Causes and diagnosis of AA amyloidosis and relation to rheumatic diseases

INTRODUCTION — 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 A protein (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 (JIA), 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".)

CAUSES AND RELATION TO RHEUMATIC DISEASES — Multiple chronic inflammatory conditions, among them rheumatologic, autoinflammatory, chronic infectious, and other disorders, have been associated with the development of AA amyloid [1,2]. The most common organ system involved in this form of 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. During the 20^th century, AA amyloidosis has become less common and the contribution of AA amyloid to large series of amyloidosis has gradually decreased. The underlying causes of chronic inflammation have also changed; inflammatory arthritides have become the most common underlying disease, replacing chronic infections, particularly tuberculosis [3] and osteomyelitis, which had historically been the predominant causes. With widespread availability of highly effective antimicrobial agents, the infectious causes have become less common in much of the world [4], and it is anticipated that therapeutic advances in the treatment of rheumatologic and other inflammatory disorders with highly effective biologic agents will result in fewer patients developing amyloidosis [5].

Both the annual incidence and population prevalence of AA amyloidosis appear to be decreasing in national surveys from some western countries, presumably reflecting advances in therapeutics of the underlying disorders [6-8]. The overall autopsy incidence of AA amyloidosis in western nations ranges from 0.5 to 0.86 percent [9,10]. In the United Kingdom, the estimated incidence of AA amyloidosis was 0.166 per 100,000 in 2008 [8].

The list of chronic inflammatory conditions reported in association with AA amyloidosis is extensive, including chronic inflammatory arthritides, vasculitides, inflammatory bowel disease, periodic fever syndromes, chronic infections, neoplasms, and other disorders (table 1).

The following frequencies of underlying disorders have been found in large series of patients with AA amyloidosis from two large centers in the United States [9,11,12]:

●Idiopathic – 21 to 29 percent

●Rheumatoid arthritis (RA) or juvenile idiopathic arthritis (JIA) – 12 to 21 percent

●Inflammatory bowel disease – 16 to 17 percent

●Spondyloarthritis/psoriasis – 10 to 12 percent

●Familial Mediterranean fever – 4 to 5 percent

Two series of patients with AA amyloidosis in the United Kingdom, the larger of which included 374 subjects, found the following associated diseases [13-15]:

●Adult RA – 23 to 51 percent

●JIA – 11 to 17 percent

●Chronic infection – 9 to 15 percent

●Hereditary periodic fever syndromes (eg, familial Mediterranean fever) – 9 to 11 percent

●Ankylosing spondylitis (AS) – 0 to 12 percent

●Psoriatic arthritis – 4 percent

●Crohn disease – 2 to 5 percent

In some other parts of the world, hereditary periodic fevers and infections are responsible for a larger proportion of cases of AA amyloid [16]. As an example, in Turkey, familial Mediterranean fever is the cause of more than 60 percent of cases [17]. In Armenia, and among Armenian populations in surrounding countries, familial Mediterranean fever is common, and the carrier rate for MEFV gene mutations approaches one in five individuals. Further genetic work in this population has shown that MEFV M694V (the commonest mutation underlying familial Mediterranean fever) is associated with a greater risk of developing AA amyloidosis. A further genetic contribution to the risk of AA amyloidosis is homozygosity for the SAA1.1 allele, and patients who are homozygous for both MEFV M694V and SAA1.1 have a sevenfold increased risk of developing renal amyloidosis, compared with other SAA1 genotypes [18,19].

Other conditions that may be associated with AA amyloid include neoplasms, particularly renal cell carcinoma [20], non-Hodgkin lymphoma [21], Waldenström macroglobulinemia [22] and other gammopathies [23], Castleman disease [24-26], and non-neoplastic conditions such as cystic fibrosis [27,28], abuse of injected drugs [29], and hidradenitis suppurativa [30,31]. In the United Kingdom experience, the contribution of AA amyloidosis due to chronic infection due to recreational drug use rose from 1 percent in 1990 to 1997 to 13 percent in 2007 to 2014 [8], an experience mirrored in a series of intravenous drug users in San Francisco [29].

A striking change since 1990 has been the increasing proportion of patients with underlying inflammation of unknown etiology even after extensive investigation by experienced centers. In a study of the changes in causation over 25 years, AA amyloidosis of unknown etiology rose from 10 to 27 percent of new cases [8]. Some of this might be explained by the obesity epidemic, as this has been identified as an emerging cause of AA amyloid, with resultant renal disease, in association with findings suggesting low-grade but chronic inflammation probably due to cytokine production by adipocytes [32,33].

Geographic variation may result from additional factors beyond causative or associated disease prevalence and the availability of effective therapies. Studies of the prevalence of AA amyloidosis complicating juvenile arthritis from the 1960s and 1970s reported an almost 100-fold variation between the United States and Poland [34-36]. As a subsequent example, in familial Mediterranean fever, the development of AA amyloidosis is related to severity and duration of disease and homozygosity for the M694V variant, but in a large study, geography was identified as the leading risk factor [37]. Whether the country of origin reflects genetic factors associated with ethnicity or environmental factors is not yet clear. (See "Clinical manifestations and diagnosis of familial Mediterranean fever".)

Rheumatoid arthritis — Susceptibility to AA amyloidosis in RA is related to duration of the disease activity, greater disability, and higher levels of inflammation. Amyloidosis is more likely to occur in patients with poorly controlled, seropositive, severe, and longstanding disease occurring in association with other extraarticular manifestations. Renal, gastrointestinal, and cardiac manifestations of amyloidosis are most common, but in the majority of patients, the disease remains subclinical.

The reported postmortem incidence of amyloid complicating adult RA has generally ranged from 10 to 25 percent, although studies of patients from the 1930s and 1940s reported 60 percent involvement [38]. Similar values of 7.1 to 29 percent have been found with subcutaneous fat pad aspirates or gastrointestinal biopsies in living patients with RA in studies published between 1993 and 2004 [39-44]. In these studies, AA amyloid was clinically overt in only 25 to 50 percent, even after long periods of follow-up sampling, indicating the majority of cases were subclinical [40,42].

Symptomatic disease diagnosed pre-mortem has been reported in 2 to 11 percent, with considerable variation among geographic areas [38,42]. In a 1999 population-based series of 1666 subjects with RA who had died in Finland, the prevalence of amyloidosis was 5.8 percent [45]. The yield of amyloid among patients with RA and renal disease ranges from 10 to 30 percent [46-48].

The clinical spectrum of amyloidosis in RA was evaluated in a report of 124 patients from Japan [41]. The following observations were noted:

●Major manifestations and their frequency included:

•Nephropathy – 59 percent (see "Renal amyloidosis")

•Gastrointestinal symptoms – 58 percent (see "Gastrointestinal amyloidosis: Clinical manifestations, diagnosis, and management")

•Cardiomyopathy – 40 percent (see "Cardiac amyloidosis: Epidemiology, clinical manifestations, and diagnosis")

●The mean duration of RA at diagnosis of amyloidosis was 15.4 years

Similar findings were noted in a retrospective review of 91 Dutch patients with AA amyloidosis due to RA [49]. Nephropathy was the most common presenting symptom, being manifested as proteinuria (70 percent) or impaired renal function. Other organ systems were less frequently involved: cardiomyopathy (9 percent), gastrointestinal symptoms (24 percent), and hepatomegaly (19 percent).

The development of amyloidosis has traditionally been associated with a relatively poor prognosis, unless the underlying RA can be effectively treated. It has been estimated to be the cause of death of 2 to 8 percent of adult patients coming to autopsy [38]. A 1994 report from Japan found a four-year survival rate of 58 percent from the time of diagnosis of amyloidosis, with renal failure contributing to 39 percent of deaths [41]; a subsequent series over a decade later reported an improvement to 67 months in the mean survival following the diagnosis of AA amyloidosis [50]. Prognosis may be significantly impacted by whether amyloid deposition is glomerular or purely vascular in RA patients with AA deposition [51].

Similarly, a study from Finland found that the diagnosis of amyloidosis shortened the lifespan of RA patients by 7.7 years [45]; a reevaluation of autopsy material for the period from 1952 to 1991 from Finland reported a 30 percent incidence of AA amyloid compared with 18 percent detected on routine testing, indicating that a significant proportion of patients may not have been appreciated by standard histologic analysis [52,53]. In contrast with the time period sampled above, subsequent (1987 to 1997) surveys from Finland appeared to confirm a decreasing incidence of AA amyloid among RA patients, possibly reflecting the impact of newer drugs and treatment regimens and of more aggressive treatment standards for early disease [6].

Juvenile idiopathic arthritis — In early reviews, juvenile chronic polyarthritis, also known as juvenile idiopathic arthritis (JIA), accounted for 43 percent of cases of amyloidosis occurring under age 18, with a 4 to 6 percent incidence reported among 389 cases of systemic JIA (Still's disease) followed over a 10-year period [34].

Renal involvement, manifested clinically as proteinuria, occurs in almost all affected patients. Symptomatic disease is also relatively common. One report, for example, found the following frequency of symptoms [54]:

●Edema – 53 percent

●Hypertension – 25 percent

●End-stage kidney disease – 2.5 percent

●Severe abdominal pain, hepatomegaly, and splenomegaly – approximately 20 percent each

●Diarrhea – 13 percent

●Ascites – 2.5 percent

Amyloidosis had been estimated to be the cause of death of 43 to 47 percent of European patients with JIA in the mid-20^th century, but the introduction of more effective treatments that lessen the chronic inflammation associated with systemic JIA has been associated with a dramatic reduction in the incidence of JIA-associated AA amyloidosis. Serial retrospective reviews from the United Kingdom's National Amyloidosis Centre showed a drop in JIA as an association for AA amyloid from 25 percent for the period 1990 to 1997 to 2 percent for 2007 to 2014 [8]; similarly, no cases have been documented in the Finnish registry since 1991 [38,55]. (See "Systemic juvenile idiopathic arthritis: Treatment".)

Ankylosing spondylitis — AS, a form of axial spondyloarthritis, is a well-established cause of AA amyloidosis, and AA amyloidosis was more common among AS patients than RA patients in a multicenter study from Turkey [56]. Renal involvement is the primary clinical manifestation.

The Medical Research Council studies, performed in Britain in the 1950s, found a 6 percent incidence of amyloidosis in patients dying with AS; the diagnosis was made pre-mortem in only 11 of 25 affected patients [57]. A 7 to 9 percent incidence has been reported in a series in which random rectal or fat pad biopsies were performed [58,59]. Subsequently, a 4.3 percent incidence was reported, primarily in patients with severe chronic disease [59,60].

Systemic lupus erythematosus — AA amyloidosis has been described in only a small number of patients with systemic lupus erythematosus (SLE) [61]. The reason for the lower incidence of amyloidosis in SLE relative to RA is unknown but may be due to characteristically lower serum amyloid A protein (SAA) levels [62]. An increased predilection for circulating SAA to undergo proteolytic cleavage in RA compared with SLE has also been proposed [63].

Other rheumatic diseases — Scattered case reports have noted AA amyloidosis in a number of other rheumatic diseases. These include reactive arthritis (formerly Reiter syndrome) [64], psoriatic arthritis [65], Behçet syndrome [66], Takayasu arteritis [67,68], Whipple's disease [69], polymyalgia rheumatica [70], giant cell (temporal) arteritis [71], polyarteritis nodosa [72], gout [73], Sjögren's disease [74], and immunoglobulin (Ig)G4-related disease [75].

'Hereditary' AA amyloidosis — AA amyloidosis is not directly inherited, but there is evidence for genetic predisposition; in children with familial Mediterranean fever, multivariate analysis has shown that the presence of a family history of amyloidosis plus consanguinity was associated with a sixfold increased risk of developing AA amyloidosis [76] (see "The autoinflammatory diseases: An overview"). In one well-described family, AA amyloid occurred over multiple generations linked to a variant in the SAA1 promoter [77].

AA amyloidosis in the spectrum of autoinflammatory diseases — AA amyloidosis may complicate autoinflammatory diseases characterized by monogenic inheritance.

These include familial Mediterranean fever and other periodic fever syndromes, which may also have rheumatic symptoms, and are discussed separately:

●Familial Mediterranean fever (see "Clinical manifestations and diagnosis of familial Mediterranean fever")

●Cryopyrin-associated periodic syndromes (see "Cryopyrin-associated periodic syndromes and related disorders")

●Tumor necrosis factor receptor-1 (TNFR1) associated periodic syndrome (see "Tumor necrosis factor receptor-1 associated periodic syndrome (TRAPS)")

●Mevalonate kinase deficiency (see "Hyperimmunoglobulin D syndrome: Clinical manifestations and diagnosis")

In these syndromes, AA amyloidosis may precede the characteristic clinical phenotype [78,79], which for familial Mediterranean fever has been designated "phenotype 2." Overlap between inflammation, IgM kappa gammopathy, and the occasional development of AA amyloid may also be found in Schnitzler syndrome, characterized by recurrent episodes of urticarial rash [80]. Lastly, AA amyloid may complicate sporadic autoinflammatory diseases that include JIA [81], adult-onset Still's disease [82], gout [73], and there has been one case report of AA amyloidosis in the newly described disease VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic), which is due to an acquired somatic mutation in UBA1 [83].

Idiopathic AA amyloidosis — In small but increasing numbers, the underlying cause of the chronic inflammatory state remains obscure, despite an extensive evaluation for underlying inflammatory or infectious causes [14]. In three well-characterized single-center series of patients with AA amyloidosis from the United States, approximately 20 percent of cases were found to be idiopathic at diagnosis, with a small percentage revealing a known association later in the course [11,12,84]. In two subsequent large series of patients with AA amyloid seen at referral centers in the United Kingdom and Italy, the underlying disease remained unknown in 19 and 32 percent, respectively [8,85].

Changing face of disease and survival — The observation that AA amyloidosis is becoming less common [8] may be a reflection of advances in treatment of inflammatory arthritis in the era of biologic agents. This has both reduced the incidence of AA amyloidosis, and, when it does develop, has improved outcomes in what were previously the commonest pathologies underlying AA amyloidosis. In addition, the older age of the United Kingdom cohort (62 years in 2007 to 2014 versus 54 years in 1990 to 1997) may well reflect both the impact of better treatments, such as biologics, and more willingness to aggressively investigate and manage older patients. In the latest cohort, there was a significantly increased proportion of patients in end-stage kidney disease (29 versus 15 percent) compared with the earliest – a both unexpected and disappointing observation. Possible explanations include age-related decreased renal reserve resulting in more rapid loss of renal function in the presence of AA amyloidosis. While overall survival does not appear to have changed despite new effective therapies, age at death has increased significantly over the last 25 years, suggesting improved general management and supportive care, including renal transplantation [8].

The median survival among cohorts of patients with AA amyloidosis has improved from 24.5 months in a series of 64 in 1991 from the United States [86] to 140 months in 375 patients from the United Kingdom in 2007 [14] and 143 months for 200 patients in Italy in 2017 [85].

CLINICAL MANIFESTATIONS — AA amyloidosis can affect a variety of organs, including the kidneys and heart. These and other manifestations are discussed in detail elsewhere. (See "Overview of amyloidosis", section on 'Clinical manifestations'.)

The most common organ system involved in AA amyloid is the kidney (approximately 90 percent). This is usually characterized by glomerular amyloid deposition, typically leading to the nephrotic syndrome (picture 1A-D) [8,11-15]. However, variant forms occur in which the deposits are predominantly vascular [87] or tubular [88], with some evidence indicating that the AA protein in these forms is biochemically distinct (picture 2A-B) [87-89]. Patients with these variant forms of renal amyloid may present with progressive renal failure, a relatively bland urinary sediment, and little proteinuria, or they may show signs of primary tubular dysfunction such as arginine vasopressin resistance (AVP-R, previously called nephrogenic diabetes insipidus) [51]. (See "Renal amyloidosis".)

DIAGNOSIS — Tissue biopsy is necessary to confirm the presence of amyloid, although the diagnosis of AA amyloidosis may be suggested by clinical features and by the presence of a predisposing rheumatic or a chronic inflammatory disease (eg, nephrotic syndrome occurring in the setting of longstanding rheumatoid arthritis [RA]), and additional laboratory testing may be needed to exclude other conditions. (See "Overview of amyloidosis", section on 'Diagnosis' and 'Differential diagnosis' below.)

Diagnostic approach — We take the following approach to diagnosis:

●In all patients with suspected AA amyloidosis, we recommend tissue biopsy to confirm the presence of amyloid. The abdominal fat is a generally safe and reasonably sensitive site for initial biopsy. In patients with a negative fat aspiration biopsy, we perform a biopsy of a clinically involved organ. (See 'Biopsy' below and "Overview of amyloidosis", section on 'Selection of biopsy site'.)

Alternatives to abdominal fat biopsies for screening include rectal and gingival biopsies. Amyloidosis is very unlikely in a patient with a negative screening biopsy and a negative biopsy of adequate tissue from an affected organ by a laboratory with expertise in these techniques.

Scintigraphy with radioisotope labeled serum amyloid P component (SAP) is also a useful screening technique for suspected amyloidosis, but its availability has been limited to the United Kingdom and the Netherlands, and it is not available in the United States. (See 'Serum amyloid P component scintigraphy' below and "Overview of amyloidosis", section on 'Imaging'.)

●In patients in whom amyloid is present on biopsy, further immunofluorescence or immunohistochemical staining for AA protein and for kappa and lambda light chains is indicated to confirm the diagnosis of AA amyloidosis and to exclude immunoglobulin light chain (AL; primary) amyloidosis. (See 'Biopsy' below.)

●Positive immunohistochemical staining of amyloid deposits with monospecific anti-AA protein antiserum is highly specific for AA amyloidosis when performed in expert centers. For confirmation of the diagnosis, to exclude AL amyloidosis, and if immunohistochemistry is equivocal or unavailable, we test serum and urine for monoclonal immunoglobulins by performing serum immunofixation and test serum for free light chains. (See 'Laboratory testing' below.)

Biopsy — Biopsy of the subcutaneous fat, rectal or gingival tissue, or a clinically involved organ is used to document the presence of amyloid. These individual techniques are discussed in more detail elsewhere. (See "Overview of amyloidosis", section on 'Selection of biopsy site'.)

The fat pad biopsy can establish the diagnosis in up to 80 percent of cases and can be combined with immunoelectron microscopy and mass spectroscopy.

Numerous studies support the use of a biopsy of the rectal mucosa and submucosa, with a sensitivity of approximately 75 to 85 percent for the detection of amyloid deposits. However, some series have shown lower sensitivity than abdominal fat aspiration. Considering that the involvement of the gastrointestinal tract may be focal, vascular, and subtle, sampling of multiple locations in the gastrointestinal tract (eg, stomach, small bowel, or colon) may also be useful for diagnosis [90].

Immunofluorescence (as well as immunohistochemical and immunoelectron) microscopy with a monospecific anti-AA protein antiserum is typically markedly positive in AA amyloidosis (picture 1D) [91,92] (see 'Diagnosis' above). Absence of staining for lambda or kappa light chains further helps to distinguish AA from AL amyloidosis. These analyses should be performed by centers with expertise in these techniques.

For further analysis, amino acid sequencing and mass spectroscopy of amyloid deposits have been utilized to identify the precursor protein [93-95] and are available commercially [96]. Quantitation of AA amyloid in abdominal fat pad aspirates has been demonstrated using an enzyme-linked immunosorbent assay (ELISA); this approach may have utility for comparing patient population and for monitoring AA deposition serially [94]. A full proteomics approach combined with immunoelectron microscopy of fat pad aspirates establishes the diagnosis of AA amyloidosis in 70 to 80 percent of cases [97].

Laboratory testing — We obtain a serum C-reactive protein (CRP) level and an erythrocyte sedimentation rate (ESR) to assess the acute phase response for evidence of an inflammatory state. These are sometimes useful for monitoring of therapy [12]. However, other than the biopsy-related studies (see 'Biopsy' above), laboratory testing has little role in confirming the presence of AA amyloidosis. An important limitation regarding the ESR as a measure of inflammation in some patients with amyloidosis is the elevation seen in this assay in patients with chronic kidney disease and proteinuria, even in the absence of inflammation.

Demonstration of a sustained inflammation with a raised CRP, ESR (except in patients with chronic kidney disease, in whom the test may be elevated without inflammation), or other hepatic acute phase response testing is suggestive of chronic inflammation that might result in AA amyloidosis. We typically perform such testing every two to four weeks over at least a two-month period to assess inflammatory activity. It would be very unusual to have AA amyloidosis with a normal ESR and CRP. Serum amyloid A protein (SAA), which is also predominantly synthesized in the liver, would be an alternative (and superior) marker for AA amyloid. However, SAA quantitation is not always available outside specialist centers. In the United States, it is available through the multi-biomarker disease activity (MBDA) test (Vectra DA) or inflammatory bowel disease diagnostic panels. Proinflammatory cytokine measurements can be obtained either individually or as part biomarker screens [12].

Tests for monoclonal immunoglobulins in serum, such as immunofixation and measurement of free immunoglobulin light chains, are useful in excluding AL amyloidosis but must be interpreted with caution, as incidental monoclonal gammopathies are present in 5 to 8 percent of patients over 70 years of age, and in some cases of AL amyloidosis, the clone may not be detected in the serum. (See "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis" and "Laboratory methods for analyzing monoclonal proteins".)

Serum amyloid P component scintigraphy — Amyloid fibrils avidly bind both apolipoprotein E and serum amyloid P component (SAP). Tissue amyloid deposits may be identifiable by scintigraphy following the intravenous injection of technetium- or radioiodine-labeled SAP. The sensitivity and specificity of SAP scanning are discussed in detail elsewhere. This test is available in the United Kingdom and the Netherlands but is not available in the United States. (See "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis", section on 'Serum amyloid P component scintigraphy'.)

Other imaging modalities — Potential ligands for imaging of AA amyloid include antibodies with reactivity to the subunit protein, peptides that bind to tissue AA, and 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) [98-100].

DIFFERENTIAL DIAGNOSIS — In the presence of biopsy-established amyloidosis, the differential diagnosis of AA amyloidosis includes the following:

●Immunoglobulin light chain amyloidosis – Immunoglobulin light chain (AL; primary) amyloidosis is due to the tissue deposition of fragments of monoclonal immunoglobulin light chains. The plasma cell proliferation in this disorder leads to the presence of a paraprotein in the serum (as an M protein on protein immunoelectrophoresis or immunofixation or as evidenced by increased serum free light chains) or urine (as monoclonal light chains) in approximately 90 percent of cases. Although virtually all patients have multisystem amyloid deposition, it is not uncommon to present with organ-dominant disease. (See "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis".)

Patients who have a monoclonal gammopathy of undetermined significance (MGUS) may require additional diagnostic studies, as approximately 10 percent of such patients have been found to have a type of amyloidosis other than AL amyloid.

●Hereditary amyloidosis – Heritable amyloidoses result from mutations in gene coding for one of several different proteins. A thorough family history aids in the exclusion of these heritable disorders. AA-specific immunohistochemical staining on biopsy will confirm AA amyloidosis and thus exclude a hereditary form. (See ''Hereditary' AA amyloidosis' above and "Genetic factors in the amyloid diseases".)

●Dialysis-related amyloidosis – Dialysis-related amyloidosis is due to deposition of fibrils derived from beta-2 microglobulin, which accumulates in patients with end-stage kidney disease who are being maintained for prolonged periods of time by dialysis. This disorder has a predilection for osteoarticular structures. Although dialysis-related amyloidosis is associated with chronic hemo- or peritoneal dialysis, the amyloid rarely involves the kidney itself. Dialysis-related amyloidosis is almost exclusively a disease of patients on long-term renal replacement therapy. (See "Dialysis-related amyloidosis".)

●Age-related (senile) systemic amyloidosis – Deposition of otherwise normal (wild-type) transthyretin in myocardium and other sites is referred to as age-related (senile) systemic amyloidosis. Age-related systemic amyloidosis very rarely affects the kidney, the major target organ being the heart. Localization of amyloid deposition to the myocardium, immunohistochemistry with antibodies to transthyretin, and proteomic testing may also be used to distinguish this form of amyloid from AA. (See "Cardiac amyloidosis: Epidemiology, clinical manifestations, and diagnosis" and "Overview of amyloidosis", section on 'Wild-type transthyretin systemic amyloidosis'.)

●Organ-specific localized amyloidosis – The coincidental occurrence of organ-specific amyloidosis in a patient with a systemic rheumatic or chronic inflammatory disorder could cause confusion with AA amyloidosis, but localized AA amyloid is rare. When found, localized amyloidosis is usually AL-type amyloidosis that is diagnosed on histology or mass spectrometry; it is very rarely hereditary. It has been reported in association with sarcoidosis, Sjögren's disease, and occasionally other conditions. (See "Overview of amyloidosis", section on 'Organ-specific amyloid'.)

SUMMARY AND RECOMMENDATIONS

●AA amyloidosis (previously known as secondary [AA] amyloidosis) is a disorder characterized by the extracellular tissue deposition of fibrils that are predominantly composed of fragments of serum amyloid A (SAA) protein, an acute phase reactant. AA amyloidosis may complicate a number of chronic inflammatory conditions. The incidence appears to be falling and in western nations ranges from 0.5 to 0.86 percent. (See 'Introduction' above and 'Causes and relation to rheumatic diseases' above.)

●The most common underlying disorders associated with AA amyloidosis in the United States and Europe include rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), ankylosing spondylitis (AS), inflammatory bowel disease, psoriatic arthritis, familial periodic fever syndromes, chronic infections, and certain neoplasms. Inflammation of unknown etiology appears to be responsible for an increasing proportion, perhaps reflecting more effective treatment of the inflammatory arthritides and inflammatory bowel disease with biologic agents. (See 'Causes and relation to rheumatic diseases' above.)

In some eastern Mediterranean countries (eg, Turkey, Armenia), familial Mediterranean fever and certain MEFV mutations are more common causes and associations with AA amyloidosis than in North America and Europe. Chronic infections are responsible for a larger proportion of patients with AA amyloid in the developing world than in the United States and Europe. It may precede and/or complicate familial Mediterranean fever and tumor necrosis factor receptor-1 (TNFR1) associated periodic syndrome monogenic autoinflammatory diseases, as well as complicate sporadic and hereditary diseases such as Schnitzler syndrome, JIA, and adult-onset Still's disease. Susceptibility to AA amyloidosis among the various rheumatic diseases is determined by duration and severity of inflammation with contributions from additional genetic and environmental factors. (See 'Causes and relation to rheumatic diseases' above.)

●We recommend tissue biopsy in all cases of suspected AA amyloidosis to confirm the presence of amyloid. The abdominal fat is a generally safe and reasonably sensitive site for initial biopsy. If a fat aspiration biopsy is negative, then we obtain a biopsy of a clinically involved organ. Alternative sites to the abdominal fat pad for the screening biopsy include the rectum and gingiva. (See 'Diagnosis' above and "Overview of amyloidosis", section on 'Selection of biopsy site'.)

●In patients in whom amyloid is present on biopsy, further immunofluorescence or immunochemical staining is indicated for identification of AA protein and, in some cases, for kappa and lambda light chains. (See 'Diagnosis' above and 'Biopsy' above.)

●We perform testing of serum and urine for monoclonal immunoglobulins and of serum for free light chains to help exclude immunoglobulin light chain (AL; primary) amyloidosis. (See 'Diagnosis' above and 'Laboratory testing' above.)

●In the presence of biopsy-established amyloidosis, the differential diagnosis of AA amyloidosis includes AL amyloidosis, hereditary amyloidosis, dialysis-related amyloidosis, age-related systemic amyloidosis, and organ-specific amyloidosis. (See 'Differential diagnosis' above.)