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Rheumatology 2001; 40: 192-195
© 2001 British Society for Rheumatology

Anticardiolipin antibodies in Behçet's disease: a reassessment

S. Tokay, H. Direskeneli, S. Yurdakul2 and T. Akoglu1

Departments of Rheumatology and,
1 Haematology–Immunology, Faculty of Medicine, Marmara University and
2 Department of Rheumatology, Cerrahpasa Medical Faculty, University of Istanbul, Istanbul, Turkey


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
Objective. To assess the frequency and clinical relevance of anticardiolipin antibodies (aCL) in Behçet's disease (BD).

Methods. IgG, IgM and IgA aCL isotypes were investigated by ELISA in 128 patients with BD, 143 healthy controls and 20 systemic lupus erythematosus (SLE) patients.

Results. The IgA binding index (BI) was slightly elevated in BD compared with healthy controls (120±53 vs 107±46, P=0.02), whereas IgG and IgM aCL levels were not significantly different (IgG, BD 2.5±2.4 G phospholipid (GPL), healthy controls 2.8±3.6 GPL, P=0.6; IgM, BD 0.7±0.9 M phospholipid (MPL), healthy controls 0.9±1.3 MPL, P=0.6). The frequency of aCL positivity was 7% in BD (IgG 0.8%, IgM 1.6%, IgA 4.6%), 50% in SLE and 5.6% in healthy controls. IgA BI was elevated in the HLA-B5-negative group compared with HLA-B5-positive patients (P<0.005). In a literature review, the frequency of aCL was found to be 9.5% in studies from Turkey compared with 25.5% in other series (P<0.0001).

Conclusion. These results do not suggest a primary role for aCL in BD. A significantly lower frequency of aCL in Turkish BD patients than in other series indicate that regional determinants, whether environmental or genetic, might also play a role in controlling aCL production in BD.

KEY WORDS: Autoantibodies, Anticardiolipin antibodies, Behçet's disease.


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
Behçet's disease (BD) is a chronic, inflammatory vasculitis characterized by mucocutaneous, ocular, vascular, arthritic and neurological involvement [1]. The cause and pathogenesis of BD are unclear, but various immunological abnormalities associated with both humoral and cellular immune systems have been reported [2].

Anticardiolipin antibodies (aCL) are antibodies against the phosphodiester group of negatively charged phospholipids. Recurrent thrombosis, fetal loss and thrombocytopenia have been reported to be associated with the presence of aCL, especially in autoimmune diseases such as systemic lupus erythematosus (SLE) [3]. BD is also characterized by recurrent vascular thrombosis and vasculitis. Although some previous studies suggest an increased frequency of aCL in BD, the low numbers of patients in most of these studies, especially patients with thrombotic complications, make it difficult to draw definite conclusions [4–25].

Ethnic and geographical differences in BD related to the clinical manifestations, such as gastrointestinal involvement, positive pathergy reaction and HLA-B51, are well known [26, 27], and aCL levels might be influenced by these factors. Therefore, this study aimed to assess the frequency and clinical relevance of aCL in a large group of Turkish BD patients and compare them with published series.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
Patients
Patients with BD (n=128; 45 females, 83 males; mean age 33.8±5.7 yr) attending the Behçet's Disease Outpatient Clinics of Marmara and Cerrahpasa Medical Faculties in Istanbul were studied. All patients fulfilled the International Study Group Criteria for BD [28]. All BD patients had oral ulcers. Skin manifestations were present in 94% of the patients, genital ulcers in 85%, ocular involvement in 61%, vascular involvement in 43% and articular involvement in 33%. The pathergy test was positive in 67% (81/121) and HLA-B5 in 67% (57/85). Fifty-five per cent of the patients were using an immunosuppressive treatment at the time of the study. Twenty-one patients (16%) were not on any treatment.

In the control group there were 20 patients with SLE (19 females, one male; mean age 31.0±4.2 yr), classified according to the 1982 American College of Rheumatology criteria, and 143 healthy controls (72 females, 71 males; mean age 33.7±6.1 yr).

ELISA method for aCL
aCL were determined according to the method of Gharavi et al. [29] using the standard ELISA method. One GPL was defined as the binding activity of 1 µg/ml IgG aCL, and 1 MPL was defined as the binding activity of 1 µg/ml IgM. As no standardized control serum for IgA was available, a pool of sera was created by mixing the sera of 10 healthy controls and an IgA binding index (BI) was calculated as follows: (optical density of test serum/optical density of standard serum)x100.

Statistical methods
The non-parametric Mann–Whitney U-test was used to compare IgM and IgG concentrations and the BI for IgA between groups. The {chi}2 test was used to compare aCL positivity in different experiments.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
No significant differences were observed for IgG and IgM aCL levels between BD patients and healthy controls (Table 1Go). IgA aCL was significantly elevated only in the BD group compared with the healthy controls (BI 120±53 vs 107±46, P=0.02). In SLE patients, IgG, IgM and IgA aCL antibodies were significantly elevated compared with other groups (P<0.01, P<0.005 and P<0.0001 respectively).


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  		TABLE 1. aCL levels in patients with BD and SLE and healthy controls

 
When the cut-off point was taken to be a value greater than 3 standard deviations above the mean of healthy controls, values above 13.6 GPL, 4.7 MPL and a BI above 244 were positive, and the frequency of aCL positivity was 7% in BD (IgG 0.8%, IgM 1.6%, IgA 4.6%), 50% in SLE and 5.6% in healthy controls.

IgA aCL levels were significantly elevated in HLA-B5-negative patients compared with the HLA-B5-positive group (BI 147±63 vs 113±58, P<0.005). aCL levels were not significantly different when patients were classified according to vascular involvement (IgG 2.4 vs 2.6 GPL, IgM 0.7 vs 0.8 MPL; IgA BI 126 vs 118; all P>0.05). Similarly, no correlation was observed with any isotype and any other clinical manifestation, disease duration, pathergy reaction, erythrocyte sedimentation rate or immunosuppressive treatment.

In a subgroup of 40 patients with BD, serum IgA levels were also measured, but no correlation was found between serum IgA and IgA aCL levels (r=0.09, P=0.48).

In a pooled analysis of 23 studies in the literature which investigated aCL in BD, including the present study, the frequency of aCL was 19.2% (180/937) (Table 2Go). However, when six studies from Turkey were analysed separately, the frequency was only 9.5% (35/368) compared with 25.5% (145/569) in the remaining 17 studies (P<0.0001).


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  		TABLE 2. Frequencies of IgG and/or IgM aCL antibodies in BD (literature review)

 


   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
In the literature, the frequency of aCL in BD ranges between 0 and 50%. Hull et al. [4] first reported 19% positivity for aCL and found an association between increased IgM and IgG aCL levels and retinal vasculitis. A similar relationship with uveitis was later suggested in two other studies. Pereira et al. [7] observed IgG aCL positivity in three of 10 patients (30%) with ocular disease and a lower frequency in patients taking corticosteroids (27.3 vs 55.6%). In a recent study, Alper et al. [23] also found IgG aCL positivity in 33% of patients with ocular involvement compared with 3% in patients without ocular disease. Zouboulis et al. [12] reported high IgM aCL titres in patients with cutaneous vasculitis and erythema nodosum. Apart from these studies, no correlation was observed with any specific manifestation of BD and aCL antibodies, especially with thrombotic events, as might be expected.

In our study, which includes the largest number of patients reported, we found the frequency of IgG and IgM aCL to be 2.4% in BD, 50% in SLE and 5.6% in healthy controls. While the frequencies in the SLE and control groups were similar to those in other studies, we did not find increased IgM and IgG aCL titres in BD. We were also unable to show any significant association between aCL titres and vascular or ocular involvement, disease duration, pathergy positivity, a high erythrocyte sedimentation rate or immunosuppressive treatment.

These results are in agreement with most previous reports, especially studies from Turkey, where a significantly lower mean frequency of aCL (9.5%) was reported compared with other series (25.5%). This interesting observation might be linked to methodological differences, as 2 S.D. [13], 3 S.D. [4, 5, 10, 16] and 4 S.D. [8] above the mean of normal subjects have been accepted as the cut-off for positivity in different series, which might have influenced the results. Alternatively, regional determinants, whether environmental or genetic, might also affect the presence of aCL as they do for other autoantibodies. A low frequency of aCL was observed previously in SLE patients from Malaysia [30]. Variability of aCL isotype distribution was also reported in Afro-Caribbean patients compared with Hispanics and African Americans [31].

Discrepancies in the clinical manifestations of BD in different countries have also been suggested for gastrointestinal manifestations, with a lower prevalence observed in Turkey compared with series from Japan and Korea [26]. Similarly, the pathergy test and HLA-B51 positivity are reported to be more prevalent among patients from countries where the disease is prevalent (Turkey, Japan), compared with series from the UK and the USA [27]. However, a problem with this type of analysis is the fact that the country of origin of the paper does not necessarily reflect the ethnicity of the patients studied. Studies such as those from European countries with high rates of immigration from the Mediterranean region may have a problem with diverse ethnic backgrounds of the patients. However, in only one study from Germany is this issue addressed, and the ethnic background of the patients is given (19 Turkish, eight German, one each Italian, Yugoslavian and Libyan). No association of aCL with nationality was reported in this study [12].

We only found a slight increase of IgA aCL in BD patients, especially in the HLA-B5-negative group. An increase in the number of B cells of the IgA isotype without an overall change in the number of circulating B cells has been reported previously in BD, and cytophilic IgA1 has been found to be increased in circulating T cells, which was suggested to be related to mucosal involvement [32]. In the HLA-B5-negative group, mucocutaneous involvement is common, and the increased IgA aCL BI in this group in our study might reflect an increased immune response of the IgA isotype. On the other hand, no correlation was found between serum IgA levels and IgA aCL in our study, and we cannot exclude a slight, specific increase in IgA aCL.

In conclusion, we did not observe high titres of aCL in a very large group of BD patients from Turkey, with the exception of low titres of IgA antibodies. The discrepancy between various studies on BD with respect to the presence of aCL indicates that the classification of BD as an aCL-associated disease is still controversial, and that there may be regional differences in the frequency of aCL.


   Acknowledgments
 
The authors thank Professor H. Yazici for help in the preparation of this paper.


   Notes
 
Correspondence to: Haner Direskeneli, Resit Pasa Sok, 36/5, Kiziltoprak 81031, Kadiköy, Istanbul, Turkey Back


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Submitted 26 April 2000; Accepted 2 September 2000


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