2 Rheumatological complications of sickle cell disease D. R. P O R T E R R. D. S T U R R O C K
HAEMOGLOBIN AND ITS GENETIC VARIANTS Haemoglobin consists of two beta chains, two alpha chains and four haem molecules. Normal human haemoglobin is designated haemoglobin (Hb) A. Genetic mutations of the gene encoding the beta chain may result in a single amino acid substitution, or amino acid deletion. More rarely, a point mutation in the globin chain termination codons results in elongated chains, or 'frame shift' mutations (from the loss of a single nucleotide base) alter all the subsequent genetic code triplets. The result of such mutations depends on the effect on the solubility, stability and 02 affinity of the haemoglobin complex. In sickle cell haemoglobin (Hb S) there is a point mutation of the gene encoding for the beta chain, resulting in the substitution of valine for glutamic acid at position 6. In the heterozygote (sickle cell trait) there is a mixture of Hb A and Hb S. In the homozygote (sickle cell anaemia) the majority of the haemoglobin is Hb S, with some fetal haemoglobin (Hb F). Hb S undergoes liquid crystal formation in hypoxic conditions, and the molecules aggregate in rod-like structures that then form into helices. The presence of other types of haemoglobin affects this process: for instance Hb F is excluded from the sickling process, and high Hb F concentration leads to less sickling. The crystallization of Hb S molecules causes red cell membrane damage and the red cells assume the characteristic sickle cell morphology. The process is reversible, but with increasing loss of red cell membrane and reduced red cell membrane permeability, the cell becomes irreversibly sickled; this leads to reduced red cell survival secondary to mechanical fragility and loss of membrane deformability (Mohandas et al, 1979). The sickled red cells aggregate in the microvasculature, resulting in increased blood viscosity, reduced blood flow, vascular stasis, and hence more hypoxia. More red cells sickle and the process accelerates leading, in some cases, to tissue infarction. Hb C has a lower solubility than Hb A, and in homozygous Hb C disease there is a tendency for the haemoglobin to crystallize. The resultant increase in red cell fragility and destruction in the microvasculature leads to a mild Bailli&e's Clinical Rheurnatology--
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haemolytic anaemia and splenomegaly that is rarely of clinical significance. Hb D is the term given for Hb variants with changes at position 6 (like Hb S) but that do not cause sickling. There are several variants resulting in a clinical picture ranging from very mild to a moderately severe anaemia, mild haemolysis and splenomegaly. Neither Hb C disease nor Hb D disease cause sickling or rheumatological disease, but the double heterozygotes for Hb S and Hb C or Hb D (Hb SC, Hb SD) behave in a similar fashion to sickle cell homozygotes. Double heterozygotes for Hb S and B thalassaemia (Hb SB thal) behave in a similar way.
SICKLE CELL ANAEMIA The sickle cell gene is common throughout Africa, parts of the Mediterranean, the Middle East and anywhere with a significant population originating from these areas. The gene is common because it appears to confer some resistance to malarial infection in the heterozygote.
Sickle cell trait
In the heterozygote there are rarely any deleterious clinical sequelae. It requires a high level of hypoxic stress, such as a poorly conducted general anaesthetic or high altitude, to cause sickling. There is no increased incidence of rheumatological conditions in sickle cell trait (Dorwart et al, 1977). In such patients receiving a general anaesthetic, care should be taken to maintain adequate oxygenation and hydration.
Sickle cell disease
Although the molecular and genetic basis of sickle cell anaemia is well understood, it is not entirely clear why the clinical expression of the disease is so variable. The disease varies from a mild haemolytic anaemia to a crippling disease punctuated by frequent sickle crises (see below). The concentration of Hb F, socioeconomic variables and the availability of prompt medical therapy for infection probably all have a role in determining the severity of the disease. Typically, patients with sickle cell disease present in childhood with a haemolytic anaemia and intermittent crises. These crises take the form of painful (thrombotic) crises caused by tissue infarction, haemolytic or aplastic crises resulting in sudden worsening of the anaemia, or sequestration crises in which blood rapidly sequestrates in the spleen resulting in severe anaemia. It is the painful crises that lead to many of the rheumatological manifestations of the disease. The treatment of these crises is similar: analgesia, adequate hydration, the treatment of intercurrent infection and the maintenance of an adequate haemoglobin by transfusion or partial exchange transfusion.
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RHEUMATOLOGICAL MANIFESTATIONS OF SICKLE CELL ANAEMIA Hand-foot syndrome This syndrome only occurs in young children, typically between 6 months and 2 years of age, and may be the presenting feature of sickle cell anaemia. There is a dramatic peripheral, symmetrical, diffuse swelling of the fingers and toes, with tenderness, warmth and oedema (Haggard, 1961) (Figure 1). There may be a fever and neutrophil leucocytosis (Watson et al, 1963). X-rays are initially normal, but subsequently areas of marrow density or lytic areas with a periosteal reaction may be seen. It seems likely that the syndrome is caused by infarction of marrow, cortical bone and periosteum. It may occur only in young children simply because older children and adults do not have bone marrow in the phalangeal bones. If there is damage to an epiphyseal plate, a finger may be permanently damaged and shortened. The hand-foot syndrome has been reported in both Hb SC disease (Karpathios et al, 1977) and Hb SB thal disease (Haggard, 1961). Bone infarction Bone infarction is a common occurrence during a painful crisis. Clinically, there is severe pain associated with bony tenderness, and often fever. The
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principal differential diagnosis is acute osteomyelitis, which will be discussed below. Initially, plain X-rays are normal but isotope bone scanning is a more sensitive method of detecting areas of bone infarction showing 'cold areas' of deficient isotope uptake (Hammel et al, 1973). Magnetic resonance (MR) imaging may offer more sensitivity and specificity; however, isotope bone scans will show 'cold areas' over both new and old infarcts while MR imaging can distinguish between the two by the presence or absence of oedema in and around the infarct (Rao et al, 1986). Following the acute phase of bone infarction, the plain radiographs become abnormal. Cortical bone infarction causes cortical thickening and sclerosis, with a periosteal reaction whereas bone marrow infarcts cause bone marrow fibrosis and either lytic or sclerotic appearances on X-ray (Bohrer, 1970). Avascular necrosis
If bone infarction occurs as the result of the occlusion of an end-artery serving an articular surface, avascular necrosis of periarticular bone and cartilage occurs. Although it is thought that most tissue infarction occurs as a result of microvascular occlusion, it has been shown that large vessel occlusion may occur in cerebral arteries (Stockman et al, 1972). Whether avascular necrosis of the femoral head, for instance, occurs because of microvascular damage (Sherman, 1959) or larger vessel occlusion is not known. Avascular necrosis of the femoral head is the commonest site, followed, in descending order of frequency, by the humeral head, tibial plateau, fibula, radius, ulna and calcaneum (Bohrer, 1970). As with any bone infarct, MR scanning and isotope bone scanning are the most sensitive methods of detecting avascular necrosis. On plain radiographs, the bones are initially normal and develop localized sclerosis with patchy lucency, sometimes between areas of sclerosis and normal bone. The femoral head becomes flattened and eventually collapses. There is no effective treatment; bed rest has been advocated in an attempt to allow the bone to revascularize and recover before weight bearing causes the bone to collapse. Core decompression has been used, with apparent success, but has not been subjected to controlled trials (Allen and Andrews, 1983). Frequently joint replacement surgery is required. Joint effusions
Arthropathy associated with sickle cell disease Joint effusions quite commonly occur, often during a crisis. The joint may be warm and tender. Joint aspiration is required to exclude septic arthritis, acute gout and haemarthrosis. The synovial fluid aspirates characteristically have normal glucose concentration, and low 'non-inflammatory' white cell counts (Schumacher et al, 1973), although fluid with high 'inflammatory' white cell counts may be seen (Orozco-Azcala and Baum, 1973). Sickled blood cells may be seen in the effusion whatever the cause. The arthritis
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most commonly affects the knees and other large joints; it is usually selflimiting over a period of 2-14 days, and intra-articular corticosteroids are of no value. The effusions may occur as a result of synovial venocclusion: synovial biopsy shows minimal inflammatory infiltrate, but occlusion of small vessels with thrombus can be identified (Schumacher et al, 1973). However, isotope bone scans can often demonstrate 'cold areas', suggesting bone infarction in areas adjacent to joints with effusions (Aiani et al, 1976). It is not clear whether synovial or adjacent bone infarction is the more important aetiological factor in the development of these effusions.
Gout As a result of the chronic haemolysis in sickle cell anaemia, there is increased turnover of porphyrin metabolism, and increased urate production. In children and most adults, this is compensated for by an increased urate clearance and hyperuricosuria. However, in 40% of adults, mild impairment of renal tubular urate secretion leads to hyperuricaemia (Diamond et al, 1979). Chronic renal failure from a glomerulopathy may occur in older patients, and this also predisposes them to hyperuricaemia. Acute gout may occur (Left et al, 1983).
Haemarthrosis Haemarthrosis of the knee has been described complicating a painful crisis, and bone infarction of the tibial plateau (Saheb, 1973). Infection
Infection is the single commonest cause of death in patients with sickle cell anaemia. In one series, two thirds of 166 sickle cell patients required hospitalization with a bacterial infection over an 11 year period (BarrettConnor, 1971). Children with sickle cell anaemia often have splenomegaly, but over the first ten years of life, there is recurrent splenic infarction. It is known that there is an increased risk of severe bacterial infections in patients who have undergone splenectomy following traumatic splenic rupture (Heier, 1980). It seems likely that patients with sickle cell anaemia have splenic dysfunction as a result of multiple splenic infarcts, partially explaining their susceptibility to infection. Other abnormalities of immune function such as impaired micro-organism phagocytosis, impaired opsonization and reduced alternative complement pathway activation have been demonstrated (Hand and King, 1978).
Septic arthritis Septic arthritis is uncommon (Barrett-Connor, 1971). In one series, it only occurred in the presence of acute osteomyelitis (Ebong, 1980). It may occur in a joint contiguous to a bone affected by acute osteomyelitis, but more commonly it occurs secondary to haematogenous, rather than local spread.
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There is often multiple joint involvement. Diagnosis may be made with joint aspirate or blood culture. The commonest joints affected are the hips, ankles, shoulders and knees. The organisms responsible are usually Gram-negative bacilli, and less often Gram-positive cocci. While culture results are awaited, blind antibiotic therapy should include adequate cover for Salmonella, E. coli, other Gram-negative bacilli and staphylococci. Bony ankylosis, and necrosis of the femoral epiphysis are recognized complications (Ebong, 1980). The efficacy of treatment may be limited by impaired synovial blood flow consequent on local vascular stasis secondary to sickling; in severe infection, the use of exchange transfusion has been advocated as an adjunct to antibiotic therapy (Palmer, 1975).
Osteomyelitis Acute osteomyelitis is much more common in patients with sickle cell anaemia than in control populations (Barrett-Connor, 1971), and salmonella osteomyelitis is particularly common (Engh et al, 1971). Differentiation of acute osteomyelitis from a simple bone infarct is difficult, and of some importance. Both conditions may be accompanied by bone pain and tenderness, fever and leukocytosis. Early diagnosis relies on culture of blood and marrow aspirate. Ebong (1986) reported 76 cases of acute osteomyelitis in 207 sickle cell patients with skeletal complications, presenting over 5 years. In 42%, the osteomyelitis was multifocal and in 50%, the causative organism was a Salmonella sp. In 17 patients chronic osteomyelitis developed; these patients tended to have presented late and many had open drainage (Ebong, 1986). It may be that prompt antibiotic therapy and the use of needle marrow aspiration will reduce the incidence of chronic osteomyelitis. Chronic osteomyelitis may be complicated by sinus formation and pathological fracture. Septic arthritis can also complicate acute osteomyelitis as discussed above. Initially, there are no radiological changes in affected bones and the early changes are indistinguishable from the features of bone infarction. However, later changes of longitudinal intracortical diaphyseal fissuring, overabundant involucrum formation, and the presence of multiple sites all strongly suggest osteomyelitis. Miscellaneous
Rhabdomyolysis has been described in a patient with sickle cell anaemia who was severely ill with salmonella gastroenteritis (requiring bowel resection for bowel gangrene) and acute salmonella osteomyelitis (Devereux and Knowles, 1985). A case of focal necrotizing myositis in association with sickle cell anaemia has also been reported (Dorwart and Gabuzde, 1985). INVESTIGATIONS Sickle cell anaemia is diagnosed on the basis of anaemia, a positive sickle cell test, and the presence of Hb S on haemoglobin electrophoresis.
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Radiology The radiological appearances of bone infarcts, avascular necrosis and osteomyelitis have already been discussed. However, there are other skeletal changes associated with sickle cell anaemia. Bone marrow expansion results in a pattern of coarse trabeculation on X-ray, with increased total bone width (Figure 2). The skull may show a 'hair-on-end' appearance (Barton and Cockshott, 1962). Osteoporosis is common, and protrusio acetabuli was seen
Figure 2. Coarse bony trabecular pattern in sickle cell disease.
in most cases in one series (Martinez et al, 1984). The vertebral bodies may have a characteristic biconcave 'fish vertebra' deformity that develops between 10 and 20 years of age. The long bones sometimes show a 'cortex within a cortex' appearance, with a layer of dense medullary bone separated from the inner layer of cortex by a lucent line (Reynolds, 1977). Irregular sclerosis of the sacroiliac joints, mimicking sacroileitis, has been reported, and this may be secondary to bone infarcts affecting the sacroiliac joints (Schumacher et al, 1973).
Other investigations The ESR in sickle cell patients in remission is abnormally low for their haematocrit. During a crisis or intercurrent infection the ESR rises. A raised
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ESR indicates present or recent crisis or infection (Lawrence and Fabry, 1986). The alkaline phosphatase rises during crisis, and this is of bony origin (Brody et al, 1975). HAEMOGLOBIN SC DISEASE
This is much less common than sickle cell disease, although it is very common in West Africa. Hb SC disease is characterized by a mild anaemia, a positive sickling test and the presence of Hb S and Hb C on haemoglobin electrophoresis. The clinical course is similar to that of mild sickle cell anaemia; most of the complications are less common in Hb SC disease but thrombotic episodes (particularly to the lungs) and proliferative retinopathy appear to be more common. This may relate to the higher haematocrit of the typical Hb SC patient. The hand-foot syndrome, avascular necrosis and bone infarction have all been reported in Hb SC disease (Haggard, 1961; Ballas et al, 1982; Smith and Conley, 1984). The serum urate is lower than in sickle cell anaemia, in keeping with the milder haemolysis. There are conflicting reports regarding the relative incidence of avascular necrosis in Hb SC disease and sickle cell anaemia; some authors found avascular necrosis to be more common in Hb SC disease (Chung and Ralston, 1969) and others found the opposite (Ballas et al, 1982). The investigation and treatment of patients with Hb SC is similar to that for sickle cell anaemia. Exchange transfusions may be required more often to reduce the percentage of Hb S in the blood because of the relatively high haematocrit of Hb SC patients (Weatherall, 1987). HAEMOGLOBIN SICKLE [~ THALASSAEMIA DISEASE
The clinical course of Hb S 13-thal is variable. Hb S [3-thal+ patients have a mild haemolytic illness, whereas Hb S [3-thai~ patients have a similar clinical course to sickle cell anaemia patients. The same rheumatological manifestations are seen (Karpathios et al, 1977; Left et al, 1983; Smith and Conley, 1984). HEREDITARY RED CELL ENZYME DEFICIENCIES
The commonest hereditary red cell enzyme deficiencies are glucose-6phosphate dehydrogenase deficiency (G6PDH deficiency) and pyruvate kinase deficiency (PK deficiency), and in neither are there direct rheumatological manifestations. However, patients with G6PDH deficiency are susceptible to drug-induced oxidant haemolysis. It is important, therefore, to be aware that G6PDH deficiency is common in patients originating from Africa, India, Asia and some parts of the Mediterranean. Patients with
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G6PDH deficiency should not be treated with sulphasalazine or chloroquine for rheumatic disorders. PK deficiency causes a chronic haemolytic anaemia, and this may result in bone marrow expansion and X-ray changes similar to those seen in [3-thalassaemia.
REFERENCES Alani A, Schumacher H, Dorwart B & Kuhl D (1976) Bone marrow scan evaluation of arthropathy in sickle cell disorders. Archives of Internal Medicine 136: 436. Allen B & Andrews B (1972) Bilateral aseptic necrosis of calcanei in an adult male with sickle cell anaemia. New England Journal of Medicine 287: 846. Ballas S, Lewis C, Noone A e t al (1982) Clinical haematoiogical and biochemical features of sickle cell disease. American Journal of Hematology 13: 37. Barrett-Connor E (1971) Bacterial infection and sickle cell anaemia. An analysis of 250 infections in 166 patients and a review of the literature. Medicine 50: 97. Barton C & Cockshott W (1962) Bone changes in haemoglobin sickle cell disease. American Journal of Roentgenology 88: 523. Bohrer S (1970) Acute long bone diaphyseal infarcts in sickle cell disease. British Journal of Radiology 43: 685. Brody J, Ryan W & Haider M (1975) Serum alkaline phosphatase isoenzyme in sickle cell anaemia. Journal of the American Medical Association 232: 738. Chung S & Ralston E (1969) Necrosis of femoral head associated with sickle cell anaemia and its genetic variants. Journal of Bone and Joint Surgery 51A: 33. Devereux S & Knowles S (1985) Rhabdomyolysis and acute renal failure in sickle cell anaemia. British Medical Journal 290: 1707. Diamond H, Meisel A & Holden D (1979) The natural history of urate overproduction in sickle cell anaemia. Annals oflnternal Medicine 90: 752. Dorwart B, Goldberg M, Schumacher H & Alani A (1986) Absence of increased frequency of bone and joint disease with haemoglobin AS or AC. Annals oflnternal Medicine 86: 66. Dorwart B & Gabuzde T (1985) Symmetric myositis and faciitis: complication of sickle cell anaemia during vasocclusion. Journal of Rheumatology 12: 590. Ebong W (1980) Treatment of severely ill patients with sickle cell anaemia and associated septic arthritis. Clinical Orthopaedics and Related Research 149: 145. Ebong W (1986) Acute osteomyelitis in Nigerians with sickle ceil disease. Annals of the Rheumatic Diseases 45: 911. Engh C, Hughes J, Abrams R & Bowerman J (1971) Osteomyelitis in the patient with sickle cell disease. Diagnosis and management. Journal of Bone and Joint Surgery 53: 1. Haggard M (1961) Sickle cell anaemia in the first two years of life. Journal of Pediatrics 58: 785. Hammel C, De Nardo S, De Nardo G & Lewis J (1973) Bone marrow and bone mineral scintigraphic studies in sickle cell disease. British Journal of Haematology 25: 593. Hand W & King N (1978) Serum opsonization of salmonella in sickle cell anemia. American Journal of Medicine 64: 388. Heier H (1980) Splenectomy and serious infection. Scandinavian Journal of Haematology 24: 5. Karpathios T, Nicolaidou P, Korkgs A & Thomaidis T (1977) The hand-foot syndrome in sickle cell beta thalassaemic disease. Journal of the American Medical Association 238: 1540. Lawrence L & Fabry M (1986) ESR during steady state and painful crises in sickle cell anemia. American Journal of Medicine 81: 801. Left R, Aldo-Benson M & Fife R (1983) Tophaceous gout in a patient with sickle cell thalassaemia. Case report and review of the literature. Medicine 50: 97. Martinez S, Apple S, Baber C, Putnam C & Rosse W (1984) Protrusio acetabuli in sickle cell anaemia. Radiology 151: 43. Mohandas N, Phillips W & Beisis M (1979) Red blood cell deformability and haemolytic anemia. Seminars in Hematology 16: 95. Orozco-Azcala J & Baum J (1973) Arthritis during sickle cell crisis. New England Journal of Medicine 288: 420.
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Palmer D (1975) Septic arthritis in sickle cell thalassaemia. Pathophysiology of impaired response to infection. Arthritis and Rheumatism 18: 339. Rao V, Fishman M, Mitchell D et al (1986) Painful sickle crisis: bone marrow patterns observed with MR imaging. Radiology llil: 211. Reynolds J (1977) Radiological manifestations of sickle cell hemoglobinopathy. Journal of the American Medical Association 238: 247. Saheb F (1973) Arthropathy in sickle cell disease. New England Journal of Medicine 288: 971. Schumacher H, Andrews R & McLaughlin G (1973) Arthropathyin sickle cell disease. Annals of lnternal Medicine 78: 203. Sherman M (1959) Pathogenesis of disintegration of the hip in sickle cell anemia. Southern Medical Journal 52: 632. Smith C & Conley C (1988) Clinical features of the genetic variants of sickle cell disease. Bulletin of Johns Hopkins Hospital 94: 289. Stockman J ~Nijno M, Mishkin M & Oski F (1972) Occlusion of large cerebral vessels in sickle cell anemia. New England Journal of Medicine 287: 846. Watson R, Burke H, Megas H & Robinson M (1963) Hand-foot syndrome in sickle cell disease in young children. Paediatrics 71: 975. Weatherall D (1987) Sickling disorders. In Weatherall D, Ledingham J & Warrall D (eds) Oxford Textbook of Medicine, pp 122-126. Oxford: Oxford Medical Publications.
HAEMOGLOBIN AND ITS GENETIC VARIANTS Haemoglobin consists of two beta chains, two alpha chains and four haem molecules. Normal human haemoglobin is designated haemoglobin (Hb) A. Genetic mutations of the gene encoding the beta chain may result in a single amino acid substitution, or amino acid deletion. More rarely, a point mutation in the globin chain termination codons results in elongated chains, or 'frame shift' mutations (from the loss of a single nucleotide base) alter all the subsequent genetic code triplets. The result of such mutations depends on the effect on the solubility, stability and 02 affinity of the haemoglobin complex. In sickle cell haemoglobin (Hb S) there is a point mutation of the gene encoding for the beta chain, resulting in the substitution of valine for glutamic acid at position 6. In the heterozygote (sickle cell trait) there is a mixture of Hb A and Hb S. In the homozygote (sickle cell anaemia) the majority of the haemoglobin is Hb S, with some fetal haemoglobin (Hb F). Hb S undergoes liquid crystal formation in hypoxic conditions, and the molecules aggregate in rod-like structures that then form into helices. The presence of other types of haemoglobin affects this process: for instance Hb F is excluded from the sickling process, and high Hb F concentration leads to less sickling. The crystallization of Hb S molecules causes red cell membrane damage and the red cells assume the characteristic sickle cell morphology. The process is reversible, but with increasing loss of red cell membrane and reduced red cell membrane permeability, the cell becomes irreversibly sickled; this leads to reduced red cell survival secondary to mechanical fragility and loss of membrane deformability (Mohandas et al, 1979). The sickled red cells aggregate in the microvasculature, resulting in increased blood viscosity, reduced blood flow, vascular stasis, and hence more hypoxia. More red cells sickle and the process accelerates leading, in some cases, to tissue infarction. Hb C has a lower solubility than Hb A, and in homozygous Hb C disease there is a tendency for the haemoglobin to crystallize. The resultant increase in red cell fragility and destruction in the microvasculature leads to a mild Bailli&e's Clinical Rheurnatology--
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221 Copyright9 1991,byBailli6reTindall Allrightsofreproductionin anyformreserved
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haemolytic anaemia and splenomegaly that is rarely of clinical significance. Hb D is the term given for Hb variants with changes at position 6 (like Hb S) but that do not cause sickling. There are several variants resulting in a clinical picture ranging from very mild to a moderately severe anaemia, mild haemolysis and splenomegaly. Neither Hb C disease nor Hb D disease cause sickling or rheumatological disease, but the double heterozygotes for Hb S and Hb C or Hb D (Hb SC, Hb SD) behave in a similar fashion to sickle cell homozygotes. Double heterozygotes for Hb S and B thalassaemia (Hb SB thal) behave in a similar way.
SICKLE CELL ANAEMIA The sickle cell gene is common throughout Africa, parts of the Mediterranean, the Middle East and anywhere with a significant population originating from these areas. The gene is common because it appears to confer some resistance to malarial infection in the heterozygote.
Sickle cell trait
In the heterozygote there are rarely any deleterious clinical sequelae. It requires a high level of hypoxic stress, such as a poorly conducted general anaesthetic or high altitude, to cause sickling. There is no increased incidence of rheumatological conditions in sickle cell trait (Dorwart et al, 1977). In such patients receiving a general anaesthetic, care should be taken to maintain adequate oxygenation and hydration.
Sickle cell disease
Although the molecular and genetic basis of sickle cell anaemia is well understood, it is not entirely clear why the clinical expression of the disease is so variable. The disease varies from a mild haemolytic anaemia to a crippling disease punctuated by frequent sickle crises (see below). The concentration of Hb F, socioeconomic variables and the availability of prompt medical therapy for infection probably all have a role in determining the severity of the disease. Typically, patients with sickle cell disease present in childhood with a haemolytic anaemia and intermittent crises. These crises take the form of painful (thrombotic) crises caused by tissue infarction, haemolytic or aplastic crises resulting in sudden worsening of the anaemia, or sequestration crises in which blood rapidly sequestrates in the spleen resulting in severe anaemia. It is the painful crises that lead to many of the rheumatological manifestations of the disease. The treatment of these crises is similar: analgesia, adequate hydration, the treatment of intercurrent infection and the maintenance of an adequate haemoglobin by transfusion or partial exchange transfusion.
223
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RHEUMATOLOGICAL MANIFESTATIONS OF SICKLE CELL ANAEMIA Hand-foot syndrome This syndrome only occurs in young children, typically between 6 months and 2 years of age, and may be the presenting feature of sickle cell anaemia. There is a dramatic peripheral, symmetrical, diffuse swelling of the fingers and toes, with tenderness, warmth and oedema (Haggard, 1961) (Figure 1). There may be a fever and neutrophil leucocytosis (Watson et al, 1963). X-rays are initially normal, but subsequently areas of marrow density or lytic areas with a periosteal reaction may be seen. It seems likely that the syndrome is caused by infarction of marrow, cortical bone and periosteum. It may occur only in young children simply because older children and adults do not have bone marrow in the phalangeal bones. If there is damage to an epiphyseal plate, a finger may be permanently damaged and shortened. The hand-foot syndrome has been reported in both Hb SC disease (Karpathios et al, 1977) and Hb SB thal disease (Haggard, 1961). Bone infarction Bone infarction is a common occurrence during a painful crisis. Clinically, there is severe pain associated with bony tenderness, and often fever. The
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224
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principal differential diagnosis is acute osteomyelitis, which will be discussed below. Initially, plain X-rays are normal but isotope bone scanning is a more sensitive method of detecting areas of bone infarction showing 'cold areas' of deficient isotope uptake (Hammel et al, 1973). Magnetic resonance (MR) imaging may offer more sensitivity and specificity; however, isotope bone scans will show 'cold areas' over both new and old infarcts while MR imaging can distinguish between the two by the presence or absence of oedema in and around the infarct (Rao et al, 1986). Following the acute phase of bone infarction, the plain radiographs become abnormal. Cortical bone infarction causes cortical thickening and sclerosis, with a periosteal reaction whereas bone marrow infarcts cause bone marrow fibrosis and either lytic or sclerotic appearances on X-ray (Bohrer, 1970). Avascular necrosis
If bone infarction occurs as the result of the occlusion of an end-artery serving an articular surface, avascular necrosis of periarticular bone and cartilage occurs. Although it is thought that most tissue infarction occurs as a result of microvascular occlusion, it has been shown that large vessel occlusion may occur in cerebral arteries (Stockman et al, 1972). Whether avascular necrosis of the femoral head, for instance, occurs because of microvascular damage (Sherman, 1959) or larger vessel occlusion is not known. Avascular necrosis of the femoral head is the commonest site, followed, in descending order of frequency, by the humeral head, tibial plateau, fibula, radius, ulna and calcaneum (Bohrer, 1970). As with any bone infarct, MR scanning and isotope bone scanning are the most sensitive methods of detecting avascular necrosis. On plain radiographs, the bones are initially normal and develop localized sclerosis with patchy lucency, sometimes between areas of sclerosis and normal bone. The femoral head becomes flattened and eventually collapses. There is no effective treatment; bed rest has been advocated in an attempt to allow the bone to revascularize and recover before weight bearing causes the bone to collapse. Core decompression has been used, with apparent success, but has not been subjected to controlled trials (Allen and Andrews, 1983). Frequently joint replacement surgery is required. Joint effusions
Arthropathy associated with sickle cell disease Joint effusions quite commonly occur, often during a crisis. The joint may be warm and tender. Joint aspiration is required to exclude septic arthritis, acute gout and haemarthrosis. The synovial fluid aspirates characteristically have normal glucose concentration, and low 'non-inflammatory' white cell counts (Schumacher et al, 1973), although fluid with high 'inflammatory' white cell counts may be seen (Orozco-Azcala and Baum, 1973). Sickled blood cells may be seen in the effusion whatever the cause. The arthritis
RHEUMATOLOGICAL COMPLICATIONS OF SICKLE CELL DISEASE
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most commonly affects the knees and other large joints; it is usually selflimiting over a period of 2-14 days, and intra-articular corticosteroids are of no value. The effusions may occur as a result of synovial venocclusion: synovial biopsy shows minimal inflammatory infiltrate, but occlusion of small vessels with thrombus can be identified (Schumacher et al, 1973). However, isotope bone scans can often demonstrate 'cold areas', suggesting bone infarction in areas adjacent to joints with effusions (Aiani et al, 1976). It is not clear whether synovial or adjacent bone infarction is the more important aetiological factor in the development of these effusions.
Gout As a result of the chronic haemolysis in sickle cell anaemia, there is increased turnover of porphyrin metabolism, and increased urate production. In children and most adults, this is compensated for by an increased urate clearance and hyperuricosuria. However, in 40% of adults, mild impairment of renal tubular urate secretion leads to hyperuricaemia (Diamond et al, 1979). Chronic renal failure from a glomerulopathy may occur in older patients, and this also predisposes them to hyperuricaemia. Acute gout may occur (Left et al, 1983).
Haemarthrosis Haemarthrosis of the knee has been described complicating a painful crisis, and bone infarction of the tibial plateau (Saheb, 1973). Infection
Infection is the single commonest cause of death in patients with sickle cell anaemia. In one series, two thirds of 166 sickle cell patients required hospitalization with a bacterial infection over an 11 year period (BarrettConnor, 1971). Children with sickle cell anaemia often have splenomegaly, but over the first ten years of life, there is recurrent splenic infarction. It is known that there is an increased risk of severe bacterial infections in patients who have undergone splenectomy following traumatic splenic rupture (Heier, 1980). It seems likely that patients with sickle cell anaemia have splenic dysfunction as a result of multiple splenic infarcts, partially explaining their susceptibility to infection. Other abnormalities of immune function such as impaired micro-organism phagocytosis, impaired opsonization and reduced alternative complement pathway activation have been demonstrated (Hand and King, 1978).
Septic arthritis Septic arthritis is uncommon (Barrett-Connor, 1971). In one series, it only occurred in the presence of acute osteomyelitis (Ebong, 1980). It may occur in a joint contiguous to a bone affected by acute osteomyelitis, but more commonly it occurs secondary to haematogenous, rather than local spread.
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There is often multiple joint involvement. Diagnosis may be made with joint aspirate or blood culture. The commonest joints affected are the hips, ankles, shoulders and knees. The organisms responsible are usually Gram-negative bacilli, and less often Gram-positive cocci. While culture results are awaited, blind antibiotic therapy should include adequate cover for Salmonella, E. coli, other Gram-negative bacilli and staphylococci. Bony ankylosis, and necrosis of the femoral epiphysis are recognized complications (Ebong, 1980). The efficacy of treatment may be limited by impaired synovial blood flow consequent on local vascular stasis secondary to sickling; in severe infection, the use of exchange transfusion has been advocated as an adjunct to antibiotic therapy (Palmer, 1975).
Osteomyelitis Acute osteomyelitis is much more common in patients with sickle cell anaemia than in control populations (Barrett-Connor, 1971), and salmonella osteomyelitis is particularly common (Engh et al, 1971). Differentiation of acute osteomyelitis from a simple bone infarct is difficult, and of some importance. Both conditions may be accompanied by bone pain and tenderness, fever and leukocytosis. Early diagnosis relies on culture of blood and marrow aspirate. Ebong (1986) reported 76 cases of acute osteomyelitis in 207 sickle cell patients with skeletal complications, presenting over 5 years. In 42%, the osteomyelitis was multifocal and in 50%, the causative organism was a Salmonella sp. In 17 patients chronic osteomyelitis developed; these patients tended to have presented late and many had open drainage (Ebong, 1986). It may be that prompt antibiotic therapy and the use of needle marrow aspiration will reduce the incidence of chronic osteomyelitis. Chronic osteomyelitis may be complicated by sinus formation and pathological fracture. Septic arthritis can also complicate acute osteomyelitis as discussed above. Initially, there are no radiological changes in affected bones and the early changes are indistinguishable from the features of bone infarction. However, later changes of longitudinal intracortical diaphyseal fissuring, overabundant involucrum formation, and the presence of multiple sites all strongly suggest osteomyelitis. Miscellaneous
Rhabdomyolysis has been described in a patient with sickle cell anaemia who was severely ill with salmonella gastroenteritis (requiring bowel resection for bowel gangrene) and acute salmonella osteomyelitis (Devereux and Knowles, 1985). A case of focal necrotizing myositis in association with sickle cell anaemia has also been reported (Dorwart and Gabuzde, 1985). INVESTIGATIONS Sickle cell anaemia is diagnosed on the basis of anaemia, a positive sickle cell test, and the presence of Hb S on haemoglobin electrophoresis.
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Radiology The radiological appearances of bone infarcts, avascular necrosis and osteomyelitis have already been discussed. However, there are other skeletal changes associated with sickle cell anaemia. Bone marrow expansion results in a pattern of coarse trabeculation on X-ray, with increased total bone width (Figure 2). The skull may show a 'hair-on-end' appearance (Barton and Cockshott, 1962). Osteoporosis is common, and protrusio acetabuli was seen
Figure 2. Coarse bony trabecular pattern in sickle cell disease.
in most cases in one series (Martinez et al, 1984). The vertebral bodies may have a characteristic biconcave 'fish vertebra' deformity that develops between 10 and 20 years of age. The long bones sometimes show a 'cortex within a cortex' appearance, with a layer of dense medullary bone separated from the inner layer of cortex by a lucent line (Reynolds, 1977). Irregular sclerosis of the sacroiliac joints, mimicking sacroileitis, has been reported, and this may be secondary to bone infarcts affecting the sacroiliac joints (Schumacher et al, 1973).
Other investigations The ESR in sickle cell patients in remission is abnormally low for their haematocrit. During a crisis or intercurrent infection the ESR rises. A raised
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ESR indicates present or recent crisis or infection (Lawrence and Fabry, 1986). The alkaline phosphatase rises during crisis, and this is of bony origin (Brody et al, 1975). HAEMOGLOBIN SC DISEASE
This is much less common than sickle cell disease, although it is very common in West Africa. Hb SC disease is characterized by a mild anaemia, a positive sickling test and the presence of Hb S and Hb C on haemoglobin electrophoresis. The clinical course is similar to that of mild sickle cell anaemia; most of the complications are less common in Hb SC disease but thrombotic episodes (particularly to the lungs) and proliferative retinopathy appear to be more common. This may relate to the higher haematocrit of the typical Hb SC patient. The hand-foot syndrome, avascular necrosis and bone infarction have all been reported in Hb SC disease (Haggard, 1961; Ballas et al, 1982; Smith and Conley, 1984). The serum urate is lower than in sickle cell anaemia, in keeping with the milder haemolysis. There are conflicting reports regarding the relative incidence of avascular necrosis in Hb SC disease and sickle cell anaemia; some authors found avascular necrosis to be more common in Hb SC disease (Chung and Ralston, 1969) and others found the opposite (Ballas et al, 1982). The investigation and treatment of patients with Hb SC is similar to that for sickle cell anaemia. Exchange transfusions may be required more often to reduce the percentage of Hb S in the blood because of the relatively high haematocrit of Hb SC patients (Weatherall, 1987). HAEMOGLOBIN SICKLE [~ THALASSAEMIA DISEASE
The clinical course of Hb S 13-thal is variable. Hb S [3-thal+ patients have a mild haemolytic illness, whereas Hb S [3-thai~ patients have a similar clinical course to sickle cell anaemia patients. The same rheumatological manifestations are seen (Karpathios et al, 1977; Left et al, 1983; Smith and Conley, 1984). HEREDITARY RED CELL ENZYME DEFICIENCIES
The commonest hereditary red cell enzyme deficiencies are glucose-6phosphate dehydrogenase deficiency (G6PDH deficiency) and pyruvate kinase deficiency (PK deficiency), and in neither are there direct rheumatological manifestations. However, patients with G6PDH deficiency are susceptible to drug-induced oxidant haemolysis. It is important, therefore, to be aware that G6PDH deficiency is common in patients originating from Africa, India, Asia and some parts of the Mediterranean. Patients with
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G6PDH deficiency should not be treated with sulphasalazine or chloroquine for rheumatic disorders. PK deficiency causes a chronic haemolytic anaemia, and this may result in bone marrow expansion and X-ray changes similar to those seen in [3-thalassaemia.
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