Rituximab offers no benefit over placebo to patients with active or moderate-to-severe Graves' orbitopathy

Prevention of Graves' orbitopathy (GO) remains an elusive goal. To date, there is no effective measure to prevent GO, a potentially sight-threatening disease. Some patients with mild disease benefit from selenium treatment, but other systemic therapies are generally not offered due to potential adverse effects. Intravenous corticosteroids, helpful for the inflammatory signs and symptoms of GO, are associated with significant adverse effects. Treatment requires repeated infusions over many weeks and nearly 30 percent of patients relapse.

Orbital decompression, a complex surgical procedure, is typically offered when the disease is severe, other treatment modalities have failed or inactive disease requires rehabilitative surgery. Therapeutic intervention is offered for patients with active disease, severe disease or both.

A literature review published by Mario Salvi, M.D., and others in The Journal of Clinical Endocrinology & Metabolism in 2013 suggests that rituximab may benefit patients with GO. Rituximab is a humanized chimeric anti-CD20 monoclonal antibody that depletes both B lymphocytes in the intermediate stages of maturation and short-lived plasma cells.

Based on that review and similar reports, a multidisciplinary team that included James A. Garrity, M.D., Ophthalmology, at Mayo Clinic's campus in Rochester, Minnesota, designed a double-masked, randomized controlled trial to study the efficacy of rituximab in patients with GO. "While rituximab might be of benefit, improvement in disease activity over time is also compatible with the natural history of GO," says Dr. Garrity.

The study was designed by Rebecca S. Bahn, M.D., an emeritus specialist in endocrinology at Mayo Clinic in Rochester, Minnesota, and Marius N. Stan, M.D., Endocrinology, at Mayo Clinic in Rochester, Minnesota, with that context in mind. Results appeared in The Journal of Clinical Endocrinology & Metabolism in 2014.

Participation criteria

Mayo Clinic endocrinologists, ophthalmologists or both evaluated 636 patients with GO over the study period. Fifty-nine patients met the following inclusion criteria:

  • Ages 18-80 years with moderate-to-severe and active GO with a clinical activity score greater than or equal to 4/7
  • Euthyroid for at least six weeks (defined by normal free thyroid hormone levels)
  • Evidence of disease progression (through changes in disease activity, severity or both) during the previous two months or lack of improvement in the prior six months (assessed through patient questioning and by review of outside medical records from the referring ophthalmologist or endocrinologist, patient photographs, or both)
  • Previous steroid treatment was acceptable if discontinued greater than or equal to four weeks before enrollment

"Each eligible patient was given the choice of trial participation, treatment with IV glucocorticoids, orbital decompression surgery if appropriate or close observation," says Dr. Garrity, "and the potential for disease progression was discussed."

Twenty-five patients with active moderate-to-severe GO opted to participate in the trial: 12 were enrolled in the placebo arm and 13 in the rituximab arm. Participants received either two infusions of rituximab (1,000 mg each) via IV or two saline infusions, given two weeks apart.

Patients were re-evaluated every two months for the first six months. Those who showed deterioration were removed from the trial and offered appropriate therapeutic options.

Primary and secondary endpoints

Baseline assessment of participants included medical history, physical examination by an endocrinologist, ocular evaluation by an ophthalmologist, orbital CT, thyroid-stimulating hormone, free thyroxine, thyrotropin receptor antibody levels and CD 19+ B cell count. The treatment groups were similar in all parameters at baseline.

"Our primary endpoint was a reduction in clinical activity score, assessed as a continuum and separately as improvement by greater than or equal to two points at 24 weeks," says Dr. Garrity. "Twenty-one patients completed the study to the primary endpoint. We found no differences in the proportions of patients showing clinical activity score improvement at 24 weeks."

Secondary endpoints included success and failure rates; proportions showing clinically significant improvement in proptosis, lid fissure width, diplopia score, lagophthalmos and disease severity; orbital fat, muscle volume or both; and quality of life as assessed by the SF-12 Health Survey.

Patients were re-evaluated at eight, 16, 24 and 52 weeks. There were no differences between groups in any of the secondary endpoints at either 24 or 52 weeks, but there were four adverse events in three of 12 patients receiving placebo and 11 adverse events in eight of 13 patients treated with rituximab. Five of six of the moderate or severe adverse events occurred in patients treated with rituximab, including two patients who developed an optic neuropathy.

"Our study indicates that rituximab offers no additional benefit over placebo to patients with active and moderate-to-severe GO," says Dr. Garrity, "and carries non-negligible adverse effects."

For more information

Salvi M, et al. Potential utility of rituximab for Graves' orbitopathy. The Journal of Clinical Endocrinology & Metabolism. 2013;98:4291.

Stan MN, et al. Randomized controlled trial of rituximab in patients with Graves' orbitopathy. The Journal of Clinical Endocrinology & Metabolism. 2014;100:432.