Osteo-articular manifestations of amyloidosis

Whether it is overload disease or mispleated proteins, amyloid is a great pretender. This is especially true for all of the osteo-articular manifestations of amyloid light chain (AL) amyloidosis, which may mimic rheumatoid arthritis, polymyalgia rheumatica, a myeloma or a bone tumour. To improve the prognosis, AL amyloidosis must be considered in front of atypical osteo-articular manifestations. Amyloidosis Ab2 M of chronic haemodialysis (members’ arthropathy and destructive spondylitis) is a specific entity that needs to be differentiated from other osteoarthropathies of chronic renal failure. It has become exceptional since the progress of haemodialysis. Finally transthyretin amyloidosis(ATTR) can be responsible for carpal tunnel syndrome(CTS) in its genetic and senile form. Although amyloidosis is rare, it represents one of the aetiologies of CSC, regardless of its type. In the specific context of haemodialysis, this poses no difficulty for the clinician. Yet AL amyloidosis must be considered more often, as must senile amyloidosis ATTR in the elderly. It seems obvious that the anatomo-pathologic analysis with specific staining with Congo red – see typing – should be systematically performed in the case of surgical neurolysis.

Amyloidosis is defined by the extracellular deposit of proteins which share common tinctorial affinities, a fibril aspect under electron microscopy and spatial conformation called beta pleated. Once regarded as a mere overload disease, it is currently considered as a disease of misfolded proteins. Indeed, it is certain that abnormalities of spatial pattern play an essential role in the responsibility for the pathology of many proteins whose amyloid fibre is the final common way. They involve both changes in the conformation of proteins and other major in vivo interactions between amyloid protein and the extracellular matrix. In most cases, amyloidosis represents the bulk of histopathological lesions and its pathogenic role is certain. In other cases, it is only one elementary lesion of the disease and its role is controversial.

The amyloidosis responsible for osteo-articular manifestations are the AL immunoglobulin amyloidosis, the beta2-microglobulin amyloidosis in patients under haemodialysis and finally the amyloidosis of transthyretin (genetic and senile).

Rheumatological manifestations of immunoglobulin amyloidosis are numerous and often indicative of the disease. Deposits affect joint and periarticular structures. The most common presentation is a progressively developing bilateral symmetric polyarthritis with negative immunology and absent specific structural abnormalities. Carpal tunnel syndrome (CTS) is very common and should suggest the aetiology. Other clinical representations are rarer as an isolated bone tumour (amyloidoma) or integrating systemic AL amyloidosis.

β 2-Microglobulin amyloidosis occurs in patients under chronic haemodialysis. It is responsible for CTS, arthralgia and above all a specific destructive spondyloarthropathy. The transthyretin amyloidosis also causes CTS.

Introduction

Amyloidosis is a group of diseases characterised by the presence of specific pathological lesions (called amyloid). Hereunder, we consider only those varieties of amyloidosis responsible for osteo-articular manifestations: amyloid light chain (AL) amyloidosis (amyloid light chain immunoglobulin), beta 2-microglobulin (β 2-M) amyloidosis in haemodialysis patients and transthyretin amyloidosis (ATTR) in its genetic and senile form. They are indeed amyloidoses – diseases in as much as the amyloid deposits have a direct pathophysiological role in the bone lesions observed (arthropathy, tunnel syndrome and bone amyloidoma). Other forms of localised deposits whose pathogenic character is not established will be briefly mentioned. However, associated amyloid (AA) amyloidosis that complicates chronic inflammatory diseases will not be discussed here as it does not affect the osteo-articular apparatus. However, it is recalled that rheumatoid arthritis (RA) and ankylosing spondylitis in Western countries are the leading cause of AA amyloidosis.

Amyloidosis: general

Amyloidosis is defined by the deposition of extracellular proteins that share a tinctorial affinity, a fibrillar aspect on electron microscopy and a spatial conformation called beta pleated. Substantial advances have been made in understanding the clinical, biochemical and genetic features of amyloidosis. Viewed as simple overload diseases in the past, they are currently seen as diseases of mispleated proteins. Indeed, it is certain that spatial configuration abnormalities are critical in the pathological responsibility of many proteins for which the amyloid fibre is the final common pathway. However, the mechanisms of fibril formation remain poorly understood. They involve changes in the conformation of proteins and also major in vivo interactions between amyloid protein and the extracellular matrix.

Amyloidosis constitutes a prototype of the disease of the extracellular medium overload. This characteristic is expressed in the clinical dimension of the disease: the tissue accumulation of amyloid deposits causes, sometimes considerably, an increase in volume of the main target organs of amyloidosis in their multisystemic form. This is the hypertrophy of the spleen, liver, kidney and heart chambers. It is found to a lesser degree in the osteo-articular system in the form of ‘tumorous’ lesions.

Recognising a large biochemical variety of amyloid deposits ( Table 1 ) demands from the clinician an accurate diagnosis of the nature of the amyloid substance, which requires the comparison of clinical, laboratory and histopathological data. Whereas the diagnosis of amyloidosis disease relies on Congo red staining, typing amyloidosis requires an immunohistochemical study: of the immunofluorescence of the binding of antibodies directed against light chains of immunoglobulin by the deposits, coupled with the study of immunoperoxidase of antibodies against the other major amyloid proteins (AA and ATTR in particular). As concerns osteo-articular amyloidosis, the three amyloid proteins to be considered are the light chains of immunoglobulin, β 2-M and transthyretin (TTR). This analysis is particularly useful to differentiate the various forms of amyloidosis in the carpal tunnel. In very rare cases, it is difficult to differentiate between various varieties, even after a thorough immunochemical study. Modern techniques of analysis of the deposits using proteomics are progressively applied in the diagnosis of amyloidosis .

Table 1

Amyloid fibril proteins and their precursors in human, international nomenclature (from Sipe ).

Amyloid protein	Precursor	Systemic (S) or localized (L)	Syndrome or involved tissue
AA	AoSAA	S	Reactive, secondary to chronic inflammation
AL	Light chain of immunoglobulin	S, L	Primary or myeloma associated
AH	Heavy chain of immunoglobulin	S
ATTR	Mutated TTR	S	Hereditary
ATTR	Wild type TTR	S, L	senile
AApoA1	ApoA1	S L	Hereditary Aorta, meniscus, vertebral discus
AApoAII	ApoAII	S	Hereditary
AApo AIV	ApoAIV	S	Ageing
AGel	Gelsolin	S	Hereditary
AFib	Fibrinogen Aα chain	S	Hereditary
ALys	Lysozyme	S	Hereditary
Aβ2M	β2-microglobulin	S	Associated with dialysis
ACys	cystatin C	S	Hereditary
Aβ	Aβ protein precursor AβPP	L	Alzheimer’s disease, ageing
Abr ^a	ABriPP	L	Hereditary dementia, British
ADan	ADanPP	L	Hereditary dementia, Danish
APrP	Prion protein	L	Spongiform encephalopathies
ACal	Procalcitonin	L	C-cell thyroid cancer
AIAPP	Islet amyloid polypeptide	L	Langerhans islets, insulinoma
AANF	Atrial natriuretic peptide	L	Cardiac atria
APro	Prolactin	L	Ageing hypophyse, prolactinoma
AMed	Lactadherin	L	Senile aortic media
AIns	Insuline	L	Iatrogenic
AKer	Keratoepithelin	L	Hereditary corneal dystrophies
ALac	Lactoferrin	L	Cornea
AOaap	Odontogenic ameloblast associated protein	L	Odontogenic tumour
ASemI	Semenogline I	L	Vesicula seminalis
ATau	Tau	L	Alzheimer’s disease, fronto-temporal dementia, senile brain