TUTORIAL PRESENTATION

APPROACH TO A CASE OF VASCULITIS

Moderator :Dr. Saroj Purohit

What is Vasculitis?

Inflammation of blood vessels

occlusion aneurysm

ischemia hemorrhage

WHICH BLOOD VESSELS WHICH BLOOD VESSELS ARE AFFECTED?ARE AFFECTED?

• ANY BLOOD VESSEL CAN BE AFFECTED:

– ARTERIES– ATERIOLES– CAPILLARIES– VENULES– VEINS

• CAN DAMAGE VIRTUALLY ANY ORGAN OR TISSUE

Predominantly Small Vessel Vasculitides

Immune complex mediated

1.Goodpasture's disease (anti–glomerular basement membrane disease)2.Cutaneous leukocytoclastic angiitis (“hypersensitivity vasculitis”) 3.Henoch-Schönlein purpura 4.Hypocomplementemic urticarial vasculitis 5.Essential cryoglobulinemia6.Erythema elevatum diutinum

ANCA-associated disorders

1.Wegener's granulomatosis 2.Microscopic polyangiitis 3.Churg-Strauss syndrome 4.Renal-limited vasculitis

Secondary Forms of Vasculitis

• Connective tissue disorders – rheumatoid vasculitis, – lupus erythematosus, – Sjögren's syndrome, – inflammatory myopathies

• Inflammatory bowel disease • Paraneoplastic • Infection • Drug-induced vasculitis:

Pathogenesis Antigens

(Microbes, drugs, tumor, autoantigens) + Antibodies Formation of immune complexes ↓

Deposition of complexes in and around blood vessels ↓

Activation of complement cascade and generation of C3 and C5a (anaphylatoxins)

↓ Mast cell degranulation and generation of

chemokines and cytokines

cont….. Increased vascular permeability, neutrophil chemotaxis, further deposition of immune complexes ↓Appearance of neutrophils with phagocytic activity, and release of proteolytic enzymes (e.g. collagenase and

elastase) ↓ Destruction of vessels, formation of platelet thrombi ↓ Ischmia, hemorrhage, and necrosis of tissues involved ↓ Clinical signs and symptoms

APPROACH TO A PATIENT OF VASCULITIS

• The vasculitic syndrome display a multitude of variable presentations.

• Hence there can be no uniform laid down guidelines or evaluation scale

for the diagnosis of these disorders.

• High degree of suspicion, a detailed history,meticulous physical

examination and appropriate laboratory tests to determine organ systems

involved and the extent of involvement are the components of the

diagnostic process.

When to suspect vasculitis

Presence of following findings alone or in combination or other bizarre systemic manifestations should raise the suspicion of vasculitis -– Occlusive arterial disease or hypertension in young adults.– Unexplained fever, weight loss.– Unexplained proteinuria with or without casts.– Splinter haemorrhages in nails – cutaneous lesions - palpable purpura, erythema, subcutaneous

nodules or urticaria.– Sudden retinal vascular disease without hypertension or diabetes.

• Persistent headache with sudden visual impairment (monocular blindness) in elderly.

• Jaw claudication• Sudden appearance of peripheral neuropathy - wrist drop,

foot drop.• Cerebrovascular/cardiovascular events in young.• Unexplained finding of pulmonary nodular/cavitatory lesions.

Clinical presentation

Predominantly cutaneous vasculitis• Usual presentation is in the form of palpable

purpura, urticaria, bullous ulcers or splinter haemorrhages.

• Mainly limited to lower extremities. • Salient features are:-

• Absence of systemic involvement.• Negative serology• Small vessel leucocytoclastic vasculitis• Better prognosis

Manifestations of Systemic vasculitis

Cont…

DIAGNOSTIC WORKUPLaboratory investigations

• Full blood count with differential white cell count• Markers of inflammation: ESR,CRP• Electrolytes and hepatic transaminases, glucose• Urinalysis for protein and blood• Blood cultures (if pyrexial)• Serology—ANA ,dsDNA , ANCA,C3 and C4,ASLO titre,

viral titres (e.g. hepatitis B and hepatitis C, possibly HIV, CMV, parvovirus B19 and others if recent infection).

• Others-rheumatoid factor, electrophoresis, immune complexes.

• Skin biopsy • Organ biopsy• Angiography• Other radiological investigations• X-ray, CT scanning and MRI• 2D Echocardiography• Renal and hepatic function tests

Mimicks of vasculitis

Clinical finding according to vessel involvement

LARGE VESSEL VASCULITIS

GIANT CELL ARTERITIS(Temporal or Cranial Arteritis)

• Transmural inflammation-> intimal hyperplasia-> luminal occlusion

• Fragmentation of internal elastic lamina

• Cellular immune response involving T-cells, APCs, macrophages

• Symptoms are due to end-organ ischemia

GIANT CELL ARTERITISPresentation

• Temporal Headache• Scalp tenderness• Thickened temporal

arteries• Jaw claudication• Acute visual loss• Weight loss, anorexia,

fever, night sweats, malaise & depression

Laboratory Findings

• Erythrocyte sedimentation rate > 50

• 22% of patients with biopsy-proven GCA have normal ESR

• Therefore, normal ESR does NOT rule out GCA

• Mild-moderate anemia of chronic disease

• Deranged LFT(1/3)• CRP- Raised

GIANT CELL ARTERITISHistopathology

• Granulomatous cell infiltration

• Giant cells• Disruption of internal

elastic lamina• Proliferation of intima• Occlusion of lumen

Treatment

• Goal: Reduce the symptoms and to prevent visual loss• If clinical suspicion is high, treatment should NOT be

delayed for biopsy

• Glucocorticoids• Methotrexate • Infliximab• Azathioprine• Imatinib mesylate • Surgery

MEDIUM VESSEL VASCULITIS

Polyarteritis nodosa

• Inflammatory necrotizing vasculitis • Tends to occur at bifurcations & branchings of small and

medium sized muscular arteries but not venules• Involvement of the renal and visceral arteries is characteristic• involvement of the arterioles of the renal glomeruli or the

pulmonary arteries does not occur but can involve bronchial arteries

• Mediated by deposition of circulating immune complexes • Age 40-60 yrs• Association--hepatitis B ,Hairy cell leukemia• fibrinoid necrosis occlusion of the vessel lumen, thrombosis,

and ischemia of the tissue supplied by the vessel.• Produces aneurysmal dilatation ( upto 1 cm ) of the artery

ACR classification• 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 >90 mmHg • Elevated levels of serum blood urea nitrogen (>40 mg/dL) or

creatinine (>1.5 mg/dL)• Evidence of hepatitis B virus infection via serum antibody or

antigen serology• Characteristic arteriographic abnormalities not resulting from

noninflammatory disease processes• A biopsy of medium- or small-sized artery containing

polymorphonuclear cells • 3/10 sensitivity/specificity-82-87%

TREATMENT

• Less severe cases - glucocorticoids

• Severe cases - combination of prednisone and cyclophosphamide

• PAN with hepatitis B - antiviral therapy in combination with glucocorticoids and plasma exchange.

SMALL VESSEL VASCULITIS

Cutaneous small vessel vasculitisSYN : Cutaneous leukocytoclastic vasculitis • Hypersensitivity angiitis/vasculitis

• Cutaneous necrotizing venulitis.• Affect mainly cutaneous post-capillary venules,• cutaneous small vessel vasculitis (CSVV) is the most common

type of vasculitis in dermatology.• 50% of cases – idiopathic • 15–20% - infection• 15–20% - inflammatory diseases (collagen vascular disorders)• 10–15% - medications• 5% - malignancy.

• Histopathology.• swelling of endothelium• fibrinoid necrosis of vessel

walls• Extravasation of erythrocytes• Infiltrate of neutrophils with

karyorrhexis of nuclei(i.e. leukocytoclasia)

Clinical features• The major cutaneous manifestation of CSVV is palpable purpura, ranging

in size from 1 mm to several centimetres.

• Purpura may progress to papules, nodules, vesicles, plaques,bullae or

pustules.

• Other cutaneous findings include oedema, livedo reticularis and urticaria.

Lesions typically occur in areas prone to stasis (ankles and lower legs).

• Typically spare intertriginous regions.

• Usually asymptomatic,pruritus,pain or burning may be experienced, as

well as systemic symptoms including fever, arthralgia, myalgia and

anorexia may occur.

Wegener’s GranulomatosisClassical triad -

• systemic small vessel vasculitis• Necrotizing granulomatous inflammation of both the upper and lower

respiratory tracts, and• Glomerulonephritis Pathology• Preferentially involves venules, capillaries and arterioles • may involve medium sized arteries• Characterized by the presence of granulomatous inflammatory lesions

– Focal accumulations of lymphocytes, macrophages, epithelioid cells and multinucleated giant cells

• Granulomas are similar to granulomas associated with intracellular infections

• Predominant cell type is CD4+ T cells and macrophages

Respiratory tract• Upper

– Purulent sinus drainage– Nasal mucosal ulceration with epistaxis / necrosis/perforations of nasal septum– Saddle nose deformity– Otitis media / hearing loss

• Tracheal inflammation and sclerosis of subglotic region : stridor and airway stenosis

• Lower– Fleeting focal infiltrates Cavitary lesions

• Massive pulmonary hemorrhage and hemoptysis - caused by alveolar capillaritis 80% will progress to paucimmune GN

• Renal• GN is characterized by

– Focal fibrinoid necrosis– Crescent formation – Absent/paucity of Ig/C3/C4 deposits– ESRD within 2 yrs in 40% cases

Other signs and symptoms • Cutaneous manifestations –

– Most common -palpable purpura – II most common- Oral ulcers

• Other skin lesions-– Tender subcutaneous nodules– Papules– Vesicles and petechiae– Non-specific ulcer

– Pyoderma gangrenosum.• Migratory arthritis, ocular involvement (scleritis, corneal

ulceration and orbital disease)• Peripheral (mononeuritis multiplex) or central nervous system

involvement• Risk of venous thrombosis

Treatment• Induction

– Oral cyclophosphamide 2mg/kg with prednisone 1mg/kg– Usually for 3 to 6 months– IV cyclophosphamide 15mg/kg as monthly pulse

• Maintenance– Azathioprine 2mg/kg and prednisone 5 to 10mg(low dose)– Methotrexate 15 to 20mg per week and low dose prednisone

• Relapse– 80% experience one or more within 10yrs– Usually when treatment is being tapered or stopped– Need to re-start cyclophosphamide

Churg Strauss syndromeChurg Strauss syndrome• Also known as Allergic Granulomatosis• Small vessel autoimmune vasculitis leading to necrosis • Site: Blood vessels of the lungs (MC) GI Tract Peripheral nerves Heart, skin, and kidneys• ACR criteria for the diagnosis ofACR criteria for the diagnosis of

Churg-Strauss syndromeChurg-Strauss syndrome • Presence of 4 or more criteria:- (1) H/O Bronchial asthma (2) Eosinophilia >10% in Peripheral Blood (3) Paranasal sinusitis (4) Pulmonary infiltrates (Transient) (5) Histology: vasculitis with extravascular eosinophils (6) Mononeuritis multiplex or Polyneuropathy

PathologyPathology

Necrotising vasculitis of small vessels

Granulamatous reaction present in tissue and in the wall of vessels

Clinical manifestationClinical manifestation

• Prodromal phase –– seen in second and third decades – characterized by atopic disease, allergic rhinitis, and

asthma.• Eosinophilic phase –

– peripheral blood eosinophilia – eosinophilic infiltration of multiple organs, especially

the lung and GIT. • Vasculitic phase –

– third & fourth decades – life-threatening systemic vasculitis of small vessels.

• Severe asthmatic attacks and migratory pulmonary infiltrates (MC)• Mononeuritis multiplex (72%)• Allergic rhinitis and sinusitis (60%)• Skin lesions: Palpable purpura, cutaneous & subcutaneous nodules• Gastrointestinal tract — abdominal pain , diarrhea , gastrointestinal

bleeding.• Musculoskeletal — Myalgias, migratory polyarthralgias, and frank

arthritis.

• Cardiovascular — Heart failure and cardiac rhythm abnormalities

• Renal involvment: 50% patients have rapidly progressive or acute renal insufficiency , while the others isolated proteinuria or microscopic hematuria.

ManagementManagement• Striking eosinophillia >1000 cells/µl (80%)• Anaemia• Raised ESR, Raised fibrinogen• P-ANCA : Positive (48%)• RFT:Elevated serum BUN and creatinine level• Urine: proteinuria, microscopic hematuria & RBC casts• Corticosteroids - clinical remission in 90% • Severely affected patients, recalcitrant disease or

those with poor prognostic factors such as cardiac, GI, renal or CNS involvement-– Cyclophosphamide+ Corticosteroids– Intravenous immunoglobulin (IVIG)

Henoch-Schönlein Purpura Also referred to as anaphylactoid purpura• characterized by

– palpable purpura (most commonly distributed over the buttocks and lower extremities)

– arthralgias– gastrointestinal signs and symptoms

Glomerulonephritis

• Usually seen in children • most patients range in age from 4 to 7 years; • may also be seen in infants and adults• male-to-female ratio is 1.5:1

Clinical featuresPediatric patients

– palpable purpura (nearly all cases)– polyarthralgias Gastrointestinal involvement (70%)

• colicky abdominal pain • nausea, vomiting• diarrhea, or constipation • passage of blood and mucus per rectum• bowel intussusception

Renal – 10-50%Mild GN,proteinuria,microscopic hematuria

Adults– Cutaneous vasculitis– Arthritis– Peripheral neuropathy– Glomerulonephritis (MPGN) – Life-threatening RPGN or vasculitis of the CNS, gastrointestinal tract, or

heart occurs infrequently

ACR criteria

• Palpable purpura• Bowel angina• Gastrointestinal bleeding• Hematuria• Age at onset ≤20 years• No new medication

• 3/6 carry sensitivity/specificity-87%

Management• Skin/renal biopsy( IFA)-

– Leucocytoclastic vasculutis with IgA and c 3 deposition• Lab studies

– Mild leucocytosis– Normal platelet count and complement level– Eosinophilia

• IgA level elevated• Prognosis is excellent and most patients recover completely

• 1–5% of children progress to ESRD

• Treatment is similar for adults and children.

• Glucocorticoids - prednisone, in doses of 1 mg/kg per day and tapered according to clinical response- effective in the treatment of abdominal pain and arthritis– not benefit in skin or renal disease– does not appear to shorten the duration of active disease or lessen the chance of recurrence.

• Dapsone (100 mg once daily)- shorten the duration, beneficial effect on the cutaneous lesions• factor XIII replacement• ranitidine• RPGN - intensive plasma exchange combined with cytotoxic drugs.

• Disease recurrences have been reported in 10–40% of patients.

Urticarial Vasculitis• 5–10% Of patients with chronic urticaria have urticarial vasculitis (UV).

• Chronic disease,presents as urticarial lesions that most often occur on the

trunk or proximal limbs, frequently with associated angio-oedema

• Lesions persist for greater than 24 h, often demonstrate purpura and

post-infl ammatory pigmentation.

• Two types –

– UV associated with hypocomplementaemia, and

– UV without hypocomplementaemia(normocomplementaemic UV).

Pathology

– Histopathological features are those of leukocytoclastic

vasculitis with a perivasculer neutrophilic infiltrate

C/F

• Fixed annular wheals• >24 hr• pain and burning

sensation rather then itching

• hyperpigmentation on resolution

• Systemic symptoms and signs

Treatment • majority of patients respond to systemic

corticosteroids.• indomethacin 25mg three times daily to 50mg four

times daily.• Colchicine 0.6mg two or three time daily.• Dapsone up to 200mg / day • Low dose oral methotrexate• Dapsone plus pentoxifylline