Abstract
Hypocomplementemic urticarial vasculitis syndrome (HUVS) is a type III hypersensitivity reaction characterized by urticaria with persistent acquired hypocomplementemia. Although HUVS is uncommon, it is important for physicians to be familiar with this disease, as the initial presentation is often life-threatening angioedema. The author reports the case of a 47-year-old white woman with a history of HUVS. She presented to an outpatient clinic complaining of a rash and difficulty swallowing. Urticaria and angioedema were diagnosed. The patient was given epinephrine in the clinic and then transferred to the hospital. Laboratory testing confirmed urticaria, and the patient was given intravenous methylprednisolone sodium succinate and an additional dose of epinephrine. After 1 week, the patient's angioedema improved.
First described in 1973, hypocomplementemic urticarial vasculitis syndrome (HUVS) is a form of severe vasculitis associated with several systemic findings including leukocytoclastic vasculitis, angioedema, pulmonary manifestations, arthritis, arthralgia, glomerulonephritis, and uveitis.
1 Laboratory findings include low complement levels of the classical complement, principally C1q, C2, C4, and the presence of anti-C1q antibodies. Treatment, which varies with disease severity, involves corticosteroids and other immunosuppressive agents. This disease is associated with high rates of morbidity and mortality, most commonly caused by chronic obstructive pulmonary disease and acute laryngeal edema.
2
A 47-year-old woman with a known diagnosis of HUVS presented to an outpatient rheumatology clinic with a chief complaint of “my throat feels like it is closing.” The patient's initial symptoms included urticaria on her arms and trunk and angioedema of the face, lips, and throat. In addition, she complained of a headache with blurry right-sided vision. The patient was presumed to have angioedema secondary to HUVS. She was given a 0.3-mg epinephrine injection at the outpatient rheumatology clinic and then transported to the intensive care unit at the local hospital because of airway compromise.
This patient was first diagnosed as having HUVS 1 year before presentation by her rheumatologist after presenting with muscle pains in her hands and shoulders, general fatigue, dizziness, and hair loss. She reported developing redness and a rash on her cheeks and nose with sun exposure as well as recurrent, painful wheals that left hyperpigmentation of her skin when resolved. She also experienced swelling in her tongue and lips on a monthly basis, for which she was treated with methotrexate and prednisone with good response. The patient also met the diagnostic criteria for systemic lupus erythematosus (SLE) and was started on hydroxychloroquine sulfate and prednisone. Hydroxychloroquine was discontinued because of adverse effects, but the patient was receiving 15 mg of prednisone daily when she presented to the clinic
Findings from a biopsy of skin wheals and a hematoxylin and eosin stain confirmed urticaria, and the direct immunoflourescence was consistent with HUVS. Results of laboratory testing are presented in the
Table.
The patient received methylprednisolone sodium succinate (125 mg intravenously) and diphenhydramine hydrochloride (50 mg intravenously) as well as another single dose of 0.3 mg epinephrine. As the angioedema symptoms improved, oral prednisone was started (60 mg daily) and methylprednisolone sodium succinate was discontinued. After test results confirmed the patient did not have a glucose-6-phosphate dehydrogenase (G6PD) deficiency, dapsone (50 mg twice daily) was started. The patient was discharged after a 1-week hospital course and received a prescription for 0.3 mg subcutaneous epinephrine for emergency purposes. The patient had no return of angioedema symptoms at 2-week follow-up.
Hypocomplementemic urticarial vasculitis syndrome refers to a constellation of signs and symptoms with a specific set of diagnostic criteria as defined by Schwartz et al
3 (
Figure). Additional clinical findings may include pseudotumor cerebri, Raynaud phenomenon, chronic obstructive pulmonary disease (COPD), and pericarditis. Angioedema is the initial clinical presentation in 50% of patients with HUVS.
4,5 Patients commonly have SLE overlap, secondary Sjögren syndrome, or both. Although 2% of patients with normal complement urticarial vasculitis meet the diagnostic criteria for SLE, 50% of those with HUVS meet the criteria.
1,4
Primary urticaria and HUVS have several differences. Primary urticaria is extremely pruritic, persists for 2 to 8 hours, and blanches with pressure. The vasculitic urticaria of HUVS may be pruritic but is more commonly painful and burning, lasting 24 to 72 hours. Lesions of HUVS also leave residual hyperpigmentation due to red blood cell extravasation, do not blanch under pressure, and are usually smaller (0.5-5 cm) than primary urticaria, which may coalesce into large lesions up to 10 cm.
1,5
Biopsy results of HUVS skin lesions reveal hypersensitivity vasculitis, which demonstrates injury to the endothelial cells, erythrocyte extravasation, fibrin deposition, and neutrophilic infiltrate. A lupus band test can detect SLE; in a positive finding, direct immunofluorescence demonstrates deposition of IgM, C3, or both at the dermal-epidermal junction as well as involvement of the vessels in the superficial dermis.
4, 5 In the present case, the patient's biopsy results were positive for findings consistent with the lupus band test.
Hypocomplementemic urticarial vasculitis syndrome is a type III hypersensitivity reaction with deposition of immune complexes. The C1q molecule has a collagen-like region that forms a binding site for antibodies. IgG molecules bind to the Fc portion of C1q molecules, activating the classical complement pathway. Activation of the pathway stimulates mast cell release, chemotaxis of neutrophils, and increased vessel permeability, or angioedema.
1,5 Immune complexes are formed and the serum levels of complement are depleted.
C1q autoantibodies may also have a role in pulmonary findings.
4,6 One theory includes the cross-reactivity of C1q antibodies with pulmonary surfactant apoproteins that contain collagen-like regions similar to C1q.
7 Lymphoproliferative disorders are also associated with C1q autoantibodies. Although B-cell lymphomas are the most common disorder, chronic lymphocytic leukemia and multiple myeloma have also been reported to occur. In these disorders, circulating paraproteins are thought to activate C1 via the classical complement pathway and lead to the depletion of C1q esterase inhibitors. This process can also directly lead to angioedema because of the resultant circulating immune complex.
4,6
In a 2004 review of urticarial vasculitis and HUVS, Davis and Brewer
4 found that vasculitis may be platelet mediated. When platelet-activating factor was injected, vessel destruction was demonstrated within 32 hours.
4
Treatment of patients with HUVS depends on the presenting symptoms as well as the degree of systemic involvement. Glucocorticoids, dapsone, and antihistamines are the primary therapeutic interventions. Other drugs often used are methotrexate, hydroxychloroquine sulfate, colchicine, and cyclosporine.
1,8,9
Because of its success in treatment and its tolerability, dapsone has emerged as the preferred therapy for HVUS. Dapsone has been shown to be particularly effective in patients with pulmonary involvement.
5,9 Laboratory evidence indicates that dapsone may be effective in treating patients with HUVS by inhibiting the adherence of neutrophils to both IgA and IgG classes of antibasement membrane antibodies. This inhibition reduces the neutrophil-mediated inflammatory response in HUVS.
9 Because dapsone is a sulfone, patients should be checked for G6PD deficiency before starting treatment to avoid the risk of severe hemolysis.
5 Those patients with a class III variant of G6PD deficiency may be treated with dapsone if no viable alternative exists. Methemoglobinemia is another potential adverse effect of dapsone, and patients should be monitored for this complication.
7
The prognosis for patients with HUVS is largely dependent on the degree of systemic manifestations, with angioedema, COPD, and cardiac manifestations—including recurrent pericarditis and cardiac tamponade—presenting the biggest treatment challenges.
Pulmonary complications are the leading causes of morbidity and mortality in patients with HUVS. In addition to COPD, other findings include asthma, cough, dyspnea, hemoptysis, pleuritis, and pleural effusions.
2,5,6 Tracheal stenosis has also been reported.
7 Most patients with HUVS and COPD are tobacco smokers; however, the degree of lung damage in these patients is disproportionate to the level of tobacco use. Pulmonary findings are a result of vasculitis in the lungs releasing elastase.
2,7 Smoking is thought to recruit neutrophils and accelerate this process. Patients with HUVS should avoid smoking and inhaling second-hand smoke.
7
Because patients with HUVS can develop angioedema at any time during the course of the disease, physicians should instruct them on emergency management of symptomatic angioedema. Epinephrine may be useful for initial management of symptoms, but it should not be relied on as the sole treatment because patients can progress very rapidly to airway compromise. Therefore, patients should be instructed to call for emergency assistance with the first appearance of symptoms. High-dose steroids are the primary treatment for patients with acute angioedema.
4,8 All physicians should be aware of the difference between the more common and benign primary urticaria and the less common but potentially life-threatening HUVS.