Vasculitides

• Definition: A heterogeneous group of disorders defined by immune-mediated inflammation of blood vessel walls, producing luminal narrowing (ischemia) or wall destruction (aneurysm, rupture, hemorrhage). The organ pattern follows the caliber of vessel involved, which is why the Chapel Hill Consensus size-based scheme drives both the differential and the workup.
• Why it matters: Untreated large-vessel disease blinds; untreated ANCA-associated disease destroys kidneys within weeks; untreated Kawasaki disease scars coronary arteries for life. Nearly every vasculitis is a time-sensitive diagnosis in which empiric immunosuppression precedes biopsy confirmation.

Epidemiology worth recalling

• Giant cell arteritis: the most common systemic vasculitis of adults; essentially never occurs before age 50, incidence rises steeply with each decade, women affected more than men, and rates are highest in people of Northern European (especially Scandinavian) ancestry. Roughly half of patients have coexisting polymyalgia rheumatica.
• Kawasaki disease: the most common vasculitis of early childhood in the US after IgA vasculitis; peak incidence under age 5, boys slightly more than girls, markedly higher in children of Japanese and other East Asian ancestry. It is the leading cause of acquired heart disease in children in developed countries.
• IgA vasculitis (Henoch–Schönlein purpura): the most common childhood vasculitis worldwide, typically following an upper respiratory infection.
• ANCA-associated vasculitis (GPA, MPA, EGPA): uncommon, peak onset in middle-aged and older adults, White patients over-represented for GPA; MPA is relatively more frequent in East Asian populations.
• Takayasu arteritis: rare; classically women under 40, disproportionately Asian.
• Polyarteritis nodosa: now rare in the US, largely because hepatitis B vaccination and antiviral therapy removed its dominant trigger.

Infection-triggered (mechanism: immune complex deposition or molecular mimicry)

• Hepatitis B: the classic driver of polyarteritis nodosa; viral antigen–antibody complexes lodge in medium-artery walls and fix complement. Modifiable — vaccination and antiviral therapy have made HBV-PAN uncommon in the US.
• Hepatitis C: mixed cryoglobulinemic vasculitis; cryoprecipitating IgM rheumatoid factor–IgG complexes cause small-vessel injury.
• Preceding upper respiratory infection: precipitates IgA vasculitis in children via galactose-deficient IgA1 immune complexes.
• **Chronic nasal Staphylococcus aureus carriage**: associated with relapse in granulomatosis with polyangiitis.

Drug- and exposure-related (modifiable)

• Drug-induced ANCA vasculitis: hydralazine, propylthiouracil, minocycline, and levamisole-adulterated cocaine classically produce high-titer MPO/p-ANCA, often with antihistone or multiple autoantibodies. Withdrawal of the offending agent is part of therapy.
• Silica dust exposure and cigarette smoking: both associated with increased risk of ANCA-associated vasculitis.
• Levamisole cocaine additionally causes retiform purpura of the ears and neutropenia.

Host and genetic (non-modifiable — the stem's demographic clues)

• Age over 50: an absolute prerequisite for giant cell arteritis; GCA is linked to *HLA-DRB1\*04*.
• Age under 40 and female sex: Takayasu arteritis.
• Age under 5 and East Asian ancestry: Kawasaki disease, with susceptibility loci including ITPKC implicating calcineurin–NFAT signaling.
• Northern European ancestry: GCA and PR3-ANCA GPA; HLA-DP and alpha-1 antitrypsin (SERPINA1) variants associate with PR3 disease, since alpha-1 antitrypsin is the physiologic inhibitor of proteinase 3.
• Atopy/asthma: precedes eosinophilic granulomatosis with polyangiitis by years.

• Distractor to avoid: leukotriene receptor antagonists were historically blamed for EGPA, but the association is generally attributed to unmasking of underlying disease as steroids are tapered rather than direct causation.

Large-vessel disease (GCA, Takayasu) — granuloma at the internal elastic lamina

• Adventitial dendritic cells activated through toll-like receptors recruit CD4+ T cells that polarize along Th1 (IFN-γ) and Th17 (IL-17) lines. IFN-γ drives macrophage fusion into multinucleated giant cells, which cluster at the internal elastic lamina and fragment it with matrix metalloproteinases.
• Macrophage-derived PDGF and VEGF provoke myofibroblast migration and concentric intimal hyperplasia — the lumen occludes from the inside, so symptoms are ischemic (jaw claudication, vision loss, pulseless upper extremities) rather than hemorrhagic early on. Late loss of elastic lamina produces thoracic aortic aneurysm.
• IL-6 from the lesion drives fever, malaise, anemia of inflammation, thrombocytosis, and the markedly elevated ESR — and explains why IL-6 receptor blockade works and why it also abolishes CRP as a monitoring tool.
• Intracranial arteries lose most of their elastic tissue and vasa vasorum as they penetrate the dura, which is why GCA characteristically spares them and blinds via the posterior ciliary arteries rather than causing intracerebral vasculitis.

ANCA-associated small-vessel disease — a neutrophil respiratory burst against the endothelium

• Priming cytokines (TNF-α, C5a, infection) translocate PR3 or MPO from azurophilic granules onto the neutrophil surface. Circulating ANCA cross-links these antigens and Fcγ receptors, triggering degranulation, reactive oxygen species, and NETosis directly against capillary and venule endothelium.
• Released enzymes cause fibrinoid necrosis with few or no immune deposits — hence pauci-immune glomerulonephritis with crescents, and alveolar capillaritis producing hemoptysis.
• The alternative complement pathway amplifies the loop through C5a, the rationale for the C5a receptor antagonist avacopan.

Immune-complex and medium-vessel disease

• IgA vasculitis: galactose-deficient IgA1 complexes deposit in dermal, gut, and mesangial vessels, fixing complement via the alternative pathway.
• PAN: transmural necrotizing inflammation with fibrinoid necrosis of medium muscular arteries at branch points weakens the media, producing microaneurysms alternating with stenosis; a hallmark is that lesions in the same patient are of differing histologic age.
• Kawasaki disease: a necrotizing arteritis of the coronary and other medium arteries in which the lesions evolve largely synchronously, destroying the media and producing coronary aneurysms with subsequent myofibroblastic luminal narrowing.

Giant cell arteritis — the stem is a woman over 70 of Northern European descent

• New temporal or occipital headache with scalp tenderness (combing hair hurts) from inflamed superficial temporal artery; the vessel may be thickened, nodular, and pulseless.
• Jaw claudication: pain in the masseters that builds with chewing — the most specific symptom, reflecting demand ischemia through a stenosed maxillary artery.
• Amaurosis fugax or sudden painless monocular vision loss from arteritic anterior ischemic optic neuropathy; fundus shows a pallid, swollen disc. This is the emergency.
• Polymyalgia rheumatica overlap: proximal shoulder/hip girdle aching and morning stiffness without true weakness.
• Constitutional: fever of unknown origin, weight loss, anemia — all IL-6 driven.

Kawasaki disease — the stem is a toddler, often of East Asian ancestry

• Fever ≥5 days unresponsive to antipyretics, plus the CRASH features: Conjunctivitis (bilateral, nonexudative, limbal sparing), Rash (polymorphous, truncal, non-vesicular), Adenopathy (cervical, usually unilateral and large), Strawberry tongue with cracked red lips, and Hands/feet erythema and edema followed by periungual desquamation in the subacute phase.
• Extreme irritability, sterile pyuria, and a reactivated BCG scar are supporting clues.

Granulomatosis with polyangiitis

• Upper airway first: chronic sinusitis, otitis, epistaxis, nasal crusting, and ultimately saddle-nose deformity from septal cartilage destruction; subglottic stenosis presents as stridor or hoarseness.
• Lower airway: cough and hemoptysis with cavitary nodules; frank diffuse alveolar hemorrhage causes hypoxemia with a rising DLCO.
• Kidney: hematuria with dysmorphic RBCs and RBC casts, rising creatinine over days to weeks.

Cross-cutting findings

• Palpable purpura on dependent surfaces signals small-vessel disease.
• Mononeuritis multiplex (e.g., wrist drop plus contralateral foot drop) reflects vasa nervorum infarction and is a hallmark of PAN and EGPA.
• Livedo reticularis, digital gangrene, and new hypertension point to medium-vessel disease with renal artery involvement.

Step 1 — inflammatory screen and organ survey (all suspected vasculitis)

• ESR and CRP: markedly elevated in GCA and Takayasu; a completely normal ESR and CRP makes GCA unlikely though not impossible.
• CBC and chemistries: normocytic anemia, thrombocytosis, and in EGPA a striking peripheral eosinophilia.
• Urinalysis with microscopy is the single most important bedside test — dysmorphic RBCs and RBC casts identify glomerulonephritis and convert an outpatient workup into an urgent one.
• Chest imaging: CT for cavitary nodules (GPA) or fleeting infiltrates (EGPA).

Step 2 — serology

• ANCA by indirect immunofluorescence with antigen-specific PR3 and MPO ELISA; antigen specificity, not the staining pattern, is what current classification uses.
• Hepatitis B and C serologies, cryoglobulins, complement (C3/C4), and HIV to exclude secondary causes. Low complement argues against ANCA disease and for cryoglobulinemia or lupus.
• Do not order ANCA for suspected GCA, Takayasu, or Kawasaki — it is negative and misleads.

Step 3 — confirmation

• Temporal artery biopsy remains the reference standard for GCA; take a generous segment because inflammation is patchy (skip lesions), and biopsy remains informative for a couple of weeks after steroids are started — never delay treatment for it. The 2021 ACR/Vasculitis Foundation guideline favors biopsy over ultrasound in the US setting, while color Doppler halo sign and large-vessel cross-sectional imaging are accepted adjuncts.
• Tissue biopsy of the most accessible involved organ (kidney, skin, lung, nerve) for ANCA disease: pauci-immune necrotizing crescentic glomerulonephritis on immunofluorescence.
• Conventional or CT angiography for PAN (beads-on-a-string microaneurysms of renal/mesenteric arteries) and for Takayasu (long smooth stenoses of the aortic arch branches).
• Echocardiography at diagnosis and in follow-up is mandatory in Kawasaki disease per the AHA 2017 statement, with coronary dimensions expressed as body-surface-area–adjusted Z scores.

• Criteria: the ACR/EULAR 2022 classification criteria cover GCA, Takayasu, GPA, MPA, and EGPA; PAN is still classified using the older 1990 ACR criteria. All are classification, not diagnostic, criteria — apply them only after vasculitis is established and mimics excluded. Kawasaki disease uses the AHA clinical case definition (fever ≥5 days plus 4 of 5 principal features), with a supplemental laboratory algorithm for incomplete disease.

Immediate action — treat before you confirm

• Suspected GCA: start high-dose glucocorticoids the moment the diagnosis is entertained. Per the 2021 ACR/Vasculitis Foundation guideline, use IV pulse methylprednisolone when there is vision loss or amaurosis, and high-dose oral prednisone without visual involvement; arrange biopsy afterward. Vision already lost rarely returns — treatment protects the fellow eye.
• Diffuse alveolar hemorrhage or rapidly rising creatinine: airway/oxygenation support, pulse glucocorticoids, and urgent nephrology/rheumatology involvement.

Definitive immunosuppression by disease

• GCA: glucocorticoid taper plus IL-6 receptor antagonist (tocilizumab) as the preferred steroid-sparing agent (ACR/VF 2021); methotrexate is an alternative. Add low-dose aspirin only for specific ischemic indications, not routinely.
• Takayasu: glucocorticoids plus a nonglucocorticoid immunosuppressant, with TNF-α inhibitors or tocilizumab for refractory disease (ACR/VF 2021).
• Severe GPA/MPA: glucocorticoids plus rituximab (anti-CD20), which the ACR/VF 2021 guideline conditionally prefers over cyclophosphamide for both induction and maintenance. Avacopan, an oral C5a receptor antagonist, is an approved glucocorticoid-sparing adjunct. Plasma exchange is not routine — reserve it for selected severe renal disease or alveolar hemorrhage, reflecting PEXIVAS.
• EGPA: glucocorticoids; anti–IL-5 therapy (mepolizumab) for non-severe or relapsing disease, cyclophosphamide or rituximab when there is life-threatening organ involvement.
• PAN: glucocorticoids ± cyclophosphamide; if HBV-associated, antiviral therapy is central, with a short steroid course and plasma exchange rather than prolonged immunosuppression.
• Kawasaki: IVIG 2 g/kg as a single infusion plus aspirin, given within 10 days of fever onset (AHA 2017). Aspirin is switched to low-dose antiplatelet therapy once afebrile. Refractory fever after IVIG warrants a second IVIG dose, glucocorticoids, or infliximab.

Supportive and contraindicated

• Prophylaxis: Pneumocystis prophylaxis with trimethoprim-sulfamethoxazole during cyclophosphamide/rituximab-plus-steroid therapy, mesna and hydration with cyclophosphamide, calcium/vitamin D and bisphosphonate consideration for steroid-induced osteoporosis, and hepatitis B screening before rituximab.
• Avoid: revascularization or bypass during active large-vessel inflammation (restenosis risk); live vaccines during induction; delaying steroids in GCA for biopsy scheduling.

Disease complications — emergencies first

• Permanent monocular blindness (GCA) — EMERGENCY: posterior ciliary artery occlusion causing arteritic AION. Signaled by amaurosis fugax or a pallid swollen optic disc; untreated, the second eye follows within days.
• Diffuse alveolar hemorrhage (GPA/MPA) — EMERGENCY: capillaritis floods alveoli. Signaled by hemoptysis (which may be absent), a falling hematocrit with new bilateral infiltrates, and a rising DLCO.
• Rapidly progressive glomerulonephritis — EMERGENCY: crescent formation. Signaled by creatinine doubling over days with RBC casts; delay costs nephrons permanently and can commit the patient to dialysis.
• Coronary artery aneurysm, thrombosis, and myocardial infarction (Kawasaki) — giant aneurysms carry the highest risk; signaled by Z-score enlargement on serial echocardiography. Kawasaki-related MI in a child may present only as shock, vomiting, or pallor.
• Mesenteric or renal artery infarction (PAN): postprandial abdominal pain, GI bleeding, bowel perforation, or new severe renin-mediated hypertension.
• Intussusception (IgA vasculitis): classically ileoileal, from a submucosal hematoma acting as a lead point — suspect with colicky pain and bloody stools.
• Late structural sequelae: thoracic aortic aneurysm and dissection years after GCA; aortic regurgitation and limb claudication in Takayasu; subglottic stenosis and saddle-nose deformity in GPA.

Treatment complications

• Glucocorticoids: hyperglycemia, osteoporotic vertebral fracture, avascular necrosis, cataract, adrenal suppression on abrupt withdrawal, and opportunistic infection.
• Cyclophosphamide: acrolein-mediated hemorrhagic cystitis (prevent with mesna and hydration), later urothelial carcinoma, myelosuppression, and gonadal failure — counsel on fertility preservation.
• Rituximab: hypogammaglobulinemia with recurrent sinopulmonary infection, hepatitis B reactivation, and rare progressive multifocal leukoencephalopathy.
• Tocilizumab: suppresses CRP and fever, so it can mask infection; risk of GI perforation, particularly with diverticular disease.
• Avacopan: hepatotoxicity requiring transaminase monitoring.
• IVIG: aseptic meningitis, volume overload, and blunting of live measles/varicella vaccine responses for months.

• Suspected GCA: the single best next step is high-dose glucocorticoids, not the biopsy. Steroids first, temporal artery biopsy after — a long segment, because skip lesions cause false negatives. Vision lost before treatment does not come back.
• ***Jaw claudication* is the most specific GCA symptom**, and multinucleated giant cells fragmenting the internal elastic lamina is the histologic buzzword. Intracranial arteries lose most of their elastic tissue and vasa vasorum as they penetrate the dura, which is why GCA characteristically spares them and blinds via the posterior ciliary arteries rather than causing intracerebral vasculitis.
• Kawasaki disease is the exception to the "no aspirin in children" rule. IVIG 2 g/kg plus aspirin within 10 days of fever onset substantially reduces coronary aneurysm risk (AHA 2017); every patient gets an echocardiogram.
• **Fever ≥5 days plus *CRASH*** — Conjunctivitis, Rash, Adenopathy, Strawberry tongue, Hands/feet changes — with periungual desquamation appearing in the subacute phase. Exudative conjunctivitis or vesicular rash should push you toward an infectious mimic instead.
• c-ANCA/PR3 plus saddle nose, cavitary lung nodules, and RBC casts = GPA. Renal biopsy shows pauci-immune necrotizing crescentic glomerulonephritis — no immune deposits on immunofluorescence, the tested detail — while airway and lung tissue show necrotizing granulomatous inflammation.
• Rituximab, not cyclophosphamide, is the conditionally preferred induction agent for severe GPA/MPA in the ACR/Vasculitis Foundation 2021 guideline; plasma exchange is no longer routine.
• The one association examiners love: hepatitis B and polyarteritis nodosa — and PAN spares the lungs and glomeruli, which is precisely how you separate it from ANCA-associated disease.
• Common distractor: ordering ANCA in a 78-year-old with headache and an ESR over 100. GCA, Takayasu, Kawasaki, PAN, and IgA vasculitis are all ANCA-negative; a negative ANCA never excludes vasculitis, and a positive one in the wrong clinical setting can be drug-induced (hydralazine, propylthiouracil, levamisole-adulterated cocaine).

• Classified by vessel size: large (aorta), medium (named arteries), small (arterioles/capillaries)
• ANCA-associated vasculitides (GPA, MPA, EGPA) are necrotizing and affect small vessels
• c-ANCA/PR3 = GPA; p-ANCA/MPO = MPA or EGPA
• Skin and joint involvement common across multiple vasculitides
• Diagnosis often requires tissue biopsy confirming vasculitis with fibrinoid necrosis

• GPA: Sinusitis + hemoptysis + glomerulonephritis (c-ANCA+); upper/lower respiratory + systemic symptoms
• EGPA: Asthma + eosinophilia + peripheral neuropathy (p-ANCA+)
• MPA: Rapidly progressive glomerulonephritis without upper respiratory involvement
• PAN: Abdominal pain, testicular pain, peripheral neuropathy (hepatitis B risk)
• IgA vasculitis: Palpable purpura on buttocks/legs + arthritis + abdominal pain + hematuria
• GCA: Temporal headache, jaw claudication, vision loss in elderly (>50 years); elevated ESR/CRP

1. 1.Forgetting IgA vasculitis is the most common systemic vasculitis in children worldwide; often missed if HSP not in differential for "palpable purpura + hematuria"
2. 2.PAN does NOT involve glomerulonephritis or lungs—distinguishes it from ANCA vasculitides; look for hepatitis B serology
3. 3.GCA/Takayasu are large vessel vasculitides and ANCA-negative—don't order ANCA; use ESR/CRP, temporal artery biopsy, or imaging instead

• Small vessel ANCA-associated (GPA, MPA, EGPA): Corticosteroids + immunosuppression (cyclophosphamide or rituximab for induction; azathioprine or rituximab for maintenance)
• IgA vasculitis: Supportive care; corticosteroids for severe skin/GI; ACE inhibitors if renal involvement
• PAN: Corticosteroids ± cyclophosphamide if severe; antivirals if hepatitis B+
• GCA: High-dose corticosteroids acutely (avoid vision loss); taper gradually; consider tocilizumab (IL-6 inhibitor) for steroid-sparing
• Takayasu: Corticosteroids + immunosuppression (TNF-α inhibitors showing promise)