Hello.
I am Dr. Kalampokis,
and today we are going to talk
about Behcet's disease.
The next slide summarizes
the learning objectives
of this talk.
So by the end of this talk,
you should be able to-- one,
understand the epidemiology
and pathogenesis of Behcet's
disease; number two,
describe
the clinical presentation
and diagnostic criteria
of Behcet's disease;
and number three,
summarize the laboratory
abnormalities in the treatment
of Behcet's disease.
In the next slide,
we have an outline of the talk,
basically, in the structure
of the talk.
And first, we're going
to discuss a historical note
related to the name of Behcet's
disease.
Then we'll briefly review
the epidemiology of Behcet's
disease.
After that, we'll move on
to describing the pathogenesis,
with an emphasis
on genetic and immune system
factors.
Then we'll summarize
the clinical presentation
and diagnostic criteria.
And finally, we're going to talk
about the main laboratory
abnormallities
and current treatment approaches
to Behcet's disease.
So this slide describes
the historical note that I
mentioned earlier.
So as you have already seen
in most texts,
the first description
of the syndrome was attributed
to Hulusi Behcet.
However, in 1930, Benediktos
Adamantiades, a Hellen,
or Greek, ophthalmologist,
presented in a lecture
with the title, "A case
of relapsing iritis
with hypopyon,"
in a 20-year-old male patient
with the three cardinal signs
of the disease.
And he suggested that these were
signs of a single disease
entity.
Then seven years later, in 1937,
Dr. Behcet,
a Turkish dermatologist,
described actually a series
of three patients
with oregenital ulcers
and hypopyon uveitis.
However, as you can see
by the paper cited on the top
of the slide, by Dr. Feigenbaum,
in fact, Hippocrates was
the first one to really describe
the disease entity.
And that happened thousands
of years
before Behcet and Adamantiades
or anybody else did that.
And we move to the next slide,
which describes the epidemiology
of Behcet's disease.
On the left part of the slide,
you see a map
from my recent paper,
the January of 2012,
basically depicting
the distribution of the case
of Behcet's disease
around the world.
And as you can notice
from the figure, most cases
are along the old Silk Route,
which is the segment between 30
north
and 45 north
of geographical latitude.
The highest prevalence
of the disease is in Turkey,
where it's been seen up to 421
out of 100,000 people.
Countries with the lowest
prevalence include the UK,
Spain, Sweden, Portugal,
and the US.
In those countries,
the prevalence ranges
between 0.3 and 6.4 per 100,000.
The usual launch of the disease
is the third decade of life.
The disease is rather
uncommon in childhood
or after the age of 50 years.
However, it does exist.
Children represent about 5%
of cases.
They're usually teenagers.
The overall sex distribution
appears to be equal.
However, there is some sex
predilection
in certain geographic locations.
For example, there's
a male preponderance
in the Middle East
and Mediterranean.
Whereas there is a female
preponderance more commonly seen
in Asian countries, particularly
Japan and Korea.
So the average time
between the first major symptom,
which is usually
an oral ulceration,
to the second major symptom
in children, is 8.8 years, which
means that many times
in children, we see initially
an incomplete form
of the disease.
And finally, patients
with a parent with Behcet's
disease, they have disease onset
at a younger age, and they tend
to have a more severe disease
course and worse prognosis,
a phenomenon known
as genetic anticipation.
The next slide summarizes
a few important points
about the pathogenesis
of Behcet's disease.
So Behcet's disease
is at the crossroad
between autoimmune and
autoinflammatory syndromes,
meaning that both innate
adaptive immune responses are
involved.
Genetic factors are particularly
important for the pathogenesis,
with both MHC and non-MHC genes
being involved.
However, most prominent
associations are with MHC class
one molecules.
In particular, HLA-51 attributes
about a calculated 20%
of the total genetic risk
for Behcet's disease.
And HLA-A26 is something that
has also been shown
by multiple studies
to confer a risk for Behcet's
disease.
Endothelial cell factors have
also been implicated,
although it seems unclear
whether they're important
causally
or whether they just represent
secondary abnormalities related
to chronic inflammatory
responses.
Also, certain environmental
agents have been proposed to act
as potential triggers.
Oral flora and, in particular,
streptococcus sanguis are
supported by most evidence,
although other bacteria and even
viruses,
including herpes viruses,
have been implicated.
There is also accumulating
evidence
that microbial components,
such as Heat Shock Protein 65,
may resemble several proteins
such as the human Heat Shock
Protein 60, which carries
a significant homology with Heat
Shock Protein 65
through a phenomenon known
as molecular mimicry.
And these may trigger
cross-reactive lymphocyte clones
against [INAUDIBLE] proteins
such as the retinal S-antigen.
Please note that Heat Shock
Proteins are proteins that act
as alarm signals after being
released by injured cells.
The next slide introduces
the immune system factors
involved in Behcet's disease
and summarizes the most
important points.
It is very important to mention
that Behcet's disease is
a strictly human disease,
and there are no animal models
related to this.
And that obviously limits
greatly the experimental options
in this study, especially
of disease pathogenesis.
However, from human studies,
several immune system
abnormalities have been
described.
And these are summarized
in the next slide and include,
but are not limited to,
the following--
a polyclonal expansion
of gamma delta T cells
in the sites of inflammation.
Gamma delta T cells are
important for mediating
mucosal immunity,
and their expansion has been
implicated in the pathogenesis
of a number
of autoimmune diseases,
such as rheumatoid arthritis.
Elevated levels
of several cytokines in tissue
samples of Behcet's disease
patients have been described,
including interleukin-21,
interleukin-6, interleukin-8,
and interleukin-15.
Also, T cell responses
in the Behcet's disease
are skewed towards TH1 and TH17
phenotypes,
with the TH17 phenotype being
the most prevalent.
And for those of you who are not
familiar
with TH1, TH17 phenotypes,
I would just like to mention
that TH1 responses are mediated
mainly by means of interferon
gamma and TGF-beta.
They target mainly
the innate part
of our immune system,
particularly macrophages,
immune cells
of the cellular immune response,
as T cells are also involved.
The ultimate goal of a T H1
response
is to maximize the killing
efficacy of macrophages,
as well as support
the proliferation
of cytotoxic CD8 positive T
cells.
On the other hand,
TH17 responses are mediated
mainly
by interleukin-17A and
interleukin-17F.
[INAUDIBLE] are all involved
in the recruitment, activation,
and migration of the neutrophils
at the sites of injury.
Neutrophils, once they arrive
there, also secrete
IL-21 and IL-22.
Finally, the last point
of this slide
mentions anti-endothelial cell
antibodies, which have been
detected
in a variable frequency,
from 18% to 50%
of patients
in different studies.
However, these findings
at this point are of unclear
significance.
The slide summarizes
the current evidence
on the immunopathogenesis
of Behcet's disease
and demonstrates a proposed
model of how the disease occurs
and progresses.
So the current understanding
of Behcet's disease, in general,
is
that environmental triggers act
on a genetically susceptible
host, which also has
some immune system
abnormalities.
And all these three factors
together, they result
in the development
of inflammatory lesions.
So as you can see,
on the left part of the slide,
we have genetic factors
interplaying
with environmental triggers.
Then the middle section
of the slide,
we have immune system factors.
And then at the right part
of the slide, we see what's
happening
in the inflammatory lesions.
So now, starting
with genetic factors,
on the upper left part
of the slide, identified genes
include both MHC complex genes,
such as HLA-B51 and HLA-A26,
and non-MHC genes,
such as polymorphisms
of interleukin-10 or of the TNF
alpha promoter or also
for the common subunit
of the interleukin-12,
interleukin-23 receptor.
On the left the lower part
of the slide, we see a box that
includes some of the proposed
environmental triggers
for Behcet's disease, which
include bacteria,
in particular, streptococcus
sanguis,
as well as viruses
such as herpes viruses.
And then, as we mentioned
earlier, molecular mimicry
events between human HSP 60,
bacterial HSP 65
and the retinal S-antigens
are thought to be particularly
important in triggering
autoreactive lymphocyte clones.
So following the interplay
of genetic and environmental
triggers, on the left part
of the slide,
then the next initiating factor
for the disease, which
is an immune system factor,
are antigen presenting cells,
or APCs.
So it's the dark cell that you
see lying between the two boxes
with genetic factors
and environmental triggers.
Now, these antigen presenting
cells present
antigenic fragments
in the context of make MHC
[INAUDIBLE] T cells, which
following
additional interactions depicted
on the figure with CD40
and CD154,
as well as CD 80/86 and CD28
get activated.
Macrophages also produce
a number
of other pro-inflammatory
cytokines,
such as IL-1 and IL-6, which are
not shown in the figure.
Now, moving a little bit
to the right from the APC,
you see a T cell there depicted
in blue.
So T cells in Behcet's disease
are thought to be
nonspecifically
hyperresponsive
to bacterial antigens.
Now, in the case that the MHC
present
the antigenic determinant is
class one,
then cytotoxic CD8 positive T
cells are generated that mediate
damage directly
and through stimulation
of activated neutrophils
with interferon gamma and TMF
alpha.
These you can see
at the right part of the figure,
which depicts an activated
neutrophil carrying
on its surface CD11A, CD10,
and CD14.
Then, in the case
of CD4 positive T cells,
when antigenic determinants are
presented in the context
of MHC2,
macrophage-derived cytokines
are critical, as you can see
in the figure.
IL-12 promotes
the differentiation of naive T
cells, TH zeroes, what we call,
to TH1 or TH2 cells.
And then IL-21 enhances
TH1 differentiation.
Also, IL-23 promotes TH17
responses that we earlier
mentioned.
From the cytotoxic the cells,
the gamma delta T cells have
been particularly implicated
in mediating cytotoxic damage.
TH1 cells,
through cytokine production,
such as interleukin-8 gamma
and TNF alpha
activate neutrophils,
macrophages, and cytotoxic T
cells.
TH17 cells, as we mentioned
earlier, they mediate damage
through the production of IL-17,
which activates neutrophils
and also cytotoxic T cells.
Finally, macrophages and APCs
also secrete IL-18, which
directly activates neutrophils.
In fact, neutrophils in Behcet's
disease, they're thought to be
in a prime, hyperresponsive
state.
And they also produce IL-18,
which could create,
as we mentioned earlier,
because they're not
the only cells making IL-18,
they create a self-feeding loop
which augments
the inflammatory response.
Finally, on the right upper part
of the slide,
you can see
that endothelial cell
abnormalities and tissue factors
have been proposed to play
a critical role in determining
tissue damage.
There are a number of things
on the slide with question
marks,
such as regulatory T cells, NK
cells, B cells,
and autoantibodies.
But the role of all
these immune system factors
in the development
of the Behcet's disease
remains to be determined,
and that is why there are
these red question marks there.
So the next slides moves
through
the clinical presentation
of the features of the Behcet's
disease.
First of all,
make clear that Behcet's disease
is really
a chronic multi-organ
inflammatory disease
with prominent feature
of vasculitis,
vasculitis meaning inflammation
of blood vessels of pretty much
any size.
Most large, medium,
and small sized vessels can be
involved.
So as you can see in the slide,
the involvement of nearly
every organ system
in the human body
has been reported.
The course is typically
characterized
by spontaneous relapses
and remissions.
And the classic presented
triad consists of mouth ulcers,
genital ulcers, and ocular
disease, typically uveitis.
As we mentioned earlier,
the triad is often
incomplete in children, who
usually presents
with several years
of oral ulcers
prior to the development
of the second or third symptom
that will eventually satisfy
the full triad
and qualify for the diagnosis.
The next slide describes
in a little bit more detail
a frequency of involvement
of different organ systems.
So mouth ulcers, which are also
usually the first presenting
sign of the disease,
occur in 47% to 86% of patients;
genital ulcers also very
common in 57% to 93%
of patients.
30% to 70% of patients
have ocular involvement,
and which in up to 25%
of those patients
can lead to blindness.
Then 38% to 99% of patients,
they have a variety of skin
lesions, which usually present
as papulopustular lesions.
But they may also present
as erythema nodosum.
Neurological involvement has
been described in 5% to 10%
of patients,
with a remarkable difference
between children and adults
in the sense
that in adults, neuro-Behcet's
disease involves the brain
parenchyma.
Whereas in children, it usually
presents as [INAUDIBLE] venous
thrombosis.
Vascular disease occurs
in 7% to 49% of the patients.
It may involve both arteries
and veins.
And it can manifest in the form
of thrombosis, vasculitis,
and pulmonary aneurysms.
Articular involvement, either
in the form of arthralgia
or arthritis,
occurs in 45% to 60%.
And then, 3% to 26% of patients
may present
with gastrointestinal disease
which resembles in presentation
Crohn's disease.
And gastrointestinal involvement
is more
common in Asian populations,
in particular in Japan.
International Study Group
for Behcet's Disease
proposed diagnostic criteria
for the disease,
since there is
no specific laboratory test that
diagnoses the disease.
To meet the definition
of Behcet's disease, based
on [INAUDIBLE] physician
observing oral ulcers at least
three times
in a 12-month period,
along with two or more
of the following--
a recurrent genital ulceration
observed, again, by a physician
of patient;
eye lesions in the form
of arterial or posterial
uveitis; or cutaneous lesions,
either as erythema nodosum,
or the papulopustular lesions
that we mentioned earlier.
Other forms of skin involvement
include pseudofolliculitis
and acneiform nodules.
A fourth minor criteria includes
the pathergy test.
So a positive pathergy test
within 24 to 48 hours
qualifies
as a minor diagnostic criteria
for Behcet's disease.
The pathergy test, for those
of you who are not familiar,
involves a skin prick
with a needle
and an exaggerated reaction
manifesting as a papulopustular
lesion at the site of injury.
Before moving to the next slide,
I would like to mention
that this criteria have not been
validated ever in children.
And although we do use
this criteria
in pediatric Behcet's disease,
obviously, since there is such
a big lag
between the first and second
symptom,
we may be underdiagnosing
Behcet's disease in children.
So the next slide describes
laboratory abnormalities, as
well as summarizes treatment
options in Behcet's disease.
As we mentioned earlier,
there are no laboratory tests
specific for Behcet's disease.
No specific abnormalities,
such as increased
inflammatory parameters
and anemia of chronic disease
have been described.
Also, serum levels
of several cytokines
may be elevated, such as TNF
alpha interferon gamma,
interleukin-1 beta,
interleukin-6, interleukin-8.
However, their diagnostic value,
at this point,
remains to be determined.
Treatment of Behcet's disease
generally consists of drugs that
manipulate the immune system.
The choice of therapy
is determined by the severity
of the disease
and the specific organ
involvement.
Corticosteroids,
azathioprine, methotrexate,
cyclophosphamide,
cyclosporine A, thalidomide, TNF
alpha blockers, interferon alpha
and sulfasalazine, as well as
colchicine have all shown
efficacy.
And then, a few notes
about the different
medications-- cyclosporine A
should be avoided in patients
with neurologic involvement,
since the drug is
neurotoxic by itself.
Also,
anticoagulant, antiplatelet and
antifibrinolytic agents are not
recommended, since the risk
for pulmonary embolism
is very rare.
And on the other hand,
the risk of major bleeding
in case
of concomitant pulmonary
aneurysms is much higher.
So basically, the use
of these drugs is not justified
from a risk assessment
standpoint.
There are a couple studies that
show the efficacy
of benzathine penicillin G.
And there are also multiple case
reports of good responses
to interleukin-6 and TNF alpha
blockade.
The future target
of the disease-- and there are
some rare reports about this,
and I think you can infer this
from the slide summarizing
the pathogenesis--
appears to be interleukin-21.
So let's summarize,
in this slide,
what we learned today
about Behcet's disease.
Behcet's disease-- recurrent
multisystem
inflammatory disorder,
with features
of both autoinflammation
and autoimmunity.
The current understanding
of its pathogenesis
is that environmental triggers
on a genetically predisposed
host with immune system
abnormalities,
resulting
in inflammatory lesions that may
involve any organ system.
Behcet's disease
immunopathogenesis involves
multiple aspects
of the human immune system,
including gamma delta T cells,
TH1 and TH17 responses,
as well as a variety
of cytokines,
such as IL-1, IL-6, IL-8,
18, 21 and 23.
Neutrophils are also
particularly
important in mediating damage.
The classic triad of the disease
is mouth ulcers, genital ulcers,
and eye disease.
As we mentioned,
pediatric-onset disease shows
differences
with adult-onset disease,
with the most prominent
difference being
the central nervous system
involvement, where in kids
manifests as [INAUDIBLE]
venous thrombosis,
whereas in adults,
manifests
as parenchymal disease.
We also mentioned that children
may not satisfy
the diagnostic criteria
for Behcet's disease
for many years
after the onset
of the first symptom,
and that this criteria have
never been validated
in children.
The diagnosis is clinical,
and there is absolutely
no specific laboratory test
or imaging test
available to diagnose
the disease.
And finally, the treatment
involves manipulation
of the human immune system
by immunosuppressants
or immunomodulators.
The next slide just shows you
at least a few references
that I would recommend you
to look at if you want to gain
deeper understanding
of the disease
and its pathogenesis.
And finally, I would like
to acknowledge the people who
helped me out with making
this presentation.
First of all, the patients
and their families which have
been and will be always
the best teachers about anything
in clinics.
I would like to thank Dr. Lisa
Criscione-Schrieber, who
is the section editor,
for her help with preparing
the slides,
as well as
my pediatric rheumatology
supervisors at Duke-- Dr. Laura
Schanberg, Dr. Egla Rabinovich,
Dr. Heather Van Mater, and Dr.
Jeffrey Dvergsten.
