Urticarial vasculitis

INTRODUCTION — Urticarial vasculitis (UV) is considered a clinicopathologic entity consisting of two elements:

●Clinical manifestations of urticaria

●Histopathologic evidence of cutaneous leukocytoclastic vasculitis (LCV) of the small vessels, largely involving the postcapillary venules [1-4]

UV may predominantly involve the skin or affect other organ systems (picture 1A-F) [5]. Hypocomplementemia, when present, may be associated with extensive vasculitis and systemic features that most commonly involve the musculoskeletal, pulmonary, renal, and/or gastrointestinal systems. Although UV is most commonly idiopathic, it can occur in association with autoimmune diseases, drug reactions, infections, or malignancy. Discussion of UV is confounded by the lack of accepted criteria for distinguishing UV from other cutaneous vasculitides and associated conditions.

The epidemiology, clinical features, laboratory and biopsy findings, differential diagnosis, treatment, and prognosis of UV are reviewed here. A more general discussion of urticaria and related conditions is presented elsewhere. (See "Chronic spontaneous urticaria: Clinical manifestations, diagnosis, pathogenesis, and natural history".)

TERMINOLOGY — Urticarial vasculitis (UV) is characterized by a variety of cutaneous, systemic, and serologic features, which have resulted in a confusing array of names for the disorder(s) [6].

UV likely represents a continuum of disease, ranging from urticaria with minimal vasculitis, to life- or organ-threatening systemic vasculitis with minimal urticaria. Some patients have low complement levels, a feature that is associated with more severe disease and with systemic involvement. By comparison, patients with normal complement levels are more likely to have mild disease (sometimes referred to as normocomplementemic urticarial vasculitis [NUV]). The annual incidence of hypocomplementemic urticarial vasculitis syndrome (HUVS) per million inhabitants in a Swedish study was estimated to be 0.7 (95% CI 0.4-1.1), 1.3 (95% CI 0.6-1.9) for women and 0.2 (95% CI 0-0.4) for men [7].

Urticarial vasculitis is sometimes discussed as a clinical feature that is part of another diagnosis, and sometimes as a primary diagnosis or syndrome. Based upon complement levels and presence and/or absence of specific systemic findings, the terms that appear with UV as a distinct diagnostic entity are:

●Hypocomplementemic urticarial vasculitis syndrome (HUVS) [8]

●Hypocomplementemic urticarial vasculitis (HUV) [9]

The distinctions between these two syndromes are discussed below.

Hypocomplementemic urticarial vasculitis syndrome — HUVS has been recognized as a specific autoimmune disorder involving six or more months of urticaria with hypocomplementemia, in the presence of various systemic findings [1,8,10-16].

These systemic findings typically include:

●Arthritis or arthralgias

●Mild glomerulonephritis

●Uveitis or episcleritis

●Recurrent abdominal pain

HUVS can occur independently or can be associated with other conditions [5]. (See 'Associated conditions' below.)

Diagnostic criteria for HUVS have been proposed (table 1) [13]. However, these criteria lack specificity, and a diagnosis of HUVS should not be made without a skin biopsy. (See 'Diagnosis' below.)

A biopsy showing cutaneous small vessel vasculitis with a characteristic immunofluorescence staining is essential to the diagnosis (see 'Immunofluorescence' below). When measured, C1q levels are frequently found to be low, although the specificity and positive predictive value of this finding are not clear and patients with systemic lupus erythematosus may also have decreased C1q levels [13]. Thus, whether a depressed C1q level is necessary to diagnose HUVS is unresolved. Antibodies to the collagen-like region of C1q (C1q precipitins) are present in most patients with HUVS. Although this test is not clinically available , the C1q solid-phase test for immune complexes and the enzyme-linked immunosorbent assay (ELISA) for anti-C1q autoantibodies give nearly equivalent results [17,18]. (See 'Pathophysiology' below.)

Hypocomplementemic urticarial vasculitis — HUV is the term used to describe patients with UV and hypocomplementemia who do not meet diagnostic criteria for HUVS. In general, patients with HUV have cutaneous disease and few or no systemic manifestations.

PATHOPHYSIOLOGY — Urticarial vasculitis (UV) is believed to result from the formation of immune complexes in the blood that then deposit in vessel walls. In support of this hypothesis are the findings on skin biopsy (see 'Histology' below), the association of UV with some disorders in which the antigen-antibody complexes are well defined (eg, hepatitis B, hepatitis C), and the observation that removal of immune complexes by plasmapheresis is temporally associated with the resolution of the urticarial lesions [19-21].

The antigens eliciting the formation of antibodies are not known in many cases of UV. Medications and viruses (particularly hepatitis B and C) have been implicated as the target antigen in some cases [22,23]. There have also been reports demonstrating the development of UV in association with infliximab, glatiramer acetate, and the injection of hyaluronic acid dermal filler agents [24-26].

In some patients with UV (particularly those with hypocomplementemic urticarial vasculitis syndrome [HUVS]), a collagen-like region on C1q has been implicated as the antigenic target [5,19]. The autoantibody is referred to as a C1q precipitin. A causative role of these specific autoantibodies in the pathogenesis of UV has not been established [8,17,21,27-29].

Once antigen-antibody complexes have formed, they can activate the classical complement pathway. This generates C3a and C5a, which cause mast cell degranulation resulting in urticarial eruptions. C3a and C5a also cause increased vessel permeability and chemotaxis of neutrophils. Infiltrating neutrophils release proteolytic enzymes, causing further tissue destruction and edema [20].

It has been hypothesized that IL-1 may play a role in the pathogenesis of UV. This is based on both the theoretical observation that features of UV have been noted in autoinflammatory disorders in which IL-1 is thought to play a role, as well as and practical observations in which anakinra (an IL-1 antagonist) and canakinumab (a long-acting fully humanized monoclonal anti-IL-1-beta antibody) have been reported to successfully treat UV [30,31]. (See 'Severe systemic disease' below.)

In addition to environmental factors, genetic factors are thought to play a role in the development of HUVS. A study including two families with autosomal-recessive HUVS found that mutations in DNASE1L3 were associated with a familial form of HUVS and HUVS associated with SLE [32]. (See 'Systemic lupus erythematosus' below.)

HISTOLOGY — Histologic findings in leukocytoclastic vasculitis (LCV), which are observed in urticarial vasculitis (UV) as well as other disorders, include the following [2,4,22,33-35]:

●Injury and swelling of endothelial cells, usually of the postcapillary venules

●Extravasation of red blood cells

●Fragmentation of leukocytes with nuclear debris (leukocytoclasis)

●Fibrin deposition in and around the vessels

●Perivascular infiltrate composed mostly of neutrophils

Leukocytoclasis and fibrinoid deposits are probably the most important aspects of LCV, as they represent direct signs of vessel damage.

A continuum exists in the amount and type of blood vessel inflammation seen histologically in UV, ranging from a sparse perivascular infiltrate with no leukocytoclasis to a dense infiltrate with frank leukocytoclasis and fibrin deposition in the most severe forms [21,33,36]. These more severe findings, typically with a neutrophilic infiltrate, are seen in patients with hypocomplementemic urticarial vasculitis syndrome (HUVS). Rarely, lymphocytic, as opposed to leukocytoclastic, vasculitis may be observed [37].

Immunofluorescence — Direct immunofluorescence reveals deposits of immunoglobulins, complement, or fibrin around blood vessels in most patients with UV [19,38]. Deposits also may be present in the basement membrane zone of the dermal-epidermal junction (picture 2A-B). Active urticarial lesions stain positive for immunoglobulin and complement deposits approximately 80 percent of the time [39]. The findings can also be seen in nonlesional skin.

These findings are not specific to UV and are also frequently seen in patients with systemic lupus erythematosus (SLE) [33]. Thus, the finding of immunoglobulin and complement deposits within the basement membrane zone should prompt consideration of both diagnoses [36].

EPIDEMIOLOGY — Urticarial vasculitis (UV) is a rare diagnosis. In a study from Sweden, the annual incidence rate per million inhabitants was estimated as 0.7 (95% CI, 0.4, 1.1), and the point prevalence on 31 December 2015 was 9.5 per million (95% CI, 4.5, 14.5) [40].

As an example, the prevalence of UV in patients with chronic urticaria varies from 5 to 20 percent in adults, depending on the definition of vasculitis used [3,19,33,41-45]. (See "Chronic spontaneous urticaria: Clinical manifestations, diagnosis, pathogenesis, and natural history".)

Women comprise 60 to 80 percent of reported patients [19,39,46]. The peak reported incidence is in the fourth decade of life [36,39].

UV has also been described in children; the youngest reported case occurred in a patient one year of age [47]. In a study of children with leukocytoclastic vasculitis, UV accounted for only 9 percent of cases [48].

CLINICAL PRESENTATION

Dermatologic findings — The urticarial plaques (or wheals) of urticarial vasculitis (UV) can be found anywhere on the body (picture 1A-F). In a series of 57 patients with hypocomplementemic UV, urticarial lesions were typically more pruritic than painful and were associated with angioedema in 51 percent of patients, purpura in 35 percent, and livedo reticularis in 14 percent [49]. Several of the following features can help distinguish UV wheals from those in common urticaria (table 2), although none is diagnostic:

●Common urticaria is pruritic and not painful. By comparison, up to one-third of patients with UV report burning and tenderness as well as pruritus [39,49].

●The urticarial plaques of UV last longer than those in chronic urticaria, persisting for more than 24 hours in two-thirds of patients, and sometimes for up to 72 hours. The urticarial plaques may resolve without a trace but may also be associated with residual purpura or hyperpigmentation in up to 35 percent. (See "Chronic spontaneous urticaria: Clinical manifestations, diagnosis, pathogenesis, and natural history", section on 'Clinical manifestations'.)

●When examined with a diascope (a magnifying lens or glass slide applied to the skin over several drops of contact solution), wheals can have a central dark red or brown macule, signifying underlying purpura and vasculitis (picture 3) [50].

●UV can present as angioedema when the vasculitis involves the capillary or postcapillary venules of the deeper layers of the dermis and submucosa [22]. Swelling resembling angioedema has been reported in approximately 40 percent of UV patients in some series, and residual bruising is typical [39]. Edema can develop in areas of focused pressure, causing confusion in differentiating UV from delayed pressure urticaria. In such cases, skin biopsy would demonstrate the distinguishing finding of leukocytoclastic vasculitis (LCV) in UV [19]. Patients with UV can also develop laryngeal edema, although this is uncommon [8].

●Other associated cutaneous disorders include livedo reticularis, erythema multiforme-like eruptions, and rarely bullous eruptions (table 3) [11,22,51,52]. Raynaud phenomenon may occur [53].

Systemic symptoms — The many systemic manifestations associated with UV (table 3) are presented in the following section, categorized by organ system. In a series of 57 patients with hypocomplementemic UV, extracutaneous manifestations included constitutional symptoms in 56 percent of patients as well as musculoskeletal involvement in 82 percent, ocular involvement in 56 percent, pulmonary involvement in 19 percent, gastrointestinal involvement in 18 percent, and kidney involvement in 14 percent [49]. The skin findings can occur at the same time as or precede systemic manifestations.

Musculoskeletal — Arthralgias and arthritis are the most common systemic manifestation of UV, with roughly 50 percent of patients reporting arthralgias, usually accompanying cutaneous disease [38,39]. Joint pain is usually migratory and transient, frequently affecting the hands, elbows, feet, ankles, and knees. Frank arthritis is seen in up to 50 percent of cases of HUVS.

Jaccoud's arthropathy is seen in hypocomplementemic urticarial vasculitis syndrome (HUVS), although it is more often associated with systemic lupus erythematosus (SLE) [54-58]. It is characterized by the typical deformities of rheumatoid arthritis (ulnar deviation, swan neck deformities, and subluxations) in the absence of radiographic evidence of joint destruction (unlike true rheumatoid arthritis) [59]. It may be associated with an increased risk of aortic and mitral valvulopathy, warranting echocardiographic evaluation in these patients [60,61].

The involvement of muscle is not well documented and may be largely subclinical. There are reports of muscle biopsies showing myositis [15].

Renal — Renal disease is characterized by proteinuria and hematuria, with a number of different disease entities described histologically. The renal disease of UV may not be distinguishable from that of other entities. These include proliferative glomerulonephritis, focal necrotizing vasculitis, crescentic glomerulonephritis, membranoproliferative glomerulonephritis, and tubulointerstitial nephritis [38,62-64]. In a cohort of patients with HUVS, renal involvement was reported in 14 percent [49].

Mild nonprogressive renal disease is typical of UV, although there have been occasional reports of end-stage kidney disease requiring hemodialysis [19,65]. In contrast, HUVS patients typically have moderate to heavy proteinuria and mild renal failure.

The renal involvement of UV tends to be more severe in children [66]. Although UV is rare in the pediatric population, it should be considered when a combination of urticaria, glomerulonephritis, arthritis or arthralgias, and pulmonary disease coexist [62].

Pulmonary — Pulmonary involvement, a leading cause of morbidity and mortality in UV, may include cough, dyspnea, hemoptysis, chronic obstructive pulmonary disease (COPD), asthma, pleuritis, and pleural effusions [14,39,67-70]. Tracheal stenosis has also been reported [9]. In a cohort of patients with HUVS, pulmonary involvement was reported in 19 percent [49].

The most common pulmonary manifestations are COPD and asthma, seen in up to 20 percent of patients with HUVS and in 5 percent of patients with normocomplementemic UV [36,39]. Most patients with COPD and UV are also smokers, although the amount of lung disease present is typically far greater than would be expected for the level of tobacco exposure, and there have even been reports of patients with COPD and UV who never smoked [13,39,71,72].

Pulmonary destruction is postulated to occur from vasculitis within the lung tissue, leading to neutrophilic release of elastase and the development of emphysematous lung disease. Smoking is thought to accelerate this process by helping to recruit neutrophils [13]. Thus, patients with UV or HUVS should not smoke and should avoid second-hand smoke.

An interesting speculation is that anti-C1q antibodies may cross-react with pulmonary surfactant apoproteins, which also contain a C1q collagen-like binding region. This crossreactivity could be a contributing factor to the pulmonary disease [73].

Gastrointestinal — Gastrointestinal symptoms, seen in up to one-third of patients, include substernal pain, abdominal pain, nausea, vomiting, and diarrhea. Hepatomegaly and splenomegaly have been reported. Gastrointestinal bleeding is not associated with UV [33,38,51]. These symptoms are most likely due to gastrointestinal vasculitis, as cases of biopsy-proven gastrointestinal vasculitis in patients with HUVS have been described [74].

Other organ systems — Involvement of other organ systems is less frequently observed.

●Ophthalmologic – Ophthalmologic involvement varies, but has been reported in up to 56 percent of patients with UV in case series [22]. Eye findings can include episcleritis, uveitis, and conjunctivitis [38,39,75,76]. A rare case of serpiginous choroidopathy with subsequent blindness was reported, as has optic atrophy. (See "Episcleritis".)

●Cardiovascular – Cardiac disease is rare in UV. Findings have included pericarditis, tamponade, valvular disease, and pericardial effusion [68,73,77]. Valvular disease has been seen in patients with HUVS and Jaccoud's arthropathy.

●Neurologic – Central nervous system (CNS) involvement includes pseudotumor cerebri (the most common CNS manifestation), aseptic meningitis, cranial nerve palsies, peripheral neuropathy, and transverse myelitis [68,78-82].

LABORATORY FINDINGS — The most common abnormal laboratory results associated with urticarial vasculitis (UV) include [20,83]:

●Elevated erythrocyte sedimentation rate (ESR)

●Hypocomplementemia (usually decreased C1q, C3, and C4)

●Circulating immune complexes by the C1q solid phase test and/or anti-C1q antibody assay

●Positive antinuclear antibodies (ANA)

Erythrocyte sedimentation rate — Although commonly elevated, the ESR is not related to the severity of the disease or to the extent of systemic involvement [20,84]. Data from a small case series suggest that an elevated ESR may also be detected in patients with typical urticaria without evidence of vasculitis [33].

Hypocomplementemia — Hypocomplementemia is a sensitive marker for systemic disease and correlates with severity of illness [36,39,46,63,85]. In patients with UV, decreased C1, C1q, C2, C3, and/or C4 levels, as well as a reduction in the CH50/100, due to activation of the classical complement pathway, may be found. C1q, C3, and C4 are probably the most commonly reduced components. A depressed C1q level and a normal C1 inhibitor level is found in most patients with hypocomplementemic urticarial vasculitis syndrome [1,5,20,36,49], as discussed above. (See "Overview and clinical assessment of the complement system".)

Antinuclear antibodies — A large percentage of patients with UV are ANA-positive, some in high titers. Although UV patients are anti-double-stranded deoxyribonucleic acid (dsDNA) antibody negative as a rule, distinguishing some patients with UV from those with systemic lupus erythematosus (SLE) may be challenging. Many patients with UV meet criteria set forth by the American College of Rheumatology (ACR) for the diagnosis of SLE [20,86]. (See 'Associated conditions' below.)

Other laboratory tests — Other laboratory findings may include positive hepatitis B or C serologies, elevated Epstein-Barr virus titers, or positive serologies for Borrelia species. Abnormal laboratory values suggesting specific organ involvement (particularly renal disease) may be observed. (See 'Laboratory studies' below.)

ASSOCIATED CONDITIONS — Although most cases are idiopathic, there are a variety of systemic diseases and exposures associated with urticarial vasculitis (UV). Their causal role has not been established.

Systemic lupus erythematosus — UV and systemic lupus erythematosus (SLE) have overlapping features and there is speculation that hypocomplementemic urticarial vasculitis syndrome (HUVS) is within the spectrum of SLE.

Some overlapping features of HUVS and SLE include arthritis, glomerulonephritis, and the presence of hypocomplementemia and antinuclear antibodies (ANA) [36,87]. Autoantibodies against C1q can also be found in both HUVS and SLE, particularly in SLE patients with glomerulonephritis. By contrast, there are some distinguishing features of HUVS that are not typically observed in patients with SLE. In a review of the literature comparing SLE and HUVS, distinguishing features included angioedema (up to 50 percent), chronic obstructive pulmonary disease (COPD; 20 to 50 percent), and eye involvement (uveitis/episcleritis; 30 percent) [87].

HUVS can be a presenting feature of SLE, or more commonly, it can develop in patients with longstanding SLE [88-90]. Patients that have both UV and a "lupus-like" syndrome have also been described [91].

Sjögren's syndrome — Patients with Sjögren's syndrome may develop UV, and these patients commonly demonstrate the anti-Ro (SSA) antibody [92].

Medication use — Medications from virtually every drug class have been associated with the development of UV [93] (see "Overview of cutaneous small vessel vasculitis"); over-the-counter diet pills have also been associated with UV [94].

Infections and vaccinations — Infections may be associated with the development of UV. These include hepatitis B [23], hepatitis C [95], Lyme disease [96], infectious mononucleosis [97], and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection [98].

There are rare reports of urticarial vasculitis occurring in association with vaccination, including coronavirus disease 2019 (COVID-19) vaccination [99-102].

Serum sickness — Serum sickness is a disease in which non-human proteins form immune complexes that cause vasculitis and urticarial eruptions. Biopsies of these urticarial lesions sometimes show signs of dermal venulitis and inflammation leading to the diagnosis of UV [53,103]. However, the term serum sickness is generally applied to a self-limited condition occurring in temporal association with an identifiable exogenous trigger. (See "Serum sickness and serum sickness-like reactions".)

Complement disorders — Inherited complement deficiencies of C3 or C4, and secondary C3 deficiency due to the presence of C3 nephritic factor have been associated with UV [104-107]. (See "Inherited disorders of the complement system".)

Malignancy — Malignancy has also been implicated in UV, albeit rarely. Specifically, Hodgkin lymphoma, IgA myeloma, metastatic adenocarcinoma of the colon, metastatic malignant testicular teratoma, acute nonlymphocytic leukemia, acute myeloid leukemia, agnogenic myelodysplasia, essential thrombocythemia and myelofibrosis [108], and B-cell non-Hodgkin lymphoma have been noted in association with UV [109-115].

Miscellaneous — A variety of other miscellaneous conditions have been seen in association with UV. These include monoclonal IgG gammopathy [116], idiopathic thrombocytopenia purpura [39], polycythemia vera [117], cryoglobulinemia [118], inflammatory bowel disease [39], striae distensae of pregnancy [119], IgG4-related disease [120], and rarely cold urticaria [121-123] and solar or local heat urticaria [20,124]. Cogan syndrome, a rare inflammatory disorder characterized by interstitial keratitis and vestibule-auditory dysfunction, has been infrequently seen in patients with UV (see "Cogan syndrome"). Muckle-Wells syndrome, an autosomal dominant systemic inflammatory disorder, is also associated with the development of UV, deafness, and renal amyloidosis [125,126]. (See "Cryopyrin-associated periodic syndromes and related disorders", section on 'Muckle-Wells syndrome'.)

DIAGNOSTIC APPROACH — The diagnosis of urticarial vasculitis (UV) should be considered in the presence of persistent or recurrent urticaria with suggestive clinical characteristics (table 1), serologic findings, or evidence of systemic disease (table 3).

History — The history should address the following:

●Symptoms of systemic disease

●Preceding infections

●Preceding drug ingestion

●Prior associated conditions (see 'Associated conditions' above)

●Behavior and characteristics of the urticarial lesions (table 2)

●Response of the skin lesions to treatment

Physical examination — Physical examination is directed at determining the physical characteristics of the urticarial lesions and detecting signs of systemic disease. (See 'Dermatologic findings' above and 'Systemic symptoms' above.)

Skin biopsy — If UV is suspected, skin biopsy of one or more early lesions is obtained in order to establish the presence of leukocytoclastic vasculitis (LCV). By definition, the diagnosis of UV requires the presence of both characteristic clinical manifestations and pathologic evidence of LCV. Thus, a biopsy should always be performed to establish the diagnosis of UV, even if the clinical presentation appears typical of UV or hypocomplementemic urticarial vasculitis syndrome (HUVS).

In addition to routine histologic evaluation for LCV, direct immunofluorescence should be performed [19]. Perivascular and/or basement membrane zone deposits of immunoglobulin or complement frequently are present in UV. However, these findings are not exclusive to UV and the absence of immunoreactant deposits does not exclude the diagnosis. (See 'Histology' above.)

The punch biopsy is our preferred procedure for obtaining tissue for routine histologic evaluation and direct immunofluorescence. We typically obtain two 4 mm punch biopsies from lesional skin. Our tissue sample for direct immunofluorescence is usually one-half of one of the punch biopsy specimens (split vertically with a scalpel) as this procedure allows for an additional tissue sample for routine histologic evaluation. Alternatively, the entire specimen from the second punch biopsy can be sent for direct immunofluorescence. (See "Skin biopsy techniques", section on 'Punch biopsy'.)

Unlike the tissue for routine hematoxylin and eosin staining, tissue for direct immunofluorescence should not be preserved in formalin. Formalin interferes with the performance of immunofluorescence. Options for preserving tissue for direct immunofluorescence include preservation in Michel's medium or prompt freezing in liquid nitrogen followed by transport to an appropriate laboratory.

If the results do not demonstrate LCV and clinical suspicion for UV remains high, we suggest repeat biopsy on a newly developed lesion. Multiple biopsies are sometimes needed to establish the diagnosis.

Laboratory studies — If LCV is confirmed, then an evaluation for hypocomplementemia and the presence of systemic disease is required. The following tests should be performed in patients who meet both the clinical and pathologic criteria for UV and HUVS:

●Complement studies (CH50, C3, C4 and C1q levels)

●Complete blood count with differential

●Urinalysis

●Serum creatinine and blood urea nitrogen

●ESR

●Hepatitis B surface antigen

●Hepatitis C serologies

●Antinuclear antibodies (ANA)

●Anti-double stranded-DNA (ds-DNA)

●Anti-Ro, -La, -Sm, and -RNP antibodies

●Anti-neutrophil cytoplasmic antibodies (ANCA), particularly enzyme immunoassays for antibodies to proteinase-3 and myeloperoxidase (PR3- and MPO-ANCA)

●Rheumatoid factor and/or anti-cyclic citrullinated peptides (anti-CCP)

●Immunofixation electrophoresis

●Cryoglobulins and cryofibrinogens

In addition, C1q precipitin (anti C1q antibody) assays have become available in a number of laboratories. When available, these assays should also be obtained as a decreased C1q level due to anti C1q antibodies is characteristic of HUVS.

Other investigations should be guided by findings from the history and physical examination [53]. As an example, chest imaging and pulmonary function tests are appropriate in patients with pulmonary symptoms. Skeletal radiographs are useful to evaluate patients with arthritis. Echocardiogram to assess for valvular heart disease should be considered in patients suspected to have Jaccoud's arthropathy. (See 'Musculoskeletal' above.)

Malignancy is rarely associated with UV, and screening patients for underlying malignancy, beyond the age-appropriate recommendations, is not reasonable unless a thorough history and physical exam leads to a strong suspicion of occult cancer [118].

DIAGNOSIS — The diagnosis of urticarial vasculitis (UV) is confirmed by the presence of both:

●Clinical manifestations of urticaria

●Histopathological evidence of leukocytoclastic vasculitis (LCV)

The presence or absence of hypocomplementemia and/or associated conditions can help determine whether UV can be further delineated into hypocomplementemic urticarial vasculitis syndrome (HUVS), hypocomplementemic urticarial vasculitis (HUV), or normocomplementemic urticarial vasculitis (NUV) and/or whether UV is associated with another pathogenic process. (See 'Terminology' above and 'Associated conditions' above.)

DIFFERENTIAL DIAGNOSIS — Other diseases to consider in the diagnosis of urticarial vasculitis (UV) are described below.

●Common urticaria – Certain clinical features can help distinguish UV wheals from those in common urticaria, although these are not diagnostic (table 2) (see 'Dermatologic findings' above). Histopathologically, acute urticaria has marked dermal edema in the absence of endothelial cell swelling, leukocytoclasis, or red blood cell extravasation. A sparse leukocytic perivascular infiltrate may occasionally be seen [4,22]. Complement levels are normal.

Chronic urticaria may have perivascular infiltrates composed of T cells, macrophages, and eosinophils. In contrast to UV, leukocytoclasis and fibrinoid degeneration are always absent, red cell extravasation is rarely seen, and immunofluorescence staining of immunoglobulins and complement is negative [127,128]. Complement levels are normal. (See "Chronic spontaneous urticaria: Clinical manifestations, diagnosis, pathogenesis, and natural history".)

●Erythema multiforme (EM) minor – EM minor is an acute eruption characterized by distinctive target or iris lesions with a predilection for the extensor surfaces of the extremities, as well as the palms and soles (picture 4). EM minor can be preceded by infections (typically Herpes virus or Mycoplasma) and has a benign clinical course. Histology of EM minor shows a perivascular mononuclear infiltrate. Complement levels are normal. Although the appearance of the lesions of EM minor can be similar to that of UV, the two can usually be distinguished by the larger clinical picture and the pathology. In contrast, EM major is a more severe blistering disease involving the mucous membranes that would not be confused with UV. (See "Erythema multiforme: Pathogenesis, clinical features, and diagnosis".)

●Acquired angioedema – Angioedema in an adult patient with a depressed C1q level should also prompt consideration of acquired C1-inhibitor deficiency, a condition that is associated with B-cell lymphomas in a substantial percentage of patients [129]. Like hypocomplementemic urticarial vasculitis syndrome (HUVS), there are a number of reports suggesting an association between acquired angioedema/acquired C1-inhibitor deficiency and systemic lupus erythematosus (SLE) and lupus-like conditions [130-136]. A difference between HUVS and acquired C1-inhibitor deficiency is that urticaria is not seen in the latter. (See "Acquired C1 inhibitor deficiency: Management and prognosis".)

●Neutrophilic urticarial dermatosis – Neutrophilic urticarial dermatosis is characterized by an urticarial eruption with the histopathologic features of a perivascular and interstitial neutrophilic infiltrate with intense leukocytoclasia without vasculitis or edema. In addition, the urticarial lesions in this condition generally resolve within 24 hours. Purpura, angioedema, and facial swelling are generally not seen with neutrophilic urticarial dermatosis. In a report of nine patients with neutrophilic urticarial dermatosis, seven had associated systemic diseases including adult-onset Still's disease, SLE, and Schnitzler syndrome, suggesting an association with systemic inflammatory diseases [137].

●Other – Although UV may occasionally exist in patients with the following syndromes, the skin lesions in such patients are generally distinct from UV:

•AHA syndrome – The AHA syndrome consists of arthritis (A), hives (H), and angioedema (A). Flares may be associated with emotional stress, anxiety, exercise, and excessive alcohol consumption [138].

•Cryopyrin-associated periodic syndromes – In patients presenting with a persistent history of recurrent urticarial plaques associated with signs of systemic inflammation including fevers and elevated inflammatory markers (C-reactive protein [CRP]/serum amyloid A, leukocytosis, and a negative connective tissue disease workup), the cryopyrin-associated periodic syndromes (CAPS) should be considered in addition to other autoinflammatory diseases [139]. (See "Autoinflammatory diseases mediated by inflammasomes and related IL-1 family cytokines (inflammasomopathies)", section on 'Cryopyrin-associated periodic syndromes'.)

•Schnitzler syndrome – Schnitzler syndrome, which is often unrecognized, is a form of chronic urticaria associated with monoclonal gammopathy (most often IgM kappa) and additional features, which may include bone pain, skeletal hyperostosis, arthralgias, lymphadenopathy, and intermittent fevers [140-147]. Hematologic malignancy is reported in between 15 and 45 percent of patients [140,146], and up to 1.5 percent of patients with a monoclonal IgM gammopathy may have the syndrome [147]. Initial reports of this syndrome described UV as a feature of this syndrome, but subsequent studies demonstrated that a neutrophilic urticarial dermatosis is most common. Indeed, a retrospective analysis of 20 patients seen at the Mayo Clinic did not identify leukocytoclastic vasculitis (LCV) in any of the patients studied [146].

This condition responds very well to inhibition of the interleukin (IL)-1 pathway, with the most evidence supporting the use of anakinra as the first line of therapy. The role of IL-1 signaling in disease pathogenesis is highlighted by treatment response to anakinra [145,148-151] (an IL-1 receptor antagonist), rilonacept (an IL-1 binding and neutralizing fusion protein), and canakinumab (a monoclonal antibody against IL-1 beta) [152,153].

The largest study to demonstrate the long-term effectiveness of IL-1 inhibition in patients with Schnitzler syndrome included 29 patients treated with anakinra, all of whom were found to have a sustained improvement in disease activity [151]. After a median follow-up period of 36 months of anakinra administration, 24 patients were in complete remission and five patients were in partial remission. Severe infections were observed in six patients, but no lymphoproliferative diseases occurred during treatment with anakinra.

Three patients unresponsive to IL-1 inhibition have been described who responded to IL-6 pathway inhibition with tocilizumab [154], the anti-IL-6 receptor antibody, suggesting the possibility of an alternative disease mechanism in some patients. Symptomatic improvement occurs in some patients with treatment using pefloxacin [155].

TREATMENT — The treatment of urticarial vasculitis (UV) is often challenging and therapy is not standardized. Management is guided by the clinical presentation, and agents are chosen based upon the severity of the disease and presence of systemic involvement. Systemic glucocorticoids are considered the mainstay of therapy for UV, and additional agents described below are typically added when necessary. The approach outlined here is based upon case and series reports of successful therapies. Randomized and controlled trials have not been performed.

Mild disease — Patients with mild disease are usually treated symptomatically. Common symptoms associated with UV include urticaria and arthralgias or arthritis.

●Antihistamines – If urticaria is a prominent feature of the disease, then antihistamines may be helpful to manage pruritus. These drugs do not impact the course of the disease, and one preparation has not been shown to be superior to another for this condition [21,22,38,63]. We start with a nonsedating agent, such as loratadine (10 mg once daily), fexofenadine (60 mg once or twice daily), or cetirizine (10 mg once daily). The doses of these nonsedating agents may be increased above the standard doses. Our approach to increasing the dose of some of these agents is discussed in detail separately. (See "Chronic spontaneous urticaria: Standard management and patient education", section on 'Up-dosing of second-generation agents'.)

If the patient is still having unmanageable pruritus, the sedating antihistamines are added, in addition to the less-sedating agents above. Diphenhydramine and chlorpheniramine are over-the-counter options. Prescription agents include doxepin, hydroxyzine, or promethazine. The patient should be informed about side effects (drowsiness, headache, dry mouth, constipation, dizziness, and confusion) (see "Chronic spontaneous urticaria: Standard management and patient education"). However, additional therapies are often needed to clear the skin lesions and prevent additional lesions from appearing.

●Nonsteroidal antiinflammatory drugs (NSAIDs) – NSAIDs are commonly used to treat the arthralgias and arthritis of UV, with good results in up to 50 percent of patients [39,46]. We begin with ibuprofen up to 800 three or four times daily or naproxen 500 mg twice a day. Indomethacin, 25 mg three times daily, increasing as needed to a maximum dose of 50 mg four times daily, is another option, although this medication can cause gastrointestinal irritation and headaches.

Moderate disease — Glucocorticoids with or without dapsone are typically used as initial therapy for patients with mild to moderate disease (no organ- or life-threatening disease manifestations such as renal failure) who have not responded to antihistamines and NSAIDs. Some prefer initial combination therapy in patients who are anticipated to require a glucocorticoid for more than two to three months. Among patients in whom dapsone is contraindicated, we initiate therapy with either the combination of glucocorticoids plus colchicine, or colchicine alone. Another alternative is hydroxychloroquine.

●Glucocorticoids – Systemic glucocorticoids are used to gain control of the disease in patients with significant illness or systemic involvement. Most patients with hypocomplementemia require this therapy to achieve control of the illness [33,39] The dosing of glucocorticoids varies and is usually dictated by the severity of systemic illness. We begin treatment at doses between 0.5 and 1 mg/kg per day or equivalent. Benefits from glucocorticoids are usually noticeable within a day or two of initiation. We typically give these medications for at least a week before making an assessment about clinical response. Rarely, a patient may require glucocorticoid doses of 1.5 mg/kg per day.

Typically, once control of disease is established, the dose of glucocorticoids is gradually reduced week by week to the lowest dose that will control the disease. Some patients can be tapered off glucocorticoid therapy over time, although many cannot and require protracted use. Because of the long-term sequelae of glucocorticoids, glucocorticoid-sparing therapies should be considered in such patients and efforts made to find adjunctive treatments that might allow for lowering of the chronic glucocorticoid dose.

●Dapsone – Dapsone can be initiated alone or in combination with glucocorticoids, or it can be reserved for patients who develop disease recurrence with attempts to taper glucocorticoid therapy. It has been used successfully in a limited number of case reports to treat skin involvement of UV and hypocomplementemic urticarial vasculitis syndrome (HUVS). Dapsone is relatively inexpensive, usually well tolerated (with certain important exceptions noted below), although patients require close monitoring initially [46,72,84,156-160].

We start with a dose of 50 mg once daily and increase to 100 mg once daily if needed. Pentoxifylline acts synergistically with dapsone and can be added as adjunctive therapy, although we generally use dapsone as a single agent initially [161].

Because dapsone is a sulfone, patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency may experience severe hemolysis when exposed to this drug, and G6PD levels should be checked prior to initiating therapy with this agent [22]. Other side effects of therapy with dapsone include headaches, nonhemolytic anemia, and agranulocytosis, requiring intermittent complete blood counts (CBCs) for monitoring. Practices for monitoring patients while on dapsone vary. Our approach is to check a CBC usually weekly for the first month, then monthly for six months, and then semiannually thereafter [162]. For additional information on monitoring, refer to the drug interactions program included within UpToDate. Although rare, dapsone hypersensitivity syndrome is a potentially fatal complication [163] characterized by fever, hemolytic anemia, lymphocytosis, and transaminitis. Finally, methemoglobinemia can occur with dapsone [164].

●Colchicine – Colchicine has been used effectively to treat cutaneous manifestations of UV, and it is used as an alternative to dapsone. Complete blood cell counts should be ordered after initiation of treatment to screen for cytopenias associated with this drug [22]. We use colchicine for UV at starting doses of 0.5 to 0.6 mg orally per day. This drug may also be administered twice daily (ie, 0.25 to 0.3 mg twice daily). If minimal to no response is noted after a few weeks, the dose of colchicine may be increased to 1.5 to 1.8 mg per day (or 0.75 to 0.9 mg twice daily).

●Hydroxychloroquine – Hydroxychloroquine may be a beneficial therapy for patients with UV and limited skin involvement [63,165]. It is given at a dose of 400 mg per day for patients weighing more than 70 kg and 200 mg once daily for patients weighing less than 70 kg. Hydroxychloroquine can be used alone or in combination with glucocorticoids. There have been case reports in the literature showing complete clearing of cutaneous disease and normalization of renal function when hydroxychloroquine is used with low-dose prednisone [166]. Monitoring of patients receiving hydroxychloroquine is discussed separately (See "Antimalarial drugs in the treatment of rheumatic disease".)

Severe systemic disease — For patients with refractory symptoms or those with organ-threatening or life-threatening disease manifestations, we use other agents in combination with glucocorticoids. The assistance of a rheumatologist with experience in the management of vasculitides is suggested for patients with evidence of significant systemic disease. Based on limited data from case reports and small case series, along with our own experience, we generally use the following agents listed in order of preference: mycophenolate mofetil, methotrexate, azathioprine, and cyclosporine. We rarely use cyclophosphamide given the potential toxicity and limited benefit. Finally, as more evidence becomes available for the use of rituximab, anakinra, canakinumab, and omalizumab, these may become preferred. These treatments, along with a few others that have been used, are described below.

●Mycophenolate mofetil – Mycophenolate mofetil was reported as effective maintenance therapy in one case of HUVS after symptoms were controlled with glucocorticoids and cyclophosphamide [167]. Doses of 0.5 to 1 g twice daily are suggested. (See "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases".)

●Methotrexate – Methotrexate can be used as a steroid-sparing agent [168]. While methotrexate is often effective, there is a case report describing an exacerbation of UV with methotrexate use [169].

●Azathioprine – Azathioprine has been associated with beneficial results in the setting of UV [22,53,170]. When used in combination with prednisone, azathioprine is associated with marked beneficial improvement in renal disease [13,33,121,171] and cutaneous involvement of HUVS [172].

The starting dose is 1 mg/kg daily. This may be increased by 0.5 mg/kg daily if no effect is apparent after a few weeks. The maximum recommended dose is 2.5 mg/kg daily. Testing for deficiency of one or both alleles for thiopurine methyltransferase (TPMT), the enzyme required to metabolize azathioprine, prior to the initiation of therapy is discussed separately. (See "Pharmacology and side effects of azathioprine when used in rheumatic diseases".)

●Cyclosporine A – Cyclosporine A has been used effectively in HUVS, particularly for renal and pulmonary disease [5,173,174]. Cyclosporine A has also been a useful agent to use when attempting to taper glucocorticoid therapy [66]. Initial dosing is 2 to 2.5 mg/kg daily. If no response is noted after a few weeks, this dosing can be increased to 5 mg/kg daily. Details regarding side effects of cyclosporine A, including nephrotoxicity and hypertension, are presented separately. (See "Pharmacology of cyclosporine and tacrolimus", section on 'Side effects'.)

●Rituximab – Rituximab has been used in several patients with recalcitrant UV with a variable degree of success [175,176].

●Anakinra – A dramatic response to anakinra has been described in patients with Schnitzler syndrome and UV unresponsive to other therapies [30,148,149]. (See 'Differential diagnosis' above.)

●Canakinumab – An open-label pilot study of 10 patients with UV reported significant improvements across several outcome measures including a mean reduction in UV activity score, an improvement in patient and clinician global assessment of disease activity scales, a decrease in inflammatory markers, and a decrease in serum cytokine levels of the 1L-1 pathway. There were no serious adverse events [31].

●Omalizumab – A few case reports describe the successful use of omalizumab in a dose of 150 to 300 mg subcutaneously every four weeks for patients with urticarial vasculitis refractory to antihistamines, glucocorticoids, and other immunosuppressive treatments including azathioprine and cyclosporine [177,178].

Other therapies — Interferon alfa has been used in UV associated with hepatitis C or A infection, either alone or in combination with ribavirin [5,111,179-181]. Other therapies reported in the literature include cyclophosphamide, intravenous immunoglobulin, anti-B-cell therapy, and monoclonal antibody therapy. However, these are limited to single case reports and further evaluation is needed before they can be recommended [19,22,175,182-185]. Therapies that most likely offer little benefit and are not recommended include calcium channel blockers, pentoxifylline as a single agent, and dietary manipulations [5,186].

PROGNOSIS — Urticarial vasculitis (UV) is a complicated disease with an unpredictable outcome. It is usually benign, with no permanent sequelae, in the majority of patients with normal complement levels. The average duration of disease is three to four years, although individual cases extending beyond 20 years have been reported [38,39]. In the largest series studied, patients with UV had no other disease manifestations over a 12-year span [51].

Patients with hypocomplementemia have more severe disease and may experience significant morbidity and mortality [19]. However, they rarely die as a direct result of the disease, even in the setting of multisystem involvement [38].

Pulmonary involvement is a leading cause of morbidity and mortality, due largely to complications of chronic obstructive pulmonary disease (COPD) [51]. There have been rare reports of fatal episodes of laryngeal edema [8].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Urticarial vasculitis" and "Society guideline links: Vasculitis".)

SUMMARY AND RECOMMENDATIONS

●Description – Urticarial vasculitis (UV) is a clinicopathologic entity consisting of urticaria and evidence of leukocytoclastic vasculitis on skin biopsy. UV predominantly involves the skin but may affect other organs, particularly the lungs, kidney, and gastrointestinal tract. Hypocomplementemia, when present, may be associated with extensive vasculitis and systemic features. (See 'Introduction' above.)

●Terminology – Hypocomplementemic urticarial vasculitis syndrome (HUVS) is recognized as a specific autoimmune disorder involving six or more months of urticaria, with hypocomplementemia, in the presence of various systemic findings (table 1). (See 'Terminology' above.)

●Pathophysiology – The pathophysiology of UV is believed to involve the deposition of immune complexes in vessel walls, complement activation, and mast cell degranulation due to C3a and C5a with resultant urticaria. (See 'Pathophysiology' above.)

●Histology – Leukocytoclasis, or fragmentation of leukocytes with nuclear debris, and fibrinoid deposits are important histopathologic findings that represent direct signs of vessel damage. Immunofluorescence reveals deposits of immunoglobulins, complement, or fibrin around blood vessels in most patients. (See 'Histology' above.)

●Clinical presentation – The urticarial lesions of UV can be found anywhere on the body (picture 1A-F). Certain features can help distinguish UV wheals from those in common urticaria (table 2), although none is diagnostic. Systemic findings (table 3) most often involve the musculoskeletal, renal, and pulmonary systems. (See 'Clinical presentation' above.)

●Associated conditions – UV is most commonly idiopathic, although it can occur in association with autoimmune diseases, drug reactions, infections, or malignancy. (See 'Associated conditions' above.)

●Diagnosis – The diagnosis of UV requires the presence of urticaria with leukocytoclastic vasculitis (LCV) on skin biopsy. If LCV is present, then further testing is indicated to define the presence and extent of systemic disease and evaluate for associated conditions. (See 'Diagnosis' above and 'Skin biopsy' above and 'Laboratory findings' above and 'Differential diagnosis' above.)

●Treatment recommendations – UV is often difficult to treat, and therapy is based upon case reports and small series. Management is guided by the clinical presentation, and agents are chosen based upon the severity of the disease and presence of systemic involvement. Systemic glucocorticoids are considered the mainstay of therapy for UV, and additional agents are typically added.

•Mild disease

-Antihistamines are used to manage pruritus if urticaria is a prominent feature of the disease. These drugs do not impact the course of the disease, and one preparation has not been shown to be superior to another for this condition. We start with a nonsedating agent such as loratadine (10 mg once daily), fexofenadine (60 mg once or twice daily), or cetirizine (10 mg once daily). (See 'Mild disease' above.)

-Nonsteroidal antiinflammatory drugs (NSAIDs) may be used to treat the arthralgias and arthritis associated with UV. (See 'Mild disease' above.)

•Moderate disease – Glucocorticoids in combination with either dapsone, colchicine, or hydroxychloroquine are typically used as initial therapy for patients with mild to moderate disease, although there is more experience with glucocorticoids and dapsone. This approach is typically reserved for patients who do NOT have organ- or life-threatening manifestations of the disease (eg, renal failure) and who have not responded to antihistamines and NSAIDs. (See 'Moderate disease' above.)

•Severe systemic disease – For patients with refractory symptoms or those with organ- or life-threatening disease manifestations, we use other agents in combination with glucocorticoids. The assistance of a rheumatologist with experience in the management of vasculitides is suggested for patients with evidence of significant systemic disease. (See 'Severe systemic disease' above.)

Based on limited data from case reports and small case series, along with our own experience, we generally use the following agents listed in order of preference: mycophenolate mofetil, methotrexate, azathioprine, and cyclosporine. We rarely use cyclophosphamide, given the potential toxicity and limited benefit. (See 'Severe systemic disease' above.)

As more evidence becomes available for the use of rituximab, anakinra, canakinumab, and omalizumab, these agents may become preferred. (See 'Severe systemic disease' above.)

●Prognosis – UV is a benign and self-limited disease for the majority of patients, although symptoms can last for decades in some individuals. (See 'Prognosis' above.)