(G 1991 Harwood Academic Publishers GmbH
Autoimmunitv. 1991, Vol. 9. pp. 69-75 Reprints available directly from the publisher Photocopying permitted by license only
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THE 'PRIMARY' ANTIPHOSPHOLIPID SYNDROME: ANTIPHOSPHOLIPID ANTIBODY PATTERN AND CLINICAL FEATURES OF A SERIES OF 23 PATIENTS JOSEP FONT, ALFONS LOPEZ-SOTO, RICARD CERVERA, JOAN BALASCH'. LUCIO PALLARES, MARGARITA NAVARRO, XAVIER BOSCH and MIGUEL INGELMO
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Svsiemic Auioimmunc Diseases Research Group, Department of Internal Medicine. 'Department of Obstetrics and Gynaecology. Hospiial Clinic i Provincial, Barcelona, Spain (Received October I . 1990; in final form November 20, 1990)
Twenty-three patients with the 'primary' antiphospholipid syndrome were studied over 2-6 years. Twentytwo (96%) had antiphospholipid antibodies detected by ELISA (87% had antibodies to thromboplastin and 70% to cardiolipin). and I8 out of the 21 tested patients (86%) had lupus anticoagulant activity by coagulative assays. Mean age of the cohort was 29.9 years and the sex ratio (fema1e:male)4.75:l. Eleven patients presented 18 venous and/or arterial thrombosis and 13 had 25 foetal losses (84% occurred during the second and third trimester). Other clinical features were migraine, livedo reticularis, and epilepsy. Three patients had relatives with systemic lupus erythematosus. Thrombocytopaenia was seen in 33%. antinuclear antibodies in low or moderate titre in 30%, and haemolytic anaemia in 13%. During the follow-up, two patients presented recurrent thrombosis despit anticoagulant therapy, one of them dying because of recurrent pulmonary thromboembolism. Four patients achieved successful term pregnancies after treatment with aspirin and a further patient after treatment with aspirin and low dose prednisolone. No patient developed systemic lupus erythematosus or any other definable connective tissue disease. The 'primary' antiphospholipid syndrome may exist as a distinct clinical entity and all younger patients presenting with thrombotic events, foetal losses and/or thrombocytopaenia, without any evidence of a well defined disease, should be tested for antiphospholipid antibodies in order to rule out this syndrome. KEY WORDS: Anticardiolipin antibodies. lupus anticoagulant, thrombosis, foetal loss.
A syndrome consisting of repeated episodes of thrombosis and/or recurrent foetal loss, associated with raised levels of antiphospholipid antibodies is now the subject of considerable attention'-'*. In addition, features such as thrombocytopaenia, haemolytic anaemia, and several neurological disorders have occasionally been related to this ~yndrorne'~.'~. First recognized in patients with systemic lupus erythematosus'* and later in other rheumatologic and non-rheumatologic conditions'', it is now well known that the association of these antibodies with such clinical events may be independent of any underlying disease. The term 'primary' antiphospholipid syndrome has been introduced as a means of categorizing and studying these patients who
do not have any features of systemic lupus erythematosus or any other well defined disease'"''. Among the diversity of antiphospholipid antibodies, those directed against cardiolipin received a greater attention due to their sensitive, reproducible and reliable detection by enzyme linked immunosorbent assay (ELISA)". Several studies suggest that these antibodies are closely related to the lupus anticoagulant activity"," detected by coagulation assays. However, some patients have anticardiolipin antibodies without evidence of lupus anticoagulant activity, and vice versa". In order to avoid the cumbersome and laborious procedure to detect 'the lupus anticoaguland activity, several a ~ t h o r s ' ~ have .'~ proposed the use of an ELISA technique using thromboplastin as antigen and have found a good correlation with lupus anticoagulant activity. In this sutdy, we present data on a cohort of 23 patients who had one or more episodes of thrombosis and/or foetal losses, associated with raised levels of antiphospholipid antibodies, detected by ELISA techniques and coagulation assays, in absence of any definable underlying connective tissue disease.
Address reprint request to: Josep FONT, M.D. Servei de Medicina lnterna General. Hospital Clinic i Provincial. Villarroel, 170. 08036-Barcelona. SPAIN. Supported in part by Grant DGICYT PM 89-0108 from the Ministerio de Educacion y Ciencia (Spain). X. Bosch, MD. is a Research Fellow sponsored by a grant from the Hospital Clinic i Provincial of Barcelona. 69
70
J . FONT
PATIENTS AND METHODS
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Pa tien ts
Twenty-three patients were selected on the basis of the presence of one or more episodes of thrombosis (1 1 cases) and/or foetal losses (1 3 cases), together with antiphospholipid antibodies (antiphospholipid syndrome). They were attending the Departments of Internal Medicine or Obstetrics and Gynecolocy at our hospital during the last six years. Individuals attending both departments were routinely tested for antiphospholipid antibodies if the clinical features suggested that these may be elevated. All had medical, family, social and environmental histories taken and underwent routine physical examination. None of these patients had systemic lupus erythematosus. according to the American Rheumatism Association revised criteria’5. The mean follow-up after diagnosis of the antiphospholipid syndrome was 2.98 -i- 1.41 years (range 2 to 6). The diagnosis of venous thrombosis was based on clinical presentation and confirmed by venogram. One patient with clinical and arteriographic features of obliteration of the left superficial femoral artery and another one with clinical, electrocardiogram, and laboratory evidence of myocardial infarction, were defined as having arterial thrombosis. The term ‘foetal loss’ used here included spontaneous abortion, missed abortion and foetal death in any part of the pregnancy. Patients with a history of foetal loss were routinely screened for systemic diseases, diabetes mellitus, thyroid dysfunction, chromosome abnormalities in a parent, uterine abnormalities, and endometrial and hormonal luteal phase defects.
ei a /
consisting of a low (3-5 SD), moderate (5-7 SD), and high ( > 7 SD) titer. Patients were included in this study if the antiphospholipid antibodies remained positive on at least two occasions separated by a minimum interval of eight weeks. Lupus anticoagulan t act i v i t j -
The following tests were carried out in all patients (except in two who were on antiocagulant therapy) to detect lupus anticoagulant activity. according to the methods previously reported”.’*: prothrombin time, activated partial thromboplastin time, kaolin clotting time, diluted Russell’s viper venom time and tissue thromboplastin inhibition test. The reagents used were: rabbit brain thromboplastin (Symplastin, General Diagnostics) for prothrombin time and tissue thromboplastin inhibition test bovine thromboplastin (Thrombofax. Ortho Diagnostics) for dilute Russell‘s viper venom time and platelet factor 3 plus activator from rabbit brain tissue (Automated APTT. General Diagnostics) for activated partial thromboplastin time. The positive value for every coagulation test was defined as greater than 3 SD above the mean normal value of the control group. In order to rule out a deficit in a coagulation factor, each assay was also performed with a mixture of patient’s and control plasma ( l / l ) , vol/vol). Patients were considered to have lupus anticoagulant when at least two of these assays were shown to be positive. Serological test for syphilis
A macroscopic rapid plasma reagin (RPR, Kinckerbocker) was used in a 18 mm circle card test.
Determination of antiphospholipid antibodies
Other 1aborator.y studies
IgG and IgM anticartdiolipin antibodies were measured by ELISA as described by Gharavi et al.”, with minor modifications of our own8. Control serum samples from 100 normal blood donors were used to standardise the assay. The final value of the results was considered after correction by substraction of non-specific binding to uncoated wells. Results were expressed as negative, low, moderate and high positive. according to recommendations of the recent workshop on standardization of the anticardiolipin antibody test26. The ELISA for thromboplastin was performed according to a method previously reported by 11~’~. Results were expressed as binding index. A positive value was defined as binding index greater than 3 standard deviations (SD) above the mean of 150 normal subjects. In addition, the positive patients were arbitrarily divided into three subgroups
Antinuclear antibodies were determined by indirect immunofluorescence with mouse liver as substrate. Anti-double-stranded DNA antibodies were determined by Farr’s ammonium sulphate precipitation technique. Antibodies to extractable nuclear antigens (Ro, La, U-nRNP, and Sm) were detected by counterimmunoelectrophoresis”. Antineutrophil cytoplasm antibodies were detected using an indirect immunofluorescence assay on ethanol-fixed neutrophils3”.Complement components (C3, C4) were estimated by radial immunodiffusion and CH50 by Lachmann and Hobart’s haemolytic technique3’. RESULTS Antiphospholipid antibod?. pattern
Twenty-two out of 23 patients (96%) had antiphospholipid antibodies detected using ELISA: 20 (87%)
‘PRIMARY’ ANTIPHOSPHOLIPID S Y N D R O M E Table I
Description of phospholipid reactivity patterns in 23 patients with primary antiphospholipid syndrome. Porirnr n.
I 2 3 4
5 6 7 8 9
10
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II I? 13 14 I5 16 17 18 19
20 21
-33
23
uTPA
UCL IgG
lgM
IgG
kM
-
-
+++
-
+++ ++
++ -
++ -
+++ ++ +++ +- + +
-
+
+++ ++
+++ +t
++
++ -
+
+++ ++ +++ ++ -
-
-
-
+ + + +
-
-
-
+
++
-
-
-
-
+++
-
++
++
++
++ ++
-
-
+++ +
++
-
-
+ +++ ++
-
++
+ +
+
+- +
-
RPR
+ + +
-
+++
LA
-
++ -
++ -
-
ND -
+
-
+
-
+
+
+ + + + + + +
-
ND -
-
-
aCL = anli-cardlolipin antibodies: aTPA = anti-lhromboplaslin antibodies; LA = lupus anticoagulant. R P R = rapid plasma reapin: ND = no1 determined. + = low positive: + + = moderatc powive: + + + = high positive.
were positive for thromboplastin and 16 (70%) for cardiolipin. Titres ranged from moderate to high levels in most (Table I). Eighteen out of 21 patients (86%) were found to have lupus anticoagulant activity. All but one (case no. 17) had antibodies against thromboplastin and 11 had antibodies against cardiolipin. Only 3 patients ( 1 3%) had biological flase positive standard tests for syphilis as detected by RPR technique. Clinicul jindings
Mean age ( k S D ) of the entire cohort was 29.96 k 8.42 years (limits: 22-55). Nineteen patients were female and 4 were male (ratio: 4.751). Eleven patients (7 female and 4 male) presented 18 thrombotic events (Table 2). They cosisted of deep vein thromboses (9 cases) affecting both upper and lower extremities, pulmonary thromboembolism (4 cases). portal ( I case), mesenteric ( I case) and brain sinus ( 1 case) thromboses. The deep vein thromboses were often multiple. Arterial occlusions were present in only 2 patients. They consisted of peripheral arterial thrombosis and myocardial infarction. Thirteen patients experienced a total of 25 episodes of foetal loss (Table 3) with a mean of 2.33 k 1.95 (range 1 to 8) per patient. Only two of these patients
71
had a normal pregnancy. Twenty-one (84%) episodes of spontaneous foetal loss occurred during the second and third trimester and 4 (16%) during the first trimester of pregnancy. All patients with foetal losses were positive for lupus anticoagulant and had antibodies against thromboplastin, but only 8 had antibodies against cardiolipin, mainly of the IgG isotype. Standard tests for foetal loss were normal in all except two patients who presented a delayed ovulation. Other clinical manifestations were livedo reticularis (1 case), migraine ( I case) and epilepsy ( I case). No murmurs or any other clinical manifestation suggesting heart valve lesions were detected. No history of autoimmune hypothyroidism, skin vasculitis, or any other related immunological disorder was present. Family history disclosed that 3 (13%) patients had relatives with systemic lupus erythematosus. Laboratory findings
The laboratory findings of the 23 patients are documented in Table 4. Thrombocytopaenia (platelet count lower than 100 x lO’/l on two occasions at least two weeks apart) was the most common laboratory feature, evident in 8 patients (35%). Haemolytic anaemia (positive Coombs’ test associated with low level of haptoglobin and reticulocytosis) was present in 3 (13%) patients. Seven patients (30%) had antinuclear antibodies varying from low positive titre ( < 1:50) in 4 cases to moderately elevated ( 1 : 100) in 3 . Anti double-stranded DNA antibodies. antibodies to extractable nuclear antigens, antineutrophil cytoplasm antibodies and rheumatoid factor were not demonstrable in any patient. Complement components were normal in all cases. No significant correlation was found between the class and/or isotoype of antiphospholipid antibodies and any other clinical or immunological feature. The main clinical and laboratory features of the series are summarized in Figure I . Therapy and follow-up
All patients with thrombosis received anticoagulant therapy. However, one patient presented recurrent thrombotic events despite anticoagulant therapy and another patient died because of recurrent pulmonary thromboembolism complicated with pulmonary hypertension and chronic respiratory failure. Seven patients with recurrent foetal loss received aspirin ( 100 mg/day) from one month before attempting pregnancy and this was maintained until delivery in pregnant women. Clomiphene citrate (50 mg/day/5 days) was added in the two patients with
72
J . FONT et a/.
Table 2 Thrombotic events: Descriptions of patients affectwed with reference to antiphospholipid antibodies Patient
Age
aCL
aTPA
LA
RPR
n.
+ +
29 39 5s 32 2s 29 22 51 22 24 32
1
2 5 6 7 10
13 15 16 17
20
+
ND -
+ +
ND
-
+ +
Descriptions of thrombosis
DVTs, AM1 DVTs. PE DVTs Portal + mesenteric DVTs DVTs DVTs DVTs, PE Brain sinus DVTs. PE DVTs, PE, femoral artery
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aCL = anti-cardioltpin antibodies: aTPA = anti-thrornboplastin antibodies: LAS = lupus anticoagulant; RPR = rapid plasma reapin: DVT = deep venous thrombosis; acute myocardial infarction: PE = pulmonary embolism; ( - 1 = negative test: ( + I = positive test: ND = not determined AM1
-
delayed ovulation. Four patients achieved successful term pregnancies. One woman presenting with chorioamnionitis and sepsis due to a group B streptococcus at 29 weeks’ gestation had an intrauterine foetal death. However, this patient achieved successful term pregnancy after treatment with aspirin (100 mg/day) and prednisolone (1 5 mg/day). The remaining two aspirin-treated patients are not yet pregnant. None of the patients developed systemic lupus erythematosus or other well defined connective tissue disease during the follow-up.
DISCUSSION In this paper we have examined the clinical and serological characteristics of a series of a highly selected and specific group of patients attending our Hospital. All these patients were selected because of the presence of Table 3 Description of patients with fetal loss with reference to antiphospholipid antibodies ~
Patient n.
7
3 4 8 9 II I2 14 18 19
21 17
&_
’3
Age
39 28 25 28 23 28 28 24 36 30 29 26 24
CL
~~
TPA LA
+ + + + + + + + + + + + +
RPR
Details o$,frtal loss’
+ + -
aCL = anti-cardiolipin antibodies. aTPA = anti-throbmoplasun antibodies: LA = lupu\ anticoagulant: RPR = rapid plasma rcagin *numhcr of fetal loss irnonthb of prcpnancy at which fetal loss occurredl &patiems with lwc childr. one in each CdSC
antiphospholipid antibodies and a group of clinical manifestations considered as major clues for the diagnosis of the antiphospholipid syndrome, namely venous and/or arterial thrombosis and foetal l o ~ s e s ~In~ -all ~ ~cases, . systemic lupus erythematosus was excluded according to the American Rheumatism Association revised criteria2’ and no other diagnosis was possible during a follow-up ranging 2 to 6 years. Seventeen of these patients fulfilled the previously defined criteria for ‘primary’ antiphospholipid syndrome”. The remaining 6 patients only had a single foetal loss and thus should be considered as having a probable ‘primary’ antiphospholipid syndrome. To the most common clinical features of our group of patients were recurrent foetal loss and venous and/ or arterial thrombosis. Preliminary studies have found antiphospholipid antibodies in up to 30% of an unselected population of women with repeated and in up to 20% of young patients with venous and/or arterial thrombosis who do not suffer from systemic lupus erythematosus or any other well delineated autoimmune disorder”. Some of our patients had features previously described but not clearly associated with raised levels of antiphospholipid antibodies, such as haemolytic I , livedo r e t i c u l a r i . ~ ~ ’migraine4’ ~, .anamemia8mo.3n~ and epipepsyI4. Despite the low prevalence of these features in our series, probably due to selection bias, it appears that our patients display a range of clinical features similar to those previously reported with the antiphospholipid syndrome. It is of interest that some of the patients with the ‘primary’ antiphospholipid syndrome have relatives with systemic lupus erythemtosus ( I 3%). Unfortunately, antiphospholipid antibodies could not be tested in the patients’ relatives. This familial aggregation seem to be related mainly to the class 111 of the major histocompatibility complex, and some relationship to systemic lupus erythematosus still seems to
'PRIMARY' ANTIPHOSPHOLIPID SYNDROME
73
I
T HROMEOTIC EVENTS
FETAL LOSS
THR(SMB0CYTOPENIA /A"A IHEMOLYTIC ANEMIA MIGRAINE LIVEDO RETICULARIS
EPILEPSY RELATIVES WITH SLE
0
20
60
40
80
100
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P E RCEN TAGE
Figure I
Summary of the main clinical and laboratory features of the series, expressed as percentage of the series.
loom in patients with this syndrome4. O.ther interestl), which is ing clinical features are the sex ratio (4.75: lower than that found in lupus patients (9:1)4' but in agreement with other series of patients with 'primary' antiphospholipid ~yndrome".'~.'~, and the younger age of our patients, most of them being less than 40 years of age. One patient of our series died because of recurrent pulmonary thromboembolsim complicated with pulmonary hypertension. The presence of pulmonary hypertension has been previously reported in patients
with the 'primary' antiphospholipid syndrome, both following repeated episodes of pulmonary thromboembolism and resembling the 'primary' idiopathic variety with clear lung fields and no evidence of t hrom boem bolism 19.20. Among the laboratory data, it is of note that thrombocytopaenia was found to be the most common feature. This raises the possibility of a pathogenic involvement of platelets in the mechanisms of production of the antiphospholipid syndrome". In addition, other striking immunological features in our
Table 4 Description of laboratory findings in 23 patients with primary antiphospholipid syndrome Patient
Thrombocympenia
Hemol. anemia
n.
1
2 3 4 5 6 7 8 9 10
II
12 13 14 15 16
ANA = antinuclear antibodies: ds-DNA = anti double-stranded D N A antibodies; ENAs = extractable nuclear anrisns antibodies: RF = rheumatoid factor
ANA
ds-DNA
ENAs
RF
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74
J. F O N T er a /
5. Harris EN. Gharavi AE. Boey ML. er a/. Anticardiolipin patients were haemolytic anaemia and antinuclear antibodies: detection by radioimmunoassay and association antibodies varying from low positive titre to with thrombosis in systemic lupus erythematosus. Lancer moderately elevated. These findings also suggest that 1983; 2 121 1-1214 many of these patients have a condition which is 6 . Glueck HI. Kant KS. Weiss MA. Pollack VE. Miller MA. Coots M. Thrombosis in systemic lupus erythematosus. related to systemic lupus erythematosus. Nevertheless, Relation to the presence of circulating anticoagulants. Arch none of our patients developed any well-defined Iniern Med 1985: 145: 1389-1395 disease during the follow-up. 7. C o l a ~ oCB. Male D K . Anti-phospholipid antibodies in There is a close relationship between the lupus antiSyphillis and a thrombotic subset of SLE: distinct profiles of coagulant activity and the detection of negatively epitope specificity. Clin ESJJImmunol 1985; 59: 449-456 8. Cervera R, Font J. Lopez-Soto A, er al. lsotype distribution of charged antiphospholipid antibodies using solid phase anticardiolipin antibodies in systemic lupus erythematosus. techniques".". Of interest is the recent description of Prospective analysis of a series of 100 patients. Ann Rheum Dis a small subgroup of patients with the antiphospholi1990; 4 9 109-1 13 pid syndrome who have only raised levels of anticar9. Harris EN. Chan JKH. Asherson RA. Aber VR, Gharavi AE. Hughes GRV. Thrombosis, recurrent fetal loss. and thromdiolipin antibodies or lupus anticoagulant activity", bocytopenia. Predicitive value of the anticardiolipin antibody as we have found in our series. In addition. although test. Arch Inrern Med 1986: 146 2153-2156 it is generally held that IgG antibodies are more 10. Petri M. Rheinschmidt M. Whiting-O'Keefe Q. Hellman D. closely associated with pathology, in a few cases only Corash L. The frequency of lupus anticoagulant in systemic IgM antibodies could be detected. According to these lupus erythematosus. A study of sixty consecutive patients by acitvated partial thromboplastin time. Russell viper venom findings, tests for the lupus anticoagulant as well as time. and anticardiolipin antibody level. .4nn Inrcrti Med 1987: the ELISA test for IgG and IgM antibodies against 106 524-531 cardiolipin must be carried out in all patients with I . Triplett DA. Brandt JT. Musgrave KA. Orr C A . The relationclinical features suggesting antiphospholipid ship between lupus anticoagulants and antibodies to phospphotipid. JAMA 1988; 2 5 9 50-554 syndrome. It is noteworthy that antibodies to 2. Lockshin MD. Druzin ML. Goei S, er a / . Antibodiy to carthromboplastin have the best correlation with lupus diolipin as a predictor of fetal distress or death in pregnant anticoagulant, as we had previously r e p ~ r t e d ? ~ . patients with systemic lupus erythematosus. N Enxl J Mcd Consequently, we suggest that this method could be 1985; 3 1 3 152-156 added to the laboratory screening for antiphospholi3. Khamashta MA, Cervera R. Asherson RA, rr ul. Association of antibodies against phospholipids pid antibodies. . . with heart valve disease in systemic lupus-erythematosus. Lancer 1990; 335: 154 I - I544 Finally, it should be noted that four patients 14. Asherson RA. Harris EN. Anticardiolipin antibodies. Clinical achieved successful term pregnancies after treatment associations. Pos/Rrad MedJ 1986: 62: 1081-1087 with aspirin and a further patient after treatment with 15. Manoussakis MN. Gharavi AE. Drosos AA. Kitridou RC. aspirin and low dose prednisolone. However. a correct Moutsopoulos H M . Anticardiolipin antibodies in unselected autoimmune rheumatic disease patients. Cliri Immutiol Iniappreciation of the apparently beneficial effect of 1987; 44:297-307 aspirin and/or prednisolone would require a 16. munoparhol Asherson RA. A 'primary' antiphospholipid syndrome? J randomized and controlled trial. Rheumatol 1988: IS: 1742-1 746 Our data are consistent with the previously reported 17. Mackworth-Young C G , Loizous S . Walport MJ. Primar) antiphospholipid syndrome: features of patients with raised hypothesis that 'primary' antiphospholipid syndrome anticardiolipin antibodies and no other disorder. A m Rhcum may exist as a distinct clinical entity". It seems to Di.s 1989; 48: 362-367 show an overlap with other connective tissue disorders 18. Asherson RA. Khamashta MA, Gil A. rr ul. Cerebrovascular but does not appear to be merely a "subset" of disease and antiphospholipid antibodies in systemic lupus systemic lupus erythematosus. Further study of these erythematosus. lupus-like disease, and the primary antiphospholipid syndrome. Am J Med 1989; 8 6 391-399 patients may lead to a better understanding of its 19. Alarcon-Segovia D. Sanchez-Guerrero J. Primary antiphospathogenesis. therapy and prognosis. pholipid syndrome. J Rheumarol 1989: 16: 482-488
References I.
Hughes GRV. Harris EN, Gharavi AE. The anticardiolipin syndrome. J . Rheumaro/ 1986: 13: 486-489 2. Sontheimer RD. The anticardiolipin syndrome. A new way to slice an old pie. or a new pie to slice? Arch Dermarol 1987: 123: 590-595 3. Mueh JR. Herbst KD, Rapaport SI. Thrombosis in patients with the lupus anticoagulant. Ann Inrern Med 1980: 9 2 156I59 4. Boey ML, ColaGo CB, Gharavi AE, Elkon KB, Loizou S, Hughes GRV. Thrombosis in systemic lupus erythematosus: striking association with the presence of circulating lupus anticoagulant. Br Med J 1983; 287: 1021-1023
20. Asherson RA. Khamashta MA, Ordi-Ros J. er a / . The "primary" antiphospholipid syndrome: Major clinical and serological features. Medicine iEalriniore/ 1989: 68: 366-374 21. Gharavi AE. Harris EN. Asherson RA. Hughes GRV. Anticardiolipin antibodies: isotype distribuiton and phospholipid specificity. Ann Rheum Dis 1987; 46: 1-6 22. Staub HL. Khamashta MA. Harris EN. Chahade WH, Baguley E. Hughes GRV. Antiphospholipid syndrome and lupus anticoagulant in the absence of binding to negatively charged phospholipids (abstract). Arrhrifis Rheum 1989; 32 (suppl): 122 23. Branch, DW, Rote NS, Scott JR. The demonstration of lupus anticoagulant by enzyme-linked immunoadsorbent assay. CIin Immunol Immunopathol 1986; 39 298-307 24. Lopez-Soto A, Casals FJ. Font J. Cervera R, Ingelmo M. Detection of antiphospholipid antibodies by ELISA-method
‘PRIMARY’ ANTIPHOSPHOLIPID SYNDROME
25. 26.
27. 28. 39.
Autoimmunity Downloaded from informahealthcare.com by University of Auckland on 12/04/14 For personal use only.
30. 31. 32.
33. 34.
35. 36. 37.
7.5
with bovine thromboplastin as antigen. Throm Res 1989; 53: 38. Deleze M, Alarcon-Segovia D, Oria CV. Occurrence of both 623-628 hemolytic anemia and thrombocytopenic purpura (Evans’ Tan EM, Cohen AS, Fries J. et al. The 1982 revised criteria for syndrome) in systemic lupus erythematosus. Relationship to classification of SLE. Arrhriris Rheum 1982; 25 1271-1272 antiphospholipid antibodies. J Rheumarol 1988; 15: 61 1-615 Harris EN,Gharavi AE, Patel SP, Hughes GRV. Evaluation 39. Hazeltine M, Rauch J, Danoff D, Esdaile JM, Tannenbaum of the anti-cardiolipin antibody test: resport of an internationH. Antiphospholipid antibodies in systemic lupus erythemaal workshop held 4 April 1986. Clin Exp Immunol 1987; 68: tosus: Evidence of an association with positive Coombs’ and 2 I 5-222 hypocomplementemia. J Rhewnafol 198; 15: 80-85 Thiagarajan P. Shapiro SS, In: Methods in Hematology: 40. Balestrieri G, Tincani A, Allegri F, Martinelli M, Sinico A. Disorders of thrombin formation other than hemophilia. Cattaneo R. Antiphospholipid antibodies and red cell membrane. Clin Exp Rheumalol 1988; 6 197 Colman RV (ed). Livinston. New York. p 101-103, 1983 Green D, Hougie C, Kazmier FJ, el al. Report of the working 41. Deleze M, Alarcon-Segovia D, Oria CV, rr al. Hemocytopenia party on acquired inhibitors of coagulation: studies of the in systemic lupus erythematosus. Relationship to antiphos“lupus” anticoagulant. Thromb Haemosfas 1983; 4 9 144-146 pholipid antibodies. J Rheumarol 1989; 16 926-930 Johnson AM. Immunoelectrophoresis. In: Rose NR, 42, Asherson RA, Mayou SC, Merry P, Black MM, Hughes Friedman H, Fahey JL ed. Manual of Clinical Laboratory GRV. The spectrum of livedo reticularis and anticardiolipin Immunology. 3rd ed. American Society for Microbiology. antibodies. Br J Dermarol 1 2 0 215-221 Washington, 1986: 20-21 43. McHugh NJ, Maymo J, Skinner RP, James I, Maddison PJ. Andrassy K, van der Woude FJ. Detection of ANCA by Anticardiolipin antibodies, livedo reticularis. and major cereimunofluorescence techniques. Nefh J Med 1990; 36: 128-131 brovascular and renal disease in systemic lupus erythemaLachmann PJ. Hobart MJ. Complement technology. tows. Ann Rheum Dis 1988; 47: 110-1 I5 Handbook of rxperimental immunology. Vol 1. Blackwell 44. Weinstein C. Miller H, Axtens R, Buchanan R. Littlejohn JO. Livedo reticularis associated with increased titers of anticarScient Publi. London, 1978 diolipin antibodies in systemic lupus erythematosus. Arch Alarcon-Segovia D. Deleze M, Oria CV, et al. AntiphospholiDermalol 1987; 123 596-600 pid antibodies and the antiphospholipid syndrome in systemic lupus erythematosus. A prospective analysis of 500 consecu- 45. Levine SR, Joseph R, D’Andrea G, Welch KMA. Migraine tive patients. Medicine (Bdtimore) 1989: 68:353-365 and the lupus anticoagulant. Report ofcases and review of the Mackworth-Y oung C. Antiphospholiprd antibodies: more literature. Cephalalgia 1987; 7: 93-99 than just a disease marker? Immunol Today, 1990; 11: 60-65 46. Alarcon-Segovia D. Pathogenetic potential of antiphospholipid antibodies. J Rheumarol 1988; 1 5 890-893 Harris EN. Antiphospholipid antibodies. Br J Haernarol1990; 74: 1-9 47. Tala1 N. The etiology of systemic lupus erythematosus. In: Barbui T, Cortelazzo S. Galli M. ct al. Antiphospholipid Dubois’ Lupus erythematosus. Wallace DJ, Dubois EL. ed. Lea & Febiger. Philadelphia 1987: 39-43 antibodies in early repeated abortions: a case-controlled study. Feril Sieril 1988; 5 0 589-592 48. Khamashta MA, Harris EN, Gharavi AE, el al. Immune Balasch J, Font J. Lopez-Soto A. ct al. Antiphospholipid mediated mechanism for thrombosis: antiphospholipid antibodies in unselected patients with repeated abortion. Hum antibody binding to platelet membranes. Ann Rheum Dis 1988; Reprod 1990; 5 43-46 47: 849-854 Cervera R. Font J, Khamashta MA, Hughes GRV. Antiphospholipid antibodies: which and when? Postgrad Med J 1990; 66: 889-891
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THE 'PRIMARY' ANTIPHOSPHOLIPID SYNDROME: ANTIPHOSPHOLIPID ANTIBODY PATTERN AND CLINICAL FEATURES OF A SERIES OF 23 PATIENTS JOSEP FONT, ALFONS LOPEZ-SOTO, RICARD CERVERA, JOAN BALASCH'. LUCIO PALLARES, MARGARITA NAVARRO, XAVIER BOSCH and MIGUEL INGELMO
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Svsiemic Auioimmunc Diseases Research Group, Department of Internal Medicine. 'Department of Obstetrics and Gynaecology. Hospiial Clinic i Provincial, Barcelona, Spain (Received October I . 1990; in final form November 20, 1990)
Twenty-three patients with the 'primary' antiphospholipid syndrome were studied over 2-6 years. Twentytwo (96%) had antiphospholipid antibodies detected by ELISA (87% had antibodies to thromboplastin and 70% to cardiolipin). and I8 out of the 21 tested patients (86%) had lupus anticoagulant activity by coagulative assays. Mean age of the cohort was 29.9 years and the sex ratio (fema1e:male)4.75:l. Eleven patients presented 18 venous and/or arterial thrombosis and 13 had 25 foetal losses (84% occurred during the second and third trimester). Other clinical features were migraine, livedo reticularis, and epilepsy. Three patients had relatives with systemic lupus erythematosus. Thrombocytopaenia was seen in 33%. antinuclear antibodies in low or moderate titre in 30%, and haemolytic anaemia in 13%. During the follow-up, two patients presented recurrent thrombosis despit anticoagulant therapy, one of them dying because of recurrent pulmonary thromboembolism. Four patients achieved successful term pregnancies after treatment with aspirin and a further patient after treatment with aspirin and low dose prednisolone. No patient developed systemic lupus erythematosus or any other definable connective tissue disease. The 'primary' antiphospholipid syndrome may exist as a distinct clinical entity and all younger patients presenting with thrombotic events, foetal losses and/or thrombocytopaenia, without any evidence of a well defined disease, should be tested for antiphospholipid antibodies in order to rule out this syndrome. KEY WORDS: Anticardiolipin antibodies. lupus anticoagulant, thrombosis, foetal loss.
A syndrome consisting of repeated episodes of thrombosis and/or recurrent foetal loss, associated with raised levels of antiphospholipid antibodies is now the subject of considerable attention'-'*. In addition, features such as thrombocytopaenia, haemolytic anaemia, and several neurological disorders have occasionally been related to this ~yndrorne'~.'~. First recognized in patients with systemic lupus erythematosus'* and later in other rheumatologic and non-rheumatologic conditions'', it is now well known that the association of these antibodies with such clinical events may be independent of any underlying disease. The term 'primary' antiphospholipid syndrome has been introduced as a means of categorizing and studying these patients who
do not have any features of systemic lupus erythematosus or any other well defined disease'"''. Among the diversity of antiphospholipid antibodies, those directed against cardiolipin received a greater attention due to their sensitive, reproducible and reliable detection by enzyme linked immunosorbent assay (ELISA)". Several studies suggest that these antibodies are closely related to the lupus anticoagulant activity"," detected by coagulation assays. However, some patients have anticardiolipin antibodies without evidence of lupus anticoagulant activity, and vice versa". In order to avoid the cumbersome and laborious procedure to detect 'the lupus anticoaguland activity, several a ~ t h o r s ' ~ have .'~ proposed the use of an ELISA technique using thromboplastin as antigen and have found a good correlation with lupus anticoagulant activity. In this sutdy, we present data on a cohort of 23 patients who had one or more episodes of thrombosis and/or foetal losses, associated with raised levels of antiphospholipid antibodies, detected by ELISA techniques and coagulation assays, in absence of any definable underlying connective tissue disease.
Address reprint request to: Josep FONT, M.D. Servei de Medicina lnterna General. Hospital Clinic i Provincial. Villarroel, 170. 08036-Barcelona. SPAIN. Supported in part by Grant DGICYT PM 89-0108 from the Ministerio de Educacion y Ciencia (Spain). X. Bosch, MD. is a Research Fellow sponsored by a grant from the Hospital Clinic i Provincial of Barcelona. 69
70
J . FONT
PATIENTS AND METHODS
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Pa tien ts
Twenty-three patients were selected on the basis of the presence of one or more episodes of thrombosis (1 1 cases) and/or foetal losses (1 3 cases), together with antiphospholipid antibodies (antiphospholipid syndrome). They were attending the Departments of Internal Medicine or Obstetrics and Gynecolocy at our hospital during the last six years. Individuals attending both departments were routinely tested for antiphospholipid antibodies if the clinical features suggested that these may be elevated. All had medical, family, social and environmental histories taken and underwent routine physical examination. None of these patients had systemic lupus erythematosus. according to the American Rheumatism Association revised criteria’5. The mean follow-up after diagnosis of the antiphospholipid syndrome was 2.98 -i- 1.41 years (range 2 to 6). The diagnosis of venous thrombosis was based on clinical presentation and confirmed by venogram. One patient with clinical and arteriographic features of obliteration of the left superficial femoral artery and another one with clinical, electrocardiogram, and laboratory evidence of myocardial infarction, were defined as having arterial thrombosis. The term ‘foetal loss’ used here included spontaneous abortion, missed abortion and foetal death in any part of the pregnancy. Patients with a history of foetal loss were routinely screened for systemic diseases, diabetes mellitus, thyroid dysfunction, chromosome abnormalities in a parent, uterine abnormalities, and endometrial and hormonal luteal phase defects.
ei a /
consisting of a low (3-5 SD), moderate (5-7 SD), and high ( > 7 SD) titer. Patients were included in this study if the antiphospholipid antibodies remained positive on at least two occasions separated by a minimum interval of eight weeks. Lupus anticoagulan t act i v i t j -
The following tests were carried out in all patients (except in two who were on antiocagulant therapy) to detect lupus anticoagulant activity. according to the methods previously reported”.’*: prothrombin time, activated partial thromboplastin time, kaolin clotting time, diluted Russell’s viper venom time and tissue thromboplastin inhibition test. The reagents used were: rabbit brain thromboplastin (Symplastin, General Diagnostics) for prothrombin time and tissue thromboplastin inhibition test bovine thromboplastin (Thrombofax. Ortho Diagnostics) for dilute Russell‘s viper venom time and platelet factor 3 plus activator from rabbit brain tissue (Automated APTT. General Diagnostics) for activated partial thromboplastin time. The positive value for every coagulation test was defined as greater than 3 SD above the mean normal value of the control group. In order to rule out a deficit in a coagulation factor, each assay was also performed with a mixture of patient’s and control plasma ( l / l ) , vol/vol). Patients were considered to have lupus anticoagulant when at least two of these assays were shown to be positive. Serological test for syphilis
A macroscopic rapid plasma reagin (RPR, Kinckerbocker) was used in a 18 mm circle card test.
Determination of antiphospholipid antibodies
Other 1aborator.y studies
IgG and IgM anticartdiolipin antibodies were measured by ELISA as described by Gharavi et al.”, with minor modifications of our own8. Control serum samples from 100 normal blood donors were used to standardise the assay. The final value of the results was considered after correction by substraction of non-specific binding to uncoated wells. Results were expressed as negative, low, moderate and high positive. according to recommendations of the recent workshop on standardization of the anticardiolipin antibody test26. The ELISA for thromboplastin was performed according to a method previously reported by 11~’~. Results were expressed as binding index. A positive value was defined as binding index greater than 3 standard deviations (SD) above the mean of 150 normal subjects. In addition, the positive patients were arbitrarily divided into three subgroups
Antinuclear antibodies were determined by indirect immunofluorescence with mouse liver as substrate. Anti-double-stranded DNA antibodies were determined by Farr’s ammonium sulphate precipitation technique. Antibodies to extractable nuclear antigens (Ro, La, U-nRNP, and Sm) were detected by counterimmunoelectrophoresis”. Antineutrophil cytoplasm antibodies were detected using an indirect immunofluorescence assay on ethanol-fixed neutrophils3”.Complement components (C3, C4) were estimated by radial immunodiffusion and CH50 by Lachmann and Hobart’s haemolytic technique3’. RESULTS Antiphospholipid antibod?. pattern
Twenty-two out of 23 patients (96%) had antiphospholipid antibodies detected using ELISA: 20 (87%)
‘PRIMARY’ ANTIPHOSPHOLIPID S Y N D R O M E Table I
Description of phospholipid reactivity patterns in 23 patients with primary antiphospholipid syndrome. Porirnr n.
I 2 3 4
5 6 7 8 9
10
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II I? 13 14 I5 16 17 18 19
20 21
-33
23
uTPA
UCL IgG
lgM
IgG
kM
-
-
+++
-
+++ ++
++ -
++ -
+++ ++ +++ +- + +
-
+
+++ ++
+++ +t
++
++ -
+
+++ ++ +++ ++ -
-
-
-
+ + + +
-
-
-
+
++
-
-
-
-
+++
-
++
++
++
++ ++
-
-
+++ +
++
-
-
+ +++ ++
-
++
+ +
+
+- +
-
RPR
+ + +
-
+++
LA
-
++ -
++ -
-
ND -
+
-
+
-
+
+
+ + + + + + +
-
ND -
-
-
aCL = anli-cardlolipin antibodies: aTPA = anti-lhromboplaslin antibodies; LA = lupus anticoagulant. R P R = rapid plasma reapin: ND = no1 determined. + = low positive: + + = moderatc powive: + + + = high positive.
were positive for thromboplastin and 16 (70%) for cardiolipin. Titres ranged from moderate to high levels in most (Table I). Eighteen out of 21 patients (86%) were found to have lupus anticoagulant activity. All but one (case no. 17) had antibodies against thromboplastin and 11 had antibodies against cardiolipin. Only 3 patients ( 1 3%) had biological flase positive standard tests for syphilis as detected by RPR technique. Clinicul jindings
Mean age ( k S D ) of the entire cohort was 29.96 k 8.42 years (limits: 22-55). Nineteen patients were female and 4 were male (ratio: 4.751). Eleven patients (7 female and 4 male) presented 18 thrombotic events (Table 2). They cosisted of deep vein thromboses (9 cases) affecting both upper and lower extremities, pulmonary thromboembolism (4 cases). portal ( I case), mesenteric ( I case) and brain sinus ( 1 case) thromboses. The deep vein thromboses were often multiple. Arterial occlusions were present in only 2 patients. They consisted of peripheral arterial thrombosis and myocardial infarction. Thirteen patients experienced a total of 25 episodes of foetal loss (Table 3) with a mean of 2.33 k 1.95 (range 1 to 8) per patient. Only two of these patients
71
had a normal pregnancy. Twenty-one (84%) episodes of spontaneous foetal loss occurred during the second and third trimester and 4 (16%) during the first trimester of pregnancy. All patients with foetal losses were positive for lupus anticoagulant and had antibodies against thromboplastin, but only 8 had antibodies against cardiolipin, mainly of the IgG isotype. Standard tests for foetal loss were normal in all except two patients who presented a delayed ovulation. Other clinical manifestations were livedo reticularis (1 case), migraine ( I case) and epilepsy ( I case). No murmurs or any other clinical manifestation suggesting heart valve lesions were detected. No history of autoimmune hypothyroidism, skin vasculitis, or any other related immunological disorder was present. Family history disclosed that 3 (13%) patients had relatives with systemic lupus erythematosus. Laboratory findings
The laboratory findings of the 23 patients are documented in Table 4. Thrombocytopaenia (platelet count lower than 100 x lO’/l on two occasions at least two weeks apart) was the most common laboratory feature, evident in 8 patients (35%). Haemolytic anaemia (positive Coombs’ test associated with low level of haptoglobin and reticulocytosis) was present in 3 (13%) patients. Seven patients (30%) had antinuclear antibodies varying from low positive titre ( < 1:50) in 4 cases to moderately elevated ( 1 : 100) in 3 . Anti double-stranded DNA antibodies. antibodies to extractable nuclear antigens, antineutrophil cytoplasm antibodies and rheumatoid factor were not demonstrable in any patient. Complement components were normal in all cases. No significant correlation was found between the class and/or isotoype of antiphospholipid antibodies and any other clinical or immunological feature. The main clinical and laboratory features of the series are summarized in Figure I . Therapy and follow-up
All patients with thrombosis received anticoagulant therapy. However, one patient presented recurrent thrombotic events despite anticoagulant therapy and another patient died because of recurrent pulmonary thromboembolism complicated with pulmonary hypertension and chronic respiratory failure. Seven patients with recurrent foetal loss received aspirin ( 100 mg/day) from one month before attempting pregnancy and this was maintained until delivery in pregnant women. Clomiphene citrate (50 mg/day/5 days) was added in the two patients with
72
J . FONT et a/.
Table 2 Thrombotic events: Descriptions of patients affectwed with reference to antiphospholipid antibodies Patient
Age
aCL
aTPA
LA
RPR
n.
+ +
29 39 5s 32 2s 29 22 51 22 24 32
1
2 5 6 7 10
13 15 16 17
20
+
ND -
+ +
ND
-
+ +
Descriptions of thrombosis
DVTs, AM1 DVTs. PE DVTs Portal + mesenteric DVTs DVTs DVTs DVTs, PE Brain sinus DVTs. PE DVTs, PE, femoral artery
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aCL = anti-cardioltpin antibodies: aTPA = anti-thrornboplastin antibodies: LAS = lupus anticoagulant; RPR = rapid plasma reapin: DVT = deep venous thrombosis; acute myocardial infarction: PE = pulmonary embolism; ( - 1 = negative test: ( + I = positive test: ND = not determined AM1
-
delayed ovulation. Four patients achieved successful term pregnancies. One woman presenting with chorioamnionitis and sepsis due to a group B streptococcus at 29 weeks’ gestation had an intrauterine foetal death. However, this patient achieved successful term pregnancy after treatment with aspirin (100 mg/day) and prednisolone (1 5 mg/day). The remaining two aspirin-treated patients are not yet pregnant. None of the patients developed systemic lupus erythematosus or other well defined connective tissue disease during the follow-up.
DISCUSSION In this paper we have examined the clinical and serological characteristics of a series of a highly selected and specific group of patients attending our Hospital. All these patients were selected because of the presence of Table 3 Description of patients with fetal loss with reference to antiphospholipid antibodies ~
Patient n.
7
3 4 8 9 II I2 14 18 19
21 17
&_
’3
Age
39 28 25 28 23 28 28 24 36 30 29 26 24
CL
~~
TPA LA
+ + + + + + + + + + + + +
RPR
Details o$,frtal loss’
+ + -
aCL = anti-cardiolipin antibodies. aTPA = anti-throbmoplasun antibodies: LA = lupu\ anticoagulant: RPR = rapid plasma rcagin *numhcr of fetal loss irnonthb of prcpnancy at which fetal loss occurredl &patiems with lwc childr. one in each CdSC
antiphospholipid antibodies and a group of clinical manifestations considered as major clues for the diagnosis of the antiphospholipid syndrome, namely venous and/or arterial thrombosis and foetal l o ~ s e s ~In~ -all ~ ~cases, . systemic lupus erythematosus was excluded according to the American Rheumatism Association revised criteria2’ and no other diagnosis was possible during a follow-up ranging 2 to 6 years. Seventeen of these patients fulfilled the previously defined criteria for ‘primary’ antiphospholipid syndrome”. The remaining 6 patients only had a single foetal loss and thus should be considered as having a probable ‘primary’ antiphospholipid syndrome. To the most common clinical features of our group of patients were recurrent foetal loss and venous and/ or arterial thrombosis. Preliminary studies have found antiphospholipid antibodies in up to 30% of an unselected population of women with repeated and in up to 20% of young patients with venous and/or arterial thrombosis who do not suffer from systemic lupus erythematosus or any other well delineated autoimmune disorder”. Some of our patients had features previously described but not clearly associated with raised levels of antiphospholipid antibodies, such as haemolytic I , livedo r e t i c u l a r i . ~ ~ ’migraine4’ ~, .anamemia8mo.3n~ and epipepsyI4. Despite the low prevalence of these features in our series, probably due to selection bias, it appears that our patients display a range of clinical features similar to those previously reported with the antiphospholipid syndrome. It is of interest that some of the patients with the ‘primary’ antiphospholipid syndrome have relatives with systemic lupus erythemtosus ( I 3%). Unfortunately, antiphospholipid antibodies could not be tested in the patients’ relatives. This familial aggregation seem to be related mainly to the class 111 of the major histocompatibility complex, and some relationship to systemic lupus erythematosus still seems to
'PRIMARY' ANTIPHOSPHOLIPID SYNDROME
73
I
T HROMEOTIC EVENTS
FETAL LOSS
THR(SMB0CYTOPENIA /A"A IHEMOLYTIC ANEMIA MIGRAINE LIVEDO RETICULARIS
EPILEPSY RELATIVES WITH SLE
0
20
60
40
80
100
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P E RCEN TAGE
Figure I
Summary of the main clinical and laboratory features of the series, expressed as percentage of the series.
loom in patients with this syndrome4. O.ther interestl), which is ing clinical features are the sex ratio (4.75: lower than that found in lupus patients (9:1)4' but in agreement with other series of patients with 'primary' antiphospholipid ~yndrome".'~.'~, and the younger age of our patients, most of them being less than 40 years of age. One patient of our series died because of recurrent pulmonary thromboembolsim complicated with pulmonary hypertension. The presence of pulmonary hypertension has been previously reported in patients
with the 'primary' antiphospholipid syndrome, both following repeated episodes of pulmonary thromboembolism and resembling the 'primary' idiopathic variety with clear lung fields and no evidence of t hrom boem bolism 19.20. Among the laboratory data, it is of note that thrombocytopaenia was found to be the most common feature. This raises the possibility of a pathogenic involvement of platelets in the mechanisms of production of the antiphospholipid syndrome". In addition, other striking immunological features in our
Table 4 Description of laboratory findings in 23 patients with primary antiphospholipid syndrome Patient
Thrombocympenia
Hemol. anemia
n.
1
2 3 4 5 6 7 8 9 10
II
12 13 14 15 16
ANA = antinuclear antibodies: ds-DNA = anti double-stranded D N A antibodies; ENAs = extractable nuclear anrisns antibodies: RF = rheumatoid factor
ANA
ds-DNA
ENAs
RF
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74
J. F O N T er a /
5. Harris EN. Gharavi AE. Boey ML. er a/. Anticardiolipin patients were haemolytic anaemia and antinuclear antibodies: detection by radioimmunoassay and association antibodies varying from low positive titre to with thrombosis in systemic lupus erythematosus. Lancer moderately elevated. These findings also suggest that 1983; 2 121 1-1214 many of these patients have a condition which is 6 . Glueck HI. Kant KS. Weiss MA. Pollack VE. Miller MA. Coots M. Thrombosis in systemic lupus erythematosus. related to systemic lupus erythematosus. Nevertheless, Relation to the presence of circulating anticoagulants. Arch none of our patients developed any well-defined Iniern Med 1985: 145: 1389-1395 disease during the follow-up. 7. C o l a ~ oCB. Male D K . Anti-phospholipid antibodies in There is a close relationship between the lupus antiSyphillis and a thrombotic subset of SLE: distinct profiles of coagulant activity and the detection of negatively epitope specificity. Clin ESJJImmunol 1985; 59: 449-456 8. Cervera R, Font J. Lopez-Soto A, er al. lsotype distribution of charged antiphospholipid antibodies using solid phase anticardiolipin antibodies in systemic lupus erythematosus. techniques".". Of interest is the recent description of Prospective analysis of a series of 100 patients. Ann Rheum Dis a small subgroup of patients with the antiphospholi1990; 4 9 109-1 13 pid syndrome who have only raised levels of anticar9. Harris EN. Chan JKH. Asherson RA. Aber VR, Gharavi AE. Hughes GRV. Thrombosis, recurrent fetal loss. and thromdiolipin antibodies or lupus anticoagulant activity", bocytopenia. Predicitive value of the anticardiolipin antibody as we have found in our series. In addition. although test. Arch Inrern Med 1986: 146 2153-2156 it is generally held that IgG antibodies are more 10. Petri M. Rheinschmidt M. Whiting-O'Keefe Q. Hellman D. closely associated with pathology, in a few cases only Corash L. The frequency of lupus anticoagulant in systemic IgM antibodies could be detected. According to these lupus erythematosus. A study of sixty consecutive patients by acitvated partial thromboplastin time. Russell viper venom findings, tests for the lupus anticoagulant as well as time. and anticardiolipin antibody level. .4nn Inrcrti Med 1987: the ELISA test for IgG and IgM antibodies against 106 524-531 cardiolipin must be carried out in all patients with I . Triplett DA. Brandt JT. Musgrave KA. Orr C A . The relationclinical features suggesting antiphospholipid ship between lupus anticoagulants and antibodies to phospphotipid. JAMA 1988; 2 5 9 50-554 syndrome. It is noteworthy that antibodies to 2. Lockshin MD. Druzin ML. Goei S, er a / . Antibodiy to carthromboplastin have the best correlation with lupus diolipin as a predictor of fetal distress or death in pregnant anticoagulant, as we had previously r e p ~ r t e d ? ~ . patients with systemic lupus erythematosus. N Enxl J Mcd Consequently, we suggest that this method could be 1985; 3 1 3 152-156 added to the laboratory screening for antiphospholi3. Khamashta MA, Cervera R. Asherson RA, rr ul. Association of antibodies against phospholipids pid antibodies. . . with heart valve disease in systemic lupus-erythematosus. Lancer 1990; 335: 154 I - I544 Finally, it should be noted that four patients 14. Asherson RA. Harris EN. Anticardiolipin antibodies. Clinical achieved successful term pregnancies after treatment associations. Pos/Rrad MedJ 1986: 62: 1081-1087 with aspirin and a further patient after treatment with 15. Manoussakis MN. Gharavi AE. Drosos AA. Kitridou RC. aspirin and low dose prednisolone. However. a correct Moutsopoulos H M . Anticardiolipin antibodies in unselected autoimmune rheumatic disease patients. Cliri Immutiol Iniappreciation of the apparently beneficial effect of 1987; 44:297-307 aspirin and/or prednisolone would require a 16. munoparhol Asherson RA. A 'primary' antiphospholipid syndrome? J randomized and controlled trial. Rheumatol 1988: IS: 1742-1 746 Our data are consistent with the previously reported 17. Mackworth-Young C G , Loizous S . Walport MJ. Primar) antiphospholipid syndrome: features of patients with raised hypothesis that 'primary' antiphospholipid syndrome anticardiolipin antibodies and no other disorder. A m Rhcum may exist as a distinct clinical entity". It seems to Di.s 1989; 48: 362-367 show an overlap with other connective tissue disorders 18. Asherson RA. Khamashta MA, Gil A. rr ul. Cerebrovascular but does not appear to be merely a "subset" of disease and antiphospholipid antibodies in systemic lupus systemic lupus erythematosus. Further study of these erythematosus. lupus-like disease, and the primary antiphospholipid syndrome. Am J Med 1989; 8 6 391-399 patients may lead to a better understanding of its 19. Alarcon-Segovia D. Sanchez-Guerrero J. Primary antiphospathogenesis. therapy and prognosis. pholipid syndrome. J Rheumarol 1989: 16: 482-488
References I.
Hughes GRV. Harris EN, Gharavi AE. The anticardiolipin syndrome. J . Rheumaro/ 1986: 13: 486-489 2. Sontheimer RD. The anticardiolipin syndrome. A new way to slice an old pie. or a new pie to slice? Arch Dermarol 1987: 123: 590-595 3. Mueh JR. Herbst KD, Rapaport SI. Thrombosis in patients with the lupus anticoagulant. Ann Inrern Med 1980: 9 2 156I59 4. Boey ML, ColaGo CB, Gharavi AE, Elkon KB, Loizou S, Hughes GRV. Thrombosis in systemic lupus erythematosus: striking association with the presence of circulating lupus anticoagulant. Br Med J 1983; 287: 1021-1023
20. Asherson RA. Khamashta MA, Ordi-Ros J. er a / . The "primary" antiphospholipid syndrome: Major clinical and serological features. Medicine iEalriniore/ 1989: 68: 366-374 21. Gharavi AE. Harris EN. Asherson RA. Hughes GRV. Anticardiolipin antibodies: isotype distribuiton and phospholipid specificity. Ann Rheum Dis 1987; 46: 1-6 22. Staub HL. Khamashta MA. Harris EN. Chahade WH, Baguley E. Hughes GRV. Antiphospholipid syndrome and lupus anticoagulant in the absence of binding to negatively charged phospholipids (abstract). Arrhrifis Rheum 1989; 32 (suppl): 122 23. Branch, DW, Rote NS, Scott JR. The demonstration of lupus anticoagulant by enzyme-linked immunoadsorbent assay. CIin Immunol Immunopathol 1986; 39 298-307 24. Lopez-Soto A, Casals FJ. Font J. Cervera R, Ingelmo M. Detection of antiphospholipid antibodies by ELISA-method
‘PRIMARY’ ANTIPHOSPHOLIPID SYNDROME
25. 26.
27. 28. 39.
Autoimmunity Downloaded from informahealthcare.com by University of Auckland on 12/04/14 For personal use only.
30. 31. 32.
33. 34.
35. 36. 37.
7.5
with bovine thromboplastin as antigen. Throm Res 1989; 53: 38. Deleze M, Alarcon-Segovia D, Oria CV. Occurrence of both 623-628 hemolytic anemia and thrombocytopenic purpura (Evans’ Tan EM, Cohen AS, Fries J. et al. The 1982 revised criteria for syndrome) in systemic lupus erythematosus. Relationship to classification of SLE. Arrhriris Rheum 1982; 25 1271-1272 antiphospholipid antibodies. J Rheumarol 1988; 15: 61 1-615 Harris EN,Gharavi AE, Patel SP, Hughes GRV. Evaluation 39. Hazeltine M, Rauch J, Danoff D, Esdaile JM, Tannenbaum of the anti-cardiolipin antibody test: resport of an internationH. Antiphospholipid antibodies in systemic lupus erythemaal workshop held 4 April 1986. Clin Exp Immunol 1987; 68: tosus: Evidence of an association with positive Coombs’ and 2 I 5-222 hypocomplementemia. J Rhewnafol 198; 15: 80-85 Thiagarajan P. Shapiro SS, In: Methods in Hematology: 40. Balestrieri G, Tincani A, Allegri F, Martinelli M, Sinico A. Disorders of thrombin formation other than hemophilia. Cattaneo R. Antiphospholipid antibodies and red cell membrane. Clin Exp Rheumalol 1988; 6 197 Colman RV (ed). Livinston. New York. p 101-103, 1983 Green D, Hougie C, Kazmier FJ, el al. Report of the working 41. Deleze M, Alarcon-Segovia D, Oria CV, rr al. Hemocytopenia party on acquired inhibitors of coagulation: studies of the in systemic lupus erythematosus. Relationship to antiphos“lupus” anticoagulant. Thromb Haemosfas 1983; 4 9 144-146 pholipid antibodies. J Rheumarol 1989; 16 926-930 Johnson AM. Immunoelectrophoresis. In: Rose NR, 42, Asherson RA, Mayou SC, Merry P, Black MM, Hughes Friedman H, Fahey JL ed. Manual of Clinical Laboratory GRV. The spectrum of livedo reticularis and anticardiolipin Immunology. 3rd ed. American Society for Microbiology. antibodies. Br J Dermarol 1 2 0 215-221 Washington, 1986: 20-21 43. McHugh NJ, Maymo J, Skinner RP, James I, Maddison PJ. Andrassy K, van der Woude FJ. Detection of ANCA by Anticardiolipin antibodies, livedo reticularis. and major cereimunofluorescence techniques. Nefh J Med 1990; 36: 128-131 brovascular and renal disease in systemic lupus erythemaLachmann PJ. Hobart MJ. Complement technology. tows. Ann Rheum Dis 1988; 47: 110-1 I5 Handbook of rxperimental immunology. Vol 1. Blackwell 44. Weinstein C. Miller H, Axtens R, Buchanan R. Littlejohn JO. Livedo reticularis associated with increased titers of anticarScient Publi. London, 1978 diolipin antibodies in systemic lupus erythematosus. Arch Alarcon-Segovia D. Deleze M, Oria CV, et al. AntiphospholiDermalol 1987; 123 596-600 pid antibodies and the antiphospholipid syndrome in systemic lupus erythematosus. A prospective analysis of 500 consecu- 45. Levine SR, Joseph R, D’Andrea G, Welch KMA. Migraine tive patients. Medicine (Bdtimore) 1989: 68:353-365 and the lupus anticoagulant. Report ofcases and review of the Mackworth-Y oung C. Antiphospholiprd antibodies: more literature. Cephalalgia 1987; 7: 93-99 than just a disease marker? Immunol Today, 1990; 11: 60-65 46. Alarcon-Segovia D. Pathogenetic potential of antiphospholipid antibodies. J Rheumarol 1988; 1 5 890-893 Harris EN. Antiphospholipid antibodies. Br J Haernarol1990; 74: 1-9 47. Tala1 N. The etiology of systemic lupus erythematosus. In: Barbui T, Cortelazzo S. Galli M. ct al. Antiphospholipid Dubois’ Lupus erythematosus. Wallace DJ, Dubois EL. ed. Lea & Febiger. Philadelphia 1987: 39-43 antibodies in early repeated abortions: a case-controlled study. Feril Sieril 1988; 5 0 589-592 48. Khamashta MA, Harris EN, Gharavi AE, el al. Immune Balasch J, Font J. Lopez-Soto A. ct al. Antiphospholipid mediated mechanism for thrombosis: antiphospholipid antibodies in unselected patients with repeated abortion. Hum antibody binding to platelet membranes. Ann Rheum Dis 1988; Reprod 1990; 5 43-46 47: 849-854 Cervera R. Font J, Khamashta MA, Hughes GRV. Antiphospholipid antibodies: which and when? Postgrad Med J 1990; 66: 889-891
