Correspondence

Rituximab Therapy for the Type B Syndrome of Severe Insulin Resistance

N Engl J Med 2004; 350:310-311January 15, 2004

Article

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 1Figure 1Changes in Glycosylated Hemoglobin Values and Antibody Status over Time.).

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

4 References

1. 1

   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
   Full Text | Web of Science | Medline

2. 2

   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
   CrossRef | Web of Science | Medline

3. 3

   Johnson PWM, Glennie MJ. Rituximab: mechanisms and applications. Br J Cancer 2001;85:1619-1623
   CrossRef | Web of Science | Medline

4. 4

   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
   CrossRef | Web of Science | Medline

Citing Articles (5)

Citing Articles

1. 1

   F. Ovalle. (2010) Clinical approach to the patient with diabetes mellitus and very high insulin requirements. Diabetes Research and Clinical Practice 90:3, 231-242
   CrossRef

2. 2

   Mirnaluci Paulino Ribeiro Gama, Thaísa Hoffmann Jonasson, Jeanne Debortoli Gama, Patrícia Zeni Lima Teixeira de Freitas, Ana Carolina Ossowski, Rafaela Cristina Perraro, Bárbara Vicente de Souza, Gislaine Custódio. (2010) Extreme Insulin-Resistance Syndrome Associated With Alpha-1 Antitrypsin Deficiency. The Endocrinologist 20:3, 137-140
   CrossRef

3. 3

   Baris Akinci, Serkan Yener, Firat Bayraktar, Sena Yesil. (2010) Allergic reactions to human insulin: a review of current knowledge and treatment options. Endocrine 37:1, 33-39
   CrossRef

4. 4

   Kathleen A Page, Stephanie Dejardin, C Ronald Kahn, Rohit N Kulkarni, Kevan C Herold, Silvio E Inzucchi. (2007) A patient with type B insulin resistance syndrome, responsive to immune therapy. Nature Clinical Practice Endocrinology & Metabolism 3:12, 835-840
   CrossRef

5. 5

   A. P. Coll, D. Morganstein, D. Jayne, M. A. Soos, S. O'Rahilly, J. Burke. (2005) Successful treatment of Type B insulin resistance in a patient with otherwise quiescent systemic lupus erythematosus. Diabetic Medicine 22:6, 814-815
   CrossRef