Urticarial Vasculitis

 

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]).^3,4

Pathophysiology

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.^5,6 The presence of antineutrophilic cytoplasmic antibodies is rare.

 

History

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:

• Drug induced, such as ACE inhibitors, penicillin, sulfonamides, fluoxetine, cimetidine, diltiazem, thiazides, potassium iodide, non-steroid inflammatory drugs, and glatiramer acetate.⁷
• Rheumatic disease, such as SLE and Sjögren syndrome: Urticarial vasculitis has also been reported with immunoglobulin A and immunoglobulin M monoclonal gammopathies, mixed cryoglobulins, and hematologic and solid malignancies.⁸
• Viral disease, such as hepatitis B, hepatitis C,⁹ and infectious mononucleosis

Urticarial vasculitis is divided into hypocomplementemic and normocomplementemic categories, as follows¹⁰ :

• 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.⁵ 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.

Physical

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.

 

Causes

The etiology of urticarial vasculitis has not been elucidated. Associated conditions are listed in History.

 

Laboratory Studies

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.

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.

Imaging Studies

Obtain chest x-ray films for urticarial vasculitis patients with hypocomplementemia and pulmonary symptoms.

Other Tests

If the patient is hypocomplementemic and has pulmonary symptoms, consider ordering pulmonary function tests.

Procedures

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.

Histologic Findings

On biopsy, histologic findings are those of a leukocytoclastic vasculitis, defined as damage to the small vessels in the papillary and reticular dermis

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.

Medical Care

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.

Consultations

Consultation with the following specialists may be needed:

• Dermatologist: Skin biopsy is evaluated by a dermatologist/dermatopathologist to confirm the diagnosis.
• Rheumatologist: Consult a rheumatologist when SLE is suspected or if the patient has the hypocomplementemic variant with systemic symptoms.
• Allergist/immunologist: A guideline summary from the American Academy of Allergy, Asthma and Immunology, Consultation and referral guidelines citing the evidence: how the allergist-immunologist can help, may be helpful.¹²

Medication

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. 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^13,14 and rituximab, has been reported in the literature. However, larger studies have not been performed with these agents.

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.

Hydroxyzine (Atarax, Vistaril)

Antagonizes H1 receptors in periphery. May suppress histamine activity in subcortical region of CNS. Can be used for symptomatic control. The recommended antihistamine for pregnant patients is diphenhydramine. Has been used safely in children.

Diphenhydramine (Benadryl, Benylin, Diphen, AllerMax)

For symptomatic relief of symptoms caused by release of histamine in hypersensitivity reactions.
In pregnancy, use 25-50 mg PO q6h prn.

Anti-inflammatory agents

These agents modulate the immune system to reduce inflammation.

Colchicine

Alkaloid extract that inhibits microtubule formation. Often used for treatment of acute gout. Has been reported effective for urticarial vasculitis. 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.

Sulfone antibiotics

Used for infectious diseases (eg, leprosy); however, sulfones are effective in inflammatory diseases. 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.

Dapsone (Avlosulfon)

Preferred sulfone. Other sulfones must be metabolized to dapsone for their effect. Mechanism of action is similar to that of sulfonamides in which competitive antagonists of PABA prevent formation of folic acid, inhibiting bacterial growth.
Dosing guidelines for dermatologic use have been well described in dermatitis herpetiformis. Most case reports about effect in urticarial vasculitis use dermatitis herpetiformis dosing guidelines. Has been used extensively in chronic bullous disease of childhood.

Antimalarials

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.

Hydroxychloroquine (Plaquenil)

Preferred antimalarial agent because of its low toxicity and high effectiveness profile. Usually well tolerated if carefully monitored by prescribing physician. Therapy is required for 4-8 weeks before evaluating effectiveness.

Nonsteroidal anti-inflammatory agents

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.

Indomethacin (Indocin)

Only NSAID reported effective in urticarial vasculitis. Rapidly absorbed; metabolism occurs in liver by demethylation, deacetylation, and glucuronide conjugation; inhibits prostaglandin synthesis.

Cytotoxic agents

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.

Azathioprine (Imuran)

Purine precursor that affects formation of adenine and guanine. Results in impaired DNA synthesis in immunocompetent cells such as lymphocytes, which are dividing rapidly during inflammatory process. Has slow onset of action; rarely used as monotherapy.

Glucocorticoids

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, combination of prednisone and another medication may be required.

Prednisone (Deltasone)

Although is most effective, adverse effect profiles preclude it from use as a first-line agent. Consider only after failure of antihistamines, indomethacin, colchicine, dapsone, or hydroxychloroquine. 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.