International Journal of Women’s Dermatology xxx (xxxx) xxx

Contents lists available at ScienceDirect

International Journal of Women’s Dermatology

Review

Urticarial vasculitis
Stephanie L. Gu BS a,⇑, Joseph L. Jorizzo MD a,b
a
Department of Dermatology, Weill Cornell Medicine, New York, NY, United States
b
Department of Dermatology, Wake Forest University School of Medicine, Winston-Salem, NC, United States

a r t i c l e i n f o a b s t r a c t

Article history: Urticarial vasculitis is a rare clinicopathologic entity that is characterized by chronic or recurrent epi-
Received 22 August 2020 sodes of urticarial lesions. Skin findings of this disease can be difficult to distinguish visually from those
Received in revised form 23 December 2020 of chronic idiopathic urticaria but are unique in that individual lesions persist for 24 hours and can
Accepted 21 January 2021
leave behind dusky hyperpigmentation. This disease is most often idiopathic but has been linked to cer-
Available online xxxx
tain drugs, infections, autoimmune connective disease, myelodysplastic disorders, and malignancies.
More recently, some authors have reported associations between urticarial vasculitis and COVID-19, as
Keywords:
Urticarial vasculitis
well as influenza A/H1N1 infection. Urticarial vasculitis can extend systemically as well, most often
Hypocomplementemic urticarial vasculitis affecting the musculoskeletal, renal, pulmonary, gastrointestinal, and ocular systems. Features of leuko-
Hypocomplementemic cytoclastic vasculitis seen on histopathologic examination are diagnostic of this disease, but not always
Urticarial vasculitis syndrome seen. In practice, antibiotics, dapsone, colchicine, and hydroxychloroquine are popular first-line thera-
Leukocytoclastic vasculitis pies, especially for mild cutaneous disease. In more severe cases, immunosuppressives, including
methotrexate, mycophenolate mofetil, azathioprine, and cyclosporine, as well as corticosteroids, may
be necessary for control. More recently, select biologic therapies, including rituximab, omalizumab,
and interleukin-1 inhibitors have shown promise for the treatment of recalcitrant or refractory cases.
Ó 2021 The Authors. Published by Elsevier Inc. on behalf of Women’s Dermatologic Society. This is an
open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Contents

Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Epidemiology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Clinical presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Cutaneous findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Laboratory findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Systemic involvement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Histologic findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Differential diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Study approval . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

⇑ Corresponding author.
E-mail address: stg4002@med.cornell.edu (S.L. Gu).

https://doi.org/10.1016/j.ijwd.2021.01.021
2352-6475/Ó 2021 The Authors. Published by Elsevier Inc. on behalf of Women’s Dermatologic Society.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Please cite this article as: S.L. Gu and J.L. Jorizzo, Urticarial vasculitis, International Journal of Women’s Dermatology, https://doi.org/10.1016/j.
ijwd.2021.01.021
S.L. Gu and J.L. Jorizzo International Journal of Women’s Dermatology xxx (xxxx) xxx

Introduction also explain the angioedema and true urticaria lesions lasting
<24 hours that occur in approximately 50% of affected patients.
Urticarial vasculitis is a rare clinicopathologic entity that man- These lesions are distinct from and should not be conflated with
ifests as a result of inflammatory injury to the small vessels of the the hallmark lesions of urticarial vasculitis, which last >24 hours.
skin. This condition is characterized by chronic or recurrent epi- Furthermore, proteolytic enzymes are released from neutrophils,
sodes of urticarial lesions showing features of leukocytoclastic vas- and the sum of these changes leads to the characteristic tissue
culitis on histopathologic specimens. Findings can be limited to the damage and edema in urticarial vasculitis. Eosinophils may also
skin or extend systemically, affecting various organs, including the play a role in the pathogenesis of this disease because the infiltra-
musculoskeletal, renal, pulmonary, gastrointestinal, and ocular tion of these cells is significantly greater than that seen in urticaria
systems (Fig. 1). (Kamyab et al., 2019). Lastly, a role of interleukin 1 (IL-1) has been
suggested given the utility of IL-1 inhibitors in the treatment of
this disease (Bettuzzi et al., 2019; Krause et al., 2013).
Epidemiology The cause of urticarial vasculitis is often unknown, but there
have been numerous reports of cases triggered by drugs, infections,
Due to the rarity of this condition, the exact prevalence of autoimmune connective disease, myelodysplastic disorders, or
urticarial vasculitis is unclear. One study conducted in Sweden malignancy. Some drugs that have been implicated include cime-
estimated an annual incidence of 0.7% with a point prevalence of tidine, diltiazem, potassium iodide, fluoxetine, nonsteroidal anti-
9.5 per million as of December 2015 (Sjöwall et al., 2018). In inflammatory drugs, methotrexate, telmisartan, enalapril, leve-
patients presenting with chronic urticarial lesions, prevalence is tiracetam, and over-the-counter diet pills (Borcea and Greaves,
estimated to range from 2% to 20%, and approximately 5% when 2000; Cherrez et al., 2015; Cicek et al., 2008; Koregol et al., 2015;
the histologic criteria of leukocytoclastic vasculitis are met Mahajan et al., 2015; Mangal and Kumaran, 2014). Of note, sys-
(O’Donnell and Black, 1995; Venzor et al., 2002). temic medications may be over-implicated as the cause of urticar-
Urticarial vasculitis condition more commonly affects women ial vasculitis. For example, many patients start methotrexate,
and peaks in frequency during the fourth and sixth decades of life which takes 4 to 8 weeks to see full benefit, while simultaneously
(Jachiet et al., 2015; Sjöwall et al., 2018). Urticarial vasculitis very stopping prednisone, a regimen change that is associated with a
rarely affects children and even less frequently affects infants, with rapid rebound of underlying diseases.
only two reported cases of the latter in the literature (Kaur and Many cases are also a manifestation of underlying infections;
Thami, 2003; Koch et al., 2008). associations with streptococcus, tuberculosis, hepatitis B and C,
Epstein–Barr virus, mycoplasma, COVID-19, influenza A/H1N1, tri-
Pathogenesis chomoniasis, and Lyme disease have all been reported (Baigrie
et al., 2020; de Perosanz-Lobo et al., 2020; Gökçe et al., 2020;
Urticarial vasculitis is thought to be immune-complex mediated Kim et al., 2010; Kolkhir et al., 2019; Nasiri et al., 2020; Scott
and as such is classified as a type III hypersensitivity reaction et al., 2014; Tsai et al., 2018). Links between urticarial vasculitis
(Mehregan and Gibson, 1998). Antibodies complex with antigens, and various autoimmune diseases, including systemic lupus ery-
which may be autologous or of exogenous origin, and activate thematosus, Sjogren’s syndrome, rheumatoid arthritis, inflamma-
complement through the classical pathway. C3a and C5a are then tory bowel disease, Schnitzler’s syndrome, and Muckle–Wells
generated, inducing mast-cell degranulation and the release of syndrome, similarly have been suggested (Baigrie et al., 2020;
chemokines and cytokines (Venzor et al., 2002). This process may Swaminath et al., 2011; Tsai et al., 2018). In fact, urticarial vasculi-

Fig. 1. Diagnostic algorithm for evaluation of urticarial lesions.

2
S.L. Gu and J.L. Jorizzo International Journal of Women’s Dermatology xxx (xxxx) xxx

tis can fulfill many diagnostic criteria for systemic lupus erythe-
matosus, such that some authors have proposed a continuum of
disease between these entities (Dincy et al., 2008). Urticarial vas-
culitis has also been reported to occur in patients with
immunoglobulin (Ig) G-4 related diseases (Takao et al., 2016;
Tokura et al, 2014; Wakamatsu et al., 2011).
In addition, urticarial vasculitis can manifest as a paraneoplastic
finding. The associated malignancies in the literature include mul-
tiple myeloma, myelodysplastic syndrome, colonic adenocarci-
noma, signet ring cell carcinoma, renal carcinoma, non-Hodgkin
lymphoma, metastatic teratoma from testicular tumor, and chronic
lymphocytic leukemia (Ducarme et al., 2003; Jachiet et al., 2018;
Kassim et al., 2015; Shah et al., 2007; Wilson et al., 2002; Younis,
2018). Cold contact was noted in some reports to produce leukocy-
toclastic vasculitis locally at the site of application; however, cry-
opyrinopathies can be associated with urticarial vasculitis, and
cryoglobulins should be evaluated in such cases (Pérez-Bustillo
and Sánchez-Sambucety, 2012).
Environmental exposures appear to play a significant role in the
development and progression of this disease, but some reports
have pointed to a genetic component as well. Familial cases of
hypocomplementemic urticarial vasculitis syndrome, a more sev-
ere and systemic form of urticarial vasculitis, have been docu-
mented in a pair of identical twins, as well as among three
siblings (Ozçakar et al., 2013a; Wisnieski et al., 1994). One gene-
mapping study revealed an association between such cases and a
Fig. 2. Cutaneous lesions of urticarial vasculitis, characterized by well-demarcated
homozygous frameshift mutation in DNASE1L3, which encodes erythematous border and central pallor.
for a protein in the deoxyribonuclease I family (Ozçakar et al.,
2013b).

and Maurer, 2014). Patients with normal complement levels are

Clinical presentation
classified as having normocomplementemic urticarial vasculitis
and generally have a better prognosis with few systemic complica-
Cutaneous findings
tions. Patients with depressed levels of complement have a higher
risk of complications and are either classified as having hypocom-
Patients most often present with classical indurated wheals that
plementemic urticarial vasculitis when systemic involvement is
can be difficult to distinguish clinically from chronic idiopathic
little to none or hypocomplementemic urticarial vasculitis syn-
urticaria (Fig. 2). However, unlike the latter, which is characterized
drome when systemic involvement is significant (Buck et al.,
by lesions that generally resolve within 2 to 8 hours and by defini-
2012). Notably, hypocomplementemia is often indicative of an
tion within 24 hours, lesions of urticarial vasculitis last >24 h, often
underlying systemic disease (Chang and Carr, 2007). Circulating
persisting for several days, and may leave behind a residual ecchy-
immune complexes and autoantibodies involved in the disease
motic hyperpigmentation that is not seen in chronic idiopathic
process can also be detected, including anti C1q, which is found
urticaria. These wheals are often non- or only partially blanchable
in 50% of patients with hypocomplementemic urticarial vasculitis
with a central dark-red or brown macule. Additionally, individual
and 100% of patients with hypocomplementemic urticarial vasculi-
urticarial vasculitis lesions tend to range from 0.5 to 5 cm in diam-
tis syndrome (Damman et al., 2020). In addition, some studies have
eter, whereas those seen in true urticaria can coalesce and become
shown an elevation in antithyroid antibodies at a prevalence
very large (>10 cm) or serpiginous. When present, symptoms tend
higher than in chronic spontaneous urticaria, although the rele-
to be described as painful and/or burning, as opposed to true urti-
vance of this finding remains unclear (Cherrez-Ojeda et al., 2019).
caria, which is more often frankly pruritic (Wisnieski, 2000).
Other appropriate laboratory tests include complete blood
Recent reports demonstrate the usefulness of dermoscopy in
count, chemistry profile, creatinine, hepatitis and liver studies, uri-
evaluating lesions because the extent of vascular necrosis is usu-
nalysis, renal function tests, and antinuclear antibody (Koç et al.,
ally small enough where frank purpura is not apparent, thus
2017; Zuberbier and Maurer, 2014). Anti-DNase B may be a useful
requiring the usage of magnification for accurate visualization
metric as well because postinfectious leukocytoclastic vasculitis
(Dahl, 1994; García-García et al., 2020). Episodes of urticarial vas-
can occur and, when present, is most often due to a streptococcal
culitis persist on average from 4 to 8 weeks and resolve within
infection (Baigrie et al., 2020). A chest x-ray and pulmonary func-
1 year in 30% to 40% of patients (Koç et al., 2017; Zuberbier and
tion tests are also recommended in patients demonstrating rele-
Maurer, 2014). Chronic versions that last months to years have also
vant symptoms because pulmonary involvement is the leading
been described (Koç et al., 2017).
cause of mortality in this disease (Chang and Carr, 2007). Serum
levels of D-dimers may also be elevated (Criado et al., 2013; Roy
Laboratory findings et al., 2013). Additionally, antinuclear antibodies are detectable
in approximately half of patients with hypocomplementemic
An elevated erythrocyte sedimentation rate and hypocomple- urticarial vasculitis, which further supports the speculation that
mentemia are the most common laboratory abnormalities the severe end of the urticarial vasculitis disease spectrum over-
observed in urticarial vasculitis. Unlike erythrocyte sedimentation laps with and meets many criteria for lupus (Dincy et al., 2008;
rate, which is generally nonspecific, hypocomplementemia is a Jachiet et al., 2015).
useful predictor for this disease (Venzor et al., 2002; Zuberbier
3
S.L. Gu and J.L. Jorizzo International Journal of Women’s Dermatology xxx (xxxx) xxx

Systemic involvement The lungs are another common site of involvement, with
approximately 20% to 30% of patients developing chronic obstruc-
In addition to cutaneous abnormalities, patients with urticarial tive pulmonary disease (COPD; Venzor et al., 2002). This number
vasculitis can exhibit symptoms in multiple organ systems, which increases to up to 50% in patients with hypocomplementemic
result in a myriad of systemic findings. Overall, these tend to occur urticarial vasculitis (Zuberbier and Maurer 2014). This finding is
more frequently in hypocomplementemic patients or among those most common in young patients who smoke tobacco and is more
expressing anti-C1q antibodies (Jachiet et al., 2015). Musculoskele- extensive in patients with hypocomplementemic urticarial vasculi-
tal symptoms, including arthralgias and myalgias, are the most tis than would be expected based on the degree of smoking alone
common extracutaneous finding in patients (Koç et al., 2017; (Koç et al., 2017). As such, screening for COPD in afflicted patients
Kolkhir et al., 2020). is crucial and smoking cessation in all patients who present with
Renal involvement is estimated to occur in approximately 20% this disease is strongly recommended. The exact role urticarial vas-
of patients with hypocomplementemic urticarial vasculitis, but culitis plays in the development of COPD remains unclear, but the
this figure can range from 9% to 60% depending on the case series binding of C1q precipitins to pulmonary alveoli surfactant proteins
used for analysis. Patients most frequently show evidence of has been proposed as a contributing factor (Buck et al., 2012).
glomerular impairment, primarily resulting from membranoprolif- Pleuritis is another possible involvement, often manifesting as
erative glomerulonephritis (Boyer et al., 2020). Other observed chest pain or shortness of breath (Koç et al., 2017). These types
renal histologies include extracapillary, extramembranous, mesan- of complications are particularly recalcitrant to treatments, with
gial, crescentic, focal-proliferative, and segmental hyalinosis many patients requiring lung transplantation, and tend to worsen
glomerulonephritis (AlHermi et al., 2017). Some patients have dif- with disease progression. Overall, pulmonary involvement, espe-
fuse interstitial involvement in association with the aforemen- cially in smokers, is associated with poor short-term vital progno-
tioned pathologies, but very rarely do these occur in isolation. sis and is the leading cause of mortality for urticarial vasculitis
The most common renal symptoms are hematuria and proteinuria, (Jara et al., 2009; Raoufi et al., 2016). Upper-respiratory tract afflic-
with a small minority eventually developing kidney failure requir- tions, including laryngeal edema, may occur as well (Alomari et al.,
ing dialysis. Fortunately, even patients with extensive kidney 2019).
involvement maintain a fairly good prognosis (Boyer et al., 2020). Gastrointestinal symptoms occur in up to 30% of patients. These
commonly manifest as abdominal pain, nausea, vomiting, and diar-
rhea (Davis and van der Hilst, 2018). Cases of intestinal ischemia
secondary to urticarial vasculitis have also been reported (Wong
et al., 2016). Ocular inflammation has been observed as well, fre-
quently manifesting as uveitis, most often posterior, episcleritis,
and conjunctivitis (Zuberbier and Maurer 2014). These complica-
tions occur in approximately 10% of patients and up to 30% of those
with hypocomplementemic urticarial vasculitis syndrome (Jachiet
et al., 2015). Other rare extracutaneous pathologies include peri-
carditis, pericardial effusion, pseudotumor cerebri, cranial nerve
palsies, and transverse myelitis (Koç et al., 2017).

Histologic findings

Urticarial vasculitis is a leukocytoclastic vasculitis and most

often affects the postcapillary venules of the skin. Because the pre-
sentation of this condition can vary, a lesional biopsy is considered
the gold standard for diagnosis among clinicians (Kolkhir et al.,
2020). As is the case with small vessel vasculitis, demonstration
of the full histologic picture requires biopsy of the lesion at the
exact stage of evolution and is influenced by therapy. Although
not always seen, common diagnostic features include damage to
the dermal vessels (including endothelial swelling and associated
luminal occlusion), karyorrhexis of neutrophils with production
of nuclear dust, and extravasation of erythrocytes into the dermis.
Fibrinoid changes of the vessel walls are also often seen (Zuberbier
and Maurer 2014). Inflammatory infiltrate can be detected in the
walls of the vessels and perivascularly and is generally composed
of neutrophils, eosinophils, and/or lymphocytes. As lesions age,
the infiltrate tends to shift from neutrophil or eosinophil dominant
to primarily lymphocytic (Damman et al., 2020). Neutrophil extra-
cellular traps have also been found in some patients, and investiga-
tors postulate that this feature is potentially reflective of the
severity of the disease (Bonnekoh et al., 2019). Deposits of IgM,
IgG, and less frequently of IgA, C1q, C4, C3, or fibrinogen, are com-
Fig. 3. (A) Papillary edema with perivascular neutrophil-predominant infiltrate monly found within the vessel walls on immunopathology (Fig. 3;
associated with leukocytoclastic vasculitis, characterized by karyorrhexis, extra- Zuberbier and Maurer 2014).
vasated erythrocytes, and swelling of endothelial cells. Numerous scattered
interstitial eosinophils and mast cells can be seen (hematoxylin and eosin, 100).
These classic histopathologic findings of this disease have been
(B) Perivascular neutrophils, eosinophils (green arrow) and mast cells (red arrow; shown to last only 24 to 48 hours, making selection of the ideal
hematoxylin and eosin, 300). lesions for biopsy an important clinical endeavor (Koç et al.,
4
S.L. Gu and J.L. Jorizzo International Journal of Women’s Dermatology xxx (xxxx) xxx

2017). Clinicians should also realize that systemic therapy may treating clinician should work with the specialists managing the
influence histologic findings. Some reports suggest histology other patient’s relevant condition to arrive at a more stable or effective
than that described herein, but these other findings can be treatment for its management. Examples in the literature include
explained by lesions that are too early, too late, or influenced by patients with hepatitis, mycoplasma, trichomoniasis, and malig-
systemic therapy (Kamyab et al., 2019; Lee et al., 2007). nancy associated urticarial vasculitis, all of whom reported
Although there are characteristic features to look for on improvement in symptoms after appropriate treatment of the
histopathologic examination, patients will not necessarily demon- underlying conditions (Kolkhir et al., 2019). Patients should also
strate all these findings and among those who do, a substantial abstain from usage of or exposure to any complicit drugs or
amount of variation can exist. In mild cases, the infiltrate can be antigens.
sparse and perivascular with minimal leukocytoclasis and little Commonly used first-line medications in the treatment of this
to no evidence of fibrinoid deposits. This can be quite disparate disease include oral antibiotics (e.g., doxycycline), colchicine (stan-
from more severe cases, where frank leukocytoclasis and fibrin dard therapy in most neutrophilic dermatoses, including cuta-
deposition can readily be found (Dincy et al., 2008). neous small-vessel vasculitis), and dapsone. Hydroxychloroquine
As with disease severity, hypocomplementemia is a useful pre- can also be used but is generally reserved for patients with co-
dictor for histologic features of urticarial vasculitis. In hypocom- occurring systemic lupus erythematosus. These medications have
plementemic urticarial vasculitis, perivascular and interstitial been shown to have efficacy comparable with that of corticos-
eosinophil and neutrophil infiltration, neutrophil count, erythro- teroids while exhibiting fewer adverse effects and are preferable
cyte extravasation, and nuclear dust formation are all more exten- in mild cases limited to cutaneous involvement (Jachiet et al.,
sive when compared with findings typical for 2018). Various nonsteroidal anti-inflammatory drugs can also be
normocomplementemic urticarial vasculitis (Damman et al., given and are especially useful for addressing musculoskeletal
2020). Some authors also found that eosinophilic predominant symptoms (Koç et al., 2017). Antihistamines fail to address the
infiltrates occurred more often in normocomplementemic patients, pathogenesis of this disease and as such are ineffective in most
whereas those that were neutrophil dominant were more typical of patients with urticarial vasculitis (Venzor et al., 2002). However,
hypocomplementemic patients (Mehregan et al. 1992). these medications can be added to help treat the angioedema
and true urticaria lesions that occur in up to 50% of patients.
Differential diagnosis Immunosuppressives, including methotrexate, mycophenolate
mofetil, azathioprine, and cyclosporine, are often used as second-
There are several potential differential diagnoses for urticarial line therapies (Kolkhir et al., 2019). Weekly methotrexate can be
vasculitis. As mentioned earlier, chronic idiopathic urticaria can administered to patients with cutaneous or minimal systemic dis-
present similarly to urticarial vasculitis, but these two conditions ease (Stack, 1994). These drugs have been shown to be more effec-
can be distinguished by the disparate duration of their individual tive when paired with corticosteroids, with particular utility in
lesions. Schnitzler’s syndrome, an autoinflammatory condition, is refractory cases (Jachiet et al., 2018). Cyclophosphamide has his-
another possibility to consider. On biopsy, lesions of Schnitzler’s torically been used as well but has fallen out of favor due to its
syndrome are similar to urticarial vasculitis in that they have a pri- toxic effects (Venzor et al., 2002).
marily neutrophilic infiltrate; however, unlike urticarial vasculitis, Usage of corticosteroids is often necessary for control of cuta-
they do not demonstrate any evidence of vasculitis on histopatho- neous or systemic symptoms but is generally reserved for
logic examination (Dingli and Camilleri, 2015). Other differential moderate-to-severe cases or when other first-line treatments have
diagnoses include Well’s syndrome, erythema migrans, tumid failed. This therapy is effective in resolving cutaneous disease in
lupus erythematosus, and urticarial multiforme (Table 1; Emer approximately 80% of patients and has been shown to significantly
et al., 2013). decrease joint, ocular, gastrointestinal, and pulmonary symptoms
(Kolkhir et al., 2019). Patients have also exhibited immunological
changes, including depression of inflammatory markers and
Treatment
increase in complement levels, which correlate with cutaneous
improvement (Jachiet et al., 2018). However, usage of glucocorti-
Clinically, treatment of urticarial vasculitis can be difficult due
coids comes with its own set of challenges, and many patients
to the lack of large randomized or controlled trials evaluating the
experience a relapse in symptoms when treatment is discontinued.
efficacy of existing therapies. Currently, there are no drugs that
Several biologic medications have also been promising for the
have been approved by the U.S. Food and Drug Administration
treatment of urticarial vasculitis and are especially useful in refrac-
for usage in this disease, and in practice regimens are based on
tory cases when conventional avenues of therapy have been
the limited information available from case studies (Kolkhir
exhausted. Rituximab (anti-CD20), which is often paired with cor-
et al., 2018). The medications used in individual cases are generally
ticosteroids, hydrochloroquine, or cyclosporine, has been shown to
dictated by the severity of disease, and it is preferred to begin with
yield higher response rates and is associated with an increased
more accessible treatments with fewer side effects (Table 2). How-
time to treatment failure when compared with corticosteroids
ever, before any treatment is given, it is important to address any
and conventional immunosuppressives (Jachiet et al., 2018;
underlying conditions that may be contributing. If present, the

Table 1
Differential diagnoses and features of urticarial vasculitis.

Differential diagnosis Features

Chronic idiopathic urticaria Individual lesions lasting <24 hours
Well’s syndrome Usually a small number of lesions with intensively eosinophilic infiltrate on histology
Erythema migrans Annular erythema and other features of Lyme borreliosis
Tumid lupus erythematosus Annular plaques on sun-exposed areas that are fixed and have a characteristic histology
Urticarial phase of bullous pemphigoid Evolves to characteristic blistering lesions with diagnostic routine microscopic and immunomicroscopic changes
Schnitzler syndrome Chronic urticarial rash showing neutrophilic dermal infiltrate on histology; no evidence of vasculitis present
Urticarial multiforme Classic target lesion with violaceous or dusky center that may blister

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S.L. Gu and J.L. Jorizzo International Journal of Women’s Dermatology xxx (xxxx) xxx

Table 2
Therapeutic ladder for urticarial vasculitis.

Oral antibiotics
Mild disease (cutaneous involvement only)
Colchicine
Dapsone
Hydroxychloroquine
Nonsteroidal anti-inflammatory drugs
Methotrexate
Mycophenolate mofetil
Azathioprine
Cyclosporine
Prednisone
Intravenous immunoglobulin
Rituximab
Omalizumab
Interleukin-1 inhibitors

Severe (significant systemic

involvement) or refractory disease
Add if angioedema and urticarial lesions lasting <24 hours present Low-sedation antihistamines
 Levocetirizine
 Cetirizine
 Loratadine
 FexofenadineDoxepin (low dose)

Swaminath et al., 2011). Omalizumab (anti-IgE) is another option, This disease is often idiopathic, but it can also be linked to some
and several recent case reports have supported the efficacy of this infections, drugs, autoimmune disorders, and malignancies. When
medication in the treatment of urticarial vasculitis (Cherrez-Ojeda a cause is known, treatment of the underlying disease or disorder
et al, 2018; Nucera et al., 2017). Omalizumab seems to be espe- or removal of the complicit antigen should be completed before
cially effective in treating normocomplementemic patients, with any other therapies are administered. Currently used medications
investigations into its utility for hypocomplementemic urticarial for the treatment of urticarial vasculitis include dapsone and col-
vasculitis yielding inconsistent results (de Brito et al., 2018). Suc- chicine, hydroxychloroquine, immunosuppressives, corticos-
cessful usage of this medication in conjunction with methotrexate teroids, and select biologics.
has also been documented (Garbayo-Salmons et al., 2020). The
mechanism of action of omalizumab and its role in the pathogen- Conflicts of interest
esis of urticarial vasculitis has yet to be elucidated and may or may
not be the same mechanism by which it exerts its efficacy in the None.
treatment of chronic urticaria (Fueyo-Casado et al., 2017).
Usage of IL-1 inhibitors (anakinra and canakinumab) as treat-
Funding
ment has also shown promising results. Studies have demon-
strated a concurrent improvement in both serological markers
None.
and clinical disease in response to this therapy. The efficacy of
these medications has led some authors to propose a role of IL-1
in the development of urticarial vasculitis, but the exact link Study approval
remains unclear (Bettuzzi et al., 2019; Botsios et al., 2007;
Krause et al., 2013). Intravenous immunoglobulin has also been The author(s) confirm that any aspect of the work covered in
effective in treating cutaneous and systemic symptoms in some this manuscript that has involved human patients has been con-
patients (Staubach-Renz et al., 2007; Yamazaki-Nakashimada ducted with the ethical approval of all relevant bodies.
et al., 2009; Table 2).
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