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Rheumatology Advance Access originally published online on December 26, 2007
Rheumatology 2008 47(2):142-144; doi:10.1093/rheumatology/kem324
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© The Author 2007. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Anti-Saccharomyces cerevisiae antibodies (ASCA) in spondyloarthropathies: a reassessment

S. Z. Aydin, P. Atagunduz, M. Temel, M. Bicakcigil, D. Tasan and H. Direskeneli

Department of Rheumatology, Marmara University, Faculty of Medicine, Istanbul, Turkey.

Correspondence to: P. Atagunduz, Department of Rheumatology, Marmara University, Faculty of Medicine, Istanbul, Turkey. E-mail: pamiratagunduz{at}yahoo.com


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 Supplementary data
 References
 
Objectives. Seronegative spondyloarthropathies, especially ankylosing spondylitis (AS), is shown to be associated with inflammatory bowel disease. Anti-Saccharomyces cerevisiae antibodies (ASCA) is a valid serological marker for Crohn's disease. Presence of ASCA is controversial in AS. In this study, we aimed to investigate the prevalence of ASCA in spondyloarthropathies and its relationship with disease activity and severity.

Methods. One hundred and seventy-five patients with AS, 47 patients with undifferentiated spondyloarthropathy (uSpA) and 103 healthy controls (HCs) were studied. All patients were questioned for demographic features and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) scores. Radiological damage is assessed by Bath Ankylosing Spondylitis Radiology Index (BASRI) and modified Stroke Ankylosing Spondylitis Spinal Score (mSASSS). ASCA levels were measured with standard ELISA kits.

Results. There was an overall increased prevalence of ASCA IgA in AS and uSpA compared with HCs (20.6 and 19.1% vs 5.8%, P = 0.0008 and P = 0.02, respectively). No association was observed between ASCA positivity and erythrocyte sedimentation rate, C-reactive protein levels and BASDAI scores. However, ASCA-positive patients had higher BASRI scores [median BASRI: 7 (2–12) vs 6 (2–12); P = 0.037]. Although not reaching significance, they also had reduced chest expansion and higher Bath Ankylosing Spondylitis Functional Index (BASFI) scores. ASCA-positive AS patients also required anti-tumour necrosis factor therapy more frequently (P = 0.006).

Conclusions. ASCA IgA seems to be more prevalent in AS and uSpA. ASCA can also be a marker of radiological damage and a more severe course in AS.

KEY WORDS: ASCA, Spondyloarthropathies, Radiographic assessment, Severity


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 Supplementary data
 References
 
The relationship between spondyloarthropathies and inflammatory bowel disease has been shown in many studies [1–6]. The ileocolonoscopic studies of patients with ankylosing spondylitis (AS) revealed inflammatory changes in 60% of asymptomatic patients [1–4]. On the other hand, joint and spine involvement in Crohn's disease (CD) is observed in up to 26% of the patients with a similar pattern of AS [5–6].

Anti-Saccharomyces cerevisiae antibodies (ASCA) are elevated in CD. It has been suggested as a serological marker for the diagnosis of undetermined inflammatory bowel disease, especially by combining with perinuclear anti-neutrophil cytoplasmic antibodies rising in 45–80% of the patients with ulcerative colitis (UC) [7–10].

Depending on the close relationship between AS and CD, ASCA has also been investigated in AS. Two previous studies showed an increased prevalence of ASCA IgA positivity in AS; however, a third study failed to show the same results [11–13]. A group of undifferentiated spondyloarthropathy (uSpA) patients were included in two of these studies and ASCA IgA were found to be elevated also in both of them [11–12].

Although there seems to be a weak correlation, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels are used as markers to determine disease activity in AS. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) is a scoring system based on self-assessment of the patient and has been accepted as a valid tool for determining disease activity [14]. ESR and CRP levels were investigated and found to be correlated with ASCA positivity [11]. There are also unpublished data investigating the relationship between BASDAI scores and ASCA positivity, observing no association [15–16]. The relationship between ASCA and radiological involvement has previously not been studied.

In this study, we aimed to investigate the positivity of ASCA in AS and uSpA and the relationship between ASCA positivity and BASDAI, Bath Ankylosing Spondylitis Functional Index (BASFI) scores, ESR, disease duration and radiological damage [Bath Ankylosing Spondylitis Radiology Index (BASRI) and modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS), respectively].


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 Supplementary data
 References
 
Patients
One hundred and seventy-five patients with AS and 47 patients with uSpA followed in the Rheumatology Department of Marmara University, Faculty of Medicine were investigated. One hundred and three healthy controls (HCs) were also included. AS diagnosis was based on the revised New York criteria and uSpA was classified according to the European Spondylarthropathy Study Group Preliminary Criteria [17, 18]. Age, gender, disease duration, therapies, BASDAI scores, ESR and HLA-B27 positivity were recorded. BASRI and mSASSS scores were calculated by an experienced rheumatologist, using lateral cervical, two-sided lumbar and sacroiliac radiographic films in AS patients.

The study was approved by the Ethical Committee of Marmara University Medical School and informed consent was obtained from all patients and controls.

Detection of ASCA
Sera of patients and controls were collected by centrifugation of venous blood samples and stored at –20°C. ASCA IgA and IgG were detected by using the commercial kit, BINDAZYMETM EIA Kit (The Binding Site Ltd, Birmingham, UK). The manufacturer's instructions were followed. Duration of all incubations were 30 min. Ten microlitres of samples were diluted with 1000 µl of sample diluent. Samples were then added to the mannan-coated wells. After washing, 100 µl of conjugate-containing peroxidase-labelled rabbit anti-human IgA and IgG were dispensed. The bound conjugate was visualized with 100 µl of 3,3',5,5' tetramethylbenzidine substrate. One hundred microlitres of phosphoric acid were added to each well to stop the reaction. The optical density of each well was determined at 450 nm on a microplate reader. The quantitative ASCA IgA and IgG results were obtained in U/ml units and accepted as positive according to the cut-off values by the manufacturer's instructions.

Statistical analysis
Comparison among the groups was done by either Mann–Whitney U-test or unpaired t-test, according to the variability. Normality was tested with the Kolmogornov–Smirnov test and visual analysis of normality Q–Q plot. Variables were compared using Fisher's exact test. Statistical analysis was performed with SPSS statistical package (version 13.0 for Windows) and P-values <0.05 were considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 Supplementary data
 References
 
The female/male ratio was similar in AS and HC (69/106 vs 41/62); more female patients were observed in uSpA (33/14). Mean age was similar in AS, uSpA and HC (39.7, 38 and 38.5 yrs, respectively). HLA B27 positivity was higher in AS than uSpA (73 vs 34%; P < 0.0001). AS patients also had a longer disease duration (13 ± 9.3 yrs vs 6.6 ± 6.2 yrs; P<0.0001).

ASCA in AS
ASCA IgA positivity was higher in AS compared with HC (20.6% vs 5.8%, P = 0.0008) (Table 1). Although higher, IgG positivity did not reach a significant difference between AS and HC (10.9% vs 5.8%; P = 0.2). ASCA positivity for either IgA or IgG was also higher in the AS group (26.9 vs 10.7%, P = 0.001). HLA-B27 positivity, age and disease duration were independent from ASCA (Table 2). Disease phenotype including peripheral arthritis and uveitis, ESR and CRP levels were similarly unrelated to ASCA status. BASDAI scores in AS were also comparable in both groups.


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  		TABLE 1. ASCA IgA and IgG prevalence in the study group

 

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  		TABLE 2. Patient characteristics in AS according to ASCA positivity

 
Although not significant, chest expansion was more limited in ASCA-positive patients [median (range): 2.5 (1–6) vs 3 (1–9) cm; P = 0.076]. Other Bath Ankylosing Spondylitis Metrology Index (BASMI) scores were similar in both groups. The ASCA-positive group, although not significant, tended to have higher BASFI scores [median (range): 37 (0–78) vs 19.5 (0–92); P = 0.23]. When therapy choices were analysed, a significantly higher percentage of ASCA-positive patients required anti-tumour necrosis factor (TNF) therapy compared with ASCA negatives (P = 0.006) (Table 2).

Radiological damage in AS and ASCA
BASRI scores were available in 111 AS patients. ASCA IgA/IgG-positive patients had higher BASRI levels [median BASRI (range): 7 (2–12) vs 5.5 (2–12); P = 0.037]. The comparison of mSASSS scores of 89 patients, however, failed to show any difference according to ASCA-positivity [median mSASSS (range): ASCA-positive group 11 (0–72) vs 5 (0–72) ASCA-negative group; P = 0.31].

ASCA in uSpA
The number of ASCA IgA-positive and either ASCA IgA or IgG-positive patients were increased in uSpA vs HC (P = 0.02 and P = 0.049, respectively) (Table 1). ASCA IgG positivity were similar in both groups. Age, gender, HLA-B27 positivity and disease phenotype were similar between ASCA-positive and -negative groups. Therapy was also independent from ASCA status, but as only one patient had anti-TNF therapy, this conclusion is based on methotrexate and sulphasalazine usage.


   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
Supplementary data
 References
 
ASCA is used as a serological marker to differentiate CD from UC and combining with p-anti-neutrophil cytoplasmic antibody (ANCA) increases its sensitivity. However, ASCA is not specific for CD and a high prevalence has also been shown in coeliac disease, autoimmune liver disease cystic fibrosis and Behçet's disease [19–22]. In our study, ASCA IgA or IgG positivity rates were increased in AS and uSpA. Parameters about disease activity such as ESR, CRP and BASDAI scores were found to be similar in ASCA-positive and -negative groups. However, markers of disease severity such as anti-TNF treatment and BASRI scores were higher in ASCA-positive patients.

Prevelance of ASCA positivity in spondyloarthritis is controversial in the literature (supplementary data available at Rheumatology Online; Table 3). Hoffman et al. [11] found that ASCA IgA, but not IgG levels, were increased in AS and uSpA. Török et al. [12] investigated ASCA only in HLA-B27-positive patients and the results were similar to Hoffman et al.; mean IgA levels were higher in both AS and uSpA [12]. ASCA IgA positivity was increased in AS, but not in uSpA. However (as the authors agreed), the cut-off was too high for detecting ASCA. The positivity in AS was 5/51 compared with 0/145 in healthy controls; and none of the other patient groups had positive ASCA IgA. A subgroup analysis with limited number of patients for the relationship of bowel inflammation with IgA levels showed no correlation. Riente et al. [13] studied ASCA in AS and psoriatic arthritis. This study failed to show an increased prevalence of ASCA either by comparing means or frequencies in both groups [13]. In an unpublished (only in abstract form) study, Fernández-Sueiro et al. [15] found a suprisingly high ASCA IgG in AS, comparable with CD (61.8% in AS vs 8.1% in HCs). No association was observed between BASDAI scores and ASCA positivity [15]. Our study failed to show any relationship between HLA-B27 and ASCA, similar to Hoffman et al. and Fernández-Sueiro et al. (unpublished data) [11, 16].

The most reasonable explanation for the controversial results in the literature is the methodological difference between the assays. There are two studies comparing ASCA assays; both of them found a large range in sensitivity and specificities [8, 23]. The two studies using the same kit had found similar results in AS, supporting the role of assay-related factors [11, 12]. Another issue is the wide range of both ASCA IgA and IgG levels. ASCA positivity seems to be a better marker than ASCA levels. Patient profile can also be different between the studies as radiological scores were not mentioned in any of them.

The relationship between disease severity and ASCA is not studied previously. In our study, we have shown that ASCA-positive patients had radiologically more severe disease and require anti-TNF therapy more frequently; and although statistically not significant, had reduced chest expansion and higher BASFI scores. As our study is cross-sectional, whether ASCA presence is the result of or a pathogenic factor for disease severity and radiological damage is unclear. However, we may hypothesize that AS patients with advanced disease may have increased intestinal involvement and ASCA positivity may be a bystander marker of ongoing antigenic stimulus. In this hypothesis, ASCA positivity may be a reflection of higher disease activity. Another possibility may be increased intestinal permeability (as shown by ASCA positivity) in AS patients causing a higher radiological damage as a result of ongoing antigenic stimulus. This way, ASCA or similar antigenic stimulus can be a pathogenic factor for a more severe disease course. Further studies investigating ASCA presence, radiological damage and intestinal involvement in AS may clarify this issue.

Formula

Disclosure statement: The authors have declared no conflicts of interest.


   Supplementary data
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Supplementary data
References
 
Supplementary data are available at Rheumatology Online.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Supplementary data
 References
 

  1. Meuwissen SG, Dekker-Saeys BJ, Agenant D, Tytgat GN. Ankylosing spondylitis and inflammatory bowel disease. I. Prevalence of inflammatory bowel disease in patients suffering from ankylosing spondylitis. Ann Rheum Dis (1978) 37:30–2.[Abstract/Free Full Text]
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Submitted 5 August 2007; revised version accepted 1 November 2007.
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