The pathobiology of vasculitis
DINAH V. PARUMS
Vasculitis can be defined as inflammation of vessel walls accompanied by a demonstrable structural change. The inflammation may be acute or chronic and the structural change may be accompanied by necrosis, often termed fibrinoid necrosis, or by fibrosis. The terms vasculitis, arteritis, and angiitis are used synonymously.
Inflammation and necrosis of vessels may be produced by infections with micro-organisms, by many chemical and physical agents, and by hypersensitivity phenomena. The pathological and clinical effects are widely variable depending upon the size and type of the vessels involved, their number and distribution, the chronicity of the lesions, and the presence of complications. The variable distribution throughout the body of vessels affected produces a highly variable and often bizarre clinical picture; circulation of vital organs (brain, heart, kidneys) may be affected. Acute forms of the disease may run a rapid course with all the lesions at the same stage of development; chronic forms show a more prolonged course with lesions in various stages of development and periods of remissions and exacerbations.
Complications include thrombosis, rupture of vessels with haemorrhage, vascular occlusion, and aneurysm formation (see Table 2 170 in Section 7.2).
CLASSIFICATION OF VASCULITIS
Few other diseases cause as much diagnostic and clinical controversy as the vasculitides and there is still no single, universally accepted classification system. This is largely because the pathogenesis of many of the vasculitic syndromes remains poorly understood, but also because of their varied clinical presentation and because their clinical and pathological features frequently overlap (see Section 7.9.3) 36.
An aetiological classification of vasculitis
A classification system is only of value if it aids diagnosis and thus allows the most appropriate clinical management to be carried out. A clinicopathological classification based on the size of the affected vessel is given in Table 1 171. Although the most rational and memorable form of classification is one based on aetiology, in most instances the aetiology is unclear or unknown.
Infectious vasculitis is the only form of the condition which is completely understood. Small, medium-sized, and large vessels may be infected by pyogenic bacteria, mycobacteria, fungi, Rickettsia, viruses, protozoa, or spirochaetes (Treponema pallidum). With regard to the last, syphilis deserves special mention.
Syphilitic disease of the large arteries is rare, since it occurs in the tertiary stage of the disease, which is now seldom left untreated for the long periods required for this to occur. Syphilitic aortitis has four main manifestations: syphilitic aortitis, syphilitic aneurysm, aortic insufficiency, and syphilitic coronary ostial stenosis. In syphilitic aortis the inflammatory process actively disrupts and destroys the lamellar units which make up the aortic media, resulting in replacement fibrosis. The inflammation is most prominent at the vasa vasorum which are surrounded by chronic inflammation featuring abundant plasma cells. These vessels may undergo endarteritis obliterans. Although these appearances are seen mainly in the ascending aorta and the arch, the descending aorta may also be affected. The intima may show the classical ‘tree bark’ appearance of intimal thickening.
A number of conditions characterized by inflammation and segmental necrosis of small vessels are attributed to immunologically mediated injury and are grouped under the generic term ‘necrotizing vasculitis’. Necrotic regions often contain considerable amounts of fibrin (fibrinoid necrosis) (Fig. 1) 211.
Immune complexes have been implicated in the pathogenesis of various forms of vasculitis in humans. In some patients, these immune complexes have been shown to contain hepatitis B virus, hepatitis A virus, cytomegalovirus, HTLV–1, HTLV–3, or parvovirus.
The model for these forms of vasculitis is that seen in experimentally induced serum sickness (the Arthus reaction). Immune complexes may also lodge in the glomerular basement membranes, producing an acute necrotizing glomerulonephritis.
Acute (hypersensitivity (leucocytoclastic) vasculitis)
Patients may have a history of short duration (weeks) of hypersensitivity to drugs or foreign proteins. Small veins, arteries, and capillaries are affected. Lesions may be self-limited and regress, may cause death, or may progress to become chronic. Renal glomeruli may be affected, particularly in some distinct syndromes such as Henoch–Schönlein purpura, vasculitis associated with malignancy, and essential mixed cryoglobulinaemia. There is clinical, histological, and probably aetiological overlap between hypersensitivity vasculitis and the vasculitis seen in some of the collagen vascular diseases.
Chronic—polyarteritis nodosa and the polyarteritis group
Although these lesions may be produced experimentally by repeated exposure to an antigen, in man a specific antigen is rarely isolated. Hypertension is often present but no causal relation has been established. The natural history is one of months or years of remission, exacerbation, and eventual death: 60 per cent of patients die within 1 year.
Lesions at various stages may be seen, even within the same vessel. The more common form, polyarteritis nodosa, affects both arteries and veins, mainly in the kidneys, skin, heart, liver, gastrointestinal tract, pancreas, skeletal muscle, peripheral nervous system, and central nervous system, but not in the lungs. It is a disease which affects mainly young adults, with a female to male ratio of 3 : 1.
Kawasaki disease (mucocutaneous lymph node syndrome) is a form of polyarteritis which occurs in infancy and childhood, classically in children under 5 years, and most commonly in those under 1 year of age. The child presents with a fever, rash, and oedema of the palms and soles; desquamation of the fingertips may be present. There is also an acute, non-suppurative swelling of the cervical lymph nodes. Death, which occurs in less than 1 per cent of patients, is due to myocardial infarction following involvement of the coronary arteries. This disease is likely to be an infantile form of polyarteritis nodosa.
Erythema nodosum is a vasculitis of the skin and subcutaneous tissue, usually in the lower extremities, which occurs in association with many disorders that exhibit hypersensitivity phenomena, including sarcoidosis and inflammatory bowel disease.
Among the conditions which may be termed ‘granulomatous vasculitis’ are included Wegener's granulomatosis, lymphomatoid granulomatosis, Churg–Strauss syndrome, necrotizing sarcoidal vasculitis, and bronchocentric granulomatosis. Because these usually present with symptoms and signs in the respiratory tract they have been termed by some as ‘pulmonary angiitis and granulomatosis’: this term is now out of date. Lymphomatoid granulomatosis, which was thought to be similar in many ways to Wegener's granulomatosis, is now known to be a T-cell lymphoma.
Autoantibodies to neutrophil cytoplasmic components including antineutrophil cytoplasmic antibody are associated with Wegener's granulomatosis and have been detected throughout the spectrum of vasculitis, excluding giant cell arteritis. In addition to providing evidence for an autoimmune aetiology for vasculitis, such serological findings may form the basis of new classification systems (see Section 7.9.3) 36.
Giant cell arteritis (temporal arteritis; cranial arteritis) presents with focal granulomatous inflammation of medium and small arteries (especially cranial vessels) of the elderly. This inflammation is localized to and destroys elastin fibres (Fig. 2) 212, and probably represents an autoimmune reaction to components of elastin. There is a female to male ratio of 3:1. Patients present with headache, throbbing temporal pain and tenderness, or with fever and malaise. The disease usually follows a benign course over 6 to 12 months, but blindness and death may occur. There is a dramatic response to steroids. Giant cell aortitis which may affect the thoracic or abdominal aorta and which may be associated with dissecting aneurysm formation is present in 10 per cent of patients.
Wegener's granulomatosis is an acute, necrotizing granulomatous disease of the arteries, veins, and adjacent tissues of the upper respiratory tract. It may be associated with focal or diffuse glomerulonephritis. There is a dramatic response to cyclophosphamide.
Churg–Strauss syndrome is a multisystem vasculitis which involves pulmonary and splenic vessels and is associated with bronchial asthma and eosinophilia. The vascular lesions resemble polyarteritis nodosa histologically.
Takayasu's arteritis (pulseless disease) presents as a clinical syndrome of ocular disturbance, and marked weakness of pulse in the upper extremities, related to fibrous thickening of the aortic arch with narrowing or obliteration of the origins of the great vessels. It may also affect the origin of large vessels in the abdominal aorta, e.g. renal arteries. It is predominantly seen in young women (female to male ratio of 9 : 1), with an average age of onset of 30 years. Aneurysms, haemorrhage, and thrombosis are common.
Thromboangiitis obliterans (Buerger's disease) is characterized by segmental, thrombosing, obliterative acute and chronic inflammation of arteries and veins, usually of the legs, leading to gangrene. It is almost exclusively seen in young male cigarette smokers.
Vasculitis of collagen vascular disease
The collagen vascular diseases include arthritis, myositis, carditis, and vasculitis. There is considerable overlap between the hypersensitivity and granulomatous categories of vasculitis in these conditions.
Rheumatoid arteritis occurs in a small number of men with rheumatoid arthritis affecting the spine (rheumatoid spondylitis). This is a true panarteritis, with necrosis and fibrosis of the media, obliteration of vasa vasorum, and intimal thickening. Between 25 and 30 per cent of patients have an aortitis, which may feature giant cells.
Behçet's syndrome, originally described as the triple symptom complex of recurrent oral and genital ulcers and relapsing iritis, is now recognized as a systemic disease which may involve any organ. The disease is most prevalent in patients from the Mediterranean, the Middle East, and Japan (prevalence 1 in 10 000). It is seen more commonly in men in the third decade of life. The vascular lesions consist of thrombophlebitis, arterial thrombosis, and aneurysm formation.
Endocarditis, myocarditis, pericarditis, valvular heart disease, atherosclerosis, and hypertensive heart disease are all seen in systemic lupus erythematosus. Lupus vasculitis causes a polyarteritis type of necrotizing vasculitis in small and medium-sized systemic, cerebral, and pulmonary vessels. It may also affect large vessels, including the aorta, producing a variety of lesions including a giant cell granulomatous aortitis.
The classic vascular lesion of scleroderma is seen most commonly in the kidney where it resembles the lesion seen in malignant hypertension.
Dermatomyositis is a multisystem disease characterized by vascular inflammation affecting primarily the skin and muscle. It is part of a continuum that includes polymyositis (in which the skin is spared).
Relapsing polychondritis is a systemic disease characterized by recurrent inflammation and destruction of cartilaginous structures of the ears, nose, trachea, larynx, and joints. Systemic vasculitis occurs, which shows histological similarity to polyarteritis nodosa.
Sjögren's syndrome is a chronic lymphoproliferative disorder. Small vessel, hypersensitivity vasculitis, either lymphocytic or leucocytoclastic, occurs in 10 to 15 per cent of patients.
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