WROCŁAW, Poland — Treatment with rituximab (Rituxan, Roche) led to greater inactivation of moderate to severe Graves' orbitopathy compared with the standard treatment of intravenous methylprednisolone. In addition, disease inactivation was maintained even after treatment with rituximab was stopped, according to new data from a prospective series of patients.
And of note, this outcome was achieved with a single, lower dose of rituximab, of just 500 mg, compared with the dose usually used in autoimmune diseases such as rheumatoid arthritis (cumulative dose of 2000 mg) and in non-Hodgkin's lymphoma.
"This is appealing from both a cost and a safety angle," remarked Mario Salvi, MD, an endocrinologist at the University of Milan, Italy, in an interview with Medscape Medical News.
"The fact that we observed similar results with a lower dose of rituximab than normal suggests a disease-modifying effect of rituximab and [indicates] that Graves' orbitopathy is an organ-specific autoimmune disease found at a very limited location in the body, in contrast to other systemic autoimmune diseases," he added.
Dr. Salvi reported on an interim analysis of his series of patients, at 24 weeks after treatment initiation, at the European Congress of Endocrinology (ECE) 2014.
But Robin P. Peeters, MD, an endocrinologist from Erasmus University Medical Center, Rotterdam, the Netherlands, noted that a similar trial was conducted in the United States and reported at the American Thyroid Association meeting last year, by Rebecca Bahn, MD, of Mayo Clinic, Rochester, Minnesota. However, this had a very different outcome: it suggested no effect of rituximab on Graves' orbitopathy, only more side effects with this treatment.
Dr. Salvi said that trial compared rituximab with placebo, rather than his own, which pitched it against the standard treatment of intravenous steroids.
Still, he did not have an adequate explanation for the conflicting findings. "It seems strange that comparing with nothing has no effect. I think the main difference was selection of patients with differences in disease duration prior to therapy start. I guess that these patients [in the US trial] were not monitored well before treatment," Dr. Salvi observed.
Single, Low Dose of Rituximab Seems to Be Sufficient
Dr. Salvi and his colleagues started their prospective randomized controlled trial comparing rituximab with intravenous methylprednisolone in patients with Graves' orbitopathy, a hyperthyroid condition, in 2007. But because Graves' orbitopathy is a rare disease, it was difficult to recruit patients, he explained. To make matters even more challenging, at the start of the trial in 2007, rituximab exclusion criteria were very strict, further limiting enrollment.
The majority of patients included in the study had active disease with a clinical activity score of greater than 4/10 or 3/7. Patient ages were between 18 and 75 years, both smokers and nonsmokers, with normal free thyroid hormone levels for at least 6 to 8 weeks prior to the start of therapy. Previous steroid treatment had to have been stopped for at least 3 months prior to treatment with rituximab.
A total of 32 patients were randomized, with half given intravenous methylprednisolone and the remainder given rituximab, of which 1 patient refused therapy. Mean disease duration was very short (6.6 and 4.5 months in the intravenous methylprednisolone and rituximab groups, respectively).
Patients were treated for 3 months. Treatment efficacy was evaluated at 6 months, with follow-up at 12 to 18 months. Between 6 and 12 months relapse events were recorded, and between 12 and 18 months residual disease was monitored.
Dosing for intravenous methylprednisolone was 830 mg/day, given weekly for 6 weeks, followed by 415 mg/day weekly for a further 6 weeks.
The 15 patients given rituximab initially received 1000 mg/week for 2 weeks, but this protocol was later amended to a 500-mg single dose due to the discovery that B-cell depletion was being obtained even with a single dose.
"We believe that now we can definitely use lower doses. This became the standard treatment used for Graves' orbitopathy," Dr Salvi explained. He told Medscape Medical News he has now demonstrated that even a 100-mg dose can induce depletion and perhaps amelioration of the condition.
Use of just a single dose will mean that the therapy is cheaper than for other approved indications, he said: around €1700 for 500 mg compared with €6600 for a 2 x 1000-mg course of rituximab. A 100-mg dose would be even cheaper.
Rituximab is approved for use in rheumatoid arthritis and non-Hodgkin's lymphoma only; no commercial interest has been shown in gaining an indication for Graves' orbitopathy, Dr. Salvi told Medscape, so any use for this is off label.
Disease 100% Inactive at 6 Months With Rituximab
The primary end point in the study is reduction in clinical activity score of equal to 2 or more points or a clinical activity score below 3.
At 24 weeks, the clinical activity score in patients on rituximab had reduced to around 0.6, while in those on intravenous methylprednisolone it had reduced to around 2.4. The clinical activity score at the start for all patients was around 4.5 on a scale of 0 to 6.
Dr. Salvi declined to give exact figures, stating that he was submitting the results to a journal for publication.
"When we summarize the data on disease inactivation at 12 weeks and 24 weeks, we see that at 12 weeks there is no real difference, because around 80% of patients have inactive disease, but the difference is noticeable at 24 weeks. At this point, we saw 100% of patients on rituximab were still inactive vs 69% of patients treated with steroids," he reported.
The figure of around 70% inactivity on intravenous methylprednisolone is the figure commonly reported in this patient group on steroids, he added.
"The finding of 100% [of patients with inactive disease] is hard to believe, but the conclusion is that this is observed in a prospective well-designed study, but only in a small number of patients currently."
He added that data "on quality-of-life parameters," a secondary end point, were also better after patients received rituximab compared with methylprednisolone.
Dr. Salvi was the lead author of a review on the use of rituximab in Graves' orbitopathy, published last year in the Journal of Clinical Endocrinology and Metabolism, which concluded that the available data "suggest that rituximab does significantly affect the activity and severity of Graves' orbitopathy" (J Clin Endocrinol Metab. 2013;98: 4291–4299).
However, he and his coauthors concluded that further controlled trials are needed, to "help decide whether rituximab is to be used in any patients with active Graves' orbitopathy or only in those with otherwise-unresponsive disease of a severe degree."
Dr. Salvi and Dr. Peeters have declared no relevant financial relationships.
European Congress of Endocrinology 2014; May 5, 2014; Wrocław, Poland.Abstract S10.1.
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Cite this: Rituximab Inactivates Graves' Orbitopathy, New Data Show - Medscape - May 07, 2014.