Arthritis Care & Research
Vol. 63, No. 5, May 2011, pp 766 774
DOI 10.1002/acr.20439
2011, American College of Rheumatology
CLINICOPATHOLOGIC CONFERENCE
A 26-Year-Old White Man With a Systemic Lupus
Erythematosus Flare and Acute Multiorgan
Ischemia: Vasculitis or Thrombosis?
JULIE CHERIAN,1 ROLAND DUCULAN,2 ISABELLE AMIGUES,3 MARY K. CROW,2
KYRIAKOS A. KIROU2
CASE PRESENTATION
Chief symptom
A 26-year-old white man with a systemic lupus erythem-
atosus (SLE) are and acute multiorgan ischemia.
History of the present illness
The patient was in his usual state of health until 2 months
before admission, when he developed pain and stiffness in
his right shoulder, neck, and back after playing softball.
His symptoms progressively worsened despite manipula-
tion by a chiropractor, and he developed new pain in his
soles. This was diagnosed as plantar fasciitis and he was
given a topical steroid injection and a short course of
methylprednisolone. This treatment improved his pain,
but at its completion, he developed disabling diffuse ar-
thralgias in his shoulders, elbows, knees, and feet, along
with fevers, anorexia, and weight loss. Worsening symp-
toms prompted hospitalization in another institution 3
weeks before admission, where he was febrile up to 103F
and hypertensive (144/100 mm Hg). An extensive evalua-
tion revealed elevated inammatory markers, including
erythrocyte sedimentation rate (ESR; 102 mm/hour), C-re-
active protein level (56 mg/liter), positive antinuclear an-
tibodies (ANAs; 1:640), strongly positive anti double-
stranded DNA (anti-dsDNA) titers, low levels of C4 (9
Supported by the Mary Kirkland Center for Lupus Re-
search.
1
Julie Cherian, MD: Stony Brook University Hospital,
Stony Brook, New York; 2Roland Duculan, MD, Mary K.
Crow, MD, Kyriakos A. Kirou, MD: Mary Kirkland Center
for Lupus Research, Hospital for Special Surgery, New
York, New York; 3Isabelle Amigues, MD: Teaching Hospital
Lyon Sud, Pierre Benite, Rhone Alpes, France.
Drs. Crow and Kirou have led a patent application for an
interferon assay.
Address correspondence to Kyriakos A. Kirou, MD, Mary
Kirkland Center for Lupus Research, Hospital for Special
Surgery, 535 East 70th Street, New York, NY 10021. E-mail:
kirouk@hss.edu.
Submitted for publication October 21, 2010; accepted in
revised form January 18, 2011.
766
AND
mg/dl, normal range 16 38), prolonged prothrombin time
(16.2 seconds, normal range 10 13), prolonged activated
partial thromboplastin time (60 seconds, normal range 27
38), and positive lupus anticoagulant (LAC) by dilute Rus-
sells viper venom time. His urine analysis showed pro-
teinuria (0.440 gm protein/gm creatinine), hematuria
(1125 red blood cells [RBCs]/high-power eld [hpf]), and
pyuria (310 white blood cells [WBCs]/hpf). Antibodies to
Sm/RNP, Ro/SSA, and La/SSB; anticardiolipin antibodies;
antineutrophil cytoplasmic antibodies (ANCAs); and anti
cyclic citrullinated peptide antibodies were negative, and
creatine phosphokinase was normal. An infectious disease
evaluation was performed and was negative for all patho-
gens, including Lyme disease, human immunodeciency
virus, and viral hepatitis. Renal ultrasound and Doppler
were performed and were negative for renal pathology and
venous thrombosis. He was placed on prednisone 10 mg
orally twice daily, losartan 50 mg daily, and aspirin 81 mg
daily, and his fevers resolved with some improvement in
joint pains. Two weeks before admission, he was evalu-
ated by a rheumatologist who discontinued aspirin in an-
ticipation of a kidney biopsy to rule out lupus nephritis.
Laboratory evaluation again revealed persistent protein-
uria (2), hematuria (10 20 RBCs/hpf), C4 hypocomple-
mentemia (C3 111 mg/dl, C4 9 mg/dl), and strongly posi-
tive anti-dsDNA. The patient could not tolerate tapering of
prednisone to 15 mg and he stayed at 17.5 mg daily.
He presented to our clinic 3 days before admission and
his scheduled kidney biopsy. Over the course of the pre-
vious week he had developed a few small tender erythem-
atous skin lesions and some skin excoriation on his ngers
and palms. He also experienced numbness of his ngertips
and bilateral soles for 2 or 3 days. Weight loss of 30 33
pounds over the course of 3 months with decreased appe-
tite, nausea, and mild diarrhea was noted. On examina-
tion, he appeared ill with a blood pressure (BP) of 140/100
mm Hg, and a heart rate of 96 beats per minute. There were
a few erythematous lesions on his palate, as well as small
tender erythematous nonblanching lesions in his palms,
ngertips, and toe tips with rare splinter hemorrhages. He
had dysesthesia/hypoesthesia in bilateral palms and n-
Clinicopathologic Conference
Figure 1. Electrocardiogram demonstrating ST elevations in precordial leads in V1V6.
gertips, as well as bilateral soles extending to the lateral
side of his ankles. In addition, there was mild weakness of
toe dorsiexion at the left second, third, and fourth toes, as
well as left foot dorsiexion (4 of 5). There was bilateral
joint line tenderness in his metacarpophalangeal joints
and ankles. The overall picture suggested inadequately
treated severe SLE with nephritis, arthritis, mononeuritis
multiplex, and vasculitis. On the same day, one dose of
pulse glucocorticoids (GC) of 1 gm intravenous (IV) meth-
ylprednisolone was administered, and prednisone was in-
creased to 60 mg daily. Losartan was increased to 100 mg
daily and he was started on amlodipine 5 mg daily, hy-
droxychloroquine (HCQ) 400 mg, esomeprazole 40 mg
daily, alendronate 70 mg weekly, as well as calcium and
vitamin D.
On Monday, 3 days later, the patient was brought back to
the clinic in a wheelchair, looking pale and very weak.
Over the weekend, his BP had remained high, despite
medications. His nausea, malaise, and diarrhea had wors-
ened and he had developed overnight postprandial mid-
abdominal pain consistent with abdominal angina. He de-
nied chest pain or dyspnea, although later he admitted to
chest discomfort, which was only perceived after it re-
solved. His BP was 133/87 mm Hg and his heart rate was
111 beats per minute, with no fever or hypoxia. Electro-
cardiogram demonstrated sinus tachycardia and elevated
ST segments on precordial leads (V1V6) (Figure 1). He
was transferred to the coronary care unit.
Medical history
His medical history was positive for mononucleosis in
high school and right knee arthroscopy for a meniscal
injury.
767
Family history
The patients parents were alive and well at ages 59 (fa-
ther) and 55 (mother) years. His paternal grandfather died
at the age of 32 years from a cerebrovascular accident. A
paternal great uncle had rheumatoid arthritis.
Social history
The patient had smoked for 6 years up until 5 months
before presentation. There was only social alcohol use and
no illicit drug use. He was single but in a stable relation-
ship.
Medications and allergies
His medications upon admission were prednisone (60 mg/
day), HCQ (400 mg/day), losartan (100 mg/day), amlodip-
ine 5 mg daily, and esomeprazole (40 mg/day). He had no
known drug allergies.
Physical examination and tests
Physical examination was unchanged except for the vital
signs, as noted above. Of note, there was no jugular vein
distension and no murmur, gallop, or rub. His abdomen
was soft and not tender or distended with normal bowel
sounds and no hepatosplenomegaly. His peripheral pulses
were normal throughout and the Allen test was normal
bilaterally. There was no evidence of synovitis in any
joint. Trace positive for occult blood brown stool was
noted on rectal examination. Laboratory tests revealed
anemia, elevated troponin (8.54 ng/ml that peaked to 18.7
ng/ml that night) with normal creatinine but persistent
mild proteinuria (0.3 gm protein/gm creatinine), and mi-
768 Cherian et al

Table 1. Laboratory values*

Admission Hospital day 4 3 months later Normal values

WBCs, per nl 11.1 13.1 6.46 3.510.7

Hemoglobin, gm/dl 12 11.1 14.6 1317
Platelets, per nl 210 312 164 160400
CRP level, mg/dl 3.52 0.7 01
C3, mg/dl 77 103 79152
C4, mg/dl 8.5 15.4 1638
Anti-dsDNA 4 2 Negative; scale 04
aCL IgG, units/ml 25 014
aCL IgM, units/ml 28 07
aCL IgA, units/ml 3 014
2GPI IgG, units/ml Negative 20
2GPI IgM, units/ml Negative 10
2GPI IgA, units/ml Negative 10
LAC Positive Negative
PT, seconds 12.3 23 20.7 9.411.6
PTT, seconds 40.9 39.2 43.6 22.434.8
Troponin, ng/ml 18.71 4.3 00.04
Amylase, units/liter 51 30110
Lipase, units/liter 34 23300
AST, units/liter 92 25 31 540
ALT, units/liter 77 58 46 756
Albumin, gm/dl 2.8 2.7 5 3.55

* WBCs white blood cells; CRP C-reactive protein; anti-dsDNA anti double-stranded DNA; aCL anticardiolipin antibody; 2GPI
2-glycoprotein I antibodies; LAC lupus anticoagulant; PT prothrombin time; PTT partial thromboplastin time; AST aspartate aminotrans-
ferase; ALT alanine aminotransferase.
Receiving warfarin.

croscopic hematuria (4 10 RBCs). Urine toxicology screen CASE SUMMARY

was negative. He was hypocomplementemic with an ESR
This 26-year-old white man presented with a 2-month
of 91 mm/hour, a positive anti-dsDNA and LAC (before
history of diffuse arthralgia/arthritis, fever, weight loss,
initiation of anticoagulation), and normal platelets (Table
nephritic syndrome (hypertension, proteinuria, hematu-
1). Cardiac and abdominal computed tomography (CT)
ria), and positive ANAs, anti-dsDNA, and LAC tests. His
angiograms were performed later on the day of admission. disease got progressively worse, and a few days before
The right coronary artery was the dominant vessel and admission he developed tender erythematous skin lesions
there was no evidence of signicant aortic or coronary on his palms, along with peripheral asymmetric sensory
artery plaque. Ejection fraction (EF) was 44%, with a se- and motor symptoms. Two days before admission and
verely hypokinetic to akinetic apical wall and mild dyski-
nesia of the distal anterior wall. Cardiac catheterization
was not performed because there was concern that further
instrumentation might cause thrombosis. Abdominal CT
angiograms revealed several small peripheral wedge-
shaped defects scattered throughout both kidneys consis-
tent with infarcts (Figure 2). There was no evidence of
arterial narrowing or aneurysmal formation seen in the
large and medium-sized arteries of the abdomen. Renal
veins were widely patent bilaterally. Transthoracic echo-
cardiogram conrmed segmental wall motion abnormali-
ties and showed an EF of 55%. Transesophageal echocar-
diogram was performed the next day and ruled out
endocarditis, but demonstrated linear strands on the atrial
side of mitral leaets, consistent with Lambls excres-
cences. An endoscopy was performed on the third
hospitalization day for his persistent abdominal pain and
it revealed mild Candida esophagitis, for which
nystatin swish and swallow was started. The gastric an-
trum revealed mild erythema, possibly vasculitic in Figure 2. Computed tomography angiogram scan on the day of
origin. admission showing renal infarcts.
Clinicopathologic Conference 769

despite pulse IV and high oral GC therapy, he got precip- temic small-/medium-vessel vasculitis and CAPS, as dis-
itously ill with marked abdominal symptoms and malaise cussed below.
that culminated in an acute transmural myocardial infarc-
tion (MI). Further diagnostic evaluation showed clean Systemic vasculitis in SLE
coronaries and abdominal arteries, but also multiple kid-
Our patients manifestation was consistent with small- or
ney infarcts, and gastric erythema on upper endoscopy.
medium-vessel vasculitis, but not large-vessel disease. In
fact, large-vessel vasculitis is probably rare in SLE (7). The
most common form of vasculitis in SLE is probably glo-
DIFFERENTIAL DIAGNOSIS merulonephritis, affecting the glomerular capillaries. Pul-
monary capillaritis with alveolar hemorrhage is a rare but
This patient appeared to have new onset of lupus-like
severe manifestation of the disease. Excluding these dis-
disease with 3 or 4 American College of Rheumatology
orders, vasculitis was noted in approximately 1136% of
criteria for SLE, including arthritis, ANAs, immunologic
SLE patients in two large retrospective studies, and mainly
criteria (anti-dsDNA and LAC), and possibly nephritis (1).
affected the small vessels of the skin (7,8). The most com-
His lupus was very active with rapid (over a few weeks)
mon skin lesions were erythematous punctate lesions on
development of skin vasculitis with small tender purpuric
the ngertips and palms (such as in this case), followed by
macules on his palms and splinter hemorrhages on his
palpable purpura. Histologically, leukocytoclastic fol-
nails, as well as mononeuritis multiplex 6 days before
lowed by lymphocytic vasculitis were the most common
admission. This was followed by precipitous ischemic
pathologies (8). Medium-vessel vasculitis comprised 14
involvement of multiple organs with an acute MI, abdom-
15% of all vasculitis cases and presented mainly with
inal angina, and multiple kidney infarcts. Although acute
mononeuritis multiplex, and less commonly with digital
MI is most commonly due to accelerated atherosclerosis in
necrosis and visceral involvement, with necrotizing vasc-
SLE, the latter was excluded in this case based on the
ulitis of the vessel wall on histology. There was overlap
cardiovascular imaging studies (2). Furthermore, myocar-
between the 2 entities. Lupus vasculitis appears to be
ditis was unlikely based on the regional hypokinesis nd-
associated with livedo reticularis, high disease activity,
ings in imaging studies, which were consistent with a left
antiphospholipid antibodies (aPL), high ESR, hypoco-
anterior descending artery (LAD) obstruction as the cause
mplementemia, and anti-La, among other manifestations
of ischemia.
(7,8). Small/medium-size vasculitis has rarely been re-
In order to explain the acute widespread ischemia, we
ported in the kidneys of patients with lupus nephritis and
considered such pathogenic processes as embolic disor-
morphologically resembles microscopic polyangiitis (9).
ders, vasospastic disease, paraproteinemias, thrombotic
Regarding internal organ vasculitic involvement, abdomi-
microangiopathy (TMA), catastrophic antiphospholipid
nal vasculitis with lupus enteritis is probably the most
syndrome (CAPS), and systemic vasculitis. Embolic disor-
common (7,10 12). Coronary vasculitis is rare but well
ders include septic or Libman-Sacks endocarditis, atrial
documented as a cause of acute MI (13). Angiographically,
myxoma, and atheroemboli, but there was evidence for
it manifests as a coronary aneurysm or arteritis (13,14).
none of these on our imaging studies. In addition, the
Regarding possible vasculitic processes that may affect
urine toxicology screen was negative and along with the
lupus patients, ANCA-associated vasculitis is uncommon,
negative social history practically excluded a drug-
but cryoglobulinemia is not and when present in high
induced vasospastic process. Laboratory tests were nega-
levels, it should prompt exclusion of hepatitis C (7,15).
tive for paraproteins and cryoglobulins.
Our patients tests were negative for ANCAs and cryo-
TMA, best exemplied by the thrombotic thrombocyto-
globulins and there was no angiographic evidence of cor-
penic purpura (TTP) syndrome, is characterized by diffuse
onary arteritis or polyarteritis nodosa (PAN)like abdom-
microvascular thrombosis and manifests clinically with
inal vasculitis. Nevertheless, the punctate skin lesions, the
thrombocytopenia due to consumption in platelet micro-
mononeuritis multiplex, the high inammatory markers,
thrombi and microangiopathic hemolytic anemia (MAHA)
the persistent hypocomplementemia, and the aPL were
due to the fragmentation of RBCs during their pass through
consistent with a small-/medium-vessel vasculitis due to
stenotic small vessels (3). Other systemic disorders that
active lupus.
may present similarly include such heterogeneous disor-
ders as hemolytic uremic syndrome; malignant hyperten-
sion; severe preeclampsia and hemolysis, elevated liver APS
enzymes, and low platelets syndrome; disseminated intra- Our patient arguably had at least one clinical and one
vascular coagulation; disseminated malignancy; sclero- laboratory criterion, and therefore fullled the interna-
derma renal crisis; SLE; and APS (4,5). Activation of mi- tional preliminary classication criteria (Sapporo) for
crovascular endothelial cells is believed to be an important APS, except for the fact that there were only 3 (rather than
pathogenetic factor in many of these disorders. TTP may 6) weeks between the 2 positive LAC tests (16). Unfortu-
occur in patients with SLE (2% in a recent study) (6), nately, the patient was placed immediately on anticoagu-
especially with active disease. It is treated with plasma lation therapy and could not be retested for LAC until the
exchange in addition to immunosuppressive therapy. present time. Notably, the revised criteria for APS are
There was no thrombocytopenia or hemolysis in our case stricter and require an interval of at least 12 weeks be-
to suggest TMA. tween the clinical event and the aPL test, which was not
The more likely diagnoses in our differential were sys- present in our case (17). In addition, we did not have
770
angiographic or histologic proof of thrombosis. Neverthe-
less, we strongly believe based on the available evidence
that the ischemic events in the heart (acute MI), the kid-
neys, and most likely also the gastrointestinal (GI) tract
were due to thrombosis.
Among patients with lupus, predictive factors of throm-
bosis may include male sex, LAC, constantly positive aPL,
shorter disease duration, smoking, active disease, and
higher doses of GC (18 20). Regarding the occurrence of
acute MI in young SLE patients, Korkmaz et al reviewed
the literature of 49 SLE patients who had an acute MI and
were age 35 years (13). The authors recognized 3 groups.
Group III (n 22) had atherosclerosis and had active
disease much less often than the other 2 groups and with
longer lag periods from the diagnosis of SLE. Group II (n
12) had evidence of coronary aneurysms/arteritis on an-
giogram, and group I (n 16) had either coronary throm-
bosis (n 11, according to angiography or clinical judg-
ment) or normal coronaries (n 5). The majority of these
patients (93%) had aPL, which represented a much higher
prevalence than in the 2 other groups and received anti-
coagulation and antiplatelet therapy. It was presumed that
clear coronary vessels could be due to resolution of
thrombosis/spontaneous thrombolysis, coronary vaso-
spasm, coronary emboli from Libman-Sacks endocarditis/
mural ventricular thrombus, or microthrombi. In 2 of these
cases, endomyocardial biopsy samples failed to show vas-
culitis, and in another, autopsy showed arteriolar throm-
bosis (21,22). All had presence of aPL. Spontaneous
thrombolysis of an LAD thrombus while receiving enoxa-
parine therapy has been reported in a 19-year-old patient
with APS and acute MI (23). Another SLE patient with aPL
developed acute MI due to distal LAD thrombosis after
rapid normalization of thrombocytopenia (24).
Kidney involvement in this case was characterized by
hypertension, mild proteinuria, microscopic hematuria,
and renal infarcts on CT angiograms (Figure 2). He could
have had early lupus nephritis before the development of
the cortical infarcts. In that case, the infarcts could be the
result of emboli, vasculitis, or multifocal thrombosis due
to APS. Alternatively, he could have had APS nephropa-
thy all along. Embolic disease was unlikely, given the
absence of Libman-Sacks endocarditis or cardiac thrombus
on transesophageal echocardiogram. True lupus renal vas-
culitis is very rare in SLE and there is no documented
association with cortical infarcts, making this a less likely
etiology (9). APS nephropathy almost universally is char-
acterized by hypertension, often severe and occasionally
malignant (25). Various degrees of proteinuria (usually
mild), microscopic hematuria, and renal insufciency may
be present (25). Nochy et al have analyzed the vascular
pathology of this disease in 16 patients with primary APS
(25). TMA, the single acute histologic form of microthrom-
bosis, was seen in 31% of the patients in conjunction with
brous intimal hyperplasia in all of them. The latter was
the more common pathology seen (75%), and could be
associated with arteriolar brous or brocellular occlu-
sions (68%) or organizing thrombosis (37%). Focal cortical
atrophy (62%), involving the subcapsular cortex in an
irregular distribution, was characterized by an ensemble
of dense interstitial brosis, massive tubular atrophy, and
Cherian et al
thyroidization; brous intimal hyperplasia with organized
thrombosis and arteriolar occlusions; and groups of glob-
ally sclerotic and/or cystic glomeruli. The authors consid-
ered this lesion analogous to the cortical infarcts on CT
imaging and as a way to differentiate this disease from
other TMA-associated disorders (with the exception per-
haps of malignant hypertension). They considered both
focal cortical atrophy and brous intimal hyperplasia le-
sions as a possible consequence of tissue ischemia and the
activation of the reninangiotensin system. In view of the
above, and given the lack of histologic data in our case, we
cannot be sure whether at the onset of his renal disease,
our patient had early lupus nephritis, APS nephropathy,
or both. It is very likely, however, that his renal infarcts
were due to multifocal thrombosis in renal vessels too
small to be visualized on a CT angiogram (such as arcuate,
interlobular arteries), including TMA, which does not al-
ways manifest with MAHA and thrombocytopenia (25).
Abdominal angina was a prominent symptom of our
patient and was associated with nausea, diarrhea, and
antral erythema on esophagogastroduodenoscopy. The
symptoms suggested bowel ischemia, but a CT angiogram
was negative for vasculitis and thrombosis. A presentation
of acute abdominal pain was examined in a few lupus
studies. In one, presentation in lupus (n 15) was com-
pared to that of PAN (n 5), and was found to be more
insidious (on average, 34 days compared to 11 days before
crisis) and less often with acute surgical abdomen (11).
Symptoms often had a cramping quality and were associ-
ated with anorexia, nausea, vomiting, and diarrhea, such
as in our patient. Vasculitis occurred in 82% of those
requiring laparotomy and affected smaller vessels (and
less extensive areas of ischemia) compared to PAN. In
another study, acute abdominal pain in 36 active SLE
patients was due to vasculitis (by histopathology; n 19),
mesenteric or hepatic arterial thrombosis (n 3), and
nonSLE-related complications (n 14), whereas all 15
patients with quiescent disease had nonSLE-related prob-
lems (10). In both of these studies, central nervous system
lupus, thrombocytopenia, and cutaneous vasculitis were
more common in SLE patients with GI vasculitis. A third
study of acute abdominal pain in 38 SLE patients demon-
strated multifocal ischemic lupus enteritis based on sev-
eral CT imaging features, including bowel wall thickening
in the absence of mesenteric thrombosis (11). These pa-
tients had a drop of their WBCs at presentation compared
to control patients. The authors hesitated to call these
enteritis cases vasculitis without histologic proof, and con-
sidered the possibility of reversible ischemic bowel dis-
ease, given the improvement after high-dose GC therapy.
The outcome in this study was much better, perhaps be-
cause of earlier treatment from the onset of symptoms.
CAPS
CAPS is an accelerated form of APS characterized by mul-
tiorgan failure and a mortality rate of approximately 44%,
even after therapy (26,27). Classication criteria for the
syndrome are shown in Table 2 (25). Only approximately
1% of patients with APS present with CAPS (26). The
CAPS Registry has been created to assist the study of this
Clinicopathologic Conference
Table 2. Preliminary criteria for the classication of
catastrophic antiphospholipid syndrome (CAPS) (26)
1. Evidence of involvement of 3 or more organs, systems,
and/or tissues
Usually clinical evidence of vessel occlusions
conrmed by imaging techniques when appropriate.
Renal involvement is dened by a 50% rise in serum
creatinine, severe systemic hypertension ( 180/100
mm Hg), and/or proteinuria ( 500 mg/24 hours)
2. Development of manifestations simultaneously or in
less than a week
3. Conrmation by histopathology of small-vessel
occlusion in at least one organ or tissue
For histopathologic conrmation, signicant evidence
of thrombosis must be present, although vasculitis
may coexist occasionally
4. Laboratory conrmation of the presence of
antiphospholipid antibodies (aPL): lupus
anticoagulant and/or anticardiolipin antibodies
If the patient had not been previously diagnosed as
having an APS, the laboratory conrmation requires
that presence of aPL must be detected on 2 or more
occasions at least 6 weeks apart (not necessarily at
the time of the event), according to the proposed
preliminary criteria for the classication of denite
APS
Denite CAPS
All 4 criteria
Probable CAPS
All 4 criteria except for involvement of only 2 organs,
systems, and/or tissues
All 4 criteria, except for the absence of laboratory
conrmation at least 6 weeks apart due to the early
death of a patient never tested for aPL prior to the
CAPS event
1, 2, and 4
1, 3, and 4 and the development of a third event in
more than a week but less than a month, despite
anticoagulation
rare syndrome and is available free online (www.med.
ub.es/MIMMUN/FORUM/CAPS.htm). Approximately 70%
of patients are female. Among all patients, 46% have pri-
mary APS, 40% have SLE, 5% have lupus-like disease,
and 9% have other autoimmune diseases. In at least half of
the cases, a precipitating factor has been implicated: in-
fection (22%), surgery (10%), anticoagulation withdrawal
(8%), medication (7%), obstetric complications (7%), neo-
plasia (5%), and SLE are (3%). The manifestations of
CAPS depend on organ involvement as well as the devel-
opment of systemic inammatory response syndrome
(SIRS) (28). Intraabdominal thrombotic complications af-
fecting the kidneys, adrenal glands, spleen, intestine, and
pancreas are most common, and patients frequently pres-
ent with abdominal pain or discomfort. The most common
manifestations according to organ distribution include re-
nal disease (71%), pulmonary (64% with adult respiratory
distress syndrome more prevalent than pulmonary embo-
lism, and with pulmonary hemorrhage less often), cerebral
(62%; infarcts, encephalopathy, seizures, or cerebral ve-
nous occlusions), cardiac (51%; mostly valve disease), and
skin (50%; livedo reticularis, purpura, or skin necrosis).
MIs were the presenting features in 25% of patients. Only
771
5% of cases had peripheral nerve involvement, as our
patient did. SIRS is probably the underlying mechanism of
adult respiratory distress syndrome, cerebral edema, and
myocardial dysfunction, and is due to cytokine activation
such as tumor necrosis factor, interleukin-1, interleukin-6,
and macrophage migration inhibitory factor (28). The pres-
ence of SLE is a poor prognostic factor in CAPS (29). Our
patient had at least indirect evidence of thrombotic in-
volvement in at least 3 organs/tissues: his heart, the kid-
ney, and the GI tract. His manifestations developed simul-
taneously, starting with his GI symptoms. Therefore, if we
allow for the lack of conrmation of his LAC test at least 6
weeks apart, he appears to fulll the classication criteria
for probable CAPS (26). The precipitating factor in our
case was active SLE are with vasculitis.
HOSPITAL AND CLINIC COURSE
The patient was treated aggressively for severe SLE-
related vasculitis and CAPS. He was given anticoagula-
tion therapy with IV eptibatide (24 hours), clopidogrel
(3 days), IV heparin as a bridge to oral warfarin, and
aspirin 81 mg daily. Methylprednisolone 20 mg was
infused every 8 hours, and IV cyclophosphamide 500
mg was infused on hospitalization day 5. Losartan was
continued and beta-blockers were added. The patient
felt relief in his chest on the second hospital day, and
relief of abdominal pains on day 4. He received ucona-
zole for 3 days for Candida esophagitis and was
switched to nystatin thereafter. He was discharged from
the coronary care unit on day 6 on warfarin, aspirin
81 mg, methylprednisolone 64 mg daily, HCQ 400 mg,
losartan, atenolol, esomeprazole, atovaquone (for Pneu-
mocystis jiroveci pneumonia prophylaxis), alendronate
weekly, calcium, and vitamin D. He received additional
IV cyclophosphamide 1,000 mg 2 weeks later, and there-
after 4 more monthly infusions of IV cyclophosphamide
(at 0.75 mg/m2 of body surface area) before he was
started on azathioprine 150 mg daily. His GC dosage was
tapered to methylprednisolone 8 mg/day by 4 months,
and was discontinued by 6 months. The international
normalized ratio has been maintained between 2 and 3.
His proteinuria resolved by 3 months, and microscopic
hematuria resolved by 8 months. His hand numbness
resolved within 1 month but the symptoms in his feet
did not improve with persistent residual mild left foot
weakness and bilateral hypoesthesia. During his treat-
ment he developed GC-induced myopathy and acne,
which resolved with tapering of steroids. A repeat car-
diac nuclear exercise test 6 months later revealed apical
scar but no ischemia and a normal EF. A transthoracic
echocardiogram 1 year later showed mild apical
hypokinesis and was otherwise normal. No lupus ares
have occurred during followup. Anti-dsDNA titers
normalized 2 months after hospitalization but then
increased again to 23 (scale of 1 4). C4 levels have
remained somewhat decreased, ranging from 12
18 mg/dl (normal range 16 38) over the last 2 years,
whereas C3 levels have been normal.
772
DISCUSSION
This was a challenging case of a young man who within a
period of 2 months developed clinical manifestations of
active SLE with vasculitis in his skin and peripheral
nerves, and then became precipitously ill with multiorgan
ischemia, most likely due to CAPS. He was aggressively
treated with antiplatelet agents and anticoagulation as
well as GC and cyclophosphamide and achieved rapid and
lasting recovery.
Differentiation between systemic vasculitis and diffuse
vascular thrombosis, mainly due to CAPS, and TTP can be
a challenge in a patient with SLE and severe multiorgan
ischemia. Because of the severity of the presentation, phy-
sicians often need to make prompt therapeutic decisions
based on limited available data that are derived mainly
from blood tests and imaging studies, such as in our case.
We did not consider it necessary to perform a biopsy, as
this might have delayed the institution of anticoagulation
therapy and was unlikely to change our management. A
biopsy of the skin lesions or the sural nerve would prob-
ably show vasculitis, judging from the available literature
and the fact that mononeuritis multiplex is relatively rare
in CAPS (7,8,27). A biopsy of the kidney would have
probably shown APS nephropathy features (such as focal
cortical atrophy) with or without early class III/IV prolif-
erative lupus nephritis. Again, we thought we needed to
treat for both inammation/vasculitis and CAPS, and
therefore the distinction would not matter. Therapy for
CAPS for a nonlife-threatening condition calls for effec-
tive anticoagulation with IV heparin and high doses of GC
(30). In our case, we also used cyclophosphamide for his
severe vasculitis. Notably, this therapy is associated with
improved survival in SLE-CAPS, but a worse outcome in
patients with primary CAPS (29). We did not use plasma
exchange or IV gamma globulin therapy, as his condition
appeared to improve rapidly on our regimen and there was
no clinical evidence for a TTP-like illness, including the
absence of MAHA and thrombocytopenia.
We avoided direct instrumentation of the coronaries, out
of concern that this might injure the endothelium and thus
aggravate the prothrombotic state in this acute setting.
Indeed, surgical procedures are thought to be the initiating
factor in 10% of patients with CAPS (27), and periopera-
tive management of APS patients asks for minimization of
the time without anticoagulation (31). In addition, some
authors recommend minimization of intravascular manip-
ulation for access and monitoring in APS patients periop-
eratively (31).
Blood vessel inammation in SLE is the result of the
interplay of many factors and it may represent a spectrum
of pathologies, from frank vasculitis to a leukoocclusive
vasculopathy (32). Important pathogenic factors in lupus
blood vessel involvement include activated endothelial
cells with up-regulation of their adhesion molecules, acti-
vated neutrophils expressing CD11b/CD18 (CR3), acti-
vated platelets, and complement activation, all features of
active disease (3236). When associated with local im-
mune complex deposition, these factors may lead to vas-
culitis modeled by the Arthus lesion, or otherwise may
lead to a leukoocclusive vasculopathy modeled by the
Cherian et al
Shwartzman phenomenon (32). Such leukothrombi have
been observed in central nervous system lupus with brain
infarcts and lupus enteritis cases, and have been proposed
as the cause of pulmonary leukosequestration with revers-
ible hypoxemia and SIRS (32,36). A rapid response to
high-dose GC has been noted (36). Endothelial apoptosis
and dysfunction associated with impaired vascular repair
have also been noted in patients with lupus (35,37). They
are likely mediated by high levels of type I interferon
(IFN), and are perhaps responsible for the early atheroscle-
rosis in SLE (37). We and other groups have previously
shown that high messenger RNA expression by quantita-
tive real-time polymerase chain reaction of type I IFN
inducible genes in peripheral blood mononuclear cells
from patients with SLE is associated with high disease
activity in a cross-sectional study (38), and that this cor-
relates with type I IFN activity in the serum (39). Our
patient indeed had high levels of type I IFN in his serum 2
days before admission, consistent with high disease activ-
ity and perhaps vascular activation (Kirou KA and Crow
MK: unpublished observations). These levels dropped dra-
matically early after aggressive therapy with only a small
increase several months later.
The mechanisms by which aPL induce thrombosis in
APS have not been fully elucidated, but likely include
activation of complement, endothelial cells, monocytes,
and platelets (40,41). A more widespread activation of
endothelial cells and complement may be more prominent
in CAPS. Interestingly, eculizumab (C5 inhibitor) has been
used successfully along with anticoagulation and immu-
nosuppression to prevent CAPS recurrence in a patient
after renal transplantation (42). Nevertheless, a link be-
tween active vascular inammation and thrombosis in lu-
pus is self-intuitive, and we believe that our patients
lupus are was probably the trigger for his LAC-mediated
thrombosis. In fact, several studies have suggested a link
between inammation and thrombosis and were recently
reviewed (43). For example, active vasculitis in ANCA-
associated vasculitides as well as Behcets disease is asso-
ciated with deep venous thrombosis (43). It is believed that
disruption of the endothelial layer due to the vasculitic
process exposes active tissue factor, which in turn leads to
activation of coagulation factors. Tissue factor may also be
expressed in circulating detached endothelial cells or ac-
tivated by cytokines in intact endothelium. Interestingly,
in a mouse model of TMA induced by aPL, genetic reduc-
tion of tissue factor levels prevented glomerular injury
(41).
In addition to anticoagulation with IV heparin, we also
used a combination of potent antiplatelet agents to treat
our patient whose dominant clinical manifestation was the
acute MI. It is not possible to dissect the relative contribu-
tion of antiplatelet agents and anticoagulation to the nal
successful outcome. Of note, the role of antiplatelet agents
in CAPS is not clear (44). In cases associated with severe
thrombocytopenia, these agents should be avoided until
platelet numbers recover with therapy. Interestingly, the
surviving cases of group I patients with acute MI in the
study by Korkmaz et al received both antiplatelet and
anticoagulant agents (13).
Our patient developed CAPS right after therapy with
Clinicopathologic Conference
pulse GC and while off aspirin therapy. Discontinuation of
aspirin probably contributed to the development of CAPS.
It is unclear whether GC also contributed to his thrombo-
sis. However, data from Cushings syndrome patients, an-
ecdotal evidence of thrombosis after GC, and limited evi-
dence from a lupus cohort study may support such a
possibility (18,45,46). It may be prudent to try to initiate
high-dose GC therapy, or at least pulse GC, only after
initiation of anticoagulation therapy in patients with
CAPS/probable CAPS, and thereafter make an effort to
taper the dose of GC as fast as the clinical condition would
allow. Whether aspirin alone would sufce in other pa-
tients at high risk for thrombosis (but without thrombosis
yet) is unknown, but probably a good idea. The high risk
for thrombosis in our case, we believe, was due to the
presence of the LAC and vascular inammation. Of course,
in vasculitis cases where LAC is absent, such as in Weg-
eners granulomatosis, rapid control of the vascular in-
ammation with GC is necessary and should largely negate
any prothrombotic effects of GC themselves.
In conclusion, we have presented the case of a young
male SLE patient with positive LAC who very quickly after
his diagnosis progressed to develop severe systemic vasc-
ulitis and then probable CAPS. He was successfully
treated with aggressive anticoagulation, antiplatelet, and
immunosuppressive therapy with an excellent, rapid, and
long-lasting response. Rapid recognition of the syndrome
and proper management are critical for a favorable out-
come in this disease.
FINAL DIAGNOSIS
Probable catastrophic antiphospholipid syndrome trig-
gered by lupus vasculitis.
AUTHOR CONTRIBUTIONS
All authors were involved in drafting the article or revising it
critically for important intellectual content, and all authors ap-
proved the nal version to be published. Dr. Kirou had full access
to all of the data in the study and takes responsibility for the
integrity of the data and the accuracy of the data analysis.
Study conception and design. Cherian, Duculan, Amigues, Crow,
Kirou.
Acquisition of data. Cherian, Duculan, Amigues, Kirou.
Analysis and interpretation of data. Cherian, Duculan, Amigues,
Crow, Kirou.
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