Clinical Biology of the Hemoglobinopathies

The hemoglobinopathies comprise a group of genetic disorders characterized by the presence of variant hemoglobins in circulating erythrocytes. Clinical manifestations differ dramatically based on the physicochemical behavior of the abnormal hemoglobin, and how the variant protein chains interact with other hemoglobin chains, the erythrocyte membrane, ion transporters, and oxygen. Some variant hemoglobins exhibit abnormal oxygen-dissociation curves or erythrocyte fragility resulting in dyspnea, fatigue, or hemolysis. Relevant to rheumatologic manifestations, the red cells of patients with sickle cell variants are structurally rigid, and as they traverse the microvasculature are unable to deform in small vessels; they occlude the vascular lumina and abnormally adhere to endothelial cells. As a result, patients with homozygous hemoglobin S disorder (sickle cell anemia, Hgb SS) exhibit a broad range of clinical syndromes caused by variable intensity of the intracellular sickling process and resultant vaso-occlusion. The degree of hemoglobin sickling dictates the complications and is affected by several factors, including the presence and amount of alternative hemoglobin forms (e.g., fetal hemoglobin, Hgb F). Our molecular understanding of this process has grown over the past 30 years,¹ and greater understanding has contributed to the development of management strategies for treating and limiting these vaso-occlusive episodes.

Sickling and vaso-occlusion occur more in tissues with low oxygen tension and lower pH. Ischemic phenomena, sometimes with lasting sequelae, seem to be particularly common in kidney, eye, bone, synovium, muscle, and skin. Other striking organ involvement may include stroke, mitral valve damage, splenic infarction with hypofunction, and acute pulmonary syndromes. Under certain conditions, these complications may mimic systemic inflammatory, autoimmune, or primary thrombotic disorders.

As a result of chronic hemolysis, some of the hemoglobinopathies such as the thalassemias (imbalanced synthesis of normal globin chains) result in hyperplastic marrow with skeletal abnormalities.² Patients may require frequent transfusions, which can lead to syndromes associated with iron overload, or painful joint complications from the required use of iron chelators.

Clinical Features of Musculoskeletal Syndromes Linked to Hemoglobinopathies

The recurrent painful crisis is the hallmark of sickle disease, with marked pain in the muscles and joints, as well as in the abdomen and chest. These episodes involve muscles and joints and are sometimes difficult to localize; frequently, the pattern of pain is repeated in recurrent crises. Pain that is clearly localized to an isolated area, such as a single shoulder, right upper quadrant, buttock, or groin, warrants aggressive and rapid evaluation. The pain may be severe enough to require narcotics, but extreme diligence must be paid to the development of individualized pain control care plans to limit the expectation and delivery of escalating narcotics in all patients. Painful crises may begin as early as 6 months of age as the concentration of fetal hemoglobin F wanes, permitting sickling to occur more readily.

Avascular necrosis (AVN; osteonecrosis) and ischemic bone syndromes are common in both adults and children with sickle cell anemia (but are not usually seen in patients with heterozygous Hgb S disease—sickle trait³). In very young children, repeated vaso-occlusive crises involving growing small bones of the hands and feet cause the hand-foot syndrome, characterized by diffuse painful hand/foot swelling, which may be accompanied by low-grade fever. Radiographic changes may be seen approximately 10 days after the onset of symptoms; these consist of subperiosteal new bone formation in the hands and feet. Cortical thinning, multiple irregular intramedullary deposits, and areas of spotty destruction and formation of periosteal new bone may appear later. These changes can lead to a “moth-eaten” appearance.⁴ AVN is often multifocal but characteristically affects the femoral heads.⁵ The pain may be of acute onset or may progress insidiously from intermittent pain to pain with use, and finally to constant discomfort or severe pain at rest. Frequently, this condition is diagnosed in young to middle-aged patients who have experienced years of vaso-occlusive crises. Presumably, it occurs as the result of multiple ischemic and occlusive episodes, resulting in bone death as well as progressively increased intraosseous pressure. The prevalence of femoral head AVN is likely greater than 40%. Humeral heads are frequently affected. AVN can mimic a true arthritis with the presence of significant synovial effusion. The pathogenesis of these noninflammatory effusions is not certain, but they may result from hydrostatic pressure increases in vessels draining into the necrotic bone.

Noninfectious arthritis is well described in the setting of acute vaso-occlusive crisis.^6–8 Most patients have homozygous SS disease, but a few may have hemoglobin SC (Hgb SC) disease or hemoglobin S-beta thalassemia (β-thalassemia). Crystal-induced arthritis and infection should be excluded by synovial fluid analysis and culture as appropriate. Some of the effusions (monoarticular or oligoarticular) accompany painful crises and joint examination may reveal that adjacent bone is more tender than the joint capsule itself. Almost all synovial fluids are noninflammatory, hence the possibility that bone infarction with a “sympathetic” or transudative effusion offers a pathologic explanation for these effusions. Polyarthritis with minimal or mildly inflammatory fluid has been described in the setting of crisis.⁷ In a series of 70 patients with sickle disease (including Hgb SC disease and Hgb S-thalassemia) followed prospectively, 32 had joint manifestations (30 with Hgb SS disease),⁶ indicating that if carefully looked for, articular involvement is fairly common. Most cases of acute monoarticular and oligoarticular arthritis happened in the setting of a painful crisis, but a very significant subgroup (44%) exhibited arthritis and fever as major symptoms (infection was excluded). In this series, synovial fluid analyses were striking. Sickle cells were seen in many of the synovial fluid samples—an observation that has been noted by others. Whereas cultures were negative and no crystals were observed, many of the synovial fluid samples were inflammatory in cellular appearance with neutrophilic predominance. Nonetheless, arthritis lasted only a mean of 5 days.⁶ An ankle arthritis associated with new or worsening distal leg ulcers has also been described⁸; both may result from occlusive small vessel disease. The synovial histopathology in sickle cell–associated arthritis is generally fairly bland—minimal inflammation with some intimal proliferation and vascular congestion with occasional thrombosis has been reported.⁹

Joint and bone infections are well-recognized complications in patients with sickle cell disease, although they are not particularly common. Salmonella is an unusual cause of musculoskeletal infection associated with sickle disease.¹⁰ It is more frequent in children than in adults, and more frequently will result in osteomyelitis rather than septic arthritis. Reasons for susceptibility to this specific organism remain unclear. Patients with sickle cell anemia exhibit potentially altered gut mucosal integrity due to small vessel ischemic injury, splenic infarction with dysfunction, and decreased complement activation, all of which may render patients at increased relative risk. Moreover, damage to joints from repetitive ischemic injury provides a nidus for bacterial “seeding.” The diaphysis is most commonly involved in osteomyelitis, although infection may involve the epiphysis, and bacteria may thereby migrate to the joint space.

In a recent retrospective study of 2000 consecutive adults with sickle cell disease, 59 (3%) were found to have had septic arthritis.¹¹ The hip was involved in 61% of recorded cases—a disturbing observation in that this is a joint that physicians are often reluctant to aspirate and for which it is often tempting on clinical grounds to attribute acute pain to hip AVN. Also of note, in this study from France, no cases of Salmonella were reported. Most infections were due to Staphylococcus aureus, as observed in other series of patients with septic arthritis without sickle disease. A relatively large proportion of gram-negative infections theoretically could be due to increased bacterial translocation across the bowel mucosa. The authors documented a strong association in these adults with the presence of previous childhood osteomyelitis or AVN. Overall, Salmonella infection seems to be more strongly associated with osteomyelitis in patients with sickle cell disease¹⁰ than in those with arthritis. It is important to note that osteomyelitis may be multifocal.

Sickle cell disease is associated with hyperuricemia, likely due to increased uric acid generation associated with hemolysis and erythroid proliferation. Gout has been described in young patients with sickle disease. Although an infrequent occurrence in young patients, it is generally unexpected and can be confused with other more common causes of acute joint pain in these patients.¹²

Patients with thalassemias have rarely been described as having arthritis or joint pain associated with their dysregulated hemoglobin synthesis. However, chelation therapy with deferiprone, which is often needed to reverse the iron load from frequent transfusions, has been associated with multiple musculoskeletal complications.¹³ Arthralgias seem to be particularly common, perhaps in 20% of patients, although arthritis has been described. Whether some of these patients may have been experiencing a reaction to periarticular and synovial iron overload, and not directly to the drug, is difficult to ascertain given short-term follow-up after drug withdrawal. Successful response to nonsteroidal anti-inflammatory therapy has been suggested by several authors to indicate a useful palliative therapy.¹⁴