6.8 The Vasculitides

1. Large-Vessel & Medium-Vessel Vasculitides

1. Giant Cell Arteritis (GCA / Temporal Arteritis)

• Epidemiology: Most common systemic vasculitis in adults; occurs exclusively in patients age >= 50 years (peak incidence 70–80 years), female predominance (2–3:1), Northern European ancestry.
• Clinical Presentation: New onset unilateral temporal headache, scalp tenderness (pain with brushing hair), jaw claudication (fatigue/pain in masseter muscles while chewing; highest positive likelihood ratio ~4.0 for GCA), tongue claudication, constitutional symptoms (fever, weight loss), and prominent tender, nodular, pulseless temporal arteries.
• Polymyalgia Rheumatica (PMR) Overlap: Up to 50% of GCA patients have concurrent PMR (symmetric aching and morning stiffness >45 min in shoulders, neck, and pelvic girdle without true muscle weakness; dramatic response to low-dose prednisone 15–20 mg/day).
• Catastrophic Complication: Ischemic Optic Neuropathy (Anterior Ischemic Optic Neuropathy [AION]) secondary to posterior ciliary artery occlusion. Presents as painless transient monocular vision loss (amaurosis fugax) rapidly progressing to permanent, irreversible blindness in the affected eye, with high risk of contralateral eye involvement within days if untreated.
• Diagnostic Workup:
  • Markedly elevated ESR (typically >50 to >100 mm/h) and elevated CRP; normocytic anemia and thrombocytosis.
  • Temporal Artery Biopsy (Gold Standard): Transmural granulomatous inflammation with mononuclear cell infiltration, internal elastic lamina disruption, and multinucleated giant cells. Biopsy segment should be >=2–3 cm to avoid false negatives due to skip lesions.
  • Color Doppler Ultrasound: Demonstrates a hypoechoic circumferential mural edema around the temporal artery lumen ("halo sign").
• EMERGENCY Management Protocol:
  • MANDATORY Rule: Initiate immediate high-dose corticosteroids IMMEDIATELY upon clinical suspicion, BEFORE obtaining a temporal artery biopsy! Never delay steroid therapy for diagnostic testing.
  • Visual Symptoms Present: IV Methylprednisolone 1,000 mg daily for 3 consecutive days, followed by oral Prednisone 1 mg/kg/day (60 mg daily).
  • Uncomplicated GCA (No Visual Symptoms): Oral Prednisone 60 mg daily.
  • Biopsy remains histopathologically diagnostic up to 2 to 4 weeks after initiating steroids.
  • Steroid-Sparing Biologic: Tocilizumab (IL-6 receptor antagonist) is FDA-approved to maintain remission and reduce cumulative corticosteroid toxicity (GiACTA trial).

2. Takayasu Arteritis ("Pulseless Disease")

• Epidemiology: Granulomatous panarteritis targeting the aorta and its primary major branches. Predominantly affects young females (<40 years old), most frequently of Asian ancestry.
• Clinical Presentation: Early constitutional phase (fever, malaise, weight loss, night sweats) followed by vascular occlusive phase: upper extremity claudication, asymmetric peripheral pulses, blood pressure difference >10 mmHg between upper extremities, subclavian/carotid arterial bruits, lightheadedness, renovascular hypertension (renal artery stenosis), and aortic root dilation with aortic regurgitation.
• Diagnostics: Non-invasive CT Angiography (CTA) or Magnetic Resonance Angiography (MRA) demonstrating diffuse concentric vessel wall thickening, luminal narrowing, occlusion, and post-stenotic aneurysmal dilation of the aortic arch, subclavian, carotid, and renal arteries.
• Management: High-dose oral corticosteroids (Prednisone 1 mg/kg/day) + steroid-sparing immunosuppressive agents (Methotrexate, Azathioprine, Tocilizumab, or Anti-TNF biologics). Surgical revascularization or endovascular stenting is reserved for fixed, flow-limiting stenoses once active vascular inflammation is quiescent.

3. Polyarteritis Nodosa (PAN)

• Pathophysiology: Systemic necrotizing vasculitis targeting medium-sized muscular arteries, causing transmural fibrinoid necrosis, internal elastic lamina destruction, microaneurysm formation, vascular thrombosis, and downstream organ infarction. Characteristically SPARES the pulmonary circulation (no pulmonary involvement) and does not involve small arterioles/glomeruli (no glomerulonephritis).
• Etiology: Idiopathic, or secondary to Hepatitis B Virus (HBV) infection (~30% of secondary cases, driven by HBsAg-anti-HBs immune complex deposition), and rarely Hepatitis C or Hairy Cell Leukemia.
• Clinical Presentation:
  • Systemic: Fever, weight loss, malaise.
  • Renal: Renovascular hypertension (renal artery vasculitis leading to severe ischemia/renin release), flank pain from renal wedge infarctions. Note: Urinalysis shows minimal proteinuria without red cell casts (no GN).
  • Neurologic: Mononeuritis multiplex (asymmetric motor/sensory peripheral neuropathy, e.g., wrist drop [radial nerve] or foot drop [peroneal nerve]) in 50–70% of patients.
  • Gastrointestinal: Severe postprandial abdominal pain ("intestinal angina"), mesenteric ischemia, bowel perforation, cholecystitis.
  • Cutaneous: Livedo reticularis, painful subcutaneous nodules along arterial tracks, digital ischemia/gangrene, and lower extremity ulcerations.
  • Genitourinary: Testicular pain or tenderness (orchitis).
• Diagnostics: Negative ANCA (PAN is seronegative). Biopsy of symptomatic site (sural nerve, skin nodule, muscle) showing transmural necrotizing arteritis with fibrinoid necrosis. Mesenteric or Renal Angiography demonstrating multiple small aneurysms (microaneurysms 1–5 mm) and irregular segmental stenoses ("string of beads" appearance).
• Treatment:
  • Idiopathic PAN: Glucocorticoids (Prednisone 1 mg/kg/day); add Cyclophosphamide for severe, organ-threatening, or life-threatening disease (Five-Factor Score >=1).
  • HBV-Associated PAN: Short-term corticosteroids + plasma exchange + antiviral therapy with Entecavir or Tenofovir (avoids prolonged immunosuppression that exacerbates viral replication).

2. Small-Vessel Vasculitides

1. ANCA-Associated Vasculitides (AAV)

AAVs are characterized by necrotizing small-vessel vasculitis with few or no immune deposits (pauci-immune), strongly associated with Antineutrophil Cytoplasmic Antibodies (ANCA) targeting proteinase-3 (PR3) or myeloperoxidase (MPO).

| Feature | Granulomatosis with Polyangiitis (GPA / Wegener) | Microscopic Polyangiitis (MPA) | Eosinophilic Granulomatosis with Polyangiitis (EGPA / Churg-Strauss) | | :--- | :--- | :--- | | Serology | c-ANCA / PR3-ANCA positive (85–90%) | p-ANCA / MPO-ANCA positive (70–80%) | p-ANCA / MPO-ANCA positive (40–50%) (predominantly in patients with glomerulonephritis/neuropathy) | | Pathology | Necrotizing granulomatous inflammation of upper/lower respiratory tract + pauci-immune necrotizing crescentic glomerulonephritis. | Non-granulomatous necrotizing vasculitis of small vessels + pauci-immune necrotizing crescentic glomerulonephritis. | Eosinophil-rich necrotizing granulomatous inflammation involving respiratory tract + necrotizing vasculitis. | | Upper Airway | Severe destructive disease: chronic purulent/bloody rhinosinusitis, nasal crusting, saddle-nose deformity (nasal septal perforation), subglottic stenosis, mastoiditis, serous otitis media. | Lacks destructive upper airway disease. | Severe allergic rhinitis, nasal polyposis, chronic pansinusitis. | | Lower Airway | Multiple cavitary pulmonary nodules, thick-walled cavitary lesions, alveolar hemorrhage, cough, hemoptysis. | Diffuse alveolar hemorrhage without lung cavities; interstitial fibrosis. | Severe, adult-onset refractory asthma, transient migratory pulmonary infiltrates. | | Renal | Rapidly Progressive Glomerulonephritis (RPGN): hematuria, RBC casts, proteinuria, rapid doubling of creatinine. | RPGN (pauci-immune crescentic GN): identical to GPA. | Glomerulonephritis is less frequent and milder. | | Unique Features | Proptosis from retro-orbital pseudotumor. | Pure pulmonary-renal syndrome without granulomas or asthma. | Marked peripheral eosinophilia (>1,500/µL or >10%), mononeuritis multiplex (75%), eosinophilic myocarditis/cardiomyopathy (primary cause of mortality). | | Induction Therapy | High-dose Glucocorticoids + Rituximab (preferred) OR Cyclophosphamide.<br/>Avacopan (oral C5a receptor antagonist) to eliminate glucocorticoid toxicity. | High-dose Glucocorticoids + Rituximab OR Cyclophosphamide. | Mild: Glucocorticoids.<br/>Severe (FFS >=1): Glucocorticoids + Cyclophosphamide/Rituximab.<br/>Refractory/Asthma: Mepolizumab (Anti-IL-5). |

2. Immune-Complex Small-Vessel Vasculitides

Cryoglobulinemic Vasculitis

• Pathophysiology: Precipitation of circulating cryoglobulins (cold-insoluble immunoglobulins) in small vessels. Type II and Type III Mixed Cryoglobulinemia consist of immune complexes formed by polyclonal IgG and IgM with Rheumatoid Factor (RF) activity directed against the Fc portion of IgG.
• Etiology: Strongly associated with chronic Hepatitis C Virus (HCV) infection (>90% of cases); less commonly associated with SLE, Sjögren syndrome, or B-cell lymphoproliferative disorders.
• Classic Clinical Triad (Meltzer Triad):
  1. Palpable Purpura (predominantly on lower extremities, dependent areas).
  2. Arthralgias / Polyarthritis (non-erosive).
  3. Asthenia / Peripheral Neuropathy (sensorimotor polyneuropathy or mononeuritis multiplex).
• Renal Involvement: Membranoproliferative Glomerulonephritis (MPGN) with subendothelial immune deposits, hematuria, RBC casts, nephrotic/nephritic syndrome.
• Diagnostic Laboratory Profile:
  • Positive circulating serum cryoglobulins (cryocrit).
  • Markedly depressed Complement C4 with normal or mildly reduced C3.
  • Strongly positive Rheumatoid Factor (RF).
  • Positive HCV antibody and elevated HCV RNA viral load.
  • Skin biopsy showing leukocytoclastic vasculitis (LCV).
• Management:
  • Mild-to-Moderate Disease: Direct-Acting Antiviral (DAA) therapy (e.g., Sofosbuvir/Velpatasvir or Glecaprevir/Pibrentasvir) for HCV eradication leads to complete vasculitis remission.
  • Severe / Organ-Threatening Disease (Rapidly progressive MPGN, severe neuropathy, digital gangrene): Plasma exchange (plasmapheresis) to rapidly clear circulating cryoglobulins + Rituximab + systemic glucocorticoids, followed by DAA antiviral therapy once acute inflammation is controlled.

IgA Vasculitis (Henoch-Schönlein Purpura - HSP)

• Pathophysiology: Small-vessel leukocytoclastic vasculitis mediated by tissue deposition of IgA1-dominant immune complexes in dermal postcapillary venules, intestinal vessels, and renal mesangium. Frequently preceded by an upper respiratory tract infection.
• Classic Clinical Tetrad:
  1. Palpable Purpura: Non-thrombocytopenic purpura and petechiae distributed symmetrically over the lower extremities and buttocks.
  2. Arthralgias / Arthritis: Transient, non-migratory oligoarthritis of knees and ankles without joint destruction.
  3. Gastrointestinal Symptoms: Colicky, postprandial abdominal pain, nausea, vomiting, melena, and risk of intussusception in children/young adults.
  4. Renal Disease: IgA Nephropathy (Berger-like) presenting with microscopic or macroscopic hematuria, red cell casts, and proteinuria.
• Diagnostics: Normal platelet count and coagulation studies (rules out thrombocytopenic purpura). Skin punch biopsy demonstrates leukocytoclastic vasculitis with prominent granular perivascular IgA and C3 deposition on direct immunofluorescence (DIF).
• Management: Supportive care, hydration, and NSAIDs for mild disease and arthralgias. Systemic glucocorticoids (Prednisone 1 mg/kg/day) for severe abdominal pain or progressive glomerulonephritis.