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The Vasculitis Syndromes¶

Chapter 375 | Part 11: Immune-Mediated, Inflammatory, and Rheumatologic Disorders · Part 11 – Rheumatology & Immunology · Chapter 375

Key Clinical Points¶

Vasculitis is a clinicopathologic process characterized by inflammation and damage to blood vessels, leading to compromised lumen and tissue ischemia.
Classified as Primary (e.g., GPA, MPA, EGPA, IgA vasculitis, Cryoglobulinemic vasculitis, PAN, Kawasaki disease, GCA, Takayasu arteritis) or Secondary (e.g., Drug-induced, Infection-associated, Cancer-associated).
Pathogenesis involves three main mechanisms: Pathogenic immune-complex formation, Production of antineutrophilic cytoplasmic antibodies (ANCA), and Pathogenic T lymphocyte responses/granuloma formation.
ANCA types: cANCA (targeting Proteinase-3) is highly specific for GPA (>90%); pANCA (targeting Myeloperoxidase) is associated with MPA, EGPA, and isolated necrotizing crescentic glomerulonephritis.
GPA presents with a classic triad of upper/lower respiratory tract disease and glomerulonephritis; prevalence is 3 per 100,000.
Diagnosis requires tissue biopsy to rule out infection or malignancy; ANCA has high predictive value (90%) in active glomerulonephritis but lower value (30–60%) in isolated sinus/lung disease.
Management involves identifying and removing antigens, treating underlying diseases, and initiating immunosuppression (Glucocorticoids, Cyclophosphamide, Methotrexate, Rituximab).
Reduced-dose glucocorticoids are noninferior to standard-dose for GPA.
Cyclophosphamide requires monitoring for bladder toxicity; Methotrexate requires monitoring for hepatotoxicity and pneumonitis.
Rituximab requires mandatory Hepatitis B screening before initiation.
Differential diagnosis must exclude infections (e.g., endocarditis, histoplasmosis) and malignancies (e.g., lymphoma).
Primary Central Nervous System Vasculitis (PCNSV) is characterized by 'beading' on cerebral arteriograms.

DEFINITION & OVERVIEW¶

• Definition: A clinicopathologic process characterized by inflammation and damage to blood vessels, leading to compromised lumen and tissue ischemia. • Scope: Can be the primary/sole manifestation of a disease or a secondary component of another disease; can be localized (e.g., skin) or multisystemic. • Classification (Table 375-1): • Primary Vasculitis Syndromes: Granulomatosis with polyangiitis (GPA), Microscopic polyangiitis (MPA), Eosinophilic granulomatosis with polyangiitis (EGPA/Churg-Strauss), IgA vasculitis (Henoch-Schönlein), Cryoglobulinemic vasculitis, Polyarteritis nodosa (PAN), Kawasaki disease, Giant cell arteritis (GCA), Takayasu arteritis, Behçet’s disease, Cogan’s syndrome, Single-organ vasculitis, Cutaneous leukocytoclastic angiitis, Cutaneous arteritis, Primary central nervous system vasculitis, Isolated aortitis. • Secondary Vasculitis Syndromes: Drug-induced, Infection-associated (HCV, HBV), Cancer-associated, and those associated with systemic disease (Lupus, Rheumatoid, Sarcoid).

ETIOLOGY & PATHOPHYISIOLOGY¶

• General Mechanism: Often mediated by immunopathogenic mechanisms in response to antigenic stimuli; influenced by genetic predisposition and environmental factors. • Immune-Complex Mediated (Table 375-2): • Associated Syndromes: IgA vasculitis, Lupus vasculitis, Serum sickness/cutaneous vasculitis, HCV-associated cryoglobulinemic vasculitis, HBV-associated vasculitis. • Mechanism: Antigen-antibody complexes form in antigen excess → deposit in vessel walls (permeability increased by histamine, bradykinin, leukotrienes) → activation of complement (C5a) → neutrophil infiltration → release of enzymes causing tissue damage. • ANCA-Associated Vasculitis: • cANCA (Cytoplasmic): Targets Proteinase-3 (29-kDa); associated with GPA (>90% of active cases). • pANCA (Perinuclear): Targets Myeloperoxidase; associated with MPA, EGPA, isolated necrotizing crescentic glomerulonephritis, and some GPA. • Pathogenic T Lymphocyte Responses & Granuloma Formation: • Mechanism: Cytokines like IFN-γ activate HLA class II on endothelial cells → interaction with CD4+ T lymphocytes. Endothelial cells secrete IL-1 (activating T lymphocytes). IL-1 and TNF-α induce adhesion molecules (ELAM-1, VCAM-1) to enhance leukocyte adhesion. • Associated Syndromes: Giant cell arteritis, Takayasu arteritis, GPA, EGPA.

CLINICAL FEATURES¶

• General Warning Signs: Palpable purpura, pulmonary infiltrates, microscopic hematuria, chronic sinusitis, mononeuritis multiplex, unexplained ischemic events, and glomerulonephritis with multisystem disease. • Granulomatosis with Polyangiitis (GPA): • Epidemiology: Prevalence 3 per 100,000; mean age of onset 40–60 years; rare in blacks; ~15% are <19 years old. • Upper Airway (95%): Paranasal sinus pain/drainage, purulent/bloody nasal discharge, mucosal ulceration, saddle nose deformity. • Lung (85–90%): Cough, hemoptysis, dyspnea; imaging shows multiple, bilateral, nodular or cavitary infiltrates. • Eye (52%): Conjunctivitis to sclerouveitis, proptosis. • Skin (46%): Papules, vesicles, palpable purpura, ulcers, subcutaneous nodules. • Renal (77%): Focal/segmental glomerulitis → rapidly progressive crescentic glomerulonephritis; primary cause of mortality. • Other: Arthralgias/arthritis (67%), Fever (50%), Cough (46%), Skin abnormalities (46%). • GPA Manifestation Frequency (Table 375-5): • Glomerulonephritis: 18% at onset → 77% throughout course. • Sinusitis: 51% at onset → 85% throughout course. • Polyarteritis Nodosa (PAN) (Table 375-6): • Renal (60%): Renal failure, hypertension. • Skin (43%): Rash, purpura, nodules, cutaneous infarcts, livedo reticularis, Raynaud’s phenomenon. • Takayasu Arteritis (Table 375-7): • Subclavian: 93% abnormality → Arm claudication, Raynaud’s. • Abdominal aorta: 47% abnormality → Abdominal pain, nausea, vomiting. • Aortic arch/root: 35% abnormality → Aortic insufficiency, heart failure. • Coronary: <10% abnormality → Chest pain, myocardial infarction.

DIFFERENTIAL DIAGNOSIS¶

• General Rule: Exclude infections and malignancies before initiating immunosuppression. • Infectious Mimics (Table 375-3): • Bacterial endocarditis, Disseminated gonococcal infection, Pulmonary histoplasmosis, Coccidioidomycosis, Syphilis, Lyme disease, Rocky Mountain spotted fever, Whipple’s disease. • Non-Infectious Mimics (Table 375-3): • Coagulopathies: Antiphospholipid syndrome, Thrombotic thrombocytopenic purura. • Neoplasms: Atrial myxoma, Lymphoma, Carcinomatosis. • Drug Toxicity: Cocaine, Levamisole (causes cutaneous infarction), Amphetamines, Ergot alkaloids, Methysergide, Arsenic. • Other: Sarcoidosis, Atheroembolic disease, Goodpasture’s syndrome, Amyloidosis, Fibromuscular dysplasia, Segmental arterial mediolysis (SAM), Reversible cerebral vasoconstrictive syndrome.

DIAGNOSTIC APPROACH¶

Clinical Presentation: Identify systemic signs (purpura, infiltrates, hematuria) and local findings (sinusitis, lung nodules).
Laboratory & Imaging: • ANCA Testing: High specificity for GPA if positive in active glomerulonephritis (90%); lower predictive value (30–60%) in isolated lung/sinus disease. • Imaging: Cerebral arteriogram to identify 'beading' in PCNSV; CT scan for pulmonary infiltrates/cavities.
Tissue Biopsy: • Primary tool to rule out infection or malignancy. • Lung: High yield for granulomatous vasculitis. • Renal: Confirms pauci-immune glomerulonephritis.
Decision Logic (Flowchart 375-1): • Step 1: Categorize to specific syndrome → Determine extent and severity of disease. • Step 2: Look for antigen? (e.g., GPA, PAN, Takayasu) • Yes → Remove antigen → Treat vasculitis. • No → Treat underlying disease. • Step 3: Look for underlying disease? (e.g., infection) • Yes → Treat underlying disease. • No → Treat vasculitis. • Step 4: Treatment Loop → Treat vasculitis → Syndrome resolves? • No → Continue treatment. • Yes → No further action.

MANAGEMENT & TREATMENT¶

Initial Strategy: • Identify and remove offending antigens (if applicable). • Treat underlying diseases (infection, malignancy, connective tissue disease). • Initiate immediate glucocorticoids/immunosuppressants for severe systemic vasculitis to prevent irreversible organ damage.
Specific Medications & Monitoring (Table 375-4): • Glucocorticoids: • Risk: Osteoporosis, Cataracts, Glaucoma, Diabetes, Infection, Cushingoid features. • Note: Reduced-dose glucocorticoids are noninferior to standard-dose in GPA. • Cyclophosphamide: • Administration: Take all at once in morning with large amount of fluid (reduce bladder injury). • Monitoring: Bladder cancer risk; monitor CBC every 1–2 weeks for first 2 months, then monthly. • Methotrexate: • Dosage: Often given with folic acid (1 mg daily) or folinic acid (5–10 mg weekly). • Contraindication: Renal insufficiency. • Monitoring: Hepatotoxicity, Pneumonitis. Monitor for 1–2 weeks for the first 2 months after initiation. • Rituximab: • Precaution: Risk of infusion reactions; use premedications. • Screening: Mandatory screening for Hepatitis B before use. • Monitoring: Toxicity/hyperlipidemia every 3–6 weeks for 6 months, then every 3 months. • Other Agents: • Mepolizumab (EGPA). • Azathioprine: Check TPMT levels prior to start. • Tocilizumab/Sarilumab: Monitor for cytopenias and hepatotoxicity.
Infection Prophylaxis: • Risk of Pneumocystis jirovecii and other fungi even with normal WBC counts. • Recommendation: TMP-SMX for GPA/MPA patients on glucocorticoids + immunosuppressants; continue if on Rituximab or with persistent lymphopenia.

COMPLICATIONS & PROGNOSIS¶

• Relapse Risk: 50–70% of remissions are associated with one or more relapses. • ANCA Correlation: ANCA titers do not correlate well with disease activity. • Venous Events: Patients with GPA have an increased incidence of venous thrombotic events (DVT/PE).

KEY PEARLS & CLINICAL TRAPS¶

• GPA Triad: Upper respiratory, lower respiratory, and glomerulonephritis. • ANCA Specificity: cANCA (PR3) → GPA; pANCA (MPO) → MPA/EGPA. • Diagnostic Thresholds: ANCA predictive value is 90% in renal disease but only 30–60% in lung/sinus disease. • Cyclophosphamide Safety: Morning dose + high fluid intake to prevent bladder injury. • Rituximab Safety: Mandatory Hep B screening before initiation. • PCNSV Finding: 'Beading' on cerebral arteriogram.

Reference Tables¶

TABLE 375-2 Potential Mechanisms of Vessel Damage in Vasculitis Syndromes Pathogenic immune-complex formation and/or…¶

Harrison's 22e, p.2893

375	The Vasculitis Syndromes Carol A. Langford, Anthony S. Fauci

TABLE 375-2 Potential Mechanisms of Vessel Damage in Vasculitis Syndromes

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
Production of antineutrophilic cytoplasmic antibodies
Granulomatosis with polyangiitis
Microscopic polyangiitis
Eosinophilic granulomatosis with polyangiitis (Churg-Strauss)
Pathogenic T lymphocyte responses and granuloma formation
Giant cell arteritis
Takayasu arteritis
Granulomatosis with polyangiitis
Eosinophilic granulomatosis with polyangiitis (Churg-Strauss)

TABLE 375-1 Vasculitis Syndromes¶

Harrison's 22e, p.2893

PRIMARY VASCULITIS SYNDROMES

SECONDARY VASCULITIS
SYNDROMES

Granulomatosis with polyangiitis
Microscopic polyangiitis
Eosinophilic granulomatosis with
polyangiitis (Churg-Strauss)
IgA vasculitis (Henoch-Schönlein)
Cryoglobulinemic vasculitis
Polyarteritis nodosa
Kawasaki disease
Giant cell arteritis
Takayasu arteritis
Behçet’s disease
Cogan’s syndrome
Single-organ vasculitis
Cutaneous leukocytoclastic angiitis
Cutaneous arteritis
P rimary central nervous system
vasculitis
Isolated aortitis

Vasculitis associated with probable
etiology
Drug-induced vasculitis
Hepatitis C virus–associated
cryoglobulinemic vasculitis
Hepatitis B virus–associated
vasculitis
Cancer-associated vasculitis
Vasculitis associated with systemic
disease
Lupus vasculitis
Rheumatoid vasculitis
Sarcoid vasculitis
Others

TABLE 375-3 Conditions That Can Mimic Vasculitis Infectious Diseases¶

Harrison's 22e, p.2894

Infectious Diseases
Bacterial endocarditis
Disseminated gonococcal infection
Pulmonary histoplasmosis
Coccidioidomycosis
Syphilis
Lyme disease
Rocky Mountain spotted fever
Whipple’s disease
Coagulopathies/Thrombotic Microangiopathies
Antiphospholipid syndrome
Thrombotic thrombocytopenic purpura
Neoplasms
Atrial myxoma
Lymphoma
Carcinomatosis
Drug Toxicity
Cocaine
Levamisole
Amphetamines
Ergot alkaloids
Methysergide
Arsenic
Other
Sarcoidosis
Atheroembolic disease
Antiglomerular basement membrane disease (Goodpasture’s syndrome)
Amyloidosis
Migraine
Fibromuscular dysplasia
Heritable disorders of connective tissue
Segmental arterial mediolysis (SAM)
Reversible cerebral vasoconstrictive syndrome

TABLE 375-4 Major Toxic Side Effects of Drugs Used in the Treatment of Vasculitis a¶

Harrison's 22e, p.2896

CONVENTIONAL IMMUNOSUPPRESSIVE AGENTS
Glucocorticoids
Osteoporosis Cataracts Glaucoma Diabetes mellitus Electrolyte abnormalities Metabolic abnormalities Severe and opportunistic infections Cushingoid features	Growth suppression in children Hypertension Avascular necrosis of bone Myopathy Alterations in mood Psychosis Pseudotumor cerebri Peptic ulcer diathesis Pancreatitis
Cyclophosphamide
Methotrexate
Gastrointestinal intolerance Stomatitis Bone marrow suppression Hepatotoxicity (may lead to fibrosis or cirrhosis)	Pneumonitis Teratogenicity Severe and opportunistic infections
Azathioprine
Mycophenolate mofetil
Bone marrow suppression Gastrointestinal intolerance	Severe and opportunistic infections Teratogenicity
BIOLOGIC AGENTS AND SMALL-MOLECULE INHIBITORS
Rituximab (granulomatosis with polyangiitis and microscopic polyangiitis)
Tocilizumab (giant cell arteritis) Sarilumab (polymyalgia rheumatica)
Bone marrow suppression Hepatotoxicity Hyperlipidemia	Severe and opportunistic infections Gastrointestinal perforation Hypersensitivity reactions
Mepolizumab (eosinophilic granulomatosis with polyangiitis [Churg-Strauss])
Apremilast (Behçet’s syndrome; see Chap. 376)
Diarrhea, nausea, and vomiting Depression	Weight decrease
Avacopan (severe granulomatosis with polyangiitis and microscopic polyangiitis)

TABLE 375-5 Granulomatosis with Polyangiitis: Frequency of Clinical Manifestations in 158 Patients Studied at the…¶

Harrison's 22e, p.2897

MANIFESTATION	PERCENTAGE AT DISEASE ONSET	PERCENTAGE THROUGHOUT COURSE OF DISEASE
Kidney
Glomerulonephritis	18	77
Ear/Nose/Throat	73	92
	51 36 25 14 1 9 3
Lung	45	85
Pulmonary infiltrates Pulmonary nodules Hemoptysis Pleuritis	25 24 12 10	66 58 30 28
Eyes
Othera
Arthralgias/arthritis Fever Cough Skin abnormalities Weight loss (>10% body weight) Peripheral neuropathy Central nervous system disease Pericarditis Hyperthyroidism	32 23 19 13 15 1 1 2 1	67 50 46 46 35 15 8 6 3

Harrison's 22e, p.2901

ORGAN SYSTEM	PERCENT INCIDENCE	CLINICAL MANIFESTATIONS
Renal	60	Renal failure, hypertension
	64
Peripheral nervous system	51	Peripheral neuropathy, mononeuritis multiplex
	44
Skin	43	Rash, purpura, nodules, cutaneous infarcts, livedo reticularis, Raynaud’s phenomenon
	36
Genitourinary	25	Testicular, ovarian, or epididymal pain
	23

TABLE 375-7 Frequency of Arteriographic Abnormalities and Potential Clinical Manifestations of Arterial Involvement in…¶

Harrison's 22e, p.2903

ARTERY	PERCENTAGE OF ARTERIOGRAPHIC ABNORMALITIES	POTENTIAL CLINICAL MANIFESTATIONS
Subclavian	93	Arm claudication, Raynaud’s phenomenon
	58
Abdominal aortaa	47	Abdominal pain, nausea, vomiting
	38
Aortic arch or root	35	Aortic insufficiency, congestive heart failure
	35
Coeliac axisa	18	Abdominal pain, nausea, vomiting
	18
Iliac	17	Leg claudication
	10–40
Coronary	<10	Chest pain, myocardial infarction