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Systemic amyloidosis: a challenge for the rheumatologist


Amyloidosis comprises a group of diseases characterized by the extracellular deposition of insoluble fibrillar proteins. This mechanism generates different clinical syndromes depending on the site and extent of organ involvement. Amyloidosis is classified into categories of systemic and localized disease. Systemic amyloidosis is further subdivided into a hereditary familial form (for example, ATTR amyloidosis), a reactive form (AA amyloidosis), dialysis-related (Aβ2M) amyloidosis and immunoglobulin light chain (AL) amyloidosis. Treatment can be symptomatic, directed at the affected organ, or can be directed at reducing the production of the abnormal proteins with different strategies. Despite advances in treatment, the prognosis is still poor and depends on the underlying disease as well as the type and degree of dysfunction in involved organs. Early diagnosis is essential because patients with advanced disease are generally unable to undergo intensive therapy. Patients with systemic amyloidosis often present to a rheumatologist not only because the disease can include musculoskeletal and articular symptoms but also because it can be associated with chronic rheumatic diseases. This Review discusses the clinical features of amyloidosis and its rheumatic manifestations. The various types of amyloidosis, as well their prognosis and treatment, are also presented.

Key Points

  • Amyloidosis describes a heterogeneous group of diseases in which normally soluble plasma proteins are deposited in the extracellular space in an abnormal, insoluble, fibrillar form

  • Rheumatic diseases constitute the most frequent cause of AA amyloidosis in Western countries, and AL amyloidosis should be considered in patients with proteinuria, cardiomyopathy, hepatomegaly, neuropathy, gastrointestinal and musculoskeletal symptoms

  • Diagnosis of amyloidosis requires a multidisciplinary approach, including clinical examination, biochemical tests, imaging and genetic analysis, and should be confirmed in a tissue sample by use of Congo red staining in polarized light

  • Fine-needle aspiration of abdominal fat is an easy, noninvasive, safe, fast, and inexpensive technique that demonstrates amyloid deposits in approximately 80–88% of patients

  • Early diagnosis and unequivocal typing of the amyloid deposits are crucial for prognosis and therapy, and age of onset, the type of amyloidosis and cardiac involvement are the main negative prognostic factors

  • Current therapies center on reducing the supply of the amyloid precursor protein to decrease new amyloid formation and perhaps facilitate regression of existing deposits

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Figure 1: Appearance of amyloid protein deposit on microscopic examination.
Figure 2: Pathophysiology of amyloidosis.
Figure 3: Clinical features of AL amyloidosis.
Figure 4: Aβ2M amyloid arthropathy of the shoulder and wrist in a patient undergoing long-term hemodialysis.
Figure 5: Minor salivary gland biopsy of a patient with AL amyloidosis.
Figure 6: Flow diagram outlining the evaluation of a patient with suspected amyloidosis.


  1. 1

    Sipe, J. D. & Cohen, A. S. History of the amyloid fibril. J. Struct. Biol. 130, 88–98 (2000).

    CAS  PubMed  Article  Google Scholar 

  2. 2

    Kelly, J. W. The alternative conformations of amyloidogenic proteins and their multi-step assembly pathways. Curr. Opin. Struct. Biol. 8, 101–106 (1998).

    CAS  PubMed  Article  Google Scholar 

  3. 3

    Quintas, A., Vaz, D. C., Cardoso, I., Saraiva M. J. & Brito, R. M. Comparative calorimetric study of non-amyloidogenic and amyloidogenic variants of the homotetrameric protein transthyretin. Biophys. Chem. 15, 61–67 (2000).

    Google Scholar 

  4. 4

    Reixach, N., Deechongkit, S., Jiang, X., Kelly, J. W. & Buxbaum, J. N. Tissue damage in the amyloidoses: transthyretin monomers and nonnative oligomers are the major cytotoxic species in tissue culture. Proc. Natl Acad. Sci. USA 101, 2817–2822 (2004).

    CAS  PubMed  Article  Google Scholar 

  5. 5

    Dubrey, S. W., Cha, K., Skinner, M., LaValley, M. & Falk, R. H. Familial and primary (AL) cardiac amyloidosis: echocardiographically similar diseases with distinctly different clinical outcomes. Heart 78, 74–82 (1997).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  6. 6

    Liao, R. et al. Infusion of light chains from patients with cardiac amyloidosis causes diastolic dysfunction in isolated mouse hearts. Circulation 104, 1594–1597 (2001).

    CAS  Article  Google Scholar 

  7. 7

    Obici, L., Perfetti, V., Palladini, G., Moratti, R. & Merlini, G. Clinical aspects of systemic amyloid diseases. Biochem. Biophys. Acta 1753, 11–22 (2005).

    CAS  PubMed  Google Scholar 

  8. 8

    Haas, M., Meehan, S. M., Karrison, T. G, & Spargo, B. H. Changing etiologies of unexplained adult nephrotic syndrome: a comparison of renal biopsy findings from 1976–1979 and 1995–1997. Am. J. Kidney Dis. 30, 621–631 (1997).

    CAS  PubMed  Article  Google Scholar 

  9. 9

    Kushwaha, S. S., Fallon, J. T. & Fuster, V. Restrictive cardiomyopathy. N. Engl. J. Med. 336, 267–276 (1997).

    CAS  PubMed  Article  Google Scholar 

  10. 10

    Kyle, R. A. Amyloidosis. Circulation 91, 1269–1271 (1995).

    CAS  PubMed  Article  Google Scholar 

  11. 11

    Park, M. A. et al. Primary (AL) hepatic amyloidosis: clinical features and natural history in 98 patients. Medicine (Baltimore) 8 2, 291–298 (2003).

    Article  Google Scholar 

  12. 12

    Nestle, F. O. & Burg, G. Bilateral carpal tunnel syndrome as a clue for the diagnosis of systemic amyloidosis. Dermatology 202, 353–355 (2001).

    CAS  PubMed  Article  Google Scholar 

  13. 13

    Prokaeva, T. et al. Soft tissue, joint, and bone manifestation of AL amyloidosis: clinical presentation, molecular features and survival. Arthritis Rheum. 56, 3858–3868 (2007).

    PubMed  Article  Google Scholar 

  14. 14

    Pras, M., Itzchaki, M., Prelli, F., Dollberg, L. & Frangine, B. Amyloid arthropathy: characterization of the amyloid protein. Clin. Exp. Rheumatol. 3, 327–331 (1985).

    CAS  PubMed  Google Scholar 

  15. 15

    Liepnieks, J. J., Burt, C. & Benson, M. D. Shoulder-pad sign of amyloidosis: structure of an Ig κ III protein. Scand. J. Immunol. 54, 404–408 (2001).

    CAS  PubMed  Article  Google Scholar 

  16. 16

    Merlini, G. Primary (AL) amyloidosis. Amyloid 8, 54–55 (2001).

    Google Scholar 

  17. 17

    Gertz, M. A., Kyle, R. A., Griffin, W. L. & Hunder, G. G. Jaw claudication in primary systemic amyloidosis. Medicine (Baltimore) 65, 173–179 (1986).

    CAS  Article  Google Scholar 

  18. 18

    Salvarani, C. et al. Primary systemic amyloidosis presenting as giant cell arteritis and polymyalgia rheumatica. Arthritis Rheum. 37, 1621–1626 (1994).

    CAS  PubMed  Article  Google Scholar 

  19. 19

    Churchill, C. H., Abril, A., Krishna, M., Callman, M. L. & Ginsburg, W. W. Jaw claudication in primary amyloidosis: unusual presentation of a rare disease. J. Rheumatol. 30, 2283–2286 (2003).

    PubMed  Google Scholar 

  20. 20

    Stebbing, J., Buetens, O., Hellman, D. & Stone, J. Secondary amyloidosis associated with giant cell arteritis/polymyalgia rheumatica. J. Rheumatol. 26, 2698–2700 (1999).

    CAS  PubMed  Google Scholar 

  21. 21

    Altiparmark, M. R. et al. Giant cell arteritis and secondary amyloidosis: the natural history. Scand. J. Rheumatol. 30, 114–116 (2001).

    Article  Google Scholar 

  22. 22

    Jardinet, D., Westhovens, R. & Peeters, J. Sicca syndrome as an initial symptom of amyloidosis. Clin. Rheumatol. 17, 546–548 (1998).

    CAS  PubMed  Article  Google Scholar 

  23. 23

    Gester, J. G., Landry, M. & Dudler, J. Scleroderma-like changes of the hands in primary amyloidosis. J. Rheumatol. 27, 2275–2277 (2000).

    Google Scholar 

  24. 24

    Mandl, L. A., Folkerth, R. D., Pick, M. A., Weinblatt, M. E. & Gravallese, E. M. Amyloid myopathy masquerading as polymyositis. J. Rheumatol. 27, 949–952 (2000).

    CAS  PubMed  Google Scholar 

  25. 25

    Spuler, S., Emslie-Smith, A. & Engel, A. G. Amyloid myopathy: an underdiagnosed entity. Ann. Neurol. 43, 719–728 (1998).

    CAS  PubMed  Article  Google Scholar 

  26. 26

    Gertz, M. A. & Kyle, R. A. Myopathy in primary systemic amyloidosis. J. Neurol. Neurosurg. Psychiatry 60, 655–660 (1996).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. 27

    Doriguzzi, C., Mongini, T., Troni, W. & Monga, G. Early sarcolemmal dysfunction in skeletal muscle amyloidosis. J. Neurol. 234, 52–54 (1987).

    CAS  PubMed  Article  Google Scholar 

  28. 28

    Chapin, J. E., Kornfeld, M. & Harris, A. Amyloid myopathy: characteristic features of a still underdiagnosed disease. Muscle Nerve 31, 266–272 (2005).

    PubMed  Article  Google Scholar 

  29. 29

    Choufani, E. B. et al. Acquired factor X deficiency in patients with amyloid light-chain amyloidosis: incidence, bleeding manifestations, and response to high-dose chemotherapy. Blood 97, 1885–1887 (2001).

    CAS  PubMed  Article  Google Scholar 

  30. 30

    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) 38, 499–503 (1999).

    Article  Google Scholar 

  31. 31

    Laasko, M., Mutru, O., Isomäki, H. & Koota, K. Mortality from amyloidosis and renal diseases in patients with rheumatoid arthritis. Ann. Rheum. Dis. 45, 663–667 (1986).

    Article  Google Scholar 

  32. 32

    Strobel, E. S. & Fritschka, E. Renal diseases in ankylosing spondylitis: review of the literature illustrated by case reports. Clin. Rheumatol. 17, 524–530 (1998).

    CAS  PubMed  Article  Google Scholar 

  33. 33

    Immonen, K. et al. No improvement in survival of patients with amyloidosis associated with inflammatory rheumatic diseases—data from the Finnish national registry for kidney diseases. J. Rheumatol. 35, 1334–1338 (2008).

    Google Scholar 

  34. 34

    Lehtinen, K. The mortality and causes of death of patients with “hypergamma type” of ankylosing spondylitis. Scand. J. Rheumatol. 12, 3–4 (1983).

    CAS  PubMed  Article  Google Scholar 

  35. 35

    Sokka, T., Möttönen, T. & Hannonen, P. Mortality in early “sawtooth” treated rheumatoid arthritis patients during the first 8–14 years. Scand. J. Rheumatol. 28, 282–287 (1999).

    CAS  PubMed  Article  Google Scholar 

  36. 36

    Laiho, K., Tiitinen, S., Kaarela, K., Helin, H. & Isomäki, H. Secondary amyloidosis has decreased in patients with inflammatory joint diseases in Finland. Clin. Rheumatol. 18, 122–123 (1999).

    CAS  Article  Google Scholar 

  37. 37

    Hazenberg, B. P. C. & Van Rijswijk, M. H. Where has secondary amyloid gone? Ann. Rheum. Dis. 59, 577–579 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. 38

    Suzuki, A. et al. Cause of death in 81 autopsied patients with rheumatoid arthritis. J. Rheumatol. 21, 33–36 (1994).

    CAS  PubMed  Google Scholar 

  39. 39

    Wiland, P., Wojatala, R., Goodacre, J. & Szechinki, J. The prevalence of subclinical amyloidosis in Polish patients with rheumatoid arthritis. Clin. Rheumatol. 23, 193–198 (2004).

    PubMed  Article  Google Scholar 

  40. 40

    Levine, R. A. Amyloid disease of the liver: Correlation of clinical, functional, and morphological features in forty-seven patients. Am. J. Med. 33, 349–357 (1962).

    CAS  PubMed  Article  Google Scholar 

  41. 41

    Hawkins, P. N. Serum amyloid P component scintigraphy for diagnosis and monitoring amyloidosis. Curr. Opin. Nephrol. Hypertens. 11, 649–655 (2002).

    PubMed  Article  Google Scholar 

  42. 42

    Brandt, K., Cathcart, E. S. & Cohen, A. S. A clinical analysis of the course and prognosis of forty-two patients with amyloidosis. Am. J. Med. 44, 955–969 (1968).

    CAS  PubMed  Article  Google Scholar 

  43. 43

    Gertz, M. A. & Kyle, R. A. Secondary systemic amyloidosis: response and survival in 64 patients. Medicine (Baltimore) 70, 246–256 (1991).

    CAS  Article  Google Scholar 

  44. 44

    Tanaka, F. et al. Clinical outcome and survival of secondary (AA) amyloidosis. Clin. Exp. Rheumatol. 21, 343–346 (2003).

    CAS  PubMed  Google Scholar 

  45. 45

    Joss, N., McLaughlin, K. Simpson, K. & Boulton-Jones, J. M. Presentation, survival and prognostic markers in AA amyloidosis. Q. J. Med. 93, 535–542 (2000).

    CAS  Article  Google Scholar 

  46. 46

    Lachmann, H. J. et al. Natural history and outcome in systemic AA amyloidosis. N. Engl. J. Med. 356, 2361–2371 (2007).

    CAS  Article  Google Scholar 

  47. 47

    Bergesio, F. et al. Renal involvement in systemic amyloidosis: an Italian collaborative study on survival and renal outcome. Nephrol. Dial. Transplant. 2, 941–951 (2008).

    Google Scholar 

  48. 48

    Çakar, N. et al. Familial Mediterranean fever (FMF)-associated amyloidosis in childhood: clinical features, course and outcome. Clin. Exp. Rheumatol. 19 (Suppl. 24), S63–S67 (2001).

    PubMed  Google Scholar 

  49. 49

    Kallinich, T. et al. Two familial cases with tumor necrosis factor receptor-associated periodic syndrome caused by a non-cysteine mutation (T50M) in the TNFRSF1A gene associated with severe multiorganic amyloidosis. J. Rheumatol. 31, 2519–2522 (2004).

    PubMed  Google Scholar 

  50. 50

    Schwarz, R. E., Dralle, H., Linke, R. P., Nathrath, W. B. & Neumann, K. H. Amyloid goitre and arthritides after kidney transplantation in a patient with systemic amyloidosis and Muckle–Wells syndrome. Am. J. Clin. Pathol. 92, 821–825 (1989).

    CAS  PubMed  Article  Google Scholar 

  51. 51

    Hoffman, H. M., Wanderer, A. A. & Broide, D. H. Familial cold autoinflammatory syndrome: phenotype and genotype of an autosomal dominant periodic fever. J. Allergy Clin. Immunol. 108, 615–620 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. 52

    Obici, L. et al. First report of systemic reactive (AA) amyloidosis in a patient with the hyperimmunoglobulinemia D with periodic fever syndrome. Arthritis Rheum. 50, 2966–2969 (2004).

    PubMed  Article  Google Scholar 

  53. 53

    Gejyo, F. & Narita, I. Current clinical and pathogenetic understanding of β2m- amyloidosis in long-term haemodialysis patients. Nephrology 8 (Suppl. 2), S45–S49 (2003).

    PubMed  Article  Google Scholar 

  54. 54

    Drueke, T. B. Dialysis-related amyloidosis. Nephrol. Dial. Transplant. 1, 58–64 (1998).

    Article  Google Scholar 

  55. 55

    Di Raimondo, C. R. Casey, T. T., Di Raimondo, C. V. & Stone, W. J. Pathologic fractures associated with idiopathic amyloidosis of bone in chronic hemodialysis patients. Nephron 43, 22–27 (1986).

    CAS  Article  Google Scholar 

  56. 56

    Noel, L. H. et al. Tissue distribution of dialysis amyloidosis. Clin. Nephrol. 27, 175–178 (1987).

    CAS  PubMed  Google Scholar 

  57. 57

    Gal, R., Korzets, A., Schwartz, A., Rath-Wolfson, L. & Gafter, U. Systemic distribution of beta 2-microglobulin-derived amyloidosis in patients who undergo long-term hemodialysis. Report of seven cases and review of the literature. Arch. Pathol. Lab. Med. 118, 718–721 (1994).

    CAS  PubMed  Google Scholar 

  58. 58

    Gorevic, P. D. et al. β-2 microglobulin is an amyloidogenic protein in man. J. Clin. Invest. 76, 2425–2429 (1985).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. 59

    Sethi, D. & Gower, P. E. Synovial-fluid beta-2-microglobulin levels in dialysis arthropathy. N. Engl. J. Med. 315, 1419–1420 (1986).

    CAS  PubMed  Article  Google Scholar 

  60. 60

    Moe, S. M. & Chen, N. X. The role of the synovium and cartilage in the pathogenesis of beta (2)-microglobulin amyloidosis. Semin. Dial. 14, 127–130 (2001).

    CAS  PubMed  Article  Google Scholar 

  61. 61

    Giorgetti, S. et al. Beta 2-microglobulin isoforms display a heterogeneous affinity for type I collagen. Protein Sci. 14, 696–702 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. 62

    Westermark, P., Bergstrom, J., Solomon, A., Murphy, C. & Sletten, K. Transthyretin-derived senile systemic amyloidosis: clinicopathologic and structural considerations. Amyloid 10, 48–54 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Breedveld, F. C., Markusse, H. M. & MacFarlane, J. D. Subcutaneous fat biopsy in the diagnosis of amyloidosis secondary to chronic arthritis. Clin. Exp. Rheumatol. 7, 407–410 (1989).

    CAS  PubMed  Google Scholar 

  64. 64

    Klemi, P. J., Sorsa, S. & Happonen, R. P. Fine-needle aspiration biopsy from subcutaneous fat. An easy way to diagnose secondary amyloidosis. Scand. J. Rheumatol. 16, 429–431 (1987).

    CAS  PubMed  Article  Google Scholar 

  65. 65

    Duston, M. A., Skinner, M., Meenan, R. F. & Cohen, A. S. Sensitivity, specificity, and predictive value of abdominal fat aspiration for the diagnosis of amyloidosis. Arthritis Rheum. 32, 82–85 (1989).

    CAS  PubMed  Article  Google Scholar 

  66. 66

    Libbey, C. A., Skinner, M. & Cohen, A. S. Use of abdominal fat tissue aspirate in the diagnosis of systemic amyloidosis. Arch. Intern. Med. 143, 1549–1552 (1983).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  67. 67

    Van Gameren, I. I., Hazenberg, B. P. C., Bijzet, J. & van Rijswijk, M. H. Diagnostic accuracy of subcutaneous abdominal fat tissue aspiration for detecting systemic amyloidosis and its utility in clinical practice. Arthritis Rheum. 54, 2015–2021 (2006).

    PubMed  Article  Google Scholar 

  68. 68

    Orfila, C. et al. Unsuitable value of abdominal fat tissue aspirate examination for the diagnosis of amyloidosis in long-term hemodialysis patients. Am. J. Nephrol. 8, 454–456 (1988).

    CAS  PubMed  Article  Google Scholar 

  69. 69

    Merlini, G. et al. β2-Microglobulin does not deposit in abdominal fat tissue of long-term hemodialysis patients. In Amyloid and Amyloidosis 1990: Proc. of the VIth International Symp. on Amyloidosis, held in Oslo, Norway, 5–8 August 1990 (Eds Natvig, J. et al.) 801–804 (Springer, 1991).

    Chapter  Google Scholar 

  70. 70

    Tishler, M., Pras, M. & Yaron, M. Abdominal fat tissue aspirate in amyloidosis of familial Mediterranean fever. Clin. Exp. Rheumatol. 6, 395–397 (1988).

    CAS  PubMed  Google Scholar 

  71. 71

    Livneh, A. & Langevitz, P. Diagnostic and treatment concerns in familial Mediterranean fever. Baillieres Best Pract. Res. Clin. Rheumatol. 14, 477–498 (2000).

    CAS  PubMed  Article  Google Scholar 

  72. 72

    Hazenberg, B. P. et al. Diagnostic performance of amyloid A protein quantification in fat tissue of patients with clinical AA amyloidosis. Amyloid 14, 133–140 (2007).

    CAS  PubMed  Article  Google Scholar 

  73. 73

    Giorgadze, T., Baloch, Z. W., Thaler, E. R. & Gupta, P. K. Unsuspected systemic amyloidosis diagnosed by fine-needle aspiration of the salivary gland: case report. Diagn. Cytopathol. 31, 57–59 (2004).

    PubMed  Article  Google Scholar 

  74. 74

    Hachulla, E. et al. Labial salivary gland biopsy is a reliable test for the diagnosis of primary and secondary amyloidosis. Arthritis Rheum. 36, 691–697 (1993).

    CAS  PubMed  Article  Google Scholar 

  75. 75

    Gafni, J. & Sohar, E. Rectal biopsy for the diagnosis of amyloidosis. Am. J. Med. Sci. 24 0, 332–336 (1960).

    Article  Google Scholar 

  76. 76

    Kyle, R. A., Spencer, R. J. & Dahlin, D. C. Value of rectal biopsy in the diagnosis of primary systemic amyloidosis. Am. J. Med. Sci. 251, 501–506 (1966).

    CAS  PubMed  Article  Google Scholar 

  77. 77

    Saraiva, M. J. M. Sporadic cases of hereditary systemic amyloidosis. N. Engl. J. Med. 346, 1818–1819 (2002).

    PubMed  Article  Google Scholar 

  78. 78

    Kyle, R. A. et al. A long-term study of prognosis in monoclonal gammopathy of undetermined significance. N. Engl. J. Med. 346, 564–569 (2002).

    PubMed  Article  Google Scholar 

  79. 79

    Lachmann, H. J. et al. Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis. N. Engl. J. Med. 346, 1786–1791 (2002).

    CAS  PubMed  Article  Google Scholar 

  80. 80

    Comenzo, R. L., Zhou, P., Fleisher, M., Clark, B. & Teruya-Feldstein, J. Seeking confidence in the diagnosis of systemic AL (Ig light chain) amyloidosis: patients can have both monoclonal gammopathies and hereditary amyloid proteins. Blood 107, 3489–3491 (2006).

    CAS  PubMed  Article  Google Scholar 

  81. 81

    Rocken, C., Schwotzer, E. B., Linke, R. P. & Saeger, W. The classification of amyloid deposits in clinicopathological practice. Histopathology 29, 325–335 (1996).

    CAS  Article  Google Scholar 

  82. 82

    Arbustini, E. et al. Electron and immuno-electron microscopy of abdominal fat identifies and characterizes amyloid fibrils in suspected cardiac amyloidosis. Amyloid 9, 108–114 (2002).

    CAS  PubMed  Article  Google Scholar 

  83. 83

    Lavatelli, F. et al. Amyloidogenic and associated proteins in systemic amyloidosis proteome of adipose tissue. Mol. Cell. Proteomics 7, 1570–1583 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  84. 84

    Vrana, J. A. et al. Classification of amyloidosis by laser microdissection and mass spectrometry-based proteomic analysis in clinical biopsy specimens. Blood 114, 4957–4959 (2009).

    CAS  Article  Google Scholar 

  85. 85

    Hawkins, P. N., Lavender, J. P. & Pepys, M. B. Evaluation of systemic amyloidosis by scintigraphy with 123I-labeled serum amyloid P component. N. Engl. J. Med. 323, 508–513 (1990).

    CAS  PubMed  Article  Google Scholar 

  86. 86

    Jager, P. L. et al. Kinetic studies with Iodine-123-labeled serum amyloid P component in patients with systemic AA and AL amyloidosis and assessment of clinical value. J. Nucl. Med. 39, 699–706 (1998).

    CAS  PubMed  Google Scholar 

  87. 87

    Falk, R. H., Comenzo, R. L. & Skinner, M. The systemic amyloidoses. N. Engl. J. Med. 337, 898–909 (1997).

    CAS  PubMed  Article  Google Scholar 

  88. 88

    Kyle, R. A. & Gertz, M. A. Primary systemic amyloidosis: clinical and laboratory features in 474 cases. Semin. Hematol. 32, 45–59 (1995).

    CAS  Google Scholar 

  89. 89

    Gillmore, J. D., Lovat, L. B., Persey, M. R., Pepys, M. B. & Hawkins, P. N. Amyloid load and clinical outcome in AA amyloidosis in relation to circulating concentration of serum amyloid A protein. Lancet 358, 24–29 (2001).

    CAS  Article  Google Scholar 

  90. 90

    Merlini, G. & Bellotti, V. Molecular mechanisms of amyloidosis. N. Engl. J. Med. 349, 583–596 (2003).

    CAS  Article  Google Scholar 

  91. 91

    Comenzo, R. L. et al. Dose-intensive melphalan with blood stem-cell support for the treatment of AL (amyloid light-chain) amyloidosis: survival and responses in 25 patients. Blood 91, 3662–3670 (1998).

    CAS  PubMed  Google Scholar 

  92. 92

    Comenzo, R. L. & Gertz, M. A. Autologous stem cell transplantation for primary systemic amyloidosis. Blood 99, 4276–4282 (2002).

    CAS  PubMed  Article  Google Scholar 

  93. 93

    Skinner, M. et al. High-dose melphalan and autologous stem-cell transplantation in patients with AL amyloidosis: an 8-year study. Ann. Intern. Med. 140, 85–93 (2004).

    CAS  Article  Google Scholar 

  94. 94

    Sanchorawala, V. et al. High-dose intravenous melphalan and autologous stem cell transplantation as initial therapy or following two cycles of oral chemotherapy for the treatment of AL amyloidosis: results of a prospective randomized trial. Bone Marrow Transplant. 33, 381–388 (2004).

    CAS  PubMed  Article  Google Scholar 

  95. 95

    Gertz, M. A., Lacy, M. Q. & Dispenzieri, A. Myeloablative chemotherapy with stem cell rescue for the treatment of primary systemic amyloidosis: a status report. Bone Marrow Transplant. 25, 465–470 (2000).

    CAS  PubMed  Article  Google Scholar 

  96. 96

    Bradstock, K., Clancy, R., Uther, J., Basten, A. & Richards, J. The successful treatment of primary amyloidosis with intermittent chemotherapy. Aust. NZ J. Med. 8, 176–179 (1978).

    CAS  Article  Google Scholar 

  97. 97

    Corkery, J., Bern, M. M. & Tullis, J. L. Resolution of amyloidosis and plasma-cell dyscrasia with combination chemotherapy. Lancet 2, 425–426 (1978).

    CAS  PubMed  Article  Google Scholar 

  98. 98

    Kyle, R. A. et al. A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone and colchicine. N. Engl. J. Med. 336, 1202–1207 (1997).

    CAS  PubMed  Article  Google Scholar 

  99. 99

    Palladini, G. et al. Association of melphalan and high-dose dexamethasone is effective and well tolerated in patients with AL (primary) amyloidosis ineligible for stem cell transplantation. Blood 1 03, 2936–2938 (2004).

    Article  CAS  Google Scholar 

  100. 100

    Palladini, G. et al. The combination of thalidomide and intermediate-dose dexamethasone is an effective but toxic treatment for patients with primary amyloidosis (AL). Blood 105, 2949–2951 (2005).

    CAS  PubMed  Article  Google Scholar 

  101. 101

    Sanchorawala, V. et al. Lenalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 2 trial. Blood 109, 492–496 (2007).

    CAS  PubMed  Article  Google Scholar 

  102. 102

    Reece, D. et al. Weekly and twice-weekly bortezomib in patients with systemic AL-amyloidosis: results of a phase 1 dose-escalation study. Blood 11 4, 1489–1497 (2009).

    Article  CAS  Google Scholar 

  103. 103

    Wechalekar, A. D., Lachmann, H. J., Offer, M., Hawkins, P. N. & Gillmore, J. D. Efficacy of bortezomib in systemic AL amyloidosis with relapsed/refractory clonal disease. Haematologica 93, 295–298 (2008).

    CAS  PubMed  Article  Google Scholar 

  104. 104

    Kastritis, E. et al. Treatment of light chain (AL) amyloidosis with the combination of bortezomib and dexamethasone. Haematologica 92, 1351–1358 (2007).

    CAS  PubMed  Article  Google Scholar 

  105. 105

    Gottenberg, J.-E. et al. Anti-tumor necrosis factor α therapy in fifteen patients with AA amyloidosis secondary to inflammatory arthritides: a followup report of tolerability and toxicity. Arthritis Rheum. 48, 2019–2024 (2003).

    CAS  PubMed  Article  Google Scholar 

  106. 106

    Drewe, E., Huggins, M. L., Morgan, A. G., Cassidy, M. J. & Powell, R. J. Treatment of renal amyloidosis with etanercept in tumour necrosis factor receptor-associated periodic syndrome. Rheumatology (Oxford) 43, 1405–1408 (2004).

    CAS  Article  Google Scholar 

  107. 107

    Amital, H. & Ben-Chetrit, E. Therapeutic approaches to familial Mediterranean fever. What do we know and where are we going to? Clin. Exp. Rheumatol. 22 (Suppl. 34), S4–S7 (2004).

    CAS  PubMed  Google Scholar 

  108. 108

    Duzova, A. et al. Role of A-SAA in monitoring subclinical inflammation and in colchicine dosage in familial Mediterranean fever. Clin. Exp. Rheumatol. 21, 509–514 (2003).

    CAS  PubMed  Google Scholar 

  109. 109

    Leslie, K. S. et al. Phenotype, genotype, and sustained response to anakinra in 22 patients with autoinflammatory disease associated with CIAS-1/NALP3 mutations. Arch. Dermatol. 142, 1591–1597 (2006).

    CAS  PubMed  Article  Google Scholar 

  110. 110

    Kisilevsky, R. et al. Arresting amyloidosis in vivo using small-molecule anionic sulphonates or sulphates: implications for Alzheimer's disease. Nat. Med. 1, 143–148 (1995).

    CAS  PubMed  Article  Google Scholar 

  111. 111

    Gervais, F., Chalifour, R., Kong, X., Morissette, C. & Paquette, J. GAG mimetics: advance in multiple therapeutic areas. Amyloid and Amyloidosis: the Proc. of the IXth International Symp. on Amyloidosis, Budapest, July 15–21, 2001 (Eds Bely, M. & Apathy, A.) 589–592 (2001).

    Google Scholar 

  112. 112

    Dember, L. et al. Eprodisate for the treatment of renal disease in AA amyloidosis. N. Engl. J. Med. 356, 2349–2360 (2007).

    CAS  Article  Google Scholar 

  113. 113

    Winchester, J. F., Salsberg, J. A. & Levin, N. W. Beta-2 microglobulin in ESRD: an in-depth review. Adv. Renal Replace. Ther. 10, 279–309 (2003).

    Article  Google Scholar 

  114. 114

    Yamamoto, S. & Gejyo, F. Historical background and clinical treatment of dialysis-related amyloidosis. Biochem. Biophys. Acta 1753, 4–10 (2005).

    CAS  PubMed  Google Scholar 

  115. 115

    Kelly, J. W. et al. Transthyretin quaternary and tertiary structural changes facilitate misassembly into amyloid. Adv. Protein Chem. 50, 161–181 (1997).

    CAS  PubMed  Article  Google Scholar 

  116. 116

    Cardoso, I. et al. Transthyretin fibrillogenesis entails the assembly of monomers: a molecular model for in vitro assembled transthyretin amyloid-like fibrils. J. Mol. Biol. 317, 683–695 (2002).

    CAS  PubMed  Article  Google Scholar 

  117. 117

    Kelly, J. W. Alternative conformations of amyloidogenic proteins govern their behavior. Curr. Opin. Struct. Biol. 6, 11–17 (1996).

    CAS  PubMed  Article  Google Scholar 

  118. 118

    Hammarstrom, P., Wiseman, R. L., Powers, E. T. & Kelly, J. W. Prevention of transthyretin amyloid disease by changing protein misfolding energetics. Science 299, 713–716 (2003).

    PubMed  Article  CAS  Google Scholar 

  119. 119

    Miller, S. R., Sekijima, Y. & Kelly, J. W. Native state stabilization by NSAIDs inhibits transthyretin amyloidogenesis from the most common familial disease variants. Lab. Invest. 84, 545–552 (2004).

    CAS  PubMed  Article  Google Scholar 

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Correspondence to Federico Perfetto.

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Perfetto, F., Moggi-Pignone, A., Livi, R. et al. Systemic amyloidosis: a challenge for the rheumatologist. Nat Rev Rheumatol 6, 417–429 (2010).

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