Localized amyloidosis

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The amyloidoses are of interest to rheumatologists because of their demonstrated association with long-standing inflammatory joint disease accompanied by amyloid deposition in the kidneys, liver, and spleen. However, the clinical presentation of arthropathy is rare; it has been seen in association with the deposition of AL protein, the amyloid associated with the immunoglobulin light chain; b2-microglobulin in patients with chronic renal failure. Arthropathy is occasionally associated with transthyretin (TTR) amyloid (transthyretin is the precursor of amyloid protein).

A. Primary and myeloma-associated amyloidosis. These two forms of amyloidosis are characterized by the deposition of fibrils of AL amyloid made up of the monoclonal chain of immunoglobulin, the production of which indicates an underlying monoclonal plasma cell dyscrasia. Recent data also suggest the presence of structurally abnormal light chains.

1. Clinical picture. Amyloid fibrils may localize in the synovial membrane and tendon sheaths, in the synovial fluid, and in the articular cartilage in a small percentage of patients with AL deposition. Clinical arthropathy in not common, although when seen it is chronic and may involve the small or large joints (shoulders, wrists, knees, or fingers) either symmetrically or asymmetrically. Stiffness (but not pain) is characteristic, together with swelling, limitation of motion, and subcutaneous nodules. Shoulder involvement may be particularly striking, with accumulation of amyloid at the joint producing the "shoulder pad" sign.

2. Diagnosis. Radiography may show soft-tissue swelling and generalized osteoporosis with or without lytic lesions; joint space narrowing is not seen, and erosions are rare. The diagnosis can be confirmed by an examination of the synovial fluid and, when necessary, by synovial biopsy. The synovial fluid is noninflammatory and yellow or xanthochromic, and it may contain fibrils that have the tinctorial and ultrastructural features of amyloid. Clinicians must keep in mind the importance of the differential diagnosis with rheumatoid arthritis; a biopsy of the involved tissue may be needed. Careful evaluation for the presence of primary plasma cell dyscrasia and systemic organ involvement must also be carried out.

B. Hemodialysis-related amyloidosis. The second form of amyloid deposition associated with significant articular involvement is the deposition of b2-microglobulin in patients with chronic renal failure undergoing long-term dialysis treatment. Use of the cellulose-based cuprophane dialysis membrane appears to be associated with a higher incidence of amyloidosis; the incidence is lower in patients undergoing peritoneal dialysis. Rarely does b 2-microglobulin amyloidosis develop in patients with renal failure before they begin dialysis.

1. Clinical picture and diagnosis. b2-Microglobulin amyloidosis involves the musculoskeletal system, with infiltration of the carpal ligaments, formation of bone cysts (frequently in apposition to the joints), scapulohumeral periarthritis, stiff and painful fingers, and destructive cervical spondyloarthropathy with cyst formation and occasional odontoid fracture. Cervical disease usually takes the form of vertebral end plate erosion without osteophyte formation. Rapid joint destruction then usually follows. Median nerve compression is very common with its attendant carpal tunnel syndrome.

Ultrasonography of the wrist is useful to identify the characteristic thickening of the carpal ligaments. Sonograms of the shoulder can help to distinguish amyloidosis from other forms of shoulder disease.

Radiographs will often show subchondral radiolucent bone cysts consisting of amyloid deposits and erosion. Systemic deposits are rare, and specimens obtained by abdominal fat pad aspiration (the simplest screening test) are usually negative for amyloid deposits. In patients with chronic renal failure, other conditions, such as secondary hyperparathyroidism, aluminum overload, and apatite crystal deposition, may occasionally play a contributory role in arthropathy, and such conditions should be identified.

2. Therapy. In patients with either the primary or myeloma-associated form of the disorder, amyloidosis is treated directly, the goal being to reduce the number of cells producing the amyloid precursor, with a resultant reduction in the protein product and fibril formation.

In hemodialysis-associated amyloidosis, renal transplantation can halt the disease progression but will not relieve the symptoms caused by already existing lesions. Pain cannot be relieved with surgery, but functional improvement may be obtained in joints that are accessible by arthroscopy. Proper monitoring of both the dialysis procedure and the patient's phosphate-calcium metabolism can help decrease the risk for destructive arthropathy.

II. Arthropathy in hemochromatosis Hemochromatosis is one of the most common genetic disorders characterized by excessive body stores of iron and by the deposition of hemosiderin, both of which can cause tissue damage and organ dysfunction. Approximately one in every 250-300 persons is homozygous for this mutation. Idiopathic hemochromatosis is an autosomal recessive disorder associated with two-point mutations on the HFE gene located on the short arm of chromosome 6. It rarely appears before the age of 40 unless there is a family history, and men are affected 10 times more frequently than women, who are protected by physiologic blood losses.

Increased intestinal iron absorption and visceral deposition can lead to the classic features of hepatic cirrhosis, cardiomyopathy, diabetes mellitus ("bronze" diabetes), pituitary dysfunction, sicca syndrome, and skin pigmentation. Liver abnormalities are probably the most constant manifestation. However, hemochromatosis is usually symptomless and is often detected only accidentally. Other presenting manifestations include constitutional symptoms such as weakness, lethargy, and increased sleep requirements.

Arthropathy is present in 40% to 60% of patients. It sometimes constitutes the first manifestation but more often occurs later, even following treatment. The expression of hemochromatosis with arthritis is most common in homozygotes, although the pathogenesis of the arthritis is unknown. Prolonged excessive iron ingestion, as practiced by the South African Bantu tribesmen or 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.

A. Clinical picture. Chronic progressive arthritis, predominantly affecting the second and third metacarpophalangeal and proximal interphalangeal joints and resembling rheumatoid arthritis, is the presenting feature in about one-half of all cases. Hemochromatosis can also affect the larger joints, such as the shoulders, hips, knees, and ankles. A progressive destructive osteoarthritis may be seen. The arthropathy causes stiffness and pain in the hands, often after excessive use, and symmetric, mildly tender joint enlargement without erythema or increased warmth. Sometimes, acute episodes of inflammatory arthritis may occur secondary to calcium pyrophosphate deposition. This form of chondrocalcinosis occurs in 15% to 30% of patients and involves the cartilage of the knees, wrists, intervertebral disks, and symphysis pubis.

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

B. Diagnosis. The erythrocyte sedimentation rate is normal and rheumatoid factor is absent. The synovial fluid shows good viscosity, with leukocyte counts below 1,000/mm3. During acute episodes of pseudogout, synovial fluid leukocytosis and calcium pyrophosphate crystals may be found. Radiographs show cystic lesions with sclerotic walls, joint space narrowing, sclerosis, osteophytes, and osteoporosis. These radiologic changes may mimic those of osteoarthritis. Hemochromatosis should be suspected in the presence of raised serum iron and ferritin concentrations and increased saturation of transferrin, a plasma iron-binding protein. An effective screening algorithm includes a fasting morning transferrin saturation. If the percentage is > 50% and a serum ferritin is high, HFE testing is appropriate. Needle biopsy of the liver will confirm the diagnosis. Synovial biopsy in hemochromatosis will show iron deposition in the type B cell linings of the synovium.

C. Therapy. The arthritic symptoms may be brought under control by nonsteroidal antiinflammatory drugs (NSAIDs), although sometimes arthroplasty is required. Excess iron can be removed from the body by weekly phlebotomy. Phlebotomy usually does not relieve the arthropathy, however, and the damage to the synovial membrane and cartilage seems to be irreversible.

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