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Rheumatic Manifestations of Hemoglobinopathies
CHAPTER 120
Rheumatic Manifestations of Hemoglobinopathies Carlos J. Lozada • Elaine C. Tozman KEY POINTS Hemoglobinopathies are inherited diseases caused by mutations in globin genes. Thalassemias are inherited defects in globin chain synthesis resulting in hypochromia and microcytosis. Skeletal changes in thalassemias can result in cortical thinning, osteoporosis, and vertebral compression fractures. Sickle cell disease is a single gene disorder caused by homozygous inheritance for sickle cell hemoglobin. Vaso-occlusive crises of bone occur in people with sickle cell disease and result in severe pain at the site of bony infarction, typically of long bones. The index of suspicion for septic arthritis should be high in patients with sickle cell disease who present with fever and joint pain. Hyperuricemia can be seen in people with sickle cell disease and thalassemias, but gout is uncommon.
Hemoglobin (Hb) has a tetrameric structure consisting of two pairs of α-globin and two non–α-globin polypeptide chains, each associated with a heme group. The interaction of these chains is responsible for the quaternary structure of the Hb molecule and its normal function. The fundamental role of Hb is oxygen transport. Hemoglobinopathies are inherited diseases caused by mutations in globin genes. Abnormalities in Hb can alter red blood cell shape, deformability, and viscosity. Approximately 1000 mutations have been described1; however, most are not associated with clinical disease. The gene mutations that result in sickle cell disease and thalassemia syndromes cause diseases that often involve the musculoskeletal system and will be discussed in this chapter.
THALASSEMIAS The term thalassemia is derived from a Greek term that roughly means “the sea” (Mediterranean) in the blood and was used to describe anemias in people from Italy and Greece. The term is now used to refer to inherited defects in globin chain biosynthesis.2 Individual syndromes are named according to the globin chain whose synthesis is adversely affected. For example, α-globin chains are absent or reduced in patients with α-thalassemia; β-globin chains are absent or reduced in patients with β-thalassemia; δ- and β-globin chains are absent or reduced in patients with 2018
δβ-thalassemia; and so on. Thalassemias are inherited as pathologic alleles of one or more of the globin genes located on chromosomes 11 and 16 and range from total deletion or rearrangement of the loci to point mutations that impair transcription, processing, or translation of globin messenger RNA. As a consequence of reduced globin chain production, a reduction of functioning Hb tetramers occurs. Hypochromia and microcytosis are found in all patients with thalassemia. In the milder forms of the disease, these changes may be barely detectable. Impaired globin synthesis leads to an imbalance of the individual α- and β-subunits. Free or “unpaired” α-, β-, and γ-globin chains are either highly insoluble or form homotetramers (Hb H and Hb Bart’s) that cannot release oxygen normally or are relatively unstable and precipitate as the cell ages. Excess α-globin chains, for example, continue to accumulate and precipitate in individuals with β-thalassemia. Unpaired subunits are the major sources of morbidity and mortality (Tables 120-1 and 120-2). Thalassemias have been encountered in virtually every ethnic group and geographic location, but they are most common in the Mediterranean basin and tropical or subtropical regions of Asia and Africa. The “thalassemia belt” extends from the Mediterranean across the Arabian Peninsula and through Turkey, Iran, and India to southeastern Asia and southern China. The prevalence of thalassemia in these regions ranges from 2.5% to 15%. As with sickle cell anemia, thalassemia is most common in areas affected by endemic malaria. Malaria infection in thalassemia heterozygotes results in milder disease and confers a selective advantage on reproductive fitness. The gene frequency of thalassemia has become fixed and is high in populations exposed to malaria over many centuries.
SICKLE CELL ANEMIA AND RELATED DISORDERS Sickle cell anemia is a single gene disorder caused by homozygous inheritance for sickle Hb (Hb S). Hb S is identical to normal Hb (Hb A) except for the replacement of glutamic acid, the sixth amino acid in β-globin, with valine. Hb S is capable of carrying oxygen, but once the oxygen is released, the Hb joins with other Hb S molecules to form rigid rods that bend the normally flexible, disk-shaped red blood cells into distorted narrow crescents. The sickled cells impede blood flow when they stick to the walls of blood vessels and to other blood cells. About 10% of black Americans are heterozygotes—that is, they inherit a sickle globin
CHAPTER 120 Rheumatic Manifestations of Hemoglobinopathies
TABLE 120-1 α-Thalassemias No. of Missing α Genes
Clinical Presentation
1
Silent carrier
No overt manifestations
2
Thalassemia trait
Hypochromic, microcytic with mild anemia
3
Hemoglobin H disease
Hypochromic, microcytic with hemolytic anemia, hepatosplenomegaly, and jaundice
4
Hydrops fetalis syndrome (hemoglobin Bart’s)
Severe anemia, ascites, edema, hepatosplenomegaly, cardiovascular and skeletal malformations; death in utero
TABLE 120-2 β-Thalassemia No. of Affected Genes
Clinical Presentation
1
β-thalassemia minor
Heterozygous, asymptomatic, silent carrier
2
β-thalassemia trait
Mild anemia
3
β-thalassemia intermedia
Mild anemia, typically diagnosed in late childhood
4
β-thalassemia major
Homozygous, severe anemia, extramedullary hematopoiesis, hepatosplenomegaly, skull changes, iron overload from transfusions
gene from one parent and a normal gene from the other parent and have sickle cell trait. They have no significant clinical problems unless they are subjected to marked dehydration or hypoxia.3 Rarely these individuals experience splenic infarction, stroke, or sudden death after strenuous physical activity, particularly at a high altitude. Individuals with sickle cell trait may have impaired ability to form concentrated urine (hyposthenuria), and a few have episodes of painless hematuria as a result of medullary infarction. Other internal organ damage is extremely uncommon, and heterozygotes have a normal life expectancy. One-fourth of the children of parents with sickle trait will be homozygotes and have red blood cells containing primarily Hb S and no Hb A. These individuals have severe hemolytic anemia and episodes of vaso-occlusion that cause acute bouts of pain and progressive organ damage. A similar clinical phenotype is encountered in individuals who are compound heterozygotes—that is, those who inherit the sickle gene from one parent and, from the other parent, either a β-thalassemia gene or a gene that encodes Hb C, another β-globin structural mutant. Patients with S/β0 thalassemia1 are unable to make any Hb A and are as severely affected as those with Hb SS disease. In contrast, patients with Hb S/β+-thalassemia or with Hb SC disease have less morbidity and a longer life span. The hallmark of sickle cell disease is the vaso-occlusive pain crisis,4 which is the most common clinical manifestation but can occur with varying frequency in different individuals. It results from the complex interplay between
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sickled red blood cells, neutrophils, endothelium, and plasma factors. The result is tissue hypoxia, leading to tissue death and associated pain. Episodes may be precipitated by dehydration, infection, and cold weather, although in half of the cases, no precipitating factor is found. Repeated splenic infarctions in childhood result in “autosplenectomy” and loss of splenic function by age 6 to 8 years in approximately one-half of patients.5
DIAGNOSIS OF HEMOGLOBINOPATHIES One in 12 African-Americans has sickle-cell trait, one in 40 carries Hb C, and one in 40 carries the trait for β-thalassemia.6 Latin Americans are an underappreciated population affected by sickle cell disease.7 For example, it is estimated that 30,000 people in Brazil have sickle cell disease. African and African-American patients are at increased risk of carrying Hb S and other hemoglobinopathies and should be offered preconception or prenatal screening. Hb S is also more common among individuals of Mediterranean, Middle Eastern, and Asian Indian descent. The American College of Obstetricians and Gynecologists recommends that patients at risk for having a child with hemoglobinopathy be offered prenatal genetic counseling and a variety of tests to document the Hb abnormality.8 In the United Kingdom, the Royal College of Obstetricians and Gynaecologists provides clinical guidelines for the management of sickle cell disease in pregnancy and standards of care from both hematology and the sickle cell community.9 Prenatal diagnosis can be performed with either chorionic villus sampling or amniocentesis. Because detection of α-thalassemia or α-thalassemia trait is based on molecular genetic testing and is not detectable using Hb electrophoresis, routine carrier screening is not offered. If microcytic anemia is present in the absence of iron deficiency and the Hb electrophoresis is normal, then testing for α-thalassemia should be considered, particularly among individuals of Southeast Asian descent. Sickle cell anemia can be accurately diagnosed with highperformance liquid chromatography and isoelectric focusing. Rapid methods such as solubility testing and sickling of red blood cells using sodium metabisulfite are less reliable tests. These tests are suitable for large field studies because they require only a drop of blood and use stable reagents, but they do not distinguish between homozygotes and heterozygotes. Newborn screening is mandatory in most of the United States and is well established, although not mandatory, for both sickle cell disease and thalassemias in the United Kingdom. Such screening tests vary in other areas of the world and may not be performed.7 Polymerase chain reaction is the method of choice for prenatal diagnosis.
TREATMENT Hydroxycarbamide (hydroxyurea) is the only drug approved by the U.S. Food and Drug Administration to treat sickle cell disease. It can reduce the number of painful episodes and hospitalizations, but only about two-thirds of adult patients have a response to this drug.10 Bone-marrow transplants can provide a cure because they replace the faulty hematopoietic stem cells that produce sickle cells with ones that make healthy red blood cells.11
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However, transplants are expensive, not widely available, and have associated risks such as infections and lifethreatening immune-system reactions. Gene therapy is another potentially successful treatment for sickle cell disease.12 Conventional gene therapy, also known as gene addition, typically involves inserting new genes. Usually, a harmless virus is modified with the gene to be inserted, and this “viral vector” is mixed with cells from the patient in vitro. The virus searches out the cells and inserts the gene into the cells’ DNA, after which the cells are transplanted into the patient. Gene editing is more specific when the faulty DNA sequence is removed and a piece of laboratory-created DNA is inserted. In both approaches, the modified DNA dictates the formation of a normal, working protein. A team led by Alan Flake at the Children’s Center for Fetal Research at the Children’s Hospital of Philadelphia has successfully treated sickle-cell disease in utero in mice and dogs, and trials in monkeys are under way.13 Stem cells from the mother are collected and injected into the bloodstream of the fetus. No destruction of the fetal immune system is required, because the fetal and maternal immune systems are naturally tolerant of one another.
MUSCULOSKELETAL INVOLVEMENT: SICKLE CELL DISEASE Vaso-Occlusive Crisis of Bone Bone involvement in patients with sickle cell disease is the most common clinical manifestation of the disease, both as an acute process and as a chronic symptom14 (Table 120-3). Painful osteoarticular crisis was the most common reason for emergency care of children with sickle cell disease in an African population (58.6%).15 All patients experience painful vaso-occlusive crises, which usually begin in late infancy and continue throughout life. Patients typically report pain in the chest, low back, and extremities. Abdom-
inal pain may mimic acute abdomen of other causes. Fever is often present, even in the absence of infection. Although microvascular occlusion can occur in any organ, it is common in tissues with low blood flow, such as the bone marrow, where deoxygenation and polymerization of Hb S leads to bone thrombosis, infarction, and necrosis. Spinal cord infarction can occur.16 The medullary cavity or the epiphysis of the bone is affected. Patients have severe pain in one or more areas of their bones, with tenderness, erythema, and swelling of the infarcted bone. Generalized symptoms of fever and leukocytosis occur, and most patients recover without sequelae (Figure 120-1). When infarction involves the vertebral body, collapse and a fish mouth deformity can result.17 Bone infarctions can occur in any bone, with a predilection for long bones. The most common sites are the tibia/fibula (30%), the femur (25%), and the radius, ulna, and humerus (21%).18 MRI is sensitive in detecting bone and bone marrow infarction, but this technology is not useful in distinguishing acute infarction from osteomyelitis.19
Dactylitis In young children, in the range of 1 to 2 years of age and younger than 7 years, vaso-occlusion manifests in the bone marrow of the small bones of the hands and feet and dactylitis occurs.20 Dactylitis is also called hand-foot syndrome. Patients have painful swellings of one or more digits (Figure 120-2) as extensive infarction of the marrow, medullary trabeculae, and inner layer of cortical bone occur.
TABLE 120-3 Bone and Joint Involvement in Sickle Cell Disease Vaso-occlusive crisis of bone Dactylitis Osteomyelitis Acute synovitis Septic arthritis Growth disturbance Osteopenia, osteoporosis Osteonecrosis Stress fracture Orbital compression Dental complications Vertebral collapse Sickle cell arthropathy Diffuse chondrolytic arthritis Gouty arthritis
Figure 120-1 Bony infarcts in the femur of a patient with sickle cell disease. (From The Radiology Assistant.)
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Figure 120-2 Hand of a child with sickle cell disease. (Courtesy Larry B. Mellick. From https://www.youtube.com/watch?v=AChPlzPEA7Y.)
Subperiosteal new bone formation follows, and as the episode resolves within 2 weeks, radiographs show a “motheaten” appearance of the involved digits (Figure 120-3). Rarely, involvement of the epiphysis causes premature fusion and shortened digits.
Osteomyelitis Patients with sickle cell disease have an increased risk of infections, including osteomyelitis,21 particularly from encapsulated organisms that are presumably secondary to loss of functional splenic tissue. The most common cause of osteomyelitis is Salmonella, followed by Staphylococcus aureus and Gram-negative enteric bacteria.22 One proposed explanation for the frequency of bowel organism–derived infections has been intravascular sickling leading to bowel microinfarctions.23 Diagnosis of osteomyelitis in the context of sickle cell disease is an important management issue because the clinical symptoms of pain, swelling, tenderness, and fever are similar to those of bone vaso-occlusive crisis. Elevated markers of inflammation occur in both conditions. No single laboratory test or imaging modality reliably differentiates osteomyelitis from infarction. Until a definite diagnosis can be made, treatment with anti-microbial therapy should be provided.24
Acute Synovitis and Septic Arthritis When the epiphysis is involved by infarction of sickle cell crisis, a joint effusion may develop. This presentation is an acute synovitis and is clinically indistinguishable from a septic joint.25 Synovial fluid should be examined and cultured for accurate diagnosis. In a retrospective review of 2000 consecutive adult patients with sickle cell disease, 3% had septic arthritis.26 The majority of these patients (56/59) had Hb SS. Thirty-six of the 59 infections involved the hip. Symptoms were pain, swelling, and fever higher than 38.2° C, a peripheral white blood cell count of 15,000/mm3, erythrocyte sedimentation rate greater than 24 mm/hour, and C-reactive protein greater than 20 mg/L. Cultures were positive in 96% of the joint aspirates, with staphylococcus and Gram-negative infections the most common. Prior diagnosis of osteonecrosis, osteomyelitis, and comorbid medical conditions of diabetes mellitus and use of corticosteroids and hydroxyurea were associated with septic
Figure 120-3 Radiograph of the hand of a child with sickle cell disease. (From Medscape. Available at http://img.medscape.com/pi/emed/ ckb/radiology/336139-413542-8885tn.jpg.)
arthritis. It is suggested that a clinician should have a high index of suspicion for septic arthritis in patients with sickle cell disease who present with fever and joint pain. Distant osteomyelitis was more often the source of a joint infection than contiguous osteomyelitis. If a joint infection is suspected, the patient should undergo aspiration and culture of the synovial fluid. Another form of arthritis in patients with sickle cell disease is polyarticular (80%) and symmetric (60%) in the majority of patients and generally involves the large joints of the lower extremity.27 Symptoms last less than 1 week, and radiographic changes are consistent with periarticular osteopenia, erosions of bone, and joint space narrowing.
Growth Disturbance A majority of children with SS disease will show decline in growth compared with normal peers.28 Puberty is delayed on average by 12 to 24 months, as is skeletal age. Factors such as nutritional status and inactivity could be modified and decrease the effect on growth. Delayed skeletal maturation in children also can occur.29
Osteopenia and Osteoporosis Osteopenia and osteoporosis are prevalent in Hb SS disease, especially given the young age of the patients. The lumbar spine appears to be the site most often affected. Low body
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mass index is a consistent correlate of decreased bone density, as are low vitamin D levels.30
Osteonecrosis Vaso-occlusion resulting in infarction of articular surfaces of long bone occurs most commonly in the femur, followed by the humerus.31 It was previously thought to occur with increased frequency in Hb SC disease as opposed to Hb SS disease. However, because of the increased longevity of patients with Hb SS disease, its prevalence is greatest in patients with Hb SS disease.32 By age 33 years, 50% of patients will have avascular necrosis of the femoral head. The presence of concurrent deletional α-thalassemia and a history of frequent vaso-occlusive crises are classic risk factors for femoral avascular necrosis. Patients present with chronic joint pain with progressive decrease in range of motion of affected joints. Multiple joints are commonly involved. The vast majority of untreated patients with avascular necrosis will progress to femoral head collapse within 5 years. Symptoms always preceded hip collapse. The duration to collapse was shorter with more advanced stages at study onset, and the majority of patients progress to symptomatic avascular necrosis that requires intervention.33 Avascular necrosis has been treated with a number of modalities including core decompression, osteotomy, bone grafting, surface arthroplasty, and joint replacement.34 The only randomized trial in avascular necrosis compared core decompression and physical therapy versus physical therapy alone and did not show a difference in outcome between the two arms; however, follow-up was short, and a significant number of stage III hips were included. Core decompression is a useful option in early stage avascular necrosis. Several studies associate total hip replacement in individuals with sickle cell disease with a higher rate of orthopedic and medical complications.35,36 However, other studies show a lower rate of orthopedic complications.37 Structural bone diseases in people with sickle cell disease make joint replacement technically challenging (see Chapter 103).
Iron Metabolism Red blood cell transfusions are a mainstay in the treatment of both acute and chronic sickle cell disease complications.38 Most patients receive at least one transfusion in their lifetime, usually for acute complications. Blood transfusions increase arterial oxygen pressure and Hb oxygen affinity, thereby reducing red blood cell sickling, and they also improve microvascular perfusion. Furthermore, regular blood transfusion regimens suppress endogenous erythropoiesis and therefore the production of red blood cells containing sickle Hb. Iron metabolism and consequently patterns of iron loading differ in sickle cell disease and thalassemia.39 Erythropoiesis is variably increased in sickle cell disease, but it is not ineffective. Unlike patients with thalassemia, patients with nontransfused sickle cell disease do not develop systemic iron overload because of increased iron absorption, and they may actually present with iron deficiency, possibly related to intravascular hemolysis and the resulting excessive urinary loss of iron. Inflammation, which
is part of the pathophysiology of sickle cell disease, increases synthesis of hepcidin and consequently decreases iron absorption and enhances retention of iron within the reticuloendothelial system. As a result, tissues and organs affected by iron overload are different in sickle cell disease and thalassemia. Iron-induced cardiac and endocrine dysfunction is less common in sickle cell disease. Musculoskeletal manifestations of iron overload include a symmetrical, polyarticular arthropathy with bony enlargement and minimal inflammation that can develop in 25% to 50% of patients. It notably affects the second and third metacarpophalangeal joints but also the proximal interphalangeal joints, wrists, elbows, shoulders, and hips. Osteoporosis can affect up to 25% of patients.
MUSCULOSKELETAL INVOLVEMENT: THALASSEMIAS Decreased Bone Density, Osteoporosis Skeletal changes in people with untreated thalassemia are related to bone marrow hyperplasia, resorption of cortex, rarefaction of cancellous bone with coarsening of the trabeculae, and a generalized decrease in bone density.40 In patients with thalassemia major, onset of the radiographic changes can be seen in their first year of life. Involvement of the spine, skull and facial bones, ribs, and metaphyses of long bones are typical (Figure 120-4). In the spine, osteoporosis and cortical thinning are associated with vertebral compression fractures (Table 120-4). After an initial increase in the height-to-width ratio of the vertebral body, thinning of the subchondral bone plates occurs and the bones become biconcave and wedge shaped as multiple compression fractures occur. Patients can experience scoliosis and kyphosis.41 Lateral plain radiographs of the spine may show a “bone-within-a-bone” appearance as the end plate depression is evident (Figure 120-5). MRI studies show predominance of red marrow in the vertebrae and early degeneration of the intervertebral disks of the lower thoracic and lumbar spine.42 Abnormal intravertebral iron deposition also can be seen.
Extramedullary Hematopoiesis Extramedullary hematopoiesis is seen as extraosseous extension of red marrow with symmetrical lobulated confluent masses expanding in the paravertebral and presacral spaces. These soft tissue masses have intermediate T1 signal, variable intensity of T2-weighted sequences, and mild gadolinium enhancement. Radionuclide imaging with
TABLE 120-4 Bone and Joint Involvement in Thalassemias Osteopenia, osteoporosis Bone pain Bone fractures Iron chelator arthropathy Intervertebral disk disease Spinal deformity
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technetium-labeled sulfur colloid may help define the hematopoetic nature of the masses.43 Spinal cord compression occasionally occurs as a result of epidural marrow extension. In the skull, marrow expansion causes widening with thinning of the outer table and thickening of the inner table, with remodeling of the skull (tower skull; Figure 120-6).
Iron Metabolism
Figure 120-4 Spinal involvement with vertical trabeculations in a person with thalassemia. (Case courtesy Dr. Chris O’Donnell, Radiopaedia .org, rID: 16592.)
Figure 120-5 Vertebral end plate changes in thalassemia. Vertebral end plate depression highlighted by arrows. (From Cockshot P, Middlemiss H: Clinical radiology in the tropics, Edinburgh, 1979, Churchill Livingstone.)
The anemia of thalassemia major becomes symptomatic between 6 months and 2 years of age, requiring the institution of a regular transfusion program. As a consequence of continuous anemia, erythropoiesis, although inefficient, can be intense; the bone marrow undergoes an enormous expansion with consequent distortion of facial features, and the plasma volume increases. In addition, hepatosplenomegaly develops. A regimen maintaining a minimum Hb concentration of 9.5 to 10.5 g/dL prevents all the aforementioned complications and fosters normal growth at least until puberty. Transfusion therapy results in iron overload in various tissues, and iron chelation therapy prevents accumulation of iron, promotes normal growth, and prevents death.44 Deferoxamine chelation is effective but challenging to use because of its cost and the inconvenience of prolonged subcutaneous infusions. Deferiprone, an oral iron chelator, has improved compliance and access to iron chelation therapy. However, serious complications can occur when it is used, including agranulocytosis. Mild arthralgias and/or arthritis may occur in up to 38% of patients45 and usually resolve on their own or with NSAIDs. In some patients, however, severe arthropathy related to deferiprone develops, requiring discontinuation of iron chelation therapy. In addition, erosive epiphyseal, physeal, and
Figure 120-6 Skull of a child with thalassemia. (From Azam M, Bhatti N: Hair-on-end appearance. Arch Dis Child 91:735, 2006.)
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metaphyseal changes are seen on radiographs of the long bones of the hands of symptomatic children.46
COMORBID RHEUMATIC DISEASE Autoimmune Disorders The occurrence of systemic autoimmune diseases, including rheumatoid arthritis and systemic lupus erythematosus, has occasionally been reported in patients with hemoglobinopathies.47 Some authors have suggested that their association has an increased risk.48 Several cases of mild recurrent arthritis have been reported in patients with thalassemia. Rheumatoid arthritis has rarely been described in patients with sickle cell disease.49 The prevalence and clinical features of rheumatoid arthritis in patients with thalassemia is unknown. A review of medical records of patients with either thalassemia or sickle cell disease followed up over a decade in Greece provides insight.50 Rheumatoid factor was detected in 23% of 90 patients, and anti-citrullinated protein antibodies were detected in only 2%. A low titer of positive anti-nuclear antibody (ANA) was present in nearly half of patients, and double-stranded DNA antibodies were found in one patient. Four percent of the patients with thalassemia major fulfilled American College of Rheumatology criteria for rheumatoid arthritis and received lowdose corticosteroids to control synovitis. One patient underwent methotrexate therapy. Patients with rheumatoid arthritis had no specific features that distinguished them from the other patients with hematologic disease. The nature of the rheumatoid arthritis was mild, and extraarticular features were uncommon. Abnormalities of the immune system can occur in patients with sickle cell disease. Immune deficiency and the presence of autoantibodies have been described in frequencies higher than that of control groups of Africans and Caucasians, and up to 20% of patients are positive for ANAs.51 The presence of these autoantibodies could be related to genetic factors and/or environmental influences. Although it has been suggested that a deficiency of the alternative complement pathway in patients with sickle cell disease was a predisposing factor in the development of immune complex diseases, this mechanism has not been confirmed.52 Autoimmune disease in adults with sickle cell disease may fail to be diagnosed or diagnosis may be delayed as a result of shared clinical manifestations. Bone and joint, lung, cardiac, renal, and central nervous systems may be involved in either autoimmune disease or sickle cell disease. Recognition of an autoimmune disease in patients with sickle cell disease may require a change in therapy, and the use of immunosuppressive medications may result in exacerbation of sickle cell disease.53
Gout Hyperuricemia and gout are uncommon in people with primary red blood cell disorders but have been reported in patients with sickle cell disease, Hb SC and CC disease, and thalassemias.54 Increased red blood cell turnover in sickle cell disease can lead to hyperuricemia, as can renal tubular involvement and a decrease in uric acid excretion. Two
patients with tophaceous gout and sickle cell disease have been reported.55 Appropriate therapy is treatment of the underlying hematologic disease and typical measures for acute gout. In studies from the 1970s, hyperuricemia was reported as a common feature of sickle cell disease, occurring in up to 41% of patients.56 To assess the recent prevalence of hyperuricemia and gout in adult patients with sickle cell disease, 65 consecutive patients with sickle cell disease in one center in France were studied during a 2-year period.57 Hyperuricemia was observed in only 9.2% of the patients in the cohort, and none had gout.
CONCLUSION Hemoglobinopathies, particularly sickle cell disease and the thalassemias, are often associated with significant and varied musculoskeletal manifestations, including osteonecrosis, arthropathies, and vertebral fractures. Awareness of the clinical presentations associated with these manifestations is essential so they are recognized by the physician and an effective management strategy can be formulated. The references for this chapter can also be found on ExpertConsult.com.
REFERENCES 1. Natarajan K, Townes TM, Kutlar A: Disorders of hemoglobin structure: sickle cell anemia and related abnormalities. In Kaushansky K, Lichtman MA, Beutler E, et al, editors: Williams hematology, ed 8, Chicago, 2010, McGraw-Hill, pp 709–742. 2. Giardina PJ, Rivella S: Thalassemia syndromes. In Hoffman R, Benz EJ, Jr, Silberstein LE, et al, editors: Hematology: basic principles and practice, ed 6, Philadelphia, 2013, Elsevier Saunders. 3. Al-Rimawi H, Jallad S: Sport participation in adolescents with sickle cell disease. Pediatr Endocrinol Rev 1:214–216, 2008. 4. Brousse V, Makani J, Rees DC: Management of sickle cell disease in the community. BMJ 348:g1765, 2014. 5. Brousse V, Buffet P, Rees D: The spleen and sickle cell disease: the sick (led) spleen. Br J Haematol 166:165–176, 2014. 6. Siddiqi A, Jordan LB, Parker CS: Sickle cell disease: the American saga. Ethn Dis 23:245–248, 2013. 7. Huttle A, Maestre GE, Lantiqua R, et al: Sickle cell in sickle cell disease in Latin American and the United States. Pediatr Blood Cancer 62:1131–1136, 2015. 8. ACOG Committee on Obstetrics: ACOG Practice Bulletin No.= 78: hemoglobinopathies in pregnancy. Obstet Gynecol 109:229–237, 2007. 9. Koh M, Lao ZT, Rhodes E: Managing haematological disorders during pregnancy. Best Pract Res Clin Obstet Gynaecol 27:855–865, 2013. 10. Stettler N, McKiernan CM, Melin CQ, et al: Porportion of adults with sickle cell anemia and painful crises receiving hydroxyurea. JAMA 313:1671–1672, 2015. 11. Walters MC: Update of hematopoietic cell transplantation for sickle cell disease. Curr Opin Hematol 22:227–233, 2015. 12. Field JJ, Nathan DG: Advances in sickle cell therapies in the hydroxyurea era. Mol Med 20(Suppl 1):S37–S42, 2014. 13. Loukogeorgakis SP, Flake AW: In utero stem cell and gene therapy: current status and future perspectives. Eur J Pediatr Surg 24:237–245, 2014. 14. da Silva Junior GB, Daher Ede F, da Rocha FA: Osteoarticular involvement in sickle cell disease. Rev Bras Hematol Hemoter 34:156–164, 2012. 15. Babela JR, Nzingoula S, Senga P: Sickle-cell crisis in the child and teenager in Brazzaville, Congo. A retrospective study of 587 cases. [in French]. Bull Soc Pathol Exot 98:365–370, 2005. 16. Edwards A, Clay EL, Jewells V, et al: A 19-year-old man with sickle cell disease presenting with spinal infarction: a case report. J Med Case Rep 7:210–216, 2013.
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17. Ganguly A, Boswell W, Aniq H: Musculoskeletal manifestations of sickle cell anaemia: a pictorial review. Anemia 2011:794273, 2011. 18. Powars DR, Chan LS, Hiti A, et al: Outcome of sickle cell anemia. A 4-decade observational study of 1056 patients. Medicine 84:363–376, 2005. 19. Noble J, Schendel S, Weizblit N, et al: Orbital wall infarction in sickle cell disease. Can J Ophthalmol 43:603–604, 2008. 20. Ambe JP, Mava Y, Chama R, et al: Clinical features of sickle cell anaemia in northern Nigerian children. West Afr J Med 31:81–85, 2012. 21. Isenberg DA, Shoenfeld Y: The rheumatologic complications of hematologic disorders. Semin Arthritis Rheum 12:348–358, 1983. 22. Burnett MW, Bass JW, Cook BA: Etiology of osteomyelitis complicating sickle cell disease. Pediatrics 101:296–297, 1997. 23. Anand AJ, Glatt AE: Salmonella osteomyelitis and arthritis in sickle cell disease. Semin Arthritis Rheum 24:211–221, 1994. 24. Bennett OM, Namnyak SS: Bone and joint manifestations of sickle cell anaemia. J Bone Joint Surg 72:494–499, 1990. 25. Ebong WW: Septic arthritis in patients with sickle-cell disease. Br J Rheumatol 26:99–102, 1987. 26. Hernigou P, Daltro G, Flouzat-Lachaniette C, et al: Septic arthritis in adults with sickle cell disease often is associated with osteomyelitis or osteonecrosis. Clin Orthop Relat Res 468:1676–1681, 2010. 27. Diggs LW: Bone and joint lesions in sickle cell disease. Clin Orthop 52:119–143, 1967. 28. Leonard MB, Zemel DS, Kawchak DA, et al: Plasma zinc status, growth, and maturation in children with sickle cell disease. J Pediatr 132:467–471, 1998. 29. Barden EM, Kawchak DA, Ohene-Frempong K, et al: Body composition in children with sickle cell disease. Am J Clin Nutr 76:218–225, 2002. 30. Arlet JB, Courbebaisse M, Chatellier G, et al: Relationship between vitamin D deficiency and bone fragility in sickle cell disease: a cohort study of 56 adults. Bone 52:206–211, 2013. 31. Almeida A, Roberts I: Bone involvement in sickle cell disease. Br J Hematol 129:482–490, 2005. 32. Mahadeo KM, Oyeku S, Taragin B, et al: Increased prevalence of osteonecrosis of the femoral head in children and adolescents with sickle-cell disease. Am J Hematol 86:806–808, 2011. 33. Rajpura A, Wright AC, Board TN: Medical management of osteonecrosis of the hip: a review. Hip Int 21:385–392, 2011. 34. Marti-Carvajal AJ, Agreda-Perez LH: Treatment for avascular necrosis of bone in people with sickle cell disease. Cochrane Database Syst Rev (10):CD004344, 2014. 35. Mukisi-Mukaza M, Saint Martin C, Etienne-Julan M, et al: Risk factors and impact of orthopaedic monitoring on the outcome of avascular necrosis of the femoral head in adults with sickle cell disease: 215 patients case study with control group. Orthop Traumatol Surg Res 97:814–820, 2011. 36. Enayatollahi MA, Novack TA, Maltenfort MG, et al: In-hospital morbidity and mortality following total joint arthroplasty in patients with hemoglobinopathies. J Arthroplasty 30:1308–1312, 2015. 37. Issa K, Naziri Q, Maheshwari AV, et al: Excellent results and minimal complications of total hip arthroplasty in sickle cell hemoglobinopa-
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thy at mid-term follow-up using cementless prosthetic components. J Arthroplasty 28:1693–1698, 2013. 38. Beverung LM, Strouse JJ, Hulbert ML, et al: Health-related quality of life in children with sickle cell anemia: impact of blood transfusion therapy. Am J Hematol 90:139–143, 2015. 39. Mariani R, Trombini P, Pozzi M, et al: Iron metabolism in thalassemia and sickle cell disease. Mediterr J Hematol Infect Dis 1:e2009006, 2009. 40. Bedair EM, Helmy AN, Yakout K, et al: Review of radiologic skeletal changes in thalassemia. Pediatr Endocrinol Rev 1:123–126, 2008. 41. Haidar R, Musallam KM, Taher AT: Bone disease and skeletal complications in patients with β thalassemia major. Bone 48:425–432, 2011. 42. Haidar R, Mhaidli H, Musallam KM, et al: The spine in β-thalassemia syndromes. Spine 37:334–339, 2012. 43. Tsitouridis J, Stamos S, Hassapopoulou E, et al: Extramedullary paraspinal hematopoiesis in thalassemia: CT and MRI evaluation. Eur J Radiol 30:33–38, 1999. 44. Vichinsky E, Neumayr L, Trimble S, et al: Transfusion complications in thalassemia patients: a report from the centers for disease control and prevention. Transfusion 54:972-981, quiz 971; 2014. 45. Meerpohl JJ, Schell LK, Rücker G, et al: Deferasirox for managing transfusional iron overload in people with sickle cell disease. Cochrane Database Syst Rev (5):CD007477, 2014. 46. Martinoli C, Bacigalupo L, Forni GL, et al: Musculoskeletal manifestations of chronic anemias. Semin Musculoskelet Radiol 15:269–280, 2011. 47. Cherner M, Isenberg D: The overlap of systemic lupus erythematosus and sickle cell disease: report of two cases and a review of the literature. Lupus 19:875–883, 2010. 48. Castellino G, Govoni M, Trotta F: Rheumatoid arthritis in betathalassemia trait. Rheumatology (Oxford) 39:286–287, 2000. 49. Nistala K, Murray KJ: Co-existent sickle cell disease and juvenile rheumatoid arthritis. Two cases with delayed diagnosis and severe destructive arthropathy. J Rheumatol 28:2125–2128, 2001. 50. Pliakou XI, Koutsouka FP, Damigos D, et al: Rheumatoid arthritis in patients with hemoglobinopathies. Rheumatol Int 32:2889–2892, 2012. 51. Toly-Ndour C, Rouquette A-M, Obadia S, et al: High titers of autoantibodies in patients with sickle cell disease. J Rheumatol 38:302–309, 2011. 52. Eissa MM, Lawrence JM, III, McKenzie L, et al: Systemic lupus erythematosus in a child with sickle cell disease. South Med J 88:1176– 1178, 1995. 53. Michel M, Habibi A, Godeau B, et al: Characteristics and outcome of connective tissue diseases in patients with sickle-cell disease: report of 30 cases. Semin Arthritis Rheum 38:228–240, 2008. 54. Ballou SP: Gout in haemoglobinopathies. Ann Rheum Dis 40:210–211, 1981. 55. Umesh S, Ajit NE, Shobha V, et al: Musculoskeletal disorders in sickle cell anaemia—unusual associations. J Assoc Physicians India 62:52–53, 2014. 56. Reynolds MD: Gout and hyperuricemia associated with sickle-cell anemia. Semin Arthritis Rheum 12:404–413, 1983. 57. Arlet JB, Ribeil JA, Chatellier G, et al: Hyperuricemia in sickle cell disease in France. [in French]. Rev Med Interne 33:13–17, 2012.
Rheumatic Manifestations of Hemoglobinopathies Carlos J. Lozada • Elaine C. Tozman KEY POINTS Hemoglobinopathies are inherited diseases caused by mutations in globin genes. Thalassemias are inherited defects in globin chain synthesis resulting in hypochromia and microcytosis. Skeletal changes in thalassemias can result in cortical thinning, osteoporosis, and vertebral compression fractures. Sickle cell disease is a single gene disorder caused by homozygous inheritance for sickle cell hemoglobin. Vaso-occlusive crises of bone occur in people with sickle cell disease and result in severe pain at the site of bony infarction, typically of long bones. The index of suspicion for septic arthritis should be high in patients with sickle cell disease who present with fever and joint pain. Hyperuricemia can be seen in people with sickle cell disease and thalassemias, but gout is uncommon.
Hemoglobin (Hb) has a tetrameric structure consisting of two pairs of α-globin and two non–α-globin polypeptide chains, each associated with a heme group. The interaction of these chains is responsible for the quaternary structure of the Hb molecule and its normal function. The fundamental role of Hb is oxygen transport. Hemoglobinopathies are inherited diseases caused by mutations in globin genes. Abnormalities in Hb can alter red blood cell shape, deformability, and viscosity. Approximately 1000 mutations have been described1; however, most are not associated with clinical disease. The gene mutations that result in sickle cell disease and thalassemia syndromes cause diseases that often involve the musculoskeletal system and will be discussed in this chapter.
THALASSEMIAS The term thalassemia is derived from a Greek term that roughly means “the sea” (Mediterranean) in the blood and was used to describe anemias in people from Italy and Greece. The term is now used to refer to inherited defects in globin chain biosynthesis.2 Individual syndromes are named according to the globin chain whose synthesis is adversely affected. For example, α-globin chains are absent or reduced in patients with α-thalassemia; β-globin chains are absent or reduced in patients with β-thalassemia; δ- and β-globin chains are absent or reduced in patients with 2018
δβ-thalassemia; and so on. Thalassemias are inherited as pathologic alleles of one or more of the globin genes located on chromosomes 11 and 16 and range from total deletion or rearrangement of the loci to point mutations that impair transcription, processing, or translation of globin messenger RNA. As a consequence of reduced globin chain production, a reduction of functioning Hb tetramers occurs. Hypochromia and microcytosis are found in all patients with thalassemia. In the milder forms of the disease, these changes may be barely detectable. Impaired globin synthesis leads to an imbalance of the individual α- and β-subunits. Free or “unpaired” α-, β-, and γ-globin chains are either highly insoluble or form homotetramers (Hb H and Hb Bart’s) that cannot release oxygen normally or are relatively unstable and precipitate as the cell ages. Excess α-globin chains, for example, continue to accumulate and precipitate in individuals with β-thalassemia. Unpaired subunits are the major sources of morbidity and mortality (Tables 120-1 and 120-2). Thalassemias have been encountered in virtually every ethnic group and geographic location, but they are most common in the Mediterranean basin and tropical or subtropical regions of Asia and Africa. The “thalassemia belt” extends from the Mediterranean across the Arabian Peninsula and through Turkey, Iran, and India to southeastern Asia and southern China. The prevalence of thalassemia in these regions ranges from 2.5% to 15%. As with sickle cell anemia, thalassemia is most common in areas affected by endemic malaria. Malaria infection in thalassemia heterozygotes results in milder disease and confers a selective advantage on reproductive fitness. The gene frequency of thalassemia has become fixed and is high in populations exposed to malaria over many centuries.
SICKLE CELL ANEMIA AND RELATED DISORDERS Sickle cell anemia is a single gene disorder caused by homozygous inheritance for sickle Hb (Hb S). Hb S is identical to normal Hb (Hb A) except for the replacement of glutamic acid, the sixth amino acid in β-globin, with valine. Hb S is capable of carrying oxygen, but once the oxygen is released, the Hb joins with other Hb S molecules to form rigid rods that bend the normally flexible, disk-shaped red blood cells into distorted narrow crescents. The sickled cells impede blood flow when they stick to the walls of blood vessels and to other blood cells. About 10% of black Americans are heterozygotes—that is, they inherit a sickle globin
CHAPTER 120 Rheumatic Manifestations of Hemoglobinopathies
TABLE 120-1 α-Thalassemias No. of Missing α Genes
Clinical Presentation
1
Silent carrier
No overt manifestations
2
Thalassemia trait
Hypochromic, microcytic with mild anemia
3
Hemoglobin H disease
Hypochromic, microcytic with hemolytic anemia, hepatosplenomegaly, and jaundice
4
Hydrops fetalis syndrome (hemoglobin Bart’s)
Severe anemia, ascites, edema, hepatosplenomegaly, cardiovascular and skeletal malformations; death in utero
TABLE 120-2 β-Thalassemia No. of Affected Genes
Clinical Presentation
1
β-thalassemia minor
Heterozygous, asymptomatic, silent carrier
2
β-thalassemia trait
Mild anemia
3
β-thalassemia intermedia
Mild anemia, typically diagnosed in late childhood
4
β-thalassemia major
Homozygous, severe anemia, extramedullary hematopoiesis, hepatosplenomegaly, skull changes, iron overload from transfusions
gene from one parent and a normal gene from the other parent and have sickle cell trait. They have no significant clinical problems unless they are subjected to marked dehydration or hypoxia.3 Rarely these individuals experience splenic infarction, stroke, or sudden death after strenuous physical activity, particularly at a high altitude. Individuals with sickle cell trait may have impaired ability to form concentrated urine (hyposthenuria), and a few have episodes of painless hematuria as a result of medullary infarction. Other internal organ damage is extremely uncommon, and heterozygotes have a normal life expectancy. One-fourth of the children of parents with sickle trait will be homozygotes and have red blood cells containing primarily Hb S and no Hb A. These individuals have severe hemolytic anemia and episodes of vaso-occlusion that cause acute bouts of pain and progressive organ damage. A similar clinical phenotype is encountered in individuals who are compound heterozygotes—that is, those who inherit the sickle gene from one parent and, from the other parent, either a β-thalassemia gene or a gene that encodes Hb C, another β-globin structural mutant. Patients with S/β0 thalassemia1 are unable to make any Hb A and are as severely affected as those with Hb SS disease. In contrast, patients with Hb S/β+-thalassemia or with Hb SC disease have less morbidity and a longer life span. The hallmark of sickle cell disease is the vaso-occlusive pain crisis,4 which is the most common clinical manifestation but can occur with varying frequency in different individuals. It results from the complex interplay between
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sickled red blood cells, neutrophils, endothelium, and plasma factors. The result is tissue hypoxia, leading to tissue death and associated pain. Episodes may be precipitated by dehydration, infection, and cold weather, although in half of the cases, no precipitating factor is found. Repeated splenic infarctions in childhood result in “autosplenectomy” and loss of splenic function by age 6 to 8 years in approximately one-half of patients.5
DIAGNOSIS OF HEMOGLOBINOPATHIES One in 12 African-Americans has sickle-cell trait, one in 40 carries Hb C, and one in 40 carries the trait for β-thalassemia.6 Latin Americans are an underappreciated population affected by sickle cell disease.7 For example, it is estimated that 30,000 people in Brazil have sickle cell disease. African and African-American patients are at increased risk of carrying Hb S and other hemoglobinopathies and should be offered preconception or prenatal screening. Hb S is also more common among individuals of Mediterranean, Middle Eastern, and Asian Indian descent. The American College of Obstetricians and Gynecologists recommends that patients at risk for having a child with hemoglobinopathy be offered prenatal genetic counseling and a variety of tests to document the Hb abnormality.8 In the United Kingdom, the Royal College of Obstetricians and Gynaecologists provides clinical guidelines for the management of sickle cell disease in pregnancy and standards of care from both hematology and the sickle cell community.9 Prenatal diagnosis can be performed with either chorionic villus sampling or amniocentesis. Because detection of α-thalassemia or α-thalassemia trait is based on molecular genetic testing and is not detectable using Hb electrophoresis, routine carrier screening is not offered. If microcytic anemia is present in the absence of iron deficiency and the Hb electrophoresis is normal, then testing for α-thalassemia should be considered, particularly among individuals of Southeast Asian descent. Sickle cell anemia can be accurately diagnosed with highperformance liquid chromatography and isoelectric focusing. Rapid methods such as solubility testing and sickling of red blood cells using sodium metabisulfite are less reliable tests. These tests are suitable for large field studies because they require only a drop of blood and use stable reagents, but they do not distinguish between homozygotes and heterozygotes. Newborn screening is mandatory in most of the United States and is well established, although not mandatory, for both sickle cell disease and thalassemias in the United Kingdom. Such screening tests vary in other areas of the world and may not be performed.7 Polymerase chain reaction is the method of choice for prenatal diagnosis.
TREATMENT Hydroxycarbamide (hydroxyurea) is the only drug approved by the U.S. Food and Drug Administration to treat sickle cell disease. It can reduce the number of painful episodes and hospitalizations, but only about two-thirds of adult patients have a response to this drug.10 Bone-marrow transplants can provide a cure because they replace the faulty hematopoietic stem cells that produce sickle cells with ones that make healthy red blood cells.11
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However, transplants are expensive, not widely available, and have associated risks such as infections and lifethreatening immune-system reactions. Gene therapy is another potentially successful treatment for sickle cell disease.12 Conventional gene therapy, also known as gene addition, typically involves inserting new genes. Usually, a harmless virus is modified with the gene to be inserted, and this “viral vector” is mixed with cells from the patient in vitro. The virus searches out the cells and inserts the gene into the cells’ DNA, after which the cells are transplanted into the patient. Gene editing is more specific when the faulty DNA sequence is removed and a piece of laboratory-created DNA is inserted. In both approaches, the modified DNA dictates the formation of a normal, working protein. A team led by Alan Flake at the Children’s Center for Fetal Research at the Children’s Hospital of Philadelphia has successfully treated sickle-cell disease in utero in mice and dogs, and trials in monkeys are under way.13 Stem cells from the mother are collected and injected into the bloodstream of the fetus. No destruction of the fetal immune system is required, because the fetal and maternal immune systems are naturally tolerant of one another.
MUSCULOSKELETAL INVOLVEMENT: SICKLE CELL DISEASE Vaso-Occlusive Crisis of Bone Bone involvement in patients with sickle cell disease is the most common clinical manifestation of the disease, both as an acute process and as a chronic symptom14 (Table 120-3). Painful osteoarticular crisis was the most common reason for emergency care of children with sickle cell disease in an African population (58.6%).15 All patients experience painful vaso-occlusive crises, which usually begin in late infancy and continue throughout life. Patients typically report pain in the chest, low back, and extremities. Abdom-
inal pain may mimic acute abdomen of other causes. Fever is often present, even in the absence of infection. Although microvascular occlusion can occur in any organ, it is common in tissues with low blood flow, such as the bone marrow, where deoxygenation and polymerization of Hb S leads to bone thrombosis, infarction, and necrosis. Spinal cord infarction can occur.16 The medullary cavity or the epiphysis of the bone is affected. Patients have severe pain in one or more areas of their bones, with tenderness, erythema, and swelling of the infarcted bone. Generalized symptoms of fever and leukocytosis occur, and most patients recover without sequelae (Figure 120-1). When infarction involves the vertebral body, collapse and a fish mouth deformity can result.17 Bone infarctions can occur in any bone, with a predilection for long bones. The most common sites are the tibia/fibula (30%), the femur (25%), and the radius, ulna, and humerus (21%).18 MRI is sensitive in detecting bone and bone marrow infarction, but this technology is not useful in distinguishing acute infarction from osteomyelitis.19
Dactylitis In young children, in the range of 1 to 2 years of age and younger than 7 years, vaso-occlusion manifests in the bone marrow of the small bones of the hands and feet and dactylitis occurs.20 Dactylitis is also called hand-foot syndrome. Patients have painful swellings of one or more digits (Figure 120-2) as extensive infarction of the marrow, medullary trabeculae, and inner layer of cortical bone occur.
TABLE 120-3 Bone and Joint Involvement in Sickle Cell Disease Vaso-occlusive crisis of bone Dactylitis Osteomyelitis Acute synovitis Septic arthritis Growth disturbance Osteopenia, osteoporosis Osteonecrosis Stress fracture Orbital compression Dental complications Vertebral collapse Sickle cell arthropathy Diffuse chondrolytic arthritis Gouty arthritis
Figure 120-1 Bony infarcts in the femur of a patient with sickle cell disease. (From The Radiology Assistant.)
CHAPTER 120 Rheumatic Manifestations of Hemoglobinopathies
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Figure 120-2 Hand of a child with sickle cell disease. (Courtesy Larry B. Mellick. From https://www.youtube.com/watch?v=AChPlzPEA7Y.)
Subperiosteal new bone formation follows, and as the episode resolves within 2 weeks, radiographs show a “motheaten” appearance of the involved digits (Figure 120-3). Rarely, involvement of the epiphysis causes premature fusion and shortened digits.
Osteomyelitis Patients with sickle cell disease have an increased risk of infections, including osteomyelitis,21 particularly from encapsulated organisms that are presumably secondary to loss of functional splenic tissue. The most common cause of osteomyelitis is Salmonella, followed by Staphylococcus aureus and Gram-negative enteric bacteria.22 One proposed explanation for the frequency of bowel organism–derived infections has been intravascular sickling leading to bowel microinfarctions.23 Diagnosis of osteomyelitis in the context of sickle cell disease is an important management issue because the clinical symptoms of pain, swelling, tenderness, and fever are similar to those of bone vaso-occlusive crisis. Elevated markers of inflammation occur in both conditions. No single laboratory test or imaging modality reliably differentiates osteomyelitis from infarction. Until a definite diagnosis can be made, treatment with anti-microbial therapy should be provided.24
Acute Synovitis and Septic Arthritis When the epiphysis is involved by infarction of sickle cell crisis, a joint effusion may develop. This presentation is an acute synovitis and is clinically indistinguishable from a septic joint.25 Synovial fluid should be examined and cultured for accurate diagnosis. In a retrospective review of 2000 consecutive adult patients with sickle cell disease, 3% had septic arthritis.26 The majority of these patients (56/59) had Hb SS. Thirty-six of the 59 infections involved the hip. Symptoms were pain, swelling, and fever higher than 38.2° C, a peripheral white blood cell count of 15,000/mm3, erythrocyte sedimentation rate greater than 24 mm/hour, and C-reactive protein greater than 20 mg/L. Cultures were positive in 96% of the joint aspirates, with staphylococcus and Gram-negative infections the most common. Prior diagnosis of osteonecrosis, osteomyelitis, and comorbid medical conditions of diabetes mellitus and use of corticosteroids and hydroxyurea were associated with septic
Figure 120-3 Radiograph of the hand of a child with sickle cell disease. (From Medscape. Available at http://img.medscape.com/pi/emed/ ckb/radiology/336139-413542-8885tn.jpg.)
arthritis. It is suggested that a clinician should have a high index of suspicion for septic arthritis in patients with sickle cell disease who present with fever and joint pain. Distant osteomyelitis was more often the source of a joint infection than contiguous osteomyelitis. If a joint infection is suspected, the patient should undergo aspiration and culture of the synovial fluid. Another form of arthritis in patients with sickle cell disease is polyarticular (80%) and symmetric (60%) in the majority of patients and generally involves the large joints of the lower extremity.27 Symptoms last less than 1 week, and radiographic changes are consistent with periarticular osteopenia, erosions of bone, and joint space narrowing.
Growth Disturbance A majority of children with SS disease will show decline in growth compared with normal peers.28 Puberty is delayed on average by 12 to 24 months, as is skeletal age. Factors such as nutritional status and inactivity could be modified and decrease the effect on growth. Delayed skeletal maturation in children also can occur.29
Osteopenia and Osteoporosis Osteopenia and osteoporosis are prevalent in Hb SS disease, especially given the young age of the patients. The lumbar spine appears to be the site most often affected. Low body
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mass index is a consistent correlate of decreased bone density, as are low vitamin D levels.30
Osteonecrosis Vaso-occlusion resulting in infarction of articular surfaces of long bone occurs most commonly in the femur, followed by the humerus.31 It was previously thought to occur with increased frequency in Hb SC disease as opposed to Hb SS disease. However, because of the increased longevity of patients with Hb SS disease, its prevalence is greatest in patients with Hb SS disease.32 By age 33 years, 50% of patients will have avascular necrosis of the femoral head. The presence of concurrent deletional α-thalassemia and a history of frequent vaso-occlusive crises are classic risk factors for femoral avascular necrosis. Patients present with chronic joint pain with progressive decrease in range of motion of affected joints. Multiple joints are commonly involved. The vast majority of untreated patients with avascular necrosis will progress to femoral head collapse within 5 years. Symptoms always preceded hip collapse. The duration to collapse was shorter with more advanced stages at study onset, and the majority of patients progress to symptomatic avascular necrosis that requires intervention.33 Avascular necrosis has been treated with a number of modalities including core decompression, osteotomy, bone grafting, surface arthroplasty, and joint replacement.34 The only randomized trial in avascular necrosis compared core decompression and physical therapy versus physical therapy alone and did not show a difference in outcome between the two arms; however, follow-up was short, and a significant number of stage III hips were included. Core decompression is a useful option in early stage avascular necrosis. Several studies associate total hip replacement in individuals with sickle cell disease with a higher rate of orthopedic and medical complications.35,36 However, other studies show a lower rate of orthopedic complications.37 Structural bone diseases in people with sickle cell disease make joint replacement technically challenging (see Chapter 103).
Iron Metabolism Red blood cell transfusions are a mainstay in the treatment of both acute and chronic sickle cell disease complications.38 Most patients receive at least one transfusion in their lifetime, usually for acute complications. Blood transfusions increase arterial oxygen pressure and Hb oxygen affinity, thereby reducing red blood cell sickling, and they also improve microvascular perfusion. Furthermore, regular blood transfusion regimens suppress endogenous erythropoiesis and therefore the production of red blood cells containing sickle Hb. Iron metabolism and consequently patterns of iron loading differ in sickle cell disease and thalassemia.39 Erythropoiesis is variably increased in sickle cell disease, but it is not ineffective. Unlike patients with thalassemia, patients with nontransfused sickle cell disease do not develop systemic iron overload because of increased iron absorption, and they may actually present with iron deficiency, possibly related to intravascular hemolysis and the resulting excessive urinary loss of iron. Inflammation, which
is part of the pathophysiology of sickle cell disease, increases synthesis of hepcidin and consequently decreases iron absorption and enhances retention of iron within the reticuloendothelial system. As a result, tissues and organs affected by iron overload are different in sickle cell disease and thalassemia. Iron-induced cardiac and endocrine dysfunction is less common in sickle cell disease. Musculoskeletal manifestations of iron overload include a symmetrical, polyarticular arthropathy with bony enlargement and minimal inflammation that can develop in 25% to 50% of patients. It notably affects the second and third metacarpophalangeal joints but also the proximal interphalangeal joints, wrists, elbows, shoulders, and hips. Osteoporosis can affect up to 25% of patients.
MUSCULOSKELETAL INVOLVEMENT: THALASSEMIAS Decreased Bone Density, Osteoporosis Skeletal changes in people with untreated thalassemia are related to bone marrow hyperplasia, resorption of cortex, rarefaction of cancellous bone with coarsening of the trabeculae, and a generalized decrease in bone density.40 In patients with thalassemia major, onset of the radiographic changes can be seen in their first year of life. Involvement of the spine, skull and facial bones, ribs, and metaphyses of long bones are typical (Figure 120-4). In the spine, osteoporosis and cortical thinning are associated with vertebral compression fractures (Table 120-4). After an initial increase in the height-to-width ratio of the vertebral body, thinning of the subchondral bone plates occurs and the bones become biconcave and wedge shaped as multiple compression fractures occur. Patients can experience scoliosis and kyphosis.41 Lateral plain radiographs of the spine may show a “bone-within-a-bone” appearance as the end plate depression is evident (Figure 120-5). MRI studies show predominance of red marrow in the vertebrae and early degeneration of the intervertebral disks of the lower thoracic and lumbar spine.42 Abnormal intravertebral iron deposition also can be seen.
Extramedullary Hematopoiesis Extramedullary hematopoiesis is seen as extraosseous extension of red marrow with symmetrical lobulated confluent masses expanding in the paravertebral and presacral spaces. These soft tissue masses have intermediate T1 signal, variable intensity of T2-weighted sequences, and mild gadolinium enhancement. Radionuclide imaging with
TABLE 120-4 Bone and Joint Involvement in Thalassemias Osteopenia, osteoporosis Bone pain Bone fractures Iron chelator arthropathy Intervertebral disk disease Spinal deformity
CHAPTER 120 Rheumatic Manifestations of Hemoglobinopathies
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technetium-labeled sulfur colloid may help define the hematopoetic nature of the masses.43 Spinal cord compression occasionally occurs as a result of epidural marrow extension. In the skull, marrow expansion causes widening with thinning of the outer table and thickening of the inner table, with remodeling of the skull (tower skull; Figure 120-6).
Iron Metabolism
Figure 120-4 Spinal involvement with vertical trabeculations in a person with thalassemia. (Case courtesy Dr. Chris O’Donnell, Radiopaedia .org, rID: 16592.)
Figure 120-5 Vertebral end plate changes in thalassemia. Vertebral end plate depression highlighted by arrows. (From Cockshot P, Middlemiss H: Clinical radiology in the tropics, Edinburgh, 1979, Churchill Livingstone.)
The anemia of thalassemia major becomes symptomatic between 6 months and 2 years of age, requiring the institution of a regular transfusion program. As a consequence of continuous anemia, erythropoiesis, although inefficient, can be intense; the bone marrow undergoes an enormous expansion with consequent distortion of facial features, and the plasma volume increases. In addition, hepatosplenomegaly develops. A regimen maintaining a minimum Hb concentration of 9.5 to 10.5 g/dL prevents all the aforementioned complications and fosters normal growth at least until puberty. Transfusion therapy results in iron overload in various tissues, and iron chelation therapy prevents accumulation of iron, promotes normal growth, and prevents death.44 Deferoxamine chelation is effective but challenging to use because of its cost and the inconvenience of prolonged subcutaneous infusions. Deferiprone, an oral iron chelator, has improved compliance and access to iron chelation therapy. However, serious complications can occur when it is used, including agranulocytosis. Mild arthralgias and/or arthritis may occur in up to 38% of patients45 and usually resolve on their own or with NSAIDs. In some patients, however, severe arthropathy related to deferiprone develops, requiring discontinuation of iron chelation therapy. In addition, erosive epiphyseal, physeal, and
Figure 120-6 Skull of a child with thalassemia. (From Azam M, Bhatti N: Hair-on-end appearance. Arch Dis Child 91:735, 2006.)
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PART 18 ARTHRITIS ACCOMPANYING SYSTEMIC DISEASE
metaphyseal changes are seen on radiographs of the long bones of the hands of symptomatic children.46
COMORBID RHEUMATIC DISEASE Autoimmune Disorders The occurrence of systemic autoimmune diseases, including rheumatoid arthritis and systemic lupus erythematosus, has occasionally been reported in patients with hemoglobinopathies.47 Some authors have suggested that their association has an increased risk.48 Several cases of mild recurrent arthritis have been reported in patients with thalassemia. Rheumatoid arthritis has rarely been described in patients with sickle cell disease.49 The prevalence and clinical features of rheumatoid arthritis in patients with thalassemia is unknown. A review of medical records of patients with either thalassemia or sickle cell disease followed up over a decade in Greece provides insight.50 Rheumatoid factor was detected in 23% of 90 patients, and anti-citrullinated protein antibodies were detected in only 2%. A low titer of positive anti-nuclear antibody (ANA) was present in nearly half of patients, and double-stranded DNA antibodies were found in one patient. Four percent of the patients with thalassemia major fulfilled American College of Rheumatology criteria for rheumatoid arthritis and received lowdose corticosteroids to control synovitis. One patient underwent methotrexate therapy. Patients with rheumatoid arthritis had no specific features that distinguished them from the other patients with hematologic disease. The nature of the rheumatoid arthritis was mild, and extraarticular features were uncommon. Abnormalities of the immune system can occur in patients with sickle cell disease. Immune deficiency and the presence of autoantibodies have been described in frequencies higher than that of control groups of Africans and Caucasians, and up to 20% of patients are positive for ANAs.51 The presence of these autoantibodies could be related to genetic factors and/or environmental influences. Although it has been suggested that a deficiency of the alternative complement pathway in patients with sickle cell disease was a predisposing factor in the development of immune complex diseases, this mechanism has not been confirmed.52 Autoimmune disease in adults with sickle cell disease may fail to be diagnosed or diagnosis may be delayed as a result of shared clinical manifestations. Bone and joint, lung, cardiac, renal, and central nervous systems may be involved in either autoimmune disease or sickle cell disease. Recognition of an autoimmune disease in patients with sickle cell disease may require a change in therapy, and the use of immunosuppressive medications may result in exacerbation of sickle cell disease.53
Gout Hyperuricemia and gout are uncommon in people with primary red blood cell disorders but have been reported in patients with sickle cell disease, Hb SC and CC disease, and thalassemias.54 Increased red blood cell turnover in sickle cell disease can lead to hyperuricemia, as can renal tubular involvement and a decrease in uric acid excretion. Two
patients with tophaceous gout and sickle cell disease have been reported.55 Appropriate therapy is treatment of the underlying hematologic disease and typical measures for acute gout. In studies from the 1970s, hyperuricemia was reported as a common feature of sickle cell disease, occurring in up to 41% of patients.56 To assess the recent prevalence of hyperuricemia and gout in adult patients with sickle cell disease, 65 consecutive patients with sickle cell disease in one center in France were studied during a 2-year period.57 Hyperuricemia was observed in only 9.2% of the patients in the cohort, and none had gout.
CONCLUSION Hemoglobinopathies, particularly sickle cell disease and the thalassemias, are often associated with significant and varied musculoskeletal manifestations, including osteonecrosis, arthropathies, and vertebral fractures. Awareness of the clinical presentations associated with these manifestations is essential so they are recognized by the physician and an effective management strategy can be formulated. The references for this chapter can also be found on ExpertConsult.com.
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