Childhood-Onset Systemic Lupus Erythematosus: Antiphospholipid Antibodies in 37 Patients and Their First-Degree Relatives

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Childhood-Onset

Systemic

Lupus

Erythematosus:

Antiphospholipid

Antibodies

in 37 Patients

and

Their

First-Degree

Relatives

Charles Molta, MD*; Olivier Meyer, MDX; Christine Dosquet, MD; Marcela Montes de Oca,

MDII;

Marie-Claude Babron, PhDII; Fran#{231}oiseDanon, MD9[; C#{233}cileKaplan, MD#; Sylvie Cl#{233}menceau#;

Fran#{231}oise Castellano#; and Micheline Levy,

MDII

ABSTRACT. Objective. Antiphospholipid antibodies

(aPL) are noted with increased frequency in patients with systemic lupus erythematosus (SLE). The main manifes-tations found to be associated with aPL are arterial and venous thrombotic events, thrombocytopenia, and recur-rent pregnancy loss This study is an attempt to define the

incidence of aPL in patients with childhood-onset SLE

and in their relatives and to correlate their presence with clinical manifestations, and especially, to evaluate the risk of thrombosis in aPL-positive subjects.

Methodology We studied 37 unrelated patients and 107 of their first-degree relatives. VDRL, IgG and 1gM

anticardiolipin, and IgG antiphosphatidylethanolamine

antibodies were studied in all probands during periods of clinical remission and in first-degree relatives at the time of interview. Lupus anticoagulant had only been studied in probands during an SLE flare-up.

Results. Thirty-eight percent of probands and 19% of relatives were positive for at least one aFL, with little over-lap between the different aPL studied. -No aPL-negative proband developed thrombosis. Two of the aPL-positive

probands had thrombotic events before testing, and a

third one showed thrombosis after testing. Only two pro-bands had high levels of IgG aCL and showed

thrombo-sis. The occurrence of aPL positivity in relatives was not

always related to its presence in probands. None of the

aPL-positive relatives had hadthrombosis, but recurrent

fetal loss was noted in one aPL-positive mother with SLE. Although there was a high frequency of SLE, SLE-like disease, auto-immune disorders or positive serological findings for lupus in first-degree relatives, many of these relativew did not test positive for aPL.

Conclusion. The high levels of IgG aCL may be con-sidered arisk factor for thrombosis. Findings in relatives

suggest a multifactorial origin for autoimmune disease

and antibody production. Pediatrics 199392:849-853;

sys-temic lupus erythematosus, antiphospholipid antibodies,

anticardiolipin, lupus anticoagulant, VDRL test, relatives.

ABBREVLATIONS. aPL, antiphospholipid antibodies; LAC, lupus anticoagulant; aCL, anticardiolipin antibodies; aPEA, antiphospha-tidylethanolamine; SLE, systemic lupus erythematosus; ANA, an-tinuclear antibodies.

From *the Division of Rheumatology Kaiser Permanente, Cleveland, OH;

jService de Rhumatolologie, H#{244}pital Universitaire Bichat, Paris, France;

§Laboratoire d’Immunologie, Hopital Universitaire Lariboisi#{232}re, Paris; Ilunitede Recherches d’Epidemiologie Gen#{233}tique,INSERM U 155, Paris;

#{182}Laboratoire d’Immunologie et d’Histocompatibilit#{233}, H#{244}pitalUniversitaire

Saint-Louis, Paris; and #Service d’Immunologie Leuco-plaquettaire,

Insti-hit National de Transfusion Sanguine, Paris.

Received for publication Sep 1,1992; accepted Jul 23, 1993.

Acad-emy of Pediatrics.

Phospholipids constitute a diverse family of

mol-ecules, and certain stereochemical patterns are

ca-pable of eliciting autoantibody production.

Antiphos-pholipid antibodies (aPL) have generated great

interest due to their increased association with

throm-botic (both arterial and venous) events,

thrombocy-topenia, and recurrent fetal loss.’2 Other

manifesta-tions such as hemolytic anemia and cutaneous

manifestations may also associate with aPL.

Com-monly ordered assays for aPL include the lupus

an-ticoagulant (LAC), the anticardiolipin antibodies

(aCL), and the serological test for syphilis, which

pro-duce overlapping positivities that have not been fully

categorized. Lupus anticoagulant, an in vitro

anomaly of the clotting cascade, is believed to be the

result of an IgG aPL. The various standard aCL tests

are now performed by enzyme-linked

immunosor-bent assay, and each isotype (IgG, IgA, and IgM) has

been associated with different clinical entities. Less

has been reported concerning antibodies to

phospho-lipids other than cardliolipin, although thrombosis has

been noted in a patient with LAC and antibody

re-acting with antiphosphatidylethanolamine (aPEA).3

The serological test for syphilis is the result of

cross-reactivity of patient autoantibodies with the VDRL

substrate, which is a complex mixture of cardiolipin,

phosphatidylcholine, and cholesterol.

Antiphospholipid antibodies have been reported in

adult patients with systemic lupus erythematosus

(SLE), with as many as 44% testing positive for a given

aCL.4 In the pediatric SLE population, IgG and IgM

aCL have been reported in 50% of children tested.5

This study looked at 37 unrelated patients with

childhood-onset SLE and 107 of their first-degree

rela-tives in an attempt to define further the incidence of

aPL of different types (LAC, VDRL, IgG and IgM aCL,

and IgG aPEA) in this population. The results are

re-ported as a function of clinical and serological

asso-ciations.

SUBJECTS AND METHODS

In 1986, we began a collaborative study of patients who fulfilled the American College of Rheumatology criteria for SLE,6 as well as the following conditions: patients admitted to hospitals in Paris, France, or its immediate suburbs, in whom the disease was diag-nosed before age 16 and between January 1975 and 1987. Drug-induced disease was excluded. Of the 120 SLE patients who ful-filled these conditions, 12 had had single or recurrent thrombotic episodes.8

We studied 37 unrelated patients (28 females, 9 males, average age at onset = 112 years) solely selected on the basis of family’s willingness to participate in a study on SLE. Twenty-seven of the

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children were European whites, and of these 19 were of French descent (defined as having French parents and grandparents). Four children were Algerian, 3 European-Algerian, I black from Guadeloupe, 1 European-Asian, and 1 Asian. After informed con-sent was obtained, history was elicited and physical examination was performed on all available subjects. First-degree relatives were interviewed by one of us (M.L.) with particular attention to the presence of SLE, other autoinimune disorders, thrombotic manifestations, and spontaneous abortions. Sera from 107 (36 mothers, 33 fathers, 19 sisters, and 19 brothers) of the 125 first-degree relatives were drawn at the time of interview.

Lupus anticoagulant results were obtained only for the pro-bands, during their hospitalization for an SLE flare-up; assays were performed in the hematology division of the proband’s ad-miffing hospital. If the initial activated partial thromboplastin time was prolonged, LAC was specifically studied. The test was

con-sidered positive if a prolonged activated partial thromboplastin time was not corrected by mixing 1:1 citrated patient plasma and pooled, normal plasma. In most cases, LAC detection was done on several different occasions.

Serological tests for syphilis, aCL, and aPEA were performed in the Bichat and Lariboisi#{232}re University hospital laboratories. On the same sample, assays for antinuclear antibodies (ANA) and for anti-dsDNA antibodies were performed. All of these samples were drawn during periods of clinical remission for the probands and at the time of interview for the first-degree relatives. Serologi-cal tests for syphilis were performed by VDRL using a standard commercial method (Bio Diagnostics, Paris, France). Testing for aCL and aPEA was by solid-phase immunoenzymatic assay. Briefly, 30 pL of 5% phospholipid (Sigma Chemical Co., St Louis,

MO) was placed into all Dynatech microtiter plate wells except those used as internal controls. Vacuum evaporation, at 40#{176}Cfor 45 minutes, was followed by blocking with phosphate-buffered saline-bovine serum albumin at 1% (1 hour at 37#{176}C).Each sample was incubated 2#{189}hours at 20#{176}C,then washed three times with the diluting buffer. Fifty microliters of either IgG or 1gM peroxidase (ThM Microwell Peroxidase Substrate System) was added to each well and incubated for I hour at 20#{176}C,followed by washing with phosphate-buffered saline-bovine serum albumin. Developer

so-lutions were mixed immediately before use and 100 mL of

devel-oper was quicidy added to each well, followed (after a 7-minute incubation period) by addition of 100 pL of 2.5 N sulfuric acid. Reading of the plate was then performed as soon as possible using a Dynatech MR580 MicroElisa autoreader with a wavelength set at 420 A. Standard deviations were calculated based on 50 normal control subjects, drawn randomly from a healthy donor popula-tion at the University Hospital blood bank; samples were consid-ered positive if they were greater than 2.76 SD above controls.

Samples tested for ANA were determined by indirect immu-nofluorescence on rat liver sections. Anti-dsDNA antibodies were detected by radioimmunoassay using the Farr method and by indirect immunofluorescent testing on Crithidia luciliae. HLA-A,

-B, -DR antigens were defined by standard methods of lympho-cytoxicity.9’#{176} Genetic analysis was performed according to the method developed by Field et al.”

Distribution of aPL

RESULTS

At least one of the aPL was found in 14 (38%)

pro-bands and 20 (19%) first-degree relatives (Table 1).

Three of the 37 probands tested positive for LAC, and

in all cases subsequently had other positive aPL

find-ings. One additional patient had prolonged kaolin

cephalin clofting time, but the presence of LAC had

not been sought. There was little overlap between the

different aCL and aPEA tested. No sera tested

posi-five for all three antibodies. aCL and aPEA titers

ranged from 0 to 11 SD (1.28 ± 1.51 SD for 1gM aCL,

5.33 ± 3.2 SD for IgG aCL, and 1.8 ± 2.2 SD for IgG

aPEA). Among the probands, 7 (19%) of 37 tested

positive for aCL. Levels greater than 5 SD were noted

in 2 probands for IgM aCL, 2 probands for IgG aCL,

and I proband for IgG aPEA. None of the first-degree

relatives had levels greater than 5 SD for 1gM aCL.

One father had IgG aCL equal to 5 SD. Two fathers,

2 mothers, and 2 sisters had IgG aPEA levels greater

than 5 SD.

Parents had positive aPL titers more frequently

(al-though not significantly) than probands’ siblings (17

vs 3), with fathers and mothers being equally

repro-sented. Few siblings tested positive, and all

aPL-positive results were found in the sisters of the

pro-bands. First-degree relatives testing positive were

generally unrelated, except for three

mother-daughter pairs and one mother-father pair (found to

be first cousins) (Table 2). In 9 families, aPL positivity

was detected only in the probands and in 15 other

families, only in the relatives. Positive test results in

both the probands and in at least one first-degree

rela-tive were found in 5 families (Table 2). Except for 2

families in which IgG aPEA was found in both the

proband and one parent, there was no relationship

between a positive isotype in probands and relatives

in other families. In 3 families, the proband was aPL

negative, but 2 relatives had positive test results.

TABLE 1. Distribu tion of Positive Results in Pro bands and First-Degree Relatives

Lac Positive Tests* Probands

Female Male

(n = 28) (n = 9)

First-Degree Relatives

aCL/aPEA VDRL Mother

(n = 36)

Father (n = 33)

Sister (n = 19)

Brother (n = 19)

LAC + IgG aCL + IgG aPEA + VDRL it

LAC #{247}IgG aPEA It

Prolonged KCCT #{247}IgG aCL I

LAC

IgG aCL + IgG aPEA IgMaCL+IgGaCL IgGaCL 1gM aCL IgMaCL

1gM aCL + IgG aPEA IgGaPEA + VDRL + VDRL + VDRL VDRL I 1 I 3 1 1 2 1 I I 3 4 I 1 I 5 I 2

Total 10 4 9 8 3 0

*Abbreviations: LAC, lupus anticoagulant; KCCT, kaolin cephalin dotting time; aCL, anticardiolipin antibodies; aPEA, antiphospha-tidylethanolamine.

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TABLE 2. Multiple aPL Positivity in Members of Eight Families*

Patient No. Positive Tests Mother Father Sister

aPL-positive probands

It LAC + IgG aPEA IgG aPEA

2 IgG aCL IgG aPEA IgG aPEA

3 1gM aCL IgG aPEA

4 IgG aPEA 1gM aCL

5 IgG aPEA 1gM aCL

+ IgG aPEA aPL-negative probands

6 1gM aCL 1gM aCL

+ IgG aPEA

7 1gM aCL IgG aPEA

8 IgG aCL IgG aPEA

*Abbreviations: aPL, antiphospholipid antibodies; LAC, lupus anticoagulant; aPEA, antiphosphati-dylethanolamine; aCL, anticardiolipin antibodies.

t Thrombotic event before testing.

:j:Thrombotic events after testing.

In the first-degree relatives of the 14 aPL-positive

probands, aPL positivity was found in 2 of 14

moth-ers, 3 of 13 fathers, I of 3 sisters, and 0 of 7 brothers.

In the families of the aPL-negative probands, aPL

positivity was found in 7 of 22 mothers, 5 of2O fathers,

2 of 16 sisters, and 0 of 12 brothers. When the number

of aPL-positive first-degree relatives was compared

between families of aPL-positive and aPL-negative

probands, we found no difference.

No significant association between aPL and

HLA-A, -B, -DR was found in probands, when

con-sidered collectively, or separately as in the group of

European whites.

Clinical Associations With aPL

Among the aPL-positive probands, two had had

thrombotic events associated with LAC before testing

and a third showed thrombosis after testing. The first,

a boy, had two episodes of lower extremity venous

thrombosis I and 7 years after onset of his SLE. He

was found to be positive for LAC. He subsequently

had a severe vasculitis marked by necrosis of the

ex-tremities. The second, a girl, had deep and superficial

iiofemoral venous thrombosis at onset. When tested

8 and 2 years, respectively, after disease onset during

a period of clinical remission, they were both positive

for IgG aPEA; the girl also had a positive VDRL as

well as the highest titer of IgG aCL of the series (+ 11

SD). The third patient, a girl, had a prolonged Kaolin

cephalin clotting time at onset. When tested 7 years

after onset, she was strongly positive for IgG aCL (+7

SD). She had one episode of superficial and deep

lower extremity venous thrombosis 5 years later. IgG

aCL was again found at the time of the thrombosis,

whereas VDRL and LAC remained negative. The

three other patients with high levels of 1gM aCL or

IgG aPEA did not show any thrombotic

manifesta-tion. The girl with the highest level of 1gM aCL (+10

DS) had a first cousin with the antiphospholipid

syn-drome (venous thrombosis and pulmonary

embo-lism).

Eight of the probands had had thrombocytopenia.

One was the boy described above. Three other

pro-bands with thrombocytopenia had positive aPL,

al-though not for any specific isotype (one for VDRL,

one for 1gM aCL, and one for IgG aPEA). Two

pro-bands had hemolytic anemia, one of whom also had

thrombocytopenia; neither, however, tested positive

for any of the aPL studied.

First-degree relatives had a high frequency of

cmi-cal abnormalities such as SLE (one mother, one sister),

SLE-like disease (one father, two sisters, one brother),

chronic arthritis with anti-dsDNA (one sister), and

discoid lupus (two fathers). Three mothers, three

fa-thers, and one sister had positive ANA or

anti-dsDNA findings without clinical manifestations of an

autoimmune disorder. In addition, five mothers and

one sister had photosensitivity, Raynaud’s

phenom-enom, or chorea. Three mothers and one father had

hyperthyroidism, hypothyroidism, or multiple

scle-rosis. Most of these relatives did not test positive for

aPL. However, in one family, IgG aCL was found in

a proband’s mother, who had had four spontaneous

abortions and SLE, and IgG aPEA was found in the

father, who had positive serological findings for

lu-pus (as previously mentioned, they were first

cous-ins). In another family, 1gM aCL was found in the

mother with Raynaud’s, and both 1gM aCL and IgG

aPEA were found in the proband’s sister, who had

positive serological findings for lupus. One father

with discoid lupus tested positive for VDRL, IgG aCL,

and IgG aPEA. He had the highest levels of IgG aPEA

(+9.7 SD) and was the only one to show IgG aCL (+5

SD). Lastly, IgG aPEA was found in three of the

pro-bands’ mothers, one with SLE-like disease, one with

positive serological findings for lupus, and one with

hyperthyroidism. None of the first-degree relatives

had a significant history of thrombocytopenia and

he-molytic anemia. Of the 107 first-degree relatives, one aPA-negative father had had a thrombosis

(pulmo-nary embolism). Only one aPA-positive mother with

SLE (already mentioned) had had recurrent fetal loss.

DISCUSSION

Antiphospholipid antibodies of various isotypes

occur in less than 2% of the normal adult population,

in almost 12% of the elderly, and in 23% of elderly

subjects who also test positive for ANA (without

cmi-cal symptoms of an autoimmune disorder).12

Anti-bodies have been detected in numerous rheumatic

and nonrheumatic disease rheumatic and

nonrheu-matic diseases, but the significance of these findings

(4)

needs further study. The frequency of aPL positivity

in SLE patients depends on the patients selected and

the antibodies studied. The variability of the results is

also due to the cutoff values. In 1990, Love and

San-toro,4 who reviewed 29 published series (comprising

1000 patients with SLE), found the overall incidence

of LAC to be 34% and that of aCL to be 44%. Vianna

et al,3 who have considered only positive values

ex-ceeding 5 SD, found an overall prevalence of 14% in

a series of 95 patients with SLE.

In the childhood-onset SLE population, only the

in-cidence of IgG and 1gM aCL has been reported (50%

overall), but far fewer children than adults have been

studied.5 We found that 7 (19%) of 37 patients were

positive for either IgG or 1gM aCL, a proportion

ap-preciably less than that found in the adult population;

this finding may be consistent with the natural

ten-dency for autoantibody positivity to increase with

age. The frequency of aPL positivity approached 38%,

however, when we tested for other aPL such as the

LAC, VDRL, and IgG aPEA. Serial measurements

were not performed in the proband to test the

hy-potheses that fluctuations in aCL titers occur with

dis-ease activity’4 or that subgroup changes occur in the

same subject over time.’5 Autoantibody results in

pro-bands were potentially influenced by the fact that the

sera were obtained during a period of clinical

remis-sion. It has been shown that patients with active SLE

are more frequently positive for aCL, and at higher

titers, than those with inactive disease)

The frequency of thrombotic events was first noted

in SLE patients by Bowie et al,’6 and later studies

im-plied that SLE patients with aPL have a significantly

higher incidence of thrombosis when compared with

SLE patients in general (46% vs 4.5% to 18%).’ A

tem-poral association between thrombosis and aPL

1ev-el&8 as well as a subset of thrombosis-prone SLE

pa-tients with consistently high aPL titers have been

noted.’9 The present study revealed a 21 % incidence

of thrombotic events in the aPL-positive probands,

but we are unable to comment on the temporal

rela-tionship between fluctuations in aPL titers and

throm-bosis. None of the aPL-negative probands had similar

events. It has been shown recently that SLE patients

with thrombosis are characterized by the presence of

anti-32 glycoprotein I antibodies associated with aCL

or LAC.2#{176}Therefore, the presence of such antibodies

may be of interest in evaluating the risk of thrombosis

in patients with SLE. Although the mechanisms of

action of aPL are still unclear, the presence of aPL, and more specifically the high levels of IgG aCL, should

be considered a risk factor for thrombosis and

abor-tions in SLE patients. In this study, one girl, strongly

positive for IgG aCL, subsequently developed lower

extremity venous thrombosis. The prophylactic

treat-ment of aPL-positive patients is still a matter of

dis-cussion.2 Moreover, aPL-positive patients who have

had thrombosis or abortions are at higher risk for

de-veloping such clinical events in the future)3

IgG aPEA positivity (in the absence of aCL

posi-tivity), associated with LAC and thrombosis, has

been reported in one patient with SLE as an

ex-ample of the lack of overlap sometimes found in

aPL tests.3 One of our probands presented a similar

picture of multiple thrombotic events, being positive

for aPEA and LAC and not for the presence of the

more frequently tested aCL.

First-degree relatives have been reported to have an

increased incidence of aPL positivity, with 8

(7.9%) of 101 testing positive for IgG or 1gM aCL.2’

Our results are in agreement with these findings if one

considers IgG or 1gM aCL (9/107 or 8.5% positive),

but aPL positivity increases to 19% (20/107) if

addi-tional aPL groups are sought. Mackworth-Young et

al2’ also noted that 3 of 22 families had aPL positivity

in both the proband and atleast one of the first-degree

relatives and that in 5 other families, first-degree

rela-tives were aPL positive whereas the proband was not.

We found 5 of 37 families where aPL positivity was

present in both the proband and at least one of the

first-degree relatives. Additionally, we noted the

presence of aPL positivity in 3 other families where

two relatives tested positive in the absence of

posi-tivity in the proband. In case of multiple positivity

in a family, the same isotype was not necessarily

found. The presence of aPL positivity in an affected

patient, however, does not appear to imply that

family members are at an increased risk of

produc-ing these antibodies.

The occurrence of SLE or SLE-like disease in

first-degree relatives of SLE patients has been estimated to

be 10% to 12%? In the present study, we found that

approximately one quarter of the first-degree

rela-tives had SLE, SLE-like disease, discoid lupus,

symp-toms suggestive of an autoinimune disorder, or

iso-lated, positive ANA or anti-dsDNA. Only eight

first-degree relatives tested positive for aPL. Many of

the aPL-positive relatives did not have symptoms of

autoimmune disease, and longer follow-up could

possibly allow further disease manifestations to

ex-press themselves. This seems unlikely, however, since

isolated antibody positivity (without clinical

symp-toms) was found more often in parents than in the

younger siblings. Thus, production of certain

sub-groups of aPL may be age related, and not of

long-term significance. The lack of concordance between

aPL positivity in relatives and probands from the

same family is of interest and suggests a

multifacto-rial origin for autoimmune disease and antibody

production.

ACKNOWLEDGMENTS

This study was funded by Mutuelle G#{233}n#{233}ralede l’Education Nationale (contract 3926, Paris, France).

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BROKERS FOR SURROGATE BIRTHS RULED LIABLE IN CASE ABOUT

SEXUAL DISEASE

“Baby brokers” who arrange surrogate births are responsible for protecting

parents and offspring from sexually transmitted diseases, a federal appeals court

ruled...

The ruling, the first from a federal appeals court to address the liability of people

who arrange surrogate births, involves a 1982 surrogacy attempt in Michigan. The

surrogate mother alleges that she caught cytomegalovirus, which is similar to

herpes, from the sperm donor. The child was born with mental retardation, hearing

loss and severe neuromuscular disorders linked to the virus.

As a further complication, the surrogate mother had sexual intercourse with her

husband around the time she was injected with the donor’s sperm. The child

turned out to be the son of the surrogate and her husband, not the donor.

Woo J. Brokers for surrogate births ruled liable in case about sexual disease. The Wall Street Journal.

September 17, 1992.

Noted by J.F.L., MD

(6)

1993;92;849

Pediatrics

Micheline Levy

Babron, Françoise Danon, Cécile Kaplan, Sylvie Clémenceau, Françoise Castellano and

Charles Molta, Olivier Meyer, Christine Dosquet, Marcela Montes de Oca, Marie-Claude

Patients and Their First-Degree Relatives