21 Ethnic and Geographic Variation in Antiphospholipid Syndrome

21 Ethnic and Geographic Variation in Antiphospholipid Syndrome

Wendell A. Wilson and Elena Cucurull

Introduction

During the past 20 years, studies of antiphospholipid antibodies (aPL) and antiphospholipid syndrome (APS) have been done in many countries and ethno- geographic groups. To date, the large majority of these studies reported data on sys- temic lupus erythematosus (SLE) populations, and this review largely focuses on the SLE studies. Comparisons among such studies are of interest because they may help to clarify the causes of APS, analogous to the situation in SLE, in which ethnic and geographic factors are clearly related to prevalence and severity of the disease.

Anticardiolipin Antibodies (aCL) Frequency in SLE

Routine screening for aPL now occurs in SLE clinics because of the strong experi- mental and clinical evidence of the procoagulant nature of aPL and the demonstra- tions that anticoagulation provides effective secondary prophylaxis of thrombosis or pregnancy loss in patients with aPL. Studies to date have mainly described the prevalence of aCL among populations of SLE patients and have attempted to esti- mate the prevalence of secondary APS in SLE, mainly using classification criteria for APS that predated the 1999 international (Sapporo) criteria [1]. Relatively few studies listed in Table 21.1 included lupus anticoagulant (LA) in the assay methods for aPL, probably because tests for LA are more technically demanding and require platelet-poor plasma. The studies listed in Table 21.1 thus mainly provide a point prevalence of aCL in various populations.

It is evident from Table 21.1 that aCL occur in all SLE populations studied, but with highly variable point prevalence. It is likely that assay methods [20] and patient selection contribute to this variability in prevalence as further discussed below, but some variations are of interest. IgG aCL prevalence ranged from 2% in an Afro–Caribbean clinic population to 51% in a report from India. Of even greater interest was the fact that among Afro–Caribbean (Jamaican) SLE patients, the prevalence of IgA aCL was relatively high (21%), but it was not clear whether SLE disease parameters, including disease inactivity, was related to the low frequency of IgG aCL. In the same study [4], using the same assay methods, IgG aCL was seen

258

Ta b le 2 1. 1. Prevalence and isotype distribution of anticardiolipid and lupus anticoagulant in different populations of SLE patients. Reference Ethnicity or country (n) Any aCL isotype (%) IgG aCL (%) IgM aCL(%) IgA aCL(%) LA (%) Correlation with thrombosis and/or fet al loss Cucurull et al [2] Colombian

(160) 25 18 13 15 NA Yes Cucurull et al [2] Spaniard

(160) 34 27 15 16 NA Yes Cucurull et al [3] African-American

(100) 33 18 7 24 NA Yes Molina et al [4] Afro-Caribbean

(136) 21 2 2 21 NA No Aguirre et al [5] Chilean

(129) 30 16 14 8 NA Yes Alarcon et al [6] Hispanic

(70) 7* NA NA NA NA NA Alarcon et al [6] African-American

(88) 11* NA NA NA NA NA Alarcon et al [6] Caucasian

(71) 5* NA NA NA NA NA Jones et al [7] Malaysia

(200) 16.5 13 2.5 NA NA No Sebastiani et al [8] Europe

(574) NA 23 14 14 NA Yes Sebastiani et al [9] Italy (64) 44 44 9 NA NA Yes Gourley et al [10] Ireland (95) 44 31 28 NA NA Yes Sturfelt et al [11] Sweden (59) 54 47 13 NA NA No Alarcon-Segovia et al [12] Mexico (500) 53 39 33 16 NA Yes Shrivastava et al [13] India (76) 51 51 7 5 NA No Saluja et al [14] India

(76) 27 27 1 NA NA Yes Saxena et al [15] India

(70) 19 NA NA NA 16 Yes Wong et al [16] China (91) 46 44 1 4 11 No Ninomiya et al [17] Japan (349) 35 28 NA NA 27 Yes Tsutsumi et al [18] Japan (308) NA 12 4 NA 8 Yes Chahade et al [19] Brazilian (54) 20 20 5.5 NA 17 NA

In-house ELISA test done at Louisiana State University Health Sciences Center in New Orleans.

LUMINA Study Group: LUpus in MInority populations: NAture vs Nurture. From University of Alabama at Birmingham, University of T exas-Houston Health Science Center, and University of Texas Medical Branch at Galveston.

Population comprised 164 Chinese, 26 Malay, and 10 Indian. No differences were found in the prevalence of raised aCL between th e 3 ethnic groups.

Patients from 7 European countries: 97.7% Caucasians, 3.3% other races.

Both studies from All India Institute of Medical Sciences, New Delhi. *IgG and IgM aCL and/or LA. NA = data not available.

260 Hughes Syndrome

fairly commonly among African–American and Colombian SLE patients (18% and 21%, respectively). The relative paucity of IgG and IgM aCL in Afro–Caribbean SLE patients warrants further study. In general, most studies from various countries report a mixture of aCL isotypes in individual patients, with IgG aCL being the most common and most closely associated with thromboses and fetal losses. IgA aCL is rarely present alone, except in Afro–Caribbean SLE patients. In African–American SLE patients, IgA aCL is also frequent, but often co-exists with other isotypes. In early studies in the African–American clinic population in New Orleans, we found that IgG aCL was present in 27% of SLE patients during periods of disease activity, compared with only 5% of SLE patients during periods of less active SLE [34]. Thus, disease activity may be an important variable to address in future inter-ethnic studies. SLE in African–Americans and Afro–Caribbean SLE patients is character- ized by a generally worse outcome and a higher prevalence of autoantibodies than in other ethnic or geographic groups, and it would be of interest if aPL are an excep- tion to this pattern in SLE. In a largely Afro–American obstetric pre-natal clinic population [22], the prevalence of IgG aCL was 1.25% which approximates the fre- quency of IgG aCL found in other unselected pre-natal clinic populations [23].

Significance of IgA aCL

It is also of interest that IgA aCL predominated in another Afro–Caribbean clinic population [24, 25]; these were Jamaican patients with tropical spastic paraparesis (TSP), a chronic neurologic disease that appears to be due to an autoimmune response to infection with human T-cell leukemia virus type 1 (HTLV-1). In some clinical respects, TSP resembles the progressive subset of patients with multiple sclerosis. IgA aCL occurred in 30% of TSP patients, but its relevance to clinical fea- tures of TSP has not been studied.

The mechanisms that may underlie the preponderance of IgA aCL in the above Afro–Caribbean clinic populations, are not known. It is known that HTLV-1 infec- tion is not associated with SLE in Jamaica [26]. A black South African population of SLE patients exhibited relatively high frequencies of specific antinuclear antibodies, similar to previous reports in Jamaican and African–American SLE; however, aCL, and IgA aCL in particular, was not studied in the South African SLE patients [27].

However, IgA aCL appear to be frequent in some infections among black South

Africans [28]. It is not clear whether the African origin or ancestry of these

populations correlates with the autoantibody profile. Afro–Caribbean and

African–American populations share similar, diverse geographic ancestral origins

mainly in West Africa; in addition, during the post-slavery period, there have been

extensive migrations of Afro–Caribbean peoples to the Americas. However, the

gene pool in black South Africans may be significantly different from that in West

Africa [29]. It would seem likely that methodological, and possibly, environmental

factors underlie the variations that occur in the aCL isotypes among these popula-

tions. Whether IgA aCL might contribute to a more comprehensive identification of

APS in some SLE populations is controversial [21]. Some studies have found no

additional benefit from IgA aCL testing in SLE patients who were screened for IgG

and IgM aCL, whereas some studies in other geographic or ethnic groups suggest

the opposite.

APS in SLE

Most studies that were powered to address this question in Table 21.1 reported an association of aCL with thromboses and pregnancy loss. The exceptions included a 1991 study from China (Hong Kong) that found a 44% prevalence of IgG aCL and an 11% prevalence of LA [17]. This study did not find an association of aPL with thromboses or pregnancy loss a surprising finding, in view of the very strong associ- ation of the presence of LA with these complications.

Whether anti– β

-glycoprotein I (anti– β

-GPI) assays provide additional informa- tion of clinical or other value is the subject of ongoing study. It is clear that there is a small population of patients who do not have IgG or IgM aCL but who are positive for IgG or IgM anti–β

-GPI. Whether IgA anti-β

GPI provides further value is also controversial. Clarifications of these areas will require inter-laboratory efforts to standardize anti–β

-GPI assays and to compare them with more conventional aPL assays [18, 30].

It is clear from the above that the study of the clinical epidemiology of aPL is still in its infancy. Most studies have reported data on only one ethnic and/or geo- graphic group, and comparisons between these studies are confounded by method- ologic variations or patient selection. The publication in 1999 of international consensus criteria for APS [1] should facilitate future studies. Studies of ethnic and/or geographic variation in aPL or APS are of interest for the clinical reasons mentioned above, and also because such variation may provide clues to the genetic or environmental causes of APS, as has been the case in SLE.

Genetic Factors in aPL and APS

The genetic factors that lead to aPL production are still unclear, though some evi- dence points to the possible importance of major histocompatibility complex (MHC) -DQB or -DR alleles in particular [31]. Vascular thromboses and pregnancy losses have many non-aPL causes, and there is evidence that some risk factors for these clinical complications have additive effects with other risk factors. A few studies have addressed the possibility that aPL may interact with genetic risk factors for thrombosis, for example, factor V Leiden, and the prothrombin gene mutation, that vary markedly in prevalence among ethnic groups.

APS and SLE are heterogeneous diseases, in which the basic causes may well turn

out to be as heterogeneous as the clinical presentation of these syndromes. In the

case of SLE, there is evidence that a large number of genes contribute to causation,

with some genes having relevance in many ethnic groups (e.g., C

A deficiency

alleles) and others having less general significance across ethnic groups [32]. With

increasing geographic migration and intermingling across geographic and ethnic

groups, such variations in disease parameters will become even more difficult to

interpret relative to the genetic or environmental causes of these diseases. In addi-

tion, in many communities variation in disease parameters that appear to relate to

ethnicity may more closely associate with economic variables or educational oppor-

tunities. There is as yet very little understanding of the ways by which such social

factors affect the biologic mechanisms that influence disease prevalence and

outcome in autoimmune diseases such as SLE.

Summary

Geographic and ethnic studies of aPL and APS suggest that IgG aCL prevalence may be lower among Afro–Caribbean (Jamaican) SLE patients, who interestingly have a high prevalence of IgA aCL. It is not clear whether this is generalizable to other SLE populations that have African ancestry. Further multi-ethnic studies that are inter- nally controlled for laboratory methods and SLE disease activity would be useful in confirming these reports, and exploring their clinical significance.

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