Systemic amyloidosis: a challenge for the rheumatologist amyloid... · amyloidosis is a disorder of...

nature reviews | rheumatology volume 6 | JulY 2010 | 417

Department of Internal Medicine, University of Florence (F. Perfetto, a. moggi-Pignone, r. livi, a. tempestini, m. matucci-Cerinic), Renal Unit, Azienda Ospedaliera Universitaria Careggi (F. Bergesio), Viale Pieraccini 19, 50139 Firenze, Italy.

Correpondence to: F. Perfetto [email protected]

Systemic amyloidosis: a challenge for the rheumatologistFederico Perfetto, Alberto Moggi-Pignone, Riccardo Livi, Alessio Tempestini, Franco Bergesio and Marco Matucci-Cerinic

abstract | 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.

Perfetto, F. et. al. Nat. Rev. Rheumatol. 6, 417–429 (2010); published online 8 June 2010; doi:10.1038/nrrheum.2010.84

Introductionamyloidosis includes a group of diseases characterized by the extracellular deposition of fibrillar proteinaceous tissues. when viewed microscopically under polarized light, all amyloid deposits have a typical apple-green birefringence after staining with Congo red (Figure 1), while electron microscopy (em) reveals nonbranching linear fibrils of indefinite length with an approximate diameter of 10–12 nm.1 the X-ray diffraction pattern is consistent with Pauling’s model of a cross-β fibril. amyloidosis can be acquired or inherited, localized or systemic, and at least 20 different proteins can form amyloid fibrils in vivo. the current nomenclature of amyloidosis is based on the nature of the major fibrillar protein forming the amyloid deposits, which is desig-nated protein a followed by an abbreviation of the precursor protein name. the amyloid protein name is used to name the disease. table 1 summarizes the main protein types that cause amyloidosis.

in most forms of amyloidosis, amyloid can be de po-sited into the joint and periarticular tissue, although the preference for these tissues varies considerably among specific types. the localized form of amyloidosis rarely affects the joints, whereas aβ2m amyloidosis does so almost exclusively. rheumatologists usually encoun-ter aa amyloidosis as it is a potential complication of chronic rheumatic diseases, particularly rheumatoid arthritis (ra). in addition, patients with al amyloidosis,

the most common form of systemic amyloidosis, can develop musculoskeletal and articular symptoms. this review provides an update on the incidence, clinical course, and therapy of systemic amyloidosis in light of novel approaches to diagnosis and treatment.

Pathogenesisamyloidosis is a disorder of protein conformation, in which several unrelated proteins misfold and undergo an irreversible transition from their native conformation into highly ordered fibrils that are insoluble and resistant to proteolysis. an essential prerequisite for the development of amyloidosis is a sustained supply of the specific fibril precursor, which can precipitate into tissues where it trig-gers amyloid fibril growth and tissue damage (Figure 2). in the case of amyloidosis associated with chronic inflam-matory diseases (aa amyloido sis), immuno globulin light chain amyloidosis (al amy loidosis) or dialysis- associated β2-microglobulin amy loidosis (aβ2m amyloidosis), the protein precursor (serum amyloid a [saa] protein, light-chain immunoglobulin [ig] and β2-microglobulin [β2m], respectively) circulates at high concentrations in the bloodstream. in hereditary systemic amyloidosis, a heterogeneous group of autosomal dominant, late-onset diseases caused by mutations in the genes coding for a set of plasma proteins (including transthyretin [ttr], apolipoprotein a [apoa]-i , apoa-ii, fibrinogen, gel-solin, cystatin C and lysozyme), the mutated protein cir-culates at normal concentrations and without functional defects, but the mutation makes these proteins unstable

Competing interestsThe authors declare no competing interests.

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and prone to fibril conversion. in some proteins, such as apoa-i, which is not in itself amyloido genic, a proteo-lytic cleavage generates an un stable polypeptide that un dergoes fibril aggregation.

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

Figure 1 | Appearance of amyloid protein deposit on microscopic examination. Subcutaneous fat aspirate stained with Congo red and viewed under polarized light shows the characteristic apple-green birefringence.

it is self-evident that the deposition of increased amounts of amyloid in perivascular areas, in the absence of any inflammatory response, would produce tissue damage and systemic disease. However, compel-ling evidence indicates that the accumulation of large extra cellular deposits of amyloid is not directly associ-ated with pathogenesis, and that oligomeric inter-mediates are the major cytotoxic species in various forms of amyloido genesis. in the attr amyloidoses, the misfolded ttr protein aggregates in tissues, with subsequent visceral, peripheral, and autonomic nerve dysfunction. this process is likely to require the dissoci-ation of the native ttr tetramer into its constituent monomers. misfolding within the monomer enables the formation of soluble aggregates, which become insoluble as they grow to form protofilaments. amyloid fibrils composed of four protofilaments are eventually formed from the insoluble aggregates.2,3 other evidence4 has demon strated that several quaternary structural states of wild-type and variant ttr proteins have cytotoxic effects on cells of neural lineage. these studies showed that, although ttr amyloid fibrils and soluble aggre-gates greater than 100 kDa in mass were not toxic, the incubation of monomeric ttr or relatively small pep-tides rapidly induced the formation of aggregates up to six subunits in size, and that these aggregates were responsible for the major cytotoxic effects observed in tissue culture. as for al amyloidosis, it has long been known that, although cardiac death is usually associ-ated with extensive myo cardial infiltration by amyloid de posits, the degree of infiltration alone does not corre-late with heart failure or survival.5 the infusion of ig light chains from patients with al amyloidosis causes diastolic dys function in isolated mouse hearts similar to that observed in patients with cardiac al amy loidosis.6 this finding suggests that ig light chain proteins might con tribute directly to the patho genesis and rapid pro-gression of amyloid cardio myopathy, indepen dent of extra cellular fibril deposition.

amyloid deposits also contain several nonfibrillar con-stituents, including the normal plasma glyco protein serum amyloid P component (saP) and glycos aminoglycans (GaGs). the interaction between GaGs and amyloid precursors is thought to enhance fibril formation and perhaps enhance their stability.

Clinical manifestationsthe clinical manifestations of systemic amyloidosis are polymorphic and, as mentioned above, depend on the organs involved (table 2). the following sections describe the predominant features of al, aa, aβ2m and attr amyloidoses.

al amyloidosisal amyloidosis, in which fibrils are derived from mono-clonal ig light chains, is the most common type of sys-temic amyloidosis in western countries. the median age at diagnosis is about 60 years, and it occurs predomi-nantly in men. most patients have an ig abnormality detectable by immunofixation of serum or urine, or

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detectable abnormal free light chain (FlC) level or FlC ratio in serum by nephelometric FlC assay.

the principal clinical manifestations of al amyloido-sis include nephrotic syndrome, congestive heart failure, peripheral neuropathy and hepatomegaly. more than half of all cases of al amyloidosis involve two or more organs.7 renal involvement affects about 70% of patients, leading to proteinuria and eventually to uremia.7 more than 10% of nondiabetic patients with nephrotic syn-drome aged over 44 years have al amyloidosis.8 al amyloidosis results in restrictive cardiomyopathy due to the replacement of myocardial fibers with interstitial deposits of fibrils; the infiltrated myocardium become firm, rubbery and noncompliant as a result.9 on electro-cardiography, this myocardial infiltration provokes low voltage in the limb leads or poor r-wave progression in the precordial leads. at least two-thirds of patients with al amyloidosis have echocardiographic abnormalities such as abnormal myocardial relaxation, thickened ven-tricular walls, abnormal myocardial texture (described as granular sparkling), pericardial effusion and a restric-tive filling pattern (in late-stage disease) with elevated

filling pressures.10 Hepatic involvement is present in 22% of patients, and is characterized by an unexplained increase in serum levels of alkaline phosphatase associ-ated with hepatomegaly.11 approximately 20% of patients with al amyloidosis have symptomatic involvement of the peripheral and autonomic nervous systems, and orthostatic hypotension can be the dominant syndrome. Peripheral neuropathy is axonal and demyelinating: symptoms start primarily in the lower limbs, and pares-thesias and pain precede motor changes. Bilateral carpal tunnel syndrome is present in about half of all patients and can precede the diagnosis of al amyloidosis by about 2 years.12

al amyloidosis can also present with symptoms and signs that mimic a variety of rheumatic diseases. soft tissue, joint and bone involvement can be the dominant clinical feature in about 9% of cases of al amyloidosis, more often in male patients.13 amyloid infiltration into periarticular and synovial tissues can induce stiffness and swelling of multiple joints with painful contrac-tures, mimicking ra. the most characteristic articular manifesta tion of al amyloidosis is the ‘shoulder pad’

Table 1 | Classification of forms of amyloidosis

amyloid type

Fibril protein precursor Systemic (S) or localized (l)

Clinical syndrome

AL Monoclonal Ig light chains S or L Amyloidosis associated with monoclonal plasma cell dyscrasias

AH Monoclonal Ig heavy chains S or L Amyloidosis associated with monoclonal plasma cell dyscrasias

AA Serum amyloid A protein S Reactive systemic amyloidosis associated with chronic inflammatory diseases

Aβ2M β2M S Amyloidosis associated with long-term hemodialysis

ATTR Genetically variant TTRwild type TTR

SS

Familial (autosomal dominant) amyloid polyneuropathySSA

ACys Genetically variant cystatin S Hereditary cerebral hemorrhage with cerebral and systemic amyloidosis

AGe Genetically variant gelsolin S Familial autosomal dominant systemic amyloidosis Predominant cranial nerve involvement with lattice corneal dystrophy

ALys Genetically variant lysozyme S Familial autosomal dominant systemic amyloidosisNon-neuropathic with prominent visceral involvement

AApoAI Genetically variant apoA-I S Familial autosomal dominant systemic amyloidosisPredominantly non-neuropathic with prominent visceral involvement

AApoAII Genetically variant apoA-II S Familial autosomal dominant systemic amyloidosisNon-neuropathic with prominent renal involvement

AFib Genetically variant fibrinogen A α-chain

S Familial autosomal dominant systemic amyloidosisNon-neuropathic with prominent renal involvement

ALECT2 Leukocyte chemotactic factor 2 L Acquired renal amyloidosis

AMed Lactadherin L Age-related amyloidosis localized to the aortic media

AANF Atrial natriuretic factor L Amyloidosis localized to the cardiac atriaMainly occurs in patients with atrial fibrillation

Acal (Pro)calcitonin L Occurs in C-cell thyroid tumors

APrP Prion protein L Spongiform encephalopathy

AIAPP Islet amyloid polypeptide L Amyloidosis involving islets of Langerhans

ALac Lactoferrin L Familial amyloidosis involving the cornea

Aβ AβPP L Amyloidosis associated with Alzheimer disease, aging

Abbreviations: AβPP, Aβ protein precursor; apoA-I, apolipoprotein A-I; apoA-II, apolipoprotein A-II; β2M, β2-microglobulin; Ig, immunoglobulin; SSA, senile systemic amyloidosis; TTR, transthyretin.

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sign, attributable to infiltration in the tendons and cap-sular structures of the shoulder without signs of inflam-mation, which induces swelling and limits movement.14,15 loss of shoulder-girdle muscle mass accentuates the soft-tissue infiltration by amyloid fibrils. the shoulder pad sign, together with macroglossia and cutaneous ecchymo sis around the eyes (the so-called ‘raccoon eyes’ sign; Figure 3), is considered almost pathognomonic of al amyloidosis and is found in 10% of patients.16 another infrequent manifestation of al amyloidosis is jaw clau-dication, which can lead to a misdiagnosis of giant cell temporal arteritis.17–19 the claudication is thought to be a result of amyloid fibril infiltration into the media of the arteries of the masticatory muscles. there have also been some reports of patients with long-lasting giant cell tem-poral arteritis with resultant aa amyloidosis.20,21 Patients might also present with xerostomia and xerophthalmia, caused by diffuse amyloid infiltration of lachrymal and salivary glands, which can be the first symptoms of amyloido sis.22 skin modifications resulting from amyloid

deposits can mimic systemic sclerosis,23 and amyloid-related myopathy can mimic the clinical presentation of polymyositis with elevated circulating levels of muscle enzymes.24 muscle pseudohypertrophy is another rare manifestation of al amyloidosis,25 and is the result of muscle enlargement owing to infiltration of amyloid fibrils. muscle pseudohypertrophy gives the patient an athletic appearance,26,27 and is frequently associated with macroglossia,28 stiffness, hoarseness, and difficulty in swallowing and speaking.

abnormal bleeding is frequently encountered in al amyloido sis, and severe acquired factor X deficiency (factor X levels of less than 25% of normal) occurs in approximately 2.5% of patients with al amyloidosis, usually with hepatosplenic involvement, and results from the adsorption of calcium-binding vitamin K-dependent factors to amyloid deposits.29

aa amyloidosisaa amyloidosis is a potential complication of any chronic inflammatory, infectious or neoplastic disease (Box 1), owing to chronic elevation of acute-phase reactants. aa amyloid fibrils are derived from cleav-age fragments of the circulating acute-phase reactant saa pro tein. saa is an apolipoprotein of high-density lipoprotein which, like C-reactive protein, is synthesized by hepatocytes under the transcriptional regulation of cytokines including interleukin (il)-1, il-6 and tumor necrosis factor (tnF).

the eradication of tuberculosis and other chronic infectious diseases changed the etiology of aa amyloido-sis. Currently, rheumatic diseases such as ra, ankylosing spondylitis (as), psoriatic arthritis and juvenile idio-pathic arthritis are the most frequent causes (70%) of aa amyloidosis. the reported prevalence of amyloidosis in ra varies with the diagnostic procedure used (that is, autopsy, kidney biopsy or subcutaneous fat aspiration), the clinical status (preclinical or symptomatic disease), and the type of study (case series or population-based study). a study from Finland of the autopsy records of 1,666 patients with ra revealed a prevalence of amyloido-sis of 5.8%,30 while a 10-year study of 1,000 patients with ra showed that 3.1% died of aa.31 renal aa amyloido-sis is the most common cause of renal involvement in as (62%), followed by iga nephropathy (30%).32 although its prevalence might be in decline,33 renal aa amyloidosis is a serious complication of as, with a median survival time after onset of dialysis of 2.37 years, and with a 5-year survival rate of only 30%.33,34

the reduced incidence of aa amyloidosis in ra is demonstrated by the consistent decline of annual number of biopsies positive for amyloid deposits, ranging from 60 in 1987 to fewer than 10 in 1997 studies.35–37 according to data from the national Finnish registry for Kidney Diseases,33 the number of patients with aa amyloidosis entering the renal replacement program remained con-stant from 1987 to 2002, suggesting that the number of aa amyloidosis patients with rheumatic diseases has not changed. in this analysis, the peak incidence of overt aa amyloidosis, in ra and juvenile idiopathic arthritis is

Circulating precursor of amyloid protein:■ Immunoglobulin light chain■ SAA■ TTR■ β2M■ ApoA-I or apoA-II

Increase productionProteolysisMutation AgingDecrease catabolism

Partial proteolysis(extracellular orintracellular) processing

Blood vessel depositionMechanical toxic effectsApoptosis

Tissue speci�cityunknown

Misfold protein oligomers

Amyloid �bril deposition

Tissue damage and dysfunction

GAGsSAP

Musculoskeletal systemKidney

GutHeart

LiverSpleen

PNS

Figure 2 | Pathophysiology of amyloidosis. Amyloid precursor proteins can be synthesized in excess and can reach persistently high serum concentrations in several clinical conditions (for example, SAA protein during chronic inflammatory disease or amyloidogenic monoclonal Ig light chain in plasma cell dyscrasias); decreased catabolism of the precursor protein can also lead to high serum concentrations, as is the case for β2M in chronic hemodialysis. Several proteins with intrinsic amyloidogenic properties and without evidence of overexpression, such as TTR, can cause amyloidosis later in life (for example, senile systemic amyloidosis), or can be mutated as in hereditary TTR amyloidosis. Partial proteolysis of some of these proteins induces misfolding, allowing monomers to bind and form oligomers. These oligomers aggregate and exert toxic effects on cells, while the full-blown fibrils are more inert and cause organ dysfunction through mechanical damage. Other components of amyloid fibrils, such as SAP and GAGs, promote fibrillogenesis by binding the fibril protein and could protect the amyloid fibril from tissue proteolysis. The molecular mechanisms that govern the deposition of amyloid fibrils in specific target tissues, thus leading to the different clinical amyloid syndromes, are largely unknown. Abbreviations: β2M, β2-microglobulin; GAGs, glycosaminoglycans; Ig, immunoglobulin; PNS, peripheral nervous system; SAA, serum amyloid A; SAP, serum amyloid component P; TTR, transthyretin.

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shifted towards older age, indicating a longer pre clinical phase, and an insidious appearance of aa amyloido-sis. the prevalence of the asymptomatic phase of aa amyloido sis in ra can range between 0.5% and 14%.38,39 it is unknown whether clinically silent aa amyloido-sis in patients with chronic inflammation will become symptomatic or will remain silent.

the predominant feature of aa amyloidosis at diag-nosis is renal dysfunction, manifest as proteinuria or renal failure. if left untreated, aa amyloidosis invariably progresses towards end-stage renal disease, requiring renal replacement therapy. indeed, the development of protein uria in patients with ra should always raise the suspicion of aa amyloidosis. as evident from autopsy series or radiolabeled saP component scintigraphy, patients with aa amyloidosis had hepatic and splenic involvement.40–42 However, amyloid deposits in the liver and spleen rarely lead to clinical manifestations. splenic involvement might be suspected if Howell–Jolly bodies are found in a peripheral blood smear of a non-splenectomized patient, or by frequent episodes of infections. Gastrointestinal features of aa amyloidosis include malabsorption, pseudo-obstruction, vomiting and diarrhea secondary to direct submucosal infiltration. the amyloid deposits in blood vessel walls increase the risk of gastrointestinal bleeding and perforation. Goiter can be a sign of aa amyloidosis.43 although cardio-myopathy is unusual in aa amyloidosis, it represents an unfavorable prognostic factor.43,44

Few studies have addressed the survival rates of patients with aa amyloidosis. in a 1991 study, Gertz et al.43 described a median survival time of 24 months, Joss et al.45 reported an almost doubled figure in 2000,

Table 2 | Clinical manifestations of some systemic amyloidoses according to the major site of involvement*

Site of involvement Form of amyloidosis

al aa attr SSa aapoi‡ aapoii alys aFib§ aβ2m

Kidney|| +++ +++ + - ++ ++ +++ +++ -

Heart|| +++ + +++ +++ ++ + (+) + (+)

Peripheral nervous system ++ – +++ +¶ + – – – –

Autonomic nervous system ++ ++ +++ – – – – – –

Liver ++ ++ – – ++ – ++ + (+)

Spleen + ++ – – ++ – + + (+)

Skin (+) – – – – – – – –

Gastrointestinal tract ++ + – – – – ++ – -–

Muscoloskeletal system ++ – (+)# – – – – – +++

Thyroid + + – – – – – – (+)

Adrenal glands + + – – – – – – (+)

Eyes – – ++ – – – – – –

Testis (+) – – – ++ – – – –

Tongue +++ (+) – – – – – – –

Factor X deficiency + – – -– – – – – –

*Clinically, it is difficult to distinguish AL, AA, familial (ATTR, AApoI, AApoII, Alys, AFib) and senile systemic amyloidosis from each other because of overlapping clinical presentations and a lack of an informative family history in many patients with hereditary amyloidosis. ‡In AApoI amyloidosis, mild renal failure usually develops in the absence of urinary protein loss and can remain stable for years. §AFib amyloidosis manifests with proteinuria that can rapidly progress to nephrotic range; uniquely among the hereditary amyloidoses, it has been reported in children. ||The kidney and heart are frequent sites of amyloid deposition. ¶Mainly carpal tunnel syndrome. #Charcot arthropathy. Abbreviations: +++ very common; ++ common; + rare; (+) very rare; –, does not occur.

a

b

Figure 3 | Clinical features of AL amyloidosis. a | Macroglossia in a patient with AL amyloidosis. The tongue is firm to palpation. Note the nonreducible impression in the tongue caused by the teeth. b | Periorbital purpura in the same patient. Purpura is frequently bilateral. The patient gave no history of trauma to the area of ecchymosis.

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and lachman et al.46 reported a median survival time as long as 10 years from disease onset in a large cohort of patients in the uK. in 2008 Bergesio et al.47 reported a median survival time of 79 months in patients with aa amyloidosis and renal involvement, with approxi-mately 51% of patients surviving after 5 years. in this study, multivariate analysis revealed that increased age, heart involvement and elevated serum levels of creatinine predicted decreased survival. of note, levels of serum creatinine at diagnosis were reportedly higher in patients with aa amyloidosis than in those with al amyloidosis, and the former group started dialytic therapy earlier.47 these findings highlight the danger of late referral of patients with aa amyloidosis to a nephrologist, and the need for cooperation between rheumatologists, internists and nephrologists.

aa amyloidosis also occurs in patients with hereditary autoinflammatory diseases (table 3), a group of diseases characterized by intermittent inflammation with involve-ment of various organs, including the musculoskeletal system and skin, and which lead to sustained and persis-tent production of saa protein. the most common of these disorders is familial mediterranean fever (FmF),48 which is characterized by attacks of fever and serositis. amyloidosis can also complicate other auto inflam ma-tory diseases, such as traPs (tumor necrosis factor receptor-associated periodic fever syndrome),49 muckle–wells syndrome,50 familial cold auto inflammatory syn drome,51 and hyper immunoglobulinemia D with periodic fever syndrome.52

β2-microglobulin amyloidosisaβ2m amyloidosis is caused by the deposition of fibrillar β2m and is a serious complication in patients undergoing long-term hemodialysis.53,54 the early clinical manifesta-tions of aβ2m amyloidosis include carpal tunnel syn-drome and chronic arthralgia, usually starting in the shoulders and evolving into erosive, disabling arthro-pathy of large joints. spinal involvement is charac terized radiographically by erosions of the vertebral corners, severe narrowing of the inter vertebral space, erosions with reactive sclerosis and cysts of vertebral plates with minimal osteophyte formation. as the disease pro-gresses, the vertebral body can collapse, and subluxa-tion or spondylo listhesis may occur. Ct is helpful in the assessment of the distribution and extent of destruc-tive lesions. mri shows amyloid deposits in the inter-vertebral disk, in the synovium of apophyseal joints and in the ligamentum flavum. subchondral, radio-lucent bone cysts in the shoulder, hips, and wrists affect 50–60% of patients undergoing hemodialysis for more than 10 years and may be responsible for fractures of the femoral neck, knees and vertebrae.55 ultrasonography is a cheap and reliable imaging technique for detect-ing aβ2m amyloidosis in symptomatic shoulders and wrists of patients receiving long-term hemodialysis (Figure 4). visceral organs involvement can be observed after 15 years of hemodialysis.56,57 the pathogenesis of amyloid fibril formation from β2m is multifactorial and has been associated with the duration of renal failure, the patient’s current age, the patient’s age at initiation of hemodialysis, the duration of hemo dialysis treatment and the bioincompatibility of dialysis membranes. β2m is a component of mHC class i molecules, which are pre-sented on all nucleated cells,58 and is normally present in most biological fluids including serum. this protein is catabolized in the renal tubules, and accumulates in vivo with the progression of renal failure. serum con-centrations of β2m are substantially higher in patients under going hemodialysis than in healthy individuals. However, serum β2m levels are similar in hemodialysis patients with and without aβ2m amyloidosis. moreover, its levels in synovial fluid are not elevated in patients with aβ2m amyloidosis.59 thus, although several hypotheses have been put forward,60,61 the precise mechanism of β2m amyloidogenesis remains unclear.

rheumatic diseases

Rheumatoid arthritis ■Ankylosing spondylitis ■Juvenile idiopathic arthritis ■Adult Still disease ■Psoriatic arthropathy ■Reactive arthritis ■Behçet disease ■Giant cell arteritis/polymyalgia ■rheumatica

Polyarteritis nodosa ■Takayasu arteritis ■Gout ■Oxalate arthritis ■Systemic lupus erythematosus* ■Systemic sclerosis* ■Sjögren’s syndrome* ■

Neoplastic diseases

Carcinoid tumor ■Castleman disease ■Hairy cell leukemia ■Hepatic adenoma ■Renal cell carcinoma ■Mesothelioma ■Hodgkin lymphoma ■Non-Hodgkin lymphoma ■Ovarian carcinoma ■Gastrointestinal stromal tumor ■Sarcoma of the liver ■waldenstrom macroglobulinemia ■

hereditary periodic fevers

Familial Mediterranean fever ■Tumor necrosis factor receptor- ■associated periodic syndrome

Muckle–wells syndrome ■

Hyperimmunoglobulinemia D ■syndrome

Familial cold autoinflammatory ■syndrome

inflammatory bowel diseaseCrohn disease ■

Ulcerative colitis ■

Chronic infectionsBronchiectasis ■

Chronic cutaneous ulcers ■and pressure ulcers

Chronic pyelonephritis ■

Leprosy ■

Osteomyelitis ■

Tuberculosis ■

whipple disease ■

Subacute bacterial endocarditis ■

miscellaneous

HIV/AIDS ■

Common variable ■immunodeficiency

Cyclic neutropenia ■

Sex-linked agammaglobulinemia ■

Hypogammaglobulinemia ■

Epidermolysis bullosa ■

Sarcoidosis ■

Cystic fibrosis ■

Atrial myxoma ■

Rosai–Dorfman disease ■

Sickle cell anemia ■

Schnitzler syndrome ■

Idiopathic retroperitoneal ■fibrosis

Box 1 | Conditions associated with systemic AA amyloidosis

*The association between these diseases and AA amyloidosis is unusual and only a few cases have been described in the literature.

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hereditary amyloidosisHereditary amyloidosis is a heterogeneous group of autosomal dominant, late-onset diseases, most of which are caused by a mutant ttr protein produced by the liver. the mutations occur in genes that encode plasma proteins including apoa-i, apoa-ii, fibrinogen, gelsolin, cystatin C and lysozyme (table 1). in attr amyloidosis, fibril deposition can cause heart dysfunction and sensory and autonomic neuropathy with secondary skin ulcers and Charcot arthropathy in the lower extremities. wild-type ttr protein is also a precursor of amyloid fibrils: it is responsible for senile systemic amyloidosis, which affects approximately 25% of patients over 80 years of age and predominantly involves the heart.62

Diagnosisthe diagnosis of amyloidosis requires the histological demonstration of amyloid deposits. Biopsies can be obtained from involved organs (liver, heart, or kidneys), but the fragility of blood vessels due to amyloid deposi-tion, and amyloid coagulopathy, expose the patient to an increased risk of abnormal bleeding. For this reason, the abdominal fat pad is the safest and most common biopsy site, while rectal mucosa and labial salivary glands are seldom the target of biopsy. abdominal subcutaneous fat aspiration (asFa) detects amyloid deposits in patients with al, aa and attr amyloidoses with a sensitivity ranging from 57% to 88% and a specificity of 100%.63–67

the asFa procedure is usually negative in aβ2m amyloido sis,68,69 but conflicting results have been reported in amyloidosis associated with FmF. amyloid deposits in subcutaneous fat tissue in FmF are less promi nent than in other inflammatory diseases, which might explain the reported lower sensitivity of asFa in this setting.70,71 in

a recent study,72 a semiquantitative evaluation of Congo red staining of asFa from patients with overt renal aa amyloidosis, including patients with FmF, had a sensi-tivity of 80%. notably, patients with FmF had a stain-ing score substantially lower than patients with other inflammatory diseases. therefore, to achieve highly sensitive using the Congo red staining method in FmF requires high-quality control of the staining procedure, a microscope of high quality and well-trained experts and observers. the preferred tissues for histological demon-stration of amyloid deposits are kidney tissue for FmF and synovial tissue for aβ2m amyloidosis. if the asFa test is negative or is contraindicated because of the pres-ence of local skin infection, hematoma or large umbilical hernia, a biopsy of the minor salivary glands might be useful (Figure 5).73 in patients with aa or al amyloido-sis, the minor salivary gland biopsy has a sensitivity of about 86%74 this technique is also effective in diagnosing attr amyloidosis. rectal biopsy should be deep enough to include the submucosa, where the amyloid deposits predominately occur.75 the sensitivity of rectal mucosa biopsy ranges from 75% to 85%.76

a diagnosis of amyloidosis is insufficient, however, as unequivocal identification of the deposited amyloido-genic protein is essential in order to avoid mis diagnosis and inappropriate treatment. Clinically, al, aa and inherited forms of amyloid are difficult to distinguish between. the lack of a family history of attr amyloido-sis does not exclude this diagnosis, given the consider-able number of sporadic cases that have been described.77 in addition, since monoclonal gammopathy of unknown significance is not infrequent in elderly individuals,78 this finding does not exclude types of amyloidosis other than al amyloidosis.79,80

Table 3 | Clinical features of hereditary autoinflammatory diseases

Feature autoinflammatory disease

FmF traPS hiDS FCaS mwS NomiD

Age at onset <20 years Childhood Infancy (<6 months)

Infancy (1–6 months)

<10 years <1 year

Duration of fever 1–3 days >7 days 3–7 days 1–2 days 1–2 days 1–3 days

Serositis ++ ++ + (+) (+) –

Musculoskeletal manifestations

Monoarthritis Arthritis and myalgia Polyarthralgia Arthritis and myalgia

Limb pain and arthritis

Epiphiseal bone formation

Cutaneous manifestations

Erysipeloid Monocytic fasciitis and erythematosus plaques

Macules, papules and urticaria

Cold-induced urticaria

Urticaria Urticaria

Adenopathy Rare Rare Yes Rare Rare Rare

Hearing loss No No No No Yes Yes

Amyloidosis (AA) ++ ++ + + ++ +

Mode of inheritance

Recessive Dominant Recessive Dominant Dominant Dominant

Mutated gene MEFV TNFRSF1A MVK NLRP3 NLRP3 NLRP3

Gene product Pyrin/marenostrin

TNF-R1 Mevalonate kinase

Cryopyrin Cryopyrin Cryopyrin

Abbreviations: ++, common; +, rare; (+) very rare; –, does not occur; FCAS, familial cold autoinflammatory syndrome; FMF, familial Mediterranean fever; HIDS, hyperimmunoglobulinemia D syndrome; MwS, Muckle–wells syndrome; NOMID, neonatal onset multi-system inflammatory disease; TNF-R1, tumor necrosis factor receptor superfamily member 1A; TRAPS, tumor necrosis factor receptor-associated periodic syndrome.

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in those patients with more than one potential amyloid- forming protein, it is important to perform direct tissue typing and exclusion of inherited amyloidosis (by Dna

analysis) before therapy is started. However, determining the specific type of systemic amyloidosis requires careful clinical evaluation as well as immunohistochemical analy sis and genetic testing. light-microscopy immuno-histochemical analysis can be misleading because of its low specificity for al and ttr amyloid deposits,81 while em with immunogold labeling has been used to un ambiguously characterize amyloid fibrils. em with immunogold can be performed on all biopsy specimens including asFa.82 a recently developed proteomics methodology that uses laser microdissection and the analytical power of tandem mass spectrometry has been shown to characterize with 100% specificity and sensi-tivity amyloid deposits in biopsy specimens including abdominal subcutaneous fat obtained from patients with types al, aa or attr amyloidosis.83,84 this assay over-comes many of the pro blems of immuno histochemistry, such as the limited reactivity of commercial antibodies in a subset of al amyloid deposits, or the fluorescence-like background that is created by the trapping of serum pro-teins in the amyloid deposits, referred to as ‘contamina-tion phenomena’,81 and pro mises to enhance our ability to type amyloid deposits accurately in biopsy specimens and to improve clinical care of patients with amyloidosis.

Figure 6 provides a flow chart illustrating the evalu-ation of a patient with suspected systemic amyloidosis. as all amyloid deposits contain saP, scintigraphy can be used in all types of amyloidosis, regardless of the protein source.85,86 nevertheless, saP scintigraphy cannot replace the histological demonstration of amyloido sis within an organ. saP scintigraphy is useful for identify-ing amyloid deposits in organs when biopsy is contra-indicated, providing evidence of disease progression and regression; however, the scan cannot detect amyloid deposits in the heart.86

Prognosis and therapyif untreated, amyloidosis has a poor prognosis that is greatly influenced by the type of amyloid protein involved and the extent of organ involvement and damage. it is therefore crucial that the clinician makes serious efforts to obtain a precise diagnosis of the amyloid form.80 the misdiagnosis of al amyloidosis is an infrequent but real occurrence. in a series of 350 patients diagnosed with al amyloidosis by clinical and laboratory findings and by the absence of a relevant family history, 34 patients were misdiagnosed, often because of misinterpretation of urine immunofixation findings associated with renal damage attributable to the hereditary variant of fibrino-gen a α-chain protein.79 a misdiagnosis can have cata-strophic consequences for the patient since treatment, depending on the type of amyloidosis, might include bone marrow transplantation (al amyloidosis) or liver transplantation (attr amyloidosis).

Patients with al amyloidosis have the worst prog-nosis, and the presence of heart failure is associated with a median survival of only 6 months.87,88 By comparison, patients with aa amyloidosis have a median survival of 4–10 years,43–47,89 depending to a large degree on renal and cardiac involvement. the prognosis of patients with

a b

Figure 4 | Aβ2M amyloid arthropathy of the shoulder and wrist in a patient undergoing long-term hemodialysis. a | In the shoulder, the biceps tendon is enlarged, with an inhomogeneous echo texture that indicates amyloidosis (arrow) without hypervascularization on power Doppler analysis. b | In the wrist, imaging reveals stretching of the joint capsule with solid and heterogeneous content and with cortical irregularity of the metacarpal bone (arrow).

a

b

Figure 5 | Minor salivary gland biopsy of a patient with AL amyloidosis. a | A specimen obtained via biopsy of the minor (labial) salivary gland shows amyloid deposits mainly in the interstitium (Congo red staining). b | Using immunohistochemical analysis, the amyloid deposits are positively stained with anti-λ light-chain antibody.

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attr depends on the type of mutation, the degree of cardiac involvement, and age at onset.87 the common therapeutic approach to all systemic amyloidoses is based on the observation that organ dysfunction can be recovered by reducing the supply of the amyloid pre-cursor protein.90 as discussed in the following sections, however, the various forms of systemic amyloidosis require specific treatment.

treatment of al amyloidosisin al amyloidosis, the reduction of the amyloidogenic protein concentration by chemotherapy is almost invari-ably accompanied by improved function in target organs and extended survival. nephelometry of ig FlC quantifies monoclonal proteins and assesses thera peutic response

after chemotherapy. High-dose melphalan followed by autologous stem cell transplantation (asCt) is effective in a select group of patients that are charac terized by no cardiac involvement and aged less than 70 years.91,92 in a study of 312 patients with al amyloido sis treated with high-dose melphalan and asCt, skinner et al.93 reported a median survival of 4.6 years. a complete hematologic response—defined as no evidence of an underlying plasma cell dyscrasia 1 year after treatment—was achieved in 40% of patients and was associated with prolonged survival. improvements in end-stage organ disease were greater in patients with a complete hemato-logic response. asCt is, however, associated with high rates of treatment-related mortality (13–14%), particu-larly in patients with cardiac involvement.94–96 therefore,

Clinical manifestation:amyloidosis should be

considered in differentialdiagnosis if:

First-line investigation:Diagnosis of amyloidosis

Achieve histologicaldemonstration ofamyloid deposits

Achieve diagnosis of thetype of amyloidosis:AL, AA, ATTR, Aβ2M

Start tailored therapyfor amyloid type

Assess prognosis

■ Nondiabetic nephrotic syndrome (particularly in patients with MGUS or chronic rheumatic diseases)■ Low voltage on ECG with echocardiogram showing left ventricular hypertrophy■ Hepatomegaly with no scan defects and increase levels of ALP and γGT■ Hower–Jolly bodies in a peripheral blood smear and splenomegaly■ Nondiabetic chronic demyelinating polyneuropathy and/or orthostatic hypotension■ Positive family history for sensorimotor neuropathy, vitreous opacities and cardiomyopathy■ Macroglossia, ‘shoulder pad’ sign, cutaneous ecchymosis■ Xerostomia, joint involvement, jaw claudication, skin modi�cation without immunological markers of connective tissue diseases

Perform subcutaneous fat biopsy for Congo red staining and polarized light observation

Con�rm diagnosis with biopsy positive for Congo red staining and apple green birifringence under polarized light

Echocardiography with Doppler analysis Measure serum levels of troponin, NT-pro BNP, FLC, β2M, SAA, creatinine

Supportive or speci�c therapy

Perform immuno�xation of serum and urine, andIg FLC assay

If positive, AL amyloidosis becomes a likely explanation

Perform bone marrow biopsy

If negative: perform genetic testing for mutant TTR orapoA-I, apoA-II, gersolin, lyzozyme, cistatin-C

When feasible:■ Special stains on biopsy■ Immunohistochemistry or immunogold

In patients with rheumatic disease andproteinuria or CRF, perform serum SAA assay

If increased, AA amyloidosis becomesa likely explanation

Figure 6 | Flow diagram outlining the evaluation of a patient with suspected amyloidosis. Clinical evaluation might reveal features suggestive of amyloidosis, but a histological diagnosis is mandatory. Once the diagnosis of amyloidosis has been established, the amyloid type should be defined by special staining of the biopsy and by genetic testing. Further work-up of AL amyloid deposits is required to exclude multiple myeloma and to quantify Ig FLC. The presence and extent of heart involvement is the most important negative prognostic factor, and also increases the rate of treatment-related mortality associated with aggressive therapeutic regimens, such as autologous stem cell transplantation. Renal failure remains the main cause of death in AA amyloidosis. Abbreviations: ALP, alkaline phosphatase; apoA-I, apolipoprotein A-I; apoA-II, apolipoprotein A-II; β2M, β2-microglobulin; CRF, chronic renal failure; ECG, electrocardiography; FLC, free light chains; γGT, γ-glutamyl transpeptidase; Ig, immunoglobulin; MGUS, monoclonal gammopathy of unknown significance; NT pro BNP, N-terminal portion of natriuretic peptide type B; SAA, serum amyloid A protein; TTR, transthyretin.

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patients with cardiac al amyloidosis might not be eligi-ble for asCt; instead, these patients can be treated with several other chemotherapeutic regimens. melphalan and prednisone are effective and well tolerated, with a response rate of approximately 28%.97,98 the disadvantage of this approach is the long time to response (more than 12 months in 30% of patients),97 which is inadequate for patients with rapidly progressive disease. in a study of 46 patients ineligible for asCt,99 high-dose dexa-methasone regimens led to a hematological response in 67% with a median survival of 4.5 months, and a treatment-related mortality rate of 4%. in relapses, tha-lidomide is an effective alternative,100 but this therapy is poorly tolerated in patients with poly neuropathy. a new, less toxic thalidomide analog, lenalidomide, and the pro-teasome inhibitor bortezomib, which is approved for use in multiple myeloma, show promise in the treatment of systemic al amyloidosis. in a phase ii trial lenalidomide, alone or in combination with dexamethasone, induced hemato logical responses in 16 of 24 (67%) patients with al amyloidosis who received at least three cycles of treatment.101 Bortezomib monotherapy induced a hema-tologic response in 15 of 30 (50%) patients, including a complete response in 6 (20%),102 while bortezomib in combination with dexamethasone produced hematologic responses in more than 80% of patients enrolled in two separate studies.103,104

treatment of aa amyloidosisthe goal of the therapy in aa amyloidosis is the treat-ment of the underlying disorder. treatment that sup-presses the inflammatory activity decreases circulat ing levels of the saa protein. Chronic suppression of saa levels is associated with a notable regression or stabiliza-tion of amyloid load (measured by saP scinti graphy) and results in improved long-term survival.46,89 treatment with biological agents has been shown to control the progression of renal amyloid disease in patients with ra and other autoinflammatory diseases.105,106 treatment with colchicine is necessary to prevent the development of aa amyloidosis in patients with FmF.107,108 anakinra, a recombinant form of il-1 receptor antagonist, showed favorable effects on dermato logic and rheumatic mani-festations in patients with muckle–wells syndrome and familial cold autoinflammatory syndrome. this treat-ment also resulted in the resolution of aa amyloido-sis in these patients.109 a novel therapeutic approach that uses small molecules targets aa amyloid deposit directly in the target tissue.110,111 a multicenter, random-ized, placebo-controlled study investigated the ability of eprodisate, a low- molecular-weight sulfonated mol-ecule designed to interfere with the interaction of saa and GaGs in tissues, to prevent the progression of aa amyloidosis-related nephropathy. eprodisate therapy slowed the progression of renal disease compared with placebo.112 eprodisate did not, however, affect levels of saa. the results of this study suggest that, in aa amyloidosis, eprodisate could be used as a comple ment to anti-inflammatory therapy that aims to treat the un derlying disease.

in patients with rheumatic disease, the true signifi-cance and prognostic value of unambiguous detection by asFa of amyloid deposits in the absence of visceral amyloid involvement (subclinical amyloid) is unknown. How ever, these patients must be periodically monitored for clinical symptoms or laboratory findings suggestive of amyloidosis (that is, renal function test and micro-albuminuria), since they could develop symptomatic involvement after a period of time. it should be stressed that these patients are at high risk for the rapid accelera-tion of amyloid deposition in the case of increased inflammatory activity, as a consequence of both their rheumatic disease and inter current infections, or after major surgery.

treatment of aβ2m amyloidosisin aβ2m amyloidosis, the current therapeutic approach aims to prevent amyloid deposition by promoting the clearance of β2m using high-flux dialysis membranes and columns for the adsorption of the amyloidogenic pre cursor.113,114 However, proof is lacking that amyloid de posits are decreased by long-term use of dialysis te chniques to eliminate β2m.

treatment of attr amyloidosisin patients with early-stages attr amyloidosis, liver transplantation is the only way to remove the source of the mutated ttr in the blood; however, for some patients continued amyloid deposition can occur from wild-type (normal) ttr. several studies115–117 suggest that amyloidogenic mutations destabilize the native struc-ture of ttr, thereby inducing conformational changes which lead to dissociation of the tetramers into partially unfolded species that are responsible for the major cyto-toxic effects observed in tissue culture. these findings have profound implications for the potential treatment of attr amyloidosis. if subfibrillar aggregates are pri-marily responsible for cell damage in vivo, as has been shown in vitro, then therapies that reduce fibril deposi-tion or promote fibril clearance but do not reduce aggre-gation could accelerate disease progression. the results also suggest that the best approach to preventing the pathologic effects of amyloidosis might be to stabilize the native state of the precursor protein. in the case of ttr, for example, small molecules that stabilize the tetramer would block its dissociation and prevent the formation of monomeric cytotoxic species or its nonnative early oligomers.118 several studies are ongoing to determine whether amyloid deposition can be inhibited by small-molecule therapies, including the analgesic nsaiD diflunisal, which are hypothesized to stabilize tetrameric ttr. ttr stabilizers seem to be interesting since they would impair early the process of amyloid formation and could also have a prophy lactic effect in asymptomatic genetic carriers or after liver transplantation.119

Conclusionsrheumatologists might encounter diagnostic and thera-peutic problems when they approach different amy loidos es. this applies to aa amyloidosis that complicates chronic

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rheumatic diseases and in particular ra causing nephro-pathy and various insidious internal manifestations. indeed, other type of amyloidosis such as al and aβ2m amyloidosis can include musculoskeletal and articu lar symptoms. asFa is the method of choice for routine screening for systemic amyloidosis, because it is a simple, inexpensive, fast and safe procedure with high diagnostic accuracy. in patients with long standing chronic rheu-matic diseases at risk for amyloidosis, regular asFa is recommended.

Review criteria

A PubMed search of English-language publications from 1960 to 2008 was performed with the following terms alone or in combination: “systemic amyloidosis”, “amyloidosis AL”, “amyloidosis AA”, “hereditary amyloidosis”, “ATTR”, “dialysis related amyloidosis” and names of specific antiamyloid medications. Additional full-text papers and abstracts were identified from reference lists of relevant articles or from congress proceedings. The authors also used articles from their private libraries.

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