Amyloidosis is a disorder in which extracellular deposition of an insoluble fibrous protein in the connective tissues of one or more organs ultimately leads to disruption of tissue structure and function.

There are at least 32 different proteins that result in amyloid disease.

Joint disease is a rare manifestation of amyloidosis.

The amyloidoses may be clinically classified.

The amyloid protein is a proteolysis-resistant fibrillar protein with a β-pleated sheet secondary structure. The protein consists of a homogeneous hyaline eosinophilic material, identified pathologically by three features.

Each type of amyloid disease is associated with deposition of a specific protein and the resulting organ involvement can be linked to the location, quantity, and ratio of deposition.

Prevalence is highly variable depending upon the type of amyloidosis.

Amyloidosis caused by AL protein is one of the most common forms of systemic amyloidosis with an incidence of approximately 1 case/100,000 person years of observation for Western countries.

Secondary or reactive amyloidosis is another of the more common forms of systemic amyloidosis. This type is more common in RA patients in Europe than those in the US.

Primary and myeloma-associated amyloidosis may have amyloid fibrils localized to the synovial membrane and tendon sheaths, in the synovial fluid, and in the articular cartilage in a small percentage of patients with AL deposition.

Secondary amyloidosis is characterized by renal involvement with proteinuria often accompanied by renal insufficiency.

Hemodialysis-related amyloidosis involves the musculoskeletal system with infiltration of the carpal ligaments, formation of periarticular bone cysts, scapulohumeral periarthritis, stiff and painful fingers, and destructive cervical spondyloarthropathy with cyst formation and occasional odontoid fracture.

The etiology of the amyloid should be evaluated once diagnosed. Evaluation for a primary inflammatory disease, such as RA, or for a primary plasma cell dyscrasia should be undertaken.

Patients with chronic renal failure may also have other conditions that could have an impact upon the musculoskeletal system, such as secondary hyperparathyroidism, aluminum overload, and apatite crystal deposition resulting in arthropathy.

Therapy is dependent upon the primary cause of the amyloid precursor.

Primary or myeloma-associated disease should have the goal of reducing the number of cells producing the amyloid precursor via treatment of the primary disease.

Secondary amyloidosis due to RA can be improved with optimal control of the inflammatory process and the use of daily, oral colchicine 0.6 mg twice daily.

Hemodialysis-related amyloidosis can be halted by renal transplant, but this will not reverse the symptoms from existing lesions. Modern dialysis filters may also improve the amyloid burden.

Hemochromatosis is one of the most common genetic disorders. It is characterized by excessive body stores of iron and deposition of hemosiderin, causing tissue damage and organ dysfunction.

Prolonged excessive iron intake, as the result of repeated blood transfusions for chronic hypoproliferative anemia and thalassemia, may also result in iron deposition. When not associated with tissue damage, this disorder is known as hemosiderosis; when organ damage is present, it is called secondary hemochromatosis.

Classic hereditary hemochromatosis is an autosomal recessive iron-overload disorder usually associated with a point mutation of the HFE gene located on chromosome 6. The HFE gene encodes a 343 amino acid protein expressed on the intestinal cell surface in complex with the transferrin receptor (TfR), thought to facilitate the uptake of iron into the duodenum. The phenotypic expression may vary greatly and, because of this, routine genetic testing has not been as effective in predicting outcome as it had been expected to be.

Duodenal transfer of iron to plasma is inappropriately high for body iron stores with the rate of absorption being approximately four to five times normal. Absorption of iron generally exceeds iron loss. This, along with other dysregulation of iron management, results in disease.

Approximately one in every 250 to 300 individuals is homozygous for the most common mutation. This is one of the most common genetic disorders. Prevalence is 30 to 60/10,000 individuals. The incidence is estimated to be two to four/100,000 cases/year.

Men are affected four times more frequently than women, who are protected by physiologic blood losses.

Arthropathy is present in 40% to 60% of patients, most commonly in homozygous patients.

Classic hereditary hemochromatosis consists of the triad of hepatic cirrhosis, cardiomyopathy, and “bronze” diabetes mellitus. Manifestations may also include pituitary dysfunction, sicca syndrome, skin pigmentation, weakness, lethargy, and increased sleep requirement. Liver abnormalities are probably the most constant and common manifestation.

Chronic progressive destructive arthritis, predominantly affecting the second and third metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints is the presenting feature in about half of all cases. Larger joints such as shoulders, hips, knees, and ankles may be affected.

The joint involvement presents clinically as stiffness and pain in the hands, often after excessive use, and symmetric, mildly tender joint enlargement without erythema or increased warmth.

Acute episodes of inflammatory arthritis may be secondary to calcium pyrophosphate deposition (pseudogout).

Yersinia septic arthritis is an unusual complication that may arise because of the predilection of this microbe for an iron-rich environment.

Arthritic symptoms may be brought under control by nonsteroidal anti-inflammatory drugs (NSAIDs), although sometimes arthroplasty is required. Close observation of liver function tests is needed in these patients treated with NSAIDs.

Phlebotomy removes excess iron but does not usually relieve the arthropathy. Damage to the synovial membrane and cartilage seems to be irreversible.

Hemophilia A (classic hemophilia) is caused by a factor VIII deficiency.

Hemophilia B (Christmas disease) is caused by a factor IX deficiency.

The pathogenesis of the joint disease is not well understood, but it may result from excessive iron deposition in the synovial tissue and articular cartilage. The blood in the joint remains liquid due to absence of prothrombin and fibrinogen. The plasma is gradually resorbed and the remaining red cells undergo phagocytosis by the synovial lining cells and macrophages.

Hemosiderin is found in synovial lining cells where it may be toxic, causing chronic inflammation with proliferation of the synovium and pannus formation.

One in 10,000 males is born with hemophilia A and one in 100,000 males is born with hemophilia B.

Two-thirds of all patients affected by hemophilia have hemarthrosis, the most common bleeding manifestation.

Stage 1: Acute joint hemarthrosis is usually characterized by the development of an acute effusion with warmth, tenderness, and decreased range of motion. The joints usually affected are the knees, elbows, and ankles.

Stage 2: Subacute hemophilic arthropathy often follows repeated episodes of intra-articular hemorrhage. There is persistent synovitis of the joint with thickening of the synovium, moderate effusion, and pain.

Stage 3: Chronic hemophilic arthropathy is characterized by joint deformity, fibrous ankylosis, and osteophyte overgrowth. Soft-tissue swelling and joint effusion are less common at this stage, and the pain is fluctuating and variable. Late manifestations include muscle hemorrhage, muscle cysts, contractures, and osseous pseudotumors.

Factor replacement therapy is essential to improve the longevity and prognosis of patients with hemophilia.

Acute hemarthrosis must be treated promptly with cold applications, analgesics, and joint immobilization followed by a carefully designed physiotherapy program.

Aspiration (after factor replacement) is less commonly performed, unless the joint is very tense or sepsis is suspected.

Chronic arthropathy may be treated with NSAIDs. Joint replacement can be performed in those patients who have advanced joint destruction. This demands a team approach with optimal factor replacement.

Sickle cell disease and β-thalassemia are two of the most common hemoglobinopathies that produce musculoskeletal complications. Others are the compound heterozygous states including sickle-C disease, and sickle-D disease.

β-thalassemia major is associated with osteoporosis, pathologic fractures, and epiphyseal deformities. In β-thalassemia, minor, recurrent asymmetric arthritis may be seen.