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Rituximab outperformed steroids in Graves’ ophthalmopathy
SAN JUAN, Puerto Rico — 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.
For more information:
Salvi M. Clinical: Graves’ Disease. Presented at the 83rd Annual Meeting of the American Thyroid Association; October 16-20, 2013; San Juan, Puerto Rico.
European Clinical trial: EudraCT 2007-003910-33
Disclosure: Salvi reports no relevant financial relationships.
Perspective
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Each of the investigators did an excellent job in performing their studies. These studies are complex and 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 (Stan et al.) had rituximab as the active agent vs. placebo as the control, whereas the Italian study (Salviet al.) had rituximab as the active agent vs. intravenous steroids as an active control.
The doses of rituximab were also different. Salvi, et al. reduced the dose of rituximab mid-study and the lower dose was 500 mgs. a dose l of 1000 mg earlier in the study. He noted a significant decrease in CAS in the Rituximab group at 12 weeks, In contrast, Stan, et al. used two 1,000 mg Rituximab infusions (Treated Group) or saline (Control Group) two weeks apart. Patients were assessed periodically for 52 weeks. The primary endpoint was a decrement in the CAS when studied at 24 weeks . The authors found no significant difference in CAS between the two groups.
These two studies apparently reached different conclusions; the explanations for this discrepancy are unknown, but there are several plausible reasons.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 and duration of therapy and the duration of disease prior to entry into the study. Stan, et al. noted that most 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 previous steroid treatment, but not within 3 months of the study.
It is also possible that the two studies assessed patients at different stages of progression of their ophthalmopathy. 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 discordant 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 noting 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.