Behçet Disease
Vasculopathy rather than vasculitis
Prevalence is highest in countries of the eastern Mediterranean, Middle East and East Asia,
thus the name Silk Road disease, which correlates with the frequency of HLA-B*51 carriers in
healthy population and reaches the highest figures in Turkey and Jordan (420–480/100.000).
20-40yrs, ♂= ♀(Japan, Korea, West more ♀). Men develop more serious disease. Disease
activity after 60yrs tends to decrease, leading to complete remission within 20 years in
around 60% of patients (‘burns off’). CRP can be normal and fever is usually absent. It’s
necrotizing (peri)vasculitis.
Causes
•Genetic
-HLA-B51: associated with BD in areas of high prevalence and in patients with ocular
disease (and lower risk of genital ulceration and gastrointestinal symptoms). However, 20%
of Greeks are B51 (+), so it’s not necessary to search for its positivity. Having HLA-B51
confers a 6x risk for BD development. It’s not in the criteria.
Theory of ‘MHC-I-opathy’, in which abnormal environmental barrier
function (at the skin and mucous membranes) allows a T-cell response leading to
neutrophilic inflammation (common to other HLA-associated conditions such as AS, IBD
arthritis and PsA). HLA-B51 itself might be pathogenic for the same reason as in AS.
-ERAP1 (only in HLA-B51 patients): affects the peptides to be loaded on HLA and
presented to CD8+.
-non HLA: STAT4, IL-10 and IL-23R polymorphisms.
•Molecular mimicry
-Mycobacterial heat shock proteins bear homology to human ones. A response to
mycobacterial heat shock proteins by γδT-cells.
-Streptococcal antigens (induces hypersensitivity reactions and enhances pathergy).
Behçet disease spectrum: some of the polymorphisms in the non-HLA genes (IL-12A, STAT4,
IL-10, CCR1-CCR3) were also found to be associated with recurrent aphthous stomatitis and
PFAPA syndrome, suggesting shared inflammatory mechanisms affecting oropharyngeal
mucosa with aphthous ulcers.
Criteria
, ≥4 points are required for a diagnosis of BS
Clinical
Mucocutaneous and ocular manifestations are the most frequent. Together with vascular
involvement, parenchymal neurological manifestations are the leading cause of mortality.
Fever is not common and if present, especially in young age, might lead to PFAPA diagnosis.
Overall, in men, the most usual are: erythema nodosum, ocular, neurological.
Mucocutaneous, articular and ocular disease are often at their worst in the early years of
disease, but CNS and LV disease- if they develop- typically do so later in the disease course.
Mucocutaneous (95%)
30% of BS patients have only recurrent mucocutaneous symptoms.
•Aphthous oral ulcers (90%)
painful, usually minor (<1cm) and heal without scarring, but can also be major (1-3cm) or
herpetiform (~1.2cm, but in clusters), ≥3/year. Most often on the oral mucosa, rarely on the
tongue (dx GPA). It can precede the diagnosis by an average of 6-7 years, but 15% don’t
present them upon diagnosis. Fatigue, stress, histamine-rich or -liberating food and stopping
smoking have been identified as possible triggering factors for the development of oral
ulcers, whereas in women exacerbation of oral ulcers has been reported during
menstruation. The major ulcers can leave a scar, the minor don’t.
•Genital ulcers
mostly scrotum and major labia, heal in 10–30 days, with formation of scars. Unlike oral
ulcers, genital ulcers tend to occur only in the early years following disease onset and tend
to disappear during the later course of the disease. There seems to be a negative association
between genital ulcers and (severe) eye involvement.
•Other skin
1) papulopustular lesions (70-90%): acneiform, pseudofolliculitis (not around
the hair follicle). Unlike ulcers, papulopustular lesions are common after 50yrs. Since the age
of onset in BS is usually 20-30yrs, the presence of papulopustular lesions may simply be
related to the persistence of acne vulgaris which is the most prevalent skin disease of
adolescence. Therefore, the ISG criteria require that the papulopustular lesions of BS should
be present in the post-adolescent period in the absence of GC-therapy. Papulopustular
lesions of BS are not always follicle based, while acne lesions always are.
2) erythema nodosum (40-60%): heals leaving hyperpigmentation, is more
likely to women, but less frequent compared to other lesions. BD’s EN can present also
vasculitis changes on histology, in contrast with regular EN (which is a lobular [=not
vasculitic] panniculitis).
Vasculopathy rather than vasculitis
Prevalence is highest in countries of the eastern Mediterranean, Middle East and East Asia,
thus the name Silk Road disease, which correlates with the frequency of HLA-B*51 carriers in
healthy population and reaches the highest figures in Turkey and Jordan (420–480/100.000).
20-40yrs, ♂= ♀(Japan, Korea, West more ♀). Men develop more serious disease. Disease
activity after 60yrs tends to decrease, leading to complete remission within 20 years in
around 60% of patients (‘burns off’). CRP can be normal and fever is usually absent. It’s
necrotizing (peri)vasculitis.
Causes
•Genetic
-HLA-B51: associated with BD in areas of high prevalence and in patients with ocular
disease (and lower risk of genital ulceration and gastrointestinal symptoms). However, 20%
of Greeks are B51 (+), so it’s not necessary to search for its positivity. Having HLA-B51
confers a 6x risk for BD development. It’s not in the criteria.
Theory of ‘MHC-I-opathy’, in which abnormal environmental barrier
function (at the skin and mucous membranes) allows a T-cell response leading to
neutrophilic inflammation (common to other HLA-associated conditions such as AS, IBD
arthritis and PsA). HLA-B51 itself might be pathogenic for the same reason as in AS.
-ERAP1 (only in HLA-B51 patients): affects the peptides to be loaded on HLA and
presented to CD8+.
-non HLA: STAT4, IL-10 and IL-23R polymorphisms.
•Molecular mimicry
-Mycobacterial heat shock proteins bear homology to human ones. A response to
mycobacterial heat shock proteins by γδT-cells.
-Streptococcal antigens (induces hypersensitivity reactions and enhances pathergy).
Behçet disease spectrum: some of the polymorphisms in the non-HLA genes (IL-12A, STAT4,
IL-10, CCR1-CCR3) were also found to be associated with recurrent aphthous stomatitis and
PFAPA syndrome, suggesting shared inflammatory mechanisms affecting oropharyngeal
mucosa with aphthous ulcers.
Criteria
, ≥4 points are required for a diagnosis of BS
Clinical
Mucocutaneous and ocular manifestations are the most frequent. Together with vascular
involvement, parenchymal neurological manifestations are the leading cause of mortality.
Fever is not common and if present, especially in young age, might lead to PFAPA diagnosis.
Overall, in men, the most usual are: erythema nodosum, ocular, neurological.
Mucocutaneous, articular and ocular disease are often at their worst in the early years of
disease, but CNS and LV disease- if they develop- typically do so later in the disease course.
Mucocutaneous (95%)
30% of BS patients have only recurrent mucocutaneous symptoms.
•Aphthous oral ulcers (90%)
painful, usually minor (<1cm) and heal without scarring, but can also be major (1-3cm) or
herpetiform (~1.2cm, but in clusters), ≥3/year. Most often on the oral mucosa, rarely on the
tongue (dx GPA). It can precede the diagnosis by an average of 6-7 years, but 15% don’t
present them upon diagnosis. Fatigue, stress, histamine-rich or -liberating food and stopping
smoking have been identified as possible triggering factors for the development of oral
ulcers, whereas in women exacerbation of oral ulcers has been reported during
menstruation. The major ulcers can leave a scar, the minor don’t.
•Genital ulcers
mostly scrotum and major labia, heal in 10–30 days, with formation of scars. Unlike oral
ulcers, genital ulcers tend to occur only in the early years following disease onset and tend
to disappear during the later course of the disease. There seems to be a negative association
between genital ulcers and (severe) eye involvement.
•Other skin
1) papulopustular lesions (70-90%): acneiform, pseudofolliculitis (not around
the hair follicle). Unlike ulcers, papulopustular lesions are common after 50yrs. Since the age
of onset in BS is usually 20-30yrs, the presence of papulopustular lesions may simply be
related to the persistence of acne vulgaris which is the most prevalent skin disease of
adolescence. Therefore, the ISG criteria require that the papulopustular lesions of BS should
be present in the post-adolescent period in the absence of GC-therapy. Papulopustular
lesions of BS are not always follicle based, while acne lesions always are.
2) erythema nodosum (40-60%): heals leaving hyperpigmentation, is more
likely to women, but less frequent compared to other lesions. BD’s EN can present also
vasculitis changes on histology, in contrast with regular EN (which is a lobular [=not
vasculitic] panniculitis).
