A 54-year-old woman with a history of depression presents to the clinic with a 1-year history of an intermittent rash. She was hospitalized for COVID-19 approximately 1 year ago and soon after developed a rash all over her body. The lesions persist for several days and have a burning sensation. The patient has no associated joint pain or other systemic symptoms. She tried antihistamines for the rash with no symptomatic relief. On examination, erythematous wheals are evident on her arms and legs as well as her back and abdomen.
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Urticarial vasculitis (UV) is a condition characterized by urticarial lesions with histopathologic findings of leukocytoclastic vasculitis (LCV). It was first reported by Wills and Lond in an 1890 case report describing 2 young men who presented with a purpuric rash and wheals accompanied by fever, arthritis, and angioedema.1 Almost 70 years later, in 1956, McCombs et al published a report of 2 patients with wheals and vasculitic characteristics on histology.1 Since first described in the 19th century, the condition also has been called hemorrhagic urticaria and allergic vasculitis.1
The precise prevalence of UV worldwide is unknown, largely because of its rarity; however, in patients presenting with chronic urticarial rash with histology that meets the criteria for LCV, the prevalence is estimated to be about 5%.2 In the United States, the incidence of UV is estimated to be 0.5 per 100,000 person-years with a median age at diagnosis of 51 years and a female predominance (70%-74%).3 The disease rarely affects infants and children, with only 2 reported infantile cases in the literature and diagnosis in only 1% of children with any type of vasculitis.1,2
Urticarial vasculitis is classified as a type III hypersensitivity reaction or an immune complex-mediated complement activation in the lumen of blood vessels. It generally can be divided based on serum complement levels into normocomplementemic and hypocomplementemic subtypes.1 The majority of UV cases are idiopathic in origin, although some have been tied to medications such as cimetidine, diltiazem, fluoxetine, methotrexate, nonsteroidal anti-inflammatory drugs, telmisartan, enalapril, and levetiracetam.2 Associations with underlying diseases such as autoimmune conditions, infection, myelodysplastic disorders, and malignancy also have been reported.1 Up to 20% of patients with systemic lupus erythematosus reportedly have UV (more commonly the hypocomplementemic subtype), and associations with Sjogren syndrome and inflammatory bowel disease also have been described.1,2 Infections linked to UV include streptococcal infections, tuberculosis, COVID-19, and hepatitis B and C.2
Urticarial vasculitis most commonly affects women, particularly in the fourth and sixth decades of life.2 The use of specific medications and the presence of certain underlying infectious, autoimmune, or malignant conditions have been linked to UV cases. Some investigators have proposed a genetic component to the disease, citing familial cases of the severe and systemically active form of UV called hypocomplementemic urticarial vasculitis syndrome (HUVS), which has been described in a pair of identical twins and among 3 siblings.2 In HUVS patients, cigarette smoking appears to be a strong risk factor for the development of pulmonary disease, which is a leading cause of death among UV patients.4
Patients with UV typically present with indurated wheals that are nonblanchable or are partially blanchable and have a central dark-red or dark-brown macule. When symptomatic, these lesions generally are described as painful or burning but typically are not pruritic.2 Dermoscopy can be a useful tool to identify small areas of vascular necrosis that do not present as frank purpura.5 In addition to cutaneous symptoms, 9% to 56% of patients with UV present with systemic symptoms and signs, such as angioedema, purpura, fever, asthenia, arthralgia, lymphadenopathy, abdominal pain, and/or ocular, pulmonary, or renal manifestations.1
The most common laboratory abnormalities in UV are an elevated erythrocyte sedimentation rate (ESR) and hypocomplementemia.2 Although both abnormalities are fairly nonspecific, the latter can serve as a useful prognostic marker because hypocomplementemic UV is associated with a higher risk for complications and systemic involvement.4 Biopsy of skin lesions may reveal findings of LCV, such as erythrocyte extravasation, vascular and perivascular infiltration of polymorphonuclear leukocytes with nuclear dust, and fibrinoid necrosis of vascular walls.1 Direct immunofluorescence may show deposition of complement in vessel walls.1 Clinicians also should consider complete blood cell count, renal function tests, hepatitis/liver studies, and measurement of antinuclear antibodies to evaluate for possible extracutaneous manifestations and associations listed above.2
It is important to distinguish UV from acute common urticaria and chronic idiopathic urticaria because these and many other conditions can present with urticarial rash. Schnitzler syndrome is an autoinflammatory urticarial condition that also may be mistaken for UV. Other diagnoses to consider include Wells syndrome, erythema migrans, and urticaria multiforme.2
Diagnosis of UV requires both clinical manifestations of urticaria and histopathologic evidence of LCV. Lesional biopsy (ideally performed within the first 24-48 hours of rash appearance) is considered the gold standard for diagnosis.2,5 The clinical picture often helps exclude other diagnoses. For instance, unlike in UV in which lesions last longer than 24 hours and often for several days, chronic urticaria wheals generally resolve after 2 to 8 hours. In addition, the lesions of UV can leave behind areas of hyperpigmentation not seen in chronic idiopathic urticaria. Finally, true urticarial lesions are pruritic and coalesce into large (>10 cm) lesions, whereas those in UV are asymptomatic or painful/burning and smaller (0.5-5 cm in diameter). Differentiation from Schnitzler syndrome may require biopsy; although histopathology exhibits neutrophilic infiltrate in both conditions, no evidence of vasculitis is found in Schnitzler syndrome.2
It is difficult to treat UV; no clinical algorithms exist to guide therapy and many drugs have shown limited efficacy and/or adverse effects. Antihistamines and montelukast are ineffective in most patients with UV.1 The most effective treatment is corticosteroids, which allowed for improvement or remission of cutaneous and systemic symptoms in over 80% of patients across 144 studies when used alone or in combination with other drugs.1 However, treatment must be weighed against the unfavorable side effects of steroid use. Patients with more resistant cases of UV may respond to immunosuppressive drugs such as dapsone, colchicine, cyclophosphamide, mycophenolate mofetil, cyclosporine, and azathioprine.2 The combination of 1 or more immunomodulatory agents with steroids may allow for steroid tapering and improved efficacy. Biologics such as omalizumab, anakinra, tocilizumab, and rituximab are additional options.
In this case, a punch biopsy of the patient’s rash was consistent with UV. Preliminary workup showed elevated ESR, normal antinuclear antibody titer, and normal complement levels. Her liver function tests, renal function test, and complete cell blood count were within normal limits. She was started on oral corticosteroids, which improved her rash.
Christopher Nguyen, BA, is a medical student at Baylor College of Medicine in Houston, Texas; Tara L. Braun MD, is a resident physician in the Department of Dermatology at Baylor College of Medicine; and Christopher Rizk, MD, is a dermatologist at Elite Dermatology in Houston.
1. Kolkhir P, Grakhova M, Bonnekoh H, Krause K, Maurer M. Treatment of urticarial vasculitis: a systematic review. J Allergy Clin Immunol. 2019;143(2):458-466. doi:10.1016/j.jaci.2018.09.007
2. Gu S, Jorizzo J. Urticarial vasculitis. Int J Women’s Dermatol. 2021;7(3):290-297. doi:10.1016/j.ijwd.2021.01.021.
3. Sjowall C, Mandl T, Skattum L, Olsson M, Mohammad AJ. Epidemiology of hypocomplementaemic urticarial vasculitis (anti-C1q vasculitis). Rheumatology (Oxford). 2018;57(8):1400-1407. doi:10.1093/rheumatology/key110
4. Buck A, Christensen J, McCarty M. Hypocomplementemic urticarial vasculitis syndrome: a case report and literature review. J Clin Aesthet Dermatol. 2012;5(1):36-46.
5. Garcia-Garcia B, Auban-Pariente J, Munguia-Calzada P, Vivanco B, Argenziano G, Vazquez-Lopez F. Development of a clinical-dermoscopic model for diagnosis of urticarial vasculitis. Sci Rep. 2020;10(1):6092. doi:10.1038/s41598-020-63146-w