rspНаучно-практическая ревматологияRheumatology Science and Practice1995-44841995-4492IMA-PRESS, LLC10.14412/1995-4484-2009-1307rsp-1189Research ArticleСтатьиArticlesВзаимосвязь иммуногенетических и иммунологических маркеров и их влияние на активность заболевания и рентгенологическое прогрессирование у больных ранним ревматоидным артритомRelationship of immunogenetic and immunologic markers and their influence on disease activity and radiological progression in patients with early rheumatoid arthritisДемидоваН. В.DemidovaN V-200915062009473№3 (2009)1217Copyright © Демидова Н.В., 20092009Демидова Н.В.Demidova N.V.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/1189

Цель. Изучить взаимосвязь SE (shared epitope), АЦЦП и IgМ РФ с активностью заболевания и их прогностическую значимость у больных ранним ревматоидным артритом (рРА). Материал и методы. В исследование включено 98 (78жен., 20муж.) больных с ранним РА, ср. возраст 47,9 ±13,7г., длительность симптоматики 7,4±5,8мес., РФ-положительных 67( 68,4 %), АЦЦП позитивных 63(64,3%). Наличие 1 или2 SE (SE+/ SE+ или SE+/ SE-) было определено у 63 (64,3%), а отсутствие SE у35(35,7%). У 45(45,9%) определялась совместная комбинация АЦЦП+/SE+. У38(38,7%) выявлено сочетание SE, АЦЦП и РФ. Активность РА оценивалась по интегральному индексу DAS28, функция- с помощью индекса HAQ. На иммунонефелометрическом анализаторе (BN-100, Dade Behring, Германия) определяли концентрацию С-реактивного белка (hsСРБ). IgMРФ ревматоидный фактор (РФ)-определялся иммунонефелометрическим методом на автоматическом анализаторе (BN-100, Dade Behring, Германия. АЦЦП2 определяли ИФМ с помощьюкоммерческих наборов “Axis Shield Diagnostics” (Великобритания). Геномная ДНК была выделена методом солевой экстракции с использованием хлорида натрия. Олиготипирование генов HLA-DRB1 проводилось методом полимеразной цепной реакции с использованием набора реагентов «HLA-DR-ТЕХ» (производитель- НПО «ДНК-Технология», Москва). Результаты: У SE+/ SE- и SE+/ SE+пациентов достоверно выше был уровень АЦЦП, чем в группе SE-/SE- (р=0.004). Между группой больных SE+/АЦЦП+ и всеми остальными группами были выявлены статистически значимые различия по уровню IgМ РФ: 351,7(535,8)МЕ/л и 67,8 (140,7)МЕ/л соответственно (р<0,001, тест Манн-Уитни). Через год динамического наблюдения активность заболевания (DAS28) была достоверно выше у больных при наличии SE+/SE+ (р=0,017). При первичном рентгенологическом обследовании эрозивный артрит определялся у25 (25,5%) больных рРА. Через 12 месяцев эрозивные изменения были выявлены у48(49%) больных. Достоверных различий в частоте эрозивных изменений не было выявлено между группами больных SE+/АЦЦП+ и остальными как в дебюте заболевания, так и через год (р=0,08), но имелась тенденция к более быстрому прогрессированию (новые эрозии появлялись почти в 2 раза чаще) в группах пациентов при наличии SE+ и совместном одновременном определении SE+/АЦЦП+. Заключение: Наличие SE ассоциируется с высоким уровнем АЦЦП, особенно у гомозигот. При сочетанном присутствии SE и АЦЦП уровень IgМ РФ был достоверно выше. Высокая воспалительная активность через год динамического наблюдения сохранялась у пациентов при наличии SE. У 23,5% пациентов отмечено прогрессирование эрозивных изменений в суставах в течение года наблюдения.

Relationship of immunogenetic and immunologic markers and their influence on disease activity and radiological progression in patients with early rheumatoid arthritis. Objective. To study relationship of shared epitope (SE), anti-cyclic citrullinated peptide (ACCP) antibodies and IgM rheumatoid factor (RF) with disease activity and their prognostic significance in pts with early rheumatoid arthritis (RA). Material and methods. 98 pts with early RA (78 female, 20 male, mean age 47,9±13,7 years,mean disease duration 7,4±5,8 years) were included. 67 (68,4%) from them were RF positive 17and 63 (64,3%) – ACCP positive. 1 or 2 SE (SE+/SE- or SE+/SE+) was present in 63(64,3%) pts. SE was absent in 35 (35,7%) pts. 45 (45,9%) pts had ACCP+/SE+ combination.38 (38,7%) pts were SE, ACCP and RF positive. Activity of RA was assessed with DAS28 and functional status – with Russian version of HAQ questionnaire. C-reactive protein (hsCRP) and IgM RF level was evaluated by nephelometric immunoassay (NIA) with automatic analyzer BN-100, Dade Behring, Germany. ACCP2 was measured by NIA with commercial kits “Axis Shield Diagnostics”, Great Britain. Genomic DNA was isolated by salt extraction with sodium chloride. HLA DRB1 gene olygotyping was performed by polymerase chain reaction with kits “HLA-DR-TEX” (manufacturer SIA “DNA-Technology”, Moscow). Results. ACCP level in SE+/SE- and SE+/SE+ pts was significantly higher than in SE-/SE- pts (p=0,004). IgM RF level in SE+/ACCP+ pts significantly differ from the rest: 351,7±535,8IU/l and 67,8±140,7 IU/l respectively (p<0,001, Mann-Whitney test). After one year of follow up disease activity (DAS28) was significantly higher in SE positive pts, in homozygotes (p=0,017). At baseline radiological examination erosive arthritis was present in 25 (25,5%) pts with early RA. After 12 months erosions were revealed in 48 (48,97%) pts. Erosive changes in SE+/ACCP+ pts did not differ from the rest pts at baseline and after one year of follow up (p=0,08). Conclusion. Presence of SE is associated with high ACCP level, particularly in homozygotes. In SE+/ACCP+ pts IgM RF level was significantly higher. After one year of follow up high inflammatory activity was maintained in SE positive pts. Erosive changes progressed in 23,47% of pts during one year of follow up. SE+ and SE+/ACCP+ pts showed a tendency to faster progression (new erosions appeared almost twice more frequently).

ранний ревматоидный артритантицитруллиновые антителаревматоидный факторSE-shared epitopeearly rheumatoid arthritisanti-cyclic citrullinated peptide antibodiesrheumatoid factorshared epitopeReferences<div><p>Насонова В.А., Фоломеева О.М., Эрдес Ш. Ревматические болезни в России в начале XXI века. Научно-практич. ревматол., 2003, 1, 6-10.</p><p>Эрдес Ш., Фоломеева О.М. Проблема ревматических заболеваний в России. РМЖ, 2004, 20, 1121-2.</p><p>Насонов Е.Л. Фармакотерапия ревматоидного артрита с позиций доказательной медицины: новые рекомендации. Русс. мед. журн., 2002, 10(6), 294-301.</p><p>Scott D.L. The diagnosis and prognosis of early arthritis: rationale for new prognostic criteria. Arthritis Rheum., 2002, 46(2), 286-90.</p><p>Bruynesteyn K., Landewe R., van der Linden S., van der Heijde D. Radiography as primary outcome in rheumatoid arthritis: acceptable sample size for trials with 3 months follow up. Ann. Rheum. Dis., 2004, 63, 1413-8.</p><p>Caruso Y., Santandrea S., Sarzi Puttini P. et al. Clinical, laboratory and radiographic fetures in early rheumatoid arthritis. J. Rheum., 1990,10,1263-7.</p><p>Matsuda Y., Yamanaka H., Higami K., Kashiwazaki S. Time lag between active joint inflammation and radiological progression in patients with early rheuma- toid arthritis. J Rheumatol., 1998,25(3),427-32.</p><p>Hannonen P., Mottenen T., Hakola M., Oka M. Sulfasalazine in early rheumatoid arthritis. A 48 week double-blind, prospective, placebo-controlled study. Arthritis Rheum., 1993, 36, 1501–9.</p><p>van der Horst-Bruinsma IE, Speyer I, Visser H et al. Diagnosis and course of early onset arthritis: results of a special early arthritis clinic compared to routine patient care. Br. J. Rheumatol., 1998, 37, 1084–8.</p><p>Quinn M.A., Conaghan P.G., Emery P. The thera- peutic approach of early intervention for rheumatoid arthritis: what is the evidence? Rheumatology (Oxford), 2001, 40, 1211–20.</p><p>Новиков А.А., Александрова Е.Н., Насонов Е.Л. Клиническое значение антител к циклическому цитруллинированному пептиду: новые данные. Клин. мед., 2007,85(8),4-9.</p><p>Mayer O., Labbare C., Moore D. et al. Anticitrulinated protein/peptide antibody assays in early rheumatoid arthritis for predicting five year radiographic damade. Ann. Rheum. Dis.,2003, 62, 120-6.</p><p>Lindqvist E., Eberhardt K., Bendtzen K. et al. Prognostic laboratory markers of joint damage in rheumatoid arthritis. Ann. Rheum. Dis., 2005, 64, 196-201.</p><p>Bukhari M., Lunt M., Harrison B.J. et al. Rheumatoid factor is the major predictor of increasing severity of radiographic erosions in rheumatoid arthritis: results from the Norfolk Arthritis Register Study, a large inception cohort. Arthritis Rheum., 2002, 46, 906-12.</p><p>Quinn M.A., Gough A.K., Green M.J. et al. Anti-CCP antibodies measured at disease onset help identify seronegative rheumatoid arthritis and predict radio- logical and functional outcome. Rheumatology, 2006, 45,478-80.</p><p>Kastbom A., Strandberg G., Lindroos A., Skogh T. Anti-CCP antibody test predicts the disease course during 3 years in early rheumatoid arthritis (the Swedish TIRA project). Ann. Rheum. Dis., 2004, 63, 1085-9.</p><p>Gorman J.D, Lum R.F, Chen J.J et al. Impact of shared epitope genotype and ethnicity on erosive disease: a meta-analysis of 3 240 rheumatoid arthritis patients. Arthritis Rheum., 2004, 50, 400–12.</p><p>Van der Helm-van Mil A.H, Verpoort K.N, Breedveld F.C. et al. Antibodies to citrullinated proteins and differences in clinical progression of rheumatoid arthritis. Arthritis Res. Ther., 2005, 7, 949-58.</p><p>Van Gaalen F.A., van Aken J., Huizinga T.W., et al. Association between HLA class II genes and autoantibodies to cyclic citrullinated peptides (CCPs) influ- ences the severity of rheumatoid arthritis. Arthritis Rheum., 2004, 50, 2113–21.</p><p>Miller S.A., Dykes D.D., Polesky H.F. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res., 1988, 16, 12-5.</p><p>Таукумова Л.А., Гусева И.А. Аллели HLA-DRB1 у пациентов с ревматоидным артритом. Научно-практич. ревматол., 2004, 4,29-34.</p><p>Bas S., Genevay S., Meyer O., Gabay C. Anti-cyclic citrullinated peptide antibodies, Ig M and IgA rheumatoid factora in the diagnosis and prognosis of rheu- matoid arthritis. Rheumatol.,2003,42, 677-80</p><p>Syversen S.W., Gaarder P.I., Goll G.L et al. High anti-cyclic citrullinated peptide levels and an algorithm of four variables predict radiographic progres- sion in patients with rheumatoid arthritis: results from a 10-year longitudinal study. Ann. Rheum. Dis., 2008,67,212-7.</p><p>Hill A.J., Southwood S., Sette A. et al. Cutting edge: the conversation of arginine to citrulline allows for a high-affinity peptide interaction with the rheumatoid arthritis associated HLA-DRB1*0401 MHC class II molecule. J. Immunol., 2003,171,538-41.</p><p>L De Rycke, I Peene, I E A Hoffman et al. Rheumatoid factor and anticitrullinated protein antibodies in rheumatoid arthritis: diagnostic value, associations with radiological progression rate, and extra-articular man- ifestaitions. Ann. Rheum. Dis., 2004,63,1587-93.</p><p>Berglin E., Padyukov L., Sundin U. et al. A combina- tion of autoantibodies to cyclic citrullinated peptide (CCP) and HLA-DRB1 locus antigens is strongly associated with future onset of rheumatoid arthritis. Arthritis Res. Ther., 2004, 6, 303–8.</p><p>Furuya T, Hakoda M, Ichikava N et al. Differential association of HLA-DRB1 alleles in Japanese patients with rheumatoid arthritis in relationship to autoan- tibodies to cyclic citrullinated peptide. Clin. Exp. Rheumatol., 2007,25(2),219-24.</p><p>L Michou, V N Teixeira, C Pierlot et al. Associations between genetic factors, tobacco smoking and autoantibodies in familiai fnd sporadic rheumatoid arthritis. Ann. Rheum. Dis., 2008, 67(4), 466-70.</p></div><br /><div><p>Насонова В.А., Фоломеева О.М., Эрдес Ш. Ревматические болезни в России в начале XXI века. Научно-практич. ревматол., 2003, 1, 6-10.</p><p>Эрдес Ш., Фоломеева О.М. Проблема ревматических заболеваний в России. РМЖ, 2004, 20, 1121-2.</p><p>Насонов Е.Л. Фармакотерапия ревматоидного артрита с позиций доказательной медицины: новые рекомендации. Русс. мед. журн., 2002, 10(6), 294-301.</p><p>Scott D.L. The diagnosis and prognosis of early arthritis: rationale for new prognostic criteria. Arthritis Rheum., 2002, 46(2), 286-90.</p><p>Bruynesteyn K., Landewe R., van der Linden S., van der Heijde D. Radiography as primary outcome in rheumatoid arthritis: acceptable sample size for trials with 3 months follow up. Ann. Rheum. Dis., 2004, 63, 1413-8.</p><p>Caruso Y., Santandrea S., Sarzi Puttini P. et al. Clinical, laboratory and radiographic fetures in early rheumatoid arthritis. J. Rheum., 1990,10,1263-7.</p><p>Matsuda Y., Yamanaka H., Higami K., Kashiwazaki S. Time lag between active joint inflammation and radiological progression in patients with early rheuma- toid arthritis. J Rheumatol., 1998,25(3),427-32.</p><p>Hannonen P., Mottenen T., Hakola M., Oka M. Sulfasalazine in early rheumatoid arthritis. A 48 week double-blind, prospective, placebo-controlled study. Arthritis Rheum., 1993, 36, 1501–9.</p><p>van der Horst-Bruinsma IE, Speyer I, Visser H et al. Diagnosis and course of early onset arthritis: results of a special early arthritis clinic compared to routine patient care. Br. J. Rheumatol., 1998, 37, 1084–8.</p><p>Quinn M.A., Conaghan P.G., Emery P. The thera- peutic approach of early intervention for rheumatoid arthritis: what is the evidence? Rheumatology (Oxford), 2001, 40, 1211–20.</p><p>Новиков А.А., Александрова Е.Н., Насонов Е.Л. Клиническое значение антител к циклическому цитруллинированному пептиду: новые данные. Клин. мед., 2007,85(8),4-9.</p><p>Mayer O., Labbare C., Moore D. et al. Anticitrulinated protein/peptide antibody assays in early rheumatoid arthritis for predicting five year radiographic damade. Ann. Rheum. Dis.,2003, 62, 120-6.</p><p>Lindqvist E., Eberhardt K., Bendtzen K. et al. Prognostic laboratory markers of joint damage in rheumatoid arthritis. Ann. Rheum. Dis., 2005, 64, 196-201.</p><p>Bukhari M., Lunt M., Harrison B.J. et al. Rheumatoid factor is the major predictor of increasing severity of radiographic erosions in rheumatoid arthritis: results from the Norfolk Arthritis Register Study, a large inception cohort. Arthritis Rheum., 2002, 46, 906-12.</p><p>Quinn M.A., Gough A.K., Green M.J. et al. Anti-CCP antibodies measured at disease onset help identify seronegative rheumatoid arthritis and predict radio- logical and functional outcome. Rheumatology, 2006, 45,478-80.</p><p>Kastbom A., Strandberg G., Lindroos A., Skogh T. Anti-CCP antibody test predicts the disease course during 3 years in early rheumatoid arthritis (the Swedish TIRA project). Ann. Rheum. Dis., 2004, 63, 1085-9.</p><p>Gorman J.D, Lum R.F, Chen J.J et al. Impact of shared epitope genotype and ethnicity on erosive disease: a meta-analysis of 3 240 rheumatoid arthritis patients. Arthritis Rheum., 2004, 50, 400–12.</p><p>Van der Helm-van Mil A.H, Verpoort K.N, Breedveld F.C. et al. Antibodies to citrullinated proteins and differences in clinical progression of rheumatoid arthritis. Arthritis Res. Ther., 2005, 7, 949-58.</p><p>Van Gaalen F.A., van Aken J., Huizinga T.W., et al. Association between HLA class II genes and autoantibodies to cyclic citrullinated peptides (CCPs) influ- ences the severity of rheumatoid arthritis. Arthritis Rheum., 2004, 50, 2113–21.</p><p>Miller S.A., Dykes D.D., Polesky H.F. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res., 1988, 16, 12-5.</p><p>Таукумова Л.А., Гусева И.А. Аллели HLA-DRB1 у пациентов с ревматоидным артритом. Научно-практич. ревматол., 2004, 4,29-34.</p><p>Bas S., Genevay S., Meyer O., Gabay C. Anti-cyclic citrullinated peptide antibodies, Ig M and IgA rheumatoid factora in the diagnosis and prognosis of rheu- matoid arthritis. Rheumatol.,2003,42, 677-80</p><p>Syversen S.W., Gaarder P.I., Goll G.L et al. High anti-cyclic citrullinated peptide levels and an algorithm of four variables predict radiographic progres- sion in patients with rheumatoid arthritis: results from a 10-year longitudinal study. Ann. Rheum. Dis., 2008,67,212-7.</p><p>Hill A.J., Southwood S., Sette A. et al. Cutting edge: the conversation of arginine to citrulline allows for a high-affinity peptide interaction with the rheumatoid arthritis associated HLA-DRB1*0401 MHC class II molecule. J. Immunol., 2003,171,538-41.</p><p>L De Rycke, I Peene, I E A Hoffman et al. Rheumatoid factor and anticitrullinated protein antibodies in rheumatoid arthritis: diagnostic value, associations with radiological progression rate, and extra-articular man- ifestaitions. Ann. Rheum. Dis., 2004,63,1587-93.</p><p>Berglin E., Padyukov L., Sundin U. et al. A combina- tion of autoantibodies to cyclic citrullinated peptide (CCP) and HLA-DRB1 locus antigens is strongly associated with future onset of rheumatoid arthritis. Arthritis Res. Ther., 2004, 6, 303–8.</p><p>Furuya T, Hakoda M, Ichikava N et al. Differential association of HLA-DRB1 alleles in Japanese patients with rheumatoid arthritis in relationship to autoan- tibodies to cyclic citrullinated peptide. Clin. Exp. Rheumatol., 2007,25(2),219-24.</p><p>L Michou, V N Teixeira, C Pierlot et al. Associations between genetic factors, tobacco smoking and autoantibodies in familiai fnd sporadic rheumatoid arthritis. Ann. Rheum. Dis., 2008, 67(4), 466-70.</p></div><br />

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