Клинико-морфологические варианты и факторы риска поражения почек при ревматоидном артрите
Клинико-морфологические варианты и факторы риска поражения почек при ревматоидном артрите
Чеботарева Н.В., Гуляев С.В., Андросова Т.В. и др. Клинико-морфологические варианты и факторы риска поражения почек при ревматоидном артрите. Терапевтический архив. 2020; 92 (5): 55–60. DOI: 10.26442/00403660.2020.05.000604
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Chebotareva N.V., Gulyaev S.V., Androsova T.V., et al. Clinicopatological variants and risk factors for chronic kidney disease in rheumatoid arthritis. Therapeutic Archive. 2020; 92 (5): 55–60. DOI: 10.26442/00403660.2020.05.000604
Клинико-морфологические варианты и факторы риска поражения почек при ревматоидном артрите
Чеботарева Н.В., Гуляев С.В., Андросова Т.В. и др. Клинико-морфологические варианты и факторы риска поражения почек при ревматоидном артрите. Терапевтический архив. 2020; 92 (5): 55–60. DOI: 10.26442/00403660.2020.05.000604
________________________________________________
Chebotareva N.V., Gulyaev S.V., Androsova T.V., et al. Clinicopatological variants and risk factors for chronic kidney disease in rheumatoid arthritis. Therapeutic Archive. 2020; 92 (5): 55–60. DOI: 10.26442/00403660.2020.05.000604
Исследования последних лет продемонстрировали высокий риск поражения почек и ассоциированных сердечно-сосудистых осложнений у больных ревматоидным артритом (РА), что в целом определяет прогноз этих пациентов. Однако частота хронической болезни почек (ХБП) при РА в российской когорте больных точно не установлена. Цель. Установить частоту, а также оценить морфологические варианты и факторы риска поражения почек у больных РА.
Материалы и методы. Обследованы 180 больных РА, наблюдавшихся в Клинике нефрологии, внутренних и профессиональных заболеваний им. Е.М. Тареева за период с 2014 по 2019 г. Оценивали следующие показатели: возраст, пол, длительность заболевания, наличие внесуставных появлений, а также клинико-лабораторные показатели активности заболевания, включая СОЭ, С-реактивный белок (СРБ), уровень ревматоидного фактора и индекс активности DAS28-СОЭ. Из общепопуляционных факторов риска ХБП оценивали индекс массы тела, наличие и степень артериальной гипертензии (АГ), показатели липидного и углеводного обмена. Результаты. Частота ХБП у больных РА составила 19,7%. Факторами риска развития ХБП III стадии и выше у больных РА являлись возраст, наличие и тяжесть АГ, нарушение липидного обмена, а также высокие показатели активности болезни – СОЭ, СРБ, индекса DAS28-СОЭ и длительность РА, в многофакторном регрессионном анализе независимое влияние имели длительность РА, возраст, АГ и гиперхолестеринемия. Среди морфологических вариантов поражения почек наиболее часто встречался амилоидоз (50,0%), который ассоциирован с большей длительностью заболевания и повышенным уровнем СРБ. ХГН выявлялся в 30,4% случаев, при этом преобладали мезангиальные формы гломерулонефрита. Тубулоинтерстициальный нефрит определялся в 19,6% случаев. У 31 (36,0%) из 86 больных выявлено изолированное снижение скорости клубочковой фильтрации менее 60 мл/мин. Заключение. Факторы риска ХБП у больных РА помимо общепопуляционных факторов – активность и длительность заболевания. Наиболее частой формой поражения почек является амилоидоз, который в отличие от хронического гломерулонефрита ассоциирован с персистирующим высоким уровнем белков воспаления и большей длительностью заболевания.
Recent studies have shown a high risk of chronic kidney disease and associated cardiovascular complications in patients with rheumatoid arthritis (RA), which determines the prognosis. However, the prevalence of chronic kidney disease (CKD) in RA has not been established in the Russians. Aim. Study was to examine the prevalence, risk factors and histological variants of CKD in RA. Materials and methods. 180 patients with rheumatoid arthritis were observed in the Tareev clinic of nephrology, for the period from 2014 to 2019 years. Age, gender, duration of RA, drug therapy, ESR, CRP, DAS28, renal function, proteinuria, histological variants were analyzed. Of the common population risk factors for CKD arterial hypertension, weight index, serum lipids and glucose levels were also assessed. Results. The prevalence of CKD in RA was 19.7%. Age, presence and stage of arterial hypertension, an increase in body mass index, as well as high rates of disease activity – ESR, CRP, DAS28 score and duration of RA were risk factors of CKD in RA. Age, duration of the disease, stage of AH and hypercholesterolemia were risk factors in multifactorial regression analysis. Amyloidosis was the most common histologic pattern (50.0%), followed by chronic glomerulonephritis (30.4%) and tubulo-interstitial nephritis (19.6%). Among chronic glomerulonephritis mesangial glomerulonephritis was the most frequent. Renal amyloidosis was associated with a duration of RA, presence of systemic symptoms and CRP level. An isolated decrease in GFR of less than 60 ml/min was detected in 31 (36.0%) out of 86 patients. Сonclusion. The risk factors for CKD in patients with RA are activity and duration of the disease In addition to common population factors. Amyloidosis was the most common histologic pattern associated with duration of RA and inflammatory proteins levels.
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2. Listing J, Kekow J, Manger B, et al. Mortality in rheumatoid arthritis: the impact of disease activity, treatment with glucocorticoids, TNFα inhibitors and rituximab. Ann Rheum Dis. 2015;74(2):415-21. doi: 10.1136/annrheumdis-2013-204021
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Е.Л. Насонова, В.А. Насоновой. М.: ГЭОТАР-Медиа, 2008; с. 290-331 [Nasonov EL, Karateev DE, Balabanova RM. Rheumatoid arthritis. In: Rheumatology. National Guide. Nasonov EL, Nasonova VA, ed. Moscow: GEOTAR-Media, 2008; p. 290-331 (In Russ.)].
4. Tokoroyama T, Ando M, Setoguchi K, et al. Prevalence, incidence and prognosis of chronic kidney disease classified according to current guidelines: a large retrospective cohort study of rheumatoid arthritis patients. Nephrol Dial Transplant. 2017;32:2035-42. doi: 10.1093/ndt/gfw315
5. Kim HW, Lee CK, Cha HS, et al. Effect of anti-tumor necrosis factor alpha treatment of rheumatoid arthritis and chronic kidney disease. Rheumatol Int. 2015;35(4):727-34. doi: 10.1007/s00296-014-3146-4
6. Oranskij SP. Hronicheskaya bolezn pochek pri revmatoidnom artrite: associaciya s serdechno-sosudistym riskom. Fundamentalnye issledovaniya. 2013;12:285-8 (In Russ.) http://www.fundamental-research.ru/ru/article/view?id=33321
7. Batyushin MM, Vystavkina EA. Faktory riska razvitiya i progressirovaniya hronicheskoj bolezni pochek u bolnyh revmatoidnym artritom. Sovremennye problemy nauki i obrazovaniya. 2011;5 (In Russ.) http://www.science-education.ru/ru/article/view?id=4871
8. Sarkisova IA, Rameev VV, Kozlovskaya LV. Revmatoidnyj artrit kak osnovnaya prichina razvitiya AA-amiloidoza. Klinicheskaya gerontologiya. 2009;15(2):14-20 (In Russ.)
9. Sarkisova IA, Rameev VV, Kozlovskaya LV. Faktory` riska razvitiya i progressirovaniya AA-amiloidoza u bolnykh revmatoidnym artritom. Nefrologiya i dializ. 2007;9(3):346 (In Russ.)
10. Sarkisova IA, Rameev VV, Varshavskij VA, et al. Osobennosti techeniya AA-amiloidoza u bol`ny`kh revmatoidny`m artritom. Therapeutic Archive. 2006;78(5):31-6 (In Russ.)
11. Góis M, Carvalho F, Sousa H, et al. Renal involvement in rheumatoid arthritis: analysis of 53 renal biopsies. Port J Nephrol Hypert. 2017;31(1):25-30.
12. Rebrov AP, Tyapkina MA, Voloshinova EV. Subclinical failure of kidneys in patients with rheumatoid arthritis. Lechashchij vrach. 2012;4:40-2 (In Russ.)
13. Kiseleva AG, Orlova GM, Berdnikova IA, Fereferova NM. Chronic kidney disease in rheumatoid arthritis patients. Sibirskij medicinskij zhurnal, 2007;7:90-2 (In Russ.)
14. Kochi M, Kohagura K, Shiohira Y, et al. Inflammation as a risk of developing chronic kidney disease in rheumatoid arthritis. PLoS One. 2016;11(8):e0160225. doi: 10.1371/journal.pone.0160225
15. Shankar A, Sun L, Klein BE, et al. Markers of inflammation predict the long-term risk of developing chronic kidney disease: a population-based cohort study. Kidney Int. 2011;80(11):1231-8. doi: 10.1038/ki.2011.283
16. Nakahara C, Kanemoto K, Saito N, et al. C-reactive protein frequently localizes in the kidney in glomerular diseases. Clin Nephrol. 2001;55(5):365-70.
17. Schwedler SB, Guderian F, Dämmrich J, et al. Tubular staining of modified C-reactive protein in diabetic chronic kidney disease. Nephrol Dial Transplant. 2003;18(11):2300-7. doi: 10.1093/ndt/gfg407
18. Li ZI, Chung AC, Zhou L, et al. C-reactive protein promotes acute renal inflammation and fibrosis in unilateral ureteral obstructive nephropathy in mice. Lab Invest. 2011;91(6):837-51. doi: 10.1038/labinvest.2011.42
19. Galarraga B, Khan F, Kumar P, et al. C-reactive protein: the underlying cause of microvascular dysfunction in rheumatoid arthritis. Rheumatology (Oxford). 2008;47(12):1780-4. doi: 10.1093/rheumatology/ken386
20. Tapia E, Sánchez-González DJ, Medina-Campos ON, et al. Treatment with pyrrolidine dithiocarbamate improves proteinuria, oxidative stress, and glomerular hypertension in overload proteinuria. Am J Physiol Renal Physiol. 2008;295(5):F1431-9. doi: 10.1152/ajprenal.90201.2008
21. Boers M, Croonen AM, Dijkmans BA, et al. Renal findings in rheumatoid arthritis: clinical aspects of 132 necropsies. Ann Rheum Dis. 1987;46:658-63. doi:10.1136/ard.46.9.658
22. Toblli JE, Bevione P, Di Gennaro F, et al. Understanding the mechanisms of proteinuria: therapeutic implications. Int J Nephrol. 2012;546039. doi: 10.1155/2012/546039
23. Hemmelgarn BR, Manns BJ, Lloyd A, et al; Alberta Kidney Disease Network. Relation between kidney function, proteinuria, and adverse outcomes. J Am Med Assoc. 2010;303(5):423-9. doi: 10.1001/jama.2010.39
24. Möller B, Pruijm M, Adler S, et al. Chronic NSAID use and long-term decline of renal function in a prospective rheumatoid arthritis cohort study. Ann Rheum Dis. 2015;74(4):718-23. doi: 10.1136/annrheumdis-2013-204078
25. Daoussis D, Panoulas VF, Antonopoulos I, et al. Cardiovascular risk factors and not disease activity, severity or therapy associate with renal dysfunction in patients with rheumatoid arthritis. Ann Rheum Dis. 2010;69:517-21. doi: 10.1136/ard.2008.105049
26. Salomon MI, Gallo G, Poon TP, et al. The kidney in rheumatoid arthritis. Nephron. 1974;12:297310.
27. Ramirez G, Lambert R, Bloomer A. Renal pathology in patients with rheumatoid arthritis. Nephron. 1981;29:124-6. doi: 10.1159/000182132
28. Yoshida A, Morozumi K, Suganuma T, et al. Clinicopathological study of nephropathy in patients with rheumatoid arthritis. Ryumachi. 1991;31:14-21.
29. Helin HJ, Korpela MM, Mustonen JT, Pasternack AI. Renal biopsy findings and clinicopathologic correlations in rheumatoid arthritis. Arth Rheum. 1995;38(2):242-7. doi: 10.1002/art.1780380213
30. Nakano M, Ueno M, Nishi S, et al. Analysis of renal pathology and drug history in 158 Japanese patients with rheumatoid arthritis. Clin Nephrol. 1998;50:154-60.
31. Makino H, Yoshinaga Y, Yamasaki Y, et al. Renal involvement in rheumatoid arthritis: analysis of renal biopsy specimens from 100 patients. Mod Rheumatol. 2002;12:148-54. doi: 10.3109/s101650200025
32. Scott DG, Bacon PA. Intravenous cyclophosphamide plus methylprednisolone in treatment of systemic rheumatoid vasculitis. Am J Med. 1984;76:377-84. doi: 10.1016/0002-9343(84)90654-5
33. Sumida K, Molnar MZ, Potukuchi PK, et al. Treatment of rheumatoid arthritis with biologic agents lowers the risk of incident chronic kidney disease. Kidney Int. 2018;93(5):1207-16. doi: 10.1016/j.kint.2017.11.025
34. Gonzalez-Juanatey C, Llorca J, Vazquez-Rodriguez TR, et al. Short-term improvement of endothelial function in rituximab-treated rheumatoid arthritis patients refractory to tumor necrosis factor alpha blocker therapy. Arthritis Rheum. 2008;59(12):1821-4. doi: 10.1002/art.24308
35. Popa C, Netea MG, Radstake T, et al. Influence of anti-tumour necrosis factor therapy on cardiovascular risk factors in patients with active rheumatoid arthritis. Ann Rheum Dis. 2005;64(2):303-5. doi: 10.1136/ard.2004.023119
36. Gonzalez-Gay MA, De Matias JM, Gonzalez-Juanatey C, et al. Anti-tumor necrosis factor-alpha blockade improves insulin resistance in patients with rheumatoid arthritis. Clin Exp Rheumatol. 2006;24(1):83-6.
37. Immonen K, Finne P, Gronhagen-Riska C, et al. A marked decline in the incidence of renal replacement therapy for amyloidosis associated with inflammatory rheumatic diseases. Scand J Rheumatol. 2009;38:403. doi: 10.3109/13506129.2010.549252
38. Fernández-Nebro A, Tomero E, Ortiz-Santamaría V, et al. Treatment of rheumatic inflammatory disease in 25 patients with secondary amyloidosis using tumor necrosis factor alpha antagonists. Am J Med. 2005;118(5):552-6. doi:10.1016/j.amjmed.2005.01.028
39. Nakamura T, Higashi S, Tomoda K, et al. Effectiveness of etanercept vs cyclophosphamide as treatment for patients with amyloid A amyloidosis secondary to rheumatoid arthritis. Rheumatology (Oxford). 2012;51(11):2064-9. doi: 10.1093/rheumatology/kes190
40. Gottenberg JE, Merle-Vincent F, Bentaberry F, et al. Anti-tumor necrosis factor alpha therapy in fifteen patients with AA amyloidosis secondary to inflammatory arthritides: a followup report of tolerability and efficacy. Arthritis Rheum. 2003;48(7):2019-24. doi: 10.1002/art.11163
________________________________________________
1. Hickson LJ, Crowson CS, Gabriel SE, et al. Development of reduced kidney function in rheumatoid arthritis. Am J Kidney Dis. 2014;63:206-13. doi: 10.1053/j.ajkd.2013.08.010
2. Listing J, Kekow J, Manger B, et al. Mortality in rheumatoid arthritis: the impact of disease activity, treatment with glucocorticoids, TNFα inhibitors and rituximab. Ann Rheum Dis. 2015;74(2):415-21. doi: 10.1136/annrheumdis-2013-204021
3. Nasonov EL, Karateev DE, Balabanova RM. Rheumatoid arthritis. In: Rheumatology. National Guide. Nasonov EL, Nasonova VA, ed. Moscow: GEOTAR-Media, 2008; p. 290-331 (In Russ.)
4. Tokoroyama T, Ando M, Setoguchi K, et al. Prevalence, incidence and prognosis of chronic kidney disease classified according to current guidelines: a large retrospective cohort study of rheumatoid arthritis patients. Nephrol Dial Transplant. 2017;32:2035-42. doi: 10.1093/ndt/gfw315
5. Kim HW, Lee CK, Cha HS, et al. Effect of anti-tumor necrosis factor alpha treatment of rheumatoid arthritis and chronic kidney disease. Rheumatol Int. 2015;35(4):727-34. doi: 10.1007/s00296-014-3146-4
6. Oranskij SP. Hronicheskaya bolezn pochek pri revmatoidnom artrite: associaciya s serdechno-sosudistym riskom. Fundamentalnye issledovaniya. 2013;12:285-8 (In Russ.) http://www.fundamental-research.ru/ru/article/view?id=33321
7. Batyushin MM, Vystavkina EA. Faktory riska razvitiya i progressirovaniya hronicheskoj bolezni pochek u bolnyh revmatoidnym artritom. Sovremennye problemy nauki i obrazovaniya. 2011;5 (In Russ.) http://www.science-education.ru/ru/article/view?id=4871
8. Sarkisova IA, Rameev VV, Kozlovskaya LV. Revmatoidnyj artrit kak osnovnaya prichina razvitiya AA-amiloidoza. Klinicheskaya gerontologiya. 2009;15(2):14-20 (In Russ.)
9. Sarkisova IA, Rameev VV, Kozlovskaya LV. Faktory` riska razvitiya i progressirovaniya AA-amiloidoza u bolnykh revmatoidnym artritom. Nefrologiya i dializ. 2007;9(3):346 (In Russ.)
10. Sarkisova IA, Rameev VV, Varshavskij VA, et al. Osobennosti techeniya AA-amiloidoza u bol`ny`kh revmatoidny`m artritom. Therapeutic Archive. 2006;78(5):31-6 (In Russ.)
11. Góis M, Carvalho F, Sousa H, et al. Renal involvement in rheumatoid arthritis: analysis of 53 renal biopsies. Port J Nephrol Hypert. 2017;31(1):25-30.
12. Rebrov AP, Tyapkina MA, Voloshinova EV. Subclinical failure of kidneys in patients with rheumatoid arthritis. Lechashchij vrach. 2012;4:40-2 (In Russ.)
13. Kiseleva AG, Orlova GM, Berdnikova IA, Fereferova NM. Chronic kidney disease in rheumatoid arthritis patients. Sibirskij medicinskij zhurnal, 2007;7:90-2 (In Russ.)
14. Kochi M, Kohagura K, Shiohira Y, et al. Inflammation as a risk of developing chronic kidney disease in rheumatoid arthritis. PLoS One. 2016;11(8):e0160225. doi: 10.1371/journal.pone.0160225
15. Shankar A, Sun L, Klein BE, et al. Markers of inflammation predict the long-term risk of developing chronic kidney disease: a population-based cohort study. Kidney Int. 2011;80(11):1231-8. doi: 10.1038/ki.2011.283
16. Nakahara C, Kanemoto K, Saito N, et al. C-reactive protein frequently localizes in the kidney in glomerular diseases. Clin Nephrol. 2001;55(5):365-70.
17. Schwedler SB, Guderian F, Dämmrich J, et al. Tubular staining of modified C-reactive protein in diabetic chronic kidney disease. Nephrol Dial Transplant. 2003;18(11):2300-7. doi: 10.1093/ndt/gfg407
18. Li ZI, Chung AC, Zhou L, et al. C-reactive protein promotes acute renal inflammation and fibrosis in unilateral ureteral obstructive nephropathy in mice. Lab Invest. 2011;91(6):837-51. doi: 10.1038/labinvest.2011.42
19. Galarraga B, Khan F, Kumar P, et al. C-reactive protein: the underlying cause of microvascular dysfunction in rheumatoid arthritis. Rheumatology (Oxford). 2008;47(12):1780-4. doi: 10.1093/rheumatology/ken386
20. Tapia E, Sánchez-González DJ, Medina-Campos ON, et al. Treatment with pyrrolidine dithiocarbamate improves proteinuria, oxidative stress, and glomerular hypertension in overload proteinuria. Am J Physiol Renal Physiol. 2008;295(5):F1431-9. doi: 10.1152/ajprenal.90201.2008
21. Boers M, Croonen AM, Dijkmans BA, et al. Renal findings in rheumatoid arthritis: clinical aspects of 132 necropsies. Ann Rheum Dis. 1987;46:658-63. doi:10.1136/ard.46.9.658
22. Toblli JE, Bevione P, Di Gennaro F, et al. Understanding the mechanisms of proteinuria: therapeutic implications. Int J Nephrol. 2012;546039. doi: 10.1155/2012/546039
23. Hemmelgarn BR, Manns BJ, Lloyd A, et al; Alberta Kidney Disease Network. Relation between kidney function, proteinuria, and adverse outcomes. J Am Med Assoc. 2010;303(5):423-9. doi: 10.1001/jama.2010.39
24. Möller B, Pruijm M, Adler S, et al. Chronic NSAID use and long-term decline of renal function in a prospective rheumatoid arthritis cohort study. Ann Rheum Dis. 2015;74(4):718-23. doi: 10.1136/annrheumdis-2013-204078
25. Daoussis D, Panoulas VF, Antonopoulos I, et al. Cardiovascular risk factors and not disease activity, severity or therapy associate with renal dysfunction in patients with rheumatoid arthritis. Ann Rheum Dis. 2010;69:517-21. doi: 10.1136/ard.2008.105049
26. Salomon MI, Gallo G, Poon TP, et al. The kidney in rheumatoid arthritis. Nephron. 1974;12:297310.
27. Ramirez G, Lambert R, Bloomer A. Renal pathology in patients with rheumatoid arthritis. Nephron. 1981;29:124-6. doi: 10.1159/000182132
28. Yoshida A, Morozumi K, Suganuma T, et al. Clinicopathological study of nephropathy in patients with rheumatoid arthritis. Ryumachi. 1991;31:14-21.
29. Helin HJ, Korpela MM, Mustonen JT, Pasternack AI. Renal biopsy findings and clinicopathologic correlations in rheumatoid arthritis. Arth Rheum. 1995;38(2):242-7. doi: 10.1002/art.1780380213
30. Nakano M, Ueno M, Nishi S, et al. Analysis of renal pathology and drug history in 158 Japanese patients with rheumatoid arthritis. Clin Nephrol. 1998;50:154-60.
31. Makino H, Yoshinaga Y, Yamasaki Y, et al. Renal involvement in rheumatoid arthritis: analysis of renal biopsy specimens from 100 patients. Mod Rheumatol. 2002;12:148-54. doi: 10.3109/s101650200025
32. Scott DG, Bacon PA. Intravenous cyclophosphamide plus methylprednisolone in treatment of systemic rheumatoid vasculitis. Am J Med. 1984;76:377-84. doi: 10.1016/0002-9343(84)90654-5
33. Sumida K, Molnar MZ, Potukuchi PK, et al. Treatment of rheumatoid arthritis with biologic agents lowers the risk of incident chronic kidney disease. Kidney Int. 2018;93(5):1207-16. doi: 10.1016/j.kint.2017.11.025
34. Gonzalez-Juanatey C, Llorca J, Vazquez-Rodriguez TR, et al. Short-term improvement of endothelial function in rituximab-treated rheumatoid arthritis patients refractory to tumor necrosis factor alpha blocker therapy. Arthritis Rheum. 2008;59(12):1821-4. doi: 10.1002/art.24308
35. Popa C, Netea MG, Radstake T, et al. Influence of anti-tumour necrosis factor therapy on cardiovascular risk factors in patients with active rheumatoid arthritis. Ann Rheum Dis. 2005;64(2):303-5. doi: 10.1136/ard.2004.023119
36. Gonzalez-Gay MA, De Matias JM, Gonzalez-Juanatey C, et al. Anti-tumor necrosis factor-alpha blockade improves insulin resistance in patients with rheumatoid arthritis. Clin Exp Rheumatol. 2006;24(1):83-6.
37. Immonen K, Finne P, Gronhagen-Riska C, et al. A marked decline in the incidence of renal replacement therapy for amyloidosis associated with inflammatory rheumatic diseases. Scand J Rheumatol. 2009;38:403. doi: 10.3109/13506129.2010.549252
38. Fernández-Nebro A, Tomero E, Ortiz-Santamaría V, et al. Treatment of rheumatic inflammatory disease in 25 patients with secondary amyloidosis using tumor necrosis factor alpha antagonists. Am J Med. 2005;118(5):552-6. doi:10.1016/j.amjmed.2005.01.028
39. Nakamura T, Higashi S, Tomoda K, et al. Effectiveness of etanercept vs cyclophosphamide as treatment for patients with amyloid A amyloidosis secondary to rheumatoid arthritis. Rheumatology (Oxford). 2012;51(11):2064-9. doi: 10.1093/rheumatology/kes190
40. Gottenberg JE, Merle-Vincent F, Bentaberry F, et al. Anti-tumor necrosis factor alpha therapy in fifteen patients with AA amyloidosis secondary to inflammatory arthritides: a followup report of tolerability and efficacy. Arthritis Rheum. 2003;48(7):2019-24. doi: 10.1002/art.11163