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Joints are specialized areas of the skeletal system situated between two bones, permitting postural movements: flexion, extension, rotation, etc. The ends of the bone in the joint cavity are covered with smooth hyaline cartilage (articular cartilage). The joint is held together by a joint capsule composed of collagen, which is strengthened by ligaments. The inside of the joint capsule is lined by a layer of flat synovial cells that secrete synovial fluid. The synovial fluid in the joint cavity serves as a lubricant.
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Clinical Manifestations of Joint Disease
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Joint Pain (Arthralgia)
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Most joint diseases cause pain. The term arthralgia is used when there is joint pain without evidence of acute inflammation. When pain is accompanied by other features of inflammation such as swelling, redness, and increased temperature, the term arthritis is used.
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Joint swelling is the result of an increase in synovial fluid volume. It may result from fluid exudation in inflammatory conditions or from bleeding. Swelling due to bleeding is called hemarthrosis. Fluid imparts a fluctuant feel and produces a wave when tapped that can be felt on the side opposite to tapping (fluid thrill).
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An increase in size of a joint may result from the presence of solid tissue within the cavity. This occurs in rare neoplastic lesions of joints. The distinction between a mass lesion and fluid can be made by x-ray examination, needle aspiration, and careful clinical examination: A mass lesion produces a “boggy” feel compared with the fluctuant feel of fluid, and a fluid thrill is absent.
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The movement of one articular surface on another is normally smooth and silent. Crepitus is an abnormal sensation and sound of grating that accompanies joint movement. Because the articular cartilage represents the rubbing surface of a normal joint, crepitus occurs in diseases associated with loss of articular cartilage and exposure of subchondral bone.
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Abnormal Joint Mobility
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Most joint diseases result in restricted range of motion in the affected joints due to pain or stiffness. Rarely, the range of motion may be increased, as when structural components that hold the joint together are damaged. Tearing of cruciate ligaments in the knee and the general destruction associated with neuropathic joints are examples of disorders associated with an abnormal increase of joint mobility. Increased joint mobility may also be seen in congenital diseases characterized by abnormal collagen synthesis (eg, Ehlers-Danlos syndrome).
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Evaluation of Joint Disease
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Physical examination permits detection of acute inflammation, which is characterized by swelling, redness, increased temperature, tenderness, and restriction of motion. The presence of joint swelling is best assessed by measurement of its circumference and comparing it with the normal counterpart in the case of paired joints. With some joints (eg, atlantoaxial, intervertebral), the presence of inflammation may be difficult to establish. Joint swelling may be caused by fluid (fluctuant with a fluid thrill), blood, or solid mass.
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Many joint diseases are characterized by abnormal mobility and crepitus.
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The joint space as seen on an x-ray is occupied by articular cartilage, synovium, intra-articular ligaments, and synovial fluid, all of which are normally radiolucent. Radiologic abnormalities may include (1) an increase in the joint space when there is fluid, blood, a solid mass lesion, or proliferation of the synovium; (2) decreased joint space in diseases associated with degeneration of the articular cartilage; (3) abnormalities in articular cartilage, such as opacification, and subchondral bone, such as erosion and cyst formation; and (4) the presence of abnormal loose bodies in the joint space. Magnetic resonance imaging (MRI) permits visualization of all structures and is an excellent (although expensive) method of evaluation of joints.
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Laboratory Evaluation
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Examination of aspirated synovial fluid is very useful in the diagnosis of inflammatory and metabolic diseases (Table 68-1). Fluid is cultured and examined chemically and microscopically for its protein content, specific gravity, the presence and type of inflammatory cells, and the presence of urate and calcium pyrophosphate crystals.
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Many joint diseases cause serologic abnormalities. These are considered with the individual diseases.
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Arthroscopic Examination
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Insertion of a fiberoptic arthroscope into the joint space through a small incision in the joint capsule permits direct visualization of the joint. Biopsies may be taken of synovium and mass lesions. Arthroscopy also permits repair of intra-articular injuries.
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Congenital Disorders of Joints
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Congenital Dislocation of the Hip
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Deficient development of the acetabulum in an infant allows the femoral head to ride upward out of the joint socket (subluxation) when weight-bearing begins. This defect is much more common in females and shows a familial tendency. Unless it is corrected soon after birth, abnormal stresses cause malformation of the developing femoral neck with a characteristic limp (if unilateral) or waddling gait (if bilateral).
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Treatment requires early diagnosis with splinting of the hips in abduction during the first few months of life to allow development of the acetabulum.
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Talipes Equinovarus & Calcaneovalgus (Clubfoot)
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The two forms of clubfoot represent abnormal articulation of the small bones of the foot due to abnormal intrauterine forces, abnormal fetal muscle action, or defective ligament insertion. Treatment should be started at birth.
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Infectious Diseases of Joints
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Pyogenic arthritis is usually caused by Staphylococcus aureus. Less frequently, Streptococcus pyogenes, Streptococcus pneumoniae, Neisseria gonorrhoeae, and Haemophilus influenzae are responsible. The route of infection is hematogenous, and in most patients the primary access site of the pathogen is unknown.
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Pathology & Clinical Features
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Pyogenic arthritis is an acute inflammation that commonly involves a single large joint such as the knee or hip and is characterized by severe pain, tenderness, redness, swelling, and local warmth. There is marked restriction of movement. The joint space becomes filled with a purulent exudate. High fever, often with chills and a neutrophil leukocytosis, is present in most cases.
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Diagnosis & Treatment
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The diagnosis of pyogenic arthritis is made by clinical examination. Drainage of the joint forms part of the treatment and provides fluid for culture. Antibiotic therapy is usually effective. In untreated cases, infection spreads to the articular cartilage and adjacent bone, causing destruction and permanent disability. Life-threatening bacteremia develops rarely.
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Tuberculous Arthritis
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Tuberculous arthritis has become rare in developed countries. It occurs in adults by reactivation of a dormant tuberculous focus in the joint and is often the only manifestation of tuberculosis in the body.
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Tuberculous arthritis is characterized by involvement of a single large joint, most commonly the knee, hip, or wrist. The affected joint is swollen and painful, but other features of acute inflammation are not present. Diagnosis depends on culture of joint fluid or examination of a synovial biopsy specimen.
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Lyme Disease (Lyme Borreliosis)
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Lyme disease is an infection caused by Borrelia burgdorferi. It was first described in Lyme, Connecticut. It is now prevalent in the northeastern United States but has a worldwide distribution. The disease is transmitted by ixodid ticks that become infected by biting deer and mice, which are the common reservoirs of infection.
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Lyme disease is characterized by development of a distinctive papular skin rash (erythema migrans) at the site of inoculation 1–4 weeks after the tick bite. The rash lasts several months and may be associated with spirochetemia and systemic disease. Migratory acute arthritis is one of the most common manifestations of systemic disease and may be followed by chronic arthritis. The synovial membrane shows thickening, with a lymphocytic and histiocytic infiltrate. Organisms are present in the walls of small blood vessels, blood, and synovial fluid. Myocarditis and neurologic abnormalities may also occur.
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The diagnosis of Lyme disease is confirmed by serologic tests. Demonstration of the spirochete in blood or infected tissues is rarely successful. Treatment with penicillin or tetracycline is successful if started early in the acute phase and prevents chronic arthritis and other complications.
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Viral infection of joints has been described in patients with rubella and viral hepatitis, but the incidence is low. Viral arthritis is usually transient and resolves completely.
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Immunologic Diseases of Joints
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Rheumatoid arthritis is a chronic disease of unknown cause characterized by progressive and potentially deforming arthritis.
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Rheumatoid arthritis is common in the United States and Western Europe, affecting 1–2% of the population. Females are affected two to three times more frequently than males. The highest age incidence is between 30 and 50 years. Rheumatoid arthritis is less common in tropical countries.
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The exact cause of rheumatoid arthritis is unknown (Figure 68-1). A genetic predisposition is suggested by an increased incidence in families, a 30% concordance rate in identical twins compared with 5% in fraternal twins, and an association with human leukocyte antigen (HLA)-DR4 in affected white patients. Rheumatoid factor—an autoantibody (usually IgG)—is present in the plasma of about 90% of patients with rheumatoid arthritis, but its presence is not specific for the disorder because it is present in other autoimmune diseases and in 5% of healthy persons. Immune complexes composed of rheumatoid factor and IgG have been found in the synovial fluid of some patients with rheumatoid arthritis. Complement levels are also frequently decreased in active disease, suggesting that complement activation by deposited immune complexes may play a role.
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The synovial membrane of affected joints becomes swollen, congested, and thickened due to vasodilation and hyperplasia of lining synovial cells. This is followed by proliferation of granulation tissue containing numerous lymphocytes and plasma cells (this fleshy tissue is termed pannus). T helper lymphocytes represent the dominant cell type. Local production of interleukins, tumor necrosis factor, and other cytokines accounts for many features of synovitis. Neutrophils are scarce in the synovial tissue but abundant in synovial fluid.
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The pannus eventually erodes articular cartilage, subchondral bone, and periarticular ligaments and tendons. Progressive destruction of the joint follows, with fibrosis, increasing deformity, and restriction of movement. The mechanism of destruction of cartilage and bone is not known but is probably related to synthesis of collagenase and other proteases in the pannus.
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Rheumatoid arthritis typically presents with symmetric involvement of the small joints of the hands and feet—classically, the proximal interphalangeal joints (Figure 68-2). Involvement of larger joints is the initial manifestation in a minority of patients.
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Involved joints are swollen, painful, and stiff. Stiffness is maximal in the morning after the joint has been inactive during the night. The swollen joints are warm and tender, and movement is restricted. Swelling of the proximal interphalangeal joints of the fingers produces a typical spindled appearance of the fingers. Many patients have systemic symptoms such as low-grade fever, weakness, and malaise.
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Joint deformity occurs early in severe cases. Restriction of movement may cause rapid disuse atrophy of muscles around the joint.
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Extra-Articular Manifestations
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Rheumatoid arthritis is a systemic disorder. In a minority of patients, tissues other than joints show significant pathologic change (Table 68-2). Subcutaneous rheumatoid nodules are granulomas 1–2 cm in diameter seen commonly around the elbow, usually in patients with severe disease. They are characterized microscopically by an area of fibrinoid necrosis of collagen surrounded by palisading histiocytes (Figure 68-3).
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Rheumatoid arthritis is usually slowly progressive. In 10–20% of patients, the disease remits completely after the first attack. Most other patients develop a chronic disease characterized by relapses and remissions, with slowly progressive disability from joint destruction. After 10 years of disease, about 10% of patients are severely disabled while about 50% are still fully employed.
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Poor prognostic factors include a classic pattern of disease with high levels of rheumatoid factor in the serum, the presence of rheumatoid nodules, and onset of disease before age 30 years. In such patients, progress may be rapid.
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Variants of Rheumatoid Arthritis
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Felty's syndrome occurs in older individuals with long-standing rheumatoid arthritis and high titers of rheumatoid factor. It is characterized by splenic enlargement and neutropenia. Anemia and thrombocytopenia may also occur.
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Juvenile Rheumatoid Arthritis (Still's Disease)
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Still's disease is rheumatoid arthritis in a patient under 16 years of age. It is characterized by acute onset with high fever, leukocytosis, splenomegaly, arthritis, and skin rash. There may also be pericarditis and inflammation of the iris (uveitis). Rheumatoid factor is usually not present.
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Patients with Still's disease commonly have monarticular involvement, frequently of a large joint. Growth abnormalities may occur if the disease strikes before the age of epiphysial closure.
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Fifty percent of patients with Still's disease undergo complete remission. Others progress to severe joint disease with extra-articular manifestations.
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Degenerative Joint Diseases
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Ankylosing Spondylitis
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Ankylosing spondylitis is a common disease that predominantly affects young men (males:females 3:1), with the maximum age incidence being between 15 and 30 years of age. The disease has a very strong association with HLA-B27, which is present in the cells of 95% of patients with ankylosing spondylitis, as compared with 3–7% of the general population. One to 2 percent of all persons with HLA-B27 have the disease. The cause is unknown.
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Pathology & Clinical Features
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Ankylosing spondylitis maximally affects the sacroiliac joints. Chronic inflammation is associated with fibrosis and calcification, leading to bony fusion (ankylosis) of the joints.
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Low back pain and stiffness are the common presenting symptoms. Calcification of the vertebral joints and paravertebral ligaments produces a characteristic radiologic appearance (“bamboo spine”; Figure 68-4) and marked immobility of the lower back.
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Ankylosing spondylitis progresses slowly up the vertebral column. Involvement of the costovertebral joints and thoracic spine may result in restriction of chest expansion and rarely produces respiratory failure. Rheumatoid factor is typically absent.
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A similar condition affecting the sacroiliac joints and lumbar spine occurs in psoriasis, ulcerative colitis and Crohn's disease, and Reiter's syndrome, in which arthritis is associated with urethritis and conjunctivitis.
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Extra-Articular Manifestations
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Patients with ankylosing spondylitis may show degeneration of the wall of the aorta, with dilation and incompetence of the aortic valve. Aortic dissection and rupture may also occur. Twenty-five percent of patients have eye changes, most commonly iridocyclitis. Pulmonary fibrosis occurs in a few patients.
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Ankylosing spondylitis is a slowly progressive disease that causes increasing disability from pain and stiffness of the low back. Respiratory dysfunction and aortic disease represent life-threatening complications.
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Osteoarthrosis (Osteoarthritis)
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Osteoarthrosis is a common degenerative joint disease characterized by primary abnormalities in the articular cartilage. When assessed radiologically, changes of osteoarthrosis are present in over 40% of individuals over the age of 50 years of age. Although only a few of these patients are symptomatic, osteoarthrosis is the most common cause of joint disability.
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Osteoarthrosis is a disease of the elderly. When a younger individual develops osteoarthrosis, it is almost always secondary to a predisposing abnormality in the joint. Its clinical features are very different from those of rheumatoid arthritis (Table 68-3).
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Osteoarthrosis is also frequently called osteoarthritis. The latter is an inaccurate term because it implies the presence of joint inflammation, which is not present.
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Osteoarthrosis is caused by degeneration of articular cartilage of joints (Figure 68-5). The exact cause of articular cartilage degeneration is not known. Abnormalities in the ground substance, collagen, increased activity of matrix-degrading enzymes such as collagenase and proteoglycanases, and changes in water content have all been demonstrated in the articular cartilage in patients with osteoarthrosis, but their role in pathogenesis is unknown. The role of trauma and weight-bearing stresses is controversial. Osteoarthrosis occurs mainly in the weight-bearing joints, and it has been suggested that the disease may be the result of failure of repair of repeated minor trauma. A few cases of osteoarthrosis occur secondary to articular cartilage diseases (eg, alkaptonuria) and severe trauma (eg, in football players).
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The large weight-bearing joints of the vertebral column, hips, and knees are most affected, along with the distal interphalangeal joints of the fingers. The primary abnormality is thinning and fragmentation of the articular cartilage. The normally smooth, white articular surface becomes irregular and yellow. Continued loss of articular cartilage leads to exposure of subchondral bone, which appears as shiny foci on the articular surface (eburnation). Fibrosis, increased bone formation, and cystic change frequently occur in the underlying bone. The loss of articular cartilage stimulates new bone formation, usually in the form of nodules (osteophytes) at the bone edges. Inflammation is absent.
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There is pain, stiffness, and swelling of affected joints, with no evidence of acute inflammation. Crepitus is a characteristic feature—a grating sound produced by friction between adjacent areas of exposed subchondral bone.
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Osteophytes may be visible clinically—as bony masses such as those that occur over affected distal interphalangeal joints (Heberden's nodes)—or radiologically. They may cause compressive symptoms, most notably in spinal osteoarthrosis, in which nerve and spinal cord compression may occur.
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Osteoarthrosis is a slowly progressive, chronic joint disability. Eventually, elderly sufferers may become confined to wheelchairs; recent advancements in the technique of joint replacement with prostheses have improved the outlook of these patients considerably.
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Neuropathic Joint (Charcot's Joint)
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Neuropathic joint results from loss of sensory innervation to the joint, as occurs in peripheral neuropathy, tabes dorsalis, diabetic neuropathy, and syringomyelia. The lack of pain sensation deprives the joint of its normal protective muscle and postural responses when exposed to abnormal forces. Repeated trauma then leads to progressive destruction of the joint. Large joints such as the knees are usually involved. The affected joint is swollen, unstable, and frequently shows an abnormally increased range of motion resulting from destruction of intra-articular ligamentous restraints. The joint involvement is painless.
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Metabolic Diseases of Joints
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Alkaptonuria (Ochronosis)
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Alkaptonuria is a rare autosomal recessive disease in which there is a deficiency of homogentisic acid oxidase. This defect blocks tyrosine metabolism and causes homogentisic acid to be deposited in collagen (dermis, ligaments, tendons, endocardium, the intimal surfaces of blood vessels) and cartilage (nose, ear, larynx, tracheobronchial tree, intervertebral disks, and joint spaces). All of these areas become black and radiopaque. Homogentisic acid is excreted in the urine; the urine is colorless when passed but darkens on exposure to air. In infants, this results in a blackish discoloration of wet diapers. Alkaptonuria is now routinely detected by neonatal screening tests.
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The major clinical effect of alkaptonuria is degeneration of affected cartilages, resulting in juvenile osteoarthrosis.
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Gout (Gouty Arthritis)
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Gout represents a group of diseases whose main symptoms are due to deposition of urate crystals in connective tissues or uric acid nephrolithiasis. Urate deposition commonly occurs in diseases in which abnormal uric acid metabolism causes elevated plasma uric acid levels (hyperuricemia).
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Primary gout occurs mainly in elderly men and has a strong familial tendency. The basic abnormality in urate metabolism is not known. In one third of patients, there is an increase in production of uric acid due to increased breakdown of purines, which are synthesized in excessive amounts in the liver. Lack of regulation of 5-phosphoribosyl-1-pyrophosphate (PRPP) aminotransferase, which catalyzes the first step in purine synthesis, is believed to be responsible for increased purine synthesis.
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In another one third of patients with primary gout, decreased renal clearance of uric acid is the major factor causing hyperuricemia.
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In the remaining third of patients, hyperuricemia results from a combination of increased urate production and decreased urate excretion in the kidneys. Two rare X-linked diseases—deficiency of hypoxanthine guanine phosphoribosyl transferase and overactivity of PRPP synthesis—are associated with hyperuricemia and gout.
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Secondary gout occurs in diseases in which excess breakdown of purines leads to increased uric acid synthesis. It is most commonly seen in patients with leukemia—particularly at the start of treatment, when there is marked cell necrosis, releasing nucleic acids that are catabolized to uric acid.
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Effects of Urate Deposition
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Two forms of sodium urate crystals may be deposited and produce two clinically distinct types of gout.
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Acute gouty arthritis is caused by deposition of microcrystals of sodium urate in the synovial membranes of joints. For some unknown reason, the first metatarsophalangeal joint (big toe) is affected in 85% of cases. Urate microcrystals activate kinins, are chemotactic for neutrophils, and produce an intense acute inflammation. The urate microcrystals can be recognized in joint fluid as birefringent needle-shaped crystals under polarized light.
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Chronic tophaceous gout is the result of deposition of sodium urate as large amorphous masses known as tophi. These evoke chronic—not acute—inflammation. Tophi occur commonly in the cartilage of the ear and around joints (Figure 68-6). Marked deformity may result. Gouty tophi appear microscopically as pale-pink to brown amorphous masses surrounded by a foreign-body-type granulomatous reaction (Figure 68-7). Fixation in absolute alcohol followed by examination under polarized light permits identification of urate in tissue sections.
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Calcium Pyrophosphate Deposition Disease (Chondrocalcinosis; Pseudogout)
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Calcium pyrophosphate deposition disease is a degenerative joint disease characterized by deposition of calcium pyrophosphate in the joints. The cause is not known. Most cases occur in elderly patients and involve the knee joints after trauma or surgery. Clinically, calcium pyrophosphate deposition is characterized by an acute arthritis involving one or many joints, most commonly the large joints of the lower extremity. The metatarsophalangeal joint is usually not affected. The arthritis is self-limited, lasting 1–4 weeks. The synovial fluid contains numerous leukocytes and calcium pyrophosphate crystals, which are short and rhomboid and can be distinguished from the longer, needle-shaped urate crystals by their polarization characteristics.
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Neoplasms & Nonneoplastic Tumors of Joints
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Pigmented Villonodular Synovitis
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Pigmented villonodular synovitis is an uncommon disease characterized by proliferation of the synovial membrane of joints. It occurs in adults and most commonly involves the knee joint. Clinically, there is pain, swelling, and progressively increasing joint disability.
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The cause is unknown. It is believed that the lesion is inflammatory, although its histologic resemblance to giant cell tumor of tendon sheath has led to the suggestion that it is a benign neoplastic process.
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Grossly, the synovial membrane is thickened and shows villous outgrowths that have a typical orange-brown color due to the presence of hemosiderin. Microscopically, the villi consist of proliferating synovial epithelial cells, lymphocytes, plasma cells, and histiocytes, many of which appear foamy and contain lipid and hemosiderin. Multinucleated giant cells are frequently present.
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Surgical or arthroscopic removal of the abnormal synovium is effective treatment. Local recurrence may occur, probably due to incomplete surgical removal.
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Synovial Chondromatosis
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Synovial chondromatosis is an uncommon condition of unknown cause characterized by the occurrence of multiple foci of cartilaginous metaplasia in the synovial membrane. The cartilage appears as nodules that may undergo ossification and may become detached into the joint cavity as loose bodies. The knee is commonly affected, with symptoms of pain, swelling, limitation of movement, and intermittent locking. Osteoarthrosis may result.
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Ganglion is a common cystic lesion arising in the connective tissue of the joint capsule or in a tendon sheath. It most commonly occurs around the wrist. Microscopically, a ganglion is a cystic structure filled with myxomatous tissue and lined by collagen. It has no epithelial lining and is distinct from a synovial cyst.
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Except for producing a lump, ganglions are of no significance clinically.
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Giant Cell Tumor of Tendon Sheath
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Giant cell tumor of a tendon sheath is the only common benign neoplasm that involves the synovium. It occurs either inside the joint—usually the knee—or in relation to the tendon sheaths in the hands and feet. There is some controversy about whether giant cell tumor is a true neoplasm or whether it is inflammatory (nodular synovitis). The lesion presents as a mass that may become large and cause erosion of adjacent bone. Histologically, there is an admixture of foamy macrophages, multinucleated giant cells, and fibroblasts (benign fibrous histiocytoma is an alternative name).
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Treatment is by surgical removal, which is curative.
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Synovial sarcoma is a rare malignant neoplasm arising from synovial epithelial cells. Chromosomal translocations (X,18 and p11,q11) have been reported. Synovial sarcomas occur much more commonly in relation to bursae and tendon sheaths than within joints. They therefore tend to present as extra-articular soft tissue masses, most commonly near a joint in the extremities. Microscopically, they are highly cellular neoplasms with a biphasic pattern composed of spindle cells and epithelium-lined slit-like spaces resembling synovium. The cells contain keratin intermediate filaments in addition to vimentin, a point of distinction from other soft tissue sarcomas. Synovial sarcomas are high-grade malignant neoplasms with a high rate of local recurrence as well as metastasis. They have a 5-year survival rate of about 50% after optimal treatment.
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Autoimmune Connective Tissue Diseases (Collagen Diseases)
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Autoimmune connective tissue diseases (also called collagen diseases) are a group of diseases characterized by (1) involvement of multiple tissues; (2) evidence for an autoimmune cause; (3) the presence of abnormal antibodies in the serum (Table 68-4); and (4) inflammation of small blood vessels (vasculitis), frequently with fibrinoid necrosis of the wall.
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Autoimmune connective tissue diseases include lupus erythematosus, progressive systemic sclerosis, mixed connective tissue disease, and polymyositis-dermatomyositis. Polyarteritis nodosa (see Chapter 20: The Blood Vessels), rheumatoid arthritis, and rheumatic fever (Chapter 22: The Heart: II. Endocardium & Cardiac Valves) also have some features of connective tissue diseases and are sometimes included within this category.
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Lupus erythematosus is a connective tissue disease that exists in two clinical forms: (1) systemic lupus erythematosus (SLE), which is a progressive and often severe condition involving multiple systems; and (2) discoid lupus erythematosus, in which skin involvement dominates the clinical picture, usually without systemic disease.
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SLE is common in the United States, more so in nonwhites (particularly blacks) than whites. The disease is also common in Western Europe but less so in Asia.
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Women are affected ten times more frequently than men. The usual age at onset of disease is 20–40 years.
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The cause of lupus erythematosus is unknown (Figure 68-8). There is little doubt that it is mediated by an abnormal immune response associated with the presence of a variety of antibodies and immune complexes in the plasma that are responsible for the pathologic effects seen in lupus erythematosus. The cause of this response is widely believed to be autoimmune, although there is evidence for viral and genetic influences.
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There is considerable evidence that SLE is a type III autohypersensitivity (autoimmune) disease. The formation of antinuclear antibodies (ANA) is important in pathogenesis. A variety of antinuclear antibodies are present in the serum of all patients with systemic lupus erythematosus and are tested for and characterized by immunologic techniques (Table 68-4). The presence of antibody against double-stranded deoxyribonucleic acid (DNA) is highly specific for lupus erythematosus, while antibodies against single-stranded DNA, ribonucleic acid (RNA), and nucleoproteins are also found in other connective tissue diseases.
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Immune complexes formed between antinuclear antibodies and nuclear antigens are detectable in the serum and at sites of disease activity in the walls of small blood vessels, the skin, and glomerular basement membrane. Deposition of immune complexes in the tissue (Figure 68-8) activates complement and leads to inflammation by a type III hypersensitivity reaction. Serum complement levels are frequently reduced in the active phase of SLE.
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Numerous autoantibodies other than antinuclear antibodies are also found in SLE. These include (1) rheumatoid factor (20–30%); (2) antibodies that give a false-positive reaction in serologic tests for syphilis; (3) antibodies against plasma coagulation proteins, most commonly factor VIII, producing bleeding diathesis; and (4) antibodies against antigens on erythrocytes, leukocytes, and platelets, which may lead to immune destruction of these cells in the peripheral circulation.
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SLE is known to be precipitated by drugs such as hydralazine (an antihypertensive) and procainamide (used to control cardiac arrhythmias). Drug-induced disease may be similar to idiopathic SLE, including the presence of antinuclear antibodies, but renal disease is rare. Withdrawal of the drug often causes reversal of the disease and gradual disappearance of the antinuclear antibodies.
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Infectious agents—mainly viruses—have been suggested as causing lupus erythematosus, but no infectious agent has been isolated consistently from patients' tissues.
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Genetic predisposition to SLE has been suggested because of the high concordance of clinical SLE in monozygotic twins and the increased frequency of the disease in first-degree relatives. HLA-DR2 is more common in SLE, leading to the suggestion that the presence of the corresponding immune response gene may predispose to the development of autoreactivity against nuclear antigens. The occurrence of SLE in patients with inherited deficiency of early complement factors (C1, C2, and C4) is also of interest because the genes for C2 and C4 are known to be closely linked to the HLA-DR region.
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Pathology & Clinical Features
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Pathologic and clinical features of the disease are dependent on which antibodies and immune complexes are present and what their target tissues are. Sites of immune complex deposition show evidence of complement-mediated tissue necrosis and acute inflammation. The presenting features are quite diverse (Table 68-5).
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Small Vessel Vasculitis
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Immune complex injury of arterioles is typical, with fibrinoid necrosis of the media and infiltration of the wall and perivascular tissue by neutrophils, lymphocytes, and plasma cells. Thrombosis is common and may lead to ischemia and tissue necrosis. In the skin, there may be digital gangrene and ulceration; and in the gastrointestinal tract, diarrhea, bleeding, intestinal obstruction, and perforation. These vascular changes progress to intimal fibrosis, with a characteristic laminated (onion skin) appearance.
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Hyperplasia of the Lymphoid System
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Enlargement of lymph nodes or spleen occurs in 50% of patients with SLE. This is due to nonspecific follicular and paracortical lymphocytic proliferation.
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Immune complex deposition occurs in the basement membrane of the skin, where it can be perceived as lumpy deposits by electron microscopic and immunologic techniques. The resulting complement activation and inflammation lead to a skin rash, typically over the malar regions of the face (butterfly rash). Skin biopsy of lesions shows epidermal atrophy, hyperkeratosis, vacuolar degeneration of the basal layer, and a patchy dermal perivascular lymphocytic infiltrate. Skin rash occurs some time in the course of the disease in 70% of cases.
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In patients with discoid lupus erythematosus, the skin lesion is the sole abnormality. In discoid lupus, immune complex deposition is restricted to the area of the rash; in systemic lupus, immune complex deposition is widespread even in clinically normal skin.
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Joint inflammation (arthritis) or pain (arthralgia) occurs in 90% of patients with SLE. Both large and small joints may be involved, and initial involvement may resemble rheumatoid arthritis. Joint involvement in SLE is usually mild.
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Cardiac lesions in patients with systemic lupus erythematosus include pericarditis with effusion, myocarditis, and Libman-Sachs endocarditis (see Chapter 22: The Heart: II. Endocardium & Cardiac Valves). These complications are usually not serious.
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Clinical manifestations due to central nervous system vasculitis and ischemia occur in 25% of patients. Convulsions, mental disorders (emotional lability, dementia, psychosis), cranial nerve palsies, and spinal cord dysfunction may result. The cerebrospinal fluid in such patients often shows moderately increased protein levels and a mild increase in lymphocytes.
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Renal involvement occurs in approximately two thirds of patients and represents the most common mode of death in SLE. Renal lesions are due to immune complex deposition (see Chapter 48: The Kidney: II. Glomerular Diseases), producing proliferative and membranous types of glomerulonephritis.
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The diagnosis of lupus erythematosus is based on its clinical features and confirmed by demonstration of serum antinuclear antibodies (ANA), particularly anti-double-stranded DNA. The absence of ANA virtually rules out a diagnosis of SLE because less than 5% of patients with SLE are ANA-negative (Table 68-4). Histologic examination of tissues such as the skin and kidney does not provide specific evidence of the disease but in combination with clinical features often leads to the diagnosis.
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The course of SLE is variable. Rarely, patients have a severe acute illness that is refractory to treatment. Most patients pursue a chronic course, with repeated exacerbations and remissions. Corticosteroid therapy is usually effective in controlling exacerbations, and with such therapy the survival rate is approximately 90% at 10 years.
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Most deaths are due to renal failure followed by central nervous system disease. The complications of immunosuppressive drug therapy also account for significant morbidity and many deaths.
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Patients with discoid lupus erythematosus have a chronic skin disorder. There is little danger of death unless systemic symptoms supervene (about 10% of patients develop SLE).
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Progressive Systemic Sclerosis
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Progressive systemic sclerosis (previously called scleroderma) is an uncommon connective tissue disease characterized by vasculitis affecting small vessels and widespread deposition of collagen.
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Progressive systemic sclerosis occurs more commonly in females and has its onset most frequently in the ages from 20 to 50 years.
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Progressive systemic sclerosis is probably an autoimmune disorder and is closely related to SLE. Antinuclear antibodies are usually present in the serum. The most characteristic antinuclear antibody for progressive systemic sclerosis has specificity against nucleolar RNA. Deposition of immune complexes in tissues has been demonstrated in renal and vascular lesions.
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The mechanism underlying the excessive fibrosis is unknown.
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The pathologic changes in affected tissue include vasculitis, which is identical histologically with that seen in systemic lupus erythematosus; it tends to be more chronic. Marked fibrosis dominates the histologic appearance.
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Progressive systemic sclerosis usually has an insidious onset. Systemic symptoms are uncommon. In many patients, the disease is restricted to the skin for many years before visceral involvement occurs.
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(Affected in 90% of cases.) The skin of the fingers and face is the most common first site of disease. Initially, the skin is edematous, with vasculitis and often petechial hemorrhages. Progressive fibrosis follows, involving the entire dermis and extending to the subcutaneous tissue. The epidermis becomes thin, and all adnexal structures (hair, sweat glands, etc) undergo atrophy. Enlarged vessels are frequently present and visible as telangiectases. Trophic ulceration of the skin is common, and dystrophic calcification may occur.
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Severe skin changes lead to claw-like contracted hands and restriction of facial movements (Figure 68-9).
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Gastrointestinal Tract
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(60% of cases.) The entire gastrointestinal tract may be affected, with the esophagus and small intestine showing maximal disease. Dysphagia, deficient peristalsis, and malabsorption follow. CREST syndrome is a variant of progressive systemic sclerosis consisting of calcinosis, Raynaud's phenomenon, esophageal disease, sclerodactyly (involvement of the fingers), and telangiectasia. An autoantibody to centromeres is commonly present.
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(60% of cases.) Glomerular changes result from immune complex deposition and include basement membrane thickening and mesangial hypercellularity. Small arterioles in the kidney frequently show intimal fibrosis, leading to glomerular ischemia, decreased glomerular filtration rate, and renal failure (Chapter 48: The Kidney: II. Glomerular Diseases).
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(20% of cases.) Pulmonary involvement in progressive systemic sclerosis takes the form of a diffuse interstitial pneumonitis and fibrosis identical to that seen in idiopathic pulmonary fibrosis (see Chapter 35: The Lung: II. Toxic, Immunologic, & Vascular Diseases). The end stage is a honeycomb lung with respiratory failure.
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The clinical course is usually chronic. The occurrence of symptomatic visceral disease (especially renal disease) is an ominous sign. Treatment with immunosuppressive drugs is of limited value.
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Polymyositis-Dermatomyositis
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Polymyositis-dermatomyositis is an uncommon connective tissue disease affecting women twice as frequently as men. Onset of disease is maximal between the ages of 40 and 60 years.
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The cause is unknown. An immunologic basis is likely, although the exact mechanism is not clear. Antinuclear antibodies occur in the serum of most patients, and immune complex deposition with complement activation can be demonstrated in many cases of dermatomyositis. Cell-mediated autohypersensitivity has also been implicated.
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Patients with polymyositis-dermatomyositis—particularly those over 60 years of age—are at increased risk for malignant neoplasms. Carcinoma of the lung is the most common, but carcinoma of the breast, kidney, stomach, and uterus also occur. The incidence of cancer in patients with dermatomyositis is around 8%. The basis of the relationship between polymyositis-dermatomyositis and malignant neoplasms is unknown.
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Pathology & Clinical Features
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Polymyositis-dermatomyositis is a chronic disease that affects skeletal muscle in all cases and skin in 50% of cases. Visceral involvement is uncommon.
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Skeletal muscle is involved in all cases. The proximal muscles of the limb girdles are commonly the first affected, with involvement of pharyngeal and respiratory muscles in severe cases.
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In the acute phase, affected muscles show edema, lymphocytic infiltration, myofibrillary necrosis, and phagocytosis of dead muscle. This is followed by muscle atrophy and fibrosis. Clinically, there is muscle weakness associated with pain and tenderness, with the latter feature useful in distinguishing polymyositis from muscular dystrophies. During the acute phase, serum creatine kinase and aldolase levels are greatly elevated, and creatinuria may be present when there is severe muscle necrosis.
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Muscle biopsy, demonstrating inflammatory changes, permits distinction from muscular dystrophy and other causes of myositis (see Chapter 66: The Peripheral Nerves & Skeletal Muscle).
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(50% of cases.) Skin changes are caused by vasculitis and typically take the form of a violaceous edematous rash (heliotrope rash) involving the upper eyelids, sometimes extending to the malar region of the face and neck. Dermal atrophy and calcification occur in the later stages. In 30% of patients, skin changes are associated with Raynaud's phenomenon.
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Polymyositis-dermatomyositis has a chronic course characterized by increasing disability from muscle wasting. The main danger of the disease is from the associated malignant neoplasms.
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Mixed Connective Tissue Disease
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mixed connective tissue disease (MCTD) is an uncommon disease with clinical features that overlap with one or more of the other connective tissue diseases: systemic lupus erythematosus, progressive systemic sclerosis, and polymyositis (overlap syndrome).
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Mixed connective tissue disease is characterized by the presence in the serum of a high titer of antibodies against ribonucleoprotein (Table 68-4).
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Mixed connective tissue disease should be distinguished from SLE because it tends to run a more benign course, mainly due to a lesser frequency of renal involvement.
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Soft Tissue Neoplasms
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Soft tissue neoplasms arise from any of the cells present in extraskeletal connective tissue, including fibroblasts, adipocytes, neural derivatives, vascular endothelium, smooth muscle of vessel walls, skeletal muscle, and other mesenchymal cells (Table 68-6). Neoplasms of blood vessels (see Chapter 20: The Blood Vessels), nerves (Chapter 66: The Peripheral Nerves & Skeletal Muscle), and skeletal muscle (Chapter 66: The Peripheral Nerves & Skeletal Muscle) have been considered elsewhere.
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Benign soft tissue neoplasms are very common. Lipomas and hemangiomas are among the most common neoplasms occurring in humans. Malignant soft tissue neoplasms are rare.
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Soft tissue neoplasms occur in almost any tissue of the body. They are most commonly found in the extremities and retroperitoneum. Based on their biologic behavior, soft tissue neoplasms may be classified into 3 broad pathologic subgroups. The criteria for placing a given neoplasm in one of these subgroups varies with the cell of origin of the neoplasm.
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Benign Soft Tissue Neoplasms
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Benign soft tissue neoplasms appear as well-circumscribed encapsulated nodular masses that closely resemble the tissue of origin. Lipoma, for example, appears as a mass of mature adipose tissue distinguishable as a neoplasm only because it forms a mass and is encapsulated. Local excision is curative.
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Rarely, neurofibromas and lipomas occur in families, with inheritance as an autosomal dominant trait. Generalized neurofibromatosis (von Recklinghausen's disease), which is characterized by the occurrence of multiple neurofibromas throughout the body, is discussed in Chapter 62: The Central Nervous System: I. Structure & Function; Congenital Diseases. Generalized lipomatosis (Dercum's disease) is rare and characterized by multiple lipomas, mainly subcutaneous. In these conditions, the neoplasms are usually too numerous to be removed surgically and can present a significant cosmetic problem. The benign neoplasms may rarely undergo malignant transformation into sarcomas; in neurofibromatosis, 5–10% of affected patients develop malignant neoplasms.
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Locally Aggressive Soft Tissue Neoplasms
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Locally aggressive soft tissue neoplasms are intermediate in behavior between benign and malignant. They are locally infiltrative and tend to recur after surgical excision but rarely metastasize.
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The best examples of this group are the fibromatoses (desmoid tumors), occurring in skeletal muscle. The commonest site is the rectus abdominis muscle, especially in women after pregnancy. Fibromatoses are slowly growing neoplasms that form large masses with extensive local infiltration along fascial planes. Unless excised with an adequately wide margin, the tumor recurs locally, often after several years, and considerable local destruction may ensue. Fibromatoses, despite their locally aggressive behavior, do not metastasize and in this way differ from sarcomas.
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Malignant Soft Tissue Neoplasms (Sarcomas)
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Sarcomas are malignant neoplasms derived from mesenchymal cells, subclassified according to the cell of origin. They are generally much less common than carcinomas. The most common types of sarcomas are malignant fibrous histiocytoma and liposarcoma. Rhabdomyosarcoma, leiomyosarcoma, fibrosarcoma, malignant neural neoplasms, and angiosarcoma are rare. Sarcomas usually present as a soft tissue mass, often of large size (Figure 68-10). The extremities and retroperitoneum are the most common sites.
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The biologic behavior of sarcomas is extremely variable.
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High-grade sarcomas are highly cellular neoplasms composed of poorly differentiated mesenchymal cells. They show marked nuclear abnormalities and have a high rate of mitotic figures. Because of their anaplasia, high-grade sarcomas are sometimes difficult to classify. The presence of lipoblasts (liposarcoma), cross-striations (rhabdomyosarcoma), or abnormal vascular channels (angiosarcoma) may be of help. Recognition of the cell of origin is sometimes possible by immunohistologic techniques, demonstrating factor VIII antigen (angiosarcoma) or myoglobulin, desmin, and actin (myosarcomas) or keratin (synovial sarcoma). Electron microscopy is also of value in identifying the striated muscle, lipoblastic, or Schwann-cell origin of an anaplastic sarcoma. High-grade sarcomas grow rapidly, show extensive local invasion, and tend to metastasize early through the bloodstream. Lymphatic spread is uncommon. High-grade sarcomas are usually fatal, and treatment is rarely successful.
Low-grade sarcomas are better differentiated, less cellular, and tend to resemble the tissue of origin to some extent. Cytologic abnormalities are less prominent, and the mitotic rate is usually low. These tumors are characterized by a slower growth rate, a high risk of local recurrence after surgical removal, and a relatively low risk of metastasis. Patients typically survive a long time with repeated local recurrences after surgery. The behavior of low-grade sarcomas is similar to that of locally aggressive soft tissue neoplasms.
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Recognition that a given soft tissue mass may be malignant is extremely important. Simple excision of a sarcoma invariably leaves neoplastic cells behind and makes local recurrence certain. Sarcomas should be treated initially by incisional biopsy for pathologic diagnosis, followed by excision with a wide margin of normal appearing tissue. Pathologic examination of the surgical margins at the time of surgery is advisable to ensure that the microscopic limit of the neoplasm has been reached in the excision.
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Chemotherapy and radiotherapy are of limited value except for local control of recurrences. Recently, the use of preoperative intra-arterial chemotherapy, infusing the agent into the area via the artery of supply, has proved to be of some benefit.