Vasculitides

Vasculitides are a heterogeneous group of autoimmune diseases, all characterized by inflammation of blood vessels (vasculitis) and subsequent ischemia and damage to the organs supplied by these vessels. Vasculitis may occur as a primary disease (idiopathic) or as a secondary response to an underlying disease (e.g., hepatitis B infection). Based on the size of the vessel affected, it can be classified into small-vessel, medium-vessel, or large-vessel vasculitis. While the inflammatory process may be confined to one organ, it may also involve several organ systems. Vasculitis should be considered in patients presenting with palpable purpura, pulmonary infiltrates, unexplained ischemic events, and multisystem disease. The detection of antineutrophil cytoplasmic antibodies (ANCA) in the blood is an important diagnostic marker; however, there are also ANCA-negative vasculitis syndromes. Immunosuppressive treatment is administered to stop vascular inflammation. Specific (e.g., antiviral drugs) or symptomatic (e.g., NSAIDs) management may be necessary. If the vasculitis is secondary to an underlying disease, treatment of the underlying disease should be initiated.

• Etiology
  • Primary (idiopathic)
  • Secondary; (e.g., response to hepatitis B infection, hepatitis C infection, myeloma, autoimmune diseases)

Giant cell arteritis (temporal arteritis)

See “Giant cell arteritis” for more information.

Takayasu arteritis (aortic arch syndrome)

• Definition: : granulomatous inflammation of the aorta and its major branches, resulting in thickening and stenosis of the involved blood vessels and subsequent vascular symptoms ^[1]
• Epidemiology
  • Peak incidence: 15–45 years of age
  • Asian heritage
  • ♀ > ♂ (9:1) ^[2]
• Clinical features ^[3]
  • Fever, malaise, arthralgia, night sweats
  • Vascular symptoms
    • Decreased bilateral brachial and radial pulses (so-called pulseless disease)
    • Syncope, angina pectoris
    • Bilateral carotid bruits
    • Impaired vision
    • Movement-induced muscular pain in one or more limbs
    • Raynaud phenomenon
    • Hypertension
  • Skin manifestations
    • Erythema nodosum
    • Urticaria
• Diagnostics ^[4]
  • Laboratory findings: ↑ ESR
  • Angiography (gold standard): detects vascular stenosis ^[5]
  • Biopsy of the affected vessel
    • Granulomatous thickening of the aortic arch
    • Plasma cells and lymphocytes in media and adventitia
    • Vascular fibrosis
  • A diagnosis of Takayasu arteritis requires three or more of the following diagnostic criteria to be fulfilled : ^[6]
    • Age of onset: ≤ 40 years
    • Claudication of upper or lower extremities while in use
    • Audible bruit over the subclavian artery or abdominal aorta
    • Decreased brachial artery pulse
    • Blood pressure difference > 10 mm Hg between arms
    • Abnormal arteriography of the aorta or large blood vessels in the extremities that is not due to arteriosclerosis or fibromuscular dysplasia
• Treatment ^[3]
  • Corticosteroids; if necessary, MTX or cyclophosphamide may be administered.
  • Surgical intervention (e.g., bypass) may be required if critical stenosis of the aortic arch or its branches occurs.
  • Antihypertensive treatment

In Takayasu arteritis, I can't TAKA YA pulse (pulseless disease).

Kawasaki disease (mucocutaneous lymph node syndrome)

See “Kawasaki disease” for more information.

Polyarteritis nodosa (PAN)

• Definition
  • Systemic vasculitis of the small and medium-sized vessels, which leads to tissue ischemia
  • Most commonly involves skin, peripheral nerves, muscles, joints, gastrointestinal tract, and kidneys
• Epidemiology
  • Peak incidence: 45–65 years
  • Sex: ♂ > ♀
• Etiology: often associated with hepatitis B (incidence rate has declined in the past few years from 30% to 7% as a result of vaccination) or hepatitis C infection ^[7]
• Clinical features ^[8]
  • Nonspecific symptoms
    • Fever, weight loss, malaise
    • Muscle and joint pain
  • Renal involvement (∼ 60%): hypertension, renal impairment
  • Coronary artery involvement (∼ 35%); increased risk of myocardial infarction
  • Skin involvement (∼ 40%): rash, ulcerations, nodules
  • Neurological involvement: polyneuropathy (mononeuritis multiplex), stroke
  • GI involvement: abdominal pain, melena, nausea, vomiting
  • Usually spares the lungs
• Diagnostics ^[9]
  • Blood tests
    • Serology: hepatitis B, hepatitis C
    • ↑ ESR
    • Anemia, leukocytosis
    • ANCA-negative
  • Urine analysis: proteinuria, hematuria
  • Muscle biopsy
    • Transmural inflammation of the arterial wall with leukocytic infiltration and fibrinoid necrosis
    • The inflammatory lesions are usually in various stages of development and regeneration.
  • Angiography ^[10]
    • Numerous small aneurysms and stenosis of small and medium-sized vessels of the involved organs
    • Most commonly seen in the renal arteries (pulmonary arteries are usually not affected)
• Treatment ^[8]
  • Immunosuppression: corticosteroids, cyclophosphamide
  • Antiviral therapy against HBV and HCV may be required.

PAN should be considered in young adults presenting with stroke or myocardial infarction. The diagnosis may be confirmed with a biopsy of involved tissue.

In PAN, the Pulmonary Artery is Not involved, PANmural inflammation of the arterial wall is present, and PAN is often associated with hePANitis B.

Thromboangiitis obliterans

See “Thromboangiitis obliterans” for more information.

Granulomatosis with polyangiitis

See “Granulomatosis with polyangiitis” for more information.

Granulomatosis with polyangiitis is the 'C' disease: Curvy nose (saddle nose deformity), Chronic sinusitis, Cough, Conjunctivitis and Corneal ulceration, Cardiac arrhythmias, nonCaseating granulomas on biopsy, cANCA, Corticosteroids and Cyclophosphamide as treatment.

Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome)

• Definition: : a multisystem disease characterized by necrotizing granulomatous vasculitis with eosinophilia; , which most commonly involves the lungs and the skin but can also affect the renal, cardiovascular, gastrointestinal, central, and peripheral nervous systems ^[1]
• Etiology: unknown
• Clinical features ^[11]
  • Severe allergic asthma attacks (chief complaint)
  • Allergic rhinitis/sinusitis
  • Skin nodules, palpable purpura
  • Pauci-immune glomerulonephritis
  • CNS: impaired mental status
  • Mononeuritis multiplex (loss of motor and sensory function, with wrist or foot drop), symmetric or asymmetric polyneuropathy
  • Pericarditis
  • Gastrointestinal involvement: bleeding, ischemia, perforation ^[12]
• Diagnostics
  • Peripheral blood eosinophilia
  • ↑ IgE level
  • Circulating MPO-ANCA/pANCA (∼ 40% of cases) ^[13]
  • Biopsy (confirmatory test)
    • Tissue eosinophilia
    • Necrotizing vasculitis, and necrotizing granuloma
• Treatment: immunosuppression with glucocorticoids; possible in combination with cyclophosphamide

Churg-Strauss syndrome: pANCA and polyneuropathy (foot or wrist drop), allergic rhinitis/sinusitis/asthma, vasculitis, eosinophilia, and skin nodules

Microscopic polyangiitis

• Definition: necrotizing vasculitis of small vessels, typically with pulmonary, renal, and skin involvement ^[1]
  • Manifestations are similar to granulomatosis with polyangiitis.
  • The nasopharynx is usually not affected.
• Clinical features ^[14]
  • Renal (∼ 90%): pauci-immune glomerulonephritis; with hypertension
  • Lungs (∼ 50%): pulmonary vasculitis with hemoptysis
  • Skin (∼ 40%): palpable purpura, nodules, necrosis
• Diagnostics ^[15]
  • Biopsy of involved organ
    • Fibrinoid necrosis with infiltration of neutrophils
    • No granulomas
  • Laboratory findings: MPO-ANCA/pANCA in ∼ 70% of cases
• Treatment: immunosuppression with corticosteroids and cyclophosphamide

The presentation of microscopic polyangiitis is similar to that of granulomatosis with polyangiitis, but it does not affect vessels in the upper respiratory tract (no sinusitis or rhinitis), does not involve granuloma formation, and is associated with pANCA (not cANCA).

Microscopic Polyangiitis has MyeloPeroxidase antibodies (i.e., pANCA).

On histopathology, the following leukocytoclastic vasculitis syndromes appear as nuclear debris from neutrophil leukocytes that have infiltrated blood vessel walls. ^[1]

Henoch-Schonlein purpura (immunoglobulin A vasculitis)

See “Henoch-Schonlein purpura” for more information.

Cryoglobulinemic vasculitis

• Definition: cryoglobulin-mediated vasculitis that is characterized by temperature-dependent deposition of immunoglobulins/immune complexes (IgG and IgM) in blood vessel walls and subsequent inflammation of involved vessels and surrounding tissue
• Etiology: type II and III cryoglobulinemia (mixed cryoglobulinemia)
  • Viral infection
    • 70–90% association with hepatitis C infection ^[16]
    • Formation of hepatitis C IgG and IgM rheumatoid factor → immune complex formation with hepatitis C antigen → complement activation and inflammation of blood vessels
  • Other underlying diseases: multiple myeloma, lymphoproliferative disorders, connective tissue diseases, autoimmune diseases (SLE), proliferative glomerulonephritis
• Clinical features
  • Nonspecific systemic symptoms: fatigue; , malaise, myalgia, arthralgia
  • Skin lesions (nearly 100% of cases): palpable purpura, ulceration, necrosis
  • Vasomotor symptoms: Raynaud phenomenon, acrocyanosis
  • Polyneuropathy
  • Hepatosplenomegaly
  • Glomerulonephritis (severe cases or late complication)
• Diagnostics
  • Laboratory findings
    • Cryoglobulinemia: cold-precipitable immunoglobulins or immune complexes ^[17]
    • ↑ Rheumatoid factor (in almost all cases) ^[16]
    • Hypocomplementemia (90% of cases)
    • Hepatitis C diagnostics
      • Hepatitis C RNA and anti-hepatitis C antibodies
      • ↑ Liver transaminases
  • Skin or renal biopsy
    • Inflammatory vascular changes and renal damage
    • Cryoglobulin deposits (IgG and IgM complexes) may be detected in glomeruli.
  • Investigation of underlying cause: WBC, autoimmune antibodies, liver function testing, renal function testing, imaging (angiography, CT, chest x-ray)
• Treatment ^[18]
  • Immunosuppression
    • Systemic corticosteroids and rituximab
    • Indications: moderate and severe cases (biopsy confirmed glomerulonephritis, necrotizing skin ulcers, vasculitis of the CNS, GI tract, or lungs)
    • Initial treatment to stabilize vasculitis symptoms prior to management of the underlying cause
  • Treatment of underlying diseases
    • Hepatitis C infection: multidrug approach with direct-acting antivirals
      • In mild vasculitis: first-line treatment
      • In severe vasculitis: initiate after disease stabilization with immunosuppressive therapy
    • Hepatitis B and HIV: concomitant antiviral therapy and immunosuppressive therapy in moderate and severe vasculitis
  • Plasmapheresis (combined with immunosuppressive therapy)
    • Indicated in life-threatening and/or refractory cases (e.g., RPGN, intestinal ischemia)
    • Reduces the production of immunoglobulins
  • NSAIDs may be administered to manage arthralgia and myalgia.
  • Pneumocystis pneumonia prophylaxis
    • E.g., trimethoprim-sulfamethoxazole
    • Recommended in all patients receiving immunosuppressive treatment

The triad of arthralgia, palpable purpura, and fatigue is seen in ∼ 30% of patients with mixed cryoglobulinemia.

Cryoglobulinemia is caused by Cold-precipitable immunoglobulins and associated with hepatitis C.

Cutaneous small vessel vasculitis (formerly hypersensitivity vasculitis) ^[19]

• Definition: necrotizing vasculitis of cutaneous small vessels caused by the formation of immune complexes
• Epidemiology: most common vasculitis seen in clinical practice
• Etiology
  • Drug-induced (e.g., PTU, hydralazine, allopurinol, penicillins, cephalosporin, sulfasalazine, phenytoin)
  • Infections (e.g., HIV, HCV) ^[20]
• Clinical features: Symptoms usually occur 7–10 days after drug exposure.
  • Painful, palpable purpura
  • Other skin lesions may occur: subcutaneous nodules, chronic urticaria, ulcers, vesicles
• Diagnostics
  • Skin biopsy
  • Investigation of underlying cause
  • Systemic vasculitis should be ruled out.
• Treatment: symptomatic
  • Discontinue drug intake.
  • Immunosuppression may be required.

Definition

A systemic vasculitis that is characterized by the deposition of immune complexes in arteries and veins of all sizes

Epidemiology ^[21]

• Most common from the Mediterranean region to eastern Asia, with the highest prevalence observed in Turkey and Japan
• Peak incidence: 20–40 years

Etiology

• Autoimmune and infectious triggers (e.g., precipitating HSV or parvovirus infection) have been suggested. ^[22]
• Strong HLA-B51 association

Clinical features ^[23][24]

• Recurrent painful oral aphthous ulcers: (95–100%)
  • Usually last about 1–4 weeks
  • Typically the initial presenting symptom
• Recurrent genital ulcerations (60–90%)
  • Single or multiple ulcers that resemble oral aphthous ulcers and heal with scarring
  • Most commonly affect the vulva in female and the scrotum in male individuals
• Ocular disease (50–80%)
  • Uveitis (iridocyclitis, chorioretinitis), keratitis, and/or retinal vasculitis
  • Typically bilateral
  • More common and more severe among men
  • Usually occurs 2–3 years after the onset of oral and/or genital ulcers
• Skin lesions (35–85%)
  • Erythema nodosum
  • Papulopustular lesions
  • Pyoderma gangrenosum
  • Pseudofolliculitis or acneiform eruptions
  • Dermatographism: formation of urticaria after minor pressure is applied to the skin, likely mediated by local histamine release
• Arthritis (30–70%)
  • Non-erosive, non-deforming, asymmetric mono-/oligoarthritis
  • Usually affects the knees, ankles, hands, and/or wrists
• Gastrointestinal disease: ileocecal ulceration with abdominal pain, anorexia, diarrhea, lower GI bleeding, nausea, vomiting
• Vasculopathy
  • Superficial thrombophlebitis
  • Thrombosis of large veins (e.g., deep vein thrombosis, Budd-Chiari syndrome)
  • Arterial thrombosis
  • Aneurysms (e.g., pulmonary artery aneurysms)
• Neuro-Behcet syndrome (5–10%) ^[25]
  • Parenchymal CNS disease: behavioral changes, ataxia, hemiparesis, sudden hearing loss
  • Extra-parenchymal CNS disease: cerebral venous thrombosis, intracranial hypertension

Diagnostics ^[26][27]

• Positive pathergy skin test: erythematous papule or pustule 24–48 hours after a needle prick to a depth of 5 mm
• Autoantibodies (e.g., ANA, ANCA, rheumatoid factor) are usually absent.
• Nonspecific markers of inflammation may be present during flares (e.g., ↑ ESR, ↑ CRP).

PATHERGY: Positive pathergy test, Aphthous mouth ulcers, Thrombosis (arterial and venous), Hemoptysis (pulmonary artery aneurysm), Eye lesions (uveitis, retinal vasculitis), Recurrent Genital ulcers, Young at presentation (3^rd decade)

Diagnostic criteria (International Study Group criteria)

• Recurrent oral ulceration at least three times within a 12-month period
  AND
• ≥ 2 of the following
  • Recurrent genital ulceration
  • Eye lesions
  • Skin lesions
  • Positive pathergy test

Differential diagnosis

• Crohn disease
• Aphthous stomatitis (e.g., due to vitamin B₁₂/folate/iron deficiency, gluten-sensitive enteropathy)
• Herpes infection
• Sweet syndrome
• Reactive arthritis
• SLE

Treatment ^[27][28]

• Oral ulcers and/or genital ulcers: topical corticosteroids
• Topical lidocaine for pain relief
• Skin lesions
  • Papulopustular lesions: See "Treatment“ of “Acne vulgaris”.
  • Erythema nodosum: colchicine
• Arthritis: colchicine
• Ocular disease; , CNS disease, and/or vasculopathy
  • Systemic corticosteroids
  • Immunosuppressant therapy (e.g., azathioprine, infliximab, cyclosporine A, cyclophosphamide, IFN-α, methotrexate)

References:^[11]