vasculitis review
DESCRIPTION
Review of different vasculitic disorders and how to evaluate vasculitisTRANSCRIPT
VASCULITIS
REVIEW
Vasculitis Clinicopathologic process characterized by
inflammation and necrosis of blood vessels
PATOGENESIS
classification
Vasculitis has been categorized by :- • predominant sizes of the blood vessels • presence or absence of antineutrophil
cytoplasmic antibodies (ANCA) • pattern of organ involvement• presence or absence of granulomas,
eosinophilic/ Lymphocytic infiltration
classification Small vessel vasculitis Medium-sized vessel vasculitis Large vessel vasculitis
Small vessel vasculitis• Cutaneous leukocytoclastic vasculitis• Henoch–Schönlein purpura• Urticarial vasculitis• Wegener’s granulomatosis• Churg–Strauss syndrome• Microscopic polyangiitis (polyarteritis)• Essential cryoglobulinaemia• Vasculitis secondary to connective tissue disorders • Vasculitis secondary to viral infection• Eosinophilic vasculitis• Erythema elevatum diutinum• Rheumatoid nodules• Reactive leprosy• Septic vasculitis
Medium-sized vessel vasculitis• Polyarteritis nodosa
• Kawasaki disease
• Isolated CNS Vasculitis Large vessel vasculitis
• Giant cell arteritis
• Takayasu’s arteritis
Small vessel vasculitis
leukocytoclastic vasculitis
leukocytoclastic vasculitis
skin vasculitis with palpable purpura is typically a major finding
Biopsy of these lesions reveals inflammation of the small blood vessels, most prominent in the postcapillary venules
Clinical features
palpable purpura• macular in the early stages• may progress to papules, nodules, vesicles,
plaques, bullae or pustules, • secondary findings - ulceration, necrosis and
post-inflammatory hyperpigmentation
oedema livedo reticularis urticaria
ankles and lower legs
Sites
symptoms
often asymptomatic pruritus pain burning
systemic symptoms relatively uncommon fever, arthralgia, myalgia and anorexia. presence of symptoms affecting other organ
systems should raise the suspicion of other vasculitides such as:- • HSP• mixed cryoglobulinaemia• Small vessel vasculitis associated with PAN or
with WG.
Course
resolve within several weeks or a few months
recurrent disease at intervals up to years• 10%
Aetiology idiopathic
• 50%
infection • 15–20%
collagen vascular disorders • 15–20%
medications • 10–15%
Malignancy • less than 5%
Histology:
Neutrophils enter the walls of small venules
small fragments of nuclear debris are present (nuclear dust).
Fibrin
Neutrophils and nuclear dust
Fibrin
Direct immunofluorescence
IgM, IgG, c3 within vascular walls
IgA in HSP
HENOCH-SCHÖNLEIN PURPURA
Henoch-Schönlein purpura
Tetrad• Palpable purpura • Arthritis/arthralgia • Abdominal pain • Renal disease
Less common manifestations• Orchitis, intussusception, pancreatitis,
neurological abnormalities, uveitis, carditis and pulmonary haemorrhage
Mostly in children
IgA. Deposits
Urticarial vasculitis
Lesions differ from those of simple urticaria
• lesions persist for more than 24 h
• often demonstrate purpura
• symptoms of burning (rather than itch)
• Biopsy- vasculitis
• post-inflammatory pigmentation
Churg-Strauss arteritis ( allergic granulomatosis )
classically involves the arteries of the lung and skin
Clinical signs:• allergic rhinitis • asthma• eosinophilia• systemic vasculitis •Palpable purpura
•macular or papular erythematous rash •Hemorrhagic lesions•Tender cutaneous or subcutaneous nodules
Skin lesions
WEGENER’S GRANULOMATOSIS
triad systemic small vessel vasculitis necrotizing granulomatous
inflammation of both the upper and lower respiratory tracts
glomerulonephritisusually associated with
ANCA
EPIDEMIOLOGY
Predominant age: • Mean age of onset in mid-40's
• has been described in all age groups
Predominant sex: • Male > Female (3:2)
Wegener’s granulomatosis
commonest initial manifestation• rhinorrhea
• severe sinusitis
• nasal mucosa ulcerations
• one or several nodules in the nose, larynx, trachea, or bronchi
Wegener’s granulomatosis Fever, weight loss and malaise occur The “strawberry gums” appearance
of hypertrophic gingivitis is characteristic
Nodules may appear in crops, especially along the extensor surface of the extremities
may later ulcerate
WEGENERS’ GRANULOMATOSIS
•strawberry gums•Lesion on anterior nares
Wegener’s granulomatosis
Focal necrotizing glomerulonephritis• 85%
Other organs frequently involved • joints• eyes • CNS
SIGNS & SYMPTOMS
• Pulmonary infiltrates (71%) • Sinusitis (67%) • Arthralgia/arthritis (44%) • Fever (34%) • Cough (34%) • Otitis (25%) • Rhinitis (22%)
SIGNS & SYMPTOMS
• Hemoptysis (18%) • Ocular inflammation (16%) • Weight loss (16%) • Skin rash (13%) • Epistaxis (11%) • Renal failure (11%) • Chest pain, anorexia, proptosis, dyspnea, oral
ulcers, hearing loss, headache (all < 10%)
A pyoderma gangrenosum-like irregular ulceration jagged and undermined borders is often the first manifestation of Wegener’s gramulomatosis
A limited number of erythematous, purpuric, nonblanchable papules and nodules on the dorsa of fingers and hands; a few lesions have centralareas of infarction.
A large ulcer on the palate covered by a dense, adherent, necrotic masssimilar lesions occur in the sinuses and tracheobronchialtree.
D/D from CSS
Features of CSS
• lack of upper respiratory involvement
• lack of severe glomerulonephritis• asthma • eosinophilia
c-ANCA
WG MPA 1/3 CSS 20% necrotizing and crescentic GN
1/3
c-ANCA WG Sensitivity
• 66%
• 91% if only considering active disease Specificity
• 98%
Patients with WG who are negative for ANCA/anti-PR3 usually have positive P-ANCA/anti-MPO
non ANCA reactivity may well have localized WG and a better prognosis when compared with those who are ANCA-positive
ANCA Positive infections
• malaria, HIV
connective tissue disorders• SLE, rheumatoid arthritis
GIT• IBD, chronic autoimmune liver and
biliary tract disease
some apparently healthy individuals.
Mostly P-ANCA or atypical ANCA
Perinuclear staining (p-ANCA) • nonspecific
• frequently seen in patients with other vasculitic syndromes
C-ANCA patternheavy staining in the cytoplasm while the multilobulated nuclei (clear zones) are nonreactive
P-ANCA patternStaining is limited to the perinuclear region and the cytoplasm is nonreactive
Wegener’s granulomatosis Histologically
the cutaneous lesions may demonstrate a leukocytoclastic vasculitis with or without granulomatous inflammation
WEGENERS’ GRANULOMATOSIS
•Perivascular lymphocytic infiltrate•Necrotizing/leucocytoclastic small vessel vasculitis •granulomatous inflammation
ACR criteria Nasal or oral inflammation
• oral ulcers • purulent or bloody nasal discharge
Abnormal chest radiograph • nodules• fixed infiltrates• cavities.
Abnormal urinary sediment • microscopic hematuria • red cell casts
Granulomatous inflammation on biopsy
of an artery or perivascular area.
Complications Disease related
• Destructive nasal lesions with "saddle nose" deformity
• Deafness from refractory otitis
• Necrotic pulmonary nodules with hemoptysis
• Interstitial lung disease
Complications
• Renal failure
• Foot drop from peripheral nerve disease • Skin ulcers, digital and limb gangrene
from peripheral vascular involvement
Prognosis
• Without treatment, • almost uniformly fatal with 10% 2 year survival and mean survival of 5 months
• With aggressive treatment, survival improved to 75-90% at 5 years
MICROSCOPIC POLYANGIITIS
Microscopic polyangiitisMicroscopic polyarteritis nodosaMicroscopic polyarteritis
systemic vasculitis affecting blood vessels ranging in size from capillaries to medium-sized arteries
cANCA may be positive strongly associated with
• lung involvement • (primarily alveolar haemorrhage)
• crescentic glomerulonephritis
Microscopic polyangiitis
thought by some investigators to represent part of a clinical spectrum that includes Wegener's granulomatosis, since both are associated with the presence of ANCA and similar histologic changes outside the respiratory tract.
CRYOGLOBULINAEMIC VASCULITIS
Cryoglobulinaemic vasculitis presence of
cryoglobulins• serum proteins that
precipitate in the cold and dissolve upon rewarming.
• Cryoglobulins typically are composed of a mixture of immunoglobulins and complement components.
most often due to hepatitis C virus infection. (80–90%)
SLE Myeloproliferative
disorders chronic infections
Cryoglobulinaemic vasculitis
Palpable purpura Polyarteritis-like dermal
nodules Raynaud’s phenomenon cold aggravation of the
vasculitis lesions Livedo acrocyanosis, bullae necrosis ulceration
Glomerulonephritis Arthralgia migratory myalgia
Diagnosis Cryoproteins antibodies to HCV
VASCULITIS SECONDARY TO CONNECTIVE TISSUE DISORDERS
Vasculitis secondary to connective tissue disorders
lupus erythematosus rheumatoid arthritis relapsing polychondritis Behcet's disease
Vasculitis secondary to viral infection most commonly observed hepatitis
B and C may also be seen with
• HIV
• cytomegalovirus
• Epstein-Barr virus
• Parvovirus B19
Medium sized vessel vasculitis
Medium-sized vessel vasculitis• Polyarteritis nodosa
• Kawasaki disease
• Isolated CNS Vasculitis
POLYARTERITIS NODOSA
Polyarteritis nodosa
typically affects medium-sized muscular arteries
occasional involvement of small muscular arteries
Not typically associated with ANCA
Two major forms
systemic benign cutaneous
Organ involvement
PAN can affect virtually any organ, but has a striking tendency to spare the lungs
kidney, GI tract, skin, muscles, joints, genitourinary tract, peripheral and central nervous system, heart, testes, epididymis and ovaries
ETIOLOGY Idiopathic most cases HBV infection
• (particularly in patients with a history of intravenous drug abuse)
Other associations• Other viruses including HCV• SLE • IBD• hairy cell leukemia• Minocycline
Clinical features
• Fever • Weakness • Weight loss • Malaise • Myalgia • Arthralgia• Headache • Abdominal pain and vague discomfort
SIGNS & SYMPTOMS
• Renal - hypertension, hematuria (usually microscopic), proteinuria, progressive renal failure
• Musculoskeletal - myalgia, migratory arthralgia and arthritis
• Gastrointestinal - recurrent and severe pain, hepatomegaly, nausea, vomiting and bleeding
• CNS - seizures, CVA's, headache, papillitis, altered mental states
• Peripheral nervous system - mononeuritis multiplex (most often manifested as foot drop)
• Cardiac - pericarditis, CHF associated with hypertension and/or myocardial infarction
• Genitourinary - usually asymptomatic but may have testicular, epididymal, ovarian pain. Neurogenic bladder reported.
Polyarteritis nodosacutaneous manifestations 40% of patients usually a subcutaneous nodule or
group of nodules along the course of a blood vessel.
Typically seen around the knee, anterior lower leg and dorsum of the foot
5–10-mm nodules may be tender, pulsatile or secondarily ulcerated
POLYARTERITIS NODOSAErythematous nodular lesion along vessels more prominent on lower limbs
livedo reticularis with or without ulceration
digital gangrene ‘punched-out’ ulcers purpura, urticaria,
subcutaneous hemorrhages
LABS
• Abnormal urine sediment • High neutrophil count • Anemia of chronic disease • Elevated sedimentation rate • Hypergammaglobulinemia • Hepatitis B surface antigen positive in 30%
of cases
LAB finding
P-ANCA positive in 20% C-ANCA not associated with PAN
Arteriography and cross-sectional imaging alternative to biopsy for diagnosis is
conventional mesenteric or renal arteriography
multiple aneurysms and irregular constrictions in the larger vessels with occlusion of smaller penetrating arteries
Renal arteriogram
abrupt cutoffs of small arteries
microaneurysms
Conventional angiography of hepatitic, renal, splanchnic and splenic circulations
most reliable method of demonstrating the aneurysms, stenoses and abnormal vessels in PAN
However not specific to this disorder
Histopath
inflammatory necrotizing and obliterative panarteritis that attacks the small and medium-sized arteries
Left panel: Involvement of a single small artery in the subcutis by a necrotizing vasculitis which is neutrophilic rich at its inception and then evolves into a predominance of mononuclear cells. Right panel: Inflammatory infiltrate in the adventitia with marked necrosis and fibrin deposition of the vascular wall.
•diffuse inflammation of the adventitia • marked thickening of the inner layers by loose connective tissue (arrows). •The lumen (L) is significantly narrowed.
Skin biopsy is usually not sufficient to establish the diagnosis of PAN
Tissue biopsy of affected muscle / nerve /kidney may confirm the presence of vasculitic lesions
Prognosis
• Expected course of untreated polyarteritis nodosa is poor
• Untreated--5 year survival rate 13%
• Steroid treatment may increase percentage survival rate to 50-80%
• Renal and GI signs most serious prognostic factors
major causes of death
Renal failure mesenteric, cardiac, or cerebral
infarction
ACR criteria Otherwise
unexplained weight loss > 4 kg
Livedo reticularis Testicular pain or
tenderness Myalgias (excluding
that of the shoulder and hip girdle), weakness, or polyneuropathy
Mononeuropathy or polyneuropathy
New onset diastolic blood pressure
Elevated blood urea or creatinine
Evidence of hepatitis B virus infection
Characteristic arteriographic abnormalities
biopsy of small- or medium-sized artery containing polys
Cutaneous polyarteritis nodosa absence of visceral involvement recurrent skin, joint, and muscle
involvement without involvement of vital organs
Cutaneous findings similar to those described for the systemic form
Most patient respond well to aspirin, prednisone, methotrexate, alone or in combination
Cutaneous polyarteritis nodosa
Erythematous lesions on the leg
Kawasaki disease arteritis of large, medium, and small
arteries, particularly the coronary arteries. usually occurs in children often associated with a mucocutaneous
lymph node syndrome Isolated CNS vasculitis affects medium and small arteries over a
diffuse area of the central nervous system, without symptomatic involvement of extracranial vessels.
Large vessel vasculitis
Large vessel vasculitis
Takayasu arteritis Giant cell arteritis (temporal arteritis)
Large vessel vasculitis Takayasu arteritis
• primarily affects the aorta and its primary branches.
• extremities become cool, and pain develops with use (arm or leg claudication).
• Skin lesions- minority of cases• resembling erythema nodosum or pyoderma
gangrenosum found over the legs• vasculitis of small vessels on biopsy
Hypertension is a common presenting feature
• Renal artery stenosis,• increased arterial stiffness and • increased sensitivity of the carotid sinus
reflex
blood pressure should be recorded in all four limbs
Giant cell arteritis (temporal arteritis)• inflammation most prominently involves the
cranial branches of the arteries originating from the aortic arch
•painfull arteritis•location: temporal•swelling, pain•may progress and affect eye•Over 50 years•Polymyalgia Rheumatica
Evaluation of vasculitis
Evaluation of vasculitis
clinical diagnosis histopathological confirmation assessment of the extent of the disease establish an underlying aetiology
Evaluation of vasculitis clinical diagnosis
• Purpura, livedo, cutaneous necrosis, and purple toe syndrome etc
histopathological confirmation• Punch biopsy
• Deeper elliptical Incisional biopsy • should be performed for suspected larger vessel
vasculitides
assessment of the extent of the disease • General. Myalgia, arthralgia, fever • Renal. Proteinuria, haematuria • Nervous system. Central or peripheral, diffuse or
localized • Musculoskeletal. Non-erosive polyarthritis • Gastrointestinal. Abdominal pain, gastrointestinal
bleeding • Pulmonary. Pleural effusion, pleuritis • Cardiac. Pericardial effusion
establish an underlying aetiology
Medications infections Diseases associated with immune
complexes• connective tissue diseases• malignancy• inflammatory bowel disease
VASCULITISDiagnostic approach History Physical examination Laboratory tests
History
Drugs H/O Hepatitis B or C H/O disease
• such as systemic lupus erythematosus
Physical examination
to determine • extent of vascular lesions• distribution of affected organs• presence of additional disease
Findings suggestive of an underlying vasculitic process• palpable purpura• mononeuritis multiplex
Basic laboratory analysis Blood CP/ESR urinalysis CRP serum creatinine LFTs hepatitis serologies muscle enzyme chest x-ray ECG
Blood culture
(if pyrexial)
ASO titre ANA Complement ANCA Tissue biopsy IF studies
Other investigations (When indicated)
Cryoglobulins PFTs CSF CNS imaging biopsies of artery, kidney, lung or nerve Electromyography Arteriography
• aortic arch or visceral vessels
baseline tests for possible corticosteroid or immunosuppressive therapy
Glucose G-6-PD status (dapsone)
TREATMENT
Treatment LCCV
Remove triggering agent
Minimize stasis compression
stocking elevation of
dependent areas NSAIDs Antihistamines
Oral Steroids• 30–80 mg once daily, • tapered over 2–3 weeks
Colchicine• 0.6 mg twice daily
Dapsone Azathioprine Methotrexate Biological agents
• Infliximab
• Rituximab
Treatment LCV
Symptomatic relief• Supportive therapy
• Antihistamines
• Non-steroidal anti-infl ammatory drugs
Skin lesions alone• Colchicine
• Dapsone
• Pentoxiphylline
Ulcerative skin lesions alone
• Thalidomide
• Methotrexate
• Prednisolone
Systemic disease• Prednisolone
• Azathioprine
• Cyclophosphamide
• Mycophenolate mofetil
• Ciclosporin
• Interferon-α (if hepatitis C-associated)
• Intravenous gammaglobulin
• Extracorporeal immunomodulation
• Infliximab
• Rituximab
HSP oral antihistamines systemic corticosteroids dapsone
• (100–200 mg once daily)
colchicine • (0.6 mg twice to three times daily)
hydroxychloroquine• (200 mg once to twice daily)
Dapsone plus pentoxifylline mycophenolate mofetil
• (2 g once daily)
PAN Treatment (as per severity)
Mild PAN• constitutional symptoms, arthritis, anemia, but
normal renal function, no gastrointestinal involvement, and no neurologic deficits) and those with isolated cutaneous disease
Moderate and severe PAN• renal insufficiency, or gastrointestinal, cardiac
or neurologic involvement
Mild PAN Prednisone
• 1 mg/kg per day (maximum 60 to 80 mg/day) for approximately four weeks.
• On significant improvement prednisone is tapered slowly for an overall course of approximately nine months.
• who do not respond to glucocorticoids alone, or who relapse as the dose of prednisone is tapered, treatment is as described below for severe PAN.
Moderate and severe Prednisone
• 1 mg/kg per day, maximum of 60 to 80 mg per day)
• The initial high dose is continued for two to four weeks, until significant improvement is observed.
• The dose should then be tapered slowly, for an overall course of approximately six months.
Oral cyclophosphamide, 1.5 to 2 mg per kg
unable to tolerate an oral regimen
(eg, due to gastrointestinal involvement) severe, life-threatening manifestations or worsening mononeuropathy multiplex
• Intravenous methylprednisolone be given initially for three days, followed by the oral prednisone regimen.
• Monthly intravenous infusions of cyclophosphamide (initial dose 600 to 750 milligrams/m(2) per month), rather than oral administration in this setting.
Other modalities
• plasmaphoresis. - conflicting• Renal transplantation
Patients with hepatitis B-associated PAN• combination of antiviral and immune
suppressing drugs
TREATMENT
Prednisone –
• given initially in high doses (60-100 mg/day).
• After initial 2-4 weeks may be tapered to alternate-day regimen.
• Then gradually discontinued over 2-6 months in most patients, depending on clinical course.
Wegener’s granulomatosis
TREATMENT Cyclophosphamide – in critically ill patient
• initially at a dose of 4 mg/kg/day IV for 2-3 days, then continued at 2 mg/kg/day orally.
In stable patient • may be started at 2 mg/kg/day orally.
• Dosage may need to be adjusted, based on patient response and toxicity (usually bone marrow suppression).
Cryoglobulinaemic vasculitis Treatment of underlying cause Treatment of HCV-associated
• Pegylated interferon-α with ribavirin• usual initial choice
• immunosuppressive agents • avoided, or relatively non-aggressive therapy can be used
(low-dose corticosteroids or Colchicine)
• Place in glomerulonephritis
• Rituximab• Plasmapheresis