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 AND
KYRIAKOS A. KIROU2

CASE PRESENTATION mg/dl, normal range 16 38), prolonged prothrombin time

(16.2 seconds, normal range 10 13), prolonged activated
Chief symptom partial thromboplastin time (60 seconds, normal range 27
A 26-year-old white man with a systemic lupus erythem- 38), and positive lupus anticoagulant (LAC) by dilute Rus-
atosus (SLE) are and acute multiorgan ischemia. sells viper venom time. His urine analysis showed pro-
teinuria (0.440 gm protein/gm creatinine), hematuria
History of the present illness (1125 red blood cells [RBCs]/high-power eld [hpf]), and
The patient was in his usual state of health until 2 months pyuria (310 white blood cells [WBCs]/hpf). Antibodies to
before admission, when he developed pain and stiffness in Sm/RNP, Ro/SSA, and La/SSB; anticardiolipin antibodies;
his right shoulder, neck, and back after playing softball. antineutrophil cytoplasmic antibodies (ANCAs); and anti
His symptoms progressively worsened despite manipula- cyclic citrullinated peptide antibodies were negative, and
tion by a chiropractor, and he developed new pain in his creatine phosphokinase was normal. An infectious disease
soles. This was diagnosed as plantar fasciitis and he was evaluation was performed and was negative for all patho-
given a topical steroid injection and a short course of gens, including Lyme disease, human immunodeciency
methylprednisolone. This treatment improved his pain, virus, and viral hepatitis. Renal ultrasound and Doppler
but at its completion, he developed disabling diffuse ar- were performed and were negative for renal pathology and
thralgias in his shoulders, elbows, knees, and feet, along venous thrombosis. He was placed on prednisone 10 mg
with fevers, anorexia, and weight loss. Worsening symp- orally twice daily, losartan 50 mg daily, and aspirin 81 mg
toms prompted hospitalization in another institution 3 daily, and his fevers resolved with some improvement in
weeks before admission, where he was febrile up to 103F joint pains. Two weeks before admission, he was evalu-
and hypertensive (144/100 mm Hg). An extensive evalua- ated by a rheumatologist who discontinued aspirin in an-
tion revealed elevated inammatory markers, including ticipation of a kidney biopsy to rule out lupus nephritis.
erythrocyte sedimentation rate (ESR; 102 mm/hour), C-re- Laboratory evaluation again revealed persistent protein-
active protein level (56 mg/liter), positive antinuclear an- uria (2), hematuria (10 20 RBCs/hpf), C4 hypocomple-
tibodies (ANAs; 1:640), strongly positive anti double- mentemia (C3 111 mg/dl, C4 9 mg/dl), and strongly posi-
stranded DNA (anti-dsDNA) titers, low levels of C4 (9 tive anti-dsDNA. The patient could not tolerate tapering of
prednisone to 15 mg and he stayed at 17.5 mg daily.
Supported by the Mary Kirkland Center for Lupus Re- He presented to our clinic 3 days before admission and
search. his scheduled kidney biopsy. Over the course of the pre-
1
Julie Cherian, MD: Stony Brook University Hospital, vious week he had developed a few small tender erythem-
Stony Brook, New York; 2Roland Duculan, MD, Mary K. atous skin lesions and some skin excoriation on his ngers
Crow, MD, Kyriakos A. Kirou, MD: Mary Kirkland Center
for Lupus Research, Hospital for Special Surgery, New and palms. He also experienced numbness of his ngertips
York, New York; 3Isabelle Amigues, MD: Teaching Hospital and bilateral soles for 2 or 3 days. Weight loss of 30 33
Lyon Sud, Pierre Benite, Rhone Alpes, France. pounds over the course of 3 months with decreased appe-
Drs. Crow and Kirou have led a patent application for an tite, nausea, and mild diarrhea was noted. On examina-
interferon assay.
Address correspondence to Kyriakos A. Kirou, MD, Mary tion, he appeared ill with a blood pressure (BP) of 140/100
Kirkland Center for Lupus Research, Hospital for Special mm Hg, and a heart rate of 96 beats per minute. There were
Surgery, 535 East 70th Street, New York, NY 10021. E-mail: a few erythematous lesions on his palate, as well as small
[email protected]. tender erythematous nonblanching lesions in his palms,
Submitted for publication October 21, 2010; accepted in
revised form January 18, 2011. ngertips, and toe tips with rare splinter hemorrhages. He
had dysesthesia/hypoesthesia in bilateral palms and n-

766
Clinicopathologic Conference 767

Figure 1. Electrocardiogram demonstrating ST elevations in precordial leads in V1V6.

gertips, as well as bilateral soles extending to the lateral Family history

side of his ankles. In addition, there was mild weakness of The patients parents were alive and well at ages 59 (fa-
toe dorsiexion at the left second, third, and fourth toes, as ther) and 55 (mother) years. His paternal grandfather died
well as left foot dorsiexion (4 of 5). There was bilateral at the age of 32 years from a cerebrovascular accident. A
joint line tenderness in his metacarpophalangeal joints paternal great uncle had rheumatoid arthritis.
and ankles. The overall picture suggested inadequately
treated severe SLE with nephritis, arthritis, mononeuritis
multiplex, and vasculitis. On the same day, one dose of Social history
pulse glucocorticoids (GC) of 1 gm intravenous (IV) meth- The patient had smoked for 6 years up until 5 months
ylprednisolone was administered, and prednisone was in- before presentation. There was only social alcohol use and
creased to 60 mg daily. Losartan was increased to 100 mg no illicit drug use. He was single but in a stable relation-
daily and he was started on amlodipine 5 mg daily, hy- ship.
droxychloroquine (HCQ) 400 mg, esomeprazole 40 mg
daily, alendronate 70 mg weekly, as well as calcium and
vitamin D. Medications and allergies
On Monday, 3 days later, the patient was brought back to His medications upon admission were prednisone (60 mg/
the clinic in a wheelchair, looking pale and very weak. day), HCQ (400 mg/day), losartan (100 mg/day), amlodip-
Over the weekend, his BP had remained high, despite ine 5 mg daily, and esomeprazole (40 mg/day). He had no
medications. His nausea, malaise, and diarrhea had wors- known drug allergies.
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 Physical examination and tests
chest discomfort, which was only perceived after it re- Physical examination was unchanged except for the vital
solved. His BP was 133/87 mm Hg and his heart rate was signs, as noted above. Of note, there was no jugular vein
111 beats per minute, with no fever or hypoxia. Electro- distension and no murmur, gallop, or rub. His abdomen
cardiogram demonstrated sinus tachycardia and elevated was soft and not tender or distended with normal bowel
ST segments on precordial leads (V1V6) (Figure 1). He sounds and no hepatosplenomegaly. His peripheral pulses
was transferred to the coronary care unit. 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
Medical history noted on rectal examination. Laboratory tests revealed
His medical history was positive for mononucleosis in anemia, elevated troponin (8.54 ng/ml that peaked to 18.7
high school and right knee arthroscopy for a meniscal ng/ml that night) with normal creatinine but persistent
injury. 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 Cherian et al

angiographic or histologic proof of thrombosis. Neverthe- thyroidization; brous intimal hyperplasia with organized
less, we strongly believe based on the available evidence thrombosis and arteriolar occlusions; and groups of glob-
that the ischemic events in the heart (acute MI), the kid- ally sclerotic and/or cystic glomeruli. The authors consid-
neys, and most likely also the gastrointestinal (GI) tract ered this lesion analogous to the cortical infarcts on CT
were due to thrombosis. imaging and as a way to differentiate this disease from
Among patients with lupus, predictive factors of throm- other TMA-associated disorders (with the exception per-
bosis may include male sex, LAC, constantly positive aPL, haps of malignant hypertension). They considered both
shorter disease duration, smoking, active disease, and focal cortical atrophy and brous intimal hyperplasia le-
higher doses of GC (18 20). Regarding the occurrence of sions as a possible consequence of tissue ischemia and the
acute MI in young SLE patients, Korkmaz et al reviewed activation of the reninangiotensin system. In view of the
the literature of 49 SLE patients who had an acute MI and above, and given the lack of histologic data in our case, we
were age 35 years (13). The authors recognized 3 groups. cannot be sure whether at the onset of his renal disease,
Group III (n 22) had atherosclerosis and had active our patient had early lupus nephritis, APS nephropathy,
disease much less often than the other 2 groups and with or both. It is very likely, however, that his renal infarcts
longer lag periods from the diagnosis of SLE. Group II (n were due to multifocal thrombosis in renal vessels too
12) had evidence of coronary aneurysms/arteritis on an- small to be visualized on a CT angiogram (such as arcuate,
giogram, and group I (n 16) had either coronary throm- interlobular arteries), including TMA, which does not al-
bosis (n 11, according to angiography or clinical judg- ways manifest with MAHA and thrombocytopenia (25).
ment) or normal coronaries (n 5). The majority of these Abdominal angina was a prominent symptom of our
patients (93%) had aPL, which represented a much higher patient and was associated with nausea, diarrhea, and
prevalence than in the 2 other groups and received anti- antral erythema on esophagogastroduodenoscopy. The
coagulation and antiplatelet therapy. It was presumed that symptoms suggested bowel ischemia, but a CT angiogram
clear coronary vessels could be due to resolution of was negative for vasculitis and thrombosis. A presentation
thrombosis/spontaneous thrombolysis, coronary vaso- of acute abdominal pain was examined in a few lupus
spasm, coronary emboli from Libman-Sacks endocarditis/ studies. In one, presentation in lupus (n 15) was com-
mural ventricular thrombus, or microthrombi. In 2 of these pared to that of PAN (n 5), and was found to be more
cases, endomyocardial biopsy samples failed to show vas- insidious (on average, 34 days compared to 11 days before
culitis, and in another, autopsy showed arteriolar throm- crisis) and less often with acute surgical abdomen (11).
bosis (21,22). All had presence of aPL. Spontaneous Symptoms often had a cramping quality and were associ-
thrombolysis of an LAD thrombus while receiving enoxa- ated with anorexia, nausea, vomiting, and diarrhea, such
parine therapy has been reported in a 19-year-old patient as in our patient. Vasculitis occurred in 82% of those
with APS and acute MI (23). Another SLE patient with aPL requiring laparotomy and affected smaller vessels (and
developed acute MI due to distal LAD thrombosis after less extensive areas of ischemia) compared to PAN. In
rapid normalization of thrombocytopenia (24). another study, acute abdominal pain in 36 active SLE
Kidney involvement in this case was characterized by patients was due to vasculitis (by histopathology; n 19),
hypertension, mild proteinuria, microscopic hematuria, mesenteric or hepatic arterial thrombosis (n 3), and
and renal infarcts on CT angiograms (Figure 2). He could nonSLE-related complications (n 14), whereas all 15
have had early lupus nephritis before the development of patients with quiescent disease had nonSLE-related prob-
the cortical infarcts. In that case, the infarcts could be the lems (10). In both of these studies, central nervous system
result of emboli, vasculitis, or multifocal thrombosis due lupus, thrombocytopenia, and cutaneous vasculitis were
to APS. Alternatively, he could have had APS nephropa- more common in SLE patients with GI vasculitis. A third
thy all along. Embolic disease was unlikely, given the study of acute abdominal pain in 38 SLE patients demon-
absence of Libman-Sacks endocarditis or cardiac thrombus strated multifocal ischemic lupus enteritis based on sev-
on transesophageal echocardiogram. True lupus renal vas- eral CT imaging features, including bowel wall thickening
culitis is very rare in SLE and there is no documented in the absence of mesenteric thrombosis (11). These pa-
association with cortical infarcts, making this a less likely tients had a drop of their WBCs at presentation compared
etiology (9). APS nephropathy almost universally is char- to control patients. The authors hesitated to call these
acterized by hypertension, often severe and occasionally enteritis cases vasculitis without histologic proof, and con-
malignant (25). Various degrees of proteinuria (usually sidered the possibility of reversible ischemic bowel dis-
mild), microscopic hematuria, and renal insufciency may ease, given the improvement after high-dose GC therapy.
be present (25). Nochy et al have analyzed the vascular The outcome in this study was much better, perhaps be-
pathology of this disease in 16 patients with primary APS cause of earlier treatment from the onset of symptoms.
(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 CAPS
the more common pathology seen (75%), and could be CAPS is an accelerated form of APS characterized by mul-
associated with arteriolar brous or brocellular occlu- tiorgan failure and a mortality rate of approximately 44%,
sions (68%) or organizing thrombosis (37%). Focal cortical even after therapy (26,27). Classication criteria for the
atrophy (62%), involving the subcapsular cortex in an syndrome are shown in Table 2 (25). Only approximately
irregular distribution, was characterized by an ensemble 1% of patients with APS present with CAPS (26). The
of dense interstitial brosis, massive tubular atrophy, and CAPS Registry has been created to assist the study of this
Clinicopathologic Conference 771

5% of cases had peripheral nerve involvement, as our

Table 2. Preliminary criteria for the classication of
catastrophic antiphospholipid syndrome (CAPS) (26) patient did. SIRS is probably the underlying mechanism of
adult respiratory distress syndrome, cerebral edema, and
1. Evidence of involvement of 3 or more organs, systems, myocardial dysfunction, and is due to cytokine activation
and/or tissues such as tumor necrosis factor, interleukin-1, interleukin-6,
Usually clinical evidence of vessel occlusions
and macrophage migration inhibitory factor (28). The pres-
conrmed by imaging techniques when appropriate.
Renal involvement is dened by a 50% rise in serum
ence of SLE is a poor prognostic factor in CAPS (29). Our
creatinine, severe systemic hypertension ( 180/100 patient had at least indirect evidence of thrombotic in-
mm Hg), and/or proteinuria ( 500 mg/24 hours) volvement in at least 3 organs/tissues: his heart, the kid-
2. Development of manifestations simultaneously or in ney, and the GI tract. His manifestations developed simul-
less than a week taneously, starting with his GI symptoms. Therefore, if we
3. Conrmation by histopathology of small-vessel allow for the lack of conrmation of his LAC test at least 6
occlusion in at least one organ or tissue weeks apart, he appears to fulll the classication criteria
For histopathologic conrmation, signicant evidence for probable CAPS (26). The precipitating factor in our
of thrombosis must be present, although vasculitis
case was active SLE are with 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 HOSPITAL AND CLINIC COURSE
having an APS, the laboratory conrmation requires
The patient was treated aggressively for severe SLE-
that presence of aPL must be detected on 2 or more
occasions at least 6 weeks apart (not necessarily at related vasculitis and CAPS. He was given anticoagula-
the time of the event), according to the proposed tion therapy with IV eptibatide (24 hours), clopidogrel
preliminary criteria for the classication of denite (3 days), IV heparin as a bridge to oral warfarin, and
APS aspirin 81 mg daily. Methylprednisolone 20 mg was
Denite CAPS infused every 8 hours, and IV cyclophosphamide 500
All 4 criteria mg was infused on hospitalization day 5. Losartan was
Probable CAPS continued and beta-blockers were added. The patient
All 4 criteria except for involvement of only 2 organs,
felt relief in his chest on the second hospital day, and
systems, and/or tissues
relief of abdominal pains on day 4. He received ucona-
All 4 criteria, except for the absence of laboratory
conrmation at least 6 weeks apart due to the early zole for 3 days for Candida esophagitis and was
death of a patient never tested for aPL prior to the switched to nystatin thereafter. He was discharged from
CAPS event the coronary care unit on day 6 on warfarin, aspirin
1, 2, and 4 81 mg, methylprednisolone 64 mg daily, HCQ 400 mg,
1, 3, and 4 and the development of a third event in losartan, atenolol, esomeprazole, atovaquone (for Pneu-
more than a week but less than a month, despite mocystis jiroveci pneumonia prophylaxis), alendronate
anticoagulation weekly, calcium, and vitamin D. He received additional
IV cyclophosphamide 1,000 mg 2 weeks later, and there-
rare syndrome and is available free online (www.med. after 4 more monthly infusions of IV cyclophosphamide
ub.es/MIMMUN/FORUM/CAPS.htm). Approximately 70% (at 0.75 mg/m2 of body surface area) before he was
of patients are female. Among all patients, 46% have pri- started on azathioprine 150 mg daily. His GC dosage was
mary APS, 40% have SLE, 5% have lupus-like disease, tapered to methylprednisolone 8 mg/day by 4 months,
and 9% have other autoimmune diseases. In at least half of and was discontinued by 6 months. The international
the cases, a precipitating factor has been implicated: in- normalized ratio has been maintained between 2 and 3.
fection (22%), surgery (10%), anticoagulation withdrawal His proteinuria resolved by 3 months, and microscopic
(8%), medication (7%), obstetric complications (7%), neo- hematuria resolved by 8 months. His hand numbness
plasia (5%), and SLE are (3%). The manifestations of resolved within 1 month but the symptoms in his feet
CAPS depend on organ involvement as well as the devel- did not improve with persistent residual mild left foot
opment of systemic inammatory response syndrome weakness and bilateral hypoesthesia. During his treat-
(SIRS) (28). Intraabdominal thrombotic complications af- ment he developed GC-induced myopathy and acne,
fecting the kidneys, adrenal glands, spleen, intestine, and which resolved with tapering of steroids. A repeat car-
pancreas are most common, and patients frequently pres- diac nuclear exercise test 6 months later revealed apical
ent with abdominal pain or discomfort. The most common scar but no ischemia and a normal EF. A transthoracic
manifestations according to organ distribution include re- echocardiogram 1 year later showed mild apical
nal disease (71%), pulmonary (64% with adult respiratory hypokinesis and was otherwise normal. No lupus ares
distress syndrome more prevalent than pulmonary embo- have occurred during followup. Anti-dsDNA titers
lism, and with pulmonary hemorrhage less often), cerebral normalized 2 months after hospitalization but then
(62%; infarcts, encephalopathy, seizures, or cerebral ve- increased again to 23 (scale of 1 4). C4 levels have
nous occlusions), cardiac (51%; mostly valve disease), and remained somewhat decreased, ranging from 12
skin (50%; livedo reticularis, purpura, or skin necrosis). 18 mg/dl (normal range 16 38) over the last 2 years,
MIs were the presenting features in 25% of patients. Only whereas C3 levels have been normal.
772 Cherian et al

DISCUSSION Shwartzman phenomenon (32). Such leukothrombi have

been observed in central nervous system lupus with brain
This was a challenging case of a young man who within a infarcts and lupus enteritis cases, and have been proposed
period of 2 months developed clinical manifestations of as the cause of pulmonary leukosequestration with revers-
active SLE with vasculitis in his skin and peripheral ible hypoxemia and SIRS (32,36). A rapid response to
nerves, and then became precipitously ill with multiorgan high-dose GC has been noted (36). Endothelial apoptosis
ischemia, most likely due to CAPS. He was aggressively and dysfunction associated with impaired vascular repair
treated with antiplatelet agents and anticoagulation as have also been noted in patients with lupus (35,37). They
well as GC and cyclophosphamide and achieved rapid and are likely mediated by high levels of type I interferon
lasting recovery. (IFN), and are perhaps responsible for the early atheroscle-
Differentiation between systemic vasculitis and diffuse rosis in SLE (37). We and other groups have previously
vascular thrombosis, mainly due to CAPS, and TTP can be shown that high messenger RNA expression by quantita-
a challenge in a patient with SLE and severe multiorgan tive real-time polymerase chain reaction of type I IFN
ischemia. Because of the severity of the presentation, phy- inducible genes in peripheral blood mononuclear cells
sicians often need to make prompt therapeutic decisions from patients with SLE is associated with high disease
based on limited available data that are derived mainly activity in a cross-sectional study (38), and that this cor-
from blood tests and imaging studies, such as in our case. relates with type I IFN activity in the serum (39). Our
We did not consider it necessary to perform a biopsy, as patient indeed had high levels of type I IFN in his serum 2
this might have delayed the institution of anticoagulation days before admission, consistent with high disease activ-
therapy and was unlikely to change our management. A ity and perhaps vascular activation (Kirou KA and Crow
biopsy of the skin lesions or the sural nerve would prob- MK: unpublished observations). These levels dropped dra-
ably show vasculitis, judging from the available literature matically early after aggressive therapy with only a small
and the fact that mononeuritis multiplex is relatively rare increase several months later.
in CAPS (7,8,27). A biopsy of the kidney would have The mechanisms by which aPL induce thrombosis in
probably shown APS nephropathy features (such as focal APS have not been fully elucidated, but likely include
cortical atrophy) with or without early class III/IV prolif- activation of complement, endothelial cells, monocytes,
erative lupus nephritis. Again, we thought we needed to and platelets (40,41). A more widespread activation of
treat for both inammation/vasculitis and CAPS, and endothelial cells and complement may be more prominent
therefore the distinction would not matter. Therapy for in CAPS. Interestingly, eculizumab (C5 inhibitor) has been
CAPS for a nonlife-threatening condition calls for effec- used successfully along with anticoagulation and immu-
tive anticoagulation with IV heparin and high doses of GC nosuppression to prevent CAPS recurrence in a patient
(30). In our case, we also used cyclophosphamide for his after renal transplantation (42). Nevertheless, a link be-
severe vasculitis. Notably, this therapy is associated with tween active vascular inammation and thrombosis in lu-
improved survival in SLE-CAPS, but a worse outcome in pus is self-intuitive, and we believe that our patients
patients with primary CAPS (29). We did not use plasma lupus are was probably the trigger for his LAC-mediated
exchange or IV gamma globulin therapy, as his condition thrombosis. In fact, several studies have suggested a link
appeared to improve rapidly on our regimen and there was between inammation and thrombosis and were recently
no clinical evidence for a TTP-like illness, including the reviewed (43). For example, active vasculitis in ANCA-
absence of MAHA and thrombocytopenia. associated vasculitides as well as Behcets disease is asso-
We avoided direct instrumentation of the coronaries, out ciated with deep venous thrombosis (43). It is believed that
of concern that this might injure the endothelium and thus disruption of the endothelial layer due to the vasculitic
aggravate the prothrombotic state in this acute setting. process exposes active tissue factor, which in turn leads to
Indeed, surgical procedures are thought to be the initiating activation of coagulation factors. Tissue factor may also be
factor in 10% of patients with CAPS (27), and periopera- expressed in circulating detached endothelial cells or ac-
tive management of APS patients asks for minimization of tivated by cytokines in intact endothelium. Interestingly,
the time without anticoagulation (31). In addition, some in a mouse model of TMA induced by aPL, genetic reduc-
authors recommend minimization of intravascular manip- tion of tissue factor levels prevented glomerular injury
ulation for access and monitoring in APS patients periop- (41).
eratively (31). In addition to anticoagulation with IV heparin, we also
Blood vessel inammation in SLE is the result of the used a combination of potent antiplatelet agents to treat
interplay of many factors and it may represent a spectrum our patient whose dominant clinical manifestation was the
of pathologies, from frank vasculitis to a leukoocclusive acute MI. It is not possible to dissect the relative contribu-
vasculopathy (32). Important pathogenic factors in lupus tion of antiplatelet agents and anticoagulation to the nal
blood vessel involvement include activated endothelial successful outcome. Of note, the role of antiplatelet agents
cells with up-regulation of their adhesion molecules, acti- in CAPS is not clear (44). In cases associated with severe
vated neutrophils expressing CD11b/CD18 (CR3), acti- thrombocytopenia, these agents should be avoided until
vated platelets, and complement activation, all features of platelet numbers recover with therapy. Interestingly, the
active disease (3236). When associated with local im- surviving cases of group I patients with acute MI in the
mune complex deposition, these factors may lead to vas- study by Korkmaz et al received both antiplatelet and
culitis modeled by the Arthus lesion, or otherwise may anticoagulant agents (13).
lead to a leukoocclusive vasculopathy modeled by the Our patient developed CAPS right after therapy with
Clinicopathologic Conference 773

pulse GC and while off aspirin therapy. Discontinuation of from thrombotic thrombocytopenic purpura, prognosis, and
aspirin probably contributed to the development of CAPS. outcome. Arthritis Rheum 2005;53:9825.
5. Espinosa G, Bucciarelli S, Cervera R, Lozano M, Reverter JC,
It is unclear whether GC also contributed to his thrombo-
de la Red G, et al. Thrombotic microangiopathic haemolytic
sis. However, data from Cushings syndrome patients, an- anaemia and antiphospholipid antibodies. Ann Rheum Dis
ecdotal evidence of thrombosis after GC, and limited evi- 2004;63:730 6.
dence from a lupus cohort study may support such a 6. Kwok SK, Ju JH, Cho CS, Kim HY, Park SH. Thrombotic
possibility (18,45,46). It may be prudent to try to initiate thrombocytopenic purpura in systemic lupus erythematosus:
risk factors and clinical outcome. A single centre study. Lu-
high-dose GC therapy, or at least pulse GC, only after
pus 2009;18:16 21.
initiation of anticoagulation therapy in patients with 7. Ramos-Casals M, Nardi N, Lagrutta M, Brito-Zeron P, Bove A,
CAPS/probable CAPS, and thereafter make an effort to Delgado G, et al. Vasculitis in systemic lupus erythematosus:
taper the dose of GC as fast as the clinical condition would prevalence and clinical characteristics in 670 patients. Med-
allow. Whether aspirin alone would sufce in other pa- icine (Baltimore) 2006;85:95104.
tients at high risk for thrombosis (but without thrombosis 8. Drenkard C, Villa AR, Reyes E, Abello M, Alarcon-Segovia D.
Vasculitis in systemic lupus erythematosus. Lupus 1997;6:
yet) is unknown, but probably a good idea. The high risk 235 42.
for thrombosis in our case, we believe, was due to the 9. Appel GB, Pirani CL, DAgati V. Renal vascular complications
presence of the LAC and vascular inammation. Of course, of systemic lupus erythematosus. J Am Soc Nephrol 1994;4:
in vasculitis cases where LAC is absent, such as in Weg- 1499 515.
eners granulomatosis, rapid control of the vascular in- 10. Medina G, Vera-Lastra O, Barile L, Salas M, Jara LJ. Clinical
spectrum of males with primary antiphospholipid syndrome
ammation with GC is necessary and should largely negate and systemic lupus erythematosus: a comparative study of 73
any prothrombotic effects of GC themselves. patients. Lupus 2004;13:11 6.
In conclusion, we have presented the case of a young 11. Lee CK, Ahn MS, Lee EY, Shin JH, Cho YS, Ha HK, et al.
male SLE patient with positive LAC who very quickly after Acute abdominal pain in systemic lupus erythematosus: fo-
his diagnosis progressed to develop severe systemic vasc- cus on lupus enteritis (gastrointestinal vasculitis). Ann
Rheum Dis 2002;61:54750.
ulitis and then probable CAPS. He was successfully 12. Zizic TM, Classen JN, Stevens MB. Acute abdominal compli-
treated with aggressive anticoagulation, antiplatelet, and cations of systemic lupus erythematosus and polyarteritis
immunosuppressive therapy with an excellent, rapid, and nodosa. Am J Med 1982;73:52531.
long-lasting response. Rapid recognition of the syndrome 13. Korkmaz C, Cansu DU, Kasifoglu T. Myocardial infarction in
and proper management are critical for a favorable out- young patients ( or 35 years of age) with systemic lupus
erythematosus: a case report and clinical analysis of the lit-
come in this disease. erature. Lupus 2007;16:289 97.
14. Heibel RH, OToole JD, Curtiss EI, Medsger TA Jr, Reddy SP,
Shaver JA. Coronary arteritis in systemic lupus erythemato-
FINAL DIAGNOSIS sus. Chest 1976;69:700 3.
15. Garcia-Carrasco M, Ramos-Casals M, Cervera R, Trejo O,
Probable catastrophic antiphospholipid syndrome trig- Yague J, Siso A, et al. Cryoglobulinemia in systemic lupus
gered by lupus vasculitis. erythematosus: prevalence and clinical characteristics in a
series of 122 patients. Semin Arthritis Rheum 2001;30:366
73.
16. Wilson WA, Gharavi AE, Koike T, Lockshin MD, Branch DW,
AUTHOR CONTRIBUTIONS Piette JC, et al. International consensus statement on prelim-
All authors were involved in drafting the article or revising it inary classication criteria for denite antiphospholipid
critically for important intellectual content, and all authors ap- syndrome: report of an international workshop. Arthritis
proved the nal version to be published. Dr. Kirou had full access Rheum 1999;42:1309 11.
to all of the data in the study and takes responsibility for the 17. Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL,
integrity of the data and the accuracy of the data analysis. Cervera R, et al. International consensus statement on an
Study conception and design. Cherian, Duculan, Amigues, Crow, update of the classication criteria for denite antiphospho-
Kirou. lipid syndrome (APS). J Thromb Haemost 2006;4:295306.
Acquisition of data. Cherian, Duculan, Amigues, Kirou. 18. Calvo-Alen J, Toloza SM, Fernandez M, Bastian HM, Fessler
Analysis and interpretation of data. Cherian, Duculan, Amigues, BJ, Roseman JM, et al. Systemic lupus erythematosus in a
Crow, Kirou. multiethnic US cohort (LUMINA). XXV. Smoking, older age,
disease activity, lupus anticoagulant, and glucocorticoid dose
as risk factors for the occurrence of venous thrombosis in
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