Download 4. Treatment of pyoderma gangrenosum usually involves systemic

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Title
A case of pyoderma gangrenosum successfully treated with intravenous immune globulin
Author(s)
Marta Carlesimo, MD
Dermatologist
Department of Dermatology and Plastic Surgery, University La Sapienza, Rome, Italy
Carmen Cantisani , MD
Dermatologist
Department of Dermatology and Plastic Surgery, University La Sapienza, Rome, Italy
Email: [email protected]
Elena Mari, MD
Dermatologist
Department of Dermatology and Plastic Surgery, University La Sapienza, Rome, Italy
Mauro La Pietra, MD
Dermatologist
Department of Dermatology and Plastic Surgery, University La Sapienza, Rome, Italy
Alfredo Rossi, MD, PhD
Dermatologist
Department of Dermatology and Plastic Surgery, University La Sapienza, Rome, Italy
Vincent W Li, MD
Dermatologist
Angiogenesis and Wound Center, Department of Dermatology, Brigham and Women’s Hospital,
Harvard Medical School, Boston, Massachusetts, and The Angiogenesis Foundation, Cambridge,
Massachusetts, USA
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Stefano Calvieri, MD
Dermatologist
Department of Dermatology and Plastic Surgery, University La Sapienza, Rome, Italy
Keywords: pyoderma gangrenosum; intravenous immune globulin (IVIG); neutrophilic dermatosis;
ulcerative process.
Key Points
1. Pyoderma gangrenosum is a rapidly evolving and severely debilitating skin disease. Ulcers are
often deep and painful, characterised by violaceous (intense purple-coloured) margins.
2. The aetiology of pyoderma gangrenosum is often unclear. It may be idiopathic or associated with
a history of inflammatory bowel disease, including Crohn’s disease, or haematological or rheumatic
disorders.
3. Untreated pyoderma gangrenosum may last several months or years.
4. Treatment of pyoderma gangrenosum usually involves systemic therapy with high-dose steroids.
5. Intravenous immune globulin (IVIG) may be used where ulceration is resistant to conventional
treatment.
Heading 1
Abstract
Pyoderma gangrenosum is a neutrophilic dermatosis that may be idiopathic or associated with an
underlying disease. It is the result of an exaggerated response to specific and non-specific stimuli.
First-line treatment is with a steroid, usually prednisone. In this case report, a 25-year-old man
presented with an ulcerated lesion that had appeared spontaneously one year previously. He was
treated with prednisone, but this was ineffective. Treatment with intravenous immune globulin
(IVIG), however, proved successful. IVIG contains a broad range of antibodies that act against
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bacterial and viral antigens and is used to treat inflammatory and autoimmune diseases. Its use is
therefore recommended for consideration in cases of pyoderma gangrenosum that are steroid
resistant.
Heading 1
Introduction
First described in 1930, pyoderma gangrenosum is a non-infectious neutrophilic dermatosis [1]. The
condition has an idiopathic form as well as one associated with an underlying disease such as
inflammatory bowel disease, arthritis, haematological disease, human immunodeficiency
syndromes and solid tumours [2] [3]. There is also an idiosyncratic form that can be triggered by
certain drugs [4].
The classic skin lesion of pyoderma gangrenosum usually begins with folliculocentric pustules or
fluctuant nodules with an inflammatory halo, and expands peripherally to form an ulcer with
sharply circumscribed violaceous raised edges [1]. Lesions typically affect the lower extremities
and the trunk [4]. The varied appearance of these ulcers has led to their recent clinical classification,
which includes four prototypic forms of pyoderma gangrenosum: ulcerative, pustular, bullous and
vegetative. Only the last of these classifications has no common association with underlying
systemic disease. Each form may develop into another or become ulcerative [4] [5]. The diagnosis
does not depend on histological biopsy findings and is especially challenging in its initial clinical
form. A clinical-histological approach is required in order to make the diagnosis and to exclude
other ulcerative processes involving dermal neutrophilia [4].
The first line of treatment for pyoderma gangrenosum is usually the use of systemic corticosteroids,
together with treatment of any underlying cause [5]. Many therapeutic approaches have been
reported with inconsistent results [5]. Intravenous immunoglobulin (IVIG) has been used in
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inflammatory and autoimmune diseases, but there are very few reports of its use in cases of
pyoderma gangrenosum [6] [7] [8] [9].
The following case report describes a patient with pyoderma gangrenosum recalcitrant to
conventional treatment, who was treated successfully with IVIG.
Heading 1
Presentation
A 25-year-old Caucasian male was referred to our department for evaluation of an ulcerated lesion
in the left malleolar region. This lesion had appeared spontaneously one year before as a red
violaceous papule with an inflammatory halo that ulcerated after one month. The ulcerated lesion
had sharply circumscribed, undermined and painful borders with evidence of residual bulla and
pustules (Figure 1). Surgical skin grafting was performed, but this resulted in tissue pathergy and
worsening of the ulcer. Pathergy refers to either a subnormal response to an allergen or, in the case
of pyoderma gangrenosum, an unusually intense response, in which the individual becomes
sensitive not only to the specific stimuli, but to others.
Figure 1 here
Figure 1 caption:
Figure 1 - The ulcerated lesion with sharply circumscribed and undermined borders as it
appeared after surgical skin grafting.
The clinical appearance was consistent with a diagnosis of pyoderma gangrenosum. The biopsy
specimen demonstrated a dense diffuse neutrophilic infiltrate with a mixture of lymphocytes,
plasma cells, histiocytes and occasional foreign body giant cells that extended to the subcutis.
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All laboratory evaluations were within normal limits except for the lymphocyte subpopulation (see
Table 1). These findings show an alteration in cell-mediated immune response, with an uncontrolled
response to non-specific stimuli.
Table 1: Laboratory results: lymphocyte subpopulation.
T-cell subsets: CD (cluster
Results (percentage)
Normal value (percentage)
differentiation)
CD3
68.1
59-75
CD4
21.8 (below normal value)
40-53
CD8
47.3 (above normal value)
22-36
CD56
26.5 (above normal value)
1-7
CD2
74.5
60-80
CD19
3.2 (below normal value)
4-12
CD4/CD8
0.5 (below normal value)
1.8+/-0.5
As pyoderma gangrenosum can be associated with HIV, an HIV test was performed and found to be
negative. Other diagnostic tests such as chest X-ray, abdominal ultrasound and a double contrast
barium enema, performed in order to exclude any underling diseases, revealed no abnormalities.
Heading 1
Treatment
A conventional treatment regimen for pyoderma gangrenosum was tried initially, using oral
prednisone tablets 40mg/kg/day for one month, scaling down the following month. This was
discontinued because of a lack of improvement (Figure 2).
Figure 2 here. Figure 2 caption:
Figure 2 – The ulcerated lesion after treatment with prednisone. Wound diameter has not
changed.
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Oral cyclosporine tablets 2.5mg/kg/day were then introduced for one week. However, the patient
developed hypertension and treatment was discontinued. A decision was taken to treat the patient
with IVIG, as follows:
● A dose of 27.5g was given on four consecutive days in month one
● A dose of 55g was given on two consecutive days in month three
● A dose of 55g was given over two consecutive days at intervals of three months, then five months
and then two months.
A dramatic improvement was observed in the ulcer following the first dose, resulting in rapid
healing without any significant side effects. Over a three-year follow-up period, there was no
evidence of recurrence (see Figures 3 and 4).
Figure 3 here. Figure 3 caption:
Figure 3 – Improvement of the ulcerated area after the first treatment with IVIG.
Figure 4 Here. Figure 4 caption:
Figure 4 – As IVIG treatment progressed, the ulcer size reduced dramatically.
Heading 1
Discussion
Since its first description in 1930, the aetiology of pyoderma gangrenosum has remained obscure
[1]. Many hypotheses have been proposed, but attention has focused principally on immune
abnormalities and alterations in cell-mediated immune response [10]. It is thought that pyoderma
gangrenosum may be the result of a hyperergic (or hypersensitive) reaction of the immune system
due to an altered, exaggerated and uncontrolled inflammatory response to specific and non-specific
stimuli, leading to a neutrophilic vasculitis, characterised by perivascular deposition of
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immunoreactants, mainly IgM, C3 and fibrin with direct immunofluorescence. Neutrophils appear
to play a key role in the pathogenesis of pyoderma gangrenosum. This is evidenced by the fact that
the disease responds to therapies that have antineutrophilic activity. In some patients defective cellmediated immunity has been identified including: defective leukocyte adhesion glycoproteins;
defective neutrophilic chemotaxis and intracellular killing of microbial pathogens; selective anergy
(immune unresponsiveness) to bacterial or fungal antigens; and E hypergammaglobulinaemia.
When pyoderma gangrenosum is associated with systemic disease, the therapeutic approach should
also address the underlying disorder [4] [11]. Treatment of lesions usually involves systemic
treatment, together with local therapies [5] [11]. Systemic treatments include steroids such as
prednisone 40-120mg/day until healing [8] [9] [10]. Although prednisone is a first-line treatment, it
not consistent in treating the condition successfully and the high doses required have been
associated with significant side effects.
Cyclosporine (6mg/kg) is a common therapy used either alone or in combination with steroids [12]
[13]. Systemic antibiotics have also been used, including rifampin, tetracycline, vancomycin and
mezocillin [8] [9]. Thalidomide has also been shown to be effective, especially in genital pyoderma
gangrenosum [14].
IVIG is increasingly being used for the treatment of a range of inflammatory and autoimmune
diseases [14]. IVIG is a sterile solution of immunoglobulins prepared from pooled human plasma. It
contains a broad range of antibodies including IgG, and trace IgA and IgM, which act against
bacterial and viral antigens. The mode of action is not well understood, but it appears to have
numerous immune effects [5] [12] [13] [15]. These include:
● Blocking of the Fc receptor expressed on the splenic macrophages with clearance reduction of Ic
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● Complement inhibition for the band between IVIG and C3b, C4b, without formation of lytic
complex C5b-9
● Inhibition of production of IL-1, IL-2, IL-3, IL-4, IL-5, IL-10, TNF, GM-CMSF and INF
● Neutralisation of auto-antibodies
● Neutralisation of super-antigens
● Block of Fas-receptor and apoptosis reduction of target cells
● Apoptosis induction of auto-reactive T and B cells.
IVIG, acting on various parts of the immune system, can work as a ‘reset’ mechanism for different
inflammatory and autoimmune diseases. The same mechanism may explain its success with
pyoderma gangrenosum recalcitrant to conventional treatment. In the USA, IVIG is indicated for
the
treatment
of
immunodeficiency
syndromes
(for
example
agammaglobulinaemia,
hypogammaglobulinaemia and Wiskott-Aldrich syndrome). Based on its putative mechanism of
action and its tolerability, the use of IVIG could be expanded to treat a broad range of diseases.
IVIG can be considered as a treatment modality for pyoderma gangrenosum when conventional
treatment has failed. In Europe, IVIG is a practical option (at a cost of approximately €284/55g in
Italy). In the USA it is more expensive, at approximately $2500/55g. However, the cost of IVIG is
reasonable when compared to the cost of many biologic agents, such as etanercept and infliximab.
In conclusion, IVIG should be considered as a well-tolerated and cost-effective treatment for
steroid-resistant pyoderma gangrenosum.
As style in a box
Acknowledgement
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The authors would like to thank the Associazione Romana Dermatologica.
Heading 1
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