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Vasculitis in the antiphospholipid syndrome. A cause of ischemia responding to corticosteroids

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569
VASCULITIS IN THE
ANTIPHOSPHOLIPID SYNDROME
A Cause of Ischemia Responding to Corticosteroids
EDWARD GOLDBERGER, RACHEL C. ELDER, ROBERT A. SCHWARTZ, and PAUL E. PHILLIPS
A 63-year-old woman with atherosclerotic peripheral vascular disease and the lupus anticoagulant
developed ischemia of the right lower extremity, requiring progressive amputations. Pathologic specimens revealed inflammatory vasculitis in multiple arteries. Her
serum showed anticardiolipin antibodies in high titer.
Treatment with high-dose corticosteroids reversed the
ischemic process. In patients with antiphospholipid antibodies, thrombosis is the most common pathologic
finding associated with cutaneous lesions and/or gangrene. Vasculitis, although uncommon, is known to
occur and may respond to corticosteroid therapy.
A wide variety of clinical manifestations associated with antiphospholipid antibodies (aPL) have
now been reported (1). Peripheral vascular disease
with cutaneous manifestations such as ulcers and
gangrene is a common association. In most instances,
it has been believed that this is due to ischemia from
thrombosis, with vasculitis playing little or no role. We
From the Rheumatology Section, Department of Medicine,
and the Department of Surgery, SUNY Health Science Center, and
the Department of Pathology, Crouse-Irving Memorial Hospital,
Syracuse, New York.
Edward Goldberger, MD: Rheumatology Fellow, Department of Medicine, SUNY Health Science Center (current address:
Toledo, OH); Rachel C. Elder, MD: Clinical Instructor, Department
of Pathology, SUNY Health Science Center and Crouse-Irving
Memorial Hospital; Robert A. Schwartz, MD: Assistant Professor
of Surgery, SUNY Health Science Center (current address: Syracuse, NY); Paul E. Phillips, MD, FACP, FACR: Chief of Rheumatology, Professor of Medicine and Pediatrics, SUNY Health Science
Center.
Address reprint requests to Paul E. Phillips, MD, SUNY
Health Science Center, 750 East Adams Street, Syracuse, NY
13210.
Submitted for publication July 1, 1991; accepted in revised
form December 3, 1991,
Arthritis and Rheumatism, VoI. 35, No. 5 (May 1992)
present the case of a patient with complications arising
from peripheral vascular disease. She was found to
have aPL and an active inflammatory vasculitis. She
responded well to corticosteroid therapy. The literature on the pathology of cutaneous lesions and gangrene in the aPL syndrome and systemic lupus erythematosus (SLE) is reviewed.
CASE REPORT
The patient, a 63-year-old white woman, was referred for evaluation of nonhealing surgical wounds. Pertinent medical history included a false-positive VDRL test
result during a routine pregnancy evaluation at age 28. She
was treated with penicillin but later, was told that the test
was positive because she had lupus. At that time, she was
asymptomatic, and she remained so for the next 30 years.
In 1986, testing prior to a hysterectomy revealed a
prolonged partial thromboplastin time (PTT) of 62.4 seconds
(control 21.5-31.5) and a prothrombin time (PT) of 15.2
seconds (control 10.6-12.3). Mixture of equal parts of the
patient's plasma and control plasma did not fully correct the
PTT, and the dilute Russell viper venom time was prolonged, at 42.1 seconds, with phospholipid reagent. Clotting
corrected fully when platelets were substituted for the phospholipid reagent. These features were consistent with the
presence of a lupus anticoagulant (LAC). She underwent
hysterectomy, and later, vaginal hernia repair, without complications.
In 1988, she developed thigh and buttock claudication. In August 1989, shortly after a hospital admission for
unstable angina, she developed signs of ischemia in her right
foot. Arteriography showed severe atherosclerotic lesions of
the abdominal aorta, with stenosis, narrowing, andor lesions of numerous branches including the inferior mesenteric
artery and both iliac arteries. She was treated with anticoagulants, but gangrene ensued, and she underwent surgical
amputation of the right first, second, and third toes. Because
of poor wound healing and infection, a transmetatarsal
570
GOLDBERGER ET AL
Figure 1. Anterior tibialis artery with lymphocytic inflammation
and medial and intimal hypertrophy (hematoxylin and eosin stained,
original magnification x 40).
Figure 3. Muscle with perivascular lymphoid infiltration (hematoxylin and eosin stained, original magnification x 100).
amputation and posterior tibial-tdateral plantar artery bypass were performed. After this procedure, the patient
continued to have pain and a nonhealing ulceration, which
necessitated a below-the-knee amputation (BKA) (June
1990).
Histologic sections of arteries from the amputated
leg revealed multiple, widespread focal areas of transmural
lymphoplasmacytic infiltrate (Figure I). Both medial and
intimal proliferation with areas of disrupted internal elastic
membrane were demonstrated by elastic staining (Figure 2).
Several small arteries showed thrombosis without associated
inflammation. Sections of veins showed prominent perivascular lymphoid infiltrate. Random sections of muscle also
revealed a prominent lymphoid infiltrate, mainly perivascular, without evidence of muscle degeneration (Figure 3).
Sections of the skin at the nonhealing ulcer site revealed
acute inflammation, soft tissue necrosis, prominent vascularity, and a small thrombus. The patient was referred for
rheumatologic evaluation postoperatively.
Her medical history was notable for type I1 diabetes
mellitus, which required insulin. She had longstanding hypertension, which was well controlled. She had had 2
myocardial infarctions. Other features of the medical history
and physical examination results revealed no symptoms or
signs typical of SLE or other connective tissue disease;
however, her peripheral pulses were decreased throughout,
and bruits were audible over both femoral arteries and over
the right carotid artery. There were blisters at the amputation site, but no wound breakdown or gangrene.
Findings of laboratory studies were notable for decreased hemoglobin (9.3 gm/dl) and hematocrit (28.8%)
values, normal white blood cell count (9,4Oo/pl), and elevated platelet count (519,OoO/pl). The PT was 15.7 seconds,
the PTT was 89.9 seconds, and the PTT 1 : 1 mixture with
control plasma was 64.0 seconds (all prolonged). The erythrocyte sedimentation rate (ESR; Westergren) was elevated
at 136 mdhour, as was the blood urea nitrogen value at 31
mgldl, the serum creatinine level at 1.9 mgldl, and the
glucose value at 187 mg/dl.
No proteinuria was evident (by dipstick), and a test
for rheumatoid factor gave negative results. Antinuclear
antibodies (ANA) were present at a titer >1 :2,500 (homogeneous pattern); anti-DNA antibodies were absent. IgG
anticardiolipin antibodies (aCL; tested at SmithKline
Beecham Clinical Laboratories, Philadelphia, PA) were
markedly elevated: 606 GPL units/ml (negative <3); IgM
was 6 MPL units/ml (negative <5), and IgA 25 APL units/ml
(negative < 5 ) , where 1 GPL unit = the cardiolipin-binding
activity of 1 pglml of an affinity-purified IgG aCL prepared
from a standard serum (likewise, MPL and APL).
Shortly after the initial rheumatologic evaluation, the
surgical wound from the BKA began to break down. Along
with this appeared 3 splinter hemorrhages in the nail beds of
her left hand and mottling of her left foot. She was diagnosed
as having an aPL syndrome with vasculitis, and atherosclerotic peripheral vascular disease. Because of concern that
the vasculitis was causing the failure of wound healing, she
was admitted to the hospital (July 1990) for aggressive
Figure 2. Anterior tibialis artery with disrupted internal elastic
lamina (Movat’s elastic stain, original magnification x 40).
aPL AND VASCULITIS
treatment. She received methylprednisolone250 mg intravenously every 6 hours for 72 hours, then 60 mg of prednisone
on alternate days. She also received ciprofloxacin. Within 1
month of this treatment, there was contraction and eventual
healing of the BKA wound and improved blood perfusion in
the left foot. She was able to wear an elastic stocking over
the stump, and she was fitted for a prosthesis. Over the next
4 months, the prednisone dosage was gradually reduced to
30 mg every other day.
Five months after the initial evaluation, her aCL
levels were markedly reduced, although still in the medium
range of positive: IgG 75 GPL units/ml. IgM was 7 MPL
units/ml, IgA 20 APL unitdml. The FTT was normalized at
21.6 seconds.
Subsequently, the patient was again admitted to the
hospital because of gastrointestinal (GI) bleeding. Endoscopy of the upper GI tract showed gastritis and a gastroenteric fistula. Biopsies were taken near the fistula, and the
tissues showed no signs of vasculitis. She suffered a peripheral embolus to the left foot, which was treated with intraarterial urokinase and with heparin. During this period, the
BKA stump remained well healed, and when she was
discharged from the hospital, there was no active peripheral
ischemia. At her most recent evaluation (May 1991), she was
taking prednisone (20 mg on alternate days), and there was
no evidence of wound breakdown or of vasculitis.
DISCUSSION
In recent years, associations have been reported between aPL and a number of clinical conditions. The most important clinical features have been
recurrent venous and/or arterial thromboses, thrombocytopenia, and recurrent fetal loss. Other possible
associations include skin lesions, neurologic events
(strokes, migraine headaches, and chorea), retinal
vessel thromboses, hemolytic anemia, and cardiac
lesions similar to those seen in Libman-Sacks endocarditis (1). Antiphospholipid antibodies, which
were originally described in SLE, have been detected,
along with the events described above, in patients
whose symptoms do not meet the clinical or serologic
criteria for SLE. Such patients have been considered
to have the primary antiphospholipid syndrome (2,3).
Previous reports have emphasized the role of
thrombosis in the pathology of the cutaneous manifestations of this syndrome. Reported skin lesions have
been leg ulcers, cutaneous gangrene, thrombosis of
dermal vessels, widespread cutaneous necrosis,
thrombophlebitis, necrotizing purpura, nailfold vasculitis, and livedo reticularis (4). Johannsson et al (5)
described their histopathologic findings in tissues from
6 patients with recurrent deep venous thromboses and
necrotizing purpura with painful leg ulcers. All patients had a circulating anticoagulant; some fulfilled
the American College of Rheumatology (formerly, the
American Rheumatism Association) criteria for SLE.
57 1
All had marked capillary proliferation with hemorrhage. Large and medium-sized vessels, when seen,
had thickened walls. No inflammatory cells were
present. Steroid therapy had little effect on the lesions.
Grob and Bonerandi (6) described 2 patients
and reviewed reports of others in whom cutaneous
necrosis or peripheral gangrene occurred in the setting
of SLE; some of the patients had aPL. Their 2 patients
improved on treatment with steroids, azathioprine,
and anticoagulants. They stated that all previous patients in whom histopathologic features were described had thrombosis of vessels without vasculitis
(6). However, 1 of the patients in the reviewed series
actually did have cellular infiltrates of the deep femoral
and popliteal arteries in histologic sections of an
amputated limb (7) and another patient had evidence
of healed vasculitis in a section of an amputated
digit (8).
Alegre and Winkelman (9) reviewed 26 tissue
specimens from 25 patients with lupus anticoagulant
and skin lesions. Most specimens demonstrated vascular thrombosis; other lesions described were dermal
hemorrhage, endarteritis obliterans, epidermal necrosis, capillary proliferation, and hemosiderin deposition. One specimen from the edge of an ulcer lesion
had vascular lymphocytic inflammation. One specimen from a thrombophlebitic lesion had perivascular
lymphocytic inflammation. Approximately 50% of the
patients met criteria for SLE (4).
Smith et al (10) reviewed biopsy specimens
from skin lesions of 7 patients with LAC and aCL.
Three patients met criteria for SLE. A variety of
lesions were seen. Inflammatory infiltrates, when
present, were mild, and no vasculitis was present.
Asherson et a1 (11) described 6 patients with largevessel occlusion and gangrene. Four of the patients
had SLE and 2 had “lupus-like” disease. Four of the
patients had aPL. None of the patients had biopsydemonstrated vasculitis, although thrombosis was invariably present. Corticosteroid therapy was not uniformly successful in preventing progression of gangrene
in these patients. One male patient in the series with
SLE and peripheral vascular thrombosis appeared to
have improvement of peripheral ischemia with prednisone and cyclophosphamide therapy in conjunction
with anticoagulants.
Alarc6n-Segovia et a1 (12) described 3 patients
with aPL (1 of whom had SLE) who developed arterial
occlusions, All had intimal and medial proliferation of
large and medium-sized arteries in tissue specimens
from amputated limbs. A polymorphonuclear cell infiltrate was observed and small-vessel leukocytoclastic
vasculitis was found in the skin and muscle tissues.
572
These patients showed clinical improvement on treatment with steroids and cyclophosphamide, although
amputations were sometimes required.
Our patient had the primary antiphospholipid
syndrome complicating underlying atherosclerosis.
She had inflammatory cell infiltrates involving multiple
peripheral vessels. She experienced thromboses, peripheral ischemia, gangrene, and poor wound healing.
Ischemia requiring progressive amputations occurred
despite anticoagulation therapy. Wound healing occurred with institution of high-dose corticosteroid
therapy. Treatment was associated with lowering of
aCL levels and normalization of the PTT. Thus, this
case demonstrates a patient with aPL and peripheral
gangrene having features of a systemic inflammatory
disease, with amelioration of the disease course with
corticosteroid therapy.
Clearly, the macrovascular and microvascular
complications of diabetes and atherosclerosis played a
role in the development of ischemia and its clinical
sequelae. The patient did not experience symptoms
until later in life, despite having evidence of aPL at age
28 (false-positive VDRL). Possibly, the underlying
immune dysregulation leading to the aPL syndrome
was not severe until recently. We have no information
on past laboratory evaluations, such as the ESR, the
presence and titer of ANA, and the PTT, by which we
could investigate this possibility.
It is unlikely that diabetes alone is responsible
for the clinical and pathologic findings in this case. The
pathology of vascular disease in diabetes takes the
form of atherosclerosis. This occurs at an earlier age
and is of greater severity than in nondiabetic patients,
but there is no convincing qualitative difference, at
least at the level of light microscopy (13). The use of a
broad-spectrum antibiotic (ciprofloxacin) may have
helped wound healing but would not have been expected to prevent further ischemia in a situation in
which progressive amputations were necessary. Antibiotics would also not be expected to have a favorable
impact on the laboratory markers of inflammatory
disease and increased levels of aPL.
The prevention or treatment of clinical manifestations associated with aPL remains a controversial
subject (1,14). In the absence of prospective trials,
whether to treat, and if so, with what, is a matter of
judgement. This case demonstrates that aPL can be
associated with vasculitis and laboratory markers of
inflammatory disease (anemia, thrombocytosis, elevated ESR). When such patients develop progressive
peripheral vascular disease, they may need to be
treated with corticosteroids or other immunosuppressive therapy.
GOLDBERGER ET AL
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