vasculitis review
TRANSCRIPT
VASCULITISREVIEW
Vasculitis Clinicopathologic process characterized by
inflammation and necrosis of blood vessels
PATOGENESIS
Causes of Vasculitis Infections Drugs diseases associated with immune
complexes • connective tissue diseases• inflammatory bowel disease• malignancy
Idiopathic
INFECTIONS Virus
• hepatitis B, hepatitis C, HIV, CMV, parvovirus B19
Bacteria• Examples
• group A β-haemolytic streptococci– HSP
• Superantigen of S.aureus– Kawasaki disease (TSST-1), WG
Fungai
classification
classification Small vessel vasculitis Medium-sized vessel vasculitis Large vessel vasculitis
•Small vessels •capillaries, arterioles, venules
•medium- sized vessels •such as visceral vasculature, including renal, coronary or hepatic arteries
• large vessels •aorta and its great vessels
Chapel Hill Consensus Conference classification Small vessel vasculitis
Cutaneous leukocytoclastic vasculitis Henoch–Schönlein purpura Wegener’s granulomatosisChurg–Strauss syndromeMicroscopic polyangiitisEssential cryoglobulinaemia
Medium-sized vessel vasculitisClassic polyarteritis nodosaKawasaki disease
Large vessel vasculitis Giant cell arteritis Takayasu’s arteritis
Proposed working classification of vasculitis
Small vessel vasculitis•Cutaneous small vessel vasculitis - not further classified•Henoch–Schönlein purpura•Essential mixed cryoglobulinaemia•Waldenström’s hypergammaglobulinaemic purpura•Associated with collagen vascular disease•Urticarial vasculitis•Erythema elevatum diutinum•Eosinophilic vasculitis•Rheumatoid nodules•Reactive leprosy•Septic vasculitis
Larger vessel vasculitisPolyarteritis nodosa
Microscopic polyarteritisCutaneous form Systemic form
Granulomatous vasculitis• Wegener’s granulomatosis• Allergic granulomatosis of Churg and Strauss• Lymphomatoid granulomatosisGiant cell arteritis• Temporal arteritis• Takayasu’s arteritisLarger vessel vasculitis with collagen vascular diseaseNodular vasculitis
Cont,
Chapel Hill Consensus Conference classification Small vessel vasculitis
Cutaneous leukocytoclastic vasculitis Henoch–Schönlein purpura Wegener’s granulomatosisChurg–Strauss syndromeMicroscopic polyangiitisEssential cryoglobulinaemia
Medium-sized vessel vasculitisClassic polyarteritis nodosaKawasaki disease
Large vessel vasculitis Giant cell arteritis Takayasu’s arteritis
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 legsSites
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%
Histology:
Neutrophils • enter the walls of small venules
Nuclear dust • small fragments of nuclear debris are
present Fibrin
Neutrophils and nuclear dust
Fibrin
Direct immunofluorescence
IgM, IgG, c3 within vascular walls
IgA in HSP
Chapel Hill Consensus Conference classification Small vessel vasculitis
Cutaneous leukocytoclastic vasculitis Henoch–Schönlein purpura Wegener’s granulomatosisChurg–Strauss syndromeMicroscopic polyangiitisEssential cryoglobulinaemia
Medium-sized vessel vasculitisClassic polyarteritis nodosaKawasaki disease
Large vessel vasculitis Giant cell arteritis Takayasu’s arteritis
Henoch-Schönlein purpuraIgA. Deposits Mostly in children
Tetrad
Typical sites
HSP Course & Prognosis
• majority of patients fully recover within several weeks or months
chronic • 5–10% of patients
Renal involvement • Common 40–50%• Haematuria, Proteinuria• progress to end-stage renal disease 1–3%• major factor determining the long-term
morbidity and mortality
IgA- pivotal part in HSP
Serum IgA • 50% with active disease
IgA immune complexes Deposition of IgA
• in blood vessel walls• renal mesangium
Henoch-Schönlein purpura
Less common manifestations• Orchitis (10–20% of boys), intussusception,
pancreatitis, neurological abnormalities, uveitis, carditis and pulmonary haemorrhage
evidence for streptococcal Infection 30%
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
lesions persisting for more than 24 h
Associations of urticarial vasculitis
connective tissue diseases • SLE • Sjögren’s syndrome
Other diseases• hepatitis B or C• IgM or IgA gammopathies• serum sickness • colonic cancer
Drug ingestion Physical stimuli
• Exercise, UV light ,cold
Chapel Hill Consensus Conference classification Small vessel vasculitis
Cutaneous leukocytoclastic vasculitis Henoch–Schönlein purpura Wegener’s granulomatosisChurg–Strauss syndromeMicroscopic polyangiitisEssential cryoglobulinaemia
Medium-sized vessel vasculitisClassic polyarteritis nodosaKawasaki disease
Large vessel vasculitis Giant cell arteritis Takayasu’s arteritis
WEGENER’S GRANULOMATOSIS
triad
ANCA association
cutaneous manifestations palpable purpura
• most common cutaneous manifestation Oral ulcers
• second most common other skin lesions
• subcutaneous nodules, papules, vesicles, petechiae, ulcers or pyoderma gangrenosum like lesions.
A pyoderma gangrenosum-like irregular ulceration jagged and undermined borders is often the first manifestation of Wegener’s gramulomatosis
WEGENERS’ GRANULOMATOSIS
•strawberry gums•Lesion on anterior nares
A large ulcer on the palate covered by a dense, adherent, necrotic masssimilar lesions occur in the sinuses and tracheobronchialtree.
strawberry gums
Upper Respiratory• rhinorrhea • severe sinusitis• nasal mucosa
ulcerations• Epistaxis• Otitis
Respiratory • Cough, Hemoptysis• Pulmonary infiltrates
Renal • hematuria• red cell and other
casts • proteinuria• Renal biopsy
• crescentic glomerulonephritis
General• Fever, Weight loss• Arthralgia/arthritis
"saddle nose" deformity
Investigations C-ANCA 80 %
chest X-ray Renal biopsy Other
• elevated ESR and CRP, anaemia, leukocytosis and positive rheumatoid factor
c-ANCA
WG• 80 %
MPA 1/3 CSS 20% necrotizing and crescentic GN 1/3
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• No link with disease activity• frequently seen in patients with other
vasculitic syndromes • SLE
ANCA C-ANCA
• cytoplasmic staining P-ANCA
• perinuclear and/or nuclear staining Atypical ANCA (a-ANCA)
• various patterns
classified, according to their IIF pattern on ethanol-fixed neutrophils
Immunoglobulin•IgG mostly•IgM / IgA rarely
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 leukocytoclastic 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.
Prognosis• Without treatment
• almost uniformly fatal • 2 year survival - 10%• mean survival of 5 months
• With aggressive treatment,• survival improved to 75-90% at 5
years
Chapel Hill Consensus Conference classification Small vessel vasculitis
Cutaneous leukocytoclastic vasculitis Henoch–Schönlein purpura Wegener’s granulomatosisChurg–Strauss syndromeMicroscopic polyangiitisEssential cryoglobulinaemia
Medium-sized vessel vasculitisClassic polyarteritis nodosaKawasaki disease
Large vessel vasculitis Giant cell arteritis Takayasu’s arteritis
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/papular erythematous rash •Hemorrhagic lesions•Tender cutaneous /subcutaneous nodules•livedo reticularis•new-onset Raynaud’s
Skin lesions
D/D WG/CSS Features of CSS
• lack of upper respiratory involvement • lack of severe glomerulonephritis• asthma • Eosinophilia• involvement of the GIT, spleen and heart, in
contrast with the strong association with renal disease in patients with WG.
Chapel Hill Consensus Conference classification Small vessel vasculitis
Cutaneous leukocytoclastic vasculitis Henoch–Schönlein purpura Wegener’s granulomatosisChurg–Strauss syndromeMicroscopic polyangiitisEssential cryoglobulinaemia
Medium-sized vessel vasculitisClassic polyarteritis nodosaKawasaki disease
Large vessel vasculitis Giant cell arteritis Takayasu’s arteritis
Microscopic polyangiitisSyn: Microscopic polyarteritis nodosa
Microscopic polyarteritis
systemic vasculitis affecting blood vessels ranging in size from capillaries to medium-sized arteries
strongly associated with :-• lung involvement
• (primarily alveolar haemorrhage) • necrotizing glomerulonephritis
P-ANCA commonly positive cANCA may be positive palpable purpura
absence of granulomatous inflammation or asthma suggests MPA instead of CSS or WG
Chapel Hill Consensus Conference classification Small vessel vasculitis
Cutaneous leukocytoclastic vasculitis Henoch–Schönlein purpura Wegener’s granulomatosisChurg–Strauss syndromeMicroscopic polyangiitisEssential cryoglobulinaemia
Medium-sized vessel vasculitisClassic polyarteritis nodosaKawasaki disease
Large vessel vasculitis Giant cell arteritis Takayasu’s arteritis
Cryoglobulinaemic vasculitis
Small and medium sized vessels are affected• mainly in skin and kidneys
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.
Causes hepatitis C virus
• most commonly(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• Low complement• ANA• RA factor• Band on electrophoresis
Chapel Hill Consensus Conference classification Small vessel vasculitis
Cutaneous leukocytoclastic vasculitis Henoch–Schönlein purpura Wegener’s granulomatosisChurg–Strauss syndromeMicroscopic polyangiitisEssential cryoglobulinaemia
Medium-sized vessel vasculitisClassic polyarteritis nodosaKawasaki disease
Large vessel vasculitis Giant cell arteritis Takayasu’s arteritis
Polyarteritis nodosa Typically affects medium-sized
arteries• occasional involvement of small arteries
Association with HBV No glomerulonephritis No lung parenchymal involvement Not typically associated with ANCA
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
Livedo reticularis –with or without ulceration
digital gangrene ‘punched-out’ ulcers purpura, urticaria,
subcutaneous hemorrhages
Other cutaneous feature
POLYARTERITIS NODOSAErythematous nodular lesion along vessels more prominent on lower limbs
Systemic features Constitutional
– fever, weight loss, arthralgia and malaise
kidneys • infarctions and ischaemic• nephropathy lead to hypertension and renal failure
heart • angina, myocardial infarction
gut • ischaemia, bleeding, perforation • infarction, presenting as abdominal pain
Misc• Orchitis• mononeuritis multiplex
ETIOLOGY Idiopathic most cases HBV infection
• particularly in patients with a history of intravenous drug abuse
Other viruses • hepatitis C, parvovirus B19, HIV,VZV
Other associations• streptococcal infection, SLE, IBD, malignancies,
particularly hairy cell leukemia, Minocycline, familial Mediterranean fever and Cogan’s syndrome
Vasculitis Mostly at branch points of medium sized arteries
microaneurysms
nodose swellings
may rupture
luminal thrombosis and obliteration
distal tissue ischaemia and necrosis
Investigations HbsAg P-ANCA 20% Routine investigation
• CRP / ESR (useful for monitoring disease activity)• leukocytosis with neutrophilia, thrombocytosis• haematuria, proteinuria
Tissue biopsy• Skin, affected muscle or nerve
Angiography• hepatic, renal, splanchnic and splenic circulations • most reliable method of demonstrating the aneurysms,
stenoses and abnormal vessels
Renal arteriogram
abrupt cutoffs of small arteries
microaneurysms
Histopathology inflammatory necrotizing and
obliterative panarteritis that attacks the small and medium-sized arteries• Infiltrate neutrophil-rich initially• subsequently mononuclear cells are
predominant
No granulomas
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.
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 Cutaneous findings
• similar to those described for the systemic form
Diagnosis of exclusion Treatment
• aspirin, prednisone,. Penicillin.
Cutaneous polyarteritis nodosa
Erythematous lesions on the leg
Cutaneous polyarteritis nodosa
Nodules and ulceration Livedo of legs
Chapel Hill Consensus Conference classification Small vessel vasculitis
Cutaneous leukocytoclastic vasculitis Henoch–Schönlein purpura Wegener’s granulomatosisChurg–Strauss syndromeMicroscopic polyangiitisEssential cryoglobulinaemia
Medium-sized vessel vasculitisClassic polyarteritis nodosaKawasaki disease
Large vessel vasculitis Giant cell arteritis Takayasu’s arteritis
Kawasaki disease
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 exanthem it causes is not vasculitic. Treatment
• intravenous immunoglobulin (IVIG) and aspirin
skin lesions Polymorphic skin lesions
• urticarial• morbilliform• maculopapular• erythema-multiforme-like patterns• pustules on knees or buttocks• scarlatina-like erythroderma
Swollen Hands and feet Palmoplantar erythema
• subsequent desquamation.
Chapel Hill Consensus Conference classification Small vessel vasculitis
Cutaneous leukocytoclastic vasculitis Henoch–Schönlein purpura Wegener’s granulomatosisChurg–Strauss syndromeMicroscopic polyangiitisEssential cryoglobulinaemia
Medium-sized vessel vasculitisClassic polyarteritis nodosaKawasaki disease
Large vessel vasculitis Giant cell arteritis Takayasu’s arteritis
Giant cell arteritis (temporal arteritis)• inflammation most prominently involves the
cranial branches of the arteries originating from the aortic arch
•painfull arteritis•location: temporal•Headache,swelling, •may progress and affect eye•Over 50 years•Polymyalgia Rheumatica
ACR classification criteriaGiant cell arteritis (temporal arteritis)
Age ≥ 50 years at time of disease onset Localized headache of new onset Tenderness or decreased pulse of the temporal artery ESR greater than 50Biopsy (that includes an artery)
necrotizing arteritis with predominance of mononuclear cells or granulomatous process with multinucleated giant cells
Prednisolone 40–60 mg daily should be started as soon as the diagnosis is suspected
Chapel Hill Consensus Conference classification Small vessel vasculitis
Cutaneous leukocytoclastic vasculitis Henoch–Schönlein purpura Wegener’s granulomatosisChurg–Strauss syndromeMicroscopic polyangiitisEssential cryoglobulinaemia
Medium-sized vessel vasculitisClassic polyarteritis nodosaKawasaki disease
Large vessel vasculitis Giant cell arteritis Takayasu’s arteritis
Takayasu arteritis
• primarily affects the aorta and its primary branches.
• extremities become cool, and pain develops with use (arm or leg claudication).
• Skin lesions- 1/3• resembling erythema nodosum or pyoderma
gangrenosum found over the legs• vasculitis of small vessels on biopsy
(Pulseless disease)
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
ACR classification criteriaAge at disease onset ≤ 40 years Claudication of the extremities Decreased pulsation of one or both brachial arteries Difference of systolic blood pressure at least 10 mmHg in between the arms Bruit
over one or both subclavian arteries or abdominal aorta
Arteriographic narrowing or occlusion entire aorta/its primary branchesor large arteries in the proximal upper or lower extremities,
at least three of the six criteria
Takayasu arteritis
Evaluation of vasculitis
Evaluation of vasculitis Aims & Objective
Evaluation of vasculitis clinical diagnosis
• Purpura, livedo, cutaneous necrosis, and purple toe syndrome etc• smaller vessel involvement
– palpable purpura • in dependent areas, typically the ankles
and lower legs• Medium vessel vasculitis
– Nodules raise suspicion– Livedo reticularis – multiple sites of peripheral gangrene
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 Gastrointestinal. Abdominal pain,
gastrointestinal bleeding Pulmonary. Pleural effusion, pleuritis Nervous system. Central or peripheral, diffuse or
localized Musculoskeletal. Non-erosive polyarthritis Cardiac. Pericardial effusion
establish an underlying aetiology
Medications Infections Diseases associated with immune
complexes• connective tissue diseases• malignancy• inflammatory bowel disease
VASCULITIS Diagnostic approach
History
Drugs H/O Hepatitis B or C H/O underlying disease
• SLE H/O Systemic complaints
Physical examination
to determine • extent of vascular lesions• distribution of affected organs• `presence of additional disease
Basic laboratory analysis Blood CP/ESR urinalysis CRP serum creatinine LFTs hepatitis serologies Tissue biopsy IF studies chest x-ray
Blood culture(if pyrexial)
ASO titre ANA Complement ANCA ECG
Other investigations (When indicated)
muscle enzyme 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
General measures• Remove triggering
agent• Minimize stasis• compression stocking • elevation of dependent
areas Symptomatic
• NSAIDs• Antihistamines
Oral Steroids• 30–80 mg once daily • tapered over 2–3 weeks
Colchicine• 0.6 mg twice daily
Dapsone Other modalities
• Azathioprine• Cyclophosphamide • Ciclosporin • Methotrexate• Biological agents
– Infliximab – Rituximab
•usually self-limiting
oral antihistamines systemic corticosteroids
• 1 mg/kg/day for 2 weeks• tapering over a further 2 weeks• effective in abdominal pain
arthritis, mild nephritis dapsone
• 100–200 mg once daily• shorten the duration of HSP• Improves skin lesions
colchicine • 0.6 mg twice to three times daily
hydroxychloroquine• 200 mg once to twice daily
mycophenolate mofetil • 2 g once daily
Renal disease high-dose corticosteroids
• either alone or with cyclophosphamide
Pulse steroid therapy• Followed by oral steroid and
immunosuppressants
HSPfrequently self-limitingSupporting treatment mostly
Urticarial vasculitis Systemic corticosteroids Dapsone Colchicine Antihistamines
• control of angio-oedema urticaria-like lesions in addition to above modalities
Mild• Prednisolone alone (1mg/kg per day)
Moderate/Severe• Prenisolone plus Cyclophophmide (1.5 to 2 mg per kg)
Life threatening/Intolerance to oral• Intravenous methylprednisolone be given initially for
three days, followed by the oral prednisone• 12 pulses of cyclophosphamide every 2 weeks for the first
three pulses and thereafter monthly PAN with HBV
• combination of antiviral and immune suppressing drugs
PAN
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 – 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).
IV 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.
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