Small-vessel vasculitis

The small-vessel vasculitides are the most common forms of systemic vasculitis, and the most severe forms may lead to pulmonary haemorrhage and glomerulonephritis, making them particularly relevant to the intensive care setting. It is useful to consider these diseases by the underlying pathophysiology, broadly dividing them into forms of vasculitis that are immune-complex mediated and forms of vasculitis that are pauci-immune.

The majority of the small-vessel vasculitides are mediated by immune complex deposition, whereby immune deposits in the vessel wall lead to inflammation. Examples of immune complex-mediated small vessel vasculitis include anti-glomerular basement membrane (anti-GBM) disease, IgA vasculitis (IgAV; Henoch–Schönlein purpura) and cryoglobulinaemic vasculitis .

Anti-GBM disease is a vasculitis that affects the glomerular capillaries, pulmonary capillaries or both. The disease is driven by binding of anti-GBM antibody to the basement membrane, resulting in in situ immune complex formation. While anti-GBM disease is not associated with a leucocytoclastic infiltrate, it is classified as a vasculitis since it is characterised by vascular injury induced by both cellular and humeral inflammatory mechanisms. Clinically, anti-GBM disease leads to pulmonary haemorrhage and crescentic glomerulonephritis .

IgAV is the most common childhood vasculitis, but IgAV can present at any age, most commonly after an upper respiratory tract infection. Driven by deposition of IgA-dominant immune complexes, the syndrome is clinically characterised by purpura, arthralgias and colicky abdominal pain. Ten percent of patients develop renal insufficiency and 5% will progress to renal failure . Pulmonary disease and peripheral neuropathy are rare .

Cryoglobulinaemic vasculitis is caused by deposition of mixed cryoglobulins in vessel walls (predominately the venules, capillaries and arterioles), which lead to acute inflammation. This condition is frequently associated with hepatitis C infection. The most severe cases are associated with glomerulonephritis, although milder cases may present with only purpura and arthralgias .

Some of the vasculitides are not mediated by immune complex deposition. An important group of pauci-immune vasculitides are the anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitides, which affect the small- and medium-calibre vessels, and are characterised by the presence of circulating ANCA. The three canonical forms of ANCA-associated vasculitides (AAV) include granulomatosis with polyangiitis (GPA; Wegener’s granulomatosis), eosinophilic granulomatosis with polyangiitis (EGPA; Churg–Strauss syndrome) and microscopic polyangiitis (MPA).

GPA classically presents as a clinical triad that includes granulomatous inflammation of the respiratory tract, glomerulonephritis and small-vessel vasculitis, and is often associated with the presence of ANCA antibodies directed against proteinase-3 (PR3-ANCA, also known as C-ANCA). Histologically, GPA is characterised by necrotising granulomatous inflammation with little or no immunoglobulin deposition . Many patients will ultimately develop a crescentic glomerulonephritis .

MPA lacks necrotising, granulomatous inflammation. Eighty percent of patients have ANCA antibodies, most commonly directed against myeloperoxidase (MPO-ANCA, also known as P-ANCA) . MPA is the most common cause of pulmonary-renal syndrome , although a large range of organs can be affected. Unlike polyarteritis nodosa (PAN, which only affects the medium-calibre blood vessels), MPA can involve both small- and medium-sized vessels .

EGPA is characterised by the presence of peripheral eosinophilia and MPO-ANCA . It is sometimes useful to think of EGPA as presenting in three clinically distinct phases, starting with adult-onset asthma that gradually becomes steroid-dependent, followed by a phase characterised by hypereosinophilia (which can lead to pulmonary infiltrates and myocarditis), finally leading to the onset of a small- and medium-vessel vasculitis . While vasculitis typically develops within 3 years of asthma onset, the actual time course is highly variable and can be delayed decades . A key difference between EGPA and the other ANCA-associated vasculitides is the relative infrequency of glomerulonephritis, although peripheral neuropathy (e.g., mononeuritis multiplex) and cardiac disease occur more frequently .

Medium-vessel vasculitis

Kawasaki disease (KD) is a vasculitis involving small and medium vessels that classically causes coronary artery aneurysm. While typically a childhood disease, case reports of KD in adults do exist. When compared to children with KD, adults tend to have improved mortality and fewer cardiovascular complications, despite frequent delays in diagnosis and treatment .

PAN is a necrotising vasculitis affecting small- and medium-sized muscular arteries throughout the body . Because PAN spares the arterioles, capillaries and venules, glomerulonephritis does not occur . Rather, renal disease occurs from vascular occlusion and infarct. Some forms of PAN are associated with chronic infection with hepatitis B. PAN leads to a variety of potentially life-threatening manifestations including bowel ischaemia, primary vascular nephropathy and, less commonly, coronary artery aneurysms .

Large-vessel vasculitis

The two major forms of large-vessel vasculitis are giant cell (temporal) arteritis (GCA) and Takayasu’s arteritis. These two conditions are histopathologically similar, leading some investigators to suggest that they might represent the same disease , although there are differences in their epidemiology and in the vessels that are preferentially affected. In contrast to many of the small- and medium-vessel vasculitides, inflammation in large-vessel vasculitis is driven by T-cells, antigen-presenting cells and macrophages; there is no evidence of an autoantibody component .

GCA involves the large branches of the aorta, particularly the vertebral and extracranial branches of the carotid artery . The disease tends to affect patients of Northern European heritage and almost exclusively affects individuals older than 50 years of age , with peak incidence between 75 and 85 years . Inflammation of the large vessels leads to aneurysm formation, or intimal occlusion of the vessels that leads to ischaemia. In the case of GCA-associated aortitis, complications include aortic regurgitation, aortic dissection, stroke and blindness.

Takayasu’s arteritis affects the large elastic arteries and presents clinically with loss of pulse, vascular bruits and hypertension, although it can also affect the brain, lungs, heart, gastrointestinal system and kidneys . Like GCA, Takayasu’s arteritis causes symptoms due to marked arterial wall thickening leading to luminal narrowing or occlusion. Young women in their second and third decades of life are at higher risk, particularly those of Mexican, Japanese, Southeastern Asian or Indian descent , although in the United States, most patients with Takayasu’s arteritis are Caucasian.