Transcript Vasculitisx

Vasculitis
DEFINITION
Vasculitis are a heterogeneous group of diseases characterized by
Inflammation , necrosis and damage to blood vessel walls , often with
associated organ involvement.
The vessel lumen is usually compromised, and this is associated with
ischemia of the tissue supplied by the involved vessel.
Any type, size, and location of blood vessel may be involved.
Vasculitis may be primary ( sole manifestation of a disease)
or may be secondary( component of another primary disease)
Vasculitis may be confined to a single organ, such as the skin,
or it may simultaneously involve several organ systems
Classification of Vascilites
Large vessel
.Giant cell arteritis &/or Polymyalgia rheumatica.
• Takayasu's arteritis
Medium vessel
Classical polyarteritis nodosa
• Kawasaki disease (in childhood)
Small vessel
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Microscopic polyangiitis
Wegener's granulomatosis
Churg-Strauss syndrome
Henoch-Schönlein purpura
Mixed essential cryoglobulinaemia
Others
as Behcets disease.
PATHOPHYSIOLOGY AND
PATHOGENESIS of Vasculitis
• Generally, most of the vasculitic syndromes are assumed to be
mediated at least in part by immunopathogenic mechanisms
that occur in response to certain antigenic stimuli
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it is unknown why some individuals might develop vasculitis
in response to certain antigenic stimuli,whereas others do not.
• It is likely that a number of factors are involved in the ultimate
expression of a vasculitic syndrome. These include the genetic
predisposition, environmental exposures, and the regulatory
mechanisms associated with immune response to certain
antigens.
deposition of immune complexes in vessel walls is the most
widely accepted pathogenic mechanism of vasculitis.
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The actual antigen contained in the immune complex has only
rarely been identified in vasculitic syndromes.
In this regard, hepatitis B antigen has been identified in some
patients with systemic vasculitis, most notably in polyarteritis
nodosa .
• The syndrome of essential mixed cryoglobulinemiais strongly
associated with hepatitis C virus infection
• . The mechanisms of tissue damage in
immune complex–mediated vasculitis
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antigen-antibody complexes are formed and are deposited in vessel walls
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The deposition of complexes results in activation of complement
components, particularly C5a, which is strongly chemotactic for
neutrophils.
These cells then infiltrate the vessel wall, phagocytose the immune
complexes, and release their intracytoplasmic enzymes, which damage the
vessel wall.
As the process becomes subacute or chronic,mononuclear cells infiltrate
the vessel wall.
This will compromise of the vessel lumen with ischemic changes in the
tissues supplied by the involved vessel.
Clinical features of Vasculitis
• The clinical features of vasculitis are due to a combination of
local tissue ischaemia (caused by vessel inflammation and
narrowing) and the systemic effects of widespread
inflammation.
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Systemic vasculitis should be considered in any patient with
fever, weight loss, fatigue, evidence of multisystem
involvement, rashes, raised inflammatory markers and
abnormal urinalysis.
• Early diagnosis and management are essential to prevent
irreversible organ damage.
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• Vasculitis may be difficult to distinguish from
widespread malignancy,
occult sepsis (particularly subacute bacterial endocarditis &
meningococcal septicaemia).
cholesterol emboli.
atrial myxoma .
antiphospholipid syndrome.
• The key to recognition is the presence of multisystem
involvement
Clinical Features of Vasculitis include
Constitutional symptoms
Fever
Weight loss
Fatigue
purura
Livido reticularis
Digital infarction
Musculoskeletal
Arthralgia
Arthritis
Cardiovascular
pulselessness and ⁄or bruits
common in large vessel disease
Claudication
Aneurysms
Pulmonary
Alveolar hemorrhage
Nodules
Gastrointestinal
Bowel ischemia and ⁄or infarction
Renal
Glomerulonephritis
Nephrotic syndrome
Renovascular involvement
Hypertension
Neurologic
Mononeuritis multiplex
Visual disturbance
Stroke
lightheadedness
Laboratory abnormalities
Anemia
Eosinophilia
Elevated acute phase reactions
Renal insufficiency
Active urinary sediment
Conditions That Can Mimic Vasculitis
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Infectious diseases
Bacterial endocarditis
Disseminated gonococcal infection
Pulmonary histoplasmosis
Coccidioidomycosis
Syphilis
Lyme disease
Rocky Mountain spotted fever
• Coagulopathies/thrombotic
microangiopathies
• Antiphospholipid antibody syndrome
• Thrombotic thrombocytopenic purpura
• Neoplasms
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Atrial myxoma
Lymphoma
Carcinomatosis
• Drug toxicity
• Cocaine
• Others
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Sarcoidosis
Goodpasture’s syndrome
Amyloidosis
Migraine
Cryofibrinogenemia
Emboli
cardiac emboli
cholestrol emboli
Investigations in Vasculitis
• If vasculitis is suspected, the diagnosis should ideally be
confirmed by tissue biopsy.
• Skin biopsies are easily obtained.
• Nasal septal tissue can be taken from areas of ulceration or
granulation.
• Muscle biopsy is positive in about 50% of patients with muscle
pain.
. The most important bedside test is the urine dip test for protein
and blood, and subsequent microscopy, since the prognosis of
vasculitis is often determined by the degree of renal
involvement. In patients with abnormal renal function and active
urinary sediment, renal biopsy should be considered.
• Visceral angiography
to detect microaneurysms (e.g. classical polyarteritis nodosa)
is most useful where involved tissue is not available to biopsy.
• ESR usually elevated in vasculitis
• CRP
• C-ANCA & p-ANCA
• Antineutrophil cytoplasmic antibodies (ANCA)
• are directed against enzymes present in neutrophil granules.
• Two main patterns of immunofluorescence are distinguished:
cytoplasmic (c-ANCA) and perinuclear (p-ANCA).
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c-ANCA are usually directed against proteinase 3 and are
particularly associated with Wegener's granulomatosis and ChurgStrauss syndrome.
• p-ANCA are usually directed against myeloperoxidase and
associate with microscopic polyangiitis.
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However, positive ANCAs occur in many other diseases, including
malignancy, infection (bacterial and HIV), inflammatory bowel
disease, RA, lupus and pulmonary fibrosis. Therefore, the diagnosis
of these conditions cannot be made or refuted on the ANCA test
alone.
Large Vessel Vasculitis
1- Giant cell arteritis
2- Polymyalgia rheumatica
3-Takayasu's arteritis
GIANT CELL ARTERITIS (GCA)
(Temporal Arteritis)
• GCA also known as temporal arteritis or cranial arteritis
• is a large vessel vasculitis predominately affecting branches of
the temporal and ophthalmic arteries.
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The mean age of onset is 70 years .
• 4:1 female:male ratio.
Clinical features of Giant cell arteritis
• The onset of symptoms may be abrupt but is often
insidious over the course of several weeks or months.
• The most important clinical features are:
1- Headache. This is usually the first symptom and is often
localised to the temporal or occipital region, with scalp
tenderness.
2- Jaw pain. This is brought on by chewing or talking and is
due to ischaemia of the masseters.
3-Visual disturbance.
The most important complication of GCA is monocular
blindness which is almost never reversible
The optic nerve head is supplied by the posterior ciliary
artery, vasculitis of which leads to occlusion and acute
anterior ischaemic optic neuropathy.
Damage to the optic nerve results in loss of visual acuity
and field, reduced colour perception and pupillary
defects.
Sudden visual symptoms in one eye, leading rapidly to
blindness, constitute the most common pattern.
On fundoscopy the optic disc may appear pale and swollen
with haemorrhages, but these changes may take 24-36
hours to develop.
Once blindness has occurred corticosteroids have a
negligible effect but are indicated to prevent blindness in
the other eye.
4- There may be associated constitutional
symptoms of anorexia, fatigue, weight loss,
fever, depression and general malaise.
5- Occasionally presentation is with
neurological complications that include
transient ischaemic attacks, brain-stem
infarcts and hemiparesis.
Investigations
• The ESR usually elevated above 50 mm/hour in 90% of cases. ( in
some cases the ESR may be normal mainly in those with acute
presentationis , in the this situation the CRP may be more helpful ,&
usually elevated ).
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Temporal artery biopsy should be obtained.
corticosteroid treatment should not be delayed whilst the biopsy is
organised.
Characteristic biopsy findings are fragmentation of the internal
elastic lamina with necrosis of the media in combination with a
mixed inflammatory cell infiltrate (lymphocytes, plasma cells and
eosinophils).
However, 'skip' lesions are common and a negative biopsy does not
exclude the diagnosis.
Management of GCA
• If GCA is suspected, systemic corticosteroid (prednisolone 60
mg daily) should be started immediately to prevent visual loss.
• Steroid reduction should be guided by symptoms and ESR,
aiming for approximately 10 mg daily by 6 weeks. Thereafter,
doses should be reduced by 1 mg per month
• Maintenance therapy is required for at least 1 year, and
occasionally for the rest of the patient's life.
• Relapse occurs in 30%, and is an indication to restart highdose steroids with additional immunosuppressive agents,
typically azathioprine or methotrexate
• . Patients with known GCA should be advised to take
60 mg prednisolone and seek prompt medical advice
should they experience any recurrence of headache
or visual disturbance.
•PMR
is a clinical syndrome of muscle pain and stiffness with
an increased ESR.
It is not a true vasculitis but there is a close association with
giant cell arteritis.
• The prevalence is approximately 20 per 100 000 over the age of
50.
•The mean age of onset is 70.
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•Women
are affected more often than men in a ratio of 3:1.
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The cardinal features are muscle stiffness and pain,
symmetrically affecting the proximal muscles of the neck,
upper arms and, less commonly, the buttocks and thighs.
There is marked early morning stiffness, often with night
pain.
Constitutional features of weight loss, fatigue, depression
and night sweats also occur.
On examination there may be stiffness and painful
restriction of active shoulder movement but passive
movements are preserved.
Muscles may be tender to palpation but there should not be
muscle-wasting; if there is, then primary muscle or
neurological disease is more likely
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Fibromyalgia
Hypothyroidism
Cervical spondylosis
Rheumatoid arthritis
Inflammatory myopathy (particularly inclusion
body myositis)
Systemic vasculitis
Malignancy
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ESR is elevated above 40 mm/hour In the majority
of patients
Very occasionally the ESR is low, usually in the
acute situation where there has not been sufficient
time for it to rise. In this situation the CRP may be
elevated prior to the ESR.
There may be a normochromic, normocytic
anaemia
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The only effective treatment is corticosteroids.
prednisolone should be started at a dose of 15 mg daily.
The majority of patients should have a dramatic
response within 72 hours.
If there is no response by 72 hours or an incomplete
response by 7 days, then the diagnosis is not PMR.
If there has been a good response to prednisolone, the
daily dose should be reduced to 10 mg after 4 weeks and
then by 1 mg per month, assuming that symptoms
remain controlled.
Most patients need steroids for an average of 12-18
months and osteoporosis prophylaxis with
bisphosphonates should be considered.
Some patients require steroid-sparing agents such as
methotrexate or azathioprine, particularly if
prednisolone cannot be withdrawn at 2 years or is
needed at doses greater than 7.5 mg daily.
Approximately 15-20% of patients develop features of
giant cell arteritis at some point in the course of their
disease.
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Takayasu's disease is a chronic inflammatory granulomatous
panarteritis of elastic arteries.
The vessels most commonly involved are the aorta and its branches,
and the carotid, ulnar, brachial, radial and axillary arteries.
Pulmonary arteries are occasionally affected.
It is more common in women (female:male ratio 8:1) with a typical
onset at the age of 25-30 years.
It has a world-wide distribution but is most common in Asia.
The aetiology is unknown.
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.The usual presentation is with claudication and systemic
symptoms of fever, arthralgia and weight loss.
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Clinical examination may reveal loss of pulses, bruits,
hypertension and aortic incompetence.
Laboratory investigations are usually non-specific, with high
ESR and normocytic, normochromic anaemia.
Diagnosis is usually based on angiographic findings of
coarctation, occlusion and aneurysmal dilatation.
1-Age less than 40 years.
2-Claudication of extremeties.
3-Decreased brachial artery pulse.
4-BP difference more than 10 mmHg between arms.
5-Bruit over subclavian arteries & aorta.
6-Arteriogram abnormalities:
occlution or narrowing in aorta or main branches.
Must have 3\6 criteria for diagnosis.
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The 5-year survival rate is ∼80%.
Treatment
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Most patients respond to initial high-dose oral prednisolone
(1-2 mg/kg daily).
Additional therapy with methotrexate or cyclophosphamide
is usually required.
Reconstructive vascular surgery should be avoided during
periods of active inflammation but may benefit selected patients,
especially those with hypertension secondary to aortic or renal
lesions
Medium – Sized Arteritis
1- Classical polyarteritis nodosa.
2- Kawasaki disease.
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Classical PAN is a necrotising vasculitis characterised by
transmural inflammation of medium-sized to small arteries.
PAN is a rare disorder with an annual incidence of 2 per
million in most populations.
All age groups can be affected, with a peak incidence in the
fourth and fifth decades, and a male:female ratio of 2:1.
Hepatitis B is a risk factor, and the incidence of PAN is
higher in the areas, where hepatitis B infection is endemic
Clinical presentation is with myalgia, arthralgia, fever and
weight loss in combination with manifestations of
multisystem disease.
 The most common skin lesions are palpable purpura,
ulceration, infarction and livedo reticularis .
 In 70% of patients arteritis of the vasa nervorum leads to
neuropathy which is typically symmetrical and affects both
sensory and motor function.
 Severe hypertension and/or renal impairment may occur
due to multiple renal infarctions.
glomerulonephritis is rare .
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Diagnosis is confirmed by finding multiple aneurysms and
smooth narrowing of either the mesenteric, hepatic or renal
systems on angiography.
Tissue biopsy may be definitive (muscle or sural nerve),
even in the absence of angiographic abnormality.
Treatment
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Treatment for hepatitis B-related disease is to remove the
source of the antigen, i.e. antiviral therapy.
Corticosteroids and cyclophosphamide are the treatment
of choice for idiopathic disease.
Mortality is less than 20%, although relapse occurs in up to
50% of patients
Polyarteritis Nodosa
Micro “Berry” aneurysms
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Kawasaki disease is an acute systemic disorder of childhood
that predomintely occurs in Japan( 800 cases per million in
children under the age of 5 ).
The disease resembles a viral exanthem or stevens – Johnson
syndrome.
Although the causative trigger is unknown, it has been
associated with Mycoplasma and HIV infection in some cases.
The clinical features often develop abruptly.
Fever persisting > 5 days
 Bilateral conjunctival congestion
 Erthema of lips, buccal mucosa and tongue
 Acute non-purulent cervical lymphadenopathy
 Polymorphous exanthema
 Erythema of palms and soles(oedema followed by
desquamation)
 Coronary dilatation
* Five out of six clinical features, or four out of six
clinical features with evidence of Coronary
dilatation, are required for diagnosis.
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Cardiovascular complications include myocarditis,
pericarditis, coronary aneurysms, transient coronary artery
dilatation, myocardial infarction due to coronary
thrombosis.peripheral vascular insufficieny and gangerene.
Investigations that favour KD include :
polymorphonuclear leucocytosis, thrombocytosis, raised
ESR and CRP and circulating antiendothelial cell
antibodies.
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Treatment is with aspirin (5 mg/kg daily for 14
days) and intravenous gammaglobulin (400 mg/kg daily
for 4 consecutive days).
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Steriods should be avoided because of the risk of worsenin the
coronary artery dilatation .
coronary artery changes are usually monitored weekly by
two-dimensional echo for 4 weeks, by which stage most
children have recovered.
The overall mortality is less than 2%
Relapse is rare , but if there is coronary artery involvement
long –term follow –up is necessory.
Small Vessel vasculitis
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Microscopic polyangiitis
Wegener's granulomatosis
Churg-Strauss syndrome
Henoch-Schönlein purpura
Mixed essential cryoglobulinaemia
ANCA-ASSOCIATED VASCULITIS
Microscopic polyangiitis, Wegener's granulomatosis and
Churg-Strauss syndrome can be grouped together as
'ANCA-associated vasculitis',
Sites of Involvement of ANCA Vasculitis
1. Kidney - most common (75%-90%)
2. Lung - 50%
3. Skin + Kidney - 33%
4. CNS - 25%
Classic presentation is with rapidly progressive glomerulonephritis
often associated with pulmonary alveolar haemorrhage.
Cutaneous and gastrointestinal involvement, similar to PAN, is
common.
MPA is more common than PAN, with an annual incidence of 8 per
million .
Other features include neuropathy (15%) and pleural effusions
(15%).
Patients are usually p-ANCA-positive.
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The annual incidence of WG is 5-10 per million.
The most common presentation is with upper airway
involvement (typically epistaxis, nasal crusting and
sinusitis), haemoptysis, mucosal ulceration and deafness
due to serous otitis media.
Symptoms may have been present for several months and
erroneously attributed to infection or allergy.
The most common ocular abnormality is proptosis, due to
inflammation of the retro-orbital tissue.
This may cause diplopia due to entrapment of the extraocular
muscles, or loss of vision due to optic nerve compression .
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Untreated nasal disease ultimately leads to destruction of
bone and cartilage.
Migratory pulmonary infiltrates and nodules occur in
50% of patients.
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A minority of patients present with glomerulonephritis.
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Patients are usually c-ANCA-positive.
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The annual incidence is 1-3 per million .
Most patients have a prodromal period for many years,
characterised by allergic rhinitis, nasal polyposis and
late-onset asthma that is often difficult to control.
The typical acute presentation is with a triad comprising
skin lesions (purpura or nodules), asymmetric
mononeuritis multiplex and eosinophilia on a
background of resistant asthma.
Pulmonary infiltrates and pleural or pericardial effusions
due to serositis may be present.
Up to 50% of patients have abdominal symptoms due to
mesenteric vasculitis.
Either c-ANCA or p-ANCA is present in around 40% of
cases.
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Treatment should be instituted as early as possible to prevent
irreversible damage.
Remission can be induced either with oral high-dose
prednisolone (1 mg/kg daily) and continuous oral
cyclophosphamide (2 mg/kg daily)
or
with bolus i.v. methylprednisolone and cyclophosphamide
infusion monthly.
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Doses of cyclophosphamide should be reduced in the elderly
and those with renal impairment.
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Once remission has been induced (3-6 months) the dose
of oral prednisolone is rapidly reduced and
cyclophosphamide is usually replaced with azathioprine.
Co-trimoxazole is usually given at a prophylactic dose
(960 mg thrice weekly) in conjunction with
cyclophosphamide to prevent Pneumocystis pneumonia,
unless there is a history of drug allergy.
Mesna is used with bolus cyclophosphamide to reduce
the risks of haemorrhagic cystitis.
Patients who have ANCA-positive vasculitis with acute
renal failure have a better outcome when also treated
with adjunctive plasma exchange.
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Most common systemic vasculitis in children.
Usually occurs following an upper respiratory tract infection. About
50% of cases are preceded by URI’s.
 Streptococcus is often implicated.
Vaccines, insect bites, viruses have also been reported as triggers.
Occurs more often in winter, and spring.
Rare in the summer
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Typical presentation is with :
purpura over the buttocks and lower legs.
abdominal symptoms (pain and bleeding) .
arthritis (knee or ankle).
Nephritis occurs in 40% of patients and may occur up to 4 weeks after
the onset of other symptoms
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. The diagnosis can only be confirmed by demonstrating IgA
deposition within and around blood vessel walls.
Prognosis is generally good and determined by the degree and
severity of renal involvement.
Although only 1% of patients develop end-stage renal failure,
adverse features at presentation in adults include hypertension,
abnormal renal function and proteinuria > 1.5 g/day.
Treatment
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Corticosteroids alone are effective for gastrointestinal and joint
involvement
but nephritis usually requires treatment with both pulse i.v.
steroids and immunosuppression
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Cryoglobulins are circulating immunoglobulins that
precipitate out in the cold.
They are classified into three types, types II and III are
associated with cryoglobulinaemic vasculitis.
The typical clinical features are palpable purpura over the
lower extremities, arthralgia, Raynaud's phenomenon
and neuropathy.
Type II cryoglobulinaemia is secondary to hepatitis C virus
(HCV) infection in most patients, the virus being present in
the vasculitic lesions complexed with IgG and IgM.
For HCV-positive patients, interferon-alpha is the treatment
of choice; for high HCV loads, combination with ribavirin
may be more effective .
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CLASSIFICATION OF CRYOGLOBULINS
Type I
Antibody type
Monoclonal IgM
Associations Malignant B-cell disease, e.g.
Waldenström's macroglobulinaemia, lymphoma, myeloma.
Type II ('mixed essential')
Antibody type
Monoclonal IgM and anti-IgG antibody
Associations Hepatitis C, SLE, B-cell malignancy
Type III
Antibody type Polyclonal IgM and anti-IgG antibody
Associations RA, SLE, chronic infections
Behçet's syndrome
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This is a vasculitis of unknown aetiology that
characteristically targets venules.
It is common in the countries around the Mediterranean
and in Japan where there is a strong association with
HLA-B51.
There is a wide range of clinical features, and the disease
is characterised by unpredictable exacerbations.
There are no defining investigations and the
diagnosis is made using clinical criteria .
1- Recurrent oral ulceration2- Plus two of:
a- Recurrent genital ulceration
b- Eye lesions-anterior uveitis, posterior uveitis, retinal
vasculitis
c- Skin lesions- erythema nodosum, pseudofolliculitis,
papulopustular lesions, acneiform nodules
d- Positive pathergy test
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Oral ulcers
are universal , the ulcers are usually deep and multiple, and
last for 10-30 days.
occur at least three times in a 12-month period
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Genital ulcers
are less common (60-80%).
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Skin lesions
are erythema nodosum or acneiform lesions but migratory
thrombophlebitis and vasculitis also occur.
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pathergy reaction
is hyper-reactivity at the site of minor trauma. A positive pathergy
test (a papule 2 mm or more in size developing 24 to 48 hours after
oblique insertion of a needle 5mm into the skin, generally performed
on the forearm)
pathergy test involves intradermal skin pricking with a needle, and is
positive if a pustule develops within 48 hours.
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Ocular involvement
is usually bilateral and may include anterior or
posterior uveitis or retinal vasculitis.
Neurological involvement
occurs in 5% and mainly involves the brain stem,
although the meninges, hemispheres and spinal cord can
also be involved to cause pyramidal signs, cranial nerve
lesions, brain-stem symptoms or hemiparesis.
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Recurrent thromboses also occur.
Renal involvement is extremely rare.
Differential diagnosis of oral Ulceration
Behcet's syndrome : Oral aphthae are present in almost all
patients with Behcet's.
Herpes simplex
Benign aphthous ulcers
Inflammatory bowel disease
Stevens-Johnson syndrome
Systemic lupus erythematosus.
Dental prosthetics and oral hygiene products can cause oral
irritation and ulceration.
Medications such as methotrexate
pemphigoid, pemphigus vulgaris, lichen planus, and linear IgA
disease.
TREATMEN OF BEHÇET'S SYNDROME
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Treatment of oral ulceration is with topical corticosteroid
preparations (e.g. soluble prednisolone mouthwashes,
corticosteroid pastes).
Colchicine is sometimes effective for erythema nodosum and
arthralgia.
Thalidomide (100-300 mg daily for 28 days initially) is
very effective for resistant oral and genital ulceration but is
teratogenic and neurotoxic.
Systemic disease usually requires oral corticosteroids in
combination with other immunosuppressive drugs like
(cyclosporine , cyclophosphamide , azathioprime ,
mycophenolate mophetil ….).