ARTICLE
Since the original description of pyoderma gangrenosum in 1930 by Brunsting
et al., it has been shown that this ulcerative disease can be associated
with numerous other systemic diseases such as ulcerative colitis or lupus
erythematosus [1, 2]. An association of pyoderma-like leg ulcers and antiphospholipid
syndrome has been described [2, 3] in several reports, e.g., Leyva
et al. reported a case of pyoderma gangrenosum associated with
elevated antiphospholipid antibodies, but with no underlying systemic
lupus erythematosus (SLE). Pyoderma gangrenosum does not improve with
topical treatment [2]. Aggressive systemic treatment with corticosteroids
and immunosuppressants is necessary. The mortality rate may be high due
to bacterial infections and systemic complications [4].
Case report
In May 1996, a 64-year-old woman presented with two large ulcers on
the right shank which she first noticed in July 1995 (Fig.
1). Five months before admission a posterior popliteal-tibial
circular bypass was installed. Post-operatively she developed a second
ulcer along the operation suture at the medial right shank (Fig.
2). The patient had previously undergone amputation of the contralateral
(left) shank in 1992 following an acute arterial embolism. In the same
year, further amputation of the gangrenous right hallux had been necessary.
After SLE had been diagnosed in 1985, she was continuously treated with
low dose corticosteroids and cumarin. She has three healthy children and
there was no history of miscarriage.
Physical examination was significant for very small ulcers in the oral
cavity and arthritis of both hands. Venous and arterial duplex sonography
and angiography of the right leg showed no evidence of reduced perfusion
or arteriosclerosis.
Skin examination revealed an ulcer, 10 x 12 cm in size on the lateral
side and another, 10 x 4 cm in size, on the medial side of the right leg.
The ulcers had a necrotic base and dark-red, undermined borders. There
were no pustules at the edge of the ulcers.
The following laboratory parameters were
abnormal: erythrocyte sedimentation rate 20/150 mm per hour, PTT 53.3
seconds, creatinin clearance 29 ml/min, serum electrophoresis with a decreased
albumin fraction of 44.5%, elevated alpha2-globulin fraction
of 11.2% and elevated gamma-globulin fraction of 26.2%. Serum immunoglobulins
were elevated for IgG (22.5 g/l) and IgA (10.1 g/l). Moreover, the following
serum antibodies were elevated: ANA (1:10,240), ds-DNA (200 U/ml), histone
(156 U/ml), cardiolipin IgG (100 U/ml) and IgM (8 U/ml), p-ANCA.
In the present case, the history of thromboembolism, the gangrenous
toe, the elevated IgG antibodies against cardiolipin and double-stranded
(ds) DNA confirmed the diagnosis of a secondary antiphospholipid syndrome.
Pyoderma gangrenosum was diagnosed based on the following clinical features:
rapid onset of the lesions triggered by trauma, resistance to topical
treatment and underlying SLE.
There was only a slight improvement of both ulcers with topical therapy
including antibacterial creams, occlusive hydrocolloid dressings and topical
steroids. Therefore, ten days after admission, oral treatment with methylprednisolone
at a dose of 1 mg per kg of body weight per day was started. Three weeks
later, hemorrhagic macules and papules on the patient's right thigh were
observed. This was interpreted as a dangerous progression of the disease.
Therefore, a more aggressive treatment with methylprednisolone (2 mg/kg/day)
and 200 mg cyclosporine per day was instigated. Although immunologic markers
improved with this therapeutic regimen (ds DNA from > 200 U/ml down
to 123 U/ml; cardiolipin IgG from > 100 U/ml down to 55 U/ml; cardiolipin
IgM from 8 U/ml down to 0 U/ml; histone from 165 U/ml down to 43 U/ml),
the leg ulcers continued to worsen. Finally, the patient developed septicemia.
An X-ray of the chest showed multiple nodules in the right lower lobe,
several blood cultures were positive for Staphylococcus aureus
which was also detected at the lesions on the right lower leg. Despite
treatment with broad spectrum antibiotics and antifungal drugs, respiratory
function worsened and X-rays showed progressive abscess formation in the
right lung suggestive of fulminant Staphylococcus aureus pneumonia.
Two weeks after admission to the intensive care unit, the patient died
as a consequence of untreatable respiratory failure. Permission for post-mortem
examination was not granted.
Discussion
Pyoderma gangrenosum is a rare disease. At the Mayo Clinic, only 180
cases of pyoderma gangrenosum were seen over a period of 53 years [2].
Today its association with different systemic diseases is well known [2].
Yet, the combined presentation of antiphospholipid syndrome, pyoderma
gangrenosum and underlying SLE seems to be an extremely rare event. Secondary
antiphospholipid syndrome is defined as antiphospholipid syndrome with
SLE. The diagnosis of SLE was based on the following five criteria of
the American Rheumatism Association: presence of antinuclear antibodies,
immunologic disorders, leukocytopenia, renal disorder and ulcers in the
oral cavity.
The main characteristics of pyoderma gangrenosum are rapid enlargement
of the lesion(s) with a purulent base and an undermined border surrounded
by an areola of erythema, underlying systemic disease and general resistance
to conventional treatment regimens. The diagnosis of pyoderma gangrenosum
has to be established by clinical features as histologic alterations are
unspecific and characteristic serologic or hematologic markers do not
exist [5]. About 40% of patients with SLE have high levels of antiphospholipid
antibodies such as lupus anticoagulant (LA) and cardiolipin antibodies
[6]. About half of these patients develop a secondary antiphospholipid
syndrome [6]. Dubois et al. noted leg ulcers in 5.6% of 520 SLE
patients. Skin manifestations such as ulcers with antiphospholipid syndrome
are a well known and typical epiphenomenon [6, 8, 9, 10].
Stephansson et al. found a different pattern of cutaneous alterations
in LA-positive SLE patients as compared to a group with LA-negative SLE
[9]. Several different types of ulcers, especially pyoderma gangrenosum-like
ones, were only observed in LA-positive SLE patients. Therefore, the authors
suggested including different types of ulcers in the criteria for the
antiphospholipid syndrome. These ulcers are called "pyoderma gangrenosum-like
ulcers" because they do not show the undermined border, granulation tissue
and inflammatory cell infiltration typical of pyoderma gangrenosum. Moreover,
most of these ulcers developed from other ulcers and responded poorly
to topical or systemic treatment.
Grob and Bonerandi described a patient, who had lupus anticoagulant-positive
SLE with a leg ulcer which was resistant to therapy, and a history of
deep venous thrombosis [11]. Pyoderma gangrenosum was discussed, but the
clinical features did not meet the criteria. When treated with prednisone
(0.33 mg/kg/day), azathioprine (100 mg/day) and warfarin no new episodes
of venous thrombosis occurred and the activity of lupus anticoagulant
decreased while the leg ulcer did not improve clinically.
The above mentioned literature clearly suggests
a relationship between antiphospholipid syndrome and pyoderma gangrenosum
or pyoderma gangrenosum-like ulcers. Yet, the combination of antiphospholipid
syndrome and pyoderma gangrenosum with underlying SLE seems to be a rare
event. In these cases it is often extremely difficult to define a successful
therapy which was particularly true in the case of our patient.
Because of its rapid and aggressive clinical course and its significant
mortality, an efficient treatment for pyoderma gangrenosum needs to be
established [4]. Besides topical treatment of ulcerous lesions, systemic
treatment with prednisone (40 to 120 mg per day) seems to be the most
successful therapy [2]. Other drugs such as dapsone, clofazime and minocycline
are also mentioned, but immunosuppressants such as cyclosporine, cyclophosphamide
and chlorambucil are the more promising ones [2]. Treatment of secondary
antiphospholipid syndrome is known to be difficult, too. Antiaggregant
and anticoagulant therapy with aspirin and warfarin is necessary to avoid
thrombotic complications [10]. The treatment of SLE combined with pyoderma
gangrenosum, should mainly consist of glucocorticoids combined with additional
immunosuppressants such as cyclosporine or cyclophosphamide if needed
[2, 10].
The management of pyoderma gangrenosum and secondary antiphospholipid
syndrome includes high dose glucocorticoids to delay the rapid enlargement
of ulcers and to reduce the overall activity of the disease. Besides corticosteroids,
the usefulness of immunosuppressants such as cyclosporine or cyclophosphamide
remains a matter of debate. However, there is some agreement concerning
two points: early treatment is necessary to achieve complete healing of
the ulcers; long-standing ulcers, large ulcers and associated autoimmune
diseases such as SLE or secondary antiphospholipid syndrome are negative
prognostic factors for long term survival. Therefore, high risk therapeutic
regimens may be the only chance of improving the clinical outcome in these
patients. Apart from corticosteroids and immunosuppressants, which involve
the inherent risk of severe systemic infections, diaminodiphenylsulfone
(DADPS; 25-200 mg p.d.) and/or clofazimine (Lampren™;
100-300 mg p.d.) may be used instead. Both can also have severe side effects
(e.g. methemoglobinemia for DADPS) but they do not compromise the
patient's immune system. Yet, clinical improvement under this latter,
less aggressive therapy has only been documented in a very few cases [12].
Therefore, the therapeutic dilemma between a more aggressive regimen with
higher response rates and a milder one with a decreased chance of clinical
improvement has to be solved as a function of the individual clinical
situation.
REFERENCES
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