Skip Navigation

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (23)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Gül, A.
Right arrow Articles by Saruhan-Direskeneli, G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Gül, A.
Right arrow Articles by Saruhan-Direskeneli, G.
Related Collections
Right arrow Vasculitis
Right arrow Immunogenetics
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Rheumatology 2001; 40: 668-672
© 2001 British Society for Rheumatology

Original Papers

Lack of association of HLA-B*51 with a severe disease course in Behçet's disease

A. Gül, F. A. Uyar1, M. Inanc, L. Öcal, I. Tugal-Tutkun2, O. Aral, M. Koniçe and G. Saruhan-Direskeneli1

Division of Rheumatology, Department of Internal Medicine,
1 Department of Physiology and
2 Department of Ophthalmology, Istanbul School of Medicine, University of Istanbul, Istanbul, Turkey


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objective. To investigate the previously reported association of HLA-B51 with the manifestations and severity of Behçet's disease (BD).

Methods. The study group consisted of 148 consecutive BD patients (89 male, 59 female) with a minimum disease duration of 5 yr followed up at an out-patient BD clinic in a tertiary referral centre. The patients were classified into three severity groups (mild, moderate, severe) using a modified form of the BD total activity index. HLA-B alleles were determined by DNA amplification using the polymerase chain reaction and sequential hybridization with sequence-specific oligonucleotide probes.

Results. The frequencies of genital ulceration [odds ratio (OR)=3.1, 95% confidence interval (CI) 1.3–7.5], skin findings (erythema nodosum, folliculitis or acne-like lesions) (OR=4.4, 95% CI 1.1–17.7), a positive skin pathergy test (OR=3.4, 95% CI 1.1–10.9) and eye disease (OR=1.8, 95% CI 0.9–3.7) were all higher in B*51-positive patients. By contrast, no significant association was observed between B*51 positivity and a severe disease course, and B*51 homozygosity did not exhibit a prominent association with the severity of BD. Male sex was found to be the strongest determinant of the severity of BD by logistic regression analysis (OR=4.7, 95% CI 1.9–11.2).

Conclusion. HLA-B*51 does not exhibit a strong association with a more severe disease course in BD. The involvement of other genetic and/or environmental factors seems to be required and to be more important than B*51 for the progression of BD.

KEY WORDS: Behçet's disease, HLA-B51, Uveitis, Homozygosity, Disease severity.


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 References
 
Behçet's disease (BD) is a chronic inflammatory disorder characterized by recurrent oral and genital aphthous ulceration, uveitis and skin lesions. It is now recognized as a systemic vasculitis also affecting the joints, all types and sizes of blood vessels, lungs and the central nervous and gastrointestinal systems [1].

The aetiology of BD is unknown. It has been claimed that immunological dysregulation caused by microbial agents, such as some strains of streptococci or Herpes simplex virus in genetically susceptible individuals, plays an important role in the development of the disease [2, 3]. The strongest evidence of genetic susceptibility of BD is its association with a class I HLA antigen, HLA-B51. This association has been confirmed in different ethnic groups [4–10], although the role of HLA-B51 in the pathogenesis of BD has not yet been clarified. Molecular genetic studies suggest that HLA-B51 might not be pathogenic itself, but indicate linkage disequilibrium with a susceptibility gene very close to the HLA-B locus [11, 12].

The association of HLA-B51 with specific manifestations of BD or a severe disease course has not been studied extensively and there are conflicting reports on the association of HLA-B51 with uveitis and the disease severity [4, 6, 9, 13–18]. This study aimed to investigate whether heterozygosity or homozygosity for HLA-B51 is useful in the definition of subsets of patients characterized either by the development of a particular manifestation of BD or by a more severe disease course.


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 References
 
Patients
The study group consisted of 148 consecutive BD patients (89 male, 59 female) with a minimum disease duration of 5 yr after the fulfilment of International Study Group (ISG) criteria [19], followed at the BD Outpatient Clinic of the Division of Rheumatology, Istanbul School of Medicine. All patients gave written consent prior to blood collection. The control group consisted of 191 ethnically matched, unrelated healthy volunteers.

Clinical evaluation
All of the patients were interviewed and examined, and we examined their clinical charts in the Division of Rheumatology and Department of Ophthalmology for a robust clinical classification. All relevant clinical manifestations that had developed since the onset of BD were recorded on a standard proforma. The patients were then allocated to three severity groups using a modified form of the BD total activity index described by Yazici et al. [20]: 1 (mild), patients with only mucocutaneous findings or acute attacks of arthritis; 2 (moderate), patients with one of: (i) uveitis and >=0.5 best corrected residual visual acuity on the Snellen scale, (ii) deep vein thrombosis of the lower extremities, or (iii) chronic articular disease; 3 (severe), patients with one of: (i) one or more attacks of uveitis in a year, resulting in <0.5 residual visual acuity on the Snellen scale or total loss of vision, (ii) neurological involvement, including sinus thromboses, (iii) thrombosis of the superior and/or inferior vena cavae, including the hepatic veins, (iv) arterial aneurysms and occlusions, or (v) secondary amyloidosis.

In order to investigate the association of HLA-B*51 with the severity of eye disease, patients with uveitis were classified using best corrected residual visual acuity on a Snellen scale as having mild (>=0.5 residual visual acuity) or severe (<0.5 residual visual acuity or total loss of vision) eye disease.

HLA-B typing
Genomic DNA was isolated from peripheral blood using standard methods. Broad-type genotyping of HLA-B alleles was performed by the polymerase chain reaction (PCR) and hybridization with sequence-specific oligonucleotide probes (SSOP) provided by the XIIth International HLA Workshop and Cereb et al., as described previously [21, 22].

Statistical analysis
Differences in mean age at disease onset and disease duration of the patients in the three severity groups were analysed by analysis of variance (ANOVA). Analysis of the association of HLA-B*51 with the manifestations of BD was carried out using the {chi}2 test or Fisher's exact test when appropriate, and the odds ratios (OR) with their 95% confidence intervals (95% CI) were calculated. Frequencies of HLA-B*51 positivity and homozygosity and gender differences in the three severity groups were compared with using the {chi}2 trend test. As male patients and those with a <25-yr age of onset have previously been shown to have a more severe disease course [20, 23], logistic regression analysis was used to identify separate influences of gender, age of onset and HLA-B*51. For logistic regression analysis, the mild and moderate disease severity groups were combined and compared with the severe disease group.


   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 References
 
HLA-B alleles and manifestations of BD
HLA-B*51 was positive in 93 of the BD patients (62.8%) and 47 of the healthy controls (24.6%) (OR=5.2, 95% CI 3.2–8.3). The clinical picture of BD was slightly different in B*51-positive and -negative patients; the frequencies of genital ulceration, skin findings (erythema nodosum, folliculitis or acne-like lesions), positive skin pathergy test and eye disease were higher in the B*51-positive group (Table 1Go). Patients with B*51 carried a higher risk of all of the major manifestations of BD, and the difference was statistically significant for genital ulcers (P=0.018) and skin findings (P=0.032) (Table 1Go).


View this table:
[in this window]
[in a new window]
  		TABLE 1. Frequencies of manifestations in HLA-B*51-positive and -negative BD patients

 

HLA-B*51 and disease severity
The severe disease group consisted mainly of male patients with a younger age of onset when we classified the patients according to the severity criteria mentioned above (Table 2Go). There was no significant difference in the frequency of B*51 between BD patients with a mild, moderate and severe disease course (Table 2Go).


View this table:
[in this window]
[in a new window]
  		TABLE 2. Demographic features and HLA-B*51 status of patients with BD

 
The frequency of B*51 homozygosity in B*51-positive BD patients was similar to that of B*51-positive healthy controls (19.4 and 19.1% respectively), and it was in accordance with Hardy–Weinberg equilibrium. Although the number of B*51-homozygous patients was highest in the severe disease group, the difference did not reach statistical significance (Table 2Go).

The logistic regression analysis revealed the increased risk of severe disease in male patients with BD (Table 3Go). The available data suggested a tendency to having severe disease also in patients with age of onset <25 yr and with a positive family history of BD. However, no effect of B*51 or B*51 homozygosity on the severity of BD was observed.


View this table:
[in this window]
[in a new window]
  		TABLE 3. Logistic regression analysis of disease severity in BD

 
Investigation of the effect of B*51 frequency on the severity of eye disease in 56 patients with uveitis did not reveal any significant difference between patients with mild (n=13, 68.4%) and severe (n=27, 73%) eye disease. We also did not observe a significant increase in the frequency of B*51 homozygosity in patients with severe eye disease (n=3, 23.1% of B*51-positive patients) compared with that in patients with mild eye disease (n=5, 18.5% of B*51-positive patients).

HLA-B*51 and familial aggregation
We recorded a positive family history in 30 index cases, 24 of whom had a first-degree relative with BD. The B*51 phenotype frequency was significantly higher in index patients with a family history of BD compared with other patients (83.3 vs 57.6%, OR=3.7, 95% CI 1.3–10.3, P=0.009). B*51 homozygosity was also found to be strongly associated with familial clustering in this series of patients with BD. Eight of the 30 index patients with a family history of BD were homozygous for B*51 (OR=3.9, 95% CI 1.4–11.1, P=0.006). This association was stronger for 24 index patients who had a first-degree relative with BD, because seven of them were B*51-homozygous (OR=4.2, 95% CI 1.4–12.4, P=0.005).


   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
References
 
Although the association of HLA-B51 with BD has been confirmed in different ethnic groups, it has not yet been clarified whether HLA-B51 is associated with a more severe disease course and/or a specific manifestation of BD, especially uveitis [4, 9, 13, 15–18].

This study has not revealed any remarkable influence of HLA-B*51 on the severity of BD. Since there is no validated disease severity index for BD, we have modified the BD total activity index described by Yazici et al. [20] for allocation of the patients according to disease severity. The index items are in agreement with all previous studies that have examined the problem of disease severity and/or activity in BD [23–25]. Our finding of an approximately five-fold increased risk of severe disease in male patients with BD agrees with the previous reports, as male sex and a younger age of disease onset (<25 yr) are known risk factors for disease severity in BD [20, 23]. These findings suggest that the involvement of other genetic and/or environmental factors is required and is more important than HLA-B*51 for disease progression in BD.

BD is a vasculitis with multisystem involvement, and the severity of the manifestations in different organs or systems may be a source of bias in the evaluation of the association between HLA-B*51 and disease severity. As another approach, we evaluated the influence of B*51 on the severity of eye disease. Similarly, we have not observed any strong association of B*51 allele with the development of uveitis or severe eye disease in BD patients with a minimum disease duration of 5 yr. However, the small number of patients with uveitis in this study prevents us drawing a conclusion in subgroup analyses, such as the association of B*51 homozygosity with the severity of uveitis in female patients.

The frequency of HLA-B51 antigen was higher in male patients with uveitis than in female patients without uveitis in Japan [3]. A peptide (BPD) derived from a common sequence of many HLA-B molecules, including B27 and B51, has previously been shown to share sequence homology with an epitope from the retinal S-antigen (PDS) and to be immunogenic in human and experimental uveitis [26, 27]. It was recently reported that T-cell responses against this cross-reactive epitope were increased in BD patients compared with non-BD patients with anterior uveitis and healthy controls, suggesting a pathogenic role for the development of posterior uveitis in BD [28]. However, some of the previous studies also did not show any association between HLA-B51 positivity and ocular involvement and/or the type of uveitis [6, 16, 17]. Sakamato et al. [17] could not find a difference in HLA-B51 positivity between patient groups with favourable and unfavourable (<0.5 visual acuity or blindness 3 yr after the first visit) outcome for eye disease, and they did not classify the HLA-B51 status as a prognostic factor for vision in patients with BD.

HLA-B*51 positivity and B*51-homozygosity have been found to be associated with familial clustering in our cases. Close association of HLA-B5 antigen with familial disease has been noted previously [29]. The increased B*51 frequency in the familial cases supports the important role of B*51 in the genetic tendency to BD, as does the relatively high number of HLA-DRB1 alleles with the shared epitope in rheumatoid arthritis patients with a positive family history [30].

In conclusion, B*51 heterozygosity or homozygosity does not exhibit a strong association with a more severe disease course, but is associated with familial aggregation in BD. This study confirms previous studies indicating that the male sex is the strongest risk factor for a severe disease course in BD.


   Acknowledgments
 
This study was supported by University of Istanbul Research Fund, Project No. 1076/031297. The authors are grateful to Professor Alan Silman for his critical reading of the manuscript.


   Notes
 
Correspondence to: A. Gul, Division of Rheumatology, Department of Internal Medicine, Istanbul School of Medicine, Capa, 34390 Istanbul, Turkey. Back


   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

  1. Yazici H, Yurdakul S, Hamuryudan V. Behçet's syndrome. Curr Opin Rheum1999;11:53–7.[Medline]
  2. Lehner T, Fortune F, Lavery E, Studd M. Recent advances in T-cell immunoregulation and the microbial causes of Behçet's disease. In: O'Duffy JD, Kökmen E, eds. Behçet's disease: basic and clinical aspects. New York: Marcel Dekker,1991:463–73.
  3. Sakane T, Suzuki N, Nagafuchi H. Etiopathology of Behçet's disease: immunological aspects. Yonsei Med J1997;38:350–8.[Medline]
  4. Ohno S, Ohguchi M, Hirose S, Matsuda H, Wakisaka A, Aizawa M. Close association of HLA-Bw51 with Behçet's disease. Arch Ophthalmol1982;100:1445–58.[Abstract/Free Full Text]
  5. Mizuki N, Ohno S, Tanaka H et al. Association of HLA-B51 and lack of association of class II alleles with Behçet's disease. Tissue Antigens1992;40:22–30.[Medline]
  6. Muftuoglu AU, Yazici H, Yurdakul S et al. Behçet's disease: lack of correlation of clinical manifestations with HLA antigens. Tissue Antigens1981;17:226–30.[Medline]
  7. Chajek-Shaul T, Pisanty S, Knobler H et al. HLA-B51 may serve as an immunogenetic marker for a subgroup of patients with Behçet's syndrome. Am J Med1987;83:666–72.[Web of Science][Medline]
  8. Balboni A, Pivetti-Pezzi P, Orlando P et al. Serological and molecular HLA typing in Italian Behçet's patients: significant association to B51-DR5-DQw3 haplotype. Tissue Antigens1992;39:141–3.[Web of Science][Medline]
  9. Lehner T, Batchelor JR, Challacombe SJ, Kennedy L. An immunogenetic basis for the tissue involvement in Behçet's syndrome. Immunology1979;37:895–900.[Web of Science][Medline]
  10. Kilmartin DJ, Finch A, Acheson RW. Primary association of HLA-B51 with Behcet's disease in Ireland. Br J Ophthalmol1997;81:649–53.[Abstract/Free Full Text]
  11. Mizuki N, Inoko H, Ohno S. Pathogenic gene responsible for the predisposition to Behçet's disease. Int Rev Immunol1997;14:33–48.[Medline]
  12. Ota M, Mizuki N, Katsuyama Y et al. The critical region for Behçet's disease in the human major histocompatibility complex is reduced to a 46-kb segment centromeric of HLA-B, by association analysis using refined microsatellite mapping. Am J Hum Genet1999; 64:1406–10.[Web of Science][Medline]
  13. Yurdakul S, Gunaydin I, Tuzun Y et al. The prevalence of Behçet's syndrome in a rural area in northern Turkey. J Rheumatol1988;15:820–2.[Web of Science][Medline]
  14. Azizlerli G, Aksungur VL, Sarica R, Akyol E, Ovul C. The association of HLA-B5 antigen with specific manifestations of Behçet's disease. Dermatology1994;188:293–5.[Web of Science][Medline]
  15. Gül A, Inanç M, Öcal L, Aral O, Çarin M, Koniçe M. HLA-B51 negative monozygotic twins discordant for Behçet's disease. Br J Rheumatol1997;36:922–3.[Free Full Text]
  16. Soylu M, Ersöz R, Erken E. The association between HLA-B5 and ocular involvement in Behçet's disease in southern Turkey. Acta Ophthalmol1992;70:786–9.
  17. Sakamoto M, Akazawa K, Nishioka Y, Sanui H, Inomata H, Nose Y. Prognostic factors of vision in patients with Behçet's disease. Ophthalmology1995;102: 317–21.[Web of Science][Medline]
  18. Verity DH, Wallace GR, Vaughan RW et al. HLA and tumour necrosis factor (TNF) polymorphisms in ocular Behçet's disease. Tissue Antigens1999;54:264–72.[Web of Science][Medline]
  19. International Study Group for Behcet's Disease. Criteria for diagnosis of Behçet's disease. Lancet1990;335:1078–80.[Web of Science][Medline]
  20. Yazici H, Tuzun Y, Pazarli H et al. Influence of age of onset and patient's sex on the prevalence and severity of manifestations of Behçet's syndrome. Ann Rheum Dis1984;43:783–9.[Abstract/Free Full Text]
  21. Kennedy LJ, Poulton KV, Thomson W et al. HLA class I DNA typing using sequence specific oligonucleotide probes (SSOP). In: Charron D, ed. Genetic diversity of HLA. Functional and medical implication. Paris: EDK, 1997:216–25.
  22. Cereb N, Maye P, Lee S, Kong Y, Yang SY. Locus-specific amplification of HLA class I genes from genomic DNA: locus-specific sequences in the first and third introns of HLA-A, -B and -C alleles. Tissue Antigens1995;45:1–11.[Web of Science][Medline]
  23. Dilsen N, Koniçe M, Aral O, Öcal L, Inanc M, Gul A. Risk factors for vital organ involvement in Behçet's disease. In: Wechsler B, Godeau P, eds. Behçet's disease. Amsterdam: Excerpta Medica,1993:165–9.
  24. Fresko I, Soy M, Hamuryudan V et al. Genetic anticipation in Behçet's disease. Ann Rheum Dis1998;57:45–8.[Abstract/Free Full Text]
  25. Krause I, Uziel Y, Guedj D et al. Childhood Behçet's disease: clinical features and comparison with adult-onset disease. Rheumatology1999;38:457–62.[Abstract/Free Full Text]
  26. Wildner G, Thurau SR. Cross-reactivity between an HLA-B27-derived peptide and a retinal autoantigen peptide: a clue to major histocompatibility complex association with autoimmune disease. Eur J Immunol1994;24:2579–85.[Web of Science][Medline]
  27. Märker-Hermann E, zum Büschenfelde K-HM, Wildner G. HLA-B27-derived peptides as autoantigens for T lymphocytes in ankylosing spondylitis. Arthritis Rheum1997;40:2047–54.[Web of Science][Medline]
  28. Kurhan-Yavuz S, Direskeneli H, Bozkurt N et al. Anti-MHC autoimmunity in Behçet's disease: T cell responses to an HLA-B-derived peptide cross-reactive with retinal-S antigen in patients with uveitis. Clin Exp Immunol2000; 120:162–6.[Web of Science][Medline]
  29. Arber N, Klein T, Meiner Z, Pras E, Weinberger A. Close association of HLA-B51 and B52 in Israeli patients with Behçet's syndrome. Ann Rheum Dis1991;50:351–3.[Abstract/Free Full Text]
  30. Laivoranta-Nyman S, Möttönen T, Luukkainen R et al. Immunogenetic differences between patients with familial and non-familial rheumatoid arthritis. Ann Rheum Dis2000;59:173–7.[Abstract/Free Full Text]
Submitted 30 August 2000; Accepted 14 December 2000


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Arch OphthalmolHome page
J. K. Ahn and Y. G. Park
Human Leukocyte Antigen B27 and B51 Double-Positive Behcet Uveitis
Arch Ophthalmol, October 1, 2007; 125(10): 1375 - 1380.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (23)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Gül, A.
Right arrow Articles by Saruhan-Direskeneli, G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Gül, A.
Right arrow Articles by Saruhan-Direskeneli, G.
Related Collections
Right arrow Vasculitis
Right arrow Immunogenetics
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?