Bone infarcts in a woman with systemic lupus erythematosus and antiphospholipid antibody syndrome
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《加拿大医疗协会学报》
The Case: A 48-year-old woman with systemic lupus erythematosus (SLE) diagnosed more than 20 years ago presented to our clinic with a history of generalized pain, profound fatigue, oral ulcers, dry eyes and mouth, and hair loss. She complained of severe pain in her fingers, wrists, knees, hips and ankles. She also reported significant morning stiffness and muscle soreness. In the past, she had had immune thrombocytopenic purpura, several deep venous thromboses and an episode of pulmonary embolism. She was taking warfarin (2.5 mg daily), hydroxychloroquine (200 mg twice daily), acetaminophen–propoxyphene combination therapy as required for pain, and prednisone (5 mg/d).
The patient was afebrile. There was no overt synovitis, but in addition to several fibromyalgia tender points, there was tenderness over her wrists, elbows, knees and ankles. Radiographs of her long bones showed evidence of multiple bone infarcts and avascular necroses (Fig. 1 A–D). A technetium-99m radionuclide bone scan showed evidence of a healed infarct of the right lunate and lateral femoral condyles (Fig. 1 E–G).
The antinuclear antibody titre, determined by means of indirect immunofluorescence assay (IFA), was greater than 1:640 (homogeneous pattern), and serologic tests for anti–SS-A and anti–SS-B antibodies yielded positive results. The patient had active SLE, as evidenced by an elevated erythrocyte sedimentation rate (32 mm/h), a positive enzyme immunoassay (EIA) result for anti-dsDNA antibody, confirmed by Crithidia lucillae assay by IFA (titre 279 [normal < 30] IU/mL), and low levels of complement (C3 0.6 [normal 0.7–2.6] g/L; C4 0.1 [normal 0.2–0.6] g/L). The patient had a prolonged prothrombin time of 18.6 (normal 9.9–13) seconds, an international normalized ratio (INR) of 1.7 (normal 0.9–1.2) and an activated partial thromboplastin time (aPTT) of 56.1 (normal 24.6–34) seconds. The prolonged prothrombin time was consistent with her history of warfarin therapy. The prolonged aPTT was not due to heparin, since a screening assay for heparin yielded negative results. The patient was positive for IgM anticardiolipin antibodies (16 [normal < 12] MPL units) but negative for IgG cardiolipin antibodies. The circulating anticoagulant assay (incubated aPTT mixing study) yielded a positive result for an immediate-acting inhibitor. Results of the dilute Russell viper venom test and platelet neutralization procedures were both positive. The laboratory findings were consistent with a lupus anticoagulant.
Our patient had 3 major potential causes of avascular necrosis and bone infarcts: SLE, antiphospholipid antibody syndrome and chronic steroid use.
Avascular necrosis results from death of bone marrow and trabecular bone because of an impaired blood supply. Two main forms have been described: post-traumatic and nontraumatic. The post-traumatic form develops from traumatic displacement of the bone fragments, which leads to disrupted blood supply and ischemia to the affected bone. The nontraumatic form occurs because of interrupted blood flow due to intravascular thrombi and can result from various conditions (Box 1).
Antiphospholipid antibody syndrome is referred to as "primary" when it occurs alone; however, it can also be associated with SLE, other rheumatic diseases, and certain infections and drug therapies. It is a common cause of avascular necrosis. Patients with antiphospholipid antibody syndrome may display a constellation of clinical features (Box 2).1 The syndrome is associated with the presence of anticardiolipin antibodies or lupus anticoagulant, or both. Lupus anticoagulant activity can be assessed even in the presence of warfarin therapy.2
Polyarthralgia and musculoskeletal pain in SLE is usually a result of lupus arthropathy or secondary fibromyalgia. SLE patients with bone pain should be tested for the lupus anticoagulant, and if it is present, avascular necrosis should be suspected. Avascular necrosis in SLE patients can occur even in the absence of corticosteroid use.3
Our patient had been receiving steroids intermittently for her lupus and immune thrombocytopenic purpura. The maximum (peak) dose ever received was 30 mg of prednisone daily; the maximum duration of high-dose therapy (20 mg/d) was 9 months, and it occurred 20 years before the current presentation. The patient had begun low-dose prednisone therapy (2.5–10 mg daily) a year before presentation.
The syndrome of multiple avascular necroses and bone infarcts is a rare cause of musculoskeletal pain in patients with SLE. Prevention of further progression may require reduction of the steroid dose and intensification of therapeutic anticoagulation in patients with antiphospholipid antibody syndrome, although the latter hypothesis has not been formally evaluated.
Our patient's warfarin dose was increased to achieve a therapeutic INR (2–3), mycophenolate mofetil therapy was started to treat the active SLE symptoms, and the prednisone dose was maintained at 5 mg/d. Hydroxychloroquine therapy was continued because, in addition to treating the musculoskeletal manifestations of SLE, it is known to have a prophylactic role in antiphospholipid antibody syndrome. With this regimen the patient has responded well, with a decline in her pain and no further occurrence of bone lesions.
REFERENCES
Cervera R, Piette JC, Font J, et al. Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum 2002;46:1019-27.
Tripodi A, Chantarangkul V, Clerici M, et al. Laboratory diagnosis of lupus anticoagulants for patients on oral anticoagulant treatment. Performance of dilute Russell viper venom test and silica clotting time in comparison with Staclot LA. Thromb Haemost 2002;88:583-6.
Tektonidou MG, Malagari K, Vlachoyiannopoulos PG, et al. Asymptomatic avascular necrosis in patients with primary antiphospholipid syndrome in the absence of corticosteroid use: a prospective study by magnetic resonance imaging. Arthritis Rheum 2003;48:732-6.(Soumya Chatterjee)
The patient was afebrile. There was no overt synovitis, but in addition to several fibromyalgia tender points, there was tenderness over her wrists, elbows, knees and ankles. Radiographs of her long bones showed evidence of multiple bone infarcts and avascular necroses (Fig. 1 A–D). A technetium-99m radionuclide bone scan showed evidence of a healed infarct of the right lunate and lateral femoral condyles (Fig. 1 E–G).
The antinuclear antibody titre, determined by means of indirect immunofluorescence assay (IFA), was greater than 1:640 (homogeneous pattern), and serologic tests for anti–SS-A and anti–SS-B antibodies yielded positive results. The patient had active SLE, as evidenced by an elevated erythrocyte sedimentation rate (32 mm/h), a positive enzyme immunoassay (EIA) result for anti-dsDNA antibody, confirmed by Crithidia lucillae assay by IFA (titre 279 [normal < 30] IU/mL), and low levels of complement (C3 0.6 [normal 0.7–2.6] g/L; C4 0.1 [normal 0.2–0.6] g/L). The patient had a prolonged prothrombin time of 18.6 (normal 9.9–13) seconds, an international normalized ratio (INR) of 1.7 (normal 0.9–1.2) and an activated partial thromboplastin time (aPTT) of 56.1 (normal 24.6–34) seconds. The prolonged prothrombin time was consistent with her history of warfarin therapy. The prolonged aPTT was not due to heparin, since a screening assay for heparin yielded negative results. The patient was positive for IgM anticardiolipin antibodies (16 [normal < 12] MPL units) but negative for IgG cardiolipin antibodies. The circulating anticoagulant assay (incubated aPTT mixing study) yielded a positive result for an immediate-acting inhibitor. Results of the dilute Russell viper venom test and platelet neutralization procedures were both positive. The laboratory findings were consistent with a lupus anticoagulant.
Our patient had 3 major potential causes of avascular necrosis and bone infarcts: SLE, antiphospholipid antibody syndrome and chronic steroid use.
Avascular necrosis results from death of bone marrow and trabecular bone because of an impaired blood supply. Two main forms have been described: post-traumatic and nontraumatic. The post-traumatic form develops from traumatic displacement of the bone fragments, which leads to disrupted blood supply and ischemia to the affected bone. The nontraumatic form occurs because of interrupted blood flow due to intravascular thrombi and can result from various conditions (Box 1).
Antiphospholipid antibody syndrome is referred to as "primary" when it occurs alone; however, it can also be associated with SLE, other rheumatic diseases, and certain infections and drug therapies. It is a common cause of avascular necrosis. Patients with antiphospholipid antibody syndrome may display a constellation of clinical features (Box 2).1 The syndrome is associated with the presence of anticardiolipin antibodies or lupus anticoagulant, or both. Lupus anticoagulant activity can be assessed even in the presence of warfarin therapy.2
Polyarthralgia and musculoskeletal pain in SLE is usually a result of lupus arthropathy or secondary fibromyalgia. SLE patients with bone pain should be tested for the lupus anticoagulant, and if it is present, avascular necrosis should be suspected. Avascular necrosis in SLE patients can occur even in the absence of corticosteroid use.3
Our patient had been receiving steroids intermittently for her lupus and immune thrombocytopenic purpura. The maximum (peak) dose ever received was 30 mg of prednisone daily; the maximum duration of high-dose therapy (20 mg/d) was 9 months, and it occurred 20 years before the current presentation. The patient had begun low-dose prednisone therapy (2.5–10 mg daily) a year before presentation.
The syndrome of multiple avascular necroses and bone infarcts is a rare cause of musculoskeletal pain in patients with SLE. Prevention of further progression may require reduction of the steroid dose and intensification of therapeutic anticoagulation in patients with antiphospholipid antibody syndrome, although the latter hypothesis has not been formally evaluated.
Our patient's warfarin dose was increased to achieve a therapeutic INR (2–3), mycophenolate mofetil therapy was started to treat the active SLE symptoms, and the prednisone dose was maintained at 5 mg/d. Hydroxychloroquine therapy was continued because, in addition to treating the musculoskeletal manifestations of SLE, it is known to have a prophylactic role in antiphospholipid antibody syndrome. With this regimen the patient has responded well, with a decline in her pain and no further occurrence of bone lesions.
REFERENCES
Cervera R, Piette JC, Font J, et al. Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum 2002;46:1019-27.
Tripodi A, Chantarangkul V, Clerici M, et al. Laboratory diagnosis of lupus anticoagulants for patients on oral anticoagulant treatment. Performance of dilute Russell viper venom test and silica clotting time in comparison with Staclot LA. Thromb Haemost 2002;88:583-6.
Tektonidou MG, Malagari K, Vlachoyiannopoulos PG, et al. Asymptomatic avascular necrosis in patients with primary antiphospholipid syndrome in the absence of corticosteroid use: a prospective study by magnetic resonance imaging. Arthritis Rheum 2003;48:732-6.(Soumya Chatterjee)