The Vasculitis Syndromes

Definition Inflammation and damage of blood vessels Single organ→ skin Several organ systems Primary Secondary Heterogeneity Overlap

Primary Vasculitis Syndromes Wegener´s granulomatosis Churg-Strauss syndrome Polyarteritis nodosa Microscopic polyangitis Giant cell arteritis Takayasu´s arteritis Henoch-Schönlein purpura Idiopthic cutaneous vasculitis Essential mixed cryoglobulinemia Behcet´s syndrome Isolated vasculitis of the CNS Cogan´s syndrome Kawasaki disease

Secondary Vasculitis Syndromes Drug-induced vasculitis Serum sickness Vasculitis associted with other primary diseases, infection, malignancy, rheumatic disease

Pathophysiology and Pathogenesis Immunpathogenic mechanisms Pathogenic immune complex formation and/or deposition:Hepatitis B PAN, Hepatitis C Essential mixed cryoglob. Production of antineutrophilic cytoplasmic antibodies: Wegener´s, Churg-Strauss, Microsc. polyang. Pathogenic T lymphocyte responses and granuloma formation:Giant cell, Takayasu´s, Wegener, Churg-Strauss

Approach to the patient: Vasculitis Unexplained systemic illness Angiogram of organs Definitive diagnosis→biopsy of involved tissue

Wegener´s granulomatosis

Incidence and Prevalence Prevalence: 3 per 100.000 Age of onset: 40 years Primary vasculitis syndrome→ damage of vessels Immunopathogenic mechanisms ANCA= antineutrophil cytoplasmic antibody c-ANCA= cytoplasmic ANCA (diffuse, granular cytoplasmic staining by immunofluorescence microscopy) Detectable antibodies to proteinase-3 Granuloma formation

Pathology and pathogenesis Necrotizing vasculitis of small arteries and veins + granuloma formation Lung: multiple, bilateral, nodular cavitary infiltrates Biopsy: necrotizing granulomatous vasculitis Upper airway lasions: sinuses, nasopharynx Kidney: rapidly progressive crescentic glomerulonephritis

Clinical manifestations Upper airways 95% Purulent or bloody nasal discharge Nasal septal perforation Saddle nose deformity Serous oitis media, hearing loss Subglottic tracheal stenosis→severe airway obstruction Pulmonary involvement:hemoptysis, dyspnea 85-90% Eye: scleritis, conjunctivitis, retroorbital mass laesion Skin: palpable purpura, papules, vesicles, subcutaneous nodules Heart: pericarditis, coronary vasculitis CNS: mononeuritis multiplex, cerebral vasculitis Kidney disease: 77%, proteinuria, hematuria, red blood cell casts, rapidly progressive renal failure

Laboratory findings ESR↑ Mild anemia, leukocytosis, thrombocytosis 90% positive antiproteinase-3 c-ANCA

Diagnosis of WG Tissue biopsy: necrotizing granulomatous vasculitis c-ANCA positivity

Treatment of WG Cyclophosphamide induction for severe disease: 2 mg/kg per day orally + steroids Cyclophosphamide for 1 year following the induction of complete remission Prednisone 1 mg/kg per day Improvement: 90% Complete remissions: 75% Later relapses Remission maintenance: Azathioprine, Methotrexate 2 years past remission

Treatment of WG 2 Mycophenolate mofetil 1000 mg twice a day Rituximab (anti-CD20) Trimethoprim-sulfamethoxazole

Churg-Strauss syndrome

Definition Allergic angiitis and granulomatosis Asthma, peripheral and tissue eosinophilia, extravascular granuloma formation, vasculitis of multiple organs

Incidence and Prevalence 1-3 cases per million Onset: 48 years

Pathology and Pathogenesis Necrotizing vasculitis Small and medium-sized muscular erteries, capillaries, veins, and venules Granuloma formation Infiltration of the tissues with eosinophils Lung, skin, heart, kidney. Peripheralnervous system, GI

Clinical and Laboratory Manifesttions Asthma, pulmonary infiltrates Mononeuritis multiplex Allergic rhinitis and sinusitis Skin lesions: purpura, subcutaneous nodules Eosinophilia ESR↑ p-ANCA = perinuclear ANCA (antimyeloperoxidase)

Diagnosis Asthma Peripheral blood eosinophilia Biopsy

Treatment Steroids Cyclophosphamide Survival rate:72%

Polyarteritis nodosa

Definition Multisystem, necrotizing vasculitis Small and medium-sized muscular arteries Renal and visceral arteries

Incidence and Prevalence Very uncommon disease

Pathology and Pathogenesis Segmental lesions Bifurcations and branching of arteries Aneurysmal dilatations up to 1 cm in size Kidney: arteritis without glomerulonephritis Hepatitis B antigenemia: 10-30% Circulating immune complexes composed of hepatitis B antigen

Clinical manifestations Fever, weight loss Kidney→renal failure, hypertension Joint→arthritis, arthralgia, myalgia Peripheral neuropathy, mononeuritis multiplex GI→abdominal pain, bleeding, bowel infarction and perforation, liver infarction, pancreatic infarction Skin→purpra, nodules, cutaneous infarcts, livedo reticularis Heart→congestive heart failure, myocardial infarction, pericardiis Testicular and ovarian pain CNS→cerebral vascular accident, seizure, altered mental status

Laboratory tests Leukocyte count↑ ESR↑ Anemia of chronic disease Hypergammaglobulinemia HBsAg pozitivity 30%

Diagnosis Vasculitis on biopsy material of involved organs Angiography→aneurysms of small and medium-sized arteries

Treatment Steroid Cyclophosphamide PAN + Hepatitis B virus pozitivity: Antiviral drugs+ steroid+plasma exchange

Microscopic polyangitis Glomerulonephritis→renal failure Pulmonary capillaritis→hemoptysis Mononeuritis multiplex GI vasculitis Cutaneous vasculitis Age of onset: 57 years pANCA positivity 75%

Diagnosis and Treatment Kidney,lung: histologic evidence of vasculitis Steroid +Cyclophosphamide

Giant cell arteritis and Polymyalgia rheumatica

Definition Temporal arteritis or Cranial arteritis Inflammationof medium- and large-sized arteries Temporal artery Aorta and its main branches Polymyalgia rheumatica: pain in the muscles of the neck, shouldersm lower back >50 years

Clinical and Laboratory Manifestations Fever,anemia ESR↑ Headache Temporal artery→tender, thickened, nodular Ischemic optic neuropathy→visual loss→blindness Increased risk of aortic aneurysm→ dissection

Diagnosis Biopsy of the temporal artery Giant cell arteritis

Treatment Steroid: Prednisone40-60 mg/day 1 month Treatment for≥ 2 years ESR↓ Polymyalgia rheumatica: Prednisone 10-20 mg/day

Takayasu´s arteritis Inflammatory and stenotic disease of medium- and large-sized arteries Aortic arch and its branches =Aortic arch syndrome Incidence: 1-2 cases/million/year Angiography

Frequency of angiographic abnormalities Subclavian: 93% Common carotid: 58% Abdominal aorta: 47% Aortic arch: 35% Vertebral: 35% Pulmonary: 10-40% Coronary < 10%

Clinical manifestetions Panarteritis with inflammatory mononuclear cell infiltrates Narrowing of the lumen Pulses absent ESR↑, anemia, gammaglobulin↑

Diagnosis Young woman Decrease or absence ofperipheral pulses Discrepancies in blood pressure Arterial bruits Arteriography→irregular vessel walls, stenosis, poststenotic dilatation, aneurysm formation, occlusion, evidence of increased collateral circulation

Treatment Steroid: prednisone 40-60 mg/day Methotrexate 25 mg/week Surgical correction of stenosed arteries

Henoch-Schönlein purpura Anaphylactoid purpura Palpable purpura over the buttocks and lower extremities Arthralgias GI signs→colicky abdominal pain, melena/hematochesia Glomerulonephritis→proteinuria, microscopic hematuria, red blood cell casts Small-vessel vasculitis Children 4-7 years Immune-complex deposition Serum IgA↑

Diagnosis Clinical symptoms Skin biopsy→ leukocytoclastic vasculitis

Treatment Do not require therapy Steroids: Prednisone 1 mg/kg/day

Idiopathic cutaneous vasculitis =Hypersensitivity vasculitis =Cutaneous leukocytoclastic vasculitis Dermis, small vessels Only skin involvement→palpable purpura, chronic urticaria Diagnosis: biopsy→vasculitis Etiology: drug, infection, underlying disease Treatment:microbe→antimicrobal therapy, steroids

Essential mixed cryoglobulinemia Cryoglobulins: cold-precipitable monoclonal or polyclonal immunoglobulins Cutaneous vasculitis, palpable purpura, arthralgias, glomerulonephritis Hepatitis C infection Treatment:IFN-α, Ribavirin

Behcet´s syndrome Recurrent, painful aphthous oral ulcerations in the oral cacity Recurrent genital ulcers Iritis Cutaneous lesions Treatment: topical steroids, Prednisone

Isolated vasculitis of the CNS Severe headache, focal neurologic defects Abnormal MRI of the brain Abnormal liquor Abnormal cerebral angiogram→vasculitis Brain biopsy Treatment:Prednisone+Cyclophosphamide

Kawasaki disease =Mucocutaneous lymph node syndrome Nonsuppurative cervical adenitis Children > 2 years Coronary artery aneurysms 25% Treatment:IVIG+ Aspirin

Raynaud´s Phenomenon Episodic vasoconstriction inthe fingers and toes Tip of the nose and earlobes Cold exposure pallor→cyanosis→erythema rewarming of the fingers, vasoconstriction→ischemia→reperfusion Normal population: 3-5%, women Primary and/or secondary Nailbed cutaneous capillaries viewed stereoscopic microscope

Treatment Dress warmly, calcium channel blockers, ARBs (angiotensin II receptor blockers) Losartan, iv. prostaglandins, low-dose aspirin