In a small percentage of patients with chronic urticaria, perhaps about 2% , there is an underlying small vessel vasculitis. It is important to diagnose these patients because they may have an associated systemic illness which can lead to severe complications and because the treatment of urticarial vasculitis differs from that of ordinary chronic urticaria. Clinically, the lesions of urticarial vasculitis are longer-lasting (3–7 days) than those of ordinary chronic urticaria. They are often painful or ‘burning’ and they may leave residual bruising or hyperpigmentation of the skin. Approximately 40% of patients with urticarial vasculitis will have associated angioedema. Urticarial vasculitis may occur at any age, but the median age of incidence is 43 years. Women are affected twice as often as men. Two categories of urticarial vasculitis are recognized – hypocomplementaemic and normocomplementaemic . Patients with hypocomplementaemic urticarial vasculitis syndrome (HUVS) are more likely to have an associated connective tissue disease and systemic symptoms than patients with normal complement levels  and may have IgG antibodies to the collagen-like domain of C1q . There may be associated fever, arthralgia (50%), gastrointestinal involvement with abdominal pain, nausea, vomiting and diarrhoea (20%); pulmonary disease with dyspnoea or pulmonary effusions (20%); and glomerulonephritis with haematuria and proteinuria (5–10%). Progressive renal disease is rare, unless the urticarial vasculitis is associated with SLE. Other rare manifestations include eye involvement, lymphadenopathy, splenomegaly and pericardial effusions.
Diagnosis is by skin biopsy, taken ideally from a ‘new’ lesion (within 12 h of appearance), which shows a small vessel leucocytoclastic vasculitis involving post-capillary venules, with endothelial cell swelling, a neutrophil cell infiltrate, extravasation of red blood cells and fibrinoid deposits in and around blood vessels . The condition is thought to be mediated via a type III/immune complex hypersensitivity reaction, in which antigen/antibody complexes deposit in vessel walls. This results in complement activation, neutrophil chemotaxis and infiltration and the release of proteolytic neutrophil enzymes, such as collagenases and elastases, which cause tissue damage. Immunofluorescence shows deposition of immunoglobulin and complement.
In most cases urticarial vasculitis is idiopathic, but it may be associated with connective tissue diseases such as SLE or Sjögren's syndrome; infections such as hepatitis B and C, Lyme disease and infectious mononucleosis; treatment with drugs, including ACEI, cimetidine, diltiazem, penicillins, sulphonamides and thiazides; and lymphoproliferative diseases such as mixed cryoglobulinaemia and IgM gammopathy. A specific syndrome of urticarial vasculitis and IgM gammopathy with fever, bone pain and arthralgia or arthritis –‘Schnitzler's syndrome' – was first described in 1972 [76,77].
The clinical history should indicate if a vasculitic process is likely, with the lesions lasting for several days, instead of hours, and being painful or burning, instead of itchy. Patients should be asked about drug treatment and joint, gastrointestinal and pulmonary symptoms. Examination may show purpura or hyperpigmentation at the sites of earlier lesions and, possibly, signs of an associated underlying disease such as SLE. Investigations which may be relevant include skin biopsy to confirm the diagnosis; FBC and ESR; renal and liver function tests; urine analysis; complement C3 and C4 levels and anti-C1q antibodies; ANA and extractable nuclear antigens (ENA) (often positive for Ro/SS-A and La/SS-B if the patient has Sjögren's syndrome); hepatitis, Borrelia or Epstein–Barr virus serology; immunoglobulins and protein electrophoresis and cryoglobulins and chest X-ray (CXR) and pulmonary function tests if symptoms suggest lung involvement. [Anti-neutrophil cytoplasmic antibodies (ANCA) are rarely found in urticarial vasculitis and if ANCA testing is positive an alternative diagnosis such as Wegener's granulomatosis or microscopic polyangiitis should be considered.]
Treatment of urticarial vasculitis differs from that of ordinary chronic urticaria and depends upon whether there is systemic involvement and/or an underlying medical condition. If the disease is limited to the skin, anti-histamines and NSAIDs usually relieve symptoms, although occasionally NSAID treatment may make the urticaria worse. If anti-histamines and NSAIDs are ineffective, colchicine, dapsone or hydroxychloroquine may be tried. Oral steroids may be required if there is systemic involvement. There are case reports of patients responding to rituximab  and mycophenolate mofetil . The clinical course is variable and depends upon whether there is associated hypocomplementaemia and/or systemic involvement. In most patients urticarial vasculitis remains confined to the skin, but it may persist for years.
Mastocytosis is a disease in which there is mast cell hyperplasia affecting the skin, gastrointestinal tract, bone marrow, liver, spleen and lymph nodes. Clinical features include urticaria, pruritus, flushing, nausea, vomiting, abdominal pain, diarrhoea and headache. Patients may be prone to severe anaphylactoid reactions after exposure to certain medications  and severe anaphylactic reactions after exposure to antigens to which they are sensitized, such as insect venom , because of the increased tissue load of mast cells. Mastocytosis is classified into cutaneous and systemic variants and urticaria pigmentosa is the most common form of cutaneous mastocytosis, occurring in approximately 85% of children and 95% of adults in whom mastocytosis is limited to the skin. Systemic mastocytosis varies from an indolent condition, where there is no associated haematological disease, to an aggressive mast cell leukaemia. The lesions of urticaria pigmentosa are variable in colour, macular or maculopapular and are usually symmetrical in distribution, with sparing of the extremities and face. The diagnosis of urticaria pigmentosa is made by skin biopsy, which shows a significant increase in dermal mast cells . Patients have symptoms of pruritus and dermographism and pressure on affected skin causes erythema and urtication –‘Darier's sign'. Children usually present before the age of 2 years and urticaria pigmentosa may be present at birth. They tend to have fewer, larger skin lesions than adults and they may also develop bullae, which do not occur in adults. Treatment is with H1 and H2 anti-histamines and ketotifen  (an anti-histamine with mast cell-stabilizing properties), methoxsalen with long-wave ultraviolet radiation (psoralen plus ultraviolet A,)  and topical steroids  may all be used to alleviate urticaria and pruritus. It is rare for children to develop systemic mastocytosis and urticaria pigmentosa resolves completely in about 50% of children. In contrast, urticaria pigmentosa in adults usually persists and about 50% of patients may go on to develop systemic mastocytosis. The prognosis in adults is, therefore, highly variable.
Cryopyrin-associated periodic syndromes (CAPS)
Mutations in the CIAS1 gene, which codes for cryopyrin, cause autoinflammatory syndromes, one of which is Muckle–Wells syndrome , also known as urticaria–deafness–amyloidosis (UDA). It is a rare, autosomal dominant condition which presents with spontaneous urticaria, sensorineural deafness, episodic fevers and arthralgia and it may progress to renal amyloid.