Chronic
leukocytoclastic vasculitis: case report and literature review
(Portuguese
PDF version)
José
Lacerda Brasileiro,1 Antônio Gabriel Vieira Coutinho Mendes,2
Juliana Chen,3 Izaias Pereira da Costa,4 Lídia Satsico
Aracaqui Ayres,5 Maldonat Azambuja Santos6
1.
Assistant professor and preceptor, Service of Angiology and Vascular
Surgery, Núcleo do Hospital Universitário (NHU), Universidade
Federal do Mato Grosso do Sul (UFMS), Campo Grande, MS, Brazil.
2. Former-resident, Service of Angiology and Vascular Surgery,
NHU/UFMS, Campo Grande, MS, Brazil.
3.
Undergraduate student, School of Medicine, UFMS, Campo Grande, MS,
Brazil.
4.
Chief of the Rheumatology Service, NHU/UFMS, Campo Grande, MS, Brazil.
5.
Adjunct
professor, Rheumatology discipline, UFMS, Campo Grande, MS, Brazil.
6.
Chief of the Service of Angiology and Vascular Surgery,
NHU/UFMS, Campo Grande, MS, Brazil.
Correspondence:
José Lacerda Brasileiro
Rua João Rosa Pires, 641/1002
CEP 79008-050 - Campo Grande, MS, Brazil
Phone: +55 (67) 9281.8940/321.7493
E-mail: jlbras@terra.com.br
ABSTRACT
The
authors report an idiopathic cutaneous leukocytoclastic vasculitis
case with segmented lesions in the skin.
MIAS,
39 years old, white, female, presented with cutaneous lesions that
turned to multisegmented and symmetrical type. Lesions involved
almost the whole body, especially below knee and except in the head,
the palm of the hand and feet, persisting for 7 days. At presentation,
the patient was taking penicillin. The patient assessment was based
on clinical conditions, laboratory tests, photographic documentation
and histopathological analysis that demonstrated compatible results
for leukocytoclastic vasculitis. The patient was submitted unsuccessfully
to clinical treatment with corticosteroids and immunosuppressive
agents. According to the medical literature, necrotizing cutaneous
lesions are usually immunologically related to the use of drugs
and generally respond to clinical treatment.
Key-words:
leukocytoclastic vasculitis, allergic cutaneous vasculitis, hypersensitivity
vasculitis.
J
Vasc Br 2004;3(4):392-6
Vasculitis
is a general term for a group of diseases which feature inflammation
of small blood vessels (arterioles, venules or capillaries), like leukocytoclastic
vasculitis, Wegener's granulomatosis, Churg-Strauss syndrome and Henoch-Schönlein
Purpura.
The pathogenic
mechanism of the leukocytoclastic vasculitis (also known as hypersensitivity
vasculitis) is the immune-complex deposition, typically affecting the
postcapillary venules. Although the disease affects mostly the skin,
around 50% of cases may present with systemic disorders in the kidneys,
joints, lungs, muscles, heart, gastrointestinal tract and/or peripheral
nerves.1
As for
etiology, it can be idiopathic or associated with drugs, infections
and neoplasms; it can also be a manifestation of some collagen vascular
diseases. Clinical symptoms usually begin as palpaple purpuric rashes
that may evolve to different types of lesions, according to the extent
of skin involvement. An hystopathologic examination can confirm the
diagnosis of leukocytoclastic vasculitis, revealing injured dermal blood
vessels with perivascular infiltration of neutrophils (leukocytoclasia)
and the presence of fibrinoid necrosis.2
In the
present article we report on a case of leukocytoclastic vasculitis with
abnormal clinical development and lesions. It was very difficult to
be diagnosed and did not have a positive response to first the therapeutic
treatment prescribed.
CASE
REPORT
A 39-year-old
white female attended the university hospital presenting with skin lesions
that have persisted for the last 30 days. At first, rashes were painful
and had and erythematous and macular aspect; in a short period of time
(around 12 hours) they acquired a necrotic and ulcerous aspect with
crusts that revealed underlying granulated tissue. Rashes had slow and
spontaneous healing with scarring (Figures 1 and 2). They developed
in a multisegmentar and symmetric way, predominating below knee and
saving the cephalic pole, palms and soles of the feet.
 Figure
1 - Necrotic ulcers predominating below knee.
Figure
2 - Skin with multisegmentar scarring lesions.
At onset
of rashes, the patient was in the late postoperative period of an oophorectomy.
She was taking trihydrate ampicillin (Binotal®) and sodium dipyrone,
and presented fever, emaciation, arthralgias and myalgias.
Laboratory
findings revealed ESR (erythrocyte sedimentation rate) normal or slightly
elevated (22 to 43 mm/h). The C-reactive protein test, which indicates
acute inflammation, and the C3 and C4 complement components were within
normal levels. The tests for LE cells (Lupus Erythematosus), ANF (antinuclear
factor), VDRL (Venereal Disease Research Laboratory Slide Test) and
ANCA (Antineutrtoxoplasmosis and herpes were unrevealing. The antiocardiolipin
antibodies test was negative, and image tests like thorax radiography,
electrocardiogram and abdominal ultrasound were normal. Echocardiogram
revealed pericardial thickening with small accumulation of fluid in
the pericardial space.
The skin
biopsy revealed a leukocytoclastic vasculitis compliant condition: necrosis
and epidermal infiltrate of neutrophils, dermal fragmented neutrophils
with "nuclear dust" and inflammatory infiltrate of neutrophils,
lymphocytes, histiocytes and some eosinophils that covered vessels associated
with red blood cells extravasation (Figure 3).
Figure
3 - Epidermis with fragmented neutrophils infiltrate and nuclear
dust.
The drugs
she was taking were discontinued, and she was administered prednisone
and azathioprine, which have not improved the clinical status. The patients'
history evidenced recurrent episodes of hospitalization because of lesions
persistence associated with secondary infection (around four within
a year) and intense pain, mainly in the lower limbs. In the last hospitalization,
pain and skin rashes reduced after the use of methylprednisolone pulse
therapy.
After discharge,
the patient was given prednisone and attended regular follow-up visits.
In the following 10 months, corticosteroids were progressively discontinued,
but arthralgia and skin lesions relapsed even under administration of
paracetamol.
An oral
corticoid was administered (prednisone) to control symptoms in association
with chloroquine and pentoxifylline. Currently, the patient still has
some symptoms, like arthralgia and multisegmented skin lesions, which
are in the healing phase.
DISCUSSION
The leukocytoclastic
vasculitis is a condition that affects small vessels, most commonly
the venules. The pathogenic mechanism is immune complex deposition,
usually involving IgG and IgM. Once the immune complexes are deposited,
the complement cascade is activated and leukotactic factors, particularly
C5, are produced and adhesion molecules expressed. Neutrophils migrate
and release enzymatic substances and reactive oxygen derivatives, which
eliminate antigens. The reactive inflammatory process is intense and
causes destruction of the vessel wall, which allows for fluid leakage
and extravasation of red blood cells. This process is also believed
to damage neutrophils cells with secondary release of inflammatory substances.1,3,5
Ghersetich
et al.6 observed that in the pathogenic
mechanisms of late rashes secondary to vasculitis, there may be an immune
response mediated by cells. They also report that Lengerhans cells and
lymphocytes can contribute to the continuation of the inflammatory process.
Besides, leukocytes released by cytokines (like the alpha tumor necrosis
factor) could stimulate the release of the plasminogen inhibitor activator
(PIA) and affect the release of endothelial plasminogen activator, contributing
to the reduction of the fibrinolitic activity. This would precipitate
the fibrine deposition within vessels and promote the outcome of necrotic
ulcers.
The etiology
of leukocytoclastic vasculitis is usually associated with events of
drugs hypersensitivity, however, it can be triggered by infections,
connective tissue diseases and neoplasms; it can be also classified
as idiopathic, if no reasonable cause is found. Drugs usually associated
with the disease are antibiotics (especially penicillin and sulphonamides),
thiazide diuretics, non-hormonal anti-inflammatory medication, and methimazole;
diseases associated are B and C hepatitis, herpes simplex, streptococci,
staphylococci and meningococcal infections, and lymphomas.
In the
present case report, lesions started after the use of ampicillin and
continued even when exposure to the causative medication was stopped.
Clinically,
the leukocytoclastic vasculitis is different from thrombocytopenia,
trauma or vascular vessels walls disorders by the presence of palpable
purpuric eruptions. At the onset, lesions are localized erythema and
macular purpuric eruptions or papular hives that become palpable purpuric
rashes. They usually distribute symmetrically all over the body, especially
in the lower limbs (legs and ankles) and except in the face, palms,
soles of the foot and mucosal tissues. These lesions may evolve to the
formation of vesicles and nodes, and can reach the status of necrotic
ulcers. In the case reported here, lesions acquired a necrotic multisegmentar
form. Rashes usually vary from red to purple and size and diameter may
range from 1 mm to 2 to 4 cm. Usually, these lesions are asymptomatic
or followed by complaints of itching and pain, specially in the presence
of nodes or ulcers.10 In the case of the
patient reported here, pain was present even during the administration
of paracetamol, corticosteroid, chloroquine and pentoxifylline.
In the
acute phase of the disease, hemorrhagic, purpuric and necrotic lesions
predominate, they can evolve to vesicles, hemorrhagic blisters and necrotic
areas which clear within two or three weeks. In the sub-acute phase,
rashes are purpuric, erythematous and macular or in the form of hives,
with possible nodes or small necrotic areas. The chronic phase has light
symptoms, with the predominance of erythemas, nodules and macular, papular,
purpuric and urticarial lesions, with a slight discomfort at the onset
of rashes and small intensity symptoms that precede exacerbations.6
In the
majority of cases, lesions affect only on the skin (cutaneous leukocytoclastic
vasculitis), but there may be other systemic manifestations like fever,
headache, arthralgias, myalgias and renal and gastrointestinal disorders.
Pleural, pericardial and neural involvement is not rare; the patient
reported here manifested some related symptoms, but cutaneous affection
was the most severe.
Evolution
time depends on the extension and level of organic involvement, varying
from one to 10 days. In some cases where only the skin is involved and/or
when there is no identification and discontinuation of the precipitating
agent, the leukocytoclastic vasculitis lasting period is usually short
(less than 30 days). Purpuric lesions tend to last 3 to 4 weeks, sometimes
leaving a hyperpigmented and atrophic scarring area. This clinical condition
can recidivate or become chronic with the eruption of new lesions over
months or years.10,11 Sais et al.12
observed that lesions severity was associated with the presence of arthralgia,
cryoglobulinemia and absence of fever. In the case reported here, lesions
persisted for 46 consecutive days, even with the withdrawal of the triggering
factor and maintenance of specific treatment.
There aren't
specific laboratory tests to detect the leukocytoclastic vasculitis,
they only aid the evaluation of the organic functions (blood investigations,
screening tests for inflammatory diseases, levels of serum complement,
serological tests for hepatitis B and C and herpes, FAN, ANCA, antiphospholipid
antibodies, urinalysis and thorax radiography).
Several
vascular syndromes that affect small vessels are associated with ANCA,
which are antibodies directed against proteins of the granules of neutrophils
and monocytes cytoplasm. Examples are the Wegener's granulomatosis,
the Churg-Strauss syndrome and the microscopic polyangitis. These diseases,
however, arise lately, and they are not present in all types of vasculitis.13,14
It has
been suggested that there is an association of antiphospholipid antibodies
with the leukocytoclastic vasculitis; anticardiolipine IgA (which is
not usually required) may be present in these patients, even if the
IgM and IgG forms are not.15
The American
College of Rheumatology established some criteria for the classification
of hypersensitivity vasculitis: age greater than 16 at disease onset;
history of taking a medication at onset that may have been a precipitating
factor; the presence of palpable purpura, the presence of maculopapular
rash, and a biopsy demonstrating granulocytes around an arteriole or
venule. The presence of three or more of these five criteria was associated
with a sensitivity of 71% and a specificity of 83.9%.16
The skin biopsy has a paramount role in the diagnosis of this illness,
because it allows for the assessment of the damaged vessel caliber.
It also makes possible to distinguish the leukocytoclastic vasculitis
from other non-inflammatory vasculopathies that emulate it, like perivasculitis,
embolic phenomena, and cryoglobulinemia. Biopsy should be early performed
once leukocytoclasia may not be found in old lesions, which can present
a predominance of lymphocytes around blood vessels. The histopathologic
test reveals an angiocentric inflammatory process associated with leukocytoclasia
(neutrophil segmentation), edema of endothelial cells, extravasation
of red blood cells and fibrinoid necrosis. The presence of immunoglobulins
in lesions may be observed by immunofluorescence; however, their presence
in vascular lesions is rare and does not justify the routine use of
this test.
The treatment
starts with the identification of the precipitating agent and its withdrawal.
When lesions are associated with drugs, the discontinuation may lead
to remission, but this is not the case of the patient reported here.
In the majority of cases, corticosteroids are required and may be effective
for a short period of time in the management of cutaneous vasculitis,
however, some patients may require the use of cytotoxic agents, like
cyclophosphamide, cyclosporine, chlorambucil, azathiprine and methotrexate.
Dapsone, antimalarial drugs (like chloriquine and hydroxichloriquine),
colchicines and pentoxifylline may be used as well.6
Today,
new therapeutic options are being developed, like the use of antagonists
or cytokine inhibitors (especially interleukin-1 and the tumor necrosis
factor) and the therapy with monoclonal antibodies that aim at reaching
the T-cell (CD4).6,18,19
In the
case reported here, signs, clinical symptoms, and tests findings were
in accordance with the data of the American College of Rheumatology.
This provided us with the appropriate conditions to define the diagnosis
of our patient as leukocytoclastic vasculitis secondary to the use of
ampicillin and dipyrone.
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