Vasculitis overview

 

Salient features

 

·       Cutaneous signs of vasculitis are a reflection of the size of the vessels involved

 

·       Vasculitis can be limited to the small vessels of the skin or it can be a sign of life-threatening internal organ involvement

 

·       The clinical diagnosis of cutaneous vasculitis requires histopathologic confirmation, and multiple biopsies may be required

 

Introduction

·       Vasculitis is a heterogenous group of disease characterized by inflammation, necrosis and damage of blood vessel walls and it can occur in any organ system of the body.

·       The vessel lumen is usually compromised, and this is associated with ischemia of the tissue supplied by the involved vessel.

·       Any type, size and location of blood vessel may be involved.

·       Vasculitis may be confined to a single organ, such as skin, or it may involve several organ systems.

·       Cutaneous vasculitis may be: (1) a skin-limited disease; (2) a primary cutaneous vasculitis with secondary systemic involvement; or (3) a cutaneous manifestation of a systemic vasculitis.

·       Vasculitis can affect small, medium-sized or large vessels of the arterial and/or venous systems.

·       Cutaneous vasculitis or cutaneous involvement occurs almost exclusively with vasculitis of small and medium-sized vessels.

·       Small blood vessels include arterioles, capillaries and postcapillary venules which are found in the superficial papillary dermis of the skin; eg. Henoch- schonlein purpura (HSP), urticarial vasculitis (UV) and cutaneous small vessel vasculitis (CSVV). 

·       Medium-sized vessels refer to the small arteries and veins that reside within the deep reticular dermis and subcutis septa. E.g. Polyarteritis nodosa PAN) and Kawasaki disease (KD).

·       Large vessels include the aorta and named arteries.

 

 

·       Cutaneous small vessel vasculitis (CSVV) is synonymous with cutaneous leukocytoclastic vasculitis (LCV) and refers to involvement of the postcapillary venules of the dermis by intense neutrophilic vascular inflammation.

 

Epidemiology

 

·       The incidence of biopsy-proven cutaneous vasculitis of all types is 15–60 patients per million per year. Cutaneous vasculitis occurs in all age groups (mean age in adults, 47 years; mean age in children, 7 years), has a slight female predominance, and is much more common in adults than in children. The majority of children have Henoch–Schönlein purpura.

 

 

Pathogenesis

 

·       All forms of CSVV are mediated by immune complexes that form in the presence of antigen excess. Immune complex deposition in postcapillary venules activates complement, which, in turn, induces mast cell degranulation and neutrophil chemotaxis. Neutrophils release proteolytic enzymes and free oxygen radicals, leading to damage of the vessel wall. Increased adhesiveness between inflammatory cells and the endothelium, due to enhanced expression of adhesion molecules (e.g. selectins, LFA-1), also plays a role in the pathogenesis of cutaneous vasculitis.

·       A postulated sequence of events would be the activation of the mast cell by physical stimuli, the release of vasoactive mediators, the deposition of circulating immune complexes with activation of the complement system, the influx of neutrophils, and the development of CNV.

·       Time–course analysis of CNV: At 3 hours, the number of mast cells decreased, and the eosinophil was the first cell to appear around the venules with the deposition of eosinophil peroxidase. TNF-α levels were elevated, E-selectin was expressed on endothelial cells, and an influx of neutrophils appeared within the first 24 hours with the deposition of neutrophil elastase and the development of CNV.

Pathogenesis of cutaneous vasculitis – immune complex- versus ANCA-mediated.  A In immune complex-mediated vasculitis, circulating antigens (e.g. infectious agents, medications, neoplasms) induce antibody formation. Binding of antibodies to circulating antigens creates immune complexes. Immune complex deposition within postcapillary venules activates complement and subsequently leads to an increase in adhesion molecule expression on the endothelium. Complement split products (C3a and C5a) induce mast cell degranulation and neutrophil chemotaxis. Mast cell degranulation leads to increased vascular dilation and permeability, enhancing immune complex deposition and leukocyte tethering to endothelium. Increased adhesion between inflammatory cells (especially neutrophils) and the endothelium is mediated by elevated expression of selectins (E-selectin, P-selectin) and members of the immunoglobulin superfamily (ICAM-1, VCAM-1, PECAM-1) on endothelial cells in concert with the upregulation of their corresponding ligands and receptors/adhesion molecules on leukocytes (e.g. P-selectin glycoprotein ligand-1, LFA-1, Mac-1). Neutrophils release proteolytic enzymes (such as collagenases and elastases) and free oxygen radicals that damage the vessel wall. In addition, formation of the membrane attack complex (C5–C9) on the endothelium leads to the activation of the clotting cascade and the release of cytokines and growth factors with ensuing thrombosis, inflammation and angiogenesis. B In ANCA-mediated vasculitis, intracellular proteins from neutrophils (e.g. proteinase 3 [PR3], myeloperoxidase [MPO]) become expressed on the cell surface. After formation of ANCA that recognize these antigens, binding of the autoantibodies to neutrophils leads to increased neutrophil adhesion to vessel walls and subsequent cellular activation. Neutrophils then release reactive oxygen species and other toxic mediators that result in vessel wall damage (see A). Because the vessel damage in ANCA-positive vasculitides is directly mediated by neutrophils rather than by immune complexes, they are referred to as “pauci-immune” vasculitides.

 

·       ANCA are primarily directed against intracellular neutrophilic proteins (e.g. proteinase-3, myeloperoxidase), which can translocate to the neutrophil's cell surface following primary activation by cytokines such as tumor necrosis factor (TNF)-α. Binding to the surface of neutrophils results in neutrophil-mediated vessel damage. Because the vessel damage in ANCA-positive vasculitides is directly mediated by neutrophils rather than by immune complex deposition, they are referred to as “pauci-immune” vasculitides. Formation of ANCA may be related to an impairment in neutrophil apoptosis which results in a prolonged opportunity for autoantibody development.

 

Clinical features

·       The skin lesions of CSVV usually appear 7–10 days after the triggering event. In systemic vasculitic syndromes, signs of systemic involvement often precede the appearance of associated cutaneous lesions (average, 6 months), but the interval can be as short as days or as long as years. The cutaneous findings of vasculitis depend upon the predominant size of the vessels that are involved. Cutaneous CSVV vasculitis often results in painful, palpable purpura. Leakage of blood from the vasculature into the interstitium causes purpura, which is identified by a failure to blanch on diascopy (pressure with glass). Increased pressure in the venous circulation increases blood vessel leakage and may worsen damage to the vessel walls. Purpura is therefore most apparent on the lower limbs. Prolonged standing exaggerates venous hypertension and thus increases blood leakage and purpura.

 

·       Severe cutaneous vasculitis will result in painful ischemia of the skin. Lesional skin will become hemorrhagic and then necrotic and will eventually detach, leaving erosions or ulcers, most commonly on the lower limbs. These ulcers may then become secondarily infected. The ulcers may be slow to heal, even after resolution of the vasculitis, due to venous stasis, malnutrition, anemia, lymphedema, prolonged infection or old age.

·       In medium-sized vessel vasculitis, the affected blood vessels reside within the deep reticular dermis or subcutis. As a result, the latter typically presents with livedo racemosa, retiform purpura, ulcers, subcutaneous nodules, digital necrosis or ulcers.  In general, the presence of necrosis or ulcers suggests deeper arterial involvement. The combination of palpable purpura  plus signs of medium-sized vessel disease points to a “mixed” pattern of vasculitis, as is seen in ANCA-associated vasculitides, mixed cryoglobulinemia, or autoimmune connective tissue disease-associated vasculitis. Since polyarteritis nodosa affects only medium-sized vessels, it rarely presents with cutaneous signs of small vessel involvement.

 

·       Arthralgias and arthritis as well as constitutional symptoms such as fever, weight loss and malaise can be manifestations of vasculitis of any size vessel. For patients with systemic involvement, presenting symptoms and signs (e.g. abdominal pain, paresthesias, and hematuria) will vary according to the affected organs.