ARTHRITIS & RHEUMATISM
Vol 41, No 4,April IYYII, pp 751-760
0 1998, American College of Kheumdtology
LETTERS
Updating the American College of Rheumatology
criteria for systemic lupus erythematosus: comment
on the letter by Hochberg
To the Editor:
The Diagnostic and Therapeutic Criteria Committcc
of the American College of Rheumatology (ACR) recently
decided (1) to update the 1982 revised criteria for the classi-
fication of systcmic lupus erythematosus (SLE) (2). Thc pro-
posed revisions affect criteria 10(a) and 10(d).
The deletion of criterion 10(a), “positive L E cell
preparation,” is timely. Indeed. the presence of LE cells as a
requirement for the diagnosis of SLE is both largely redundant
with criterion 11,“abnormal titer of antinuclear antibody,” and
far less specific for the diagnosis of SLE than are criteria 10(b)
and 10(c), i.e., “antibody to native DNA” and “antibody to
Sm.” respectively. Aftcr a prolonged apoptosis, the L E cell has
finally died-we salute its memory.
The other revision deals with antiphospholipid anti-
bodies (aPI,). The 1982 formulation of critcrion 10(d), rc-
stricted to false-positive tests for syphilis (FPTS), has been
extended to “an abnormal serum level of TgC or TgM anticar-
diolipin antibodies (aCL)” or ”positive test for lupus anticoag-
ulant (LAC) using a standard method” ( I ) . This revision
prompts several remarks.
The long-term duration (“at least 6 months”) specified
for FPTS is not required for aCL or LAC positivity in the 1997
updated criteria. The inclusion of this requirement for FPTS in
the 1971 and 1982 criteria was probably aimed at ruling out
false-positive reactions due to technical problems and transient
FPTS secondary to diverse acute infectious disorders. Simi-
larly, a duration rcquirement of “more than 8 weeks apart” has
been included in the historical definition of the antiphospho-
lipid syndrome (APS) proposed in 1987 by Harris et a1 (3).
Although durable aCL may also occur in the course of chronic
viral infections such as those induced by human immunodefi-
ciency virus or hepatitis C virus, I think the 6 months duration
requirement should be extcndcd both to aCL and to LAC.
LAC and, mainly, incrcascd levcls of aCL, are much
more prevalent than FPTS among patients with connective
tissue disorders, including SLE (43,and this has serious
implications. First, keeping in mind that distinguishing SLE
from rheumatoid arthritis (RA) was a major issue of the 1982
criteria for SLE, as the composition of thc control group
attests ( 2 ) , it should be noted that contrary to FPTS or LAC,
aCL positivity is not rare in RA patients, ranging from 4% to
49%’ dcpending on the series (S), and may be similar to that
obscrved in SLE patients (5). This may affect the potency of
the ACR criteria to discriminate between RA and SLE.
Second, the replacement of the FPTS requirement with aPL
positivity not only does not address our previous concerns
about the poor ability of the 1982 critcria to distinguish
between primary and SLE-associated A P S (6.7), but also
reinforces thesc concerns, given that by definition, all patients
with primary APS have aPL (3), whereas only one-third of
them have FPTS (8).
751
The rcviscd criteria for SLE wcre released in 1982, 6
years beforc the initial proposal for the concept of primary
APS (9). ‘Therefore, the control population did not include
patients with primary APS (2), a condition frequently encoun-
tered by physicians nowadays. The ACR criteria for SLE have
achieved worldwide success. They are uscd daily by rheuma-
tologists, internists, and many subspecialists, not only to clas-
sify patients with SLE, but also, perhaps by inappropriate
extension, to diagnose the disease, as attcstcd by thc interna-
tional literature. I am deeply convinced that the time has come
for a substantial revision of the ACR criteria for SLE, using a
control population that includes nonrheumatic disorders such
as primary APS. Our group is ready to participate in this
worthy collaborative effort.
Jean-Charles Piette, M D
H6pitul Pitit;-Sulp&ti<ere
Paris. Frunce
1. Hochberg MC, for the Diagnostic and ‘I’hcrapeutic Criteria Com-
mittee or the Amcrican College of Rheumatology. Updating the
American College of Rheumatology revised criteria for the classi-
fication of systemic lupus crythematosus [letter]. Arthritis Rheum
1997:40:1725.
2. Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield
NF, et al. Thc 1982 revised criteria for the classification of systemic
lupus erythematosus. Arthritis Rheum 1982;25:1271-7.
3. Harris EN, Baguley E, Ashcraon RA, Hughes GRV. Clinical and
serological features of the “antiphospholipid syndrome” [abstract].
Br J Rheumatol 1987;26 Suppl 2:19.
4. Meyer 0, Piette JC, Bourgeois P, Fallas P, Bletry 0, Jungers P, et
al. Antiphospholipid antibodies: a disease markcr in 25 patients
with antinuclear antibody negative systemic lupus erythematosus
(SLE). Comparison with a group of 91 patients with antinuclear
antibody positive SLE. J Rheumatol 1987;14:502-6.
5. Merkel PA, Chang YC, Pierangeli SS, Convery K, Harris EN.
Polisson RP. The prcvaleiicc and clinical associations of anticardio-
lipin antibodics in a large inception cohort of patients with connec-
tive tissue diseases. Am I Med 1996;101:576-83.
6. Picttc JC, Wechsler B, Frances C, Godeau P. Systemic lupus
erythematosus and the antiphospholipid syndrome: reflections
about the relevance of AKA criteria. J Rheumatol 1992;19:1835-7.
7. Piette JC, Wechsler B. Frances C, Papo T, Godeau P. Exclusion
criteria for primary antiphospholipid syndrome. J Rheumatol 1993;
20:1802-4.
8. Asherson RA, Khaniashta MA. Ordi-Ros J. Derksen RHWM,
Machin SJ, Barquinero J, et al. The “primary” antiphospholipid
syndrome: major clinical and scrological features. Medicine (Balti-
more) 1989;68:366-74.
9. Ashcrson RA. A “primary” antiphospholipid syndrome? J Rheu-
matol 1988;15:1742-6.
The role of microvasculopathy in the catastrophic
antiphospholipid syndrome: comment on the article by
Neuwelt et a1
To the Editor
Neuwelt et a1 are to be congratulated for their insight-
ful dewription of the catddrophic antiphospholipid syndrome
(CAPS) (1) Herein we otter comment regarding pathophysi-
752
ologic mechanism(s), emphasizing the role of activated vascu-
lar endothelium, and discuss the entity of reversible leukoen-
cephalopathy as observed in the case reported by Neuwelt and
coworkers, and in patients with systemic lupus erythematosus
(SLE).
The pathogenesis of microv ulopathy in auto-
immune disease may include I ) classic leukocytoclastic vascu-
litis secondary to immune complex deposition in vessel walls
(2); 2) ~hromhosisof vcsscls secondary to a noninfkammatory
vasculopathy in the setting of the APS ( 3 ) ,with recent reports
indicating a role of activated endothelium in the hypcrcoagu-
lability accompanying antiphospholipid antibodies (aPL) (4,5);
or, 3) leukor~zrombosissecondary to intravascular activation of
complement, neutrophils, and endothelium, in the absence of
local immune complex deposition (2,6). Such vaso-occlusive
plugs arc promoted by the interaction of activated ncutrophils,
displaying up-regulation of the P,-integrin CD11bICD18, with
stimulated endothelial cells expressing the adhesion molecules
intercellular adhesion molcculc 1 (ICAM-1) and E-selectin.
This paradigm was validated in a recent model of the
vascular injury underlying thrombotic strokc, wherein the
investigators showed that neutrophil-depleted or ICAM-1-
deficient mice were relatively resistant to focal cerebral isch-
emia and reperfusion injury provoked hy expcrimental intralu-
mind occlusion of the middle cerebral artery (7). Moreover,
we have shown that endothelial cell cxpression of adhesion
molecules is incrcased during SLE disease cxacerbations (8).
Similar pathogenesis has been reported to produce pulmonary
leukosequestration and transient reversible hypoxemia during
exacerbations of SLE (9). Pathologic specimens from patients
with lupus ccrebritis have revealed occlusion of small cerebral
vessels by leukoaggregatcs (2,6). Leukothrombosis, as modeled
by the Shwarztman phenomenon (2), also plays a central role
in the development of tissuc injury observed during endotoxic
shock, adult respiratory distress syndrome, and cerebral injury
following cardiopulmonary bypass (6).
With regard to the case described by Neuwelt et al, we
agree that the white matter ischemic cortical lesions, eclamp-
sia, HELLP syndrome (hcmolysis, elevated liver enzyme levels,
and low platelet count) diffuse cognitive dysfunction with
seizures, abdominal pain with mucosal petechiae, and throm-
bocytopenia were all linked by a unifying pathophysiologic
mechanism, the common denominator of which was B diffuse
microvasculopathy affecting the small vessels of multiple end
organs. Pathologic studies of skin and muscle specimens,
however, failed to reveal evidencc of immune complex depo-
sition, microthrombi, or frank vasculitis. Therefore, the rela-
tive contributions of vasculitis, thrombotic vasculopathy, or
leukothrombosis in this case arc unproven, although the
“absence of subcndothelial deposits or microthrombosis on
skin biopsy, the paucity of schistocytes on peripheral smears,
and the markedly elevated antiphospholipid levels all point to
the diagnosis of APS” ( I ) .
Serial magnetic resonance imaging (MRI) studies from
January 1994 to Deccniber 1995 in thc patient described by
Neuwelt et a1 revealed a dramatic reversal of leukoenccpha-
lopathy, implying “that the changes on neuroimaging repre-
sented subcortical edema or demyelination without infarc-
tion.” We recently treated a 25-year-old SLE patient with
hypocomplementemia, nephritis, seizures, and TgM aPL, in
whom clinical and MRI evidence of cerebral edema evolved
LETTERS
over a period of days. T2-weighted brain MRI displayed
punctate subcortical supraventricular white matter defects, and
confluent areas of high signal in parietal and occipital lobes,
which did not enhance following gadolinium injection. She
then developed cortical blindne nd was treated with hepa-
rin, intravenous methylprednisolone, intravenous gamma glob-
ulin, and plasmapheresis. Blindness and confusion resolved in
3 days, accompanied by an increase in complement component
levels and reduction in anti-DNA titers. Repeat MRI demon-
strated resolution of the parieto-occipital white matter lesions.
We believe our patient experienced an episode of
reversiblc posterior leukoenccphalopathy, as recently de-
scribed by Hinchey et al (10). Those authors concluded that
the cause of the white matter lesions is “probably a brain-
capillary leak syndrome related to hypertension, fluid reten-
tion, and possibly the cytotoxic effects of immunosuppressive
agcnts on the vascular endothelium” (10). We agree that the
white matter lesions (edema) in our patient, as in Neuwelt’s
patient with CAPS (l), are the direct result of a diffuse
microvasculopathy affecting the small vessels of the brain.
However, it is likely that the etiology of this condition occur-
ring in SLE or APS patients is related to thrombotic or
inflammatory vasculopathy, and not necessarily to hyperten-
sion or cytotoxic therapy.
In summary. we concur with Neuwelt and colleagues
that clinical entities such as thrombotic thrombocytopenic
purpura, hemolytic uremic syndrome, disseminated intravascu-
lar coagulation, preeclampsia, and APS share clinical and
pathologic features. Their common pathophysiologic substrate
is activation of vascular endothelium to express proinflamma-
tory surface adhesion molecules that interact with circulating
cellular inflammatory cells, elements of the phospholipid-
dependent coagulation factors, and platelets. The exact trigger
for this endothelial activation, the reason that clinical exacer-
bations and remissions are often separated by decades, as in
Neuwelt et al’s patient, and the precise mechanisms underlying
the ameliorative effects of anticoagulation and/or immunosup-
pression therapy all remain speculative. Additionally, we sug-
gest that some SLE patients with cerebritis experience revers-
ible leukoencephalopathy (a brain capillary leak syndrome, or
“acute cerebral distress syndrome”), mediated either by non-
inflammatory vasculopathy in the presence of aPL, or by
leukothrombosis in the presence of complement, neutrophil,
and endothelial cell activation. These patients require thcra-
pies directed at the underlying immunologic, coagulation, and
vascular pathology.
Brian D. Golden, M D
H. Michael Belmont, MD
Hospital jbr Joint Diseases Orthopedic Institute
New York University Medical Center
New York, N Y
I . Neuwelt CM, Daikh DT, Linfoot JA, Pfistcr KA, Young RG, Webb
RL, et al. Catastrophic antiphospholipid syndrome: response to
repeated plasmapheresis over threc years. Arthritis Rheum 1997;
40:1534-9.
2. Belmont HM, Abramson SB, Lie JT. Pathology and pathogenesis
of vascular injury in systemic lupus erythematosus: interactions of
inflammatory cells and activated cndothelium. Arthritis Rheum
1996;39:9-22.
3. Harris EN. Antiphospholipid syndrome. I n : Schumacher FIR,
LETTERS
Klippel JH, Koopman WJ, editors. Primer on the rheumatic
diseases. 10th ed. Atlanta: Arthritis Foundation, 1993. p. 116-7.
4. Del Papa N, Guidali L, Sala A, Buccellati C , Khamashta MA,
Ichikawak, et al. Endothelial cells as target for antiphospholipid
antibodies: human polyclonal a n d monoclonal anti-&
glycoprotein 1 antibodies react in vitro with cndothelial cells
through adherent 0,-glycoprotein I and inducc endothelial activa-
tion. Arthritis Rheum 1997;40:551-61.
5. Simantov R, LaSala JM, Lo SK, Gharavi AE, Sammaritano LR,
Salmon JE, et al. Activation of cultured vascular endothelial cells
by antiphospholipid antibodies. J Clin Invest 1995;96:2211-9.
6. Abramson SB, Weissmann G. Complement split products and the
pathogenesis of SLE. Hosp Pract 1988;23:45-55.
7. Connolly ES Jr; Winfree CJ; Springer TA, Naka Y, Liao H, Yan
SD, et al. Cerebral protection in homozygous null ICAM-1 mice
after middle cerebral artery occlusion: role of neutrophil adhesion
in the pathogenesis of stroke. J Clin Invest 1996;97:209-16.
8. Belmont HM, Buyon J, Giorno R, Abramson S. Up-regulation of
endothelial cell adhesion molecules characterizes disease activity
in systemic lupus erythematosus: the Shwartzman phenomenon
revisited. Arthritis Rheum 1994;37:376-83.
9. Abramson SB, Dobro J, Eberle MA, Benton M, Reibrnan J ,
Epstein H, et al. The syndrome of acute reversible hypoxemia in
systemic lupus erythematosus. Ann Intern Med 1991;114:941-7.
10. Hinchey J, Chaves C, Appignani B, Breen J, Pao L, Wang A, et al.
A reversible posterior leukoencephalopathy syndrome. N Engl
J Med 1996:334:494-500.
Reply
To the Editor:
We would like to thank Drs. Golden and Belmont for
their helpful comments regarding pathophysiologic mecha-
nisms in the CAPS and SLE. W e strongly concur that activated
vascular endothelium leading to noninflammatory vasculopa-
thy in the presence of aPL, or leukothrombosis in the presence
of complement, neutrophil, or endothelial cell activation, play
an important role in both the APS and SLE.
In CAPS, the ”triggering” event for endothelial activa-
tion, as in our patient, can precede the activation by decades,
and the cause remains speculative. However, the condition is
not infrequently “triggered” by some event such as infection or
surgical procedures (even minor ones such as meniscus re-
moval, dilatation and curettage, or dental extraction). It may
even occur postoperatively and may follow warfarin with-
drawal, as has been described in patients with simple APS
(1,2). Large-vessel vascular occlusions of either veins or arter-
ies (e.g., deep vein thrombosisipulmonary embolism, strokc),
so common in patients with simple APS, occur in only a
minority of patients with CAPS (1,2). The vast majority of
patients with CAPS manifest microvascular occlusions, and
unusual organs are affected, such as the adrenal glands (as
illustrated by our case, it is important to be cautious when
tapering maintenance corticosteroids and to check morning
cortisol and adrenocorticotropic hormone levels), testes, pros-
tate, small vessels of the gastrointestinal tract (as in our
patient), and pancreas. The central nervous system and renal
manifestations are dependent on this thrombotic microangi-
opathy and can occur in some cascs without brain MRI
evidence of major cerebral infarction (1,2).
Almost onc-third of paticnts with CAPS have some
features of microangiopathy without all the typical manifesta-
tions of disseminatcd intravascular coagulation, including the
753
presence of schistocytes, increased levels of fibrin degradation
products, increased levels of D-dimers, and hemolytic anemia.
Regrettably, in none of the previously described CAPS pa-
tients were any tests performed that might have provided
information on indications of endothelial damage or endothe-
lial cell stimulation, such as studies of anti-endothelial cell
antibodies themselves, von Willebrand factor antigcn, or ad-
hesion molecules such as ICAM-1 or E-selectin. One of us
(RAA) has recently prepared guidelines for the more compre-
hensive investigation of such patients (3). The role of plasma-
pheresis in this group with CAPS is still controversial, but this
therapy should certainly be considered early in this often-fatal
condition, should there be no immediate and significant re-
sponse to conventional anticoagulation, intravcnous methyl-
prednisolone, or intravenous gamma globulin therapy.
In their letter, Golden and Belmont, who have previ-
ously and concisely described the pathogenesis of vascular
injury in SLE (4),expand thcir discussion from CAPS and APS
to patients with neuropsychiatric SLE (NPSLE), and especially
lupus cerebritis. They mention that pathologic specimens from
patients with lupus cerebritis have revealed occlusion of small
cerebral blood vessels by leukoaggregates (43). Kaye et a1
previously described the results of an antemortem stereotactic
needlc biopsy of the brain in a 35-year-old SLE patient with a
rapidly progressing leukocncephalopathy (6). The brain biopsy
showed microinfarcts (with no evidence of progressive multi-
focal leukoencephalopathy suggesting infection) with a nonin-
flammatory vasculopathy, supporting the pathogenetic mech-
anisms described by Belmont, Abramson, and colleagues (43).
Golden and Bclmont recently treatcd “a 25-year-old
SLE patient with heparin, intravenous methylprednisolone,
intravenous gamma globulin, and plasmapheresis” and specu-
late on why this aggressive therapy resulted in a rcversal of
leukoencephalopathy, as was also seen in our patient with
CAPS. One of us (CMN) has previously described 31 patients
with severe NPSLE treated with intravenous cyclophospha-
mide (7). Eight patients required synchronization with plasma-
pheresis (7), but as thcsc patients were followed up over a
10-year period, 3 required long-term, intermittent plasma-
pheresis as the mainstay of their treatment (8). One of thesc
patients, a 35-year-old woman with a vaso-occlusive retinopa-
thy and intermittent sevcre organic brain syndromc (psychosis,
visual and auditory hallucinations) representing lupus cerebri-
tis, responds only to long-term periodic plasmapheresis (sec
Clinical Image on page 739 of this issue of Arthritis & Rlzeu-
matixm), similar to thc findings in the patient with CAPS
described in our case report. Certainly, plasmapheresis in
NPSLE with lupus cerebritis is quite controversial. The use of
indwelling catheters in this procedure can lead t o complica-
tions (7), and they should be used only when less invasive
treatmcnts have been tricd and when the morbidity of the
natural history of the NPSLE outweighs the potential risks of
side effects of the treatment (7). Ho\vever, we agree with
Golden and Belmont that patients with severc life-threatening
CAPS, APS. or NPSLE “require therapies directed at thc
underlying immunologic, coagulation, and vascular pathology”.
Finally, as a preliminary study in our patient with
vaso-occlusive retinopathy and lupus cerebritis rcquiring long-
term, intermittent plasmapheresis, one of us (DID) has tested
for thc presence (pre- and post-plasmaphcresis) of endothelial
immunorcactivity in the patient’s scrum at the time of a clinical