Despite data presented earlier at the American Thyroid Association Annual Meeting showing that rituximab was not effective in treating Graves’ ophthalmopathy, another presenter here said that the drug does improve disease state when compared with methylprednisolone.

“Response to rituximab was as high as 93%, compared to 69% observed after IV steroid,”Mario Salvi, MD, from the University of Milan in Italy, said. “Preliminary evidence of NOSPECS class 2 signs shows improvement after rituximab.”

Similar to the study presented earlier at the meeting, Salvi said the primary endpoint was a change of two or more points in the clinical activity score (CAS) at 24 weeks. Secondary endpoint was a reduction of disease severity by at least two NOSPECS classes.

Inclusion criteria included euthyroid for at least 6 to 8 weeks and affected by active Graves’ ophthalmopathy. Any previous steroid treatments had to be stopped at least 3 months before study inclusion.

Patients were randomly assigned to IV methylprednisolone (n=16; mean age, 50.4 years) or rituximab (Rituxan, Genentech; n=16; mean age, 51.9 years). In both groups, six patients had received previous steroid treatment. Originally, Salvi said, patients in the rituximab group were receiving 1,000 mg in two doses, but after two adverse reactions, they lowered the dosage to 500 mg. There was no difference between these two treatment dosages at 24 weeks.

At 12 weeks, the difference between the two groups was not significant, but at 24 weeks, 93% of patients in the rituximab group improved, as compared with 69% of the steroid group (P<.02).

“Rituximab was more effective than IV methyprednisolone in inactivating Graves’ orbitopathy, as assessed at 24 weeks,” Salvi said. “Graves’ orbitopathy remained invariably inactive after rituximab during follow-up.”

The researchers are confident in the response seen from methylprednisolone as it is as high as seen in recently published studies, Salvi said.

These results were preliminary and final analysis is expected shortly, he added.

PERSPECTIVE

Kenneth D. Burman

·         Both of the studies and each of the investigators did an excellent job in performing their studies. These studies are complex as it is difficult to recruit patients and to monitor them closely.

My initial impression is that the studies were designed differently. The Mayo Clinic study had rituximab as the active agent vs. placebo as the control, whereas the Italian study had rituximab as the active agent vs. intravenous steroids as an active control.

The doses of rituximab were also different. Salvi reduced the dose of rituximab mid-study and the lower dose was 500 mg/day vs. a total of 2,000 mg/day earlier in the study; the Mayo Clinic study used 2,000 mg. Salvi, et al suggested the lower dose was equally efficacious, but this needs to be explored further.

The major controversy relates to the patient population studied and whether the patients had received previous therapy, how recently this therapy had been given, the extent of therapy and the duration of disease. Stan, et al noted that about two-thirds of their patients did not receive treatment prior to the rituximab treatment, while Salvi, et al noted that six patients in each arm of their study had steroid treatment, but not within 3 months of the study.

Salvi, et al did indicate that their patients had progressive disease, which can defined by various scales. The CAS score, which was the sole measure in Salvi’s study, takes into account a multitude of factors. Stan, et al asserted that 24 of his 25 patients were classified as progressive as well. If the disease is progressive and treated early, the effect of immunomudulatory treatment is expected to be more efficacious. It is difficult to know with certainty if both studies analyzed patients at similar time points in the progression of ophthalmopathy.

Rituximab is not approved by the FDA for the treatment of Graves’ ophthalmopathy, The question now arises whether rituximab is effective in the treatment of progressive Graves’ ophthalmopathy given the apparent different results in these two clinical trials. Perhaps, the most appropriate advice is to refer these patients to large, tertiary medical centers that have extensive experience in treating patients with progressive Graves’ ophthalmopathy. Given that most physicians treating Graves’ ophthalmopathy are not experienced with using rituximab, and also give these conflicting results, it seems most prudent to not advise individual physicians to consider using rituximab therapy in this context outside of a tertiary medical center or a clinical trial.

o    Kenneth D. Burman, MD

o    Chief of the Endocrine Section at Washington Hospital Center 
Professor of Medicine 
Georgetown University

 Soure: Endocrine Today