References

rsp

Научно-практическая ревматология

Rheumatology Science and Practice

1995-44841995-4492

IMA-PRESS, LLC

10.14412/1995-4484-2004-798

rsp-935

Research Article

Статьи

Articles

Аллели HLA-DRB1 у пациентов с ревматоидным артритом

HLA-DRB1 alleles in patients with rheumatoid arthritis

Taukumova

L A

Taukumova

L A

Guseva

I A

Guseva

I A

2004

15082004

424

№4 (2004)

2934

2004

Taukumova L.A., Guseva I.A.

Данная работа распространяется под лицензией Creative Commons Attribution 4.0.

This work is licensed under a Creative Commons Attribution 4.0 License.

https://rsp.mediar-press.net/rsp/article/view/935

Цель. Изучить распределение частот аллелей HLA-DRBI и его возможных ассоциаций у пациентов русской популяции с длительно текущим РА. Материал и методы. В исследование включено 44 пациента с достоверным РА, средний возраст 53,7 г. (30-72), средняя длительность болезни 13,6 л. (5-31). Базисную терапию одним или комбинацией двух препаратов получали 95% больных. Рентгенологическая оценка изменений в кистях и стопах проводилась по методу A. Larsen. HLA-DRBI типирование выполнено методом ПЦР. Группу контроля составили 135 здоровых доноров крови. Результата!. Изучение распределения алеллсй HLA-DRBI показало, что больные с РА в 45,5% случаев имели в своем генотипе хотя бы один аллель HLA-DR*04 (п=27), в контрольной группе - в 12.6% (р<0,0005, OR=6,3). В зависимости от серопозитивности по РФ среди пациеитов- носителей DRBI*04 аллеля 20 чел. (74%) были РФ+, среди 12 РФ- больных DRB1*04 определялись у 7 (58%). Рентгенологическая деструкция суставов была достаточно выраженной как у пациентов с DR4 +. так и с DR4 92% и 71%, соответственно. Ретроспективный анализ возможного влияния НLA-статуса на выбор базисного препарата в начале болезни и на момент включения в исследование показал, что в начале болезни применялись аминохинолиновые препараты (АХП) одинаково часто у всех пациентов вне зависимости от DR4-принадлежности. На момент включения в исследование метотрексат несколько чаше назначали как в целом по группе (р<0,0012), так и у 12 DR4+ больных (44%), в сравнении с 3 DR4- -пациентами (18%), но без значимого отличия (р>0,05). У DR4(-) пациентов с меньшей костной деструкцией достоверно чаше применялся сульфасалазин ((р<0,05). Комбинация базисных препаратов с ГК у DR4+ больных использовалась более активно, но без существенного преимущества. Наличие в генотипе бального HLA-DRBI*04 аллеля определяло его взаимосвязь с фактором времени начала терапии (г=0,32, р<0,04) и функциональной способностью суставов (1=0,35, р<0,05). Заключение. РА у пациентов российской популяции характеризовался высокой частотой носи- тельства DRBI*04 аллеля и низкой частотой DRBI‘07 аллеля, выполняющего протективную роль в отношении развития заболевания. Носительство DRBI*04 аллеля, вероятно, можно включить в перечень прогностических факторов течения РА. Необходимо проведение больших проспективных долгосрочных исследований для определения роли специфических генетических маркеров, ассоциированных с тяжестью заболевания, в вопросе стратегии базисной терапии

Objective. To examine the distribution of HLA-DRBI alleles frequency in pts (pts) with protracted rheumatoid arthritis in Russian population. Material and methods. 44 pts with RA (ACR criteria) with a mean age 53,7 yrs (30-72), a mean disease duration 13,6 yrs (5-31) were included. 95% of pts were taken a monotherapy or combination of DMARDs. Radiographic damage assessment in wrists and foots was examined by Larsen method. HLA- DRBI typing was performed using PCR method. 135 health donors were a control group. Results. 27 RA pts had HLA-DRB*04 alleles (45,5%) , in control - in 12,6 %, respectively (p<0,0005, OR=6,3). DRBI*04 positive pts were 24 RF(+), along 12 RF(-) pts DR4-positive were 7 pts (74% versus 58%). Radiographic destruction was equally severe both in DR4(+) pts anf DR4(-) pts, 92% and 71% respectively (NS). Retrospective analysis of determination of the influence of DMARD choice showed that Amimalarics were applied at the onset of disease. At the present time Methotrexate was frequently administered both in all pts (p<0,0012) and in 12 DR4(+) pts (44%) in comparison with 3 DR4(-) pts (18%), (NS). The DR(-) pts who had moderate joint damage were taken Sulphasalazine. Combination therapy with DMARD and steroids was used more active in pts with DRB1*04 (NS). HLA-DRBI*04 had an association with factor of beginning time of DMARDs therapy (r=0,32, p<0,04) and a functional activity (r=0,35, p<0,05). Conclusion. The previously results showed that RA in Russian population is associated with a high frequency of DRBI*04 alleles and low frequency of DRBI*07 which had a protective role for disease course. HLA-DRBI*04 possibly could be included in the list of prognostic factors of RA. Large prospective long-term investigations are needed for the determination of specific genetic markers at the onset of RA that may be valuable for predicting the disease severity and selecting appropriate therapy.

ревматоидный артриткостная деструкциябазисная терапияфакторы прогноза

IILA-DRBIrheumatoid arthritisjoint damageDMARDs therapyHLA-DRBprediction factorsgenotypes

References1

<div>Евсеева И.В, Болдырева М.Н., Грудакова Е. и др. Им- муногенетическая характеристика коренных народностей Севера европейской территории России. Иммунология. 2001, 5, 22-26.Клинико-генетические аспекты ревматических заболеваний. Л.И. Беневоленская. В.А. Мякоткин, М.Ондра- шик, Б.Гемер. - М., Медицина, 1989, 99-141,Яковлева Д.Б., Беневоленская Л.И., Орлов-Морозов А.В., Калинина Н.М. HLA-DR при ревматоидном артрите. Тер. архив.,1981.,184.Boyum A. Separation of leukocytes from blood and bone marrow. Scand. J. Clin. Lab. Invest., 1968, 21, 97, 7782.Brown J.N., Jardelzky T.S., Gorga J.C. el al. Three-dimensional structure of the human class 2 histocompatibility antigen HLA-DRI. Nature, 1993, 364, 33-39.Combe B., Dougados М., Goupille P. et al. Prognostic factors for radiographic damage in early rheumatoid arthritis: a multiparameter study. Arthr, Rheum., 2001, 44, 1736-43.Combe B, Eliaou J-F, Daures J-P. et al. Prognostic factors in rheumatoid arthritis. Comparative study of two subsets of patients according to severity of articular damage. Br, J. Rheumatol., 1995, 34, 529-534.Crilly A., Maiden N. Capell H.A., Madhok R. Genotyping for disease associated HLA-DR beta I alleles and the need for early joint surgery in rheumatoid arthritis: a quantitative evaluation. Ann. Rheum. Dis,, 1999, 58, 114-117.Del Rincon I., Escalante A. HLA-DRBI alleles associated with susceptibility or resistance to rheumatoid arthritis, articular deformities, and disability in Mexican Americans. Arthr. Rheum., 1999,42, 1329-1338.Fries J.F., Wolfe F., Apple R. et al.HLA-DRBI genotype associations in 793 white patients from a rheumatoid arthritis inception cohort: frequency, severity and treatment bias. Arthr. Rheum., 2002, 40, 2320-2329.Gao X., Gazit E., Livneh A,. Sasny P. Rheumatoid arthritis in Israeli Jews: Shared sequences in the third hypervariable region of DRBI alleles are associated with susceptibility. J. Rheumatol., 1991. 18. 801-803.Gonzalez-Gay M.A., Hajeer A.H., Garcia-Porrua C. et al. Patients chosen for treatment with cyclosporine because of severe rheumatoid arthritis are more likely to carry HLA- DRBI shared epitope alleles, and have earlier disease onset. J. Rheumatol., 2002, 29, 271-275.Gregerson P.K., Silver J., Winchester R.J. The shared epitope hypothesis: An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthr. Rheum,, 1987, 30, 1205-12013.Harris E.D. Jr. Rheumatoid arthritis. Pathophysiology and implications for therapy. N. Engl. J. Med., 1990, 322, 12771289.Khani-Hanjani A., Horne C., Lacaille D. et al. HLA-classgene frequencies and disease severity In rheumatoid arthritis [abstact], J. Rheumatol., 1998. 25, suppl. 52, 45.Khani-Hanjani A., Lacaille D., Horne C. et al. Expression of QK/QR/RRRAA or DERAA motifs at the third hypervariable region of HLA-DRBI and disease severity in rheumatoid arthritis. J. Rheumatol., 2002, 29, 1358-1365.Larsen B.A., Alderdice C.A., Hawkin D., et al. Protective HLA-DR phenotypes in rheumatoid arthritis. J. Rheumatol., 1989, 16, 455-458.Larsen A., Dale K., Eek M. Radiographic evaluation of rheumatoid arthritis and realted cinditions by standard reference films. Acta Radiol. Diagn. 1977, 45, 491-497.MacGregor A., Oilier W., Thomson W., el al. HLA- DRBI*401/404 genotype and rheumatoid arthritis: increased association in men, young age at onset and disease severity. J. Rheumatol., 1995, 22, 1032-1036.Masi A.T., Maldonado-Cocco J.A., Kaplan S,B. et al. Prospective study of the early coutse of rheumatoid arthritis in young adults: comparison of patients with and without rheumatoid factor positivily at entry and identification of variables correlating with outcome. Semin. Arthr. Rheum., 1976, 4, 299-326.Matley D.L., Hassel A.B., Dawes РЛГ. et al. Independent association of rheumatoid factor and the HLA-DRBI shared epitope with radiographic outcome in rheumatoid arthritis. Arthr. Rheum., 2001, 44, 1529-1533.Mattey D.L., Hassel A.B., Plant M.J. The influence of HLA-DRBI alleles encoding the DERAA amino acid motif on radiological outcome in rheumatoid arthritis. Rheumatol., 1999, 38. 1221-1227.Meyer J.M., Evans Т.1., Small R.E. et al. HLA-DRBI genotype influences risk for and severity of rheumatoid arthritis. J. Rheumatol., 1999, 26, 1024-1034.Mody G.M., Hammond M.G. Dilferences in HLA-DR association with rheumatoid arthritis among migrant Indian communities in South Africa. Br. J. Rheumatol. 1994, 33, 425-427.Moreno 1., Valenzuela A., Garcia A. el al. Association of the shared epitope with radiological severity of rheumatois arthritis. J. Rheumatol., 1996, 23, 6-9.Morgan G.J., Chow W.S. Clinical features, diagnosis and prognosis in rheumatoid arthritis. Cure. Opin. Rheumatol., 1993, 5, 184-190.Nelson J.L., Boyer G., Templin D. ct al. HLA antigens and Tlingit Indians with rheumatoid arthritis. Tissue Antigens, 1992, 40, 57-63.Nepom G.T., Gersuk V. Nepom B.S. Prognostic implications of HLA genotyping in the early assessment of patients with rheumatoid arthritis. J. Rheumatol., 1996, 23, suppl. 44, 5-9.O'Dell J.R., Nepom B.S., Haire C. et al. HLA-DRBI typing in rheumatoid arthritis: predicting response to specific treatments. Arthr. Rheum., 1998, 57, 209-213.Ohta N. Nishimura Y.K., Tanimoto K. et al. Association between HLA and Japanese patients With rheumatoid arthritis. Hum. Immunol., 1982, 5, 123.Oilier W.E.R., Hajeer A. Does the HLA-DRBI shared epitope really contribute that much to the development or severity of rheumatoid arthritis? In: lsenberg D.A, Tucker L.B., editors. Controversies in Rheumatology. London, Marhn Dunitz, 1997, 1-12.Oilier W. Thomson W. Population genetics of rheumatic diseases. Rheum. Dis. Clin. North. Am., 1992, 741-759.Penzotti J.E., Doherty D., Lybrand T.P., Nepom G.T. A structural model for TCR recognition of the HLA class 2 shared epitope sequence implicated in susceptibility to rheumatoid arthritis. J. Autoimmuii., 1996, 9, 287-293.Perdgriger A., Charles G., Semana G. et al. Role of HLA- DR-DR and DR-Dq associations in the expression of extraarticular manifestations and rheumatoid factor in rheumatoid arthritis, J. Rheumatol., 1997, 24, 1272-1276.Pincus Т., Callachan L.F., Vaugh W.K. Questionnaire, walking time and button test measures of functional capacity as predictive markers for mortality in rheumatoid arthritis. J. Rheumatol., 1987, 14, 240-251.Proceedings of the Twelth International Hystocompatibility Workshop and the Confrence, V.11, 1997, EDK, Paris, France. Ed. By D. Charron., 584-595.Rau R., Herborn G., Zueger S., Fenner H. The effect of HLA-DRBI genes, rheumatoid factor, and treatment on radiographic disease progression in rheumatoid arthritis over 6 years. J. Rheumatol., 2000, 27, 2566-2575.Reveille J.D. Alarcon C.S., Fowler S.E. et al. HLA-DRBI genes and disease severity in rheumatoid arthritis. Arthr. Rheum. 1996, 39, 1802-1807.Reviron D., Perdriger A., Toussirot E. el al. Influence of shared epilope-negarive HLA-DRBI alleles on genetic susceptibility to rheumatoid arthritis. Arthr. Rheum. 2001, 44, 535-540.Salvarini C., Macchioni P., Mantovani W. et al. Extraarticular manifestations of rheumatoid arthritis and HLA antigens in northern Italy. J, Rheumatol., 1992, 19, 242-246.Sattar M.A., Al-SafTar М. Guindi RT. et al. Association between HLA_DR antigens and rheumatoid arthritis in Arabs. Ann. Rheum. Dis., 1990,49, 147-149.Scott D.L., Symmons D.P., Couton B.L., Popert A.J. Long-term outcome of treating rheumatoid arthritis: results after 20 years. Lancet, 1987, I, 1108-1111.Seglias J., Li E.K., Cohen M.G. et al. Linkage between rheumatoid arthritis susceptibility and the presence of HLA-DR4 and DR beta allelic third hypervariable region sequences in southern Chinese petsons. Arthr. Rheum., 1992, 35, 163.Seidl C., Koch U., Buhleier T. et al. Association of (Q)R/KRRAA positive HLA-DRBI alleles with disease progression in early active and severe rheumatoid arthritis. J. Rheumatol., 1999. 26. 773-776.Seidl С., Korbitzer J. Badenhoop К. et al. Protection against severe disease is conferred by DERAA-bearing HLA-DRBI alleles among HLA-DQ3 and HLA-DQ5 positive rheumatoid arthritis patients. Hum. Immunol., 2001,62, 523-529.Sellick K., Littlejohn G., Wallace C. Over R. Identifying subclasses of patients with rheumatoid arthritis through cluster analysis. J. Rheumatol., 1990, 17, 1613-1619.Singal D.P., Reid B., Green D. et al. DNA restriction fragment length polymorphism of HLA-DR2 haplotypes in normal individuals and in patients with rheumatoid arthritis. Ann. Rheum. Dis. 1990, 49, 143-146.Suarez-Almazor M.E., Tao S., Moustarah F. et al. HLA- DRI, DR4 and DRB I disease related subtypes in rheumatoid arthritis. Association with susceptibility bur not severity in a city wide community based study. J, Rheumatol., 1995, 22. 2027-2033.Thomson W„ Harrison B., Oilier B. et al. Quantifying the exact role of HLA-DRBI alleles in susceptibility to inflammatory polyarthritis: results from a large, population-based study. Arthr. Rheum., 1999, 42, 757-762.Thomson W., Pepper L., Payton T. et al. Absence of an association between HLA-DRB I*04 and RA in newly diagnosed cases from the community. Ann. Rheum. Dis., 1993, 52, 539-541.Toussirot E., Auge B., Tiberghien P. et al. HLA-DRBI alleles and shared amino acid sequences in disease susceptibility and severity in patients from eastern France J. Rheumatol., 1999, 26, 1446-1451.Van der Heijde D.M.F.M., van Riel P.L.C.M., van Leuween M.A. et al. Prognostic factors for radiographic damage and physical disability in early rheumatoid arthritis: a prospective follow-up study of 147 patients. Br. J. Rheumatol., 1992, 31, 519-525.Van Zeben D., Hazes J.M.W., Zwindernian A.H. Association of HLA-DR4 with a more progressive disease course in patients with rheumatoid arthritis. Arthr. Rheum., 1991, 34, 822-830.Van Zeben D., Hazes J.M.W., Zwinderman A.H. et al. Factors predicting outcome of rheumatoid arthritis: results of a follow-up study. J. Rheumatol., 1993, 20. 1288-1296.Wagner U., Kaltenliauser S., Sauer H. et al. HLA markers and prediction clinical course and outcome in rheumatoid arthritis. Arthr. Rheum., 1997, 40, 341-351.Weyand C.M., Goronzy JJ. Inherited and noninherited risk factors in rheumatoid arthritis. Curr. Opin. Rheumatol., 1995, 7, 206-213.Weyand C.M., Hicok K.C., Conn D.L., Goronzy J.J. The influence of HLA-DRBI genes on disease severity in rheumatoid arthritis. Ann. Intern. Med., 1992, 117, 801806.Weyand C.M., Xie C., Goronzy J.J. Homozygosity for the HLA-DRBI allele selects for extraarticular manifestations in rheumatoid arthritis. J. Clin. Invest. 1992, 89, 20332039.Zanelli E., Gonzalez-Gay M.A., David C.S. Could HLA- DRBI be the protective locus in rheumatoid arthritis? Immunol. Today. 1995. 16, 274-278.Zanelli E., Vos Koen, Visser H. et al. HLA-DQ-associaled predisposition to and dominant HLA-DR-associated protection against rheumatoid arthritis. Rheumatol., 2001, 40, 133-139.</div>

The authors declare that there are no conflicts of interest present.