The portal for rare diseases and orphan drugs

Prevalence is unknown but less than 500 cases have been reported in the literature. Women are more frequently affected than men (female to male ratio of 8:1).

Patients most commonly present during the fifth decade of life but onset during childhood has been rarely described. Patients present with generalized urticarial eruptions located on the trunk, proximal extremities and face that are often associated with itching or pain and persist for more than 24 hours, with hyperpigmentation after resolution. Angioedema is common and may also be a presenting feature. Cardiorespiratory manifestations include cough, dyspnea, pleural and pericardial effusions, and emphysema, with chronic obstructive pulmonary disease reported in less than 20% of patients. Renal disease is present in 20 to 30% of patients and is generally mild with proteinuria and hematuria caused by glomerulonephritis. However, renal insufficiency and end-stage renal failure have been reported and renal involvement tends to be more severe in patients with childhood onset. Other systemic findings include gastrointestinal symptoms (abdominal pain, nausea, diarrhea, vomiting), musculoskeletal manifestations (arthritis and transient arthralgia affecting the hands, elbows, knees, ankles, and feet), and ocular inflammation (episcleritis, uveitis and conjunctivitis).

Hypocomplementemic urticarial vasculitis (HUV) generally occurs sporadically; however, a few familial cases associated with mutations in DNASE1L3 (3p14.3) have been reported. For the majority of cases the etiology is unknown but anti-C1q autoantibodies are believed to be involved in the pathogenesis of the disorder.

Diagnosis requires the presence of two major criteria (recurrent urticaria for > 3 months and hypocomplementemia) and at least two minor criteria (leukocytoclastic vasculitis on biopsy, arthralgia and arthritis, ocular inflammation, abdominal pain, glomerulonephritis and positive anti-C1q autoantibodies).

The relationship of HUV to systemic lupus erythematosus (SLE) is complex with many overlapping features (manifestations of HUV are present in 10% of SLE patients and 50% of patients with HUV will later be diagnosed as having SLE). Other syndromes such as mixed cryoglobulinemia and Schnitzler syndrome should be excluded.

The pattern of inheritance for the familial cases associated to DNASE1L3 is autosomal recessive. Genetic counseling is recommended for at risk families.

Treatment requires tailored therapy with drugs ranging from colchicine, disulone or hydroxychloroquine to more aggressive therapy, such as steroids and immunosuppressives. For example, patients with cutaneous disease and arthralgias but no major organ involvement may be managed with colchicine, hydroxychloroquine, or dapsone; whereas patients with major organ involvement, such as glomerulonephritis, may require high doses of corticosteroids and cytotoxic agents similar to the treatment for active SLE. Response to treatment is usually accompanied by a decrease in circulating anti-C1q titer and normalization of C3 and C4 levels.

The prognosis for HUV patients is variable and influenced primarily by the severity of the rare pulmonary, cardiac and renal disease. When present, pulmonary disease is the major cause of death. Acute laryngeal edema can be life-threatening.