N.Movaffagh MD Rheumatologist The Vasculitis Syndromes N.Movaffagh MD Rheumatologist

Vasculitis is a clinicopathologic process characterized by inflammation of and damage to blood vessels The vessel lumen is usually compromised, ischemia of the tissues supplied by the involved vessel

Vasculitis Syndromes Vasculitis are primary & secondary Vasculitis may be confined to a single organ,or it may simultaneously involve several organ systems

Primary Vasculitis Syndromes Granulomatosis with polyangiitis (Wegener’s or GPA) Microscopic polyangiitis(MPA) Eosinophilic granulomatosis with polyangiitis(EGPA) (Churg-Strauss) IgA vasculitis (Henoch-Schönlein) Cryoglobulinemic vasculitis Polyarteritis nodosa Kawasaki disease Giant cell arteritis Takayasu arteritis Primary central nervous system vasculitis

Secondary Vasculitis Syndromes Vasculitis associated with probable etiology Drug-induced vasculitis Hepatitis C virus–associated cryoglobulinemic vasculitis Hepatitis B virus–associated vasculitis Cancer-associated vasculitis Lupus vasculitis Rheumatoid vasculitis Sarcoid vasculitis

Classification by Vessel Size Large-Vessel Vasculitis Takayasu’s arteritis Giant cell arteritis Medium-Vessel Vasculitis Polyarteritis nodosa Kawasaki’s disease Small-Vessel Vasculitis Anti-neutrophil Cytoplasmic Antibody–Associated Vasculitis Microscopic polyangiitis Granulomatosis with polyangiitis Eosinophilic granulomatosis with polyangiitis IgA vasculitis (Henoch-Schönlein)

PATHOPHYSIOLOGY AND PATHOGENESIS

Mechanisms of Vessel Damage in Vasculitis Syndromes Pathogenic immune-complex formation and/or deposition Production of antineutrophilic cytoplasmic antibodies Pathogenic T lymphocyte responses and granuloma formation

Pathogenic immune-complex formation and/or deposition IgA vasculitis (Henoch-Schönlein) Lupus vasculitis Serum sickness and cutaneous vasculitis syndromes Hepatitis C virus–associated cryoglobulinemic vasculitis Hepatitis B virus–associated vasculitis

PATHOGENIC IMMUNE-COMPLEX FORMATION causal role of immune complexes has not been clearly established actual antigen rarely been identified in vasculitic syndromes Ag-AB Deposition in vessel walls permeability increased deposition of complexes activation of complement (C5a) Infiltration of N in the vessel wall Phagocytose the immune complexes release their intracytoplasmic enzymes mononuclear cells infiltrate the vessel wall

Production of antineutrophilic cytoplasmic antibodies Granulomatosis with polyangiitis (Wegener’s) Microscopic polyangiitis(MPA) Eosinophilic granulomatosis with polyangiitis (Churg-Strauss)

ANCA cytoplasmic ANCA (cANCA) antibodies to proteinase-3 perinuclear ANCA (pANCA)Anti MPO pANCA pattern inflammatory bowel disease, certain drugs,and infections (endocarditis)

p-ANCA c-ANCA

ANTINEUTROPHIL CYTOPLASMIC ANTIBODIES (ANCA) Neutrophils or monocytes are primed by (TNF-α) or (IL-1), proteinase-3 and myeloperoxidase translocate to the cell membrane neutrophils then degranulate and produce reactive oxygen species ,cause tissue damage Activation of neutrophils and monocytes by ANCA also induces the release of proinflammatory cytokines such as IL-1 and IL-8

Pathogenic T lymphocyte responses and granuloma formation Giant cell arteritis Takayasu arteritis Granulomatosis with polyangiitis (Wegener’s) Eosinophilic granulomatosis with polyangiitis (Churg-Strauss)

PATHOGENIC T LYMPHOCYTE RESPONSES AND GRANULOMA FORMATION cell-mediated immune injury cytokines such as interferon (IFN) γ Vascular endothelial cells can express HLA class II interaction with CD4+ T lymphocytes

Endothelial cells can secrete IL-1 which may activate T lymphocytes IL-1 and TNF-α are potent inducers ELAM-1, VCAM-1

General Principles of Diagnosis The diagnosis of vasculitis is often considered in any patient with an unexplained systemic illness

Clinical abnormalities of vasculitis palpable purpura pulmonary infiltrates microscopic hematuria chronic inflammatory sinusitis mononeuritis multiplex unexplained ischemic events GN with evidence of multisystem disease

Palpable purpura

workup of suspected vasculitis 1.exclude other diseases(Vasculitis Mimicars) 2.workup for follow a series of progressive steps that establish the diagnosis of vasculitis

Conditions That Can Mimic Vasculitis Infectious diseases Coagulopathies/thrombotic microangiopathies Neoplasms Drug toxicity(Cocaine,Levamisole,Amphetamines) Sarcoidosis Atheroembolic disease Antiglomerular basement membrane disease Amyloidosis Migraine Reversible cerebral vasoconstrictive syndrome

definitive diagnosis of vasculitis based on biopsy of involved tissue For polyarteritis nodosa, Takayasu arteritis, primary (CNS) vasculitis arteriogram of organs

GENERAL PRINCIPLES OF TREATMENT Glucocorticoids and/or other immunosuppressive agents

Isolated idiopathic cutaneous vasculitis usually resolves with symptomatic treatment

GRANULOMATOSIS WITH POLYANGIITIS (WEGENER’S) DEFINITION Wegener’ scharacterized by : granulomatous vasculitis of the upper and lower respiratory tracts together with GN

INCIDENCE AND PREVALENCE uncommon disease prevalence of 3 per 100,000 Rare in blacks male-to-female ratio is 1:1 the mean age of onset is ∼40 years ∼15% of patients are <19 years

Wegener’s histopathologic hallmarks of Wegener’s: necrotizing vasculitis of small arteries and veins together with granuloma formation (intravascular or extravascular)

classic triad of disease : upper and lower respiratory tracts and kidney involvement

PATHOGENESIS immunopathogenesis of this disease is unclear Chronic nasal carriage of Staphylococcus aureus associated with a higher relapse rate Wegener’s there is no evidence for a role of this organism in the pathogenesis of the disease

PATHOLOGY AND PATHOGENESIS IFN-γ TNF-α IL-12 ANCA

CLINICAL AND LABORATORY MANIFESTATIONS Involvement of the upper airways in 95% sinuses and nasopharyx Nasal septal perforation saddle nose deformity Serous otitis media result of eustachian tube blockage Subglottic tracheal stenosis(active disease or scarring) may result in severe airway obstruction

Pulmonary involvement% 85-90 asymptomatic infiltrates cough, hemoptysis, dyspnea, chest discomfort

Lung involvement appears as: multiple, bilateral, nodular cavitary infiltrates Lung biopsy : necrotizing granulomatous vasculitis

Eye involvement 52% Conjunctivitis dacryocystitis episcleritis scleritis, granulomatous sclerouveitis ciliary vessel vasculitis retroorbital mass proptosis

Skin lesions 46% Papules vesicles palpable purpura ulcers subcutaneous nodules Biopsy: vasculitis,granuloma

Cardiac involvement: Pericarditis coronary vasculitis cardiomyopathy(rarely)

Renal disease 77% Renal involvement is characterized by: Focal and segmental glomerulitis Rapidly progressive crescentic GN Granuloma formation is rare

malaise, weakness, arthralgias, anorexia, and weight loss Fever may indicate activity of the underlying disease & secondary infection,usually of the upper airway deep venous thrombosis or pulmonary emboli

DIAGNOSIS necrotizing granulomatous vasculitis on tissue biopsy Pulmonary tissue(highest diagnostic yield) upper airway tissue usually reveals granulomatous inflammation with necrosis but may not show vasculitis Renal biopsy can confirm the presence of pauci-immune GN

specificity of a positive antiproteinase-3 ANCA for Wegener’s is very high(especially in active GN) ANCA with rare exceptions, should not substitute for tissue diagnosis False-positive ANCA titers(certain infectious and neoplastic diseases)

Differential Diagnoses Goodpasture’s syndrome relapsing polychondritis tumors of the upper airway or lung infectious diseases such as histoplasmosis noninfectious granulomatous diseases midline destructive diseases lymphomatoid granulomatosis

causes of midline destructive disease Upper airway neoplasms specifically extranodal (NK)/T cell lymphoma (nasal type) Cocaine-induced tissue injury (cutaneous infarction and ANCA +)

Differential Diagnoses lymphomatoid granulomatosis An Epstein-Barr virus–positive B cell proliferation that is associated with an exuberant T cell reaction

laboratory findings Elevated ESR mild anemia Leukocytosis mild hypergammaglobulinemia(particularly of the IgA class) mildly elevated Rf Thrombocytosis 90%positive antiproteinase-3 ANCA(active) ∼60–70%( Non active disease) may antimyeloperoxidase

TREATMENT Glucocorticoids Cyclophosphamide methotrexate (INDUCTION&maintenance) Azathioprine mycophenolate mofetil RITUXIMAB TMP-SMX on relapse regard to upper airway disease

EOSINOPHILIC GRANULOMATOSIS WITH POLYANGIITIS ((CHURG-STRAUSS

uncommon disease annual incidence of 1–3 per million occur at any age with the possible exception of infants mean age of onset is 48 years female-to-male ratio of 1.2:1

PATHOLOGY AND PATHOGENESIS Involves small and medium-sized muscular arteries, capillaries, veins, and venules characteristic histopathologic feature: granulomatous reactions in tissues or within the walls of the vessels. infiltration of the tissues with eosinophils

CLINICAL MANIFESTATIONS fever, malaise, anorexia, and weight loss severe asthmatic attacks and pulmonary infiltrates Mononeuritis multiplex is the second most common manifestation Allergic rhinitis and sinusitis heart disease Skin lesions(purpura and subcutaneous nodules) renal disease is less common

laboratory finding eosinophilia, levels >1000 cells/μL(>80%) elevated ESR,fibrinogen, α2-globulins ANCA antimyeloperoxidase(P-ANCA)

DIAGNOSIS evidence of asthma peripheral blood eosinophilia clinical features consistent with vasculitis biopsy with clinical manifestations

TREATMENTE prognosis of untreated EGPA is poor Echocardiography should performed in all new patients Glucocorticoids cyclophosphamide and prednisone

IgA VASCULITIS (HENOCH-SCHÖNLEIN) a small-vessel vasculitis characterized by: palpable purpura (most commonly over the buttocks and lower extremities) Arthralgia gastrointestinal signs & symptoms glomerulonephritis

INCIDENCE AND PREVALENCE usually seen in children (4 to 7 years) however, the disease may also be seen in infants and adults male-to-female ratio is 1.5:1 is not a rare disease a peak incidence in spring has been noted.

PATHOLOGY AND PATHOGENESIS number of inciting antigens have been suggested including: upper respiratory tract infections, various drugs, foods, insect bites, and immunizations IgA is the antibody class most often seen in the immune complexes

CLINICAL MANIFESTATIONS In pediatric patients, palpable purpura is seen in virtually all patients Polyarthralgia GI involvement Colicky abdominal pain usually associated with nausea, vomiting, diarrhea, constipation Renal involvement occurs in 10–50% (GN usually resolves spontaneously without therapy)

CLINICAL MANIFESTATIONS In adults, presenting symptoms are most frequently related to the skin and joints initial complaints related to the gut are less common certain studies have found that renal disease is more frequent and more severe in adults, this has not been a consistent finding Myocardial involvement

LABORATORY MANIFESTATIONS mild leukocytosis, occasionally eosinophilia normal platelet count Serum complement are normal IgA levels are elevated in about one-half of patients

DIAGNOSIS Diagnosis is based on clinical signs and symptoms. Skin biopsy specimen can be useful in confirming leukocytoclastic vasculitis with IgA and C3 deposition by immunofluorescence. Renal biopsy is rarely needed for diagnosis

TREATMENT Most patients recover completely, and some do not require therapy. Treatment is similar for adults and children glucocorticoid therapy (tissue edema, arthralgias, abdominal discomfort) however, it has not proved beneficial in the treatment of skin or renal disease

In rapidly progressive glomerulonephritis : plasma exchange combined with cytotoxic drugs