Version July 2025
INTRODUCTION —
Amyloidosis refers to the extracellular tissue deposition of fibrils that are composed of low-molecular-weight subunits derived from a variety of serum proteins. Amyloid deposits can occur in a variety of organs, with morbidity and mortality often related to the involvement of the heart, kidney, gastrointestinal tract, and nervous system. (See "Overview of amyloidosis".)
Different types of amyloidosis are derived from various fibril subunit proteins (table 1 and table 2). As an example, AL amyloidosis is derived from monoclonal immunoglobulin light chains or light-chain fragments (which may be a complication of plasma cell dyscrasias), while AA amyloidosis is derived from a fragment of serum amyloid A (SAA) protein (whose production is driven by an underlying chronic inflammatory disorder).
A variety of amyloid types are associated with musculoskeletal symptoms, including AL, transthyretin (TTR) amyloidosis (ATTR), and dialysis-related amyloidosis. The type of amyloidosis can be distinguished immunohistologically and biochemically and will drive the subsequent treatment strategy [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 [3,4]. In addition, rheumatic diseases with musculoskeletal symptoms can cause AA amyloidosis. (See "AA amyloidosis: Causes and diagnosis".)
This topic will review the musculoskeletal manifestations of the various forms of amyloidosis. Other organ-specific manifestations of amyloidosis are discussed separately:
●(See "Renal amyloidosis".)
●(See "Cutaneous manifestations of amyloidosis".)
●(See "Pleuropulmonary manifestations of amyloidosis".)
AL AMYLOIDOSIS —
Musculoskeletal manifestations of AL amyloidosis include muscle weakness (myopathy), muscle enlargement due to amyloid infiltration (pseudohypertrophy), joint disease (arthropathy), and bone lesions (osteopathy). Other manifestations of AL amyloidosis are described separately. (See "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis".)
In a retrospective cohort study of 191 patients with AL amyloidosis, soft tissue, bone, and joint manifestations occurred in 42.9 percent of patients and were the dominant organ system involved for 9.4 percent [5]. 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 almost twice as common among males as compared with females and were also more common among patients with multiple organ involvement and cardiac involvement. In addition, musculoskeletal symptoms appeared to be more prominent among the subgroup of 17 patients who had underlying multiple myeloma compared with those who had other causes of AL amyloidosis, but the results were not statistically significant.
Muscle involvement — Amyloid infiltration of muscles may cause:
●Muscle enlargement (ie, pseudohypertrophy) – Amyloid deposits can cause visible enlargement of skeletal muscles [6-9]. A large tongue (ie, macroglossia) or lateral scalloping of the tongue from impingement on the teeth is characteristic of AL amyloidosis and may be the presenting feature of the disease [10,11].
Muscle infiltration is generally associated with widespread or systemic disease. In a retrospective study conducted at a single tertiary center, 12 patients with biopsy-proven amyloid myopathy were identified over 35 years [12]. 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 myopathy or associated neuropathy [13].
●Myopathy – Myopathy may occasionally be the initial presenting feature of AL amyloidosis. It can cause proximal muscle weakness or dyspnea and wasting due to amyloid infiltration into muscle fibers [14]; rarely, the presentation can simulate polymyositis [15]. In a retrospective review of 51 patients diagnosed at a tertiary referral center with AL amyloidosis and biopsy-confirmed amyloid myopathy, presenting symptoms included muscle weakness (proximal greater than distal, 96 percent), myalgia (33 percent), macroglossia (33 percent), jaw claudication (25 percent), and hoarseness (18 percent) [16].
The diagnosis of myopathy related to AL amyloidosis may be suggested by unusual findings on magnetic resonance imaging (MRI) or positron emission tomography (PET)/computed tomography (CT) scanning and confirmed by Congo red staining on muscle biopsy [17-19]. A spectrum of light chain deposition and pathologies may be seen [20]. Laboratory findings may include elevations in cardiac troponin T (in the absence of cardiac involvement) and creatine kinase, which were noted in 42 and 34 percent of patients, respectively, in a retrospective review [16]. Electromyography often shows myopathic changes and half of patients may also have coexistent peripheral neuropathy, which may be asymptomatic [16].
Joint involvement — Amyloid deposits in AL amyloidosis can involve the synovium, leading to arthropathy. Amyloid arthropathy is a rare complication of Waldenström macroglobulinemia [21] and may occur in 0.1 to 6 percent of patients with multiple myeloma, with an onset either preceding, coincident with, or after the diagnosis of myeloma [22,23]. It can also be seen in patients with monoclonal gammopathy of uncertain significance (MGUS) [24]. (See "Epidemiology, pathogenesis, clinical manifestations, and diagnosis of Waldenström macroglobulinemia" and "Diagnosis of monoclonal gammopathy of undetermined significance".)
●Clinical features – The arthropathy in AL amyloidosis is typically 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 nontender or mildly tender, and there is usually little morning stiffness. These characteristics help distinguish this disorder from rheumatoid arthritis [25,26]. The arthritis may rarely be erosive, as has been described in patients with MGUS [24], or Charcot-like due to severe amyloid neuropathy [27].
When large joints are involved, patients may develop asymptomatic soft tissue swelling over the affected area. This occurs in up to 75 percent of patients with AL amyloidosis [28] and most commonly affects the hips [29] and/or shoulders, where it can cause a characteristic "shoulder pad" sign [30]. Several case reports have described the types of amyloid proteins noted on the biopsy of affected synovial tissue, including three subunit proteins derived from the same VkI light chain [31] and a VkIII protein [32].
Whitish subcutaneous nodules can accompany arthropathy in approximately 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 [33].
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.
A systematic review of 101 published cases of amyloid arthropathy associated with multiple myeloma reported a male-to-female ratio of 1:1 and a predominance of symmetric, polyarticular arthritis; however, 17 percent of cases were oligoarticular and 3 percent were monoarticular [34]. A diagnosis of seronegative arthritis preceded the diagnosis of multiple myeloma in 62 percent of patients, likely reflecting that arthropathy was a presenting symptom of AL amyloidosis. Typical amyloidosis-associated extraarticular manifestations were present in 61 percent of patients, including CTS, macroglossia, and/or shoulder pad and soft tissue swelling/masses.
●Laboratory and imaging findings – Synovial fluid is usually noninflammatory and bland compared with typical findings in rheumatoid arthritis, with predominantly mononuclear cells. The fluid may appear cloudy due to the presence of synovial fragments; performing Congo red staining of the spun sediment may demonstrate amyloid [22,35]. Synovial histopathology classically shows amyloid phagocytosis by synovial macrophages and the absence of infiltration by CD20+ and CD38+ cells and angiogenesis [36].
Radiographic features include juxtaarticular cyst formation and widening of the joint space early in the disease. Erosions and joint space narrowing are prominently absent. Periarticular soft tissue infiltration may be seen on MRI and/or ultrasound imaging [22,37] or, in some instances, by PET/CT [38].
●Response to treatment – Arthropathy as well as tendinopathy may improve with appropriate chemotherapy, documented by regression of lesions assessed by ultrasound or MRI [39].
Carpal tunnel syndrome — Amyloid deposition in the wrist can compress the median nerve and lead to CTS in localized or systemic AL amyloidosis [40,41]. Symptoms may include numbness, tingling, and weakness in the hand and fingers. Arthropathy involving the hand is commonly associated with CTS and is typically bilateral and symmetric. Nodular masses accumulate in the carpal tunnel and may be grossly apparent at the time of surgery [42].
Osteopathy — 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 [43-45]. Cervical spine involvement may cause significant neurologic deficits in multiple myeloma [46].
Clinical manifestations mimicking systemic rheumatic disease — Rarely, the musculoskeletal manifestations of AL amyloidosis may mimic systemic rheumatic diseases:
●Jaw claudication – Jaw claudication mimicking giant cell arteritis has been reported with AL amyloidosis [47,48]. Jaw claudication is due to predominantly vascular amyloid that compromises the lumina of the facial branches of the external carotid artery [49,50]. The diagnosis of AL amyloidosis may be suggested by the presence of a monoclonal gammopathy and abnormal serum free light chain ratio and by lack of response to glucocorticoids [48,51]. (See "Clinical manifestations of giant cell arteritis".)
●Sicca syndrome – Sicca syndrome mimicking Sjögren's disease can occur due to amyloid deposits leading to enlargement and compromised function of both parotid and lacrimal glands [52,53]. 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 [54,55]. (See "Diagnosis and classification of Sjögren's disease", section on 'Salivary gland biopsy'.)
●Skin thickening – Cutaneous disease mimicking scleroderma may be the presenting feature of AL amyloid and is usually associated with multiple myeloma [3,56]. (See "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults", section on 'Causes of scleroderma-like skin changes'.)
TRANSTHYRETIN AMYLOIDOSIS —
Transthyretin (TTR) amyloidosis (ATTR) can cause musculoskeletal symptoms through several distinct mechanisms, notably including direct deposition, ligament and vascular calcifications, and length-dependent sensorimotor neuropathy in familial amyloidotic polyneuropathy (FAP) [57]. Orthopedic procedures such as carpal tunnel release, spinal stenosis surgery, or hip and knee arthroplasties may demonstrate TTR deposition on pathology and act as a "red flag" for the early diagnosis of cardiac amyloidosis [58]. ATTR amyloidosis is described in more detail elsewhere. (See "Overview of amyloidosis", section on 'Wild-type transthyretin systemic amyloidosis'.)
Muscle involvement — Rarely, patients with ATTR may develop myopathy as the initial clinical manifestation or later in their clinical course, including one patient who developed myopathy after liver transplantation [59]. Affected patients may have muscle weakness and/or cramping and sometimes have concomitant neuropathy [60].
Amyloidosis may be a cause of myopathy and neuropathy, particularly in FAP, but is also recognized among individuals with the Ile122 variant of transthyretin cardiomyopathy [61] and those with wild-type ATTR cardiac disease and neuropathy [62]. Amyloid deposits can be detected using technetium-99m-labeled 3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) scintigraphy [60]. In addition to direct muscle involvement, amyloid angiopathy may contribute to muscle weakness and atrophy; this may be a prominent feature in some kindreds affected by the inherited form, FAP [63].
Arthropathy — Loss of sensation to a joint may result in a chronic, progressive, and destructive neuropathic arthropathy, known as Charcot neuroarthropathy. Both neuropathic arthropathy and erosive arthritis have been described in patients and/or family members affected by FAP and in some instances are associated with intraarticular deposition of variant TTR subunit proteins [64-66]. Clinical manifestations and imaging findings are similar in patients with neuropathic arthropathy related to FAP or diabetic polyneuropathy. (See "Diabetic neuroarthropathy".)
It can be difficult to distinguish when arthropathy is due to age-related, wild-type ATTR (ATTRwt) versus AL amyloidosis. Monoclonal gammopathy occurs frequently among patients with ATTRwt [67] and is also associated with arthropathy. Inflammatory amyloid arthropathy due to ATTRwt has been reported in a patient with smoldering myeloma [68]. (See 'Joint involvement' above.)
Carpal tunnel syndrome — Carpal tunnel syndrome (CTS) may be the presenting symptom of wild-type ATTR [69,70] or hereditary ATTR amyloidosis and may precede other symptoms by one or two decades [71-76]. Detection of TTR in the flexor retinaculum taken at the time of carpal tunnel release can be important in identifying patients who are at risk of subsequently developing polyneuropathy or cardiomyopathy [70,77].
Other clinical manifestations — Patients with ATTR cardiac amyloidosis have an increased incidence of preceding spinal stenosis [78], trigger finger requiring surgery [79], biceps tendon rupture [80], and osteoarthritis requiring joint replacement [81].
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 —
Osteoarticular amyloidosis refers to amyloid deposits found in bones and joints and is more common with increasing age [82]. While osteoarticular amyloidosis is often an incidental histopathologic finding, severe cases have been associated with transthyretin (TTR) amyloidosis (ATTR) [81]. Thus, we screen patients with severe osteoarticular amyloidosis for other systemic manifestations of ATTR, such as cardiomyopathy. (See "Overview of amyloidosis", section on 'Diagnosis'.)
Microdeposits of amyloid have been found in multiple types of osteoarticular tissue after sampling taken during surgery or on postmortem examinations, including synovial membranes, cartilage, fibrous capsules, tendons, intervertebral discs, and annulus fibrosis [82-88]. At least some forms of osteoarticular amyloid appear to be localized at the site of origin, since they are distant from blood vessels, deep in relatively acellular matrix material, and lack evidence of congophilic angiopathy [89]. Various types of amyloid have been identified in osteoarticular deposits, including TTR and full-length and aminoterminal fragments of apolipoprotein AI (Apo A-I) [90-93]. With increasing patient age, the proportion of Apo A-I osteoarticular amyloid decreases and the proportion of TTR increases [85].
It is unclear whether osteoarticular amyloidosis is related to earlier-onset or more rapidly developing forms of age-related musculoskeletal disease. An association with calcium pyrophosphate (CPP) crystals has been noted by several investigators, although notably the presence of CPPD deposition also increased with age [88,89,94]. Osteoarticular amyloidosis has also been postulated to contribute to osteoarthritis; in a case series examining knee cartilage, osteoarthritis-related genes were upregulated in chondrocytes that were exposed to TTR [95].
OTHER CONDITIONS POTENTIALLY ASSOCIATED WITH ISOLATED AMYLOID MYOPATHY —
While the most common causes of amyloid myopathy include AL amyloidosis and transthyretin (TTR) amyloidosis (ATTR), other causes (eg, muscular dystrophy) have been described [96].
Muscular dystrophies — Amyloid myopathy has been reported in several types of limb-girdle muscular dystrophies (LGMD) and distal muscular dystrophies. (See "Limb-girdle muscular dystrophy" and "Oculopharyngeal, distal, and congenital muscular dystrophies".)
●Dysferlin-deficient muscular dystrophy – Mutations in dysferlin can be associated with recessively inherited LGMD 2B. There have been reports of dysferlin-derived amyloid in skeletal muscle biopsies associated with mutations in the N-terminal end of the protein [97,98] which are known to trigger the NLRP3 inflammasome [99].
●Anoctamin 5 muscular dystrophy – Recessive mutations in anoctamin 5 (ANO5) cause LGMD 2L and distal muscular dystrophy. There are case reports of skeletal muscle amyloid deposits in patients with ANO5 muscular dystrophy, but it is unknown whether amyloid deposition is responsible for clinical manifestations including cardiac dysfunction, myalgias, and rhabdomyolysis (with significantly elevated creatine kinase levels, unlike most other forms of amyloid myopathy) [100,101]. (See "Limb-girdle muscular dystrophy".)
●Human heterogeneous ribonucleoprotein D-like LGMD D3 – Human heterogeneous ribonucleoprotein D-like (hnRNPDL) LGMD D3 is an autosomal dominant disease linked to a missense mutation in exon 6, which encodes hnRNPDL. Cryo-electron microscopy of fibrils of normal hnRNPDL-2 (the predominant isoform in humans) has revealed a structure that is similar to that of functional amyloid, suggesting that hnRNPDL LGMD D3 may be related to dysfunctional amyloid [102].
Inclusion body myositis — Some experts have suggested that deposition due to beta-amyloid aggregates may have an important role in inclusion body myositis (IBM), but the importance of amyloid in the etiopathogenesis of this disorder remains uncertain [103]. The clinical manifestations, diagnosis, and pathogenesis of IBM are discussed in detail separately. (See "Clinical manifestations and diagnosis of sporadic inclusion body myositis".)
SUMMARY
●AL amyloidosis – Musculoskeletal manifestations of AL amyloidosis include muscle weakness (myopathy), muscle enlargement due to amyloid infiltration (pseudohypertrophy), joint disease (arthropathy), and bone lesions (osteopathy). (See 'AL amyloidosis' above.)
•Muscle involvement – Amyloid deposits can cause visible enlargement of skeletal muscles, which is generally associated with widespread or systemic involvement. A large tongue (ie, macroglossia) or lateral scalloping of the tongue from impingement on the teeth is characteristic of AL amyloidosis and may be the presenting feature of the disease. Patients may occasionally develop myopathy with symptoms including proximal muscle weakness and dyspnea. (See 'Muscle involvement' above.)
•Arthropathy – Amyloid deposits in AL amyloidosis can involve the synovium, leading to an arthropathy that is typically low grade, subacute, progressive, and symmetric. Commonly affected joints include the shoulders, knees, wrists, and metacarpophalangeal and proximal interphalangeal joints. The joints are mildly tender to nontender and there is usually little morning stiffness. There may be associated subcutaneous nodules and/or thickening and nodularity of the palmar fascia. (See 'Joint involvement' above.)
•Carpal tunnel syndrome – Carpal tunnel syndrome (CTS) may occur with localized or systemic AL amyloidosis and is commonly associated with a bilateral, symmetric arthropathy of the hands. Nodular masses accumulate in the carpal tunnel and may be grossly apparent at the time of surgery. (See 'Carpal tunnel syndrome' above.)
●Transthyretin amyloidosis – Transthyretin (TTR) amyloidosis (ATTR) can cause musculoskeletal symptoms through several distinct mechanisms, notably including ligament and vascular calcifications and familial amyloidotic polyneuropathy (FAP). (See 'Transthyretin amyloidosis' above.)
•Muscle involvement – Rarely, patients with ATTR may develop myopathy with muscle weakness and/or cramping; this may happen as the initial clinical manifestation or later in their clinical course. (See 'Muscle involvement' above.)
•Arthropathy – Patients with ATTR complicated by neuropathy can develop a chronic, progressive, and destructive neuropathic arthropathy, known as Charcot neuroarthropathy, due to loss of sensation to a joint. Clinical manifestations and imaging findings are similar in patients with neuropathic arthropathy related to FAP or diabetic polyneuropathy. (See 'Arthropathy' above and "Diabetic neuroarthropathy".)
•Carpal tunnel syndrome – CTS may be the presenting symptom of wild-type or hereditary ATTR amyloidosis. We evaluate patients who have TTR on pathology from carpal tunnel release for evidence of other systemic manifestations of ATTR. (See 'Carpal tunnel syndrome' above.)
●Dialysis-related amyloidosis – Musculoskeletal manifestations of dialysis-related amyloidosis, including CTS, periarthritis of the shoulder, effusive arthropathy, and erosive bone lesions, are presented separately. (See "Dialysis-related amyloidosis".)
●Osteoarticular amyloidosis – Osteoarticular amyloidosis refers to amyloid deposits found in bones and joints and is more common with increasing age. While osteoarticular amyloidosis is often an incidental histopathologic finding, severe cases have been associated with ATTR. Thus, we evaluate patients with severe osteoarticular amyloidosis for other systemic manifestations of ATTR, such as cardiomyopathy. (See 'Osteoarticular amyloidosis' above.)
●Other conditions potentially associated with isolated amyloid myopathy – While the most common causes of amyloid myopathy include AL amyloidosis and ATTR, other causes have been described including several types of limb-girdle muscular dystrophies (LGMD) and distal muscular dystrophies. Some experts have suggested that deposition due to beta-amyloid aggregates may have an important role in inclusion body myositis (IBM), but the importance of amyloid in the etiopathogenesis of this disorder remains uncertain. (See 'Other conditions potentially associated with isolated amyloid myopathy' above.)
