Small-Vessel & Variable-Vessel Vasculitides
ANCA or immune complexes: read the vessel wall, name the disease
Classification and how ANCA injure vessels
Vessel size. Small-vessel vasculitis targets arterioles, capillaries and postcapillary venules, so its footprints are palpable purpura (red cells leak from inflamed dermal venules), glomerulonephritis, alveolar hemorrhage and mononeuritis multiplex. Medium-vessel disease such as polyarteritis nodosa causes nodules, livedo, infarcts and aneurysms instead. Behçet disease is a variable-vessel vasculitis that can inflame arteries and veins of any size.
Two immunologic families. Pauci-immune ANCA-associated vasculitis (GPA, MPA, EGPA) shows few or no immunoglobulin or complement deposits on immunofluorescence (IF) and a neutrophil-driven necrotizing crescentic GN. Immune-complex vasculitis (IgA vasculitis, cryoglobulinemic vasculitis, drug- or infection-triggered cutaneous vasculitis) shows granular immunoglobulin and complement, with deposit-rich GN such as mesangial IgA or membranoproliferative GN (MPGN). Anti-GBM disease gives a linear rather than granular pattern.
ANCA pathogenesis. ANCA target two neutrophil granule enzymes, proteinase 3 (PR3) and myeloperoxidase (MPO). NETs carry both antigens and feed further autoantibody production, and C5a from the alternative complement pathway amplifies the attack.
- PrimingTNF, often from an infection, moves PR3/MPO to the neutrophil surface
- ANCA bindingFab binds PR3 or MPO; Fc engages Fcγ receptors
- ActivationDegranulation, oxidative burst, neutrophil extracellular traps (NETs)
- InjuryFibrinoid necrosis of small vessels, glomerular crescents, pulmonary capillaritis
Serology. On ethanol-fixed neutrophils, cytoplasmic staining (c-ANCA) corresponds to anti-PR3 and typifies GPA; perinuclear staining (p-ANCA) corresponds to anti-MPO and typifies MPA and EGPA. The perinuclear pattern is a fixation artifact (cationic MPO drifts onto the negatively charged nucleus), and PR3/MPO immunoassays confirm the target. An atypical p-ANCA not directed at MPO accompanies ulcerative colitis and primary sclerosing cholangitis. Hydralazine, propylthiouracil, minocycline and levamisole-adulterated cocaine induce MPO-ANCA vasculitis; anti-histone antibodies instead mark drug-induced lupus, which rarely involves the kidney.
The ANCA-associated vasculitides
Granulomatosis with polyangiitis. GPA combines necrotizing granulomas of the upper and lower airways with pauci-immune crescentic GN (ELK: ENT, lung, kidney). Expect chronic sinusitis, otitis media, bloody nasal crusting, septal perforation with saddle nose, subglottic stenosis, orbital pseudotumor with proptosis, scleritis and "strawberry" gums; multiple cavitating lung nodules with hemoptysis; and hematuria with RBC casts from rapidly progressive GN (RPGN). Biopsy shows geographic necrosis with palisading histiocytes and giant cells. PR3-ANCA is found in most patients with active generalized disease.
Microscopic polyangiitis. MPA is the same vasculitis without granulomas, asthma or destructive upper-airway disease. Pulmonary capillaritis (diffuse alveolar hemorrhage) plus necrotizing GN (RPGN) makes it a classic pulmonary-renal syndrome; purpura and mononeuritis multiplex are common, and most patients carry MPO-ANCA.
Eosinophilic GPA (Churg-Strauss). EGPA moves from an allergic phase (adult-onset asthma, allergic rhinitis, nasal polyps) to an eosinophilic phase (eosinophilia >10%, migratory lung infiltrates, eosinophilic gastroenteritis) to eosinophil-rich necrotizing granulomatous vasculitis with mononeuritis multiplex (foot or wrist drop) and purpura. IgE is high, and only ~40% have ANCA (usually MPO). ANCA-positive patients have more GN and neuropathy; ANCA-negative patients have more heart disease (eosinophilic myocarditis, cardiomyopathy, pericarditis, coronary vasculitis), the leading cause of death. Montelukast has been linked to onset, probably by letting asthma steroids be tapered and unmasking the disease. Glucocorticoids are the backbone; mepolizumab (anti-IL-5) spares steroids in relapsing disease.
| Feature | GPA | MPA | EGPA |
|---|---|---|---|
| Usual ANCA | PR3 (c-ANCA) in most | MPO (p-ANCA) in most | MPO in ~40% |
| Granulomas | Necrotizing | None | Eosinophil-rich |
| Upper airway | Sinusitis, saddle nose | Minimal | Rhinitis, nasal polyps |
| Lung | Cavitating nodules | Alveolar hemorrhage | Asthma, migratory infiltrates |
| Kidney | Crescentic GN, common | Crescentic GN, very common | Less frequent, milder |
Immune-complex small-vessel vasculitis
IgA vasculitis (Henoch-Schönlein purpura). The most common childhood systemic vasculitis (ages 3–15) usually follows an upper respiratory infection. Galactose-deficient IgA1 immune complexes lodge in dermal venules and the mesangium, producing palpable purpura on the buttocks and legs, knee and ankle arthralgia, colicky abdominal pain (bowel-wall hemorrhage and edema, GI bleeding, ileoileal intussusception) and IgA nephropathy-like GN with hematuria. Platelets and coagulation are normal, unlike ITP (antibodies to glycoprotein IIb/IIIa), HUS/TTP (schistocytes; ADAMTS13 deficiency in TTP) or leukemia (blasts). Skin biopsy shows leukocytoclastic vasculitis with IgA on direct IF. Most cases are self-limited with supportive care; kidney involvement sets the long-term prognosis, and adults fare worse.
Cryoglobulinemic vasculitis. Type II mixed cryoglobulins, usually driven by hepatitis C, are complexes of monoclonal IgM with rheumatoid factor activity bound to polyclonal IgG; they precipitate in the cold and deposit in small vessels. The Meltzer triad is purpura, arthralgia and weakness; neuropathy and MPGN are common. Classical-pathway activation leaves C4 very low with C3 near normal, and RF is positive. Treat HCV with direct-acting antivirals, adding rituximab for severe vasculitis. Type I cryoglobulins (monoclonal only) come from Waldenström macroglobulinemia or myeloma and cause hyperviscosity and acral ischemia rather than true vasculitis.
Cutaneous (hypersensitivity) vasculitis. Crops of palpable purpura on the lower legs appear about 7–10 days after a new drug (β-lactams, sulfonamides, allopurinol, thiazides) or an infection. Biopsy shows neutrophils around postcapillary venules with fibrinoid necrosis, nuclear dust (leukocytoclasis) and extravasated red cells; stopping the drug usually clears it within weeks. Identical histology occurs in systemic vasculitides, so always check a urinalysis.
Anti-GBM contrast. Goodpasture disease is type II hypersensitivity against the NC1 domain of the α3 chain of type IV collagen in glomerular and alveolar basement membranes: linear IgG on IF, RPGN and pulmonary hemorrhage (smoking exposes the alveolar antigen). Treatment is urgent plasmapheresis with glucocorticoids and cyclophosphamide; some patients are also MPO-ANCA positive.
Behçet disease: a variable-vessel vasculitis
Clinical picture. Behçet disease affects young adults along the Silk Road (Turkey, Middle East, East Asia) and is linked to HLA-B51. Recurrent painful oral aphthae are joined by genital ulcers that tend to scar, uveitis (hypopyon or sight-threatening retinal vasculitis), erythema nodosum-like nodules and a positive pathergy test (sterile papule or pustule 24–48 hours after a needle prick).
Vessels of any size. Venous disease causes DVT, Budd-Chiari syndrome and cerebral venous thrombosis; pulmonary artery aneurysms can rupture with massive hemoptysis. Colchicine or apremilast (a PDE4 inhibitor) treats mucocutaneous disease; azathioprine or anti-TNF agents treat eye and major vessel disease.
Treatment principles and the PAN contrast
ANCA vasculitis therapy. Organ- or life-threatening disease is induced with high-dose glucocorticoids plus rituximab (anti-CD20 B-cell depletion) or cyclophosphamide and maintained with rituximab or azathioprine. Avacopan, an oral C5a receptor blocker, spares steroids, and TMP-SMX prevents Pneumocystis pneumonia.
Cyclophosphamide's metabolite acrolein causes hemorrhagic cystitis (prevent with mesna and hydration) and later bladder cancer; the drug also causes infertility and marrow suppression.
Polyarteritis nodosa. PAN is a necrotizing arteritis of medium-sized arteries: ANCA-negative, with no GN or capillaritis, and the lungs are spared. Renal and mesenteric microaneurysms cause renin-driven hypertension, infarcts and postprandial pain, alongside mononeuritis multiplex and livedo; the classic association is hepatitis B.
Purpura, RBC casts or alveolar hemorrhage point to small vessels; microaneurysms and infarcts without GN point to PAN.