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Introduction: Beh�et�s
Disease (BD) is classified as a form of vasculitis (see
�Vasculitis� section) involving both arteries and veins of all
sizes. While the most typical signs of BD are oral and
genital ulcers, multiple organ systems may be involved. Males
and younger patients tend to have more serious disease
activity and increased mortality rates. This condition
demonstrates a distinct geographic distribution. BD is rare
in North America, affecting only 1 in 300,000 individuals.
The highest prevalence is found in Turkey, Iran, and Japan,
following the ancient �silk route� used by traders. In these
populations, BD is perhaps several hundred times more common.
The cause of BD
is unknown. Genetic factors are believed to play a role, as
the HLA-B51 genetic marker is found in higher frequency among
Japanese and Eastern Mediterranean patients. North American,
European, and Eastern Indian patients, however, do not
demonstrate a specific genetic marker on laboratory testing.
Bacterial infections, such as streptococcus, staphylococcus,
and E. coli have been considered as possible triggers of BD,
and viruses such as herpes simplex may also play a causative
role. Various immune abnormalities may be found when studying
BD patients, including production of proteins known to
stimulate the immune system or activate white blood cells. At
this time, it is not known whether these abnormalities are
inherited or whether they are the response of the immune
system to an infection or other exposures that initiate the
inflammatory response.
Features
of BD: In general, BD demonstrates a
pattern of exacerbations and remissions. With the passage of
time, the overall disease activity tends to diminish. Most
patients present with oral and/or genital ulcers. Ocular
(eye) and central nervous system involvement may develop
several years after the initial diagnosis. While mortality
rates are low for patients exhibiting only oral and skin
involvement, loss of vision is a significant risk in patients
with ocular BD. A higher mortality risk is associated with
involvement of the central nervous system, gastrointestinal
tract, or other major organ systems.
Essentially 100%
of all patients with BD will develop recurrent mouth sores,
known as aphthous ulcerations. Mucous membrane (mouth)
lesions consist of painful, shallow ulcers that occur on the
inner lips, tongue, cheeks, and gum line. They tend to heal
without scarring in ~ 2 or 3 weeks. These ulcers are often
indistinguishable from canker sores. Genital ulcers occur in
approximately 80% of BD patients. Typical locations for these
lesions are on the scrotum and penis in males and on the vulva
or vagina in women. As opposed to the oral ulcers, these
lesions tend to result in permanent scarring after healing but
do not recur as frequently.
Cutaneous (skin)
lesions exhibit a variety of different presentations. They
may appear as red painful nodules resembling erythema
nodosum, large and painful ulcers with ragged borders
known as pyoderma gangrenosum, or flat red and inflamed
regions resembling Sweet�s syndrome. In other
patients, small vessel cutaneous vasculitis may occur, giving
rise to purpura (see �Vasculitis� section). Still
others may demonstrate pustular and acne-like lesions,
particularly in the �beard� area in men. A curious finding,
mostly in Middle Eastern patients with BD, is known as
pathergy. This phenomenon is characterized as an intense
inflammatory response in the skin after minor injury such as
blood drawing. While an uncommon finding in North American
patients, when present pathergy is quite suggestive of BD.
Eye involvement
in BD may occur in either the anterior (front) or posterior
(back) sections (or �chambers�) of the eye. Uveitis or
iritis, inflammation of the iris in the anterior
chamber of the eye, and hypopyon, pus in the anterior
chamber, are common findings in those with ocular
complications. While these conditions present with more
dramatic symptoms of redness, blurring, and pain in the
affected eye, more commonly patients experience painless
blurring in one or both eyes and note �spots� in their visual
field. For this reason, it is important for BD patients to
have regular eye examinations by an ophthalmologist to prevent
progressive vision loss and even blindness which may occur as
complications of this disease.
Arthritis in BD
is usually inflammatory and nonerosive (causing no joint
damage). Often, only 1 to 3 joints are involved, either in a
symmetric or asymmetric distribution. Joints most commonly
involved include the knees, wrists, ankles, and elbows.
Arthritis symptoms generally last a few weeks at a time and
then resolve.
Central nervous
system (CNS) involvement generally includes the lower part of
the brain know as the brainstem and the connections
between the brain and spinal cord. Patients may present with
balance problems, weakness on one side, or less commonly of
all four limbs. Non-infectious inflammation around the lining
of the brain (meningitis) may result in headaches or
behavioral problems. Patients with progressive CNS
involvement tend to have a poor prognosis.
Pulmonary (lung)
manifestations in BD may include aneurysms in the
pulmonary artery, pulmonary hypertension (elevated
pressures in the lung circulation), blood clots (emboli)
in the lungs, and scarring of lung tissue. Rarely, a
connection between an artery and the lung known as a
fistula develops and presents as sudden coughing up of
large amounts of blood. This severe complication requires
immediate recognition and treatment. Cardiac manifestations
can include heart attacks and inflammation surrounding the
lining of the heart (pericarditis).
Vascular (blood
vessel) complications include inflammation and clotting of
veins (phlebitis), which can involve small veins on the
surface of the skin or deeper veins as large as the inferior
vena cava in the center of the body. Aneurysms or swelling
around the arteries known as pseudo-aneurysms may
develop, sometimes merely after puncturing the artery with a
needle for blood drawing.
Ulcerations may
occur in the gastrointestinal tract, most often in the region
where the small intestine joins the colon. These patients may
present with abdominal pain, bleeding, or perforation of the
bowel. This latter complication requires prompt surgical
intervention to remove the involved area of intestine. Kidney
involvement is uncommon in BD, with inflammation of the kidney
(nephritis) or protein deposits in the kidney (amyloidosis)
being the major features. Amyloidosis typically develops when
treatment of chronic inflammation is less than optimal.
Diagnosis: Because of the variable course of BD,
most patients exhibiting a pattern of exacerbations and
remissions, health care providers may require several months
to make the correct diagnosis. There are no laboratory tests
or x-ray findings that reliably diagnose BD, although
nonspecific findings on such studies may aid in the evaluation
of the patient and help rule out other conditions such as
systemic lupus erythematosus (see related section). The
diagnosis of BD rests upon the history of the illness and
findings on physical examination of the patient.
Criteria for
diagnosing BD were devised in 1990 by an international
committee and include:
-
Recurrent oral
ulceration, plus 2 of the following:
-
Recurrent
genital ulceration
-
Eye lesions
-
Skin lesions
-
Positive
�pathergy test�
The pathergy test
consists of stimulating an area of previously normal skin with
a needle and observing the inflammatory response described
above in the �Features of BD� section. This test has
much more reliability in Middle Eastern populations, where
pathergy is a much more common finding. Occasionally,
biopsies of affected areas or dye studies or arteries or veins
may assist health care providers in the diagnosis of BD, but
for the most part any other investigations only supplement the
criteria listed above.
Therapy:
(See �Medications� section for further details) The broad
spectrum of findings in BD makes management of this condition
quite challenging. Depending on the symptom presentation of
BD, various specialists may need to be involved in treating
the patient, including regular eye exams, as mentioned above,
to prevent potential permanent visual loss.
Milder mucous
membrane and cutaneous lesions, including oral and genital
ulcers, can be treated with topical steroid preparations,
non-steroidal anti-inflammatory drugs (NSAIDs)
such as ibuprofen (Motrin) or naproxen (Naprosyn),
anti-histamines such as diphenhydramine
(Benadryl), colchicine, and dapsone.
Colchicine, a medication also commonly used for the treatment,
may reduce the frequency and/or severity of oral and genital
lesions. Diarrhea, nausea, and rare occurrence of suppression
of white blood cell counts at higher doses are the major side
effects of colchicine. Dapsone, a medication originally
designed for the treatment of leprosy, may be quite useful in
the treatment of skin lesions as well as oral or genital
ulcers. Patients starting dapsone should be screened for
deficiency of an enzyme known as G6PD before starting therapy,
as such individuals experience destruction of red blood cells
when receiving this drug. Most patients, however, have few
serious side effects to these medications.
More serious
mucocutaneous lesions that are unresponsive to the above
therapies may require the use of thalidomide,
methotrexate (MTX), and/or a low dose of prednisone
or other corticosteroid preparations. Thalidomide, a
medication that is available only by special request in the
United States, was taken off the market years ago due to the
occurrence of severe birth defects in children born to mothers
taking this drug. Men or women without child-bearing
potential are the best candidates to receive thalidomide.
Mild nerve damage is the other major side effect of
thalidomide that requires routine monitoring. The side
effects of MTX include suppression of the immune system,
elevation of liver enzymes, and lowering of white blood cell
counts. As discussed in other sections, cortico-steroid
medications have a wide array of side effects including weight
gain, loss of bone strength/density, elevation of blood sugar
levels, cataracts, and suppression of the immune system that
must be factored in before initiating therapy for a given
patient.
Patients with
disease involving major organs such as the eyes, heart, lungs,
or CNS require more intensive immunosuppressive therapy.
Steroids may be given alone or in combination with other
agents, and may need to be started at higher doses for more
severe disease. Other immunosuppressive medications utilized
may include azathioprine (Imuran), cyclosporine
(Neoral), cyclophosphamide (Cytoxan), and
chlorambucil (Leukeran). All of these drugs have the
potential to make patients prone to infection and lower the
blood counts. Azathioprine may additionally cause elevation
of liver enzymes, while cyclosporine may impair kidney
function, and cyclophosphamide can cause irritation of and
occasionally bleeding in the bladder if not given with
adequate fluids.
Interferon-α
(Roferon) is an injectable medication with anti-viral effects
that has a role in treating certain patients with BD. This
medication does not suppress the immune system substantially
but modifies the inflammatory response. Fever or flu-like
symptoms and a lowering of the seizure threshold are among the
side effects of interferon-α. Recently, tumor
necrosis factor (TNF) antagonists such as
etanercept (Enbrel), infliximab (Remicade), and
adalimumab (Humira) that are used in treating rheumatoid
arthritis have been utilized for treating BD, and initial
results are encouraging.
Specific
treatment recommendations vary depending on the patient�s
individual symptoms and findings. Therapy generally requires
supervision by a physician familiar with the various treatment
options and their unique risk/benefit profiles. Long-term
prognosis for BD patients is generally good as long as the
disease is recognized promptly and treated appropriately. |
