Rituximab Therapy for the Type B Syndrome of Severe Insulin Resistance
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《新英格兰医药杂志》
To the Editor: The type B syndrome of severe insulin resistance is characterized by the presence of autoantibodies to the insulin receptor1 and frequently results in symptomatic hyperglycemia that is resistant to high doses of insulin.2 Available therapies are of limited efficacy and have considerable toxic effects.2 We describe a patient with type B insulin resistance in whom treatment with rituximab (a monoclonal anti-CD20 antibody3) was associated with a striking amelioration of highly insulin-resistant diabetes mellitus.
A 40-year-old woman who had recently received the diagnosis of systemic lupus erythematosus presented with marked hyperglycemia and pronounced acanthosis nigricans. High titers of IgG anti–insulin-receptor antibodies were detected in her serum in November 1999; the antibodies inhibited the binding of insulin to cloned receptors (data not shown). Treatment with oral prednisolone, intravenous methylprednisolone, azathioprine, and methotrexate plus five courses of plasmapheresis failed to affect her profound insulin resistance. Although she was receiving 900 units of insulin per day, the glycosylated hemoglobin value was markedly elevated (20.0 percent). In February 2000, she was treated with rituximab (375 mg per square meter of body-surface area, given as an intravenous infusion once weekly for four weeks). The glycosylated hemoglobin value fell progressively to 14.0 percent by November 2000 and to 5.9 percent by April 2001, at which time insulin therapy was stopped (Figure 1).
Figure 1. Changes in Glycosylated Hemoglobin Values and Antibody Status over Time.
Antibody titers were determined by insulin-binding assays. The upper portion of the figure shows the results of immunoprecipitation of solubilized insulin receptors with serum from the patient, followed by immunoblotting with the use of antibody against the subunit of the insulin receptor. Each arrow represents one infusion of rituximab.
In October 2001, the patient's hyperglycemia returned and was again unresponsive to insulin doses greater than 500 units per day. In addition, at this time her lupus nephritis (class IV according to the World Health Organization classification) required treatment with mycophenolate (500 mg given twice daily) and prednisolone (initial dose, 60 mg per day, which was reduced by 10 mg every two weeks to a maintenance dose of 10 mg per day). The severe hyperglycemia (glycosylated hemoglobin, 15.8 percent) did not improve while she was receiving this immunosuppressive regimen. Rituximab therapy was repeated in April 2002, after the mycophenolate and prednisolone treatment had been discontinued. Six weeks after the last infusion, the titer of anti–insulin-receptor antibody fell, and glycemic control improved. By August 2002, the antibody titer had fallen to 1:13, and the glycosylated hemoglobin value to 9.3 percent; insulin therapy was discontinued. Eleven months after the last rituximab infusion, the patient has not resumed insulin therapy and has good glycemic control (glycosylated hemoglobin, 5.6 percent). Because the production of anti–insulin-receptor antibody may spontaneously remit in patients with type B syndrome,4 we cannot state definitively that rituximab was responsible for the two remissions seen in this patient.
Anthony P. Coll, M.R.C.P.
Stephen Thomas, M.R.C.P.
Ghulam J. Mufti, F.R.C.P., F.R.C.Path.
King's College Hospital
London SE5, United Kingdom
apc36@cam.ac.uk
References
Kahn CR, Flier JS, Bar RS, et al. The syndromes of insulin resistance and acanthosis nigricans: insulin-receptor disorders in man. N Engl J Med 1976;294:739-745.
Arioglu E, Andewelt A, Diabo C, Bell M, Taylor SI, Gorden P. Clinical course of the syndrome of autoantibodies to the insulin receptor (type B insulin resistance): a 28-year perspective. Medicine (Baltimore) 2002;81:87-100.
Johnson PWM, Glennie MJ. Rituximab: mechanisms and applications. Br J Cancer 2001;85:1619-1623.
Flier JS, Bar RS, Muggeo M, Kahn CR, Roth J, Gorden P. The evolving clinical course of patients with insulin receptor autoantibodies: spontaneous remission or receptor proliferation with hypoglycemia. J Clin Endocrinol Metab 1978;47:985-995.
A 40-year-old woman who had recently received the diagnosis of systemic lupus erythematosus presented with marked hyperglycemia and pronounced acanthosis nigricans. High titers of IgG anti–insulin-receptor antibodies were detected in her serum in November 1999; the antibodies inhibited the binding of insulin to cloned receptors (data not shown). Treatment with oral prednisolone, intravenous methylprednisolone, azathioprine, and methotrexate plus five courses of plasmapheresis failed to affect her profound insulin resistance. Although she was receiving 900 units of insulin per day, the glycosylated hemoglobin value was markedly elevated (20.0 percent). In February 2000, she was treated with rituximab (375 mg per square meter of body-surface area, given as an intravenous infusion once weekly for four weeks). The glycosylated hemoglobin value fell progressively to 14.0 percent by November 2000 and to 5.9 percent by April 2001, at which time insulin therapy was stopped (Figure 1).
Figure 1. Changes in Glycosylated Hemoglobin Values and Antibody Status over Time.
Antibody titers were determined by insulin-binding assays. The upper portion of the figure shows the results of immunoprecipitation of solubilized insulin receptors with serum from the patient, followed by immunoblotting with the use of antibody against the subunit of the insulin receptor. Each arrow represents one infusion of rituximab.
In October 2001, the patient's hyperglycemia returned and was again unresponsive to insulin doses greater than 500 units per day. In addition, at this time her lupus nephritis (class IV according to the World Health Organization classification) required treatment with mycophenolate (500 mg given twice daily) and prednisolone (initial dose, 60 mg per day, which was reduced by 10 mg every two weeks to a maintenance dose of 10 mg per day). The severe hyperglycemia (glycosylated hemoglobin, 15.8 percent) did not improve while she was receiving this immunosuppressive regimen. Rituximab therapy was repeated in April 2002, after the mycophenolate and prednisolone treatment had been discontinued. Six weeks after the last infusion, the titer of anti–insulin-receptor antibody fell, and glycemic control improved. By August 2002, the antibody titer had fallen to 1:13, and the glycosylated hemoglobin value to 9.3 percent; insulin therapy was discontinued. Eleven months after the last rituximab infusion, the patient has not resumed insulin therapy and has good glycemic control (glycosylated hemoglobin, 5.6 percent). Because the production of anti–insulin-receptor antibody may spontaneously remit in patients with type B syndrome,4 we cannot state definitively that rituximab was responsible for the two remissions seen in this patient.
Anthony P. Coll, M.R.C.P.
Stephen Thomas, M.R.C.P.
Ghulam J. Mufti, F.R.C.P., F.R.C.Path.
King's College Hospital
London SE5, United Kingdom
apc36@cam.ac.uk
References
Kahn CR, Flier JS, Bar RS, et al. The syndromes of insulin resistance and acanthosis nigricans: insulin-receptor disorders in man. N Engl J Med 1976;294:739-745.
Arioglu E, Andewelt A, Diabo C, Bell M, Taylor SI, Gorden P. Clinical course of the syndrome of autoantibodies to the insulin receptor (type B insulin resistance): a 28-year perspective. Medicine (Baltimore) 2002;81:87-100.
Johnson PWM, Glennie MJ. Rituximab: mechanisms and applications. Br J Cancer 2001;85:1619-1623.
Flier JS, Bar RS, Muggeo M, Kahn CR, Roth J, Gorden P. The evolving clinical course of patients with insulin receptor autoantibodies: spontaneous remission or receptor proliferation with hypoglycemia. J Clin Endocrinol Metab 1978;47:985-995.