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Small-Vessel Vasculitis: ANCA-Associated & Immune-Complex

Name: Small-Vessel Vasculitis: ANCA-Associated & Immune-Complex
Creator: Veli Bakalov, MD

ANCA or immune complex—the pattern of injury picks the therapy

Rheumatology·Vasculitis & Systemic Inflammatory Disease·6 min read·9 high-yield points·Reviewed by Veli Bakalov, MD @HemeOncBuddy

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Palpable purpura, mononeuritis multiplex, RBC-cast glomerulonephritis, and alveolar hemorrhage are the clues to small-vessel vasculitis.
GPA: PR3/c-ANCA, destructive sinonasal disease with saddle nose, subglottic stenosis, cavitating lung nodules, necrotizing granulomas, pauci-immune crescentic GN.
MPA: MPO/p-ANCA with alveolar hemorrhage and GN but no granulomas or ENT disease.
EGPA: adult-onset asthma, nasal polyps, eosinophilia, mononeuritis multiplex, and cardiomyopathy; ANCA-positive (MPO) in only ~40%.
Pulmonary–renal syndrome: send ANCA, anti-GBM, ANA/dsDNA, and complements; linear IF = anti-GBM, granular = lupus, scant = ANCA vasculitis.
Hydralazine, propylthiouracil, minocycline, and levamisole-cut cocaine cause drug-induced ANCA vasculitis—stop the drug first.
Induction: glucocorticoids + rituximab (preferred) or cyclophosphamide (mesna for cystitis; bladder cancer, infertility) ± avacopan; maintain with rituximab or azathioprine; TMP-SMX for PJP.
HCV cryoglobulinemic vasculitis: purpura, arthralgia, neuropathy, MPGN, positive RF, very low C4 → direct-acting antivirals, rituximab if severe.
Urticarial vasculitis: burning wheals lasting >24 hours that leave bruising; low complement suggests SLE.

Recognizing small-vessel vasculitis

The four clues. Inflamed capillaries, venules, and arterioles produce a recognizable set of findings: palpable, nonblanching purpura (usually on dependent legs); mononeuritis multiplex (asymmetric, stepwise infarcts of named nerves such as the peroneal nerve, causing foot drop); glomerulonephritis with dysmorphic red cells and RBC casts; and alveolar hemorrhage (hemoptysis, a falling hemoglobin, diffuse infiltrates). Constitutional symptoms—fever, weight loss, arthralgias—and a high ESR and CRP are common.

Two families. ANCA-associated vasculitis (granulomatosis with polyangiitis, microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis) is pauci-immune: immunofluorescence shows few or no immune deposits, and complement is usually normal. Immune-complex vasculitis shows granular deposits—IgA-dominant in IgA vasculitis, IgM/IgG with complement in cryoglobulinemic and urticarial vasculitis—and some forms lower complement. ANCA disease needs immunosuppression; immune-complex disease often needs its driver (HCV, a drug, an infection) removed first.

Urinalysis with microscopy and creatinineDysmorphic RBCs and RBC casts signal GN; a rising creatinine means RPGN
SerologiesPR3- and MPO-ANCA by antigen-specific immunoassay, anti-GBM, ANA/dsDNA, C3/C4, cryoglobulins, hepatitis B and C
ImagingChest CT for nodules, cavities, or hemorrhage
Biopsy an involved organKidney biopsy shows pauci-immune necrotizing crescentic GN and separates active inflammation from scarring; skin biopsy with direct IF for purpura

c-ANCA (cytoplasmic staining) corresponds to PR3 and p-ANCA (perinuclear) to MPO, but perinuclear staining is nonspecific (it occurs in ulcerative colitis and primary sclerosing cholangitis), so confirm with PR3/MPO immunoassays. In a critically ill patient, start treatment without waiting for the biopsy.

ANCA-associated vasculitis: GPA, MPA, EGPA

Granulomatosis with polyangiitis. GPA begins in the upper airway: chronic sinusitis, bloody nasal crusting, otitis media, and septal perforation leading to saddle-nose deformity, plus subglottic stenosis (stridor) and orbital masses with proptosis. The lungs develop multiple, often cavitating nodules, infiltrates, or alveolar hemorrhage, and the kidneys develop pauci-immune necrotizing crescentic GN presenting as RPGN. Biopsy shows necrotizing granulomatous inflammation with vasculitis. PR3-ANCA is present in most generalized cases, and PR3 disease relapses more often.

Microscopic polyangiitis. MPA is an MPO-ANCA vasculitis without granulomas or destructive ENT disease. Pulmonary capillaritis causes alveolar hemorrhage, and GN develops in most patients; purpura and mononeuritis multiplex also occur, and some patients present with pulmonary fibrosis.

Eosinophilic GPA. EGPA evolves from adult-onset asthma and nasal polyps, to eosinophilia (often >1,500/μL or >10%) with migratory infiltrates, to vasculitis with mononeuritis multiplex, purpura, and eosinophilic myocarditis or cardiomyopathy—the main cause of death. ANCA (usually MPO) is found in only about 40%: ANCA-positive patients have more GN, neuropathy, and purpura, whereas ANCA-negative patients have more heart and lung disease. Allergic bronchopulmonary aspergillosis and chronic eosinophilic pneumonia cause asthma with eosinophilia but not mononeuritis multiplex, and parasitic causes such as Strongyloides should be excluded before high-dose steroids.

ANCA-associated vasculitides

Feature	GPA	MPA	EGPA
ANCA	PR3 (c-ANCA) in most	MPO (p-ANCA)	MPO in ~40%
Granulomas	Yes, necrotizing	No	Yes, eosinophil-rich
ENT/airway	Destructive sinusitis, saddle nose, subglottic stenosis	Spared	Asthma, nasal polyps
Lung	Cavitating nodules, hemorrhage	Alveolar hemorrhage, fibrosis	Migratory infiltrates
Signature risk	Relapse (PR3)	Renal failure	Cardiomyopathy

All three can cause pauci-immune GN, purpura, and mononeuritis multiplex; check troponin, ECG, and echocardiogram in every EGPA patient, ANCA-positive or not.

Drug-induced ANCA and the pulmonary–renal differential

Drug-induced ANCA vasculitis. Hydralazine, propylthiouracil, minocycline, and levamisole-adulterated cocaine can induce ANCA vasculitis, typically with very high MPO titers and often dual MPO/PR3 positivity. Levamisole causes retiform purpura and necrosis of the ears and cheeks with neutropenia. Stopping the drug is the essential first step; glucocorticoids (± rituximab) are added when disease is organ-threatening.

Pulmonary–renal syndrome. Alveolar hemorrhage with RPGN demands urgent, parallel testing, because treatment differs by cause. Start pulse steroids (± plasma exchange) while results return.

Causes of pulmonary–renal syndrome

Cause	Serology	Kidney IF	Complement
GPA / MPA	PR3- or MPO-ANCA	Scant (pauci-immune)	Normal
Anti-GBM disease	Anti-GBM antibody; up to a third also ANCA-positive	Linear IgG along the GBM	Normal
SLE	ANA, anti-dsDNA	Granular "full-house" deposits	Low C3 and C4

Anti-GBM pulmonary hemorrhage classically affects young male smokers.

Treating ANCA-associated vasculitis

Induction. For organ- or life-threatening GPA or MPA, give pulse IV methylprednisolone followed by tapering prednisone, plus rituximab or cyclophosphamide. Rituximab is preferred: it is as effective as cyclophosphamide, better in relapsing disease, and spares fertility. Reduced-dose steroid tapers lower infection rates. Non-severe GPA (e.g., sinus-limited) can be induced with methotrexate plus steroids. Severe EGPA is treated similarly, while the anti-IL-5 antibody mepolizumab spares steroids in relapsing or refractory EGPA.

Cyclophosphamide toxicity: hemorrhagic cystitis from the metabolite acrolein (prevent with mesna and hydration), transitional cell bladder cancer years later (cystoscopy for unexplained hematuria), infertility and premature ovarian failure, myelosuppression, and infection. Monitor CBC and urinalysis.

Steroid sparing and plasma exchange. Avacopan, an oral C5a-receptor antagonist, permits faster glucocorticoid withdrawal with remission rates at least as good as a standard taper; monitor liver tests. Plasma exchange is no longer routine and is reserved for selected severe cases—rapidly worsening or dialysis-requiring kidney failure, or coexisting anti-GBM antibodies.

Maintenance. After remission, rituximab every 6 months (fewer relapses than azathioprine) or azathioprine is continued for about 2–4 years. Follow patients for relapse, infection, and bladder cancer.

Prophylaxis. Give trimethoprim-sulfamethoxazole for Pneumocystis prophylaxis during induction (dapsone or atovaquone if intolerant), screen for hepatitis B before rituximab, and protect bone during steroid therapy.

Immune-complex small-vessel vasculitis

Cryoglobulinemic vasculitis. Mixed cryoglobulins—type II (monoclonal IgM with rheumatoid-factor activity bound to polyclonal IgG) or type III (polyclonal)—arise mostly from hepatitis C. They cause purpura, arthralgia, weakness, peripheral neuropathy, and membranoproliferative GN. RF is positive and C4 is very low, with C3 near normal. Cryoglobulin samples must be kept at 37°C; cooling precipitates the proteins and gives a false-negative result. Treat HCV with direct-acting antivirals; add rituximab for severe disease and plasma exchange for life-threatening disease.

Adult IgA vasculitis. Palpable purpura on the legs and buttocks, arthralgia, colicky abdominal pain, and IgA nephritis. Compared with children, adults have more severe and persistent renal disease and more progression to CKD. Direct IF of skin shows IgA in small-vessel walls (and mesangial IgA in the kidney). Glucocorticoids are used for severe GI or renal disease.

Drug- or infection-triggered leukocytoclastic vasculitis. Palpable purpura appears about 1–3 weeks after a new drug (β-lactams including cephalosporins, sulfonamides) or an infection. Punch-biopsy a lesion less than 48 hours old for H&E and direct IF; leukocytoclasia means neutrophil nuclear dust around small venules with fibrinoid necrosis and extravasated red cells. Check urinalysis and creatinine for systemic involvement, then remove the trigger—skin-limited disease resolves over weeks without immunosuppression.

Urticarial vasculitis. Wheals that burn or hurt, persist beyond 24 hours, and fade with purpura or hyperpigmentation, unlike ordinary urticaria, which itches and clears within 24 hours without a trace. Antihistamines and omalizumab (therapies for chronic urticaria) do not control it; biopsy shows leukocytoclastic vasculitis. The hypocomplementemic form (anti-C1q antibodies) signals systemic disease—SLE, angioedema, arthritis, obstructive lung disease, uveitis, and GN. Options include dapsone, colchicine, hydroxychloroquine, and glucocorticoids.