Behçet's Syndrome

The n e w e ng l a n d j o u r na l of m e dic i n e
Review Article
Julie R. Ingelfinger, M.D., Editor
Behçet’s Syndrome
David Saadoun, M.D., Ph.D., Bahram Bodaghi, M.D., Ph.D.,
and Patrice Cacoub, M.D.
B
From Sorbonne Universités Assistance ehçet’s syndrome is a chronic, multisystem, inflammatory con-
Publique–Hôpitaux de Paris (AP-HP), dition with a relapsing and remitting course. This disorder has been in-
Groupe Hospitalier Pitié–Salpêtrière,
Département de Médecine Interne et Im- creasingly recognized as a syndrome because it has a broad spectrum of
munologie Clinique, Centre National de signs and symptoms, each with distinct prognostic implications for a patient’s
Références Maladies Autoimmunes Sys- quality of life, and is associated with substantial morbidity and even death.1 Over
témiques Rares, Centre National de Ré-
férences Maladies Autoinflammatoires et the past 20 years,2 several discoveries have reshaped our understanding of Behçet’s
Amylose Inflammatoire, Institut Hospitalo- syndrome, and it is currently classified as a primary systemic vasculitis affecting
Universitaire FOReSIGHT, Inflammation– veins and arteries of any size.3 The evolving classification of the disorder stems
Immunopathology–Biotherapy Depart-
ment, Clinical Investigation Center in mainly from advances in immunogenetics, facilitated by genomewide association
Biotherapy, and INSERM 959, Groupe studies and next-generation sequencing techniques, that have led to the identifica-
Hospitalier Pitié–Salpêtrière, AP-HP (D.S., tion of key genetic factors.4 In this review, we examine the most relevant and recent
P.C.), and Sorbonne Universités AP-HP,
Centre National de Références Maladies developments regarding the epidemiology, pathogenesis, and clinical expression of
Rares en Ophtalmologie, Institut Hospi- Behçet’s syndrome, as well as the differential diagnosis and emerging targeted
talo-Universitaire FOReSIGHT, Groupe therapeutics.
Hospitalier Pitié–Salpêtrière, Département
d’Ophtalmologie (B.B.) — all in Paris.
Dr. Saadoun can be contacted at d avid
.saadoun@aphp.fr or at Sorbonne Uni-
Epidemiol o gy
versités AP-HP, Groupe Hospitalier Pitié–
Salpêtrière, Département de Médecine Historically, Behçet’s syndrome occurred in regions along the ancient Silk Road.
et Immunologie Clinique, F-75013, Paris, The current epidemiology varies widely according to geographic location and ethnic
France. group. The highest prevalence is found in Turkey, with 420 cases per 100,000
N Engl J Med 2024;390:640-51. persons.5 Across Europe, a north–south gradient has emerged, with prevalence rang-
DOI: 10.1056/NEJMra2305712 ing from 0.3 to 4.9 cases per 100,000 persons in northern countries and 1.5 to
Copyright © 2024 Massachusetts Medical Society.
15.9 cases per 100,000 persons in southern regions.6 In the United States, the re-
CME ported prevalence is 5.2 cases per 100,000 persons.7 In Dutch and German studies,
at NEJM.org the frequency of Behçet’s syndrome has been higher among immigrants from
high-prevalence regions than among native residents, although the rates among
immigrants are lower than those in their countries of origin.8,9 Familial aggregation
of Behçet’s syndrome has been reported in specific populations, particularly among
patients with early-onset Behçet’s syndrome.10 The mean age at diagnosis is ap-
proximately 30 years, with the majority of patients presenting between the ages of
15 and 45 years.6 Disease activity tends to wane with advancing age.11,12 Although
there is no difference in the incidence of Behçet’s syndrome according to sex, male
patients are more likely than female patients to have severe forms of the disease.11-13
En v ironmen ta l T r ig ger s a nd Gene t ic Fe at ur e s

The pathogenesis of Behçet’s syndrome is poorly understood, but it is thought to
develop in genetically predisposed hosts after exposure to a wide range of environ-
mental triggers. Such exposures lead to the activation of cellular effectors and sig-
naling pathways, potentially resulting in tissue inflammation and damage (Fig. 1).
For example, microorganisms (bacteria, viruses, and their byproducts), consumption
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The New England Journal of Medicine

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of histamine-releasing foods (e.g., citrus fruits, cytes, which are differentiated into Th1 and Th17
nuts, and cheese), poor oral hygiene, and stress cell subtypes, and diminished regulatory T-cell
have been proposed as potential triggers.1 There activity.24-26 The Th1 response induces the produc-
is growing evidence of alterations in the balance tion of proinflammatory cytokines (e.g., tumor
of gut and salivary mucosal flora in patients with necrosis factor α [TNF-α] and interferon-γ) and
Behçet’s syndrome, suggesting that these imbal- cytotoxic T-cell activity,21 which involves both
ances may contribute to the repertoire of antigens CD8+ T cells and natural killer cells. The Th17
associated with the disorder.14,15 response results in the production of other pro-
Behçet’s syndrome includes both autoimmune inflammatory cytokines (e.g., interleukin-17 and
and autoinflammatory features. The first genetic interleukin-23) and promotes neutrophil chemo-
association reported for Behçet’s syndrome was taxis.
within the class I major histocompatibility com- Neutrophils constitute the main infiltrating
plex antigen HLA-B*51 (particularly the major cell type in Behçet’s syndrome lesions. By pro-
subtype HLA-B*51:01).10 Although the prevalence ducing excessive levels of reactive oxygen species
of HLA-B*51 varies among ethnic groups, a and releasing neutrophil extracellular traps, neu-
meta-analysis showed that Behçet’s syndrome was trophils contribute to the development of a pro-
6 times as likely to develop in HLA-B*51 carri- coagulant state in Behçet’s syndrome.27,28 Exami-
ers.16 Genomewide association studies17,18 have nation of skin biopsy specimens from patients
shown an epistatic interaction between HLA-B*51 with Behçet’s syndrome typically reveals leuko-
and the gene encoding endoplasmic reticulum cytoclastic vasculitis, neutrophilic or lymphocytic
aminopeptidase 1 (ERAP1; odds ratio, 4.56), which perivascular infiltrates, microvascular thrombi,
may interfere with antigen presentation and pro- or neutrophilic dermal infiltrates.
cessing and lead to the activation of natural In addition, the nuclear factor κB (NF-κB)
killer cells and disturbances in T-cell homeosta- proinflammatory pathway has been reported to
sis. Genes implicated in types 1 and 17 helper have a pivotal role in sensing immune responses
T-cell (Th1 and Th17) polarization, such as in Behçet’s syndrome. NF-κB intracellular signal-
IL23R–IL12RB2, STAT4, and IL10, have been found ing is heightened in antigen-presenting cells,
to be associated with Behçet’s syndrome (odds neutrophils, and Th1 and Th17 cells.24,29-31
ratio, 1.28, 1.27, and 1.45, respectively). Also re-
ported to play a role are genes involved in regulat- Cl inic a l M a nife s tat ions
ing natural killer cell activity (KLRC4; odds ratio
for protective effect, 0.78) and those involved in The heterogeneous clinical features of Behçet’s
cell chemotaxis (CCR1, CCR2, and CCR3; odds syndrome (Figs. 2 and 3) overlap throughout the
ratio for protective effect, 0.72).17,18 Single-nucle- course of the disease, with frequencies of dis-
otide polymorphisms (SNPs) and low-frequency ease-related manifestations that vary according to
variants implicated in several monogenic and ethnic group.32-35 Overall, Behçet’s syndrome can
polygenic inflammatory disorders have also been be categorized on the basis of its manifestations,
described in association with Behçet’s syn- which affect the skin, mucosa, joints, eyes, vascu-
drome.19,20 For example, TNFAIP3 and MEFV are lar system, central nervous system, and gastroin-
responsible for A20 haploinsufficiency and fa- testinal tract.1,35
milial Mediterranean fever, respectively.21 The
importance of epigenetics in Behçet’s syndrome Skin and Mucosal Manifestations
was highlighted in a 2014 study, which showed Recurrent oral ulceration, a hallmark of Behçet’s
aberrant DNA methylation in genes that regulate syndrome, is the most common clinical mani-
cytoskeletal dynamics and cell adhesion.22 In ad- festation, followed by genital ulcers, papulopus-
dition, activation histone marks have been over- tular lesions, and nodular skin lesions. Up to a
represented in natural killer cells, monocytes, third of patients present with only these manifes-
lymphocytes, and neutrophils from patients with tations throughout the course of their illness.12,35
Behçet’s syndrome.23 Oral ulcers are typically both the initial and most
Several reports have suggested that the adap- persistent symptom in Behçet’s syndrome.35 How-
tive immune response in patients with Behçet’s ever, distinguishing Behçet’s syndrome–related
syndrome is mediated by CD4+ T-helper lympho- oral ulcers from those in the general population
n engl j med 390;7 nejm.org February 15, 2024 641

Environmental Microorganisms Intestinal and salivary Molecular mimicry

triggers (e.g., streptococcus species, HSV-1) dysbiosis (e.g., heat-shock proteins)
HLA-B*51 KLRC4 TNFAIP3 IL23R–IL12RB2

Genetic
background ERAP1 MEFV FUT2 STAT4
CCR1–CCR3 TLR4 NOD2 IL10
Antigen-
presenting
cell
↓Regulatory
T cells
Cellular
effectors Th1 Th17
cells cells
Neutrophils
CD8 NK
T cells cells
Disturbed antigen Cellular NF-kB activation NETosis

Pathogenic
processing and cytotoxicity proinflammatory oxidative burst
pathways
presentation cytokines
Target
tissues
Oral and Joints Blood

genital vessels Central nervous
mucosa Skin Eyes system
(which affect up to 60% of the population)36,37 Genital ulcers may occur in Behçet’s syndrome,
can be challenging. Genetic findings suggest that and they form scars in approximately two thirds of
Behçet’s-like disorders constitute a spectrum from cases.39 These ulcers are larger, deeper, and longer-
recurrent aphthous stomatitis to PFAPA (periodic lasting than oral ulcers. Most appear on the
fever, aphthous stomatitis, pharyngitis, and cer- scrotum or labia.1,35 Papulopustular lesions, often
vical adenitis) syndrome38 (Table S1 in the Supple- described as “acne-like,” can be indistinguishable
mentary Appendix, available with the full text of from acne vulgaris both in appearance and his-
this article at NEJM.org). tologic features.40-42 Nodular lesions can be indica-

Figure 1 (facing page). Pathogenesis of Behçet’s bones and tendons or ligaments). A distinct cluster
Syndrome. of symptoms comprising acne, arthritis, and en-
Genomewide association studies performed across thesitis has been proposed, since acne-like lesions
different populations have recently provided new tend to follow these articular and periarticular
pathogenetic insights into the epistatic interaction be- manifestations, resembling peripheral spondyloar-
tween HLA-B*51 and endoplasmic reticulum amino-
thritis.40,41 However, involvement of the sacroiliac
peptidase 1 (ERAP1), type 1 and type 17 helper T-cell
(Th1 and Th 17) polarization, natural killer (NK) cell joint or spine is uncommon in Behçet’s syndrome.35
activity and cell chemotaxis. Single-nucleotide poly-
morphisms (SNPs) that are implicated in gut micro Ocular Manifestations
biome misbalance or innate immunity have been re- The eye is the most frequently affected major or-
ported in FUT2, TLR4, NOD2, and MEFV. An SNP in
gan in Behçet’s syndrome, with ocular involvement
TNFAIP3 was also identified, encoding the A20 pro-
tein that inhibits the nuclear factor κB (NF-κB) proin- occurring in approximately 50% of patients.2,12,43
flammatory pathway. Heterozygous loss-of-function Bilateral involvement is observed in 75 to 80% of
mutations in TNFAIP3 lead to haploinsufficiency A20, new cases with ocular manifestations, on average
characterized by early-onset systemic inflammation occurring 2 years after the onset of the initial
with recurrent oral, genital, and gastrointestinal ulcers
symptoms.12 Panuveitis is the most common pre-
that resemble Behçet’s syndrome. Various microor-
ganisms and their byproducts have been described sentation. Severe attacks of anterior uveitis may
among the environmental triggers potentially involved lead to a characteristic hypopyon (accumulation
in Behçet’s syndrome. A misbalance between gut and of leukocytic exudate in the anterior chamber).
salivary microbiota has been increasingly reported as However, isolated anterior uveitis occurs in ap-
well. Gene–environment interactions are followed by
proximately 10% of patients.43 Vitritis, foci of
the interaction of antigen-presenting cells with several
types of immune cells. The adaptive immune response retinitis, signs of occlusive retinal vasculitis, dif-
in Behçet’s syndrome is mediated mainly by CD4+ fuse retinal capillary leakage on angiography, and
T-helper lymphocytes, which are differentiated into the absence of granulomatous anterior uveitis or
Th1 and Th17 cell subtypes at the expense of decreased choroiditis are suggestive of Behçet’s syndrome–
regulatory T-cell activity. Th1-driven cytotoxicity in-
associated uveitis.44,45 Certain factors, including
volves CD8+ T cells and NK cells, both of which may
also be activated through direct class I major histo- male sex, posterior eye chamber involvement, a
compatibility complex antigen priming. The Th17-cell history of more than three attacks per year, and the
response leads to neutrophil chemotaxis and activa- presence of vitreous opacity with macular edema,
tion that lead to reactive oxygen species production are associated with a poor visual outcome.43,46
and release weblike structures known as neutrophil
extracellular traps. Intracellular signaling through the
NF-κB pathway further increases production of proin-
Vascular Manifestations
flammatory cytokines and has been shown to be en- Vascular Behçet’s syndrome can affect both veins
riched in several cellular effectors in Behçet’s syn- and arteries of varying calibers35 and typically fol-
drome. HSV-1 denotes herpes simplex virus type 1, lows a relapsing course.47 Overall, the estimated
and NETosis program for formation of neutrophil
5-year cumulative risk of recurrent vascular events
extracellular traps.
among patients with Behçet’s syndrome is close
to 40%.48
tive of either panniculitis or superficial thrombo- Superficial thrombophlebitis and deep-vein
phlebitis. Clinically, Behçet’s syndrome–associated thrombosis are the most common manifestation
panniculitis resembles erythema nodosum, and of vascular Behçet’s syndrome, occurring in 15 to
histopathological analysis may reveal the pres- 40% of cases. In patients with deep-vein throm-
ence of neutrophilic vasculitis.35 bosis, there is a predilection for lower limb involve-
ment, which can lead to a severe post-thrombotic
Joint Manifestations syndrome. However, pulmonary embolism is rare.
Roughly half the patients with Behçet’s syndrome Thrombotic events have also been noted in several
have joint involvement, which typically manifests other locations, including portal or suprahepatic
as nondeforming, self-limited monoarthralgia or veins (Budd–Chiari syndrome), the superior or in-
oligoarthralgia or arthritis, primarily affecting ferior vena cava, and cerebral sinuses.6,48 Thrombi
the knees, ankles, wrists, and elbows. These joint in Behçet’s syndrome adhere to vein walls and
symptoms may be accompanied by enthesopathy are considered to be a hallmark of inflammation-
(inflammation of the connective tissue between induced thrombosis.47

Ocular manifestations (50%) CNS-related manifestations (10–30%)
Hypopyon Mesodiencephalic and brain-stem

Nongranulomatous panuveitis inflammation
Retinal vasculitis Encephalitis
Meningitis
Myelitis
Neurocognitive dysfunction
Cerebral-vein thrombosis
Skin, mucosa, and articular manifestations Cardiovascular manifestations
Oral ulcers (98%) Arterial (2–18%)

Genital ulcers (60–65%) Artery aneurysms
Orchiepididymitis(6%) Arterial stenosis or thrombosis
Skin lesions (75%) Heart (6%)

Pseudofolliculitis Valvulitis
Papulopustular lesions (acne-like) Myopericarditis
Erythema nodosum Coronary arteritis
Pathergy test Venous (15–40%)
Arthralgia or arthritis (50%) Deep-venous thrombosis (e.g.,
Knees, ankles, wrists, and elbows limbs, pulmonary, suprahepatic)
Enthesopathy Superficial thrombophlebitis
Gastrointestinal manifestations (0–20%)
Mucosal ulcers
Abdominal pain
Hemorrhage or perforation or both
Figure 2. Affected Organs in Behçet’s Syndrome.

Shown are the affected organs and the frequency of clinical manifestations in Behçet’s syndrome. CNS denotes central nervous system.
Patients with arterial manifestations of Behçet’s fected.6,47 Involvement of the pulmonary artery,
syndrome primarily present with aneurysms but although rare, is highly specific for Behçet’s syn-
may also have thrombotic occlusion or stenosis. drome. Cardiac involvement (seen in 5% of pa-
The aorta and peripheral arteries are mainly af- tients), which is usually associated with vascular

A B C
D E F
Figure 3. Clinical Manifestations of Behçet’s Syndrome.

Shown are the typical features of Behçet’s syndrome, including an oral ulcer (Panel A); a papulopustular lesion (Panel B); erythema no-
dosum (Panel C); capillary impairment and vascular leakage on retinal fluorescein angiography (Panel D); a brain-stem inflammatory
lesion on a T2-weighted axial magnetic resonance imaging sequence, with an edematous, protuberant FLAIR (fluid attenuated inversion
recovery) hypersignal extending to the middle cerebellar peduncles and discrete hypertrophy (Panel E); and aneurysmal dilatation of a
pulmonary-artery branch (Panel F, arrowhead).
Behçet’s syndrome, may entail all cardiac com- renchymal neurologic Behçet’s syndrome, which
ponents and thus is associated with pericarditis, may develop within 5 years after disease onset,35
myocarditis, coronary arteritis, valvulitis, intracar- is characterized by involvement of the brain stem,
diac thrombosis, and endomyocardial fibrosis.6 particularly the mesodiencephalic junction. Mag-
netic resonance imaging scans with contrast en-
Neurologic Manifestations hancement show small, scattered inflammatory
Neurologic involvement in Behçet’s syndrome, lesions accompanied by peripheral edema.50,54 The
which accounts for less than 30% of affected main clinical symptoms are headaches, hemipa-
organ systems, is parenchymal (in approximately resis, and seizures, although parenchymal disease
75% of cases) or nonparenchymal (in approxi- infrequently has severe manifestations such as
mately 25%).12,49,50 The most common nonparen- myelitis or pseudotumor cerebri. In cases of neu-
chymal finding is cerebral-vein thrombosis, which rologic Behçet’s syndrome, progressive central
could be considered a vascular manifestation be- nervous system damage is most often seen in pa-
cause of its close association with deep-vein tients with frequent relapses, a progressive disease
thrombosis.35,47,48,51 Parenchymal manifestations course, abnormal cerebrospinal fluid results, and
may occur in parallel with ocular manifestations residual neurologic impairment during remission.49
of Behçet’s syndrome, particularly in patients
with posterior uveitis.35,52 Neuro-ophthalmologic Gastrointestinal Manifestations
manifestations, which are present in up to 10% The prevalence of gastrointestinal involvement
of patients with neurologic Behçet’s syndrome, in Behçet’s syndrome varies substantially across
may include retrobulbar optic neuritis, papil ethnic groups, with rates below 5% in Europe
ledema, and third- and sixth-nerve palsies.53 Pa- and the Middle East and up to 20% in East Asia;

Table 1. Classification Criteria for Behçet’s Syndrome.*
Variable ISG 1990 ICBD 2014

Criteria Recurrent oral ulceration† Recurrent oral ulceration (2 points)
Ocular lesions Genital ulceration (2 points)
Skin lesions Ocular lesions (2 points)
Positive pathergy test Skin lesions (1 point)
Vascular manifestations (1 point)
Neurologic manifestations (1 point)
Positive pathergy test (1 point)‡
Criteria or score needed for Recurrent oral ulceration ≥4 points
classification plus 2 other criteria
Sensitivity of criteria — % 81–85 94–95
Specificity of criteria — % 96 91–92
* The two most commonly used classifications for Behçet’s syndrome are the International Study Group for Behçet’s Disease
(ISG) classification and the International Criteria for Behçet’s Disease (ICBD). A diagnosis of Behçet’s syndrome is still pos-
sible even if not all the criteria are met. Recurrent oral ulceration is defined as minor, major, or herpetiform oral aphthous
ulcers observed by a physician or patient, recurring at least 3 times over a 1-year period; genital ulceration, as genital ulcers
or scarring observed by a physician or patient; skin lesions, as erythema nodosum, pseudofolliculitis, or papulopustular
lesions observed by a physician or patient or acneiform nodules observed by a physician in a postadolescent patient not
receiving glucocorticoids; ocular lesions, as anterior or posterior uveitis, cells in the vitreous on slit-lamp examination,
or retinal vasculitis observed by an ophthalmologist; and vascular lesion, as arterial or venous thrombosis or superficial
phlebitis. Neurologic manifestations are not specified. A pathergy test is performed with at least three skin punctures, and a
positive reaction is indicated by a papular reaction that is at least 2 mm in diameter and surrounded by erythema or the de-
velopment of a pustule reaction within 24 to 48 hours. In current clinical practice, venous or arterial Doppler is performed
when deep-vein thrombosis or peripheral arterial aneurysms are suspected. Computed tomographic angiography is recom-
mended for cases of pulmonary-artery or aorta involvement. Cerebral magnetic resonance imaging and lumbar puncture
should be considered in a patient with persistent headaches or the appearance of neurologic symptoms.
† Recurrent oral ulceration is a mandatory criterion in the 1990 ISG classification (i.e., the presence of any of the other
criterion must be accompanied by recurrent oral ulceration for a diagnosis of Behçet’s syndrome).
‡ The pathergy test is optional in the ICBD classification.
no differences in prevalence according to sex have manifestations can occur in isolation as an initial
been reported.32,33,35 Gastrointestinal ulcerations presentation. Therefore, the fulfillment of all these
may occur throughout the gastrointestinal tract, criteria should not be mandatory for the estab-
leading to a range of clinical manifestations from lishment of a therapeutic strategy.
mild to severe, including abdominal pain, diar- Ultimately, the diagnosis of Behçet’s syndrome
rhea, and gastrointestinal bleeding. These symp- is largely based on the patient’s clinical presenta-
toms may be difficult to distinguish from those tion and imaging findings,32,34 given the broad
found in patients with inflammatory bowel dis- spectrum of disorders in the differential diagno-
eases.55 sis (Table 2). Clinical indicators that strongly sug-
gest Behçet’s syndrome may aid in the diagnosis.
These indicators include genital scarring and the
Di agnosis
distinctive eye or major vascular involvement men-
Behçet’s syndrome lacks pathognomonic biologic tioned above, as well as neurologic lesions that
or histologic diagnostic features. The prevalence extend from the basal ganglia to the brain stem.1
of HLA-B51 carriage varies according to ethnic A specific 10-item algorithm with a high odds
group, and the relatively high occurrence of HLA- ratio for the diagnosis of Behçet’s syndrome–
B51 in the general population limits its useful- related uveitis has recently been reported by
ness as a diagnostic tool.1,6 The most widely used ophthalmologic experts.45
classification criteria for Behçet’s syndrome were
developed in 199056 and revised in 201457 (Table 1). Pro gnosis
However, it is important to exercise caution when
applying these criteria in clinical practice, since Major organ involvement in Behçet’s syndrome is
none of them can be used to conclusively confirm predictive of both illness severity and death. Young
or rule out Behçet’s syndrome. Moreover, severe men with Behçet’s syndrome often have a rela-

Table 2. Clinical Manifestations and Differential Diagnosis of Behçet’s Syndrome.*
Manifestation Alternative Diagnoses

Skin, mucosal, and articular
Oral ulcers Nutritional deficiencies (e.g., iron, zinc, folate, and vitamins B1, B6, and B12);
HIV or herpes virus infections; recurrent aphthous stomatitis, PFAPA; pem-
phigus, lichen planus; relapsing polychondritis, MAGIC syndrome; celiac
disease; inflammatory bowel diseases; spondyloarthropathies; systemic
lupus erythematosus; neutropenia; mevalonate kinase deficiency
Genital ulcers Herpes simplex virus infection and STDs; inflammatory bowel diseases; A20
haploinsufficiency; MAGIC syndrome; mevalonate kinase deficiency
Erythema nodosum Bacterial infection (e.g., streptococcus species); tuberculosis, leprosy, yersinio-
sis; drugs (e.g., oral contraceptives, penicillins, and sulfonamides); inflam-
matory bowel diseases; Takayasu’s arteritis; sarcoidosis; cancers
Oligoarthritis Spondyloarthropathies; inflammatory bowel diseases
Ocular
Uveitis Infections (e.g., herpes virus infection, CMV infection, tuberculosis, and syphi-
lis); sarcoidosis; multiple sclerosis; B27-associated uveitis (acute anterior
uveitis); Vogt–Koyanagi–Harada syndrome
Vascular
Deep-vein thrombosis Antiphospholipid syndrome; inflammatory bowel diseases; connective-tissue
diseases; myeloproliferative diseases; inherited thrombophilias
Artery aneurysms Infections; Takayasu’s arteritis; relapsing polychondritis
Central nervous system
Inflammatory parenchymal lesions Infections (e.g., tuberculosis, herpes, and listeriosis); primary central nervous
system lymphoma; multiple sclerosis; sarcoidosis; histiocytosis
Gastrointestinal
Gastrointestinal ulcers Inflammatory bowel disease; NSAID toxicity; infectious colitis
* For the assessment of cutaneous, mucosal, and articular manifestations, the following diagnostic approaches can be
considered to rule out differential diagnoses, depending on the context: clinical presentation, laboratory tests (i.e., he-
mogram, C-reactive protein, iron, zinc, folate, and vitamin B1, B6, and B12), immunologic tests (antidesmoglein antibod-
ies, antitransglutaminase antibodies, antinuclear antibodies, HLA-B27, and angiotensin-converting enzyme), local infec-
tious sampling, and serologic tests for infections or skin biopsy. For the assessment of uveitis, the following methods
may be used: ophthalmologic presentation and, depending on the context, laboratory tests (hemogram and C-reactive
protein), immunologic tests (HLA-B27 and angiotensin-converting enzyme), serologic tests for infections, chest com-
puted tomography, and magnetic resonance imaging (MRI) of the central nervous system. For vascular manifestations,
the diagnostic approach may involve the clinical presentation, vascular imaging, and, depending on the context, an in-
vestigation for thrombophilias (e.g., antiphospholipid antibodies, antinuclear antibodies, myeloproliferative syndrome,
and inherited factors), serologic tests for infections and blood cultures. For central nervous system involvement, the di-
agnostic workup may include the clinical presentation, MRI of the central nervous system, and, depending on the con-
text, serologic tests for infections, blood cultures, and lumbar puncture. CMV denotes cytomegalovirus, MAGIC mouth
and genital ulcers with inflamed cartilage, NSAID nonsteroidal antiinflammatory drug, PFAPA periodic fever, aphthous
stomatitis, pharyngitis, and cervical adenitis, and STD sexually transmitted disease.
tively large disease burden and appear to be most therapy became widespread.43 However, the advent
likely to have severe manifestations among per- of newer therapies has reduced this risk to an es-
sons with the disorder.12,13,35 Male sex is associated timated 13%.58
with an increased risk of death (hazard ratio, Neurologic Behçet’s syndrome can lead to dis-
4.94).13 Other findings associated with death are ability or death, particularly when parenchymal
arterial involvement (hazard ratio, 2.51) and a high involvement is present. Estimates vary, but the risk
frequency of flares (hazard ratio, 2.37).13 The most of severe disability or death ranges from approxi-
worrisome complication of ocular Behçet’s syn- mately 25% at 7 years59 to as high as 60% at 10
drome is the loss of useful vision, which was years.50 Vascular Behçet’s syndrome is the leading
estimated to occur in 25% of cases over a 10-year cause of death, which is mainly due to arterial
period, before the use of immunosuppressive aneurysms (e.g., aortic or pulmonary) and Budd–

Chiari syndrome.12,13 In cases of venous throm- manifestations. For the management of nonse-
bosis, poor recanalization and a lack of immuno- vere manifestations, first-line treatment strategies
suppressive treatment options are major predictive include topical antiinflammatory therapy and the
factors for relapse. In two large, long-term cohort use of colchicine. For major organ manifestations
studies, the estimated overall mortality was 5% and refractory conditions,63,64 glucocorticoids and
over 7.7 years and 9.8% over 20 years of the fol- synthetic or biologic immunosuppressive agents
low-up.12,13 Irrespective of a given patient’s clinical are generally used (Table S2).
phenotype, Behçet’s syndrome has a substantial
effect on quality of life, adversely affecting both Cutaneous, Mucosal, and Articular
physical functioning and psychological well- Involvement
being.60 The first-line systemic treatment for cutaneous,
mucosal, and articular manifestations of Behçet’s
syndrome is colchicine, which is used to prevent
T r e atmen t
the recurrence of mucocutaneous and joint le-
Given the heterogeneous clinical manifestations sions.61 Patients who have recurrent manifestations
of Behçet’s syndrome and the variable disease may also benefit from topical medication, in-
course among patients, individualized, multidis- cluding the use of topical glucocorticoids, anti-
ciplinary treatment is warranted.61 The overall inflammatory mouthwashes, and intraarticular
goal is prompt control of inflammation in order glucocorticoid injections. Apremilast, a phospho-
to prevent relapses and irreversible organ damage. diesterase 4 inhibitor, is a small-molecule immu-
However, there are no standardized outcome nomodulatory drug that has been approved by the
measures for assessing activity in patients with Food and Drug Administration (FDA) for the
Behçet’s syndrome, and both end points and defi- treatment of refractory oral ulcers in Behçet’s
nitions of remission vary among clinical trials.62 syndrome,65 and it is currently considered as sec-
Assessment of the therapeutic response is based ond-line therapy for this condition. Other RCTs
on a set of clinical, biologic, and radiologic ele- investigating various agents for the treatment of
ments. In practice, clinicians should assess the refractory Behçet’s syndrome have shown positive
treatment response for each disease manifestation. results, particularly in managing ulcerations.
The goals of treatment are to reduce the number, These trials have evaluated medications such as
duration, and frequency of mucocutaneous le- azathioprine, thalidomide, interferon alfa, and
sions; reduce joint pain and swelling; control ocu- etanercept, which may offer alternative treatment
lar inflammation and ensure visual acuity with options.63 Another promising target is ustekinu
regular ophthalmologic examinations; control mab, an inhibitor of interleukin-12 and interleu-
vascular inflammation and prevent new vascular kin-23, which has shown efficacy in an open-label
lesions and the post-thrombotic syndrome; and trial for treating oral ulcers that are refractory to
control neurologic inflammation and prevent new colchicine in patients with Behçet’s syndrome.66
nervous system inflammatory lesions, thrombo-
sis, and neurologic sequelae. Measurement of se- Major Organ Involvement
rum C-reactive protein levels and the use of com- A close collaboration with ophthalmologists is
parative imaging are valuable supplementary tools essential for the effective management of ocular
for assessing the effectiveness of each treatment. Behçet’s syndrome. Posterior segment involvement
Data regarding the appropriate duration of im- warrants a combination of glucocorticoids and
munosuppressive therapy in patients with Behçet’s systemic immunosuppressants, an approach that
syndrome are limited. Consequently, the decision is substantiated by RCTs evaluating the use of
to escalate or deescalate treatment depends on azathioprine, interferon alfa, TNF inhibitors, or
the severity of the clinical presentation and the cyclosporine.61 In head-to-head comparison trials,
presence or absence of factors associated with a cyclosporine was inferior to both interferon alfa
poor prognosis. Most randomized, controlled tri- and the TNF inhibitor infliximab.64 In cases of
als (RCTs) involving patients with Behçet’s syn- acute sight-threatening uveitis, the use of treat-
drome have focused on those with cutaneous, ment regimens containing infliximab or inter-
mucosal, and articular manifestations or ocular feron alfa are in accordance with European guide-

lines.64 Adalimumab, a TNF inhibitor, recently dence.64 First-line therapy generally includes the
received FDA approval for the treatment of non- use of glucocorticoids, together with 5-amino-
infectious uveitis on the basis of the results of salicylic acid derivatives for mild disease, where-
RCTs that included a small number of patients as azathioprine is recommended for those with
with Behçet’s syndrome. The efficacy and safety moderate to severe manifestations. TNF inhibi-
of adalimumab in treating Behçet’s syndrome have tors or thalidomide can be used in refractory gas-
been further supported by meta-analyses of ob- trointestinal cases.64 In cases leading to emergency
servational data.67 Isolated anterior uveitis is typi- surgery (e.g., perforation), concomitant immu-
cally managed with topical therapy, although sys- nosuppressive therapy is recommended, since it
temic immunosuppressants may be considered in appears to reduce the risk of adverse postopera-
patients with poor prognostic factors, such as tive outcomes.61
young male patients and patients with recurrent Unfortunately, high-level evidence is lacking
uveitis.61 regarding the appropriate induction immunosup-
The management of deep-vein thromboses in pressive therapy for major organ involvement in
patients with Behçet’s syndrome primarily involves Behçet’s syndrome, particularly severe or refrac-
the use of immunosuppressants; the role of anti- tory life-threatening cases.64 The choice of treat-
coagulants remains a subject of debate.1 The ment regimens usually comes down to a decision
choice of treatment depends on the site of venous between cyclophosphamide and a TNF inhibi-
involvement and whether the patient presents with tor.61,64,70-72 TNF inhibitors are reshaping the ap-
an acute or chronic thrombosis. Treatment op- proach to treatment for ocular Behçet’s syndrome
tions include mainly glucocorticoids, sometimes in by reducing the risk of blindness,58 and they hold
combination with conventional immunosuppres- promise as a potential solution for the treatment
sants, such as cyclophosphamide, azathioprine, or of severe Behçet’s syndrome overall. The results
biologic agents (e.g., TNF inhibitors).27,61,68 Arterial of a head-to-head trial comparing infliximab and
involvement in Behçet’s syndrome usually war- cyclophosphamide (ClinicalTrials.gov number,
rants the use of high-dose glucocorticoids com- NCT03371095) are awaited. An emerging option
bined with azathioprine, cyclophosphamide, or a for patients with refractory major organ involve-
TNF inhibitor as induction therapy.61 Regardless ment is tocilizumab, an interleukin-6–receptor
of the type of vascular procedure and whether it is inhibitor.73
endovascular or open surgery, preemptive immu-
nosuppressive treatment appears to be essential C onclusions
for preventing postoperative complications such
as prosthetic thrombosis or anastomotic dehis- The care of patients with Behçet’s syndrome has
cence.69 In addition, it is important in this context improved substantially in the past few decades
to address cardiovascular risk factors. as a result of advances in immunogenetics, syn-
Acute neuroparenchymal Behçet’s syndrome drome recognition, and targeted therapeutic ap-
should be managed with high-dose glucocorticoids proaches. However, unmet needs that warrant
together with an immunosuppressive agent, such further research include standardized outcome
as azathioprine or cyclophosphamide.61 In one measures in clinical trials, better diagnostic tools,
study, patients with severe neuroparenchymal identification of reliable markers for disease activ-
Behçet’s syndrome who were treated with cyclo- ity, evaluation of biologic therapeutic strategies,
phosphamide tended to have longer event-free the determination of the appropriate duration of
survival than those who received other disease- immunosuppressive therapy, and clarification of
modifying antirheumatic drugs, such as azathi- the role of anticoagulant therapy in managing
oprine or methotrexate.59 Case series provide venous thrombosis.
support for the use of a TNF inhibitor as a first- Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
line treatment in cases of severe or refractory We thank Dr. Matheus Vieira for assistance with drafting
neurologic Behçet’s syndrome.64 earlier versions of the manuscript and figures; Dr. Bertrand
Managing the relatively uncommon gastro Weschler for his mentorship and what he has taught us about
Behçet’s syndrome; and Drs. Stéphane Barete, Julien Gaudric,
intestinal involvement in Behçet’s syndrome is Marine Bravetti, and Delphine Leclercq for providing images re-
challenging because of the limited available evi- lated to Behçet’s syndrome.

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The n e w e ng l a n d j o u r na l of m e dic i n e

Julie R. Ingelfinger, M.D., Editor

En v ironmen ta l T r ig ger s a nd Gene t ic Fe at ur e s

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The New England Journal of Medicine

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Environmental Microorganisms Intestinal and salivary Molecular mimicry

HLA-B*51 KLRC4 TNFAIP3 IL23R–IL12RB2

CCR1–CCR3 TLR4 NOD2 IL10

Disturbed antigen Cellular NF-kB activation NETosis

Oral and Joints Blood

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Ocular manifestations (50%) CNS-related manifestations (10–30%)

Hypopyon Mesodiencephalic and brain-stem

Skin, mucosa, and articular manifestations Cardiovascular manifestations

Oral ulcers (98%) Arterial (2–18%)

Skin lesions (75%) Heart (6%)

Gastrointestinal manifestations (0–20%)

Figure 2. Affected Organs in Behçet’s Syndrome.

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Figure 3. Clinical Manifestations of Behçet’s Syndrome.

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Table 1. Classification Criteria for Behçet’s Syndrome.*

Variable ISG 1990 ICBD 2014

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Table 2. Clinical Manifestations and Differential Diagnosis of Behçet’s Syndrome.*

Manifestation Alternative Diagnoses

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