Urticarial
vasculitis
Overview
Urticarial vasculitis is a rare
disease that needs to be differentiated from chronic spontaneous urticaria. The
illness is characterized clinically by urticarial lesions with histological
evidence of leucocytoclastic vasculitis. It can lead to substantial morbidity
if associated with hypocomplementaemia and systemic involvement. The diagnosis
relies on lesional skin biopsy and may present challenges for both clinicians
and histopathologists. Investigation for an underlying infection or an
autoimmune‐, neoplastic‐ or drug‐related etiology may reveal a cause but many cases remain
unexplained after investigation. Management of urticarial vasculitis can be
difficult and includes H1 antihistamines, non‐steriodal
anti‐inflammatory drugs, oral corticosteroids, antimalarials and
immunosuppressive agents, but evidence of efficacy from controlled studies is
needed.
Salient features
·
Recurrent episodes of painful, persistent urticarial lesions
that last >24 hours and often resolve with residual hyperpigmentation
·
Angioedema may also be present
·
May be associated with constitutional symptoms and arthritis
·
Patients with hypocomplementemia are more likely to have
systemic involvement
·
Associated disorders include autoimmune connective tissue
diseases (especially systemic lupus erythematosus, Sjögren syndrome) and viral
infections
Introduction
Urticarial vasculitis is a rare
disease characterized clinically by persistent urticarial lesions with
histological evidence of leucocytoclastic vasculitis. Clinicopathological
correlation is essential for diagnosis. Its association with autoimmune
connective tissue diseases and potential overlap with systemic lupus
erythematosus (SLE) distinguishes this disorder from typical CSVV.
Patients with urticarial vasculitis have been categorized into two sub-groups: those with hypocomplementemia and those with normal complement levels. Distinguishing between hypocomplementaemic and
normocomplementaemic urticarial vasculitis is important since the former may
have multisystem involvement, including nephritis, whereas the latter usually
runs a benign and, ultimately, self‐limiting
course.
Epidemiology
Incidence
and prevalence
It is a rare disease that occurs in about 1–20% of patients
presenting with a chronic urticarial illness.
Age
Urticarial vasculitis occurs with
peak incidence in the fourth decade of life. The incidence of
hypocomplementaemic urticarial vasculitis syndrome (HUVS) peaks in the fifth
decade.
Sex
Women are more often affected than men.
Pathophysiology
Urticarial vasculitis affects
predominantly postcapillary venules in the superficial dermis. The vascular
endothelial damage is thought to be mediated by circulating immune complexes.
Deposition of IgG and IgM and C3 within and around the vessel wall and at the
dermal–epidermal junction is a common feature.
Hypocomplementemia in urticarial
vasculitis is consistent with complement activation via the classical
complement pathway caused, presumably, by circulating immune complexes.
Patients with HUVS usually have IgG auto antibodies directed against the
collagen‐like region of C1q and low levels of C1q.
The dynamic nature of the
inflammatory infiltrate has been reported. Eosinophils were the first cells
recruited at 3 h, followed by neutrophil predominance at 24 h. Lymphocytes are
thought to be the predominant cells in the perivascular infiltrate in the lesions
older than 48 h.
Although
urticarial vasculitis is most often idiopathic, it can be associated with
autoimmune connective tissue diseases (especially Sjögren syndrome and SLE),
serum sickness, cryoglobulinemia, infections, medications, and hematologic
malignancies.
|
Urticarial vasculitis –
associations |
|
Autoimmune connective
tissue diseases (Sjögren syndrome, SLE) |
|
Serum sickness |
|
Cryoglobulinemia |
|
Infections ·
Hepatitis
B virus ·
Hepatitis
C virus ·
Epstein–Barr
virus ·
Lyme
disease |
|
Medications ·
Cimetidine ·
Cocaine ·
Diltiazem ·
Etanercept ·
Fluoxetine ·
Infliximab ·
Methotrexate ·
NSAIDs ·
Potassium
iodide ·
Procainamide ·
Procarbazine |
|
Hematologic malignancies ·
Plasma
cell dyscrasias (IgM, IgG, IgA) ·
Leukemias ·
Lymphomas ·
Castleman
disease |
|
Solid organ malignancies – rare ·
Colon
carcinoma ·
Renal
cell carcinoma |
Pathology
Classical histopathological features
of fully developed urticarial vasculitis are: (i) endothelial cell damage and
swelling and loss of integrity of the vessel wall; (ii) fibrin deposits in the
affected postcapillary venules; (iii) neutrophil‐predominant
perivascular infiltrate with leucocytoclasis; and (iv) erythrocyte
extravasation. However, all of these features may not be present, thereby
causing diagnostic uncertainty.
By DIF, immunoglobulin G, IgM and/or
C3 within or around the vessels of lesions is seen more often in patients with hypocomplementemic than normocomplementaemic urticarial vasculitis. A
granular pattern of immunoreactants along the basement membrane zone occurs in
~80% of lesions and, when accompanied by hypocomplementemia, suggests the
diagnosis of SLE. About 70% of patients with
immunoglobulin deposition at the dermal–epidermal junction develop
glomerulonephritis.
There may be eosinophil predominance
in normocomplementaemic urticarial vasculitis, whereas patients with
hypocomplementaemic urticarial vasculitis have neutrophil‐rich perivascular infiltrates.
Clinical
features
In some cases, infection or drug intake may precede the
onset of urticarial vasculitis. Patients complain of recurrent weals, with or
without angioedema, that favor the trunk and proximal extremities. Urticarial
vasculitis is distinguished from chronic urticaria by individual lesions that
persist beyond 24 hours, are associated with burning and pain rather than
pruritus, and resolve with post inflammatory hyperpigmentation. With diascopy
or as residua, hemorrhage can be observed. However, these features are not
always present. Rarely, bullae, erythema multiforme-like lesions, livedo reticularis,
Raynaud phenomenon, and laryngeal edema are other
clinical manifestations of urticarial vasculitis. Patients often complain about fatigue, malaise or fever
associated with weals.
Recent evidence suggests that urticarial vasculitis may be
an underlying process in 20% of patients with clinical presentations of chronic
urticaria resistant to treatment with antihistamines.
Clinical variants
The most
important prognostic feature is the presence or absence of hypocomplementemia.
Patients with normal complement levels tend to have skin-limited disease,
whereas those with hypocomplementemia are much more likely to have systemic
manifestations. Hypocomplementaemic disease tends to
be more severe than normocomplementaemic disease. It remains unclear whether
there is a transition between these clinical variants over time. Therefore,
serial testing of serum complement levels over time is important for
distinction between normocomplementaemic and hypocomplementaemic urticarial
vasculitis.
The hypocomplementemic urticarial
vasculitis syndrome (HUVS) is a more severe clinical syndrome identified in about 5% of
patients with urticarial vasculitis with the following diagnostic criteria:
Two
major criteria: (1) urticaria for 6 months and (2) hypocomplementemia – plus – Two or more minor criteria: (1) vasculitis on skin
biopsy; (2) arthralgia or arthritis; (3) uveitis or episcleritis; (4) glomerulonephritis;
(5) recurrent abdominal pain; or (6) decreased C1q or presence of anti‐C1q
autoantibodies. Not all systemic features are required to make a diagnosis.
Patients with hypocomplementemia
who do not meet the criteria for HUVS are considered to have hypocomplementemic
urticarial vasculitis (but not HUVS).
Musculoskeletal involvement
is the most common extracutaneous manifestation of urticarial vasculitis.
Arthralgias of the hands, elbows, knees, ankles, and feet occur in half of all
patients with urticarial vasculitis, but up to 50% of patients with HUVS have
frank arthritis.
Up to 20%
of patients with HUVS have pulmonary symptoms
(cough, laryngeal edema, hemoptysis, dyspnea, asthma, chronic obstructive
pulmonary disease [COPD]). COPD is especially severe in smokers with urticarial
vasculitis, and it is worse than would be expected due to smoking alone.
Renal involvement,
manifesting as proteinuria or microscopic hematuria, occurs in 5–10% of
patients with HUVS.
Gastrointestinal manifestations
(abdominal pain, nausea, vomiting, and diarrhea) occur in up to 30% of
patients; cardiac and central nervous system involvement are rare, but
reported.
HUVS
shares features with SLE, but distinctive clinical findings in HUVS
include ocular inflammation (30%; conjunctivitis,
episcleritis, iritis, uveitis), angioedema (>50%), and COPD-like symptoms
(50%).
Disease
course and prognosis
Patients with normocomplementaemic urticarial vasculitis
limited to the skin tend to have a benign disease with a good prognosis.
Conversely, hypocomplementaemic urticarial vasculitis is associated with a more
severe course and more frequent systemic involvement. The most severe course is
described for HUVS with a high risk for the development of systemic lupus
erythematosus. More than 50% of patients with HUVS develop systemic lupus
erythematosus. In HUVS, chronic obstructive pulmonary disease or laryngeal
angiooedema can be a life‐threatening complication.
Prognosis in urticarial vasculitis depends on the presence
of systemic involvement. Systemic involvement may occur early on although late‐onset complications have been described. In some cases,
urticarial vasculitis may precede the onset of hematological or connective
tissue disorders.
Investigations
Diagnostic work‐up in
urticarial vasculitis
|
Initial work‐up |
Extended work‐up (dependent on
clinical presentation) |
|
·
Lesional skin biopsy (diagnostic) ·
Full blood count ·
Erythrocyte sedimentation rate ·
Biochemical profile ·
C3, C4 complement components (serial testing) ·
Antinuclear antibodies ·
Anti extractable nuclear antigens ·
Hepatitis B and C serology ·
Circulating immune complexes ·
Urinalysis |
·
Direct immunofluorescence studies of skin biopsy ·
CH50, anti‐C1q antibodies ·
Cryoglobulins ·
24‐h urine protein and
creatinine clearance ·
Serum protein electrophoresis ·
Chest X‐ray, lung function
tests ·
Assessment of visual acuity and slit lamp examination |
Lesional skin biopsy
is the cornerstone of the diagnosis of urticarial vasculitis. Several skin
biopsies may be required for the confirmation of the diagnosis of urticarial
vasculitis. Routine use of direct immunofluorescence on frozen tissue is not
recommended unless HUVS is suspected.
All patients with
urticarial vasculitis should undergo a laboratory work‐up
consisting of full blood count, blood biochemistry and erythrocyte
sedimentation rate. Urinalysis and liver function tests are essential in
laboratory work‐up for systemic involvement. Transient or
permanent microscopic hematuria or proteinuria can be observed. In the case of
abnormal urinalysis, 24‐h urine protein and creatinine clearance
should be checked. Complement profile (CH50, C3, C4 and anti‐C1q
antibodies) is important for differentiating between normocomplementaemic
disease and HUVS. Antibody screen in patients with urticarial vasculitis should
include antinuclear antibodies, antibodies against extractable nuclear
antigens, rheumatoid factor and circulating immune complexes. Testing for
hepatitis B and C is important.
In
patients with urticarial vasculitis, the most common abnormal laboratory
studies are an elevated ESR, low serum C3 and C4 levels, and a positive ANA.
HUVS is marked by low serum complement levels (which may vary, however, from
non-detectable to normal, even during attacks) plus the presence of anti-C1q
precipitin and depressed C1q levels. Although up to a third of patients with
SLE have circulating anti-C1q antibodies and up to half of patients with HUVS
have a positive ANA, patients with HUVS rarely have anti-dsDNA or anti-Sm
antibodies.
The extent of the
laboratory work‐up should be guided by the patient's history
and presentation. For example, suspicion of pulmonary involvement should
trigger a work‐up including chest X‐ray
and lung function testing. If eye involvement is suspected, ophthalmic
examination should be performed.
In general, the first line
treatments for urticarial vasculitis include H1 antihistamines and NSAIDs such
as
indomethacin (25 mg three times daily to 50 mg four times daily). Antihistamines may reduce the swelling and pain associated
with cutaneous lesions, but do not alter the course of the disease. For non‐responders, dapsone 75–100 mg/day, colchicine
1.0–1.5 mg/day and/or hydroxychloroquine 400 mg/day can be used as second line
treatments. In unresponsive patients, corticosteroids (prednisolone at doses of
40 mg/day or more) can then be considered for short‐term management. However, their prolonged use should be
avoided in view of their toxicity. For severe refractory cases,
immunosuppressive agents (cyclophosphamide, azathioprine), low-dose oral
methotrexate, ciclosporin and mycophenolate mofetil
may be beneficial. Rituximab or intravenous immunoglobulin may also be a
useful therapy for recalcitrant hypocomplementemic urticarial vasculitis.
Therapeutic algorithm
in urticarial vasculitis
|
First line treatments |
Second line treatments |
Third line treatments |
|
·
Non‐sedating H1 antihistamines ·
Non‐steroidal anti‐inflammatory
drugs |
·
Dapsone ·
Colchicine ·
Hydroxychloroquine ·
Short trials
of corticosteroids |
·
Azathioprine ·
Ciclosporin ·
Mycophenolate
mofetil ·
Methotrexate ·
Intravenous
immunoglobulins ·
Cyclophosphamide ·
?Interleukin
antagonists ·
??Omalizumab |
