Transcript Large vessel vasculitis

Approach to a Patient with
Vasculitis A student Perspective
Mohammed A. Omair
Consultant Rheumatologist
Assistant Professor
King Khalid University Hospital
King Saud Unversity
Objectives
• Review the classification of vasculitis
• Epidemiology, manifestations and treatment of different types of
vasculitis
• Vasculitis mimickers
Introduction
• Vasculitis refers to a group of heterogeneous diseases characterized by
inflammation within the wall of the blood vessels, resulting in occlusion
and/or thrombosis of vessel lumen and, ultimately, tissue ischaemia
and/or organ injury.
• Classification of systemic vasculitides is mainly based on histological
features and the size of the vessel predominantly involved, from large- to
medium and finally small-sized vessel vasculitides according to the Chapel
Hill nomenclature.
Size Matters
Chapel Hill Nomenclature (1994) Revised in 2012
Types of Vasculitides
•
Large vessel vasculitis (LVV)
•
Variable vessel vasculitis (VVV)
•
Takayasu arteritis (TAK)
•
Behcet’s disease (BD)
•
Giant cell arteritis (GCA)
•
Cogan’s syndrome (CS)
•
Medium vessel vasculitis (MVV)
•
Single-organ vasculitis (SOV)
•
Polyarteritis nodosa (PAN)
•
Vasculitis associated with systemic disease
•
Vasculitis associated with probable etiology
•
Hepatitis C virus–associated cryoglobulinemic vasculitis
•
Hepatitis B virus–associated vasculitis
•
Syphilis-associated aortitis
•
Drug-associated immune complex vasculitis
•
Kawasaki disease (KD)
•
Small vessel vasculitis (SVV)
•
Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis
(AAV)
•
Microscopic polyangiitis (MPA)
•
Granulomatosis with polyangiitis (Wegener’s) (GPA)
•
Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (EGPA)
•
Immune complex SVV
•
Drug-associated ANCA-associated vasculitis
•
Anti–glomerular basement membrane (anti-GBM) disease
•
Cancer-associated vasculitis
•
Cryoglobulinemic vasculitis (CV)
•
Others
•
IgA vasculitis (Henoch-Schonlein) (IgAV)
•
Hypocomplementemic urticarial vasculitis (HUV) (anti-C1q vasculitis)
Large Vessel Vasculitis
GCA
• Giant cell arteritis (GCA) is the most common of the vasculitis syndromes
and, being a disease of the elderly, its incidence is increasing with the
general ageing of the population.
• GCA is most feared for its early complications, namely blindness and
stroke, resulting from inflammation and subsequent occlusion of ocular
and extra cranial arteries, respectively.
• More recently, however, GCA has been recognized to also affect limb
arteries and the aorta with a high prevalence.
GCA (Horton’s disease)
• It is believed to be an old disease evidenced by a stone relief
from ancient Egypt In the grave of Pa-Aton-Ern-Hebs, built
during the Amarna period (around 1350 AD) very likely
depicts a blind harp player suffering from GCA.
• Ali Ibn Isa an ophthalmologist in Baghdad (940–1010 BC),
recommended removal of the temporal artery not only to treat
headaches, but also inflammation of the scalp muscles
associated with blindness.
• the first official case was published in 1932 by Horton.
• In their report an individual with blindness, tongue necrosis
and jaw claudication is described.
GCA
• Inflammation of the vessel wall is characterized
by infiltration of T-cells and macrophages,
presence of multinucleated giant cells,
granulomatous lesions, intimal hyperplasia and
destruction of elastic fibers.
• Dendritic cells (DCs), similar to skin-residing
Langerhans cells, have been implicated in
providing initial signals that break the immune
protection of arterial walls.
• T cells are functionally selected as well, and
belong to either the T helper (Th ) 1 or the Th 17
lineage.
• CD4+ T cells producing IFN-gama have been
identified as key regulators in the vascular lesions
of GCA
GCA why old age?
• Self tolerance is an active process within the immune
system.
• Immunosenescence refers to the changes that occur
in the immune system in the elderly population
• With advanced aging fine tuning within the immune
system is lost which results in a defect in clearing
antigens that lead to self damage and a chronic
inflammatory state called inflamm-aging.
• Cytokines, such as IL-6, TNF-α, and IL-1β, are
suspected to have an important role in sustaining
chronic inflammation.
• With advanced age spontaneous production of
cytokines leads to a pro-inflammatory environment in
which tissues are constantly ‘primed’ by cytokines.
• Remodeling of the blood vessel wall might also play a
role in the pathogenesis of GCA.
Feature of GCA
• Clinical consequences of vascular insufficiency include
headaches, scalp tenderness, claudication of the masseter
muscles, and vision loss due to ischemia in the visual
pathway.
• The headaches are often intense, throbbing, and sharp in
character, and are combined with temporal tenderness.
• On physical examination, the temporal vessels are thickened,
with nodules and absence of pulses. Other arteries of the
scalp can be involved.
• Vision loss is one of the reasons that GCA is considered a
prime ophthalmic emergency. Occlusion in branches of the
ophthalmic artery results in ischemic optic neuropathy that
causes sudden and pain-free blindness.
• Amaurosis fugax can precede complete vision loss. Patients
with blindness in one eye are at high risk to suffer additional
visual loss in the other eye.
Criteria of GCA
• Age ≥50 years at disease onset
• New onset of localized headache
• Temporal artery tenderness or decreased temporal artery pulse
• ESR ≥50 mm/hour
• Biopsy: necrotising arteriitis; mononuclear cell infiltrates or a
granulomatous process with multinucleated giant cells
• Presence of ≥3/5: sensitivity of 93% and specificity of 91% for
distinguishing GCA from other primary vasculitis syndromes
Treatment of GCA
• The golden standard for treatment of GCA is corticosteroids.
• Patients respond explicitly well, with prompt and substantial improvement of
symptoms within 24–48 hours.
• Initial doses of 60 mg of prednisone (or approx. 1 mg per kg body weight) have
been found to be effective in almost all patients.
• Once patients are stabilized on high doses of corticosteroids, daily prednisone
doses should be tapered. A reduction of 10–20% every 2 weeks has proven to be
a clinically useful guidance.
• Corticosteroids can be discontinued in most patients after approximately 2 years
of therapy. There is evidence that the disease process does not enter remission
but continues with smoldering activity
Treatment of GCA
• Although results of clinical trials have been controversial, a well-designed
clinical study with a large cohort of patients could not demonstrate any
advantage for MTX/corticosteroid combination therapy compared with
corticosteroids alone.
• From a retrospective study of 143 patients with GCA, aspirin and warfarin
were associated with a decrease in the incidence of acute ischemic events.
• Anti TNF are not efficacious in GCA.
• Many case series showed that tocilizumab improves clinical outcome in
steroid dependent or refractory patients.
Takayasu’s Arteritis (TKA)
• TKA is a systemic arteritis that predominantly manifests in
the aorta and its major branches.
• It is also known as pulseless disease or occlusive
thromboaortopathy.
• The typical patient is a female of Asian or South American
origin presenting with vascular insufficiency and
generalized inflammation in the second or third decades of
life.
• Arterial stenosis, occlusion, and aneurysms lead to various
signs and symptoms such as extremity pain, claudication,
light-headedness, bruits, absent or diminished pulses and
loss of blood pressure.
• Although TA may present with acute events such as visual
loss or stroke, it may also cause non-specific constitutional
features such as fever, malaise, anorexia, and weight loss.
TKA
• In 1830, Yamamoto reported the first case of TA.
• In 1908, Mikito Takayasu was the first to describe peculiar optic fundus
abnormalities with coronal anastomosis, which 40 years later were
interpreted as neovascularization and anastomosis secondary to ischemia
caused by theocclusion of cervical vessels.
• In 1951, Shimizu and Sano described a cohort of 31 cases and made the
connection between pulselessness, coronal anastomosis of retinal vessels,
and carotid abnormalities and called it pulseless disease.
Classification Criteria for TAK
• Age at disease onset < 40 years
• Claudication of extremities
• Decreased brachial artery pulse
• BP difference >10 mm Hg
• Bruit over subclavian arteries or aorta
• Arteriogram abnormality
• For purposes of classification, a patient shall be said to have Takayasu’s arteritis
if at least 3 of these 6 criteria are present. The presence of any 3 or more criteria
yields a sensitivity of 90.5% and a specificity of 97.8%. BP = blood pressure
(systolic; difference between arms).
Histopathology
• Microscopically, the vasculitis may be divided into an acute florid inflammatory
phase and a healed fibrotic phase.
• In the acute phase a vasa vasoritis is seen in the adventitia.
• The media is infiltrated by lymphocytes and occasional giant cells with
neovascularisation. Mucopolysaccharides, smooth muscle cells, and fibroblasts
thicken the intima.
• In the chronic phase there is fibrosis with destruction of elastic tissue.
• Infection has been considered to play a role in the pathogenesis of Takayasu
arteritis. Tuberculosis has been particularly implicated in view of the high
prevalence of infection, past or present, in affected patients
Investigation TAK
• Acute phase reactants are non-specific
• Angiography is the gold standard, but CT angiography, MRA, US and PET
all can be used in assessing stenotic lesions and aid in early diagnosis.
• MRI, US and PET can also be used for disease activity monitoring.
Investigation TAK
Treatment of TAK
• Oral corticosteroids are started at 1 mg/kg daily or divided twice daily
and tapered over weeks to months as symptoms subside.
• Steroid sparing agents such as azathioprine, MTX and CYC are frequently
used.
• Anti-TNF and anti-IL-6 have been successful in treating refractory or
steroid dependent disease.
• Bypass graft surgery is the procedure with the best long-term patency
rate.
• Percutaneous balloon angioplasty can provide good outcomes for short
lesions.
• Angioplasty and stenting have been used to treat recurrent stenosis.
Medium Vessel Vasculitis
• Polyarteritis nodosa (PAN)
• Kawasaki’s disease
Kawasaki’s Disease
• is an acute febrile vasculitic syndrome of early childhood that, although
it has a good prognosis with treatment, can lead to death from coronary
artery aneurysm in a very small percentage of patients.
• Treatment includes: aspirin and IVIG.
• Steroids, anti-TNF’s and cyclophosphamide can be used in resistant
cases
• Long term follow with serial echo is recommended.
PAN
• First described in 1866 by Kussmaul and Maier.
• It is a systemic necrotizing vasculitis that predominantly affects
medium-sized arteries, and is primary in most patients but is the
consequence of viral infections, mainly hepatitis B virus (HBV), in some.
• Many similarities between PAN and Microscopic polyangitis made it
difficult to differentiate between the 2 disorders till a strong association
with ANCA was found in MPA. In addition to the tendency to involve
arterioles, venules, and capillaries.
PAN and Hepatitis B Infection
• A link has been found between hepatitis B infection (HBV) and PAN.
• HBV can cause endothelial injury to the blood vessel wall leading to
inflammation.
• The development of PAN is usually in the first 6 months of HBV
contraction.
• The activity of HBV-PAN does not parallel that of the hepatitis.
• HBV previously caused up to 30% of PAN now with the widespread use of
vaccination it accounts to only 8% of all PAN patients.
• HCV and HIV has also been described to cause PAN.
PAN Pathology
• Vascular lesions in medium-sized muscular arteries occur mainly at
bifurcations and branch points.
• Inflammation may start in the vessel intima and progress to include the
entire arterial wall, destroying the internal and external elastic lamina,
resulting in fibrinoid necrosis.
• Aneurysms develop in the weakened vessel, carrying a subsequent risk for
rupture and hemorrhage.
• Thrombi may develop at the site of the lesions. As lesions progress,
proliferation of the intima or media may result in obstruction and
subsequent tissue ischemia or infarction.
PAN Pathology
• PAN is divided into subacute, acute, and chronic stages.
• In the subacute stage, infiltration of mononuclear cells becomes more
prominent, while in the acute stage, polymorphonuclear neutrophils
infiltrate all layers of the vessel wall.
• In the chronic stage, fibrinoid necrosis of the vessels causes thrombosis
and tissue infarction.
• Aneurysmal dilatations of the involved arteries.
• Kidney lesions show predominant arteritis without glomerulonephritis;
however, in patients with severe HTN, glomerulosclerosis may be
superimposed with glomerulonephritis. Pulmonary arteries are not
involved, and bronchial artery involvement is uncommon.
PAN
• Angiography should be considered if clinically involved tissue is
inaccessible. Conventional angiography is preferred. CT angiography or
MRA are not as sensitive for smaller abnormalities but can reveal larger
aneurysms and stenoses.
• Positive findings include aneurysms and stenoses of medium-sized
vessels.
• Aneurysms are most commonly found in the kidney, liver, and mesenteric
arteries, and their presence is associated with more severe and extensive
disease.
• Angiography has a higher yield in cases with evidence of intra-abdominal
involvement, including clinical symptoms or signs and laboratory
abnormalities of liver or renal function.
• NCS is important to detect MNP.
Classification Criteria of PAN
• Weight loss
• Livedo reticularis
• Testicular pain or tenderness
• Myalgias, weakness or leg tenderness
• Mononeuropathy or polyneuropathy
• Diastolic BP >90 mm Hg
• Elevated BUN or creatinine
• Hepatitis B virus
• Arteriographic abnormality
• Biopsy of small or medium-sized artery containing PMN
• For classification purposes, a patient shall be said to have polyarteritis nodosa if at least 3 of these 10 criteria
are present. The presence of any 3 or more criteria yields a sensitivity of 82.2% and a specificicy of 86.6%.
Treatment of PAN
• Corticosteroids are the cornerstone of treatment.
• The addition of CYC is the standard of care for patients with idiopathic
PAN.
• In contrast, for hepatitis B–related PAN, treatment consists of schemes
that include corticosteroids with antiviral agents and plasmapheresis.
• Cyclophosphamide is not routinely recommended in hepatitis B–related
PAN as the use of steroids with cyclophosphamide in these patients has
been demonstrated to enhance viral replication.
• Antiviral drugs used include vidarabine or interferon alpha-2b.
Small Vessel Vasculitis
• Microscopic polyangiitis (MPA)
• Granulomatosis with polyangiitis (Wegener’s) (GPA)
• Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (EGPA)
• Immune complex SVV
• Anti–glomerular basement membrane (anti-GBM) disease
• Cryoglobulinemic vasculitis (CV)
• IgA vasculitis (Henoch-Schonlein) (IgAV)
MPA
• One of the AAV
• Necrotizing vasculitis, with few or no immune deposits, affecting small
vessels (i.e., capillaries, venules, or arterioles).
• Necrotizing arteritis involving small and medium-sized arteries may be
present.
• Necrotizing glomerulonephritis is very common.
• Pulmonary capillaritis often occurs.
• A very important cause of pulmonary renal syndrome
History
• In 1923, Friedrich Wohlwill described 2 patients who seemed to have a novel form of this
disease, characterized by the presence of GN and nongranulomatous inflammation of the
small-caliber blood vessels.
• This ‘‘microscopic form of periarteritis nodosa’’ was gradually recognized as a new entity,
distinct from classic polyarteritis nodosa.
• In 1953, Pearl Zeek noted that this disease was pathologically similar to hypersensitivity
vasculitis, preferentially involving the arterioles and venules of the visceral organs (including
the lung) but often sparing the medium-caliber blood vessels.
• In 1950, Wainwright and Davson used the phrase microscopic polyarteritis to describe this
phenotype.
• In 1985, Caroline Savage and colleagues defined microscopic polyarteritis as a small-vessel
vasculitis associated with focal segmental glomerulonephritis and hemoptysis.
MPA an Entity between PAN and WG!
• The discovery of this new form of vasculitis has led to reclassification of
many patients.
• In 1980’s were ANCA was discovered with its 2 different patterns
perinuclear (P-ANCA) and cytoplasmic C-ANCA, this entity became a
member of AAV.
• It is most common in southern Europe with an incidence of 93/1’000’000
in Sweden compared to 2.6/1’000’000 in Germany.
VS
GPA
• Peter McBride first described the condition in 1897 in a BMJ article entitled
"Photographs of a case of rapid destruction of the nose and face".
• Heinz Karl Ernst Klinger (born 1907) would add information on the anatomical
pathology.
• but the full picture was presented by Friedrich Wegener (1907–1990), a German
pathologist , in two reports in 1936 and 1939.
• It was recently changed to granulomatosis with polyangiitis GPA
• Its hallmark features include necrotizing granulomatous inflammation and
pauci-immune vasculitis in small- and medium-sized blood vessels
GPA
• Affects both the upper and lower airways (in 90% of cases) causing
significant inflammation and destruction.
• It is a recognized cause of Otitis media, sinusitis, oral ulcers, periorbital
swelling and saddle nose.
• It also causes subglotic stenosis, lung nodules, infiltrates and an important
cause of DAH.
Classification Criteria
• Nasal or oral inflammation - Development of painful or painless oral ulcers or
purulent or bloody nasal discharge
• Abnormal chest radiography findings - Chest radiograph showing nodules, fixed
infiltrates, or cavities
• Urinary sediment - Microhematuria (>5 red blood cells [RBCs] per high-power
field [HPF]) or RBC casts in urine sediment
• Granulomatous inflammation on biopsy - Histologic changes showing
granulomatous inflammation within the wall of an artery or in the perivascular
or extravascular area (artery or arteriole)
• For the purposes of classification, a patient is said to have WG if at least 2 of
these 4 criteria are present. The presence of any 2 or more criteria yields a
sensitivity of 88.2% and a specificity of 92%
Subtypes
• Limited is a mild form with no life-threatening manifestations, and
findings are usually confined to the respiratory system.
• Severe is a more generalized disease with serious organ involvement.
• Granulomatous form involves the upper and lower airways with a
relapsing remitting course.
• Vasculitic type is usually life-threatening but when treated adequately has
a better long term outcome.
Churg-Strauss Syndrome (CSS)
• CSS or EPGA has 3 phases
• Allergic rhinitis and asthma
• Eosinophilic infiltrative disease, such as eosinophilic pneumonia or
gastroenteritis
• Systemic medium- and small-vessel vasculitis with granulomatous inflammation.
• The vasculitic phase usually develops within 3 years of the onset of asthma,
although it may be delayed for several decades.
• The most prominent symptoms and signs are those related to pulmonary,
cardiac, dermatologic, renal, and peripheral nerve involvement.
• Mononeuritis multiplex is a major clinical finding.
EPGA
• The first description of CSS was made by Churg and Strauss in 1951 on 13
patients (11 autopsied) under the title “allergic granulomatosis, allergic
• angiitis, and periarteritis nodosa.”
• Churg and Strauss emphasized the findings common to all cases: history
of asthma; blood and tissue eosinophilia; necrotizing vasculitis; and a
granulomatous response to eosinophilic necrosis
Classification Criteria of EPGA
• Asthma
• Eosinophilia >10%
• Neuropathy, mono or poly
• Pulmonary infiltrates, non-fixed
• Paranasal sinus abnormality
• Extravascular eosinophils
• For classification purposes, a patient shall be said to have Churg-Strauss
syndrome (CSS) if at least 4 of these 6 criteria are positive. The presence of any 4
or more of the 6 criteria yields a sensitivity of 85% and a specificity of 99.7%.
EPGA
• In the prodromal phase; biopsy of any involved organ will reveal heavy
eosinophilic infiltrates are the rule, but vasculitis is very rare
• The classic histologic hallmarks of the vasculitic phase are
• An eosinophil rich necrotizing vasculitis involving primarily small
arteries, arterioles, venules, and veins
• Necrotizing granulomas centered on necrotic eosinophils
Treatment of AAV
• Induction:
• Pulse steroids, cyclophosphamide, rituximab and plasma exchange
• Maintenance:
• Steroids, azathioprine, MTX and rituximab
• Cotrimixazole full dose twice a day, has been shown to reduce staph
Aureus carrier which is a cause of relapse.
• This is the only reason to wake me up anytime
Relapsing Polychondritis
• It is a rare autoimmune disorder in which the cartilaginous tissues are the
primary targets of destruction but the immune damage can spread to
involve noncartilaginous tissues like the kidney, blood vessels, and so
forth.
• It can be associated with other autoimmune diseases.
• Treatment includes; steroids and MTX or azathioprine.
Cryoglobulinemic Vasculitis
• Cryoglobulins are single or mixed immunoglobulins that undergo reversible
precipitation at low temperatures.
• A combination of hepatitis C, high RF and purpura is typical of cryoglobulinemia.
• GN, acrocyanosis, arthritis, peripheral neuropathy , retinal hemorrhage, severe
RP with digital ulceration, livedo reticularis, and arterial thrombosis are other of
many features.
• An idiopathic form also exists.
• Immune complex mediated leading to consumption of complements.
• Treatment includes: steroids, azathioprine, CYC, rituximab and plasma exchange
are the mainstay treatment.
• In HCV-related INF and ribavirin are indicated.
Preparation
• The blood specimen must be obtained in warm tubes (37°C) in the
absence of anticoagulants.
• Allow the blood sample to clot before removal of serum with
centrifugation (at 37°C).
• The period required for the serum sample to incubate (at 4°C) depends on
the type of cryoglobulin present, as follows:
• Type I tends to precipitate within the first 24 hours (at concentrations >5 mg/mL).
• Type III cryoglobulins may require 7 days to precipitate a small sample (< 1 mg/mL).
• Repeat centrifugation to determine cryocrit (volume of precipitate as a
percentage of original serum volume).
Isolated CNS Vasculitis
• Isolated central nervous system (CNS) vasculitis is a rare and
complicated disorder.
• Patients typically present with nonspecific neurologic symptoms
such as headache and encephalopathy, and have variable
progression and severity of the disease.
• Challenges to definitive diagnosis include the limitations of
currently available diagnostic modalities with high likelihood of
false-positive or false-negative findings.
• Imaging, serologic, and cerebrospinal fluid (CSF) evaluation, and
even angiography can fail to establish the diagnosis.
• The gold standard for the diagnosis of PACNS is histopathology.
Sampling of the leptomeninges as well as the underlying cortex
increases the diagnostic yield.
• Treatment includes steroids and CYC
Vasculitis Mimickers
• Are disorders that have similar presentations to systemic vasculitides.
• Many of these do not need any medical therapy.
• The challenge is more in large vessel vasculitis when biopsy is not
possible.
• Infectious mimickers can worsen with immunosuppression.
Mimickers
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