SNOWMASS, COLO. – When it comes to prescribing rituximab in patients with rheumatoid arthritis, maybe it’s time to think like a European.
In response to a persuasive French study, rheumatologists across Europe have embraced a lower-dose rituximab regimen: Patients who achieve a moderate or good EULAR response to the standard initial induction dosing of two 1,000-mg doses given intravenously 2 weeks apart receive thereafter a single 1,000-mg dose every 6 months rather than the licensed maintenance dosing of two 1,000-mg IV injections every 6 months.
Dr. Michael E. Weinblatt
“They showed that one dose every 6 months is as good as two doses every 6 months. This is a strategy that our European colleagues have actively adopted. It’s a cost-effective strategy, and I think it’s actually an appropriate strategy to use and one we’re using routinely now in our rheumatoid patients after we’ve induced a response with the initial induction dosing,” Dr. Michael E. Weinblatt, professor of medicine at Harvard Medical School, Boston, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
The French study was an open-label, prospective, multicenter, noninferiority study involving 225 rheumatoid arthritis patients with an inadequate response to anti–tumor necrosis factor (anti-TNF) agents and a 6-month moderate or good EULAR response to rituximab (Rituxan) induction therapy coupled with methotrexate. They were randomized to rituximab retreatment at 6-month intervals at either a single 1,000-mg dose or the two 1,000-mg doses as described in the product labeling. At 104 weeks, disease activity as measured by the mean disease activity in 28 joints plus C-reactive protein level area under the curve was similar in the two treatment arms. So was the safety profile (Ann. Rheum. Dis. 2014;73:1508-14).
Dr. Weinblatt also provided an update on rituximab and infections. Two studies presented at last fall’s annual meeting of the American College of Rheumatology in Boston shed new light on this perennially hot topic.
In one, Dr. Kenneth G. Saag of the University of Alabama, Birmingham, and coinvestigators provided an update from the ongoing prospective, observational SUNSTONE cohort study, whose goal is to evaluate in a real-world setting the safety of rituximab in rheumatoid arthritis patients refractory to anti-TNF therapies. At a mean 4-year duration of follow-up in 938 patients who received a mean of four courses of rituximab, 17% of patients had experienced significant infections as defined either by the Food and Drug Administration serious adverse event criteria or need for intravenous antibiotics. The key finding from this intermediate analysis: The serious infection incidence rate did not increase with time and multiple courses of rituximab.
That’s reassuring, Dr. Weinblatt observed, and so is the finding that, in the 338 SUNSTONE participants who switched from rituximab to another biologic agent, there wasn’t any associated increased risk of serious infection.
All of the biologics carry an increased risk of infection. The one rituximab-associated infection that gives rheumatologists particular pause – and that has blunted the use of the anti-B-cell agent in the United States – is progressive multifocal leukoencephalopathy (PML). Indeed, rituximab is the only biologic agent or small molecule prescribed by rheumatologists that carries a warning label about PML, and the only one whose use is restricted to patients who’ve failed a first biologic.
“That means you have to – and should – discuss this with your patients,” Dr. Weinblatt noted.
At last November’s annual ACR meeting, Dr. Leonard H. Calabrese of the Cleveland Clinic and Dr. Eamonn Molloy of St. Vincent University Hospital, Dublin, provided an analysis of data released in response to their Freedom of Information Act request that the FDA provide information on all cases of PML recorded in the agency’s Adverse Event Reporting System through August 2012. In Dr. Weinblatt’s view, these data are reassuring.
“The rates are actually quite low. It’s a rare event. It’s clearly associated with rituximab, though,” he said.
Indeed, 30 confirmed cases of PML have been associated with biologic therapies for autoimmune rheumatic diseases, including 11 in patients with RA, 11 with systemic lupus erythematosus, and 5 with dermato/polymyositis. The median age was 53 years, and 25 of the 30 patients were women. Twenty-six cases occurred in patients who had most recently been on rituximab, the other four in patients who were on anti-TNF therapies at the time. Abatacept, belimumab, tocilizumab, and anakinra were not linked to PML.
PML developed after a median of two courses of rituximab. The median time interval was 15 months from the first rituximab infusion and 5 months from the last, but many confounders were present, making it difficult to draw definitive conclusions about causality. For example, four patients with PML had been on concomitant rituximab and cyclophosphamide, and another five had received cyclophosphamide prior to going on rituximab. Eighteen of 26 rituximab-treated patients were on one or more additional immunosuppressive agents at the time they were diagnosed with PML. Two patients had previously received cancer chemotherapy. Another five had significant lymphopenia.