Vasculitis

Overview

Arteritis/angiitis/vasculitis = inflammatory vessel wall involvement. Infectious (direct invasion) vs non-infectious (chemical/mechanical/immunologic/radiation) — non-infectious more important, mostly immunologic.

Immunologic markers

• c-ANCA (proteinase-3) → active Wegener’s granulomatosis
• p-ANCA (myeloperoxidase) → microscopic polyarteritis, primary glomerular disease
• AECA → SLE, Kawasaki, Buerger’s
• Pauci-immune vasculitis → no immune complex deposits (like pauci-immune GN)

I. Infectious arteritis

Endarteritis obliterans — NOT a disease entity, nonspecific intimal fibrous proliferation → lumen obliteration. Near peptic ulcers, chronic abscesses/TB, chronic cutaneous ulcers, chronic meningitis, postpartum/postmenopausal uterine arteries. Minimal/no inflammation despite “-itis” name.

Syphilitic aortitis (~80% tertiary syphilis) — ascending aorta/arch, treponemes via mediastinal lymphatics. Gross: “tree-bark” pearly-white intimal thickenings, no fat core. Micro: vasa vasorum endarteritis/periarteritis, plasma cell/lymphocyte perivascular infiltrate, miliary gummas. Effects: aortic aneurysm, AV incompetence, coronary ostial stenosis (~20%).

Heubner’s arteritis — cerebral syphilitic arteritis, tertiary stage, causes ischaemic cerebral atrophy.

II. Non-infectious (immunologic) arteritis

PAN: necrotising vasculitis, small/medium muscular arteries, multiple organs (kidney>heart>liver>GI>muscle>pancreas>testes>NS>skin). Adult males. Immune complex + tumour antigen mediated.

3 STAGES (may coexist across/within vessels):

1. Acute — fibrinoid necrosis (media centre), neutrophil/eosinophil periarteritis (full circumference), ±thrombus, ±aneurysm
2. Healing — fibroblastic proliferation → firm nodularity, infiltrate → lymphocytes/plasma cells/macrophages
3. Healed — dense fibrosis, wall thickened, internal elastic lamina fragmented/lost, ±haemosiderin macrophages/organised thrombus

Hypersensitivity (leucocytoclastic) vasculitis: differs from PAN — venules/capillaries/arterioles (not muscular arteries). Antigen-triggered (bacteria, viruses, malaria, drugs). Includes serum sickness, HSP, mixed cryoglobulinaemia, malignancy/CTD-associated vasculitis. Two forms: leucocytoclastic (fibrinoid necrosis + fragmented neutrophils, immune complex-mediated) vs lymphocytic (delayed hypersensitivity/cellular).

Wegener’s granulomatosis: TRIAD — (1) necrotising granulomas upper/lower respiratory tract, (2) focal necrotising vasculitis (lungs/airway), (3) focal/diffuse necrotising GN. Limited form = no renal involvement. Adult males, c-ANCA+. Differs from idiopathic lethal midline granuloma (more destructive, no systemic triad).

Temporal (giant cell) arteritis: medium-large arteries, cranial (esp. temporal) but also aorta/carotid/axillary/brachial/femoral/mesenteric. >70yr, slight female preponderance. Headache, blindness (ophthalmic artery), + polymyalgia rheumatica. T-cell mediated vs internal elastic lamina. Biopsy diagnostic AND therapeutic. Giant cells in 2/3 cases.

Takayasu’s arteritis (pulseless disease/aortic arch syndrome): aorta+branches, young women. Absent arm pulses + ocular signs. MI/CHF/neuro deficits from ischaemia. Granulomatous, full-thickness mononuclear infiltrate, worse adventitia/media.

Kawasaki disease (mucocutaneous lymph node syndrome): children/infants, febrile, oral/conjunctival erosions+rash+lymphadenopathy. Hallmark: MULTIPLE CORONARY ANEURYSMS. Panarteritis resembling PAN — “infantile PAN.”

Buerger’s disease (thromboangiitis obliterans): small/medium extremity arteries+veins, young MALE SMOKERS. Intermittent claudication → gangrene. Etiology: smoking (endothelial damage/hypersensitivity, AECA+), genetic (HLA-A9/B5, Israel/Japan/India). Two stages: early (polymorphs all layers, mural thrombus with MICROABSCESSES, NO lipid, intact IEL — distinguishes from atherosclerosis) vs advanced (mononuclear, occasional granulomas, thrombus organisation, medial fibrosis).

Misc: Rheumatoid vasculitis (small/medium visceral, long-standing nodules), SLE vasculitis (small skin arteries), Rheumatic vasculitis (aorta/carotid/coronary, fibrinoid change not Aschoff nodules).

Raynaud’s disease vs phenomenon (NOT vasculitis)

Disease: functional vasospasm, young healthy women, cold-triggered. Pallor→cyanosis→redness (ischaemia→venostasis→hyperaemia). Rarely gangrene. Autonomic vasoconstriction, usually NO structural change.

Phenomenon: SAME pattern but SECONDARY to underlying disease (atherosclerosis, scleroderma, SLE, Buerger’s, myeloma, pulm HTN, ergot). HAS structural vessel change (unlike disease).

Clinical relevance

c-ANCA(PR3)/Wegener’s vs p-ANCA(MPO)/microscopic polyarteritis = top discriminator between 2 most-confused small-vessel vasculitides. PAN’s 3-stage evolution = conceptual backbone — different biopsies/segments can legitimately show different stages, not a “wrong” diagnosis. Buerger’s intact IEL + no lipid = distinguishes from atherosclerosis in young smoker with limb ischaemia. Raynaud’s disease vs phenomenon (presence/absence of underlying cause + structural change) = clinically consequential — phenomenon needs workup, disease usually doesn’t.

Overview

Arteritis, angiitis, and vasculitis all denote inflammatory involvement of a vessel wall — arteries, arterioles, venules, or capillaries. Two broad causal groups exist: infectious (direct vessel invasion by bacteria/fungi) and non-infectious (chemical, mechanical, immunologic, or radiation injury) — the non-infectious group is clinically the more important of the two, and most of it is now understood to be immunologically mediated.

Immunologic Markers in Non-Infectious Vasculitis

Serum from many patients with immunologic vasculitis shows characteristic autoantibodies:

• ANCAs (anti-neutrophil cytoplasmic antibodies) — against cytoplasmic antigens of neutrophils, macrophages, and endothelial cells; detected by neutrophil immunofluorescence in two patterns:
  • c-ANCA (cytoplasmic pattern) — specific for proteinase-3; seen in active Wegener’s granulomatosis.
  • p-ANCA (perinuclear pattern) — specific for myeloperoxidase; seen in microscopic polyarteritis and primary glomerular disease.
• AECAs (anti-endothelial cell antibodies) — seen in SLE, Kawasaki disease, Buerger’s disease.
• Pauci-immune vasculitis — a subset with no demonstrable immune complex deposits in the vessel wall (paralleling pauci-immune glomerulonephritis), pathogenesis explained by other mechanisms.

I. Infectious Arteritis

• Endarteritis obliterans — not a distinct disease but a nonspecific pattern of intimal fibrous proliferation obliterating the vessel lumen, seen near peptic ulcers, chronic abscesses/TB lesions, chronic cutaneous ulcers, chronic meningitis, and post-partum/post-menopausal uterine arteries. Despite the “-itis” suffix, there is minimal or no inflammatory infiltrate — the lumen closes purely by concentric fibrous proliferation.
• Syphilitic arteritis — most prominent in tertiary syphilis; two key sites:
  • Syphilitic aortitis (ascending aorta/arch, ~80% of tertiary syphilis) — treponemes spread via mediastinal lymphatics around the arch during secondary syphilis. Gross: dilated aorta, intima studded with pearly-white “tree-bark” thickenings separated by wrinkled normal intima (denser, more fibrous than an atheroma, lacking a fatty core). Microscopy: endarteritis/periarteritis of the vasa vasorum, perivascular plasma cells/lymphocytes/macrophages forming miliary gummas, intimal collagen thickening with hyalinisation/calcification. Effects: aortic aneurysm, aortic valve incompetence (from spread to the valve ring), coronary ostial stenosis (~20%, causing myocardial fibrosis/angina/sudden death).
  • Cerebral syphilitic (Heubner’s) arteritis — endarteritis/periarteritis of small-medium cerebral vessels; media muscle atrophy and fibrosis cause ischaemic cerebral atrophy.

II. Non-Infectious (Immunologic) Arteritis

Polyarteritis Nodosa (PAN)

A necrotising vasculitis of small and medium-sized muscular arteries across multiple organs — “polyarteritis” (not “periarteritis”) because all layers of the wall are involved. More common in adult males. Organs affected, in descending frequency: kidney, heart, liver, GI tract, muscle, pancreas, testes, nervous system, skin. Believed to result from immune complex and tumour-antigen deposition.

Gross: segmental beaded nodules, especially at bifurcations/branchings.

Pathogenesis — three sequential stages (may coexist in different vessels, or even within the same vessel):

1. Acute stage — fibrinoid necrosis at the nodule centre (media); acute inflammatory response (neutrophils, eosinophils, some mononuclear cells) around the entire circumference (periarteritis); lumen may thrombose; weakened wall may aneurysm.
2. Healing stage — fibroblastic proliferation producing firm nodularity; infiltrate shifts to lymphocytes, plasma cells, macrophages.
3. Healed stage — dense fibrosis markedly thickens the wall; internal elastic lamina fragmented/lost; haemosiderin-laden macrophages and organised thrombus may persist.

Hypersensitivity (Leucocytoclastic) Vasculitis

Also called allergic vasculitis or microscopic polyarteritis — differs from PAN by involving venules, capillaries, and arterioles rather than muscular arteries. Triggered by an identifiable antigen: bacteria (streptococci, staphylococci, mycobacteria), viruses (HBV, influenza, CMV), malarial parasite, drugs/chemicals. Encompasses serum sickness, Henoch-Schönlein purpura, mixed cryoglobulinaemia, malignancy-associated vasculitis, and connective-tissue-disease-associated vasculitis (RA, SLE).

Two histologic forms:

• Leucocytoclastic vasculitis — fibrinoid necrosis with a neutrophilic infiltrate, many neutrophils fragmented; the pattern seen with immune complex deposition.
• Lymphocytic vasculitis — predominant lymphocytic infiltrate; seen with delayed hypersensitivity/cellular immune injury.

Wegener’s Granulomatosis

A necrotising vasculitis defined by a clinicopathologic triad: (1) acute necrotising granulomas of the upper/lower respiratory tract (nose, sinuses, lungs), (2) focal necrotising vasculitis (especially lungs/upper airway), (3) focal/diffuse necrotising glomerulonephritis. A limited form lacks renal involvement. More common in adult males; c-ANCA positive. Circulating immune complexes are implicated (supported by subepithelial glomerular immunoglobulin deposits and remission with immunosuppression). Distinguished from idiopathic lethal midline granuloma (a highly destructive, progressively necrotic upper-airway disease without the same systemic pattern).

Histology: granulomas of fibrinoid necrosis with neutrophils, mononuclear cells, epithelioid cells, multinucleate giant cells, fibroblastic proliferation; segmental or circumferential necrotising vasculitis; renal lesions of focal/diffuse necrotising glomerulonephritis.

Temporal (Giant Cell) Arteritis

Granulomatous inflammation of medium-large arteries, preferentially cranial vessels (especially temporal — hence the name), though the aorta and other major arteries (carotid, axillary, brachial, femoral, mesenteric) can be involved too — “giant cell arteritis” is the more accurate general term. Typically patients are over 70, slight female preponderance; presents with headache, and blindness if the ophthalmic artery is involved; associated with polymyalgia rheumatica. Likely a T-cell-mediated immune reaction against the damaged internal elastic lamina. Biopsy is both diagnostic and therapeutically relieving.

Gross: thickened, cord-like artery, lumen reduced to a narrow slit. Histology: chronic granulomatous reaction around the internal elastic lamina, circumferential; giant cells (foreign-body/Langhans type) in two-thirds of cases; fragmented internal elastic lamina; eccentric/concentric intimal proliferation narrowing the lumen (± thrombus).

Takayasu’s Arteritis (Pulseless Disease, Aortic Arch Syndrome)

Granulomatous vasculitis of the aorta and its major branches, chiefly affecting young women; classic finding is absent pulse in both arms plus ocular manifestations; ischaemic consequences include MI, congestive heart failure, neurologic deficits. Possible autoimmune reaction to aortic tissue.

Gross: irregularly thickened aortic wall, wrinkled intima, obliterated branch lumina. Histology: severe mononuclear infiltrate through the full wall thickness (worse in adventitia/media), perivascular vasa vasorum infiltration, granulomatous change with central necrosis and Langhans’ giant cells in many cases; advanced lesions show extensive medial/adventitial fibrosis.

Kawasaki Disease (Mucocutaneous Lymph Node Syndrome)

An acute/subacute febrile illness of young children and infants — oral/conjunctival erosions, skin rash, lymphadenopathy. Etiology unknown (infectious/genetic/toxic/immunologic candidates). The most characteristic finding is multiple coronary artery aneurysms (angiography or autopsy); renal, mesenteric, hepatic, pancreatic arteries may also be involved. Histologically a panarteritis resembling PAN — leading some to consider it an infantile form of PAN.

Buerger’s Disease (Thromboangiitis Obliterans)

Occlusive inflammatory disease of small-medium arteries and veins of the extremities, chiefly young male heavy smokers. Presents as intermittent claudication (ischaemic limb pain, more often legs), progressing to gangrene requiring amputation.

Etiopathogenesis: strong association with heavy smoking (proposed direct endothelial damage → hypercoagulability/thrombosis, or tobacco hypersensitivity, supported by demonstrable AECAs); genetic susceptibility (familial occurrence, HLA-A9/HLA-B5 association; more common in Israel, Japan, and India).

Gross: segmental lesions in small-medium lower-extremity arteries, adjacent veins and nerves often co-involved within a shared fibrous tissue cuff; mural thrombi frequent.

Histology (two stages): early — polymorph infiltration through all layers, mural/occlusive thrombosis with characteristic microabscesses within the thrombus, endothelial proliferation, no lipid aggregates, intact internal elastic lamina (distinguishing it from atherosclerosis); advanced — mononuclear infiltrate, occasional epithelioid/Langhans’ giant cell granulomas, thrombus organisation/recanalisation, marked medial fibrosis in chronic cases.

Miscellaneous Vasculitides

• Rheumatoid vasculitis — small/medium visceral arteries, in patients with long-standing rheumatoid nodules.
• SLE vasculitis — mainly small skin arteries.
• Rheumatic vasculitis — aorta, carotid, coronary, visceral vessels; fibrinoid change and perivascular inflammation (rather than classic Aschoff nodules).

Raynaud’s Disease vs Raynaud’s Phenomenon (Not True Vasculitis)

Raynaud’s disease is a functional vasospastic disorder (not vasculitis) of small arteries/arterioles in the extremities of young healthy women, provoked chiefly by cold (also emotion, trauma, hormones, drugs). Classic colour sequence: pallor → cyanosis → redness (ischaemia → venostasis → hyperaemia). Rarely progresses to true gangrene; long-standing cases may show mild endothelial proliferation/intimal thickening. Mechanism: autonomic-mediated vasoconstriction, usually without structural vessel change.

Raynaud’s phenomenon is the same cold-sensitive colour-change pattern but secondary to an identifiable underlying disease — atherosclerosis, scleroderma, SLE, Buerger’s disease, multiple myeloma, pulmonary hypertension, ergot ingestion — and, unlike Raynaud’s disease, shows genuine structural vessel change (segmental inflammation, fibrinoid change in capillary walls).

Clinical Relevance

• The c-ANCA/p-ANCA split is one of the highest-yield serologic facts in this topic — c-ANCA (proteinase-3) for Wegener’s, p-ANCA (myeloperoxidase) for microscopic polyarteritis — and functions as a practical first-line discriminator between the two most commonly confused small-vessel vasculitides.
• PAN’s three-stage evolution (acute fibrinoid necrosis → healing fibroblastic nodularity → healed dense fibrosis) is the conceptual backbone of the entire topic: recognising that different biopsies from the same patient, or even different segments of the same vessel, can legitimately show different stages is what prevents a diagnostic biopsy from being misread as “wrong” simply because it doesn’t match a textbook’s single canonical picture.
• Buerger’s disease’s intact internal elastic lamina and absence of lipid aggregates are the specific histologic features that separate it from atherosclerotic occlusive disease in a young heavy smoker with limb ischaemia — a genuinely practical distinguishing point rather than an arbitrary textbook detail.
• Distinguishing Raynaud’s disease from Raynaud’s phenomenon by the presence or absence of an identifiable underlying cause (and, correspondingly, structural vessel change) is clinically consequential — Raynaud’s phenomenon demands a workup for the associated condition, while Raynaud’s disease in a young healthy woman generally does not.

• Polyarteritis nodosa: three-stage evolution (acute fibrinoid necrosis → healing → healed fibrosis)

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