Histocompatibility HLA class I in anterior uveitis patients with and without spondyloarthritis

Anterior uveitis (AU) and ankylosing spondylitis (AS) are associated with histocompatibility human leukocyte antigen (HLA)-B27. Previous genetic studies conducted in different populations have also demonstrated other genetic associations, including HLA, both  general and individual ones for AU and AS.

Objective: to investigate the association of HLA class I with AU depending on the presence or absence of spondyloarthritis (SpA).

Patients and methods. The investigators used the data of HLA class I typing in the patients referred by ophthalmologists for examination to the V.A. Nasonova Research Institute of  Rheumatology, as well as the previous databases of patients with  AS. The investigation included retrospectively two groups of patients with AU: 1) 52 patients with a confirmed diagnosis of SpA (AU + SpA); 2) 96 patients who had other types of AU (idiopathic AU  (n=52), viral uveitis (n=29), multiple sclerosis (n=2) toxoplasmosis  (n=2), sarcoidosis (n=1), tuberculosis (n=1), chlamydiasis (n=3),  Behcet's disease (n=2), juvenile chronic arthritis (n=3), and Fuchs'  heterochromic cyclitis (n=1). A control group consisted of 150 healthy test donors. The distribution of HLA class I (A, B, and Cw) was analyzed when comparing the two groups of patients with AU and each control patient group.

Results. HLA-B27 was detected in 96.1% of cases in the AU + SpA group, in 40.6% in the AU group, and in 7.3% in the controls. In HLA-27-positive patients, the risk (odds ratio (OR) for joint disease  (AU + SpA) was 315.9 (95% confidence interval (CI), 61.9–2176.7); p<0.0000001; the risk for AU was 8.7 (95% CI, 3.9–19.4);  p<0.000001. The HLA-C-locus antigens showed a high incidence of  Cw2 antigen in patients with AU + SpA and in those with AU compared to the controls (64.0, 36.3, and 10.0%, respectively): AU + SpA versus the controls (p<0.000001), AU versus the controls  (p<0.00001). In the two groups of patients with a high HLA-B27  frequency, this substantially higher rate of Cw2 antigen carriage was  natural due to the non-equilibrium coupling phenomenon, including  that for B27 and Cw2 antigens. The rate of Cw7 antigen was significantly lower in the AU + SpA group versus the controls: 12.8 and 38.7% (p=0.002). In the group of AU patients without SpA, the rate of this antigen did not differ significantly from that in the control and AU + SpA groups.

Conclusion. The analysis of the distribution of HLA class I confirmed the association of B27 antigen with AU in the Russian population. There were no associations with other antigens other than Cw2. Cw7 antigen can play a protective role against SpA, since the frequency  of this gene was not lower in AU patients compared to the controls.

1. Brewerton DA, Caffrey M, Nicholls A, et al. Letter: Acute anterior uveitis and HL-A 27. Lancet. 1974 Mar 16;1(7855):464.

2. Robinson PC, Claushuis TA, Cortes A, et al; Spondyloarthritis Research Consortium of Canada, Australio-Anglo-American Spondylitis Consortium, International Genetics of Ankylosing Spondylitis Consortium, Wellcome Trust Case Control Study 2. Genetic dissection of acute anterior uveitis reveals similarities and differences in associations observed with ankylosing spondylitis. Arthritis Rheumatol. 2015 Jan;67(1):140-51. doi: 10.1002/art.38873.

3. Spencer D, Hick H, Dick W. Ankylosing spondylitis - the role of HLA-B27 homozygosity. Tissue Antigens. 1979 Nov;14(5):379-84.

4. Moller P, Vinje O, Berg K. HLA antigens, psoriasis and acute anterior uveitis in Bechterew's syndrome (ankylosing spondylitis). Clin Genet. 1982 Mar;21(3):215-21.

5. Van der Linden S, Valkenburg HA, Cats A. Is uveitis associated with ankylosing spondylitis or with HLA-B27? Br J Rheumatol. 1983 Nov;22(4 Suppl 2): 146-7.

6. Rosenbaum JT. Why HLA-B27? My thirty-year quest: the Friedenwald lecture. Invest Ophthalmol Vis Sci. 2011 Sep 29;52(10):7712-5, 7711. doi: 10.1167/iovs.11-8247.

7. Khan MA, Kushner I, Braun WE. Association of HLA-A2 with uveitis in HLA-B27 positive patients with ankylosing spondylitis. J Rheumatol. 1981 Mar-Apr;8(2):295-8.

8. Robinson PC, Leo PJ, Pointon JJ, et al; Wellcome Trust Case Control Consortium; Australasian Osteoporosis Genetics Consortium (AOGC); Australasian Osteoporosis Genetics Consortium AOGC. The genetic associations of acute anterior uveitis and their overlap with the genetics of ankylosing spondylitis. Genes Immun. 2016 Jan-Feb;17(1):46- 51. doi: 10.1038/gene.2015.49. Epub 2015 Nov 26.

9. Дроздова ЕА. Увеит при ревматических заболеваниях: особенности клиники, диагностика, иммунопатогенез и лечение. Дисс. докт. мед. наук. Екатеринбург; 2006. [Drozdova EA. Uveitis in rheumatic diseases: features of the clinic, diagnosis, immunopathogenesis and treatment. Diss. doct. med. sci. Ekaterinburg; 2006.]

10. Пожарицкая ЕМ, Трубилин АВ, Трубилин ВН. Оценка роли гена HLA B35 в детермизме и эволюции аутоиммунных увеитов. В кн.: Тахчиди ХП, редактор. Актуальные проблемы офтальмологии. VI Всероссийская научная конференция молодых учёных. Сборник научных работ. Москва: Офтальмология; 2011. 286 с. [Pozharitskaya EM, Trubilin AV, Trubilin VN. Evaluation of the role of HLA B35 gene in the determinism and evolution of autoimmune uveitis. In: Takhchidi KhP, editor. Aktual'nye problemy oftal'mologii. VI Vserossiiskaya nauchnaya konferentsiya molodykh uchenykh. Sbornik nauchnykh rabot [Actual problems of ophthalmology. VI all-Russian scientific conference of young scientists. Collection of scientific papers]. Moscow: Oftal'mologiya; 2011. 286 p.]

11. Feltkamp TE. HLA and uveitis. Int Ophthalmol. 1990 Oct;14(5-6):327-33.

12. Ricarova R, Tesinsky P, Salficky P. HLA tying in endogenous uveitis. Cesk Oftalmol. 1993 Aug; 49(4):240-5.

13. Monowarul Islam SM, Numaga J, et al. HLA-DR8 and acute anterior uveitis in ankylosing spondylitis. Arthritis Rheum. 1995 Apr;38(4):547-50.

14. Feltkamp TE. Non-HLA-B27 genetic factors in HLA-B27 associated diseases. Clin Rheumatol. 1996 Jan;15 Suppl 1:40-3.

15. Numaga J, Islam MS, Mitsui H, Maeda H. Anterior uveitis with ankylosing spondylitis and HLA. Nippon Ganka Gakkai Zasshi. 1996 Apr; 100(4):292-5.

16. Goto K, Ota M, Maksymowych WP. Association between MIC A gene A4 allele and acute anterior uveitis in white patients with and without HLA-B27. Am J Ophthalmol. 1998 Sep;126(3):436-41.

17. Martin TM, Kurz DE, Rosenbaum JT. Genetics of uveitis. Ophthalmol Clin North Am. 2003 Dec; 16(4):555-65.

18. Van der Linden S, Valkenburg H, Cats A. Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis Rheum. 1984 Apr;27(4):361-8.

19. Van der Heijde D, Ramiro S, Landew? R, et al. 2016 update of the ASAS-EULAR management recommendations for axial spondyloarthritis. Ann Rheum Dis. 2017 Jun;76(6):978-991. doi: 10.1136/annrheumdis-2016-210770. Epub 2017 Jan 13.

20. Яздовский ВВ, Воронин АВ, Алексеев ПП. HLA-генетический профиль русской популяции. Иммунология. 1998;19(2):30-2. [Yazdovskii VV, Voronin AV, Alekseev PP. HLA- genetic profile of the Russian population. Immunologiya. 1998; 19(2):30-2. (In Russ.)].

21. Derhaag PJ, van der Horst AR, de Waal LP, Feltkamp TE. HLA-B27+ acute anterior uveitis and other antigens of the major histocompatibility complex. Invest Ophthalmol Vis Sci. 1989 Oct;30(10):2160-4.

22. Arnett FC, Hochberg MC, Bias WB. HLA-C locus antigens in HLA-B27associated arthritis. Arthritis Rheum. 1978 Nov-Dec;21(8):885-8.

23. Duquesnoy RJ, Kozin F, Rodey GE. High prevalence of HLA-B27, Cw1 and Cw2 in patients with seronegative spondyloarthritis. Tissue Antigens. 1978 Jul;12(1):58-62 .

24. Гусева ИА, Годзенко АА, Гусейнов НИ и др. Клинико-генетические особенности сочетанных форм серонегативных спондилоартритов. Терапевтический архив. 1997;69(5):43-6. [Guseva IA, Godzenko AA, Guseinov NI, et al. Clinical and genetic features of combined forms of seronegative spondyloarthritis. Terapevticheskii arkhiv. 1997; 69(5):43-6. (In Russ.)].

25. Breban M. Genetic studies of spondylarthropathies. French Spondylarthropathy Genetic Study Group. Ann Med Interne (Paris). 1998 Apr; 149(3):142-4.

26. Kozin F, Duquesnoy R, Rodey GE, et al. High prevalence of HLA-Cw1 and Cw2 antigens in spondylarthritis. Arthritis Rheum. 1978 Nov-Dec; 21(8):889-95.