Urticarial vasculitis is an eruption of erythematous wheals that clinically resemble urticaria but histologically show changes of leukocytoclastic vasculitis.[1, 2] Urticarial vasculitis may be divided into normocomplementemic and hypocomplementemic variants. Both subsets can be associated with systemic symptoms (eg, angioedema, arthralgias, abdominal or chest pain, fever, pulmonary disease, renal disease, episcleritis, uveitis, and Raynaud phenomenon). The hypocomplementemic form more often is associated with systemic symptoms and has been linked to connective-tissue disease (ie, systemic lupus erythematosus [SLE], relapsing polychondritis).[3, 4, 5, 6, 7]
The pathophysiology of urticarial vasculitis is similar to other forms of cutaneous small vessel leukocytoclastic vasculitis. Urticarial vasculitis is a type III hypersensitivity reaction in which antigen-antibody complexes are deposited in the vascular lumina. This reaction results in complement activation and chemotaxis of neutrophils. These cells release various proteolytic enzymes, such as collagenase and elastase, resulting in damage to the vascular lumina. Some authors have speculated that eosinophils may be involved in the early stages of the vasculitic lesions. Patients with hypocomplementemic urticarial vasculitis are more likely to show autoantibodies to C1q and vascular endothelial cells.[8, 9] The presence of antineutrophilic cytoplasmic antibodies is rare. Many patients ultimately prove to have SLE. Other etiologies include drug reactions and parasitic infections.[10]
The etiology of urticarial vasculitis has not been elucidated. Associated conditions are listed in History.
The exact frequency of urticarial vasculitis is not known in the United States or worldwide.
Leukocytoclastic vasculitis displayed an incidence of 45 cases per million population from a study conducted in Olmsted County, Minnesota.[11]
Previous studies varied in their definitions of the condition. However, when a study in the United Kingdom used consistent criteria restricted to patients diagnosed with vasculitis by biopsy and with urticarial lesions of more than 3 months duration, 2.1% of 1310 patients with urticaria were found to have urticarial vasculitis.
The male-to-female ratio for urticarial vasculitis is 1:2.
The median age of urticarial vasculitis involvement is 43 years, with a range of 15-90 years. While urticarial vasculitis is primarily a disease of middle-aged adults, it can be seen in persons of any age.
Urticarial vasculitis tends to become a chronic condition and patients should be educated about its course. For most patients, this is a disease that affects the skin, with a minority of patients developing systemic complications.
Urticarial vasculitis carries a good prognosis, with most occurrences resolving in months to years. Urticarial vasculitis associated with hypocomplementemia is associated with a greater incidence of coexisting disease (ie, angioedema, connective-tissue disease [primarily SLE], chronic obstructive pulmonary disease).[12, 13] Mortality is rare. Some cohorts have demonstrated systemic involvement in roughly half of the patients, including musculoskeletal and ocular complications.[14]
Since urticarial vasculitis may be chronic, educate patients about its course. For patient education resources, see the Allergy Center and Skin, Hair, and Nails Center, as well as Hives and Angioedema.
Patients with urticarial vasculitis present with an urticarial eruption, often accompanied by a painful or burning sensation. Lesions are generalized wheals or erythematous plaques, occasionally with central clearing, lasting for more than 24 hours in a fixed location (in contrast to urticaria, which resolves in minutes to hours or migrates continually). Petechiae may be noted within the lesions, and they may resolve with ecchymoses or postinflammatory hyperpigmentation. Patients may have photosensitivity, lymphadenopathy, arthralgia, angioedema (40%), fever, abdominal pain, dyspnea, and pleural and pericardial effusions.[4] Most cases of urticarial vasculitis are idiopathic.
The primary causes of urticarial vasculitis are as follows:
Urticarial vasculitis is divided into hypocomplementemic and normocomplementemic categories.[18]
Hypocomplementemia often is associated with a systemic condition, such as SLE (in which >50% of patients have hypocomplementemia).[3] In addition, as many as 71% of patients with hypocomplementemic urticarial vasculitis have a positive antinuclear antibody titer but do not fulfill the American Rheumatism Association criteria for SLE.[8] Some authors have suggested evaluation of hypocomplementemic urticarial vasculitis for immunoglobulin G antibodies to C1q. Individuals with these antibodies have a higher incidence of angioedema, ocular inflammation, glomerulonephritis, and obstructive pulmonary disease.
Normocomplementemic vasculitis can be associated with connective-tissue disease but at a much lower rate.
Lesions of urticarial vasculitis initially appear as erythematous wheals (see image below). As the lesions progress, purpura may develop. Often, the urticarial vasculitis lesions resolve with postinflammatory pigmentation. Annular or targetoid lesions may be observed.
 View Image | Raised erythematous wheals with postinflammatory hyperpigmentations suggest urticarial vasculitis. |
Check CH50, C3, C4, Clq, and antibodies to Clq in urticarial vasculitis patients. If these test results are positive, evaluate renal function and urinalysis to check for the effects of vasculitis on the kidneys.[19]
If the history suggests viral infections, obtain hepatitis B, hepatitis C, and heterophile antibody serologies.
Direct immunofluorescence may show deposition of vascular C3, fibrin, and immunoglobulins. A lupus band may be detected in patients with underlying lupus erythematosus.
If warranted, obtain antinuclear antibody and lupus serologies. Anti-SSA and anti-SSB may be seen in patients with Sjögren syndrome. Test results for antineutrophilic cytoplasmic antibodies are generally negative, and, if they are positive, the possibility of Wegener granulomatosis or microscopic polyangiitis should be considered.
Obtain chest x-ray films for urticarial vasculitis patients with hypocomplementemia and pulmonary symptoms.
If the patient is hypocomplementemic and has pulmonary symptoms, consider ordering pulmonary function tests.
Perform skin biopsy to confirm the diagnosis of urticarial vasculitis. Recent lesions, less than 48 hours in onset, are the best for biopsy. Biopsy of a lesion of less than 24 hours' duration is best for direct immunofluorescence.
On biopsy, histologic findings are those of a leukocytoclastic vasculitis, defined as damage to the small vessels in the papillary and reticular dermis (see images below).[20]
View Image | A low-power histologic image of urticarial vasculitis shows leukocytoclastic vasculitis with damage to the vessel wall and a neutrophilic infiltrate. |
View Image | A high-power view of the histology of urticarial vasculitis shows extensive fibrin deposition in the vessel walls. Surrounding the vessels is a mixed .... |
Early lesions show a perivascular neutrophilic infiltrate involving postcapillary venules. Leukocytoclasis is present, expansion of the vessel wall occurs, and the endothelium is intact. Eosinophils may be noted early. Fibrin deposition and extravasation of red blood cells ensue.
Later in the lesion's course, infiltrate may become a mixture of lymphocytes and neutrophils. Consider performing direct immunofluorescence on the skin biopsy, which may show deposition of complement and fibrin in the blood vessels and, occasionally, immunoglobulin M, immunoglobulin G, and immunoglobulin A along the basement membrane zone of the skin.
Urticarial vasculitis tends to run a chronic course. Mortality is low, unless renal or pulmonary disease occurs. The goal of treatment is to achieve long-term control with the least amount of toxicity.
A complete patient history is the basis for treatment. In the history, ask for time of onset of the lesions; duration of the lesions (eg, >24 h); whether lesions are painful or burning, rather than pruritic; and the history of resolution with purpura or hyperpigmentation. Inquire about the patient's medications, fever, arthralgia, dyspnea, abdominal pain, and symptoms of angioedema. Omalizumab has produced mixed results.[21, 22]
Consultation with the following specialists may be needed:
Once a diagnosis of urticarial vasculitis is made, follow-up care depends on the patient's complement levels. If complement level findings are normal, follow patients for symptoms and response to treatment. If complement level findings are low, follow patients for attendant complications related to the cause of their hypocomplementemia (see History).
Treatment of urticarial vasculitis is based on systemic effects of the disease, extent of cutaneous involvement, and previous response to treatment. For patients with cutaneous involvement only, antihistamines or nonsteroidal anti-inflammatory drugs (NSAIDs) may provide symptomatic relief. However, Jachiet et al report that antihistamines were therapeutically ineffective for treatment of hypocomplementemic urticarial vasculitis.[14]
If these agents fail, colchicine, hydroxychloroquine, or dapsone may be effective. If all other treatment modalities have failed or if the patient has systemic involvement, consider initiating treatment with glucocorticoids. If the patient requires long-term treatment with corticosteroids, consider every-other-day dosing of the steroid or the addition of azathioprine as a steroid-reducing agent. Response to newer agents, including mycophenolate mofetil[23, 24] and rituximab, has been reported in the literature. Rituximab-based treatment can provide higher response rates compared with corticosteroids and conventional immunosuppressive agents, which supports its use in relapsing, refractory, or severe disease.[14]
Clinical Context: Hydroxyzine antagonizes H1 receptors in the periphery. It may suppress histamine activity in the subcortical region of the CNS. Hydroxyzine can be used for symptomatic control. The recommended antihistamine for pregnant patients is diphenhydramine. Hydroxyzine has been used safely in children.
Clinical Context: Diphenhydramine is used for symptomatic relief of symptoms caused by release of histamine in hypersensitivity reactions. In pregnancy, use 25-50 mg PO q6h prn.
Antihistamines may serve as an adjunctive agent to relieve the itching or burning associated with urticarial vasculitis. Given alone, they usually provide only symptomatic relief.
Clinical Context: Colchicine is an alkaloid extract that inhibits microtubule formation. It is often used for the treatment of acute gout. Colchicine has been reported effective for urticarial vasculitis. It concentrates well in leukocytes and reduces neutrophilic chemotaxis and motility. Histologically, urticarial vasculitis presents with neutrophil involvement; therefore, colchicine possibly is useful. However, drug's effect has not been proven in clinical trials.
Clinical Context: Dapsone is the preferred sulfone. Other sulfones must be metabolized to dapsone for their effect. The mechanism of action is similar to that of sulfonamides in which competitive antagonists of PABA prevent the formation of folic acid, inhibiting bacterial growth.
Dosing guidelines for dermatologic use have been well described in dermatitis herpetiformis. Most case reports about effects in urticarial vasculitis use dermatitis herpetiformis dosing guidelines. Dapsone has been used extensively in chronic bullous diseases of childhood.
Sulfone antibiotics are used for infectious diseases (eg, leprosy); however, sulfones are effective in inflammatory diseases. The mechanism of action may involve inhibiting free radical formation by neutrophils. In most case reports, these medications are effective only in purely cutaneous forms of urticarial vasculitis.
Clinical Context: Hydroxychloroquine is the preferred antimalarial agent because of its low toxicity and high effectiveness profile. It is usually well tolerated if carefully monitored by the prescribing physician. Therapy is required for 4-8 weeks before evaluating effectiveness.
Like other medications used to treat urticarial vasculitis, antimalarials are believed to exert their effect by their anti-inflammatory properties. Antimalarials reduce neutrophilic chemotaxis. In addition, they increase pH in lysosomes, which may affect antigen presentation. This class of medications usually is effective only in cutaneous disease.
Clinical Context: Indomethacin is the only NSAID reported effective in urticarial vasculitis. It is rapidly absorbed; metabolism occurs in the liver by demethylation, deacetylation, and glucuronide conjugation. Indomethacin inhibits prostaglandin synthesis.
Nonsteroidal anti-inflammatory agents are most commonly used for relief of mild to moderate pain. The basis behind the use of indomethacin is empiric. It was used with some effectiveness on the cutaneous manifestations of the disease in several case reports.
Clinical Context: Azathioprine is a purine precursor that affects the formation of adenine and guanine. This results in impaired DNA synthesis in immunocompetent cells such as lymphocytes, which are dividing rapidly during an inflammatory process. Azathioprine has a slow onset of action; it is rarely used as monotherapy.
Azathioprine may be used as a steroid-sparing agent once other therapeutic options have been exhausted. Measurement of thiopurine methyltransferase can help ensure safe and optimal treatment with azathioprine.
Clinical Context: Although prednisone is most effective, adverse effect profiles preclude it from use as a first-line agent. Consider it only after failure of antihistamines, indomethacin, colchicine, dapsone, or hydroxychloroquine. Its effect on urticarial vasculitis likely is mediated by its anti-inflammatory effect. This class of medications decreases capillary permeability and inhibits the mitotic rate of lymphocytes.
Glucocorticoids are often the treatment of choice. However, given their long-term adverse effect profiles, they are used only for significant cutaneous disease or systemic involvement. For long-term treatment, a combination of prednisone and another medication may be required.
Raised erythematous wheals with postinflammatory hyperpigmentations suggest urticarial vasculitis.
A low-power histologic image of urticarial vasculitis shows leukocytoclastic vasculitis with damage to the vessel wall and a neutrophilic infiltrate.
A high-power view of the histology of urticarial vasculitis shows extensive fibrin deposition in the vessel walls. Surrounding the vessels is a mixed infiltrate predominately composed of neutrophils with leukocytoclasis.
Raised erythematous wheals with postinflammatory hyperpigmentations suggest urticarial vasculitis.
A low-power histologic image of urticarial vasculitis shows leukocytoclastic vasculitis with damage to the vessel wall and a neutrophilic infiltrate.
A high-power view of the histology of urticarial vasculitis shows extensive fibrin deposition in the vessel walls. Surrounding the vessels is a mixed infiltrate predominately composed of neutrophils with leukocytoclasis.
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