June 2005 : No 6

Systemic Amyloidosis in the Rheumatic Diseases

Ronan H Mullan

Barry Bresnihan

St Vincent's University Hospital, Elm Park, Dublin

Reports on the Rheumatic Diseases Series 5 : Topical Reviews

  • Systemic amyloid A (AA) amyloidosis occurs in association with chronic inflammatory disease and results from the insoluble tissue deposition of the acute-phase protein serum amyloid A (A-SAA)
  • The suppression of amyloidosis through control of inflammation in chronic disease is seen as the mainstay of current therapy
  • Future strategies aimed at the identification of susceptible patients through genetic screening, earlier and more effective disease modification in rheumatoid arthritis (RA) using biologic therapies, and novel strategies which prevent AA fibril formation will improve the long-term outcomes for these patients

Introduction

The amyloidoses are a group of diseases characterised by the pathological accumulations of a range of insoluble proteins in the extracellular matrix of tissues and organs.1 There are several different forms of amyloid protein, which are associated with a number of distinct underlying causes, including autoimmune disease, infections and malignancies. The clinical syndromes which occur in amyloidosis are dependent on the particular amyloid precursor proteins and their affinities for forming fibrils in different tissues and organs (Table 1). Symptoms occur when amyloid deposits distort normal tissue architecture and disrupt the normal functioning of tissues and organs. The deposition of amyloid may be localised to a specific tissue or be systemic, involving a number of organs. Systemic amyloid A (AA) amyloidosis, or secondary amyloidosis as it was previously known, occurs as a secondary event in both infectious and autoimmune diseases with a chronic inflammatory component. Prolonged elevation of the acute-phase protein serum amyloid A (A-SAA) may eventually lead to its deposition in an insoluble form as AA amyloid.3 The natural history of AA amyloidosis is progressive, commonly leading to organ failure and death, particularly when the inflammatory component of the underlying disease remains poorly controlled.

TABLE 1. Amyloid fibril proteins and their precursors.2 (Adapted from: Westermark P et al, Amyloid 2002;9(3):197-200 with permission of the author and Taylor & Francis Ltd, http://www.tandf.co.uk/journals.)
Amyloid protein
 Protein precursor Systemic (S) or localised (L) Clinical syndrome
AA Acute-phase serum amyloid A (A-SAA) S, L Secondary
Familial Mediterranean fever
Muckle–Wells syndrome
AL Immunoglobulin light chain S, L Myeloma-associated
Primary
AH Immunoglobulin heavy chain S, L Myeloma-associated
Primary
ATTR Transthyretin S Familial
Senile systemic
L? Tenosynovial
Aβ2M β2-microglobulin S Haemodialysis
AApoA1 Apolipoprotein A1 S Familial
L Aortic
AApoA2 Apolipoprotein A2 S Familial
Aβ Aβ protein precursor (AβPP) L Alzheimer's disease
Ageing
APrP Prion protein L Spongiform encephalopathies

Serum amyloid A

A-SAA was first discovered in the serum because of its cross-reactivity with antisera against AA peptides isolated from AA amyloid.4,5 In humans, A-SAA is a highly inducible component of the acute-phase response with levels increasing up to 1000-fold within hours of an inflammatory stimulus.6 The high degree of evolutionary homology of the SAA genes and their proteins extending from fish to mammals7 and its rapid induction during inflammation suggest an important biological role in host defence.

In common with other acute-phase proteins, A-SAA is secreted from the liver in inflammation, and is the main source of the elevated levels found in serum. A-SAA exists mainly in a bound form in serum, where it forms a complex with high-density lipoprotein (HDL) by displacing the apolipoprotein ApoA1 to become the predominant apolipoprotein of HDL. A-SAA/HDL has a reduced affinity for hepatocytes but an increased affinity for macrophages, thus facilitating the delivery of cholesterol to macrophage-rich tissues during an acute inflammatory event.3 In chronic inflammation, this shift in HDL delivery away from the liver and towards the periphery may contribute to the increased incidence of cardiovascular disease seen in diseases such as rheumatoid arthritis (RA), where accelerated cholesterol delivery to the walls of arterial blood vessels leads to the development of atherosclerotic plaques and an increase in cardiovascular mortality.

There is increasing evidence that A-SAA is an active participant in inflammatory processes and that it is not merely a marker for inflammation. Evidence of a more integral involvement between A-SAA and disease progression has been suggested by our observation that serum A-SAA levels reflect disease activity in RA with greater sensitivity than other acute-phase markers.8 In vitro studies have shown that A-SAA can increase the production of important pro-inflammatory cytokines such as tumour necrosis factor alpha (TNFα), interleukin 8 (IL-8) and IL-1β.9 Unlike other acute-phase proteins, which are produced only in the liver, A-SAA is also produced extrahepatically and specifically at sites of localised inflammation. We have previously reported high levels of A-SAA expression in RA synovial tissue, both in the lining layer where direct invasion of joint structures can occur and in perivascular regions where there is active recruitment of leucocytes from the circulation into inflamed synovial tissue (Figure 1). We have also shown coordinated expression of the A-SAA receptor in inflamed synovial tissue and the formyl peptide receptor-like 1 (FPRL1), a 7-transmembrane G protein-coupled receptor.10,11 A-SAA has been shown to be chemotactic for inflammatory cells including T-cells and monocytes.12 We have recently demonstrated that A-SAA induces the expression of cell adhesion molecules on RA synovial fibroblasts and human endothelial cells, and that it increases leucocyte adhesion to these in vitro (unpublished observations). Finally, we previously reported a role for A-SAA in matrix degradation through the production of metalloproteinases from RA synovial fibroblasts in vitro.11 Further studies examining the nature and extent of the physiological properties of A-SAA in synovial tissue are currently under way.

FIGURE 1. Acute phase protein serum amyloid A (A-SAA) synthesis in rheumatoid arthritis synovial tissue.

Pathogenesis

How soluble serum A-SAA becomes deposited as insoluble amyloid is still largely unknown. It is clear, however, from both in vivo animal models and from observational cohorts in humans that prolonged elevated levels of A-SAA due to chronic or repeated episodes of inflammation are critical to the development of AA amyloid. In animal models of chronic inflammation, high levels of A-SAA were found to be necessary before secondary amyloid formation. In humans, some inflammatory diseases such as systemic lupus erythematosus and ulcerative colitis are less frequently complicated by amyloidosis. These diseases are also characterised by lower A-SAA levels than more amyloidogenic conditions such as RA and ankylosing spondylitis (AS).3

During their formation, amyloid fibrils form complexes with a number of other proteins, including complement components, serum amyloid P (SAP) and the extracellular matrix (ECM) proteins heparan sulphate (HS) and laminin, to form a crossed β-pleated arrangement, which is largely resistant to proteolytic cleavage.13 Amyloid fibrils are characteristically composed of non-branching fibrils 7–10 nm in diameter, which stain with Congo Red to exhibit red/green birefringence under polarised light. The predominant amyloid A protein type found in AA amyloid corresponds to the N-terminal two thirds of A-SAA, although both smaller and larger protein fragments of A-SAA have also been found. Multiple proteolytic cleavages may therefore occur, initially resulting in epitopes similar to fragments found in AA amyloid, with subsequent cleavages processing the protein further. In one study mononuclear cells from healthy people were capable of mediating complete degradation of A-SAA, whereas cells from amyloidotic patients produced a protein fragment similar to the AA fragment found in amyloid deposits.3 It is possible, therefore, that AA amyloidosis may be the result of incomplete digestion of A-SAA leading to the accumulation of an insoluble intermediate product in extracellular tissues.

The importance of ECM components in amyloidogenesis has been increasingly recognised. Immunohistochemical studies have demonstrated that basement membranes (BM) are disrupted near amyloid deposits and that amyloid fibrils form in complexes with HS.14 High affinity A-SAA binding sites for HS and other ECM components have since been described.15 In experimental models of AA amyloidosis a threefold to fivefold induction of amyloid-binding proteins, including HS, laminin and collagen IV, is seen in affected tissues, and this may precede amyloid deposition.16 Furthermore, interaction of A-SAA with HS leads to a marked increase in the formation of a β-pleated sheet arrangement in vitro.15

Although a prolonged high plasma level of A-SAA is considered a prerequisite for the development of AA amyloidosis, it is clearly not the only factor predisposing individuals to its development, as evidenced by the large numbers of RA patients with high A-SAA levels who do not develop the disease. Recent studies have focused on whether a specific genetic tendency to amyloidogenesis exists in affected individuals. In humans, A-SAA is encoded by four distinct genes. SAA1 and SAA2 undergo marked transcriptional activation during inflammation. SAA3 is a pseudogene in humans, and SAA4 encodes a constitutive form of the protein that is only minimally inducible during inflammation.17-19 The SAA1 gene has five known alleles (SAA1.1–SAA1.5), at least three of which encode distinct proteins. Increased amyloidosis risk was associated with homozygosity for SAA1.1 and SAA1.3 in Caucasian and Japanese populations respectively.20,21 Furthermore, the existence of a specific single-nucleotide polymorphism has been strongly associated with amyloidogenesis in a Japanese RA cohort.22 The relationship between distinct polymorphisms of the A-SAA genes and the clinical syndrome is currently unknown, although increased rates of messenger ribonucleic acid (mRNA) transcription or an increase in the affinity of the protein for fibril formation have been suggested as possible explanations.

Epidemiology of amyloid A amyloidosis

Infectious diseases including tuberculosis, leprosy and malaria still account for the majority of AA amyloidosis seen in developing countries. The control of chronic infective diseases in the West has led to an overall decline in AA amyloidosis in these areas, with the chronic idiopathic rheumatic diseases now being the most common cause. Of these diseases, RA is the one most commonly associated with amyloidosis, with reported prevalence rates in long-standing cases of the disease of 5–20%.23,24 The reported prevalence of amyloidosis, however, varies between study populations and with the method of detection employed to diagnose the disease. A significant proportion of patients with other inflammatory arthritides can also develop amyloidosis. In a survey of 137 patients with AS, using abdominal fat aspiration, evidence of amyloid fibril deposition was found in 7% of patients.25 In a 25-year follow up of 398 patients with AS, AA amyloidosis was found to be the most common direct cause of death. Mortality was also associated with an increased number of involved joints and higher acute-phase markers.26 AA amyloidosis has been reported less frequently as a complication in other forms of inflammatory arthritis and is probably due to the more modest acute-phase response seen in these diseases.27

Recently, clinicians have questioned whether improvements in the treatment of RA in recent years have led to a decline in amyloidosis in the RA population.28 To date, however, there is no evidence to support a true fall in prevalence. In two Japanese studies of RA patients, amyloidosis was found in 18% of renal biopsies in the period 1979–1988 and in 19% of cases in 1989–1996.29 It remains possible that better suppression of inflammation in the RA population will lead to a reduction in new cases in the future, or could effect a change in the clinical presentation, with a longer pre-clinical phase and more insidious onset of symptoms.

Clinical features

The course of AA amyloidosis passes through a number of defined stages. An underlying inflammatory condition must be present, which is characterised by prolonged serum elevations in A-SAA in an individual susceptible to amyloid fibril formation. With continued elevation of the acute-phase response, a pre-clinical period of amyloidosis develops as amyloid deposition proceeds in the absence of clinical symptoms. No clear data exist regarding the length of this phase, and it is not clear that all patients with asymptomatic amyloid deposition eventually develop the clinical syndrome of amyloidosis. Clinical amyloidosis occurs when the distortion of tissue architecture by amyloid accumulations interferes with normal organ function.25

The possibility of AA amyloidosis should be considered in all patients with long-standing inflammatory disease, particularly if disease activity has been poorly controlled during this time. The clinical syndrome is most commonly dominated by progressive renal impairment. Amyloidosis should be considered in patients with long-standing (>5 years) inflammatory arthritis who develop persistent proteinuria due to renal amyloid deposition (Figure 2) in the presence of elevated acute-phase markers. Other signs of renal impairment, such as a worsening hypertension, rising serum creatinine, hypoalbuminaemia and peripheral oedema, may be present. Patients may also present with gastrointestinal features, including diarrhoea, malabsorption, gastrointestinal bleeding or bowel perforation. Hepatosplenomegaly can occur as a direct result of amyloid deposition, with infection or thrombocytopenia as a result of hypersplenism. Easy bruising due to vascular deposition may occur. Symptomatic cardiac involvement has been reported as a rare event in AA amyloidosis.32 Amyloid deposition can lead to electrocardiographic changes, including first-degree heart block, low voltages in the limb leads and Q waves in the absence of a previous myocardial infarction. Echocardiographic features include increasing thickness of the interventricular septum and reduced left inflow velocity due to impaired left ventricular relaxation. These features are mild, however, and appear not to be associated with symptomatic cardiac failure in the majority of patients. This is in marked contrast with amyloid L (AL) amyloidosis-related cardiac disease, where progressive restrictive cardiomyopathy and cardiac failure is a leading cause of mortality.33

If the underlying inflammatory disorder is left untreated, AA amyloidosis follows a relentless course with persistent proteinuria progressing towards end-stage renal disease. Overall mortality figures for symptomatic AA amyloidosis vary between studies, with median mortality rates in RA of 2–5 years being reported.34,35

FIGURE 2. Renal amyloid A (AA) amyloid deposition.

Diagnosis

The presence of biopsy-proven amyloid deposits remains the gold standard in the diagnosis of pre-clinical or clinical AA amyloidosis. Once an amyloid deposit has been identified, further immunotyping can be performed to confirm its type. Biopsy of the liver or kidney is highly sensitive when laboratory tests show dysfunction of the affected organ. However, the increased risk of a life-threatening bleed due to vascular deposition of amyloid restricts their use to cases where other biopsy techniques fail to give the diagnosis and the diagnosis is still in doubt. Both gastrointestinal and rectal biopsy are safer to perform than renal or liver biopsy and identify amyloidosis in the majority of patients (Table 2). Subcutaneous fat aspiration is a safe and straightforward procedure that can be readily carried out in the outpatient setting.36 The sensitivity of this technique is low, however, and the correct technique is required to obtain a positive result.

TABLE 2. Biopsy techniques for diagnosis of amyloid A (AA) amyloidosis.30,31
Technique Advantages Disadvantages Sensitivity
Abdominal fat aspiration Can be performed in outpatient clinic Low sensitivity
User dependent		 55–75%
Gastrointestinal Well tolerated and safer than liver or kidney biopsy More expensive to perform 68–88%
Rectal Safer than kidney or liver biopsy Uncomfortable
Risk of bleeding		 75–85%
Kidney or liver High sensitivity Risk of life-threatening bleed Approaching 100%

SAP is a normal plasma α-glycoprotein, which becomes deposited in all forms of amyloid as amyloid P (AP). AP binds to amyloid deposits through a calcium-dependent process and has been found to increase the stability of amyloid fibres by inhibiting proteolysis. Total body scintigraphy using the binding of radioiodinated SAP to amyloid is a highly sensitive and non-invasive technique which accurately quantifies the location and extent of amyloid deposits throughout the body. In addition to its aid in diagnosis and in highlighting affected organs, the test may be repeated after treatment to establish whether or not regression of amyloid deposits has occurred.37

There are no specific blood tests to confirm the presence of AA amyloidosis. Patients with active inflammatory disease will have elevated acute-phase markers, including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and A-SAA. A full assessment should also include organ function tests, both to establish their baseline function and to document any improvement or deterioration in function during follow up.

Treatment

Successful control of the underlying inflammatory process with effective suppression of the acute-phase response remains the mainstay of treatment of AA amyloidosis. By reducing the availability of the soluble precursor protein A-SAA, it is thought that further amyloid deposition may be prevented. Amyloid plaques often remain stable despite adequate suppression of the acute-phase response, but true regression of amyloid deposits following treatment has occasionally been reported, and is likely to reflect a shift in the amyloid metabolism in favour of degradation.37

A number of therapeutic approaches in RA-induced amyloidosis using different disease-modifying anti-rheumatic drugs (DMARDs) or alkylating agents with corticosteroid have proven efficacy in controlling further amyloid formation.38,39 Prognosis is improved if the serum A-SAA level is maintained at low levels (<10 mg/ml).40 Alternative treatments should be tried until adequate suppression of inflammation has been achieved.

Treatment of RA with anti-TNFα therapy provides significant and sustained improvements in disease activity without the serious side-effects associated with alkylating agents.41 Recently, case reports have demonstrated efficacy of anti-TNFα therapies in the treatment of RA-associated amyloidosis. In one report, treatment with infliximab led to rapid and complete resolution of proteinuria secondary to amyloidosis.42 In a second patient, nephrotic range proteinuria responded to etanercept after a trial of infliximab had failed to adequately control either the acute-phase response or the amyloidosis. A follow-up SAP scan after 12 months' treatment, however, showed only slight regression of amyloid deposits,43 indicating that effective long-term suppression is likely to be required to prevent a recurrence of symptomatic disease.

The observation that the proteoglycan HS is incorporated into AA amyloid and promotes amyloidogenesis has led to the development of treatments whose mechanism of action interferes with HS:AA binding. In one study, a synthetically produced low-molecular-weight (135–1000) antagonist to HS:AA binding was shown to retard AA amyloid progression in a murine model of AA amyloidogenesis. More recently, a synthetic derivative of glucosamine reduced splenic AA amyloid deposition by 60% through inhibition of HS biosynthesis.44 This approach, if used in combination with RA disease control, may improve the long-term outcome for patients with clinical AA amyloidosis.

Conclusion

Despite an increased understanding of disease pathogenesis, AA amyloidosis remains as a serious complication of idiopathic rheumatic diseases, and results in considerable morbidity and mortality. An increased understanding of genetic factors which predispose to the amyloid formation will enable clinicians to identify at-risk patients. The development of treatments which specifically inhibit the polymerisation of soluble A-SAA is a major advance and may further prevent the development of the disease and ameliorate its clinical course. Changes in the treatment of inflammatory arthritis, including the earlier use of DMARD therapy and an increasing use of biological agents, have reduced the inflammatory burden of these diseases in recent years. It will be intriguing to see if an improvement in the clinical course of these diseases through more optimal medical management will lead to a lower incidence of AA amyloidosis in the future.

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