Rituximab Plus Continuous Glucose Monitoring Linked to Remission in Treatment-Refractory Insulin Autoimmune Syndrome

Comments by David Saxon, MD and Rana Malek, MD

Rituximab plus continuous glucose monitoring caused remission of insulin autoimmune syndrome (IAS) in a patient who was refractory to a prolonged course of high-dose steroids, according to a case report in the May issue of The Journal of Clinical Endocrinology and Metabolism.

"This case report provides evidence that rituximab and continuous glucose monitoring should be considered in select patients with IAS in whom hypoglycemia is either severe or where it is prolonged and prednisone alone is not an effective therapy," said lead author David Saxon, MD, an endocrinologist at the University of Colorado Hospital and the Denver VA Medical Center.

"This study provides a therapeutic option for IAS that fails steroid treatment," commented Rana Malek, MD, who is Assistant Professor of Medicine at the University of Maryland School of Medicine in Baltimore, MD. "Rituximab has been well documented as an effective treatment in a variety of autoimmune diseases. In addition to its successful use in type B insulin resistance, rituximab also has been used to treat Graves' orbitopathy," Dr. Malek noted.

Case Background
"IAS is rare and in many reported cases, patients will have spontaneous resolution of the disease," Dr. Saxon told EndocrineWeb. "In other cases with more severe hypoglycemia, treatment with prednisone for 3 to 6 months is enough to help raise blood sugars and put the disease into remission."

older man
"Our patient [a 71-year-old man] was on high-dose prednisone for several months, but he developed many unpleasant side effects to prednisone (weight gain, easy bruising, and sleep and mood disturbances) and his insulin antibody level was still extremely high," Dr. Saxon explained. Coauthor Aaron W. Michels, MD, an expert in type 1 diabetes immunology at the Barbara Davis Diabetes Center for Childhood Diabetes at the University of Colorado School of Medicine, suggested that rituximab may work to suppress the patient's insulin autoantibodies based on knowledge from previous studies in which rituximab was used in patients with new-onset type 1 diabetes, Dr. Saxon noted.

The patient was given rituximab 1,000 mg/m2 intravenously in an inpatient setting to allow for close monitoring to detect potential worsening of hypoglycemia. The patient's insulin autoimmune antibody (IAA) level decreased from 3.4 before the infusion to 2.5 after. Ten weeks later, the patient received a second infusion of rituximab 1,000 mg/m2 and his IAA level decreased to 1.7 and eventually to a low of 1.019, followed by a slight increase to 1.66 approximately 24 weeks after the second rituximab infusion. Hypoglycemia became "mild and much less frequent" following rituximab treatment, the authors wrote.

Prednisone was tapered over the several months after the first rituximab infusion and then was discontinued. The patient's Cushingoid features completely resolved.

Weighing the Risks and Benefits of Rituximab vs Steroids
When considering rituximab versus steroids in the treatment of IAS, physicians must weigh the risks/benefits of both treatments, the experts both noted. "Since many cases of IAS remit within a few months, and rituximab is both costly and slow to work, I think the use of rituximab should be reserved for only severe refractory cases," Dr. Saxon said.

"Patients can often have resolution of IAS with steroids and tolerate that treatment quite well," Dr. Malek told EndocrineWeb. "However, steroids can result in iatrogenic Cushing's syndrome, which can make patients miserable."

On the other hand, "rituximab can have fatal infusion reactions, reactivation of hepatitis, and there is a risk of progressive multifocal leukoencephalopathy. Rituximab is a 'big gun'—it knocks out a lot of things other than just the insulin autoantibody. If you can get by with some steroids, that should be the first option," Dr. Malek said.

Benefits of Continuous Glucose Monitoring
"I do believe that continuous glucose monitoring (CGM) should be used more liberally in IAS cases," Dr. Saxon said. "Severe hypoglycemia can be life-threatening; therefore, a CGM's ability to warn a patient when their blood sugar is dropping can be extremely beneficial."

"Our patient and his wife both found the CGM to be very useful," Dr. Saxon noted. "Frequent severe hypoglycemia in our patient had led to hypoglycemic unawareness; therefore, prior to using the CGM, he had to wake himself up in the middle of the night to check his blood sugar every few hours to make sure it wasn't dropping. With the CGM he could sleep more soundly knowing that the alarm would go off if he was trending towards hypoglycemia. His wife felt much more comfortable leaving her husband alone in the house knowing that her husband was wearing the CGM."

Concluding Comments
Dr. Saxon concluded that "insulin autoimmune syndrome is a rare disease that most medical providers in the United States will not see during their career (the disease has most often been described in the Japanese population); however, hypoglycemia or suspected hypoglycemia are not infrequently encountered issues. Providers should know to include insulin autoimmune syndrome as part of their differential diagnosis for hypoglycemia."

May 23, 2016

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