Musculoskeletal manifestations of amyloidosis

INTRODUCTION — Amyloidosis refers to the extracellular tissue deposition of fibrils that are composed of low-molecular-weight subunits (5 to 25 kD) derived from a variety of serum proteins. These fibrils adopt a beta-pleated-sheet-rich configuration that is reflected in characteristic histologic changes. Amyloid deposits can occur in a variety of organs, with involvement of the heart, kidney, gastrointestinal tract, and nervous system often responsible for morbidity and mortality.

The identity of the fibril subunit protein varies with the type of amyloidosis. It is a monoclonal immunoglobulin light chain or light chain fragment in AL amyloidosis (which may be a complication of plasma cell dyscrasias), a fragment of serum amyloid A (SAA) protein in AA amyloidosis (which is a complication of chronic inflammatory disorders), and beta-2 microglobulin in dialysis-related amyloidosis. (See "Monoclonal immunoglobulin deposition disease" and "Pathogenesis of AA amyloidosis" and "Dialysis-related amyloidosis".)

A variety of amyloid types are associated with musculoskeletal disease, including AL, transthyretin (ATTR), and beta-2 microglobulin (A beta-2m) amyloidosis. These can be distinguished immunohistologically and biochemically and require different treatment strategies [1]. Musculoskeletal manifestations of amyloid deposition may be subtle, subclinical, and only apparent when a tissue biopsy is carried out [2]. Rarely, patients present with a clinical picture that simulates a known rheumatic disease. In addition, musculoskeletal disorders may be the cause rather than the result of AA amyloidosis.

The musculoskeletal manifestations of the various forms of amyloidosis are presented here. An overview of amyloidosis and the rheumatic and other disorders that can be complicated by AA amyloidosis are described separately. (See "Overview of amyloidosis" and "Causes and diagnosis of AA amyloidosis and relation to rheumatic diseases".)

AL AMYLOIDOSIS — Musculoskeletal manifestations of AL amyloid include muscle weakness (myopathy) and enlargement due to amyloid infiltration (pseudohypertrophy), disorders of the joints (arthropathy), and lesions of bone (osteopathy). Other manifestations of AL amyloidosis are described separately. (See "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis".)

Muscle involvement in AL amyloid — Amyloid infiltration of muscles may cause:

●Visible enlargement (ie, pseudohypertrophy) [3-6].

A large tongue (ie, macroglossia) or lateral scalloping of the tongue from impingement on the teeth is characteristic of AL amyloid and may be the presenting feature of the disease [7,8].

Muscle infiltration is generally associated with widespread or systemic involvement. In a retrospective study conducted at a single tertiary center, 12 patients with biopsy-proven amyloid myopathy were identified over a 35-year period [9]. Muscular pseudohypertrophy was present in one-quarter of these patients. Muscle involvement accompanied widespread organ involvement in most patients and was associated with a median survival of 12 months. A significant number of these patients had electrophysiologic abnormalities, reflecting direct involvement or associated neuropathy [10].

●Myopathy may occasionally be the initial presenting feature of AL amyloid; the diagnosis may be suggested by unusual findings on magnetic resonance imaging (MRI) or positron emission tomography (PET)/computed tomography (CT) scanning and confirmed by biopsy [11-13]. A spectrum of light chain deposition and pathologies may be seen [14]. Symptoms include proximal muscle weakness or dyspnea [15]; rarely, the presentation can simulate polymyositis [16].

A retrospective review of 51 patients seen in a tertiary referral setting with AL amyloidosis and biopsy-confirmed amyloid myopathy reported presenting symptoms of muscle weakness (proximal greater than distal) in 45 percent, myalgia (33 percent), macroglossia (33 percent), jaw claudication (25 percent), and hoarseness (18 percent). In over one-third of patients with muscle biopsies prior to referral, the initial biopsy had been misinterpreted or not fully evaluated, with further testing of the tissue or reevaluation needed to establish amyloid as the cause of myopathy; 88 percent of those tested showing myopathic changes on electromyography; 50 percent had coexistent peripheral neuropathy. Elevation of cardiac troponin T in the absence of cardiac involvement was found to be a useful indication of muscle involvement in AL amyloidosis [17].

Arthropathy due to AL amyloid — Amyloid deposits in AL amyloidosis can involve the synovium, leading to rheumatic symptoms. As an example, amyloid arthropathy is a rare complication of Waldenström macroglobulinemia [18], and an erosive arthritis has been described in patients with monoclonal gammopathy of uncertain significance [19]. Amyloid arthropathy may occur in 0.1 to 6 percent of patients with multiple myeloma, with an onset either coincident with or subsequent to the diagnosis of myeloma [20]. (See "Epidemiology, pathogenesis, clinical manifestations, and diagnosis of Waldenström macroglobulinemia" and "Diagnosis of monoclonal gammopathy of undetermined significance".)

More typically, the arthropathy in AL amyloid is low grade, subacute, progressive, and symmetric, with a predilection for the shoulders, knees, wrists, and metacarpophalangeal and proximal interphalangeal joints and, to a lesser degree, for the elbows and hips. The joints are mildly tender or nontender, and there is usually little morning stiffness.

These characteristics help distinguish this disorder from rheumatoid arthritis [21,22]. However, a potentially misleading finding is the presence of whitish subcutaneous nodules in about 60 percent of cases; these nodules are typically in and around the joint and are on the extensor surfaces of the forearms and elsewhere. A biopsy demonstrating Congo red birefringent material will clearly distinguish these lesions from rheumatoid nodules [23]. Arthropathy as well as tendinopathy may improve with appropriate chemotherapy, documented by regression of lesions assessed by ultrasound or MRI [24].

Radiographic features include juxtaarticular cyst formation, widening of the joint space early in the disease, and soft tissue infiltration in a periarticular distribution that may be demonstrable by MR and/or ultrasound imaging [20,25] or, in some instances, by 18F-FDG PET/CT [26].

Results from two large series showed the following:

●In one series, soft tissue, bone, and joint manifestations were identified for 42.9 percent of 191 patients with AL amyloidosis and were found to be the dominant organ system involvement for 9.4 percent [27]. The most common findings were macroglossia (23 percent), carpal tunnel syndrome (CTS; 13.1 percent), amyloid arthropathy (3.7 percent), and pseudohypertrophy of skeletal muscles (1.6 percent). Soft tissue and bone involvement were more common among patients with multiple organ involvement and were 3.9- to 4.3-fold higher among patients found to have underlying multiple myeloma and twofold higher among men than among women.

●A systematic review of 101 published cases of amyloid arthropathy associated with multiple myeloma reported a male-to-female ratio of 1:1, with seronegative arthritis preceding the diagnosis of multiple myeloma in 62 percent, and typical amyloidosis-associated extraarticular manifestations, including either CTS, macroglossia, or shoulder pad and soft tissue swelling/masses, were present in 61 percent. Although most cases were symmetric and polyarticular, 17 percent were oligoarticular, and 3 of 101 were monoarticular [28]. Joint fluid is usually bland compared with typical findings in rheumatoid arthritis, and synovial histopathology is distinguished by the absence of CD20+ and CD38+ cells infiltration or angiogenesis; amyloid phagocytosis by synovial macrophages is characteristic [29].

A number of other rheumatic manifestations may also be observed in AL amyloid:

●Soft tissue swelling may be prominent in up to 75 percent of cases due to a nodular hypertrophied synovium directly infiltrated by amyloid. Swelling may be particularly prominent around the glenohumeral joint, resulting in a characteristic "shoulder pad" sign [30]. Direct extraction of amyloid from tissue taken at the time of synovectomy in one case yielded three subunit proteins, all derived from the same VkI light chain as determined by their amino terminal sequence [31]. In another study, a VkIII protein was extracted from the synovium of a patient with AL amyloid manifesting as a shoulder pad sign [32].

●When the hand is involved, there may be nodularity and thickening of the palmar fascia, with 50 percent of patients developing flexion contractures and weakness. Erosions and joint space narrowing are prominently absent, and there may even be widening of the joint space radiographically. Aspirated joint fluid is usually noninflammatory, with predominantly mononuclear cells; the fluid may appear cloudy due to the presence of synovial fragments, which can be shown to contain amyloid by Congo red staining of the spun sediment [20,33].

●Hand involvement is commonly associated with CTS, which is typically bilateral and symmetric. Nodular masses accumulate in the carpal tunnel and are often grossly apparent at the time of surgery [34].

●Rarely, Charcot-like arthropathy may result from severe amyloid neuropathy [35].

Osteopathy due to AL amyloidosis — Localized solitary or multiple osteolytic lesions of bone may be filled with amyloid. These lesions may lead to pathologic fractures and bone pain, possibly suggesting an underlying malignancy [36-38], and may cause significant neurologic deficits in multiple myeloma [39].

AL amyloid simulating other rheumatic diseases — AL amyloid should be considered in the differential diagnosis of jaw claudication along with giant cell (temporal) arteritis/polymyalgia rheumatica [40,41]. Jaw claudication is due to predominantly vascular amyloid that compromises the lumina of the facial branches of the external carotid artery [42,43]. The presence of a monoclonal gammopathy and lack of response to glucocorticoids suggest the diagnosis of AL amyloid [41,44]. (See "Clinical manifestations of giant cell arteritis".)

Sicca syndrome can occur due to amyloid deposits leading to enlargement and compromised function of both parotid and lacrimal glands [45,46]. This entity may be more prevalent than previously recognized, as evidenced by the high diagnostic yield of biopsy of the minor salivary lip glands in these patients [47,48].

Nodular amyloid in the lung and skin can complicate Sjögren's disease. In some cases, however, the amyloid deposits are due to either a localized form of amyloidosis or a systemic light chain deposition due to concomitant multiple myeloma [49-52].

Cutaneous disease mimicking scleroderma may be the presenting feature of AL amyloid, usually associated with multiple myeloma [53,54].

DIALYSIS-RELATED AMYLOIDOSIS — Musculoskeletal manifestations of dialysis-related amyloidosis, including carpal tunnel syndrome (CTS), periarthritis of the shoulder, effusive arthropathy, and erosive bone lesions, are presented in detail separately. (See "Dialysis-related amyloidosis".)

OSTEOARTICULAR AMYLOIDOSIS — To a large degree, osteoarticular amyloid is an incidental histopathologic finding, and it remains unclear whether its presence identifies patients with earlier-onset or more rapidly developing forms of age-related musculoskeletal disease. Microdeposits of amyloid have been found as incidental findings in the fibrous capsules, cartilage, and synovial membranes of hip joints sampled by closed synovial membrane biopsy or at surgery for osteoarthritis [55], in fragments of menisci accessed by arthroscopy [56], in the menisci, articular cartilage, and synovial membrane of the knee in patients undergoing total joint arthroplasty for osteoarthritis [57], and in biopsies of the supraspinatus tendons of patients undergoing rotator cuff surgery [58]. These deposits can also be commonly demonstrated at postmortem examination in the hip, in the fibrocartilaginous discs of sternoclavicular joints, and in the intervertebral discs, both in the annulus fibrosus between collagen bundles and in the nucleus pulposus [59-61]. The incidence of osteoarticular amyloid varies with the age of the individual [59].

At least some forms of osteoarticular amyloid appear to be localized at the site of origin, as suggested by the lack of proximity to blood vessels or evidence of congophilic angiopathy and by the location deep in relatively acellular matrix material. A direct relationship to aging appears to be more important than to osteoarthritis [62], and an association with calcium pyrophosphate dihydrate crystals has been noted by several investigators [61-63]. Similar pathologic changes have been found in articular cartilage, joint capsules, and annulus fibrosus of the intervertebral discs of certain AKR-derived senescence-accelerated mouse (SAM/P) lines that have served as models for spontaneous age-related amyloidosis; in these animals, both apoprotein AII and serum amyloid A (SAA) were found in articular structures, with the latter correlating with systemic signs of inflammation at autopsy [64].

Amyloid extracted from the menisci of patients undergoing knee replacement surgery contains aminoterminal fragments of apolipoprotein AI (Apo A-I) [65]. Immunohistochemistry, immunostaining, and in situ hybridization suggested that the Apo A-I in the amyloid deposits originated from adjacent chondrocytes.

By contrast, a survey of osteoarthritic hips taken at the time of surgery implicated transthyretin (TTR) as the main immunoreactivity detected, assumed to be wild-type based upon the lack of mutations of affected individuals who underwent genetic testing [66,67]. While the contribution of Apo A-I to osteoarticular amyloid decreased, that of TTR increased with age [57]. TTR immunohistochemistry and western blot analysis were correlated with Congo red staining of human cartilage samples collected at the time of joint replacement, and osteoarthritis-related genes were found to be upregulated in chondrocytes exposed to amyloidogenic TTR [68]. Cartilage and synovitis histologic scores were increased in transgenic mice overexpressing wild-type human TTR following medial meniscus destabilization, a model for osteoarthritis, and also increased by intraarticular injection of aggregated TTR in wild-type mice of the same strain [69].

TRANSTHYRETIN AND JUVENILE IDIOPATHIC ARTHRITIS — In juvenile idiopathic arthritis, misfolding, aggregation, and oxidation of TTR was shown in synovial fluid, which was demonstrated to be a target for both B- and T-cell immune responses [70].

FAMILIAL AMYLOIDOTIC POLYNEUROPATHY (FAP) — Arthropathy and muscle involvement may occur in patients with familial amyloidotic polyneuropathy (FAP).

Arthropathy — Loss of sensation to a joint may result in a chronic, progressive, and destructive arthropathy. The prototype of this disorder was described by Charcot in relation to tabes dorsalis. Similar changes are seen with other neurologic disorders, such as syringomyelia and diabetic neuropathy. Erosive and Charcot-like arthropathy, in some instances associated with intraarticular amyloid deposition due to variant transthyretin (TTR) subunit proteins, has been described in specific kindreds affected by FAP [71-73].

Clinical and imaging features of the neuropathic arthropathy in patients with FAP are similar to those seen in diabetic polyneuropathy. (See "Diabetic neuroarthropathy".)

Muscle involvement — Amyloid angiopathy may contribute to muscle weakness and atrophy that may be a prominent feature in some kindreds affected by FAP [74]. Amyloid may be a cause of myopathy and neuropathy affecting individuals with the Ile122 variant of transthyretin cardiomyopathy common among African Americans [75], as well as patients with wild-type TTR cardiac disease and neuropathy [76]. Myopathy may be the initial manifestation of disease or develop de novo after liver transplantation [77].

Carpal tunnel syndrome — The presence of TTR in flexor retinaculum taken at the time of carpal tunnel release (CTR) is well recognized to occur in idiopathic and apparently localized carpal tunnel syndrome (CTS) [78], but also as a harbinger or concomitant of several TTR mutations responsible for polyneuropathy or cardiomyopathy [79-82]. CTS may be the presenting symptom of wild-type TTR amyloid [83], with approximately 98 percent showing median nerve entrapment electrophysiologically and approximately 48 percent giving a history of CTR up to 12 years preceding the diagnosis of cardiac amyloidosis [84].

Nerve involvement — Laser microdissection and mass spectroscopic-based proteomics of nerve biopsies have been shown to be an effective way of classifying and characterizing AL amyloid and FAP-associated proteins causing polyneuropathy [85]. Patients with ATTR cardiac amyloidosis have an increased incidence of preceding carpal tunnel, polyneuropathy, myopathy, osteoarthritis requiring joint replacement, and spinal stenosis [86-88].

INCLUSION BODY MYOSITIS — Some experts have suggested that amyloid deposition may have an important role in inclusion body myositis (IBM), but the importance of amyloid in the etiopathogenesis of this disorder remains uncertain [89]. The clinical manifestations, diagnosis, and pathogenesis of IBM are discussed in detail separately. (See "Clinical manifestations and diagnosis of inclusion body myositis".)

OTHER FORMS OF ISOLATED AMYLOID MYOPATHY — Although AL, mutant, and wild-type transthyretin amyloidosis (ATTR) accounted for 38 out of 52 cases of pathologically confirmed amyloid myopathy in one review, approximately 27 percent were found to be due to other disorders [90], notably including specific forms of muscular dystrophy.

DYSFERLIN-DEFICIENT MUSCULAR DYSTROPHY — Mutations in dysferlin can be associated with recessively inherited limb girdle muscular dystrophy type 2B. There have been reports of dysferlin-derived amyloid in skeletal muscle biopsies associated with mutations in the N-terminal of the protein [91,92].

ANOCTAMIN 5 MUSCULAR DYSTROPHY — Recessive mutations in anoctamin 5 (ANO5) cause limb-girdle muscular dystrophy 2L and distal muscular dystrophy, which are similar to dysferlin-deficient muscular dystrophy, including case reports of skeletal muscle amyloid deposits. This type of muscular dystrophy has a variable phenotype, including cardiac dysfunction, myalgias, and even rhabdomyolysis with significantly elevated creatinine kinase (CK) levels (unlike most other forms of amyloid myopathy), but whether there is any contribution from amyloid deposition is unknown [90,93,94].

SUMMARY AND RECOMMENDATIONS

●AL amyloid can cause muscle weakness and, in a minority of patients, can result in enlargement of muscles, termed pseudohypertrophy, due to amyloid infiltration. (See 'Muscle involvement in AL amyloid' above.)

●Amyloid deposits in AL amyloidosis can involve the synovium, leading typically to a low-grade, subacute, progressive, and symmetric arthropathy, with a predilection for the shoulders, knees, wrists, and metacarpophalangeal and proximal interphalangeal joints. The joints are mildly tender or nontender, and there is usually little morning stiffness. Nodules containing amyloid may develop. Amyloid arthropathy is an infrequent complication of multiple myeloma or other paraproteinemia. (See 'Arthropathy due to AL amyloid' above.)

●Localized solitary tumoral or multiple osteolytic lesions of bone containing amyloid may develop in patients with AL amyloidosis. These lesions may lead to pathologic fractures and bone pain. Other rheumatic manifestations of AL amyloid include jaw claudication that mimics giant cell (temporal) arteritis due to vascular amyloid and sicca syndrome due to exocrine gland involvement. (See 'Osteopathy due to AL amyloidosis' above and 'AL amyloid simulating other rheumatic diseases' above.)

●Musculoskeletal manifestations of dialysis-related amyloidosis include carpal tunnel syndrome (CTS), periarthritis of the shoulder, effusive arthropathy, and erosive bone lesions. (See "Dialysis-related amyloidosis".)

●Microdeposits of amyloid have been found as incidental findings in the fibrous tissues, cartilage, menisci, and synovial membranes of various joints and in the annulus fibrosus and nucleus pulposus in the spine. The incidence of osteoarticular amyloid increases with advancing age. Some of these deposits contain apolipoprotein AI (Apo A-I), and some have been reported to have transthyretin (TTR) immunoreactivity. (See 'Osteoarticular amyloidosis' above.)

●TTR may facilitate the upregulation of genes associated with cartilage degeneration and inflammation in osteoarthritis.

●Arthropathy and muscle involvement may occur in patients with familial amyloidotic polyneuropathy. (See 'Arthropathy' above and 'Muscle involvement' above.)

●The development of CTS in patients on chronic hemodialysis was the first observation that led to recognition and characterization of dialysis amyloidosis due to beta-2 microglobulin. CTS may complicate AL and transthyretin amyloid (ATTR) and is a frequent presentation for both variant and wild-type ATTR cardiac amyloidosis.

●Isolated amyloid myopathy with elevated creatinine kinase (CK) levels may occur in the dysferlin-deficient and anoctamin 5 (ANO5) forms of muscular dystrophy.