behecet`s

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Current Concepts

1284 October 21, 1999

The New England Journal of Medicine

B

EHET

S

D

ISEASE

T

SUYOSHI

S

AKANE

, M.D., P

H

.D.,M

ITSUHIRO

T

AKENO

, M.D., P

H

.D.,

N

OBORU

S

UZUKI

, M.D., P

H

.D.,

AND

G

ORO

I

NABA

, M.D., P

H

.D.

From the Departments of Immunology and Medicine, St. MariannaUniversity School of Medicine, Kawasaki (T.S., M.T., N.S.); and the De-partment of Ophthalmology, Uveitis Clinic, Tokyo Womens Medical Col-lege and Daini Hospital, Tokyo (G.I.) all in Japan. Address reprint re-quests to Dr. Sakane at the Departments of Immunology and Medicine,St. Marianna University School of Medicine, 2-16-1, Sugao, Miyamae-ku,Kawasaki, Kanagawa, 216-8511, Japan, or at [email protected].

1999, Massachusetts Medical Society.

EHETS disease is an inflammatory disorderof unknown cause, characterized by recurrentoral aphthous ulcers, genital ulcers, uveitis, and

skin lesions.

1,2

All these common manifestations areself-limiting except for the ocular attacks. Repeatedattacks of uveitis can cause blindness.

1-3

Behets dis-ease is not a chronic, persistent inflammatory dis-ease, but rather one consisting of recurrent attacks

of acute inflammation. Involvement of the gastroin-testinal tract, central nervous system, and large ves-sels is less frequent (Table 1), although it can be life-threatening.

1,2,4-6

Susceptibility to Behets disease isstrongly associated with the presence of the HLA-B51 allele.

7,8

Environmental factors such as infectiousagents have also been implicated in its pathogenesis.

9,10

EPIDEMIOLOGY

Cases of Behets disease cluster along the ancientSilk Road, which extends from eastern Asia to theMediterranean basin.

1,2,7

Turkey has the highest prev-alence: 80 to 370 cases per 100,000 population.

1,2

The prevalence in Japan, Korea, China, Iran, and Sau-

di Arabia ranges from 13.5 to 20 cases per 100,000,whereas it is lower in Western countries: 0.64 per100,000 in the United Kingdom and 0.12 to 0.33per 100,000 in the United States.

1,2,4,5

In Berlin,Germany, the prevalence among citizens of Turkishorigin is 21 per 100,000, which is lower than that inTurkey but far higher than that among German na-tives (0.42 to 0.55 per 100,000).

5

Behets disease israre among Japanese immigrants in Hawaii and Cal-ifornia.

5

Behets disease is somewhat more common amongfemales in Japan and Korea, whereas males are morefrequently affected in Middle Eastern countries.

2,4,5

The onset is typically in the third or fourth decadeof life.

1

The frequency within families is 2 to 5 per-

B

cent, except in Middle Eastern countries, where itis 10 to 15 percent.

5

Although the rate of concord-ance among twins is not known, one pair of mono-zygotic twins who were concordant

11

and two pairswho were discordant

12

for Behets disease have beendescribed. Epidemiologic findings suggest that both

genetic and environmental factors contribute to thedevelopment of the disease.

CAUSATION

The prevalence of the HLA-B51 allele is highamong patients with Behets disease who live in ar-eas along the Silk Road (up to 81 percent of Asianpatients have the allele) but not among white patients

who live in Western countries (13 percent).

4,5,7-9,13

InJapan, the incidence of HLA-B51 is significantly high-er among patients with Behets disease than amongthose without the disease (55 percent vs. 10 to 15percent).

4

The relative risk of the disease among car-riers of HLA-B51, as compared with that among

noncarriers, is 6.7 in Japan, whereas it is only 1.3 inthe United States.

4,13

Thus, this allele is an importantcontributor to the risk of Behets disease in areas in

which the disease is prevalent but not in Westerncountries. The allele also affects the severity of dis-ease, since it is more common among patients withposterior uveitis or progressive central nervous systemdisease than among those with milder disease.

2,4,5,8,14

More than 55 percent of patients with central nerv-ous system lesions are positive for HLA-B51.

4

In onestudy, the frequency of visual acuity below 0.01 was51 percent among HLA-B51positive patients and31 percent among HLA-B51negative patients.

8

Inanother study, 84 percent of the patients with cen-tral nervous system involvement were positive forthe allele.

14

Other HLA-related genes have been stud-ied extensively, but none have been shown to be asimportant as HLA-B51 in Behets disease.

7

Microbial infection has been implicated in the de-velopment of Behets disease. Herpes simplex virusDNA and serum antibodies against the virus havebeen found in a higher proportion of patients withBehets disease than in controls.

2,10

Other viruses, in-cluding hepatitis C virus and parvovirus B19, may alsohave some role.

2

Streptococcus sanguis

has been sug-gested as a causative agent, because the bacteria andantibodies against the bacteria are frequently found inthe oral flora and serum, respectively, of patients withthe disease.

10

However, none of these infectious agentshave been proved to cause Behets disease. In fact,the results of a series of studies led to the hypothesisthat ubiquitous antigens, including heat shock pro-tein of microorganisms, may trigger cross-reactive au-toimmune responses in patients with Behets disease.

PATHOPHYSIOLOGY

Vascular injuries, hyperfunction of neutrophils,and autoimmune responses are characteristic of Beh-

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Copyright 1999 Massachusetts Medical Society. All rights reserved.

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1285

ets disease. Biopsies confirm the presence of vascu-litis near the lesions of Behets disease, including oraland genital ulcers, erythema nodosum, posterior uvei-tis, epididymitis, enteritis, and central nervous systemlesions.

15

Large vessels are affected by a vasculitis ofthe vasa vasorum. The vascular injuries are superim-posed on the hypercoagulability that is also charac-teristic of Behets disease and that may be due in partto activated endothelial cells and activated platelets.

Active lesions, including those induced during thepathergy test by skin pricks with a sterile needle, areinfiltrated by neutrophils in the absence of infection.Neutrophils from patients with Behets disease haveincreased superoxide production, enhanced chemo-taxis, and excessive production of lysosomal enzymes,indicating that the neutrophils are overactive, whichleads to tissue injuries.

9,15

Levels of circulating tu-mor necrosis factor a

, interleukin-1

b

, and interleu-kin-8 have been reported to be elevated; thus, thesecytokines may be involved in the activation of neu-trophils and the augmented cellular interactions be-tween neutrophils and endothelial cells as a result ofenhanced expression of adhesion molecules.

15

Lymphocyte function is abnormal in patients withBehets disease.

9,16-20

Lymphocytes specific for se-lected self peptides derived from heat shock protein60, which are highly homologous with bacterial heatshock protein 65, have been found in patients withBehets disease, especially those with ocular involve-ment.

21-23

In experiments in rats, the peptides induceduveitis.

24,25

The epitopes recognized by autoreactiveantiheat shock protein T cells overlap with the B-cellepitopes of autoantibodies against heat shock pro-tein in patients with Behets disease.

23

These epitopes

are totally distinct from the rheumatoid arthritisrelated epitopes of heat shock protein 60.

22

The im-portance of the peptides derived from heat shockprotein 60 to the development of Behets disease issupported by findings that the expression of thisprotein is aberrant in the oral mucosa,

10

circulatingleukocytes, and skin of patients with Behets dis-ease, but not in normal subjects. As a result, in pa-tients with active Behets disease there is clonal ex-pansion of autoreactive T cells specific for the peptidederived from heat shock protein 60.

22

However, itremains to be determined whether the autoimmunemechanism is a primary or a secondary event in thedevelopment of Behets disease.

DIAGNOSIS

Because Behets disease does not have any path-ognomonic symptoms or laboratory findings, the di-agnosis is made on the basis of the criteria proposedby the International Study Group for Behets Dis-ease in 1990 (Table 2).

26

According to the criteria,recurrent oral ulceration must be present as well asat least two of the following: recurrent genital ulcer-ation, eye lesions, skin lesions, and a positive pather-gy test. The differential diagnosis includes chronicoral aphthosis, herpes simplex virus infection, Sweetssyndrome, and HLA-B27related syndromes such asankylosing spondylitis. The bowel symptoms of Beh-ets disease must be distinguished from those ofCrohns disease and ulcerative colitis. The neurolog-ic symptoms must be distinguished from those ofmultiple sclerosis. Because Behets disease has di-

verse clinical features, it is sometimes difficult to di-agnose complicated cases. In such instances, analysis

*Data on Japan are from Nakae et al.,

4

data on Germany are from Zouboulis et al.,

5

data on Turkeyare from Dilsen et al.,

6

and data on Greece are from Kaklamani et al.

2

NA denotes not available.

Superficial thrombophlebitis was included in skin lesions.

T

ABLE

1.

F

REQUENCIES

OF

V

ARIOUS

S

YMPTOMS

IN

P

ATIENTS

WITH

B

EHET

S

D

ISEASE

IN

J

APAN

, G

ERMANY

, T

URKEY

, AND

G

REECE

.*

S

YMPTOM

J

APAN

,1972

(N=2031)

J

APAN

,1991

(N=3316)

G

ERMANY

,1996

(N=130)

T

URKEY

,1993

(N=496)

G

REECE

,1997

(N=64)

percentage of patients

DiagnosticOral ulcersGenital ulcersEye lesionsSkin lesionsPositive pathergy test

9672678375

9873698744

9879487353

100774778

NA

10078759430

OtherArthritisEpididymitisGastrointestinal lesionsCentral nervous symptoms

Vascular lesions

546

2513

7

576

1611

9

5932NANANA

47NA

58

38

4817

320

8



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October 21, 1999


of HLA phenotypes and measurement of serum IgDlevels may help to make a diagnosis, since patients

with active Behets disease often have elevated levelsof serum IgD.

The pathergy test is useful for evaluating skin ir-ritability and is a diagnostic criterion.

26

The test con-sists of pricking a sterile needle into the patients fore-arm. The results are judged to be positive when thepuncture causes an aseptic erythematous nodule orpustule that is more than 2 mm in diameter at 24 to48 hours.

1

At the reaction site there is initially an ac-cumulation of neutrophils, followed by the accumu-lation of mononuclear cells. The pathergy test can alsobe positive in some other diseases such as Sweets syn-drome and pyoderma gangrenosum.

CLINICAL MANIFESTATIONS

Oral ulceration is usually an initial symptom and isseen in all patients at some time in the clinical course(Table 1).

1,2,27

This symptom sometimes precedesother manifestations by a number of years.

27

Painfuloral ulcers appear in the gingiva, tongue, and buccaland labial mucosal membranes. The typical lesion isround, with a sharp, erythematous border, and the sur-face is covered with a yellowish pseudomembrane(Fig. 1A). The lesions heal within about 10 days with-out scarring.

Genital ulcers usually occur on the scrotum andpenis in men (Fig. 1B) and on the vulva in women.

1,2

They are painful and morphologically similar to theoral ulcers but they are usually larger and deeper andhave an irregular margin. The lesions recur and usu-ally leave scars.

Ocular lesions occur in the uvea and retina. Ocu-lar involvement is the first manifestation of Behets

disease in about 10 percent of patients, but it usuallyappears after oral ulceration.

2

Patients with ocularlesions have various subjective symptoms, includingblurred vision, eye pain, photophobia, lacrimation,floaters, and periglobal hyperemia (probably as a re-sult of episcleritis).

Hypopyon, a visible layer of pus in the anteriorocular chamber, is characteristic of Behets disease(Fig. 1C), though it is also present in some patients

with HLA-B27related arthropathy.

2

Although theepisodes of anterior uveitis subside spontaneously, re-peated attacks lead to irreversible structural changes,such as deformity of the iris and secondary glaucoma.

3

The most serious ocular problem in patients withBehets disease is the retinal disease. Recurrent, ex-plosive attacks can involve the posterior segment asa result of vaso-occlusive lesions. Patients usually havea painless, bilateral decrease in visual acuity. Oph-thalmologic evaluations reveal hemorrhagic and ex-udative retinal lesions and a cellular infiltration in the

vitreous humor during the acute phase. Fluoresceinangiography can be used to identify retinal vasculardamage, even during remission. Sarcoidosis and viralretinitis sometimes have features indistinguishablefrom the retinal lesions of Behets disease.

3

Erythema nodosum is common in female patientsand usually occurs on the front of the legs (Fig. 1D).The lesions are painful and usually resolve spontane-ously, leaving a deeply pigmented area, but they some-times ulcerate. Pseudofolliculitis and acneiform nod-ules are common in male patients and are distributedon the back, face, and neck, especially along the hair-line. The presence of acneiform nodules in adoles-cents or in patients who are receiving corticosteroidscannot be used in the diagnosis.

26

Unlike idiopathicor other types of autoimmune-associated thrombo-phlebitis, superficial migratory thrombophlebitis ofthe arms and legs is more common in male patientsthan in female patients.

1,2

Because of the irritabilityof the skin of patients with Behets disease, shavingoften causes pseudofolliculitis and intravenous punc-tures can lead to local thrombophlebitis.

Monarthritis or polyarthritis develops in about halfof patients (Table 1). The joints most frequently af-fected are the knees, followed by the wrists, ankles,and elbows.

2,28

Histologically, there is infiltration ofneutrophils and mononuclear cells into the synovi-um and small-vessel lesions with thrombosis. De-structive changes rarely occur in the joints.

2

Gastrointestinal involvement causes abdominal pain,diarrhea, melena, and sometimes perforation.

1,2

Oralulceration is usually considered separately from thegastrointestinal involvement, because oral ulcerationis such a major and troublesome symptom. The ile-ocecal region is the most commonly affected part ofthe gastrointestinal tract, but the transverse colonand ascending colon are sometimes involved, as isthe esophagus. It is often difficult to distinguish be-

*The criteria were drawn up by the International Study Group for Beh-ets Disease.

26

For the diagnosis to be made, a patient must have recurrentoral ulceration plus at least two of the other findings in the absence of oth-er clinical explanations.

T

ABLE

2.

C

RITERIA

FOR

THE

D

IAGNOSIS

OF

B

EHET

S

D

ISEASE

.*

F

INDING DEFINITION

Recurrent oralulceration

Minor aphthous, major aphthous, or herpeti-form ulcers observed by the physician or pa-

tient, which have recurred at least three timesover a 12-month period

Recurrent genitalulceration

Aphthous ulceration or scarring observed by thephysician or patient

Eye lesions Anterior uveit is, poster ior uveit is, or cells in thevitreous on slit-lamp examination; or retinalvasculitis detected by an ophthalmologist

Sk in lesions Erythema nodosum observed by the physicianor patient, pseudofolliculitis, or papulopustu-lar lesions; or acneiform nodules observed bythe physician in a postadolescent patient whois not receiving corticosteroids

Positive pathergy test Test interpreted as positive by the physician at 24to 48 hours



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tween Behets disease and inflammatory bowel dis-eases, because of the similarity in extraintestinal symp-toms, such as oral ulceration, erythema nodosum,uveitis, and arthritis. Histologically, the intestinal ul-cers of patients with Behets disease are indistin-guishable from those of patients with ulcerative coli-tis; the finding of the granuloma formation that ischaracteristic of Crohns disease can be used to ruleout Behets disease. The pathergy test is usually neg-ative in patients with inflammatory bowel diseases.HLA typing may also be helpful in the differentialdiagnosis.

Chronic, progressive involvement of the centralnervous system occurs in 10 to 20 percent of pa-tients with Behets disease, particularly male patientsin whom the disease began at an early age.1,2,29 Clas-sically, meningitis or meningoencephalitis, neurologicdeficits such as motor disturbances and brain-stemsymptoms, and psychiatric symptoms including per-sonality changes develop more than five years afterBehets disease is diagnosed. The symptoms haveexacerbations and remissions and gradually cause ir-reversible disability. In the terminal stage, dementiabecomes evident in about 30 percent of affected pa-

Figure 1. Characteristic Lesions of Behet s Disease.

Panel A shows multiple aphthous ulcers on the buccal membrane, gingiva, and labial mucosal mem-brane (arrows). Panel B shows an active genital ulcer (short arrow) and scars (long arrows) on the scro-tum. Panel C shows hypopyon (arrow) a horizontal layer of inflammatory cells in the anterior ocular

chamber and deformity of the iris. The bright circle in Panel C is reflected light. Panel D shows newand old lesions of erythema nodosum on the front of the legs.

A B

C D



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tients.2In addition, acute aseptic meningitis or me-ningoencephalitis sometimes develops in the earlystage of the disease as part of the symptoms of acuteinflammation. It usually responds well to cortico-steroids and has a good prognosis.

Magnetic resonance imaging (MRI) and comput-

ed tomography are used to detect the neurologic le-sions. Multiple high-intensity focal lesions in the brainstem, basal ganglia, and cerebral white matter aretypical findings on T2-weighted MRI.1Electrophys-iologic examinations such as measurement of brain-stem auditory evoked potentials are also helpful inthe diagnosis of neurologic complications.2Examina-tion of cerebrospinal fluid reveals elevated proteinlevels, high IgG levels, and pleocytosis consisting ofunusually high numbers of both polymorphonuclearcells and lymphocytes.2Oligoclonal bands and anti-bodies against myelin basic protein are not found inpatients with Behets disease.

Small-vessel vasculitis is common and accounts for

much of the pathologic process in Behets disease.Large venous or arterial lesions occur in about 7 to38 percent of patients (Table 1).15Venous involve-ment, including superficial thrombophlebitis and deep

venous thrombosis, is a characteristic manifestation.Occlusion of major veins and arteries and aneurysmsoften causes bleeding, infarction, organ failure, andrestricted movement of the arms and legs. The rup-ture of such aneurysms may be fatal. Vascular lesionsin the lung, including thrombosis, aneurysm, andarteriobronchial fistula, cause recurrent episodes ofdyspnea, cough, chest pain, and hemoptysis.30Car-diac manifestations such as coronary and valvular dis-eases occur in some patients.2,15Serologically, Beh-ets disease is distinct from vasculitis characterizedby antibodies against neutrophil cytoplasm and an-tiphospholipid-antibody syndrome.15Computed to-mography, MRI, angiography, and ventilationper-fusion scintigraphy are useful for detecting vascularlesions.2

TREATMENT

The choice of the treatment depends on the pa-tients clinical manifestations (Table 3). Priority isgiven to the treatment of gastrointestinal symptoms,central nervous system involvement, and large-vessellesions, which require high-dose corticosteroids, im-munosuppressants, or both and, in some cases, sur-gical intervention. Treatment of ocular lesions re-quires more careful consideration than the treatmentof mucocutaneous symptoms. Close communicationamong the various specialists is essential for success-ful treatment.

Mucocutaneous Lesions

Topical corticosteroids are useful for oral and gen-ital ulcers.1,2Colchicine has beneficial effects on themucocutaneous symptoms, presumably by inhibiting

neutrophil function.31Thalidomide is reported to beeffective for oral and genital ulcers and pseudofollic-ulitis.32 Systemic corticosteroids are prescribed forerythema nodosum that is refractory to treatment

with colchicine.

Ocular LesionsDespite therapeutic intervention, about 25 percent

of the patients with ocular lesions eventually becomeblind.3An early age at onset and male sex are riskfactors for serious ocular symptoms.1-3Therapeuticgoals are to reduce both the severity and frequencyof ocular attacks.

Topical mydriatic agents and corticosteroid dropsare given for attacks of anterior uveitis.1Colchicineis prescribed to prevent both anterior and posterioruveitis because of its high degree of efficacy and rel-atively low toxicity. Topical injection of corticoster-oids, with systemic administration in some cases, isused for acute attacks of posterior uveitis.1Although

oral corticosteroid therapy alone has a palliative ef-fect on ocular attacks, it does not improve the visualprognosis and can even lead to secondary retinalthrombosis and cataracts. Cytotoxic agents such asazathioprine, chlorambucil, and cyclophosphamidehelp prevent ocular attacks in approximately 50 to70 percent of patients.1,2,33,35,37,42 In a single study,the rate of complete and partial responses was 50percent with corticosteroids, 66 percent with colchi-cine, and 71 percent with azathioprine.42 Azathio-prine and chlorambucil have also been reported toimprove the long-term visual prognosis.3,33

Cyclosporine is beneficial in 70 to 80 percent ofpatients with ocular lesions that have been refractoryto the conventional therapies of colchicine, cortico-steroids, azathioprine, and cyclophosphamide.38Theefficacy of cyclosporine gradually declines.2

Renal impairment, hypertension, and hyperglyce-mia are major adverse effects of treatment with cy-closporine. Serum levels of the drug (trough levels)should be measured periodically to adjust the dos-age. Although cyclosporine is rarely neurotoxic inpatients with other diseases, it causes central nervoussystem symptoms indistinguishable from those ofthe classic neurologic lesions in 20 to 30 percent ofpatients with Behets disease.39Most of the cyclo-sporine-induced symptoms subside after the discon-tinuation of the drug, and sometimes, additionaltherapy with corticosteroids helps to reduce the symp-toms. Cyclosporine-induced symptoms may lead toirreversible central nervous system disability in somepatients. Therefore, this drug is contraindicated inpatients with neurologic symptoms and patients withsubclinical neurologic lesions detected by MRI.

Recent trials of interferon alfa for Behets diseasehave shown encouraging results.2,36,40In one study,95 percent of the patients with ocular involvementhad a response to therapy with interferon alfa.40In-



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*Data are from Kastner,1Kaklamani et al.,2Nussenblatt,3Miyachi et al.,31Hamuryudan et al.,32,33Yasui et al.,34ODuffy et al.,35,36Kazokoglu et al.,37Masuda et al.,38Kotake et al.,39Zouboulis and Orfanos,40and Lee et al.41IV denotes intravenously, IM intramuscularly, and SC subcutaneously.

The efficacy of this drug for this use has been reported in controlled clinical trials.

Cyclosporine is contraindicated in patients with acute meningoencephalitis or chronic progressive central nervous system lesions.This drug should be used with caution in patients with pulmonary vascular lesions.

Low-dose aspirin is used as an antiplatelet agent.

TABLE3.TREATMENTFORBEHETSDISEASE.*

TREATMENT DOSE USEDASFIRST-LINETHERAPY USEDASALTERNATIVETHERAPY

Topical corticosteroidsTriamcinolone acetonide

ointmentBetamethasone ointmentBetamethasone drops

Dexamethasone

3 times a day topically

3 times a day topically12 drops 3 times daily

topically1.01.5 mg injected below

Tenons capsule for anocular attack

Oral ulcers

Genital ulcersAnterior uveitis, retinal vasculitis

Retinal vasculitis

Systemic corticosteroidsPrednisolone 520 mg/day orally

20100 mg/day orally Gastrointestinal lesions, acute meningo-encephalitis, chronic progressive cen-tral nervous system lesions, arteritis

Erythema nodosum, anterior uveitis, retinal vasculitis,arthritis

Retinal vasculitis, venous thrombosis

Methylprednisolone 1000 mg/day for 3 days IV Acute meningoencephalitis, chronicprogressive central nervous systemlesions, arteritis

Gastrointestinal lesions, venous thrombosis

Tropicamide drops 12 drops once or twicedaily topically

Anterior uveitis

Tetracycline 250 mg in water solution

once a day topically

Oral ulcers

Colchicine 0.51.5 mg/day orally Oral ulcers, genital ulcers, pseudo-folliculitis, erythema nodosum,anterior uveitis, retinal vasculitis

Arthritis

Thalidomide 100300 mg/day orally Oral ulcers, genital ulcers, pseudofolliculitisDapsone 100 mg/day orally Oral ulcers, genital ulcers, pseudofolliculitis, erythe-

ma nodosumPentoxifylline 300 mg/day orally Oral ulcers, genital ulcers, pseudofolliculitis, erythe-

ma nodosumAzathioprine 100 mg/day orally Retinal vasculitis, arthritis, chronic progressive cen-

tral nervous system lesions, arteriti s, venous throm-bosis

Chlorambucil 5 mg/day orally Retinal vasculitis, acute meningoencephalitis, chron-ic progressive central nervous system lesions, arteri-tis, venous thrombosis

Cyclophosphamide 50100 mg/day orally

7001000 mg/mo IV

Retinal vasculitis, acute meningoencephalitis, chronicprogressive central nervous system lesions, arteritis,

venous thrombosisRetinal vasculitis, acute meningoencephalitis, chronic

progressive central nervous system lesions, arteritis,venous thrombosisMethotrexate 7.515 mg/wk orally Retinal vasculitis, arthritis, chronic progressive central

nervous system lesionsCyclosporine 5 mg/kg of body weight/

day orallyRetinal vasculitis

Interferon alfa 5 million U/day IM or SC Retinal vasculitis, arthritisIndomethacin 5075 mg/day orally ArthritisSulfasalazine 13 g/day orally Gastrointestinal lesions Arthritis

Warfarin 210 mg/day orally Venous thrombosis ArteritisHeparin 500020,000 U/day SC Venous thrombosis Arteritis

Aspirin 50100 mg/day orally Arteritis, venous thrombosis Chronic progressive central nervous system lesionsDipyridamole 300 mg/day orally Arteritis, venous thrombosis Chronic progressive central nervous system lesionsSurgery Gastrointestinal lesions, arteritis, venous thrombosis



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terferon alfa-2a is most effective for ocular symptoms:in one study, it resulted in complete remission of theocular symptoms in 67 percent of the patients with-in four months.40

Intravenous infusions of immune globulin, plas-mapheresis, and granulocytapheresis have also been

tried in small numbers of patients, but the data arequite limited.

Arthritis

Nonsteroidal antiinflammatory drugs and colchi-cine are effective for most cases of arthritis in pa-tients with Behets disease.1,2Sulfasalazine can alsobe used,1,2but other types of disease-modifying anti-rheumatic drugs are rarely used. Low-dose cortico-steroids and azathioprine are used in patients whosearthritis is resistant to treatment with nonsteroidalantiinflammatory drugs, colchicine, or sulfasalazine.2Interferon alfa is also highly effective.2,40

Gastrointestinal Lesions

The treatments used for inflammatory bowel dis-ease are also useful for the gastrointestinal lesions ofBehets disease. Sulfasalazine and corticosteroids arethe principal drugs.1,2 The dose of corticosteroidsdepends on the severity of the lesions. Bowel rest isobligatory in patients with an acute abdomen andbleeding. Surgery is considered for patients withbowel perforation and persistent bleeding.41Invasivesurgical procedures often result in excessive infiltra-tion of inflammatory cells into the treated tissues,

with subsequent anastomotic leakage. To prevent thiscomplication, intermediate doses of corticosteroidsare given to the patients for several days after sur-gery. Even if the operation is successful, repeated op-eration because of recurrence is required in abouthalf of the patients.41

Central Nervous System Lesions

High doses of corticosteroids are administered dur-ing the acute phase of neurologic involvement, withsubsequent tapering of the dose.2 Pulsed cortico-steroid therapy is an alternative.2Corticosteroids canbe supplemented with cytotoxic agents such as cy-clophosphamide, chlorambucil, and methotrexate.2,35

Aseptic acute meningitis or meningoencephalitis inthe early phase of the disease responds well to treat-ment with corticosteroids. In contrast, chronic pro-gressive central nervous system disease is resistant toall the currently available therapies. In one study, 20percent of patients with chronic neurologic involve-ment died within seven years.43

Large-Vessel Involvement

Arteritis is treated with a combination of cortico-steroids and cytotoxic agents.1,2,15Anticoagulants andantiplatelet agents are used for deep venous throm-bosis, together with short-term administration of in-

termediate doses of corticosteroids.1,15Anticoagulantdrugs should be given carefully in patients with pul-monary-vessel disease because of the risk of poten-tially fatal hemoptysis. Half of patients die withinthree years after the onset of hemoptysis.30Surgicaltreatment may be considered for refractory large-

vessel disease.CONCLUSIONS

In spite of recent advances in treatment, the func-tional prognosis of patients with Behets disease re-mains unsatisfactory. The final goal is to elucidatethe pathogenesis of the disease and develop treat-ments aimed at the underlying pathologic process.

Supported by a research grant from the Behets Disease Research Com-mittee of Japan of the Ministry of Health and Welfare of Japan.

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13th ed. Vol. 1. Baltimore: Williams & Wilkins, 1997:1279-306.2. Kaklamani VG, Variopoulos G, Kaklamanis PG. Behets disease. Semin

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Adamantiades-Behets disease in Germany and in Europe. Yonsei Med J1997;38:411-22.6. Dilsen N, Konice M, Aral O, cal L, Inanc M, Gill A. Risk factors for

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1982;100:1455-8.9. Sakane T. New perspective on Behets disease. Int Rev Immunol 1997;14:89-96.10. Lehner T. The role of heat shock protein, microbial and autoimmuneagents in the aetiology of Behets disease. Int Rev Immunol 1997;14:21-32.11. Hamuryudan V, Yurdakul S, zbakir F, Yazici H, Hekim H. Monozy-gotic twins concordant for Behets syndrome. Arthritis Rheum 1991;34:1071-2.12. Gl A, Inan M, cal L, Aral O, arin M, Konie M. HLA-B51 neg-ative monozygotic twins discordant for Behets disease. Br J Rheumatol1997;36:922-3.13. Zouboulis CC, Bttner P, Djawari D, et al. HLA-class I antigens inGerman patients with Adamantiades-Behets disease and correlation w ithclinical manifestations. In: Wechsler B, Godeau P, eds. Behets disease.

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32. Hamuryudan V, Mat C, Saip S, et al. Thalidomide in the treatmentof the mucocutaneous lesions of the Behet syndrome: a randomized,double-blind, placebo-controlled trial. Ann Intern Med 1998;128:443-50.33. Hamuryudan V, zyazgan Y, Hizli N, et al. Azathioprine in Behetssyndrome: effects on long-term prognosis. Arthrit is Rheum 1997;40:769-74.34. Yasui K , Ohta K , Kobayashi M, Aizawa T, Komiyama A. Successful

treatment of Behet disease with pentoxifylline. Ann Intern Med 1996;124:891-3.35. ODuffy JD, Robertson DM, Goldstein NP. Chlorambucil in thetreatment of uveitis and meningoencephalitis of Behets disease. Am JMed 1984;76:75-84.36. ODuffy JD, Calamia K , Cohen S, et al. Interferon-alpha treatment ofBehets disease. J Rheumatol 1998;25:1938-44.37. Kazokoglu H, Saatci O, Cuhadaroglu H, Eldem B. Long-term effectsof cyclophosphamide and colchicine treatment in Behets disease. AnnOphthalmol 1991;23:148-51.38. Masuda K, Nakajima A, Urayama A, Nakae K, Kogure M, Inaba G.Double-masked trial of cyclosporin versus colchicine and long-term openstudy of cyclosporin in Behets disease. Lancet 1989;1:1093-6.39. Kotake S, Higashi K , Yoshikawa K, Sasamoto Y, Okamoto T, MatsudaH. Central nervous system symptoms in patients with Behcet disease re-ceiving cyclosporine therapy. Ophthalmology 1999;106:586-9.40. Zouboulis CC, Orfanos CE. Treatment of Adamantiades-Behet dis-ease with systemic interferon alfa. Arch Dermatol 1998;134:1010-6.41. Lee KS, Kim SJ, Lee BC, Yoon DS, Lee WJ, Chi HS. Surgical treat-

ment of intestinal Behets disease. Yonsei Med J 1997;38:455-60.42. Kotter I, Durk H, Saal J, Fierlbeck G, Pleyer U, Ziehut M. Therapyof Behets disease. Ger J Ophthalmol 1996;5:92-7.43. Akman-Demir G, Baykan-Kurt B, Serdaroglu P, et al. Seven-year fol-low-up of neurologic involvement in Behet syndrome. Arch Neurol 1996;53:691-4.

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