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Causes and diagnosis of AA amyloidosis and relation to rheumatic diseases

Peter D Gorevic, MD
Section Editor
Helen J Lachmann, MA, MB, BChir, MD, FRCP, FRCPath
Deputy Editor
Paul L Romain, MD


AA amyloidosis (previously known as secondary [AA] amyloidosis) is a disorder characterized by the extracellular tissue deposition of fibrils that are composed of fragments of and/or intact serum amyloid apolipoprotein A (SAA), a hepatic acute phase reactant. (See "Pathogenesis of AA amyloidosis".)

AA amyloidosis may complicate any chronic inflammatory condition, including rheumatoid arthritis (RA), juvenile idiopathic arthritis, ankylosing spondylitis (AS), inflammatory bowel disease, familial periodic fever syndromes, chronic infections, and certain neoplasms (table 1).

The major causes and approach to diagnosis of AA amyloidosis are presented here. The clinical manifestations and treatment of AA amyloidosis and the musculoskeletal and renal manifestations of amyloid diseases are discussed separately. (See "Overview of amyloidosis", section on 'Clinical manifestations' and "Treatment of AA (secondary) amyloidosis" and "Musculoskeletal manifestations of amyloidosis" and "Renal amyloidosis".)


Multiple chronic inflammatory conditions, among them rheumatologic, autoinflammatory, chronic infectious, and other disorders, have been associated with the development of AA amyloid. The most common organ system involved in AA amyloidosis is the kidney, although other organ systems are often also affected. (See 'Clinical manifestations' below and "Overview of amyloidosis", section on 'Clinical manifestations'.)

Epidemiology — The disorders most often identified as underlying AA amyloidosis have varied over time and geographically, reflecting the prevalent chronic inflammatory conditions. Inflammatory arthritides have become the most common causes, although chronic infections, particularly tuberculosis and osteomyelitis, were historically the predominant causes. With widespread availability of highly effective antimicrobial agents, the infectious causes have become less common in much of the world, and it is hoped that therapeutic advances in the treatment of rheumatologic and other inflammatory disorders with highly effective biologic agents will result in fewer patients developing amyloidosis [1].

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Literature review current through: Nov 2017. | This topic last updated: Nov 20, 2017.
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  1. Nienhuis HL, Bijzet J, Hazenberg BP. The Prevalence and Management of Systemic Amyloidosis in Western Countries. Kidney Dis (Basel) 2016; 2:10.
  2. Laiho K, Tiitinen S, Kaarela K, et al. Secondary amyloidosis has decreased in patients with inflammatory joint disease in Finland. Clin Rheumatol 1999; 18:122.
  3. Panizo N, Rivera F, López-Gómez JM, Spanish Registry of Glomerulonephritis. Decreasing incidence of AA amyloidosis in Spain. Eur J Clin Invest 2013; 43:767.
  4. Lane T, Pinney JH, Gilbertson JA, et al. Changing epidemiology of AA amyloidosis: clinical observations over 25 years at a single national referral centre. Amyloid 2017; 24:162.
  5. Simms RW, Prout MN, Cohen AS. The epidemiology of AL and AA amyloidosis. Baillieres Clin Rheumatol 1994; 8:627.
  6. Real de Asúa D, Costa R, Galván JM, et al. Systemic AA amyloidosis: epidemiology, diagnosis, and management. Clin Epidemiol 2014; 6:369.
  7. Girnius S, Dember L, Doros G, Skinner M. The changing face of AA amyloidosis: a single center experience. Amyloid 2011; 18 Suppl 1:226.
  8. Bunker D, Gorevic P. AA amyloidosis: Mount Sinai experience, 1997-2012. Mt Sinai J Med 2012; 79:749.
  9. Gillmore JD, Lovat LB, Persey MR, et al. Amyloid load and clinical outcome in AA amyloidosis in relation to circulating concentration of serum amyloid A protein. Lancet 2001; 358:24.
  10. Lachmann HJ, Goodman HJ, Gilbertson JA, et al. Natural history and outcome in systemic AA amyloidosis. N Engl J Med 2007; 356:2361.
  11. Hunter J, McGregor L. Do inflammatory rheumatic diseases still cause as much harm through amyloidosis? Amyloid 2011; 18 Suppl 1:208.
  12. Westermark P, Westermark GT. Review. Reflections on amyloidosis in Papua New Guinea. Philos Trans R Soc Lond B Biol Sci 2008; 363:3701.
  13. Ensari C, Ensari A, Tümer N, Ertug E. Clinicopathological and epidemiological analysis of amyloidosis in Turkish patients. Nephrol Dial Transplant 2005; 20:1721.
  14. Pras M, Franklin EC, Shibolet S, Frangione B. Amyloidosis associated with renal cell carcinoma of the AA type. Am J Med 1982; 73:426.
  15. Piskin O, Alacacioglu I, Ozkal S, et al. A patient with diffuse large B-cell non-Hodgkin's lymphoma and AA type amyloidosis. J BUON 2008; 13:113.
  16. Shimojima Y, Takei Y, Tazawa K, et al. Histopathological regression of systemic AA amyloidosis after surgical treatment of a localized Castleman's disease. Amyloid 2006; 13:184.
  17. Ogita M, Hoshino J, Sogawa Y, et al. Multicentric Castleman disease with secondary AA renal amyloidosis, nephrotic syndrome and chronic renal failure, remission after high-dose melphalan and autologous stem cell transplantation. Clin Nephrol 2007; 68:171.
  18. Skinner M, Pinnette A, Travis WD, et al. Isolation and sequence analysis of amyloid protein AA from a patient with cystic fibrosis. J Lab Clin Med 1988; 112:413.
  19. Stankovic Stojanovic K, Hubert D, Leroy S, et al. Cystic fibrosis and AA amyloidosis: a survey in the French cystic fibrosis network. Amyloid 2014; 21:231.
  20. Lejmi H, Jen KY, Olson JL, et al. Characteristics of AA amyloidosis patients in San Francisco. Nephrology (Carlton) 2016; 21:308.
  21. Girouard SD, Falk RH, Rennke HG, Merola JF. Hidradenitis suppurativa resulting in systemic amyloid A amyloidosis: a case report and review of the literature. Dermatol Online J 2012; 18:2.
  22. Schandorff KD, Miller IM, Krustrup D, et al. Renal amyloid A amyloidosis as a complication of hidradenitis suppurativa. Clin Nephrol 2016; 86:51.
  23. Stankovic Stojanovic K, Georgin-Lavialle S, Poitou C, et al. AA amyloidosis is an emerging cause of nephropathy in obese patients. Eur J Intern Med 2017; 39:e18.
  24. Smith ME, Ansell BM, Bywaters EG. Mortality and prognosis related to the amyloidosis of Still's disease. Ann Rheum Dis 1968; 27:137.
  25. Anttila R. Renal involvement in juvenile rheumatoid arthritis. A clinical and histopathological study. Acta Paediatr Scand Suppl 1972; 227:3.
  26. Roztropowicz-Denisiewicz K, Madyk E, Romicka A, Szymanska-Jagiello W. Variability of the course of amyloidosis in children with rheumatoid arthritis. Ped Pol 1974; 49:10.
  27. Touitou I, Sarkisian T, Medlej-Hashim M, et al. Country as the primary risk factor for renal amyloidosis in familial Mediterranean fever. Arthritis Rheum 2007; 56:1706.
  28. Husby G. Amyloidosis and rheumatoid arthritis. Clin Exp Rheumatol 1985; 3:173.
  29. Päi S, Helin H, Isomäki H. Frequency of amyloidosis in Estonian patients with rheumatoid arthritis. Scand J Rheumatol 1993; 22:248.
  30. Gómez-Casanovas E, Sanmartí R, Solé M, et al. The clinical significance of amyloid fat deposits in rheumatoid arthritis: a systematic long-term followup study using abdominal fat aspiration. Arthritis Rheum 2001; 44:66.
  31. Okuda Y, Takasugi K, Oyama T, et al. [Amyloidosis in rheumatoid arthritis--clinical study of 124 histologically proven cases]. Ryumachi 1994; 34:939.
  32. Wakhlu A, Krisnani N, Hissaria P, et al. Prevalence of secondary amyloidosis in Asian North Indian patients with rheumatoid arthritis. J Rheumatol 2003; 30:948.
  33. El Mansoury TM, Hazenberg BP, El Badawy SA, et al. Screening for amyloid in subcutaneous fat tissue of Egyptian patients with rheumatoid arthritis: clinical and laboratory characteristics. Ann Rheum Dis 2002; 61:42.
  34. Wiland P, Wojtala R, Goodacre J, Szechinski J. The prevalence of subclinical amyloidosis in Polish patients with rheumatoid arthritis. Clin Rheumatol 2004; 23:193.
  35. Myllykangas-Luosujärvi R, Aho K, Kautiainen H, Hakala M. Amyloidosis in a nationwide series of 1666 subjects with rheumatoid arthritis who died during 1989 in Finland. Rheumatology (Oxford) 1999; 38:499.
  36. Sellars L, Siamopoulos K, Wilkinson R, et al. Renal biopsy appearances in rheumatoid disease. Clin Nephrol 1983; 20:114.
  37. Bourke BE, Woodrow DF, Scott JT. Proteinuria in rheumatoid arthritis--drug-induced or amyloid? Ann Rheum Dis 1981; 40:240.
  38. Ludwin D, Alexopoulou I, Esdaile JM, Tugwell P. Renal biopsy specimens from patients with rheumatoid arthritis and apparently normal renal function after therapy with cyclosporine. Canadian Multicentre Rheumatology Group. Am J Kidney Dis 1994; 23:260.
  39. Hazenberg BP, van Rijswijk MH. Where has secondary amyloid gone? Ann Rheum Dis 2000; 59:577.
  40. Kuroda T, Tanabe N, Harada T, et al. Long-term mortality outcome in patients with reactive amyloidosis associated with rheumatoid arthritis. Clin Rheumatol 2006; 25:498.
  41. Uda H, Yokota A, Kobayashi K, et al. Two distinct clinical courses of renal involvement in rheumatoid patients with AA amyloidosis. J Rheumatol 2006; 33:1482.
  42. Koivuniemi R, Paimela L, Suomalainen R, Leirisalo-Repo M. Amyloidosis as a cause of death in patients with rheumatoid arthritis. Clin Exp Rheumatol 2008; 26:408.
  43. Koivuniemi R, Paimela L, Suomalainen R, et al. Amyloidosis is frequently undetected in patients with rheumatoid arthritis. Amyloid 2008; 15:262.
  44. Woo P. Amyloidosis in children. Baillieres Clin Rheumatol 1994; 8:691.
  45. Immonen K, Savolainen A, Kautiainen H, Hakala M. Longterm outcome of amyloidosis associated with juvenile idiopathic arthritis. J Rheumatol 2008; 35:907.
  46. Pamuk ÖN, Kalyoncu U, Aksu K, et al. A multicenter report of biologic agents for the treatment of secondary amyloidosis in Turkish rheumatoid arthritis and ankylosing spondylitis patients. Rheumatol Int 2016; 36:945.
  47. CRUICKSHANK B. Pathology of ankylosing spondylitis. Bull Rheum Dis 1960; 10:211.
  48. Gratacos J, Orellana C, Sanmarti R, et al. Secondary amyloidosis in ankylosing spondylitis. A systematic survey of 137 patients using abdominal fat aspiration. J Rheumatol 1997; 24:912.
  49. Kovacsovics-Bankowski M, Zufferey P, So AK, Gerster JC. Secondary amyloidosis: a severe complication of ankylosing spondylitis. Two case-reports. Joint Bone Spine 2000; 67:129.
  50. Singh G, Kumari N, Aggarwal A, et al. Prevalence of subclinical amyloidosis in ankylosing spondylitis. J Rheumatol 2007; 34:371.
  51. Aktas Yilmaz B, Düzgün N, Mete T, et al. AA amyloidosis associated with systemic lupus erythematosus: impact on clinical course and outcome. Rheumatol Int 2008; 28:367.
  52. Pepys MB. Serum C-reactive protein, serum amyloid P-component and serum amyloid A protein in autoimmune disease. Clin Immunol Allergy 1981; 1:77.
  53. Migita K, Eguchi K, Tsukada T, et al. Increased circulating serum amyloid A protein derivatives in rheumatoid arthritis patients with secondary amyloidosis. Lab Invest 1996; 75:371.
  54. Anderson CJ, Gregory MC, Groggel GC, Clegg DO. Amyloidosis and Reiter's syndrome: report of a case and review of the literature. Am J Kidney Dis 1989; 14:319.
  55. Mpofu S, Teh LS, Smith PJ, et al. Cytostatic therapy for AA amyloidosis complicating psoriatic spondyloarthropathy. Rheumatology (Oxford) 2003; 42:362.
  56. Kosemehmetoglu K, Baydar DE. Renal amyloidosis in Behçet's disease: clinicopathologic features of 8 cases. Int Urol Nephrol 2013; 45:785.
  57. Wada Y, Nishida H, Kohno K, et al. AA amyloidosis in Takayasu's arteritis--long-term survival on maintenance haemodialysis. Nephrol Dial Transplant 1999; 14:2478.
  58. Nakamura S, Morishita M, Yang CL, et al. An elderly female who survived more than 30 years following a diagnosis of Takayasu's arteritis, complicated by fatal intestinal amyloidosis. Clin Rheumatol 2006; 25:907.
  59. Cruz I, Oliveira AP, Lopes JM, et al. Whipple's disease and renal amyloidosis. Am J Gastroenterol 1993; 88:1954.
  60. Escribá A, Morales E, Albizúa E, et al. Secondary (AA-type) amyloidosis in patients with polymyalgia rheumatica. Am J Kidney Dis 2000; 35:137.
  61. Moraga, Sicilia JJ, Blanco J, Ubeda I. Giant cell arteritis and renal amyloidosis: report of a case. Clin Nephrol 2001; 56:402.
  62. Hočevar A, Lestan B, Šemrl SS, et al. AA amyloidosis in a polyarteritis nodosa patient treated with tocilizumab. Amyloid 2013; 20:275.
  63. Ter Borg EJ, Wegewijs MA, de Bruin P. Gout and AA Amyloidosis: A Case Report and Review of the Literature. J Clin Rheumatol 2017; 23:233.
  64. Wong BC, Wong KL, Ip MS, et al. Sjögren's syndrome with amyloid A presenting as multiple pulmonary nodules. J Rheumatol 1994; 21:165.
  65. Karim F, Clahsen-van Groningen M, van Laar JA. AA Amyloidosis and IgG4-Related Disease. N Engl J Med 2017; 376:599.
  66. Saatçi U, Ozen S, Ozdemir S, et al. Familial Mediterranean fever in children: report of a large series and discussion of the risk and prognostic factors of amyloidosis. Eur J Pediatr 1997; 156:619.
  67. Kluve-Beckerman B, Benson MD. AA amyloidosis in patients with no known inflammatory condition. Abstract PB15. XIII Intl Symposium on Amyloidosis, May 6-10, 2012.
  68. Westermark GT, Sletten K, Westermark P. Massive vascular AA-amyloidosis: a histologically and biochemically distinctive subtype of reactive systemic amyloidosis. Scand J Immunol 1989; 30:605.
  69. Hiki Y, Horii A, Kokubo T, et al. A case of rheumatoid arthritis with renal tubular amyloidosis. Nephron 1994; 68:394.
  70. Westermark GT, Sletten K, Grubb A, Westermark P. AA-amyloidosis. Tissue component-specific association of various protein AA subspecies and evidence of a fourth SAA gene product. Am J Pathol 1990; 137:377.
  71. Yang GC, Gallo GR. Protein A-gold immunoelectron microscopic study of amyloid fibrils, granular deposits, and fibrillar luminal aggregates in renal amyloidosis. Am J Pathol 1990; 137:1223.
  72. Picken MM, Pelton K, Frangione B, Gallo G. Primary amyloidosis A. Immunohistochemical and biochemical characterization. Am J Pathol 1987; 129:536.
  73. Murphy CL, Wang S, Williams T, et al. Characterization of systemic amyloid deposits by mass spectrometry. Methods Enzymol 2006; 412:48.
  74. Hazenberg BP, Bijzet J, Limburg PC, et al. Diagnostic performance of amyloid A protein quantification in fat tissue of patients with clinical AA amyloidosis. Amyloid 2007; 14:133.
  75. Lavatelli F, Perlman DH, Spencer B, et al. Amyloidogenic and associated proteins in systemic amyloidosis proteome of adipose tissue. Mol Cell Proteomics 2008; 7:1570.
  76. Dogan A. Classification of amyloidosis by mass spectometry-based proteomics. In: Amyloid & Related Disorders: Surgical Pathology & Clinical Correlations, Pickens MM, et al (Eds), Springer, 2012. p.261.
  77. Brambilla F, Lavatelli F, Di Silvestre D, et al. Reliable typing of systemic amyloidoses through proteomic analysis of subcutaneous adipose tissue. Blood 2012; 119:1844.