PRIMARY VASCULITIDES Amy Shultz, M.D.
VASCULITIS DEFINITION • Presence of WBCs in vessel wall with reactive damage of mural structures • Leads to bleeding, tissue ischemia/necrosis • Primary—idiopathic • Secondary—to another underlying disease (SLE, RA, cryglobulinemia)
HISTORY • 1866: Kussmaul & Maier—described nodular inflammation of muscular arteries • Termed periarteritis nodosa—later changed to polyarteritis nodosa (PAN)
PATHOGENESIS • Remains largely unknown • Hypothesis: (Most likely multifactorial) -Immune complex deposition/humoral responses - Pathogenic T cell responses and granuloma formation - Autoantibodies - Cytokine activation - Infectious trigger—bacteria, mycobacteria, viruses - Drugs - Genetic predisposition
VASCULITIDES • Fairly rare diseases • Presentation: highly variable making delays in diagnosis common • High morbidity and mortality • Therapeutic challenge often requiring prolonged & intensive immunosuppression.
CLASSIFICATION • Individual diseases affect blood vessels of a particular size—clinical manifestations and wide range of disease severity. • Large Vessel Vasculitis: • Takayasu arteritis • Giant cell arteritis
CLASSIFICATION • Medium vessel vasculitis: • Polyarteritis nodosa • Kawasaki disease (children) • Small vessel vasculitis: • Churg-Strauss syndrome • Wegener’s granulomatosis • Microscopic polyangiitis
TAKAYASU ARTERITIS (TA) Chronic granulomatous vasculitis that affects the aorta, its main branches, and pulmonary arteries Women affected in 80-90% of cases Age of onset: 10-40 years Worldwide distribution, but greatest prevalence in Asians. U.S. incidence rate: 2.6/million
TA (CLINICAL MANIFESTATIONS) • Systemic symptoms:Early phase • Fatigue • Malaise • Weight loss • Night sweats • Fever-low grade • Arthralgias~ 55% • Myalgias
TA (CLINICAL MANIFESTATIONS) • Vascular compromise: Late phase • Aneurysm formation and rupture • Vessel stenosis/occlusion--ischemia • Catastrophic complications: • Aortic dissection/rupture • Aortic valve regurgitation • CVA • Hypertensive crisis • MI
Subclavian Common carotid Renal Aortic arch/root Vertebral Pulmonary Coronary Arm claudication Visual changes, syncope, TIA, CVA, headaches HTN, renal failure AI, CHF Visual changes, dizziness Dyspnea, hemoptysis Chest pain, MI ARTERY MANIFESTATION
TA (HISTOPATHOLOGY) • Cell-mediated mechanisms: • Infiltrating cells mainly consist of killer cells and gamma delta T lymphocytes • All layers of large arteries affected: • Inflammation • Granuloma formation • Giant cells
TA (PHYSICAL EXAMINATION) • Asymmetric blood pressure measurements • Diminished pulses/pulseless • Bruits-subclavian, carotid, brachial, abd • HTN- RAS or decreased elasticity of aorta • Decreased hair growth, cool extremities, muscle wasting, gangrenous digits
TA(LAB ABNORMALITIES) • Nonspecific: • Elevated ESR • Elevated CRP • Normochromic, normocytic anemia • Hypoalbuminemia • Autoantibodies: • Antiendothelial cell (recent studies value?) • ANA, ANCA, anti-DNA, APL: negative
TA (IMAGING) Angiography usually necessary to confirm diagnosis and see extent of disease: Advantage: Provides clear outline of involved arteries & luminal patency Disadvantage: Does not show arterial thickening, invasive, & large dye load Helical CT angiography and MRA Becoming more popular Used to access continued disease activity Shows thickness and edema within wall
TA (CLASSIFICATION CRITERIA) • Age of onset <40 • Claudication of extremities • Decreased pulsation in 1 or both brachials • >10mmHg SBP difference between arms • Bruit over 1 or both subclavian or abd. Aorta • Angiographic narrowing of aorta or branches • Patients must meet at least 3 of the 6 criteria
TA (TREATMENT) • Corticosteroids: 60mg/day gradually tapered • Cytotoxic drugs: Chronic active disease (50%) • Methotrexate—17.5-25mg/week • Azathioprine—2mg/kg/day • Anti-TNF agents: clinical trials ongoing • Revascularization: bypass grafts vs. PTCA
GIANT CELL ARTERITIS (GCA) • Granulomatous vasculitis affecting extra-cranial branches of arteries from the aortic arch • Most common systemic vasculitis: prevalence 200 per 100,000 • Occurs almost exclusively over 50 yrs of age • Female:male ratio 2:1
PATHOGENESIS • Cell-mediated immune response against antigens in arterial wall. • Granulomatous inflammation • T cells secreting IL-2 & interferon γ • Humoral response against antigens in the arterial wall. • Immunoglobulin and complement deposits.
CLINICAL MANIFESTATIONS • In most cases insidious onset of symptoms: • Fatigue • Fever • Weight loss • anorexia • Headache most common symptom: lacinating localized to regions along arteries in the scalp.
Headache Weight loss/anorexia Jaw claudication Fever Malaise/fatigue PMR Transient visual symptom Synovitis Fixed visual symptom 68% 50% 45% 42% 40% 39% 16% 15% 14% GCA (CLINICAL MANIFESTATIONS)
GCA (PE AND LAB) • Physical exam: Nodularity, tenderness, absent pulsations, bruits of involved arteries • Fundoscopic examination in patients with visual loss: pale, swollen disc with blurred margins • Lab: Markedly elevated ESR
GCA (DIAGNOSIS) • Clinical Suspicion: Elderly patient with headache, visual symptoms, and high ESR • Diagnosis confirmed by temporal artery biopsy: • Shows panmural mononuclear cell infiltration with granulomas and giant cells • Treatment should be instituted promptly while biopsy is arranged
GCA (TREATMENT) • Prednisone 40 to 60mg/day: initial dose • In patients with acute visual loss: Solu-medrol 1g/day x 3 days • Steroids can be tapered after clinical remission achieved: ESR and CRP normalized • Most patients off steroids by 2 years. Relapse rate 26-90% (highly variable). • Methotrexate studied in 2 RCT: conflicting results in ability to decrease relapse & steroid usage
GCA( Follow-up) • Thoracic aortic aneurysms: Late manifestation • GCA patients 17 times more likely than age and sex matched people to develop these • Yearly chest x-rays are recommended for up to 10 years to identify patients with aneurysms prior to rupture.
POLYARTERITIS NODOSA (PAN) • Systemic panmural necrotizing vasculitis typically affecting small and medium-sized arteries—fibrinoid necrosis • Most cases are idiopathic • 7 to 22% of cases associated with hepatitis B infection: must be r/o in all patients • Smaller percentage found in hairy cell leukemia, hepatitis C, and HIV • Classical PAN: ANCA negative
PAN EPIDEMIOLOGY • Incidence: 0.7/100,000 • Male:female ~ 2:1 • Seen in all ages--peak 40-60 years of age • May range in severity from mild limited to 1 organ system to fulminate multisystem involvement.
PAN (CLINICAL MANIFESTATIONS) • Systemic symptoms: fatigue, weakness, fever, arthalgias, myalgias (60-70%) • PNS: Mononeuritis multiplex—motor & sensory deficits (50-70%) • Skin:livedo reticularis, digital necrosis, skin ulcers, bullous eruptions, nodules, palpable purpura (45-60%) • Renal: Extra-glomerular vasculopathy mostly some GN—renal insufficiency, hypertension, and renal infarction (40-70%)
PAN(CLINICAL MANIFESTATIONS) • GI:(30-50%)Mesenteric arteritisischemia • Stomach • Intestines • Liver • Gallbladder • Orchitis: rare seen more with HBV • Lab: non-specific (95%) • ↑ESR Normochromic/normocytic anemia • Thrombocytosis ↓albumin
PAN(DIAGNOSIS) • Visceral/renal angiography: microaneurysms, ectasia, stenoses in medium-sized vessels • Biopsy: peripheral nerve or skin—focal segmental necrotizing vasculitis with mixed cell infiltrate and no granulomata affecting medium-sized arteries.
PAN(PROGNOSIS) • Untreated: 13% 5 year survival rate • Main causes of death: renal failure, mesenteric, cardiac, cerebral infarction • Five-factor score: French vasculitis group • Proteinuria >1g/day • GI bleeding, perforation, infarct, pancreatitis • Renal insufficiency • Cardiomyopathy • CNS involvement
PAN(TREATMENT) Prednisone 1mg/kg/day Cyclophosphamide 2mg/kg + steroids Azathioprine 2mg/kg + steroids Optimal duration of therapy is unknown. Relapse rate~40% If Hep B present, must treat.
ANCA-ASSOCIATED VASCULITIS • Antineutrophilic cytoplasmic antibodies: • C-ANCA (cytoplamic pattern) antigen—proteinase-3 • P-ANCA (perinuclear pattern) antigen—myeloperoxidase Binding of C-ANCA & P-ANCA to their antigen targets in neutrophils →degranulation, respiratory burst, NO production, chemotaxis→contributes to vascular damage.
CHURG-STRAUSS SYNDROME • Allergic granulomatosis & angiitis characterized by: • Allergic rhinitis • Asthma • Peripheral blood eosinophilia • Systemic vasculitis • Slight male predominance • Mean age at diagnosis: 40 years
CHURG-STRAUSS(CLINICAL FEATURES) • Prodromal phase: 2nd to 3rd decades of life—atopic disease, allergic rhinitis, asthma • Eosinophilic phase: Peripheral blood eosinophilia and infiltration of multiple organs especially lungs and GI tract • Vasculitic phase: 3rd to 4th decades of life—systemic vasculitis
CHURG-STRAUSS(CLINICAL FEATURES) • Asthma—98-100% • Mononeuritis multiplex—50-80% • Skin: palpable purpura, rash, tender subcutaneous nodules (50-80%) • Sinusitis—20-70% • CV—pericarditis, CHF, MI (35-50%) • GI—eosinophilic gastritis:pain, bleeding, colitis (30-60%)
CHURG-STRAUSS(CLINICAL FEATURES) • Renal—focal segmental GN (10-50%) less common than in WG or MPA • Pulmonary infiltrates-40-75% • Transient patchy infiltrates • Pulmonary hemorrhage • Bilateral, nodular disease without cavitation • Pleural effusions: exudative & rich in eosinophils
CHURG-STRAUSS(LAB ABNORMALITIES) • Peripheral eosinophilia >10% • Elevated IgE levels • P-ANCA/anti-MPO—70% • Elevated ESR • Normochromic/normocytic anemia • BAL—high percentage of eosinophils
CHURG-STRAUSS (DIAGNOSIS) • Confirmed by surgical lung biopsy or biopsy of other affected tissues: • Eosinophilic infiltrates • Extensive areas of fibrinoid necrosis • Giant cell vasculitis of small arteries and veins • Necrotizing granulomas