly 600000 persons, were 0.65 and 0.46 per 100000 per year, respectively. The mean age of the group was 33.2 years, age at presentation was 25.8 years, and mean follow-up was 5.7 years. The most frequent sign was oral aphthous involvement (86%), followed by ocular manifestations (72%). The HLA-B51 antigen was present in 66% of the patients with ocular involvement. Panuveitis was present in 20/25 patients (80%), anterior uveitis in 3/25 patients, and posterior involvement in 2/25 patients. Twenty-two patients (88%) had systemic treatment that always included corticosteroids; it was associated with other treatments in 17/22 patients. Mean duration of treatment was 45.5 +/- 25.1 (SD) months. The mean recurrence-free period in the six patients in whom treatment could be interrupted was 18.0 +/- 8.8 (SD) months. Visual function was maintained at the end of the follow-up for the collective and visual outcome was correlated to visual function at presentation.

CONCLUSIONS: The incidence of Behcet's disease in Western Switzerland was comparable to that in other western nonendemic countries. With early diagnosis and appropriate therapy, the prognosis was favorable in our collective of patients.

DISEASE ASSOCIATIONS CHARACTERIZATION

Familial cases Rare, <5% of cases

PATHOGENESIS CHARACTERIZATION

GENERAL
Gene HLA-B51 is a risk factor for this disease but does not cause Behcets

Possible triggering events include infections and other environmental exposures

FAS LIGAND (CD95)

Aberrant Fas ligand expression in lymphocytes in patients with Behcet's disease.
Wakisaka S, Takeba Y, Mihara S, Takeno M, Yamamoto S, Sakane T, Suzuki N.

Department of Immunology, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.

Int Arch Allergy Immunol 2002 Oct;129(2):175-80 Abstract quote
BACKGROUND: Defects in immune responses have been reported in patients with Behcet's disease (BD). To further characterize the immune dysfunction and its contribution to the pathogenesis, we have studied Fas ligand (FasL) expression in peripheral blood lymphocytes (PBL) and mononuclear cells in the skin lesions in patients with BD.

METHODS: FasL expression in PBL was studied with RT-PCR and immunoblotting with rabbit anti-human FasL antibody. We studied the expression of FasL in cryostat sections of biopsy specimens of erythema nodosum lesions from 4 patients with BD and of a genital ulcer lesion in another patient using immunohistochemical staining. Apoptotic cell death was detected with the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) method.

RESULTS: We found that FasL mRNA and FasL protein expression was detected marginally in the unstimulated PBL, and was induced upon activation in normal individuals. PBL from patients with BD exhibited an enhanced expression of FasL mRNA and FasL protein without in vitro stimulation. Moreover, mitogen stimulation failed to augment FasL expression of their lymphocytes, suggesting a dysregulation of FasL expression of PBL in patients with BD. The skin biopsy specimens revealed that cells infiltrating into skin lesions expressed FasL and there were several TUNEL staining-positive cells in the lesions, suggesting that Fas/FasL-mediated apoptosis is involved in the development of the skin lesion and thus may be associated with the pathogenesis.

CONCLUSIONS: We found an excessive expression of FasL in circulating as well as skin-infiltrating lymphocytes and the presence of apoptotic cells in the skin lesions, suggesting that lymphocytes expressing FasL aberrantly may play a role in the development and pathogenesis of BD.

GRANULOCYTE COLONY-STIMULATING FACTOR

Elevated serum granulocyte colony-stimulating factor levels in patients with active phase of sweet syndrome and patients with active behcet disease: implication in neutrophil apoptosis dysfunction.

Kawakami T, Ohashi S, Kawa Y, Takahama H, Ito M, Soma Y, Mizoguchi M.

Department of Dermatology, St Marianna University School of Medicine, Kanagawa, Japan.

Arch Dermatol. 2004 May;140(5):570-4. Abstract quote

BACKGROUND: Sweet syndrome (SS), an acute inflammatory disease, has clinical and laboratory features similar to those of Behcet disease (BD). Serum levels of granulocyte colony-stimulating factor (G-CSF) are elevated in patients with SS, and exogenous administration of G-CSF has repeatedly been implicated in the causation of SS. Granulocyte colony-stimulating factor is a hematopoietic growth factor that regulates the production and differentiation of neutrophils.

OBJECTIVES: To clarify the role of elevated serum G-CSF levels in patients with active SS and active BD compared with those with inactive SS or BD and healthy controls. To then analyze neutrophil apoptosis in the active state of SS and BD; and to also investigate the influence of autologous serum on neutrophil apoptosis.

METHODS: Serum G-CSF was examined in 5 patients with active SS, 7 with inactive SS, 7 with active BD, 9 with inactive BD, and 5 healthy controls by means of an enzyme immunoassay kit. We measured apoptotic cells in the neutrophil fraction of peripheral blood collections in patients with active diseases and controls by means of flow cytometry.

RESULTS: Serum G-CSF level was significantly higher in patients with active SS than in those with inactive SS. The difference in serum G-CSF levels among patients with active and inactive BD was also significant. Serum G-CSF level was significantly higher in patients with active SS than in those with active BD. Neutrophil apoptosis was significantly higher in patients with active SS than healthy controls. This increased apoptosis rate was also seen in patients with active BD. The increased rate of neutrophil apoptosis was significantly suppressed when the neutrophils were cultured for 18 hours in the presence of autologous active SS serum. Similarly, neutrophil apoptosis was suppressed in the presence of autologous serum in patients with active BD, but not significantly so.

CONCLUSIONS: These findings indicate that increased production of G-CSF in patients with SS and BD may play an important role in the manifestation of these disorders. Given the suppression of neutrophil apoptosis in the active state in the presence of the influence of autologous serum, which includes elevated G-CSF level, we propose that serum G-CSF plays a significant role in the suppression of neutrophil apoptosis. Furthermore, G-CSF-induced suppression of neutrophil apoptosis appears to be deeply involved in the pathogenesis of SS and BD

HSP 60

HSP 60 expression in mucocutaneous lesions of Beh�et's disease

T�lin Ergun, MD
�mit nce, MD
Emel Ekiolu-Demiralp, MD
Haner Direskeneli, MD
Oya G�rb�z, MD
Leyla G�rses, MD
F�gen Aker, MD
Tevfik Akolu, MD

Istanbul, Turkey

J Am Acad Dermatol 2001;45:904-9. Abstract quote

Background: Heat shock protein (60 kd HSP) has been implicated in the etiology of Beh�et's disease, but its expression at sites of inflammation is unknown. Objective: Our aim was to investigate local HSP 60 expression and to quantify T-cell receptor (TCR) -positive cells, which are known to respond to HSP peptides.

Methods: Patients with active Beh�et's disease (n = 21) and controls (n = 18) were included. Flow cytometric analysis was performed on peripheral blood to investigate TCR -positive cell counts. Biopsies were performed on active skin lesions, and immunohistochemical analysis was performed by a streptavidin-biotin method using the monoclonal ML-30 antibody; HSP staining intensity and distribution were evaluated in a blinded fashion. Immunhistochemical studies were performed to quantify TCR -positive cells at lesional sites.

Results: Mucocutaneous lesions of patients with Beh�et's disease had statistically significantly increased expression of HSP 60/65. Peripheral blood TCR -positive cell counts were similar in both groups. However, lesional skin of patients with Beh�et's disease had significantly increased -positive T-cell counts.

Conclusion: Up-regulation of HSP expression was found at lesional skin sites in Beh�et's disease. The increased number of TCR -positive cells, which are known to respond to HSP peptides, may support the function of HSPs in the etiology of Beh�et's disease. However, these findings may also be an epiphenomenon that needs to be further investigated.

NITROUS OXIDE

Increased nitric oxide production in patients with Beh�et's disease: Is it a new activity marker?

Cem Evereklioglu, MD
Yusuf Turkoz, PhD
Hamdi Er, MD
H. Serhat Inaloz, MD, MS
Emin Ozbek, MD
Mustafa Cekmen, MD, PhD

Gaziantep and Malatya, Turkey

J Am Acad Dermatol 2002;46:50-4 Abstract quote

Background: The origin of Beh�et's disease (BD) is unclear. One of the prominent features of BD is vasculitis and thrombosis as a result of endothelial dysfunction. Because nitric oxide (NO) is synthesized by endothelium, we considered it as an interesting target of investigation in BD.

Objective: Our purpose was to define the level of NO in the serum of patients with BD and its relation with disease activity.

Methods: As an indicator for NO, serum total nitrite levels (end product of NO) were measured by Griess reaction in 52 consecutive patients with BD and compared with 32 age- and sex-matched healthy staff volunteers. Serum NO levels of active and inactive patients were compared.

Results: The overall serum nitrite levels in patients with BD (40.25 � 10.51 �mol/L) were significantly higher (P < .001) than those in healthy volunteers (25.09 � 5.33 �mol/L). The difference in serum total nitrite levels among patients with active BD (46.74 � 10.62 �mol/L) and inactive BD (33.24 � 3.73 �mol/L) was significant (P < .001). Significant differences were observed in serum nitrite levels between patients in the inactive period of BD and the control group (P < .001).

Conclusion: Increased NO production might be responsible for the overall inflammatory process of BD. NO seems to be related to disease activity.

T-CELLS

Expansion of gammadelta T-cells in Behcet's disease: role of disease activity and microbial flora in oral ulcers.

Bank I, Duvdevani M, Livneh A.

Department of Medicine, Chaim Sheba Medical Center, Sackler School of Medicine, Tel Hashomer, Israel.
J Lab Clin Med 2003 Jan;141(1):33-40 Abstract quote
Gammadelta T-cells participate in the immune response to infections and in autoimmunity by recognizing bacteria-derived and autologous antigens.

The goal of this study was to evaluate the involvement of gammadelta T-cells in Behcet's disease (BD). Gammadelta T-cells in the peripheral-blood mononuclear cells (PBMCs) of Israeli patients with definite BD (n = 23), normal controls (n = 16), and patients with familial Mediterrranean fever (FMF; n = 20) were evaluated by means of flow cytometry. The responses of patient and control gammadelta T-cells to medium conditioned by microorganisms cultured from an oral ulcer of a patient with active BD were compared. The proportions of CD3(+) and CD8(+) cells in the PBMCs were not significantly different between groups. In contrast, gammadelta-T-cells accounted for 7.01% +/- 4.42% of the PBMCs in BD compared with 3.56% +/- 3.45% in FMF (P < .005) and 3.7% +/- 3.15% in normal individuals (P < .009). Their numbers were significantly higher during active disease than in remission (9.45% +/- 5.08% versus 2.27% +/- 3.3%; P < .009).

The number of T-cell-receptor gammadelta(+) and Vdelta2(+) cells of BD patients, but not of controls, increased after 96 hours of culture in medium containing supernatant of microorganisms cultured from an oral ulcer in a patient with BD relative to their proportions in control medium: 58.2% vs 13.9% (P < .05) and 28% vs 9% (P < .04), respectively, of the cultured T-cells (n = 4).gammadelta T-cells are expanded in BD PBMCs during active disease.

An exaggerated proliferative response to products released by microorganisms present in oral ulcers may play a role in this phenomenon.

LABORATORY/
RADIOLOGY CHARACTERIZATION

RADIOLOGY

MRI

Arthropathy in Behcet Disease: MR Imaging Findings in Two Cases.

Choi JA, Kim JE, Koh SH, Chung HW, Kang HS.

Department of Radiology, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul 110-744, Korea. Received December 4, 2001.
Radiology 2003 Feb;226(2):387-9 Abstract quote
Arthropathy is part of the protean manifestations of Behcet disease. Imaging findings reported thus far have been based on those of conventional radiography.

Magnetic resonance imaging in two cases of Behcet disease with arthropathy demonstrated synovial thickening and effusion, as well as myositis manifested by high signal intensity on T2-weighted images.

SPECT

Decreased cerebral blood flow in neuro-Behcet's syndrome patients with neuropsychiatric manifestations and normal magnetic resonance imaging--a preliminary report.

Huang WS, Chiu PY, Kao A, Tsai CH, Lee CC.

Department of Neurology, China Medical College Hospital, No 2, Yuh-Der Road, Taichung 404, Taiwan, ROC.
J Neuroimaging 2002 Oct;12(4):355-9 Abstract quote
Involvement of the brain is one of the most important complications of Behcet's disease, but its diagnosis is difficult because of the lack of effective imaging tools.

Therefore, technetium-99m ethyl cysteinate dimer (Tc-99m ECD) single-photon emission computed tomography (SPECT) of the brain was used to detect abnormal regional cerebral blood flow in patients with neuro-Behcet's syndrome (NBS). Tc-99m ECD brain SPECT was performed to detect hypoperfusion areas of the brain in 10 NBS patients with definite neuropsychiatric symptoms or signs and normal brain magnetic resonance imaging (MRI) findings. Tc-99m ECD brain SPECT demonstrated hypoperfusion areas of the brain in all of the 10 NBS patients.

The parietal lobes were the most common areas with hypoperfusion lesions. Tc-99m ECD brain SPECT is a more sensitive and useful tool than brain MRI for detecting hypoperfusion areas of the brain in NBS patients.

LABORATORY

SERUM CYTOKINES

Cytokine profile in Behcet's disease patients. Relationship with disease activity.

Hamzaoui K, Hamzaoui A, Guemira F, Bessioud M, Hamza M, Ayed K.
Scand J Rheumatol 2002;31(4):205-10 Abstract quote
OBJECTIVE: To analyse proinflammatory Th1 and Th2 cytokines in patients with Behcet's disease (BD) in relation to disease activity.

METHODS: Forty-five BD patients (25 in active stage) were investigated with ELISA for estimation of cytokines levels. Furthermore, cytokines intracellular synthesis (IL-4 and IFN-gamma) of CD4+ T cells was studied.

RESULTS: Active and in remission BD patients showed increased serum levels of Th1 (IFN-gamma, IL-12) and Th2 (IL-4, IL-6 and IL-10) cytokines. Active BD was characterized by a higher increase of IL-6, IL-10 and a striking increase of IL-17, IL-18 and IFN-gamma, compared to remission RD. Upon in vitro stimulation, the percentages of CD4+ T cells containing IFN-gamma and CD40L were higher in active BD compared to healthy controls.

CONCLUSION: Our results suggest that the microenvironment of CD4+ T cells in active BD may induce the production of more cells committed to Th1 than in BD patients in remission and healthy controls.

GROSS APPEARANCE/
CLINICAL VARIANTS CHARACTERIZATION

VARIANTS

Central nervous system
White matter lesions with in brain and brainstem leading to headaches, confusion, strokes, personality changes, and dementia in rare cases

Aseptic meningitis

Eye Anterior uveitis or posterior uveitis

Genitals
Painful deep scrotal lesions
Painful vulvar lesions

Gastointestinal tract
Ulcerations throughout the tract favoring the terminal ileum and cecum

May clinically mimic inflammatory bowel disease, especially Crohn's disease

HEART/AORTA

Cardiac Behçet Disease Presenting as Aortic Valvulitis/Aortitis or Right Heart Inflammatory Mass: A Clinicopathologic Study of 12 Cases.

Lee I, Park S, Hwang I, Kim MJ, Nah SS, Yoo B, Song JK.

Departments of *Pathology †Internal Medicine, Division of Cardiology ‡Division of Immunology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Am J Surg Pathol. 2008 March 32(3);390-398 Abstract quote

Behçet disease is an inflammatory disorder of unknown etiology showing diverse clinical presentations. Cardiac involvement is a critical problem that requires a timely diagnosis and management. However, clinicopathologic features have not been characterized clearly.

Here, we present clinicopathologic characteristics of this uncommon disease. Patients included 8 males and 4 females, ranging from 24 to 52 years old. They were presented with abrupt heart failure and were mostly diagnosed as having cardiac Behçet disease later in the course. Upon echocardiography, 8 patients showed severe aortic regurgitation with redundant prolapsing aortic cusps and 4 patients showed irregular mass lesions in the right ventricular cavity. No one had both lesions. The aortic root was also involved with aortic valvulitis, showing severe mixed acute and chronic inflammation of various stages. There were frequent microabscess and extensive endothelial loss with fibrinous deposit. The right heart lesions showed similar histopathologic features. Four patients who initially underwent simple aortic valve replacement developed serious postoperative complications requiring reoperations. No serious complications developed after the treatment was changed to a replacement of aortic root with extensive debridement and concomitant immunosuppressive therapy.

Cardiac Behçet disease is presented as aortic valvulitis/aortitis or inflammatory mass lesion. Characteristic echocardiographic and pathologic findings seem to be helpful for the timely diagnosis of this critical disease.

Joints Arthritis

Lung Aneurysms of arteries in the lung which may rupture leading to massive lung hemorrhage

Mouth
Aphtous ulcers-painful sores in the mouth More numerous, more frequent, more painful, and larger than cases in the general population

Lips, tongue, and inside of the cheek.

Occur in virtually all patients with Behcet’s

HISTOLOGICAL TYPES CHARACTERIZATION

General A vasculitis may be present in lesional organs

VARIANTS

Erythema nodosum-like lesions
Am J Dermatopathol 2000;22:379-390
Panniculitis in a lobular or mixed septal lobular pattern
Neutrophils present in all lesions and in all stages of the disease and usually confined to the areas of fat necrosis or around inflammed vessels

Vasculitis either leukocytoclastic or lymphocytic with some occurring in same specimen in different vessels

Clinicopathologic Evaluation of Nodular Cutaneous Lesions of Beh�et Syndrome

Cuyan Demirkesen, MD
N�khet T�z�ner, MD
Cem Mat, MD
Mustafa Senocak, PhD
Nesimi B�y�kbabani, MD
Yal�in T�z�n, MD
Hasan Yazici, MD

Am J Clin Pathol 2001;116:341-346 Abstract quote

Among the cutaneous manifestations, nodular lesions are rather common in Beh�et syndrome. The histologic nature of these lesions has been a matter of controversy.

To establish their distinguishing features, biopsy specimens from nodular lesions of 24 patients with Beh�et syndrome, 25 with nodular vasculitis (NV), and 20 with erythema nodosum (EN) were compared. Statistical analysis revealed insignificant differences between most of the histologic features of Beh�et syndrome and NV. However, neutrophil-predominating infiltrate in the subcutis was more common in Beh�et syndrome, while necrosis and granuloma formation were encountered more frequently in NV. The differences between Beh�et syndrome and EN were more significant. Septal panniculitis, lymphocyte-predominating infiltrate, absence of many vascular changes as well as vasculitis, and necrosis were features in favor of EN.

Nodular lesions of Beh�et syndrome are mainly neutrophilic vascular reactions with histologic features similar to NV but significantly differing from EN associated with other systemic diseases.

SPECIAL STAINS/
IMMUNOPEROXIDASE CHARACTERIZATION

GENERAL

Immunohistology of oral lesions from patients with recurrent oral ulcers and Behcet's syndrome.

Poulter LW, Lehner T.

Department of Immunology, Royal Free Hospital and School of Medicine, London, England.

Clin Exp Immunol 1989 Nov;78(2):189-95 Abstract quote
A qualitative and quantitative immunohistological investigation was performed on biopsies of oral ulcers from patients with Behcet's syndrome (BS) and those with recurrent oral ulcers (ROU). The results were compared with control oral biopsies from patients with other diseases and normal oral mucosa. The expression of HLA-DR on the cell membrane of keratinocytes was found in 13 out of 15 lesions from patients with BS and ROU, as compared with only one out of 15 controls.

The relative density of HLA-DR was investigated quantitatively by microdensitometry and this confirmed that DR expression in the epithelial cells of patients with BS and ROU was significantly greater than in diseased and normal control oral tissues. A prominent mononuclear cell infiltration consisted predominantly of T lymphocytes and mature macrophages. Analysis of the CD4 and CD8 subsets of T cells failed to show significant differences between BS, ROU and control diseased tissues. Increased numbers of Langerhans cells were found in the epithelium by morphometric analysis with the CD1 monoclonal antibody in BS and ROU but an increased number was also found in lichen planus.

The results suggest that the immunohistological changes in oral lesions of BS and ROU manifest an enhanced immune response in the epithelium, keratinocytes express HLA-class II antigen and increased number of Langerhans cells as well as in the lamina propria with a prominent infiltration of CD4, CD8 and macrophage-like cells.

The characteristic pattern of exacerbations and remissions of oral ulceration can be interpreted by the hypothesis that an initiating microbial agent may induce a mononuclear cell infiltration, with the release of cytokines, expression of class II antigen in keratinocytes and causing ulceration, followed by down-regulation of immunity by tolerant T cells induced by the class II positive keratinocytes, leading to a remission.

DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES

APHTHOUS ULCERS

Complex aphthosis: a large case series with evaluation algorithm and therapeutic ladder from topicals to thalidomide.

Letsinger JA, McCarty MA, Jorizzo JL.

Department of Dermatology at University of California, San Fransico, CA 94118, USA.

J Am Acad Dermatol. 2005 Mar;52(3 Pt 1):500-8. Abstract quote

BACKGROUND: Recurrent aphthous stomatitis is a common problem with 20% to 50% of the population having experienced simple aphthous lesions (ie, canker sores). Complex aphthosis is the diagnosis given to patients with almost constant >3 oral aphthae or recurrent oral and genital aphthae in the absence of Behcet's disease.

METHODS: Eighty-one patients were referred to the Wake Forest University School of Medicine, Department of Dermatology from 1995 to 2001 with the diagnosis of presumptive Behcet's disease. After exclusion of patients with simple recurrent aphthous stomatitis or non-aphthous oral disease, 64 patients remained. Ten of the patients met criteria for Behcet's disease. The remaining 54 patients were evaluated and treated as patients with the diagnosis of complex aphthosis.

RESULTS: The 54 patients with complex aphthosis became the subject of this study. Twelve patients had secondary complex aphthosis with 10/12 having inflammatory bowel disease. The remaining 42 patients had primary (ie, idiopathic) complex aphthosis. The therapeutic ladder for these patients ranged from topical therapy through oral colchicine and combination oral colchicine and oral dapsone therapy to oral thalidomide therapy.

CONCLUSION: Complex aphthosis is an important condition to distinguish from Behcet's disease. Appropriate patient evaluation algorithms and treatment therapeutic ladders are proposed.

Erythema nodosum Neutrophils present only in early lesions
Predominately a septal panniculitis

PROGNOSIS AND TREATMENT CHARACTERIZATION

TREATMENT
Colchicine, cyclophosphamide and steroids for eye involvement

Azapropazone and colchicine for arthritis

Acyclovir, colchicine and topical interpheron for aphthous ulcers

In general, there are protective effects of cyclosporine and azathioprine for eye involvement and benzathine-penicillin for arthritis

INTERFERON-ALPHA

Interferon alfa combined with azathioprine for the uveitis of Behcet's disease: an open study.

Hamuryudan V, Ozyazgan Y, Fresko Y, Mat C, Yurdakul S, Yazici H.

Behcet's Syndrome Research Center, Cerrahpaa Medical Faculty, University of Istanbul, Istanbul, Turkey.

Isr Med Assoc J 2002 Nov;4(11 Suppl):928-30 Abstract quote
BACKGROUND: Eye involvement is the main cause of morbidity in Behcet's syndrome. The efficacy of the combined use of azathioprine and interferon alfa in treating this condition has not been studied.

METHODS: Ten male BD patients with retinal involvement but no irreversible structural changes were treated with azathioprine 2.5 mg/kg/day and IFN alpha 2b three times weekly for 24 weeks in an open trial. At week 24, IFN alpha was stopped and the patients continued to use azathioprine or received other immunosuppressives as indicated. Clinical response was assessed by visual acuity changes of either eye under the combination treatment and during the follow-up after stopping interferon.

RESULTS: As compared to the study entry, the mean visual acuities of either eye increased significantly at the end of the combination treatment (right eye 5.8 +/- 1.26 vs. 8.3 1.14; P = 0.043; left eye 6.3 1.15 SEM vs. 9.1 +/- 0.9 SEM; P = 0.027). The improvement in visual acuity persisted in the nine patients who were followed for 7.2 +/- 1.6 SEM months after stopping interferon. Reversible hematologic toxicity, mostly in the form of leukopenia, was detected in six patients during the combination treatment.

CONCLUSIONS: The combination of IFN alpha and azathioprine appears to be effective for eye involvement of BD. However, the frequent occurrence of myelosuppression mandates close monitoring.

Interferon Alfa-2a in the Treatment of Behcet Disease: A Randomized Placebo-Controlled and Double-blind Study.

Alpsoy E, Durusoy C, Yilmaz E, Ozgurel Y, Ermis O, Yazar S, Basaran E.

Department of Dermatology, Akdeniz University School of Medicine, 07070 Antalya, Turkey.
Arch Dermatol 2002 Apr;138(4):467-71 Abstract quote
OBJECTIVE: To determine the therapeutic efficacy of interferon alfa-2a in the treatment of Behcet disease.

DESIGN: A randomized placebo-controlled and double-blind study.

SETTING: University referral center.

PATIENTS: Fifty patients with Behcet disease were involved in the study.

INTERVENTION: The patients were given interferon alfa-2a, 6 x 10(6) IU, subcutaneously 3 times per week or placebo for 3 months, and examined clinically at weekly intervals.

MAIN OUTCOME MEASURES: For each mucocutaneous lesion and articular symptom, the mean frequency and duration were evaluated during the 3-month pretreatment, treatment, and follow-up periods. Pain for oral and genital ulcers was scored on a scale of 0 to 3. The ocular inflammatory score, the frequency of attacks, and changes in visual acuities for patients with ocular involvement were assessed before the study, at the end of treatment, and during the follow-up periods. In addition, overall responses at the end of the treatment period were graded as follows: complete remission, disappearance of all clinical signs and symptoms during treatment; partial remission, greater than a 50% decrease in the frequency, duration, and severity of pain for oral and genital ulcers and/or a decrease in the severity and frequency of ocular attacks; stable disease, less than a 50% change in the clinical signs and symptoms; and no effect or deterioration, ineffectiveness or worsening of clinical signs and symptoms.

RESULTS: Twenty-three interferon alfa-2a- and 21 placebo-treated patients, ranging in age from 16 to 55 years (mean +/- SD age, 32.38 +/- 7.94 years), were evaluable for efficacy. Interferon alfa-2a treatment significantly decreased the duration (P=.02) and pain (P=.01) of oral ulcers and the frequency of genital ulcers (P=.03) and papulopustular lesions (P=.01). The mean frequency and duration of erythema nodosum-like lesions (P=.77 and.27, respectively), thrombophlebitis (P=.29 and.61, respectively), and articular symptoms (P=.92 and.74, respectively) also decreased. But there were no statistically significant differences. An improvement in the severity and the frequency of ocular attacks occurred in 5 of 6 patients in the interferon alfa-2a-treated group and in 1 of 3 patients in the placebo-treated group. Of the 23 patients in the interferon alfa-2a-treated group, 15 responded to treatment (2 complete and 13 partial responses); and of the 21 patients in the placebo group, 3 responded to treatment (3 partial responses) (P<.005).

CONCLUSION: Interferon alfa-2a is an effective alternative treatment for Behcet disease, particularly for the management of the mucocutaneous lesions of the disease.

Thalidomide
May be effective in the treatment of mucocutaneous Behcet�s disease

Effectiveness in more severe Behcet�s disease, however, is not known

Macpherson and Pincus. Clinical Diagnosis and Management by Laboratory Methods. Twentyfirst Edition. WB Saunders. 2006.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fifth Edition. Mosby Elesevier 2008

Commonly Used Terms

Pathergy Test-The forearm is pricked with a small, sterile needle. The occurrence of a small red bump or pustule at the site of needle insertion is a positive test. Only a minority of Behcet�s patients demonstrate the pathergy phenomenon. Mediterranean patients are more likely to demonstrate pathergy. Other conditions can occasionally result in positive pathergy tests.

Vasculitis

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RADIOLOGY
MRI
Arthropathy in Behcet Disease: MR Imaging Findings in Two Cases. Choi JA, Kim JE, Koh SH, Chung HW, Kang HS. Department of Radiology, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul 110-744, Korea. Received December 4, 2001.	Radiology 2003 Feb;226(2):387-9 Abstract quote Arthropathy is part of the protean manifestations of Behcet disease. Imaging findings reported thus far have been based on those of conventional radiography. Magnetic resonance imaging in two cases of Behcet disease with arthropathy demonstrated synovial thickening and effusion, as well as myositis manifested by high signal intensity on T2-weighted images.
SPECT
Decreased cerebral blood flow in neuro-Behcet's syndrome patients with neuropsychiatric manifestations and normal magnetic resonance imaging--a preliminary report. Huang WS, Chiu PY, Kao A, Tsai CH, Lee CC. Department of Neurology, China Medical College Hospital, No 2, Yuh-Der Road, Taichung 404, Taiwan, ROC.	J Neuroimaging 2002 Oct;12(4):355-9 Abstract quote Involvement of the brain is one of the most important complications of Behcet's disease, but its diagnosis is difficult because of the lack of effective imaging tools. Therefore, technetium-99m ethyl cysteinate dimer (Tc-99m ECD) single-photon emission computed tomography (SPECT) of the brain was used to detect abnormal regional cerebral blood flow in patients with neuro-Behcet's syndrome (NBS). Tc-99m ECD brain SPECT was performed to detect hypoperfusion areas of the brain in 10 NBS patients with definite neuropsychiatric symptoms or signs and normal brain magnetic resonance imaging (MRI) findings. Tc-99m ECD brain SPECT demonstrated hypoperfusion areas of the brain in all of the 10 NBS patients. The parietal lobes were the most common areas with hypoperfusion lesions. Tc-99m ECD brain SPECT is a more sensitive and useful tool than brain MRI for detecting hypoperfusion areas of the brain in NBS patients.
LABORATORY
SERUM CYTOKINES
Cytokine profile in Behcet's disease patients. Relationship with disease activity. Hamzaoui K, Hamzaoui A, Guemira F, Bessioud M, Hamza M, Ayed K.	Scand J Rheumatol 2002;31(4):205-10 Abstract quote OBJECTIVE: To analyse proinflammatory Th1 and Th2 cytokines in patients with Behcet's disease (BD) in relation to disease activity. METHODS: Forty-five BD patients (25 in active stage) were investigated with ELISA for estimation of cytokines levels. Furthermore, cytokines intracellular synthesis (IL-4 and IFN-gamma) of CD4+ T cells was studied. RESULTS: Active and in remission BD patients showed increased serum levels of Th1 (IFN-gamma, IL-12) and Th2 (IL-4, IL-6 and IL-10) cytokines. Active BD was characterized by a higher increase of IL-6, IL-10 and a striking increase of IL-17, IL-18 and IFN-gamma, compared to remission RD. Upon in vitro stimulation, the percentages of CD4+ T cells containing IFN-gamma and CD40L were higher in active BD compared to healthy controls. CONCLUSION: Our results suggest that the microenvironment of CD4+ T cells in active BD may induce the production of more cells committed to Th1 than in BD patients in remission and healthy controls.

PROGNOSIS AND TREATMENT	CHARACTERIZATION
TREATMENT	Colchicine, cyclophosphamide and steroids for eye involvement Azapropazone and colchicine for arthritis Acyclovir, colchicine and topical interpheron for aphthous ulcers In general, there are protective effects of cyclosporine and azathioprine for eye involvement and benzathine-penicillin for arthritis
INTERFERON-ALPHA
Interferon alfa combined with azathioprine for the uveitis of Behcet's disease: an open study. Hamuryudan V, Ozyazgan Y, Fresko Y, Mat C, Yurdakul S, Yazici H. Behcet's Syndrome Research Center, Cerrahpaa Medical Faculty, University of Istanbul, Istanbul, Turkey.	Isr Med Assoc J 2002 Nov;4(11 Suppl):928-30 Abstract quote BACKGROUND: Eye involvement is the main cause of morbidity in Behcet's syndrome. The efficacy of the combined use of azathioprine and interferon alfa in treating this condition has not been studied. METHODS: Ten male BD patients with retinal involvement but no irreversible structural changes were treated with azathioprine 2.5 mg/kg/day and IFN alpha 2b three times weekly for 24 weeks in an open trial. At week 24, IFN alpha was stopped and the patients continued to use azathioprine or received other immunosuppressives as indicated. Clinical response was assessed by visual acuity changes of either eye under the combination treatment and during the follow-up after stopping interferon. RESULTS: As compared to the study entry, the mean visual acuities of either eye increased significantly at the end of the combination treatment (right eye 5.8 +/- 1.26 vs. 8.3 1.14; P = 0.043; left eye 6.3 1.15 SEM vs. 9.1 +/- 0.9 SEM; P = 0.027). The improvement in visual acuity persisted in the nine patients who were followed for 7.2 +/- 1.6 SEM months after stopping interferon. Reversible hematologic toxicity, mostly in the form of leukopenia, was detected in six patients during the combination treatment. CONCLUSIONS: The combination of IFN alpha and azathioprine appears to be effective for eye involvement of BD. However, the frequent occurrence of myelosuppression mandates close monitoring.
Interferon Alfa-2a in the Treatment of Behcet Disease: A Randomized Placebo-Controlled and Double-blind Study. Alpsoy E, Durusoy C, Yilmaz E, Ozgurel Y, Ermis O, Yazar S, Basaran E. Department of Dermatology, Akdeniz University School of Medicine, 07070 Antalya, Turkey.	Arch Dermatol 2002 Apr;138(4):467-71 Abstract quote OBJECTIVE: To determine the therapeutic efficacy of interferon alfa-2a in the treatment of Behcet disease. DESIGN: A randomized placebo-controlled and double-blind study. SETTING: University referral center. PATIENTS: Fifty patients with Behcet disease were involved in the study. INTERVENTION: The patients were given interferon alfa-2a, 6 x 10(6) IU, subcutaneously 3 times per week or placebo for 3 months, and examined clinically at weekly intervals. MAIN OUTCOME MEASURES: For each mucocutaneous lesion and articular symptom, the mean frequency and duration were evaluated during the 3-month pretreatment, treatment, and follow-up periods. Pain for oral and genital ulcers was scored on a scale of 0 to 3. The ocular inflammatory score, the frequency of attacks, and changes in visual acuities for patients with ocular involvement were assessed before the study, at the end of treatment, and during the follow-up periods. In addition, overall responses at the end of the treatment period were graded as follows: complete remission, disappearance of all clinical signs and symptoms during treatment; partial remission, greater than a 50% decrease in the frequency, duration, and severity of pain for oral and genital ulcers and/or a decrease in the severity and frequency of ocular attacks; stable disease, less than a 50% change in the clinical signs and symptoms; and no effect or deterioration, ineffectiveness or worsening of clinical signs and symptoms. RESULTS: Twenty-three interferon alfa-2a- and 21 placebo-treated patients, ranging in age from 16 to 55 years (mean +/- SD age, 32.38 +/- 7.94 years), were evaluable for efficacy. Interferon alfa-2a treatment significantly decreased the duration (P=.02) and pain (P=.01) of oral ulcers and the frequency of genital ulcers (P=.03) and papulopustular lesions (P=.01). The mean frequency and duration of erythema nodosum-like lesions (P=.77 and.27, respectively), thrombophlebitis (P=.29 and.61, respectively), and articular symptoms (P=.92 and.74, respectively) also decreased. But there were no statistically significant differences. An improvement in the severity and the frequency of ocular attacks occurred in 5 of 6 patients in the interferon alfa-2a-treated group and in 1 of 3 patients in the placebo-treated group. Of the 23 patients in the interferon alfa-2a-treated group, 15 responded to treatment (2 complete and 13 partial responses); and of the 21 patients in the placebo group, 3 responded to treatment (3 partial responses) (P<.005). CONCLUSION: Interferon alfa-2a is an effective alternative treatment for Behcet disease, particularly for the management of the mucocutaneous lesions of the disease.
Thalidomide	May be effective in the treatment of mucocutaneous Behcet�s disease Effectiveness in more severe Behcet�s disease, however, is not known

Epidemiology
Disease Associations
Pathogenesis
Laboratory/Radiologic/Other Diagnostic Testing
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Special Stains/ Immunohistochemistry/ Electron Microscopy
Differential Diagnosis
Prognosis
Treatment
Commonly Used Terms
Internet Links

EPIDEMIOLOGY	CHARACTERIZATION
INCIDENCE	Behcet syndrome
GEOGRAPHY	Japan and China Mediterranean Sea, including countries such as Turkey and Iran. Rare in the United States
SWITZERLAND
Behcet's disease in Western Switzerland: epidemiology and analysis of ocular involvement. Ambresin A, Tran T, Spertini F, Herbort C. Department of Ophthalmology, Hopital Ophtalmique Jules Gonin, Switzerland.	Ocul Immunol Inflamm 2002 Mar;10(1):53-63 Abstract quote PURPOSE: To determine the epidemiology of Behcet's disease in Western Switzerland and to study the characteristics of ocular disease. METHODS: Patients newly diagnosed with Behcet's disease, seen from January 1990 to December 1998 at Hopital Jules Gonin, La Source Eye Center, and the Division of Immunology and Allergy, University of Lausanne, were analyzed. The Japanese diagnostic criteria for Behcet's disease were used and both complete and incomplete forms were included. Incidence, proportion of cases with ocular involvement, and the characteristics of ocular disease were determined. RESULTS: During the follow-up period, a total of 35 Behcet's patients were seen in the three study centers. Twenty-five of these patients had ocular involvement. The incidences of Behcet's disease and Behcet's ocular disease in the western part of Switzerland, with a referral population of roughly 600000 persons, were 0.65 and 0.46 per 100000 per year, respectively. The mean age of the group was 33.2 years, age at presentation was 25.8 years, and mean follow-up was 5.7 years. The most frequent sign was oral aphthous involvement (86%), followed by ocular manifestations (72%). The HLA-B51 antigen was present in 66% of the patients with ocular involvement. Panuveitis was present in 20/25 patients (80%), anterior uveitis in 3/25 patients, and posterior involvement in 2/25 patients. Twenty-two patients (88%) had systemic treatment that always included corticosteroids; it was associated with other treatments in 17/22 patients. Mean duration of treatment was 45.5 +/- 25.1 (SD) months. The mean recurrence-free period in the six patients in whom treatment could be interrupted was 18.0 +/- 8.8 (SD) months. Visual function was maintained at the end of the follow-up for the collective and visual outcome was correlated to visual function at presentation. CONCLUSIONS: The incidence of Behcet's disease in Western Switzerland was comparable to that in other western nonendemic countries. With early diagnosis and appropriate therapy, the prognosis was favorable in our collective of patients.

DISEASE ASSOCIATIONS	CHARACTERIZATION
Familial cases	Rare, <5% of cases

GROSS APPEARANCE/ CLINICAL VARIANTS	CHARACTERIZATION
VARIANTS
Central nervous system	White matter lesions with in brain and brainstem leading to headaches, confusion, strokes, personality changes, and dementia in rare cases Aseptic meningitis
Eye	Anterior uveitis or posterior uveitis
Genitals	Painful deep scrotal lesions Painful vulvar lesions
Gastointestinal tract	Ulcerations throughout the tract favoring the terminal ileum and cecum May clinically mimic inflammatory bowel disease, especially Crohn's disease
HEART/AORTA
Cardiac Behçet Disease Presenting as Aortic Valvulitis/Aortitis or Right Heart Inflammatory Mass: A Clinicopathologic Study of 12 Cases. Lee I, Park S, Hwang I, Kim MJ, Nah SS, Yoo B, Song JK. *Departments of Pathology †Internal Medicine, Division of Cardiology ‡Division of Immunology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.**	Am J Surg Pathol. 2008 March 32(3);390-398 Abstract quote Behçet disease is an inflammatory disorder of unknown etiology showing diverse clinical presentations. Cardiac involvement is a critical problem that requires a timely diagnosis and management. However, clinicopathologic features have not been characterized clearly. Here, we present clinicopathologic characteristics of this uncommon disease. Patients included 8 males and 4 females, ranging from 24 to 52 years old. They were presented with abrupt heart failure and were mostly diagnosed as having cardiac Behçet disease later in the course. Upon echocardiography, 8 patients showed severe aortic regurgitation with redundant prolapsing aortic cusps and 4 patients showed irregular mass lesions in the right ventricular cavity. No one had both lesions. The aortic root was also involved with aortic valvulitis, showing severe mixed acute and chronic inflammation of various stages. There were frequent microabscess and extensive endothelial loss with fibrinous deposit. The right heart lesions showed similar histopathologic features. Four patients who initially underwent simple aortic valve replacement developed serious postoperative complications requiring reoperations. No serious complications developed after the treatment was changed to a replacement of aortic root with extensive debridement and concomitant immunosuppressive therapy. Cardiac Behçet disease is presented as aortic valvulitis/aortitis or inflammatory mass lesion. Characteristic echocardiographic and pathologic findings seem to be helpful for the timely diagnosis of this critical disease.
Joints	Arthritis
Lung	Aneurysms of arteries in the lung which may rupture leading to massive lung hemorrhage
Mouth	Aphtous ulcers-painful sores in the mouth More numerous, more frequent, more painful, and larger than cases in the general population Lips, tongue, and inside of the cheek. Occur in virtually all patients with Behcet’s

HISTOLOGICAL TYPES	CHARACTERIZATION
General	A vasculitis may be present in lesional organs
VARIANTS
Erythema nodosum-like lesions	Am J Dermatopathol 2000;22:379-390 Panniculitis in a lobular or mixed septal lobular pattern Neutrophils present in all lesions and in all stages of the disease and usually confined to the areas of fat necrosis or around inflammed vessels Vasculitis either leukocytoclastic or lymphocytic with some occurring in same specimen in different vessels
Clinicopathologic Evaluation of Nodular Cutaneous Lesions of Beh�et Syndrome Cuyan Demirkesen, MD N�khet T�z�ner, MD Cem Mat, MD Mustafa Senocak, PhD Nesimi B�y�kbabani, MD Yal�in T�z�n, MD Hasan Yazici, MD	Am J Clin Pathol 2001;116:341-346 Abstract quote Among the cutaneous manifestations, nodular lesions are rather common in Beh�et syndrome. The histologic nature of these lesions has been a matter of controversy. To establish their distinguishing features, biopsy specimens from nodular lesions of 24 patients with Beh�et syndrome, 25 with nodular vasculitis (NV), and 20 with erythema nodosum (EN) were compared. Statistical analysis revealed insignificant differences between most of the histologic features of Beh�et syndrome and NV. However, neutrophil-predominating infiltrate in the subcutis was more common in Beh�et syndrome, while necrosis and granuloma formation were encountered more frequently in NV. The differences between Beh�et syndrome and EN were more significant. Septal panniculitis, lymphocyte-predominating infiltrate, absence of many vascular changes as well as vasculitis, and necrosis were features in favor of EN. Nodular lesions of Beh�et syndrome are mainly neutrophilic vascular reactions with histologic features similar to NV but significantly differing from EN associated with other systemic diseases.