Rituximab fails in kidney disorder
Thursday, 12 April 2012- The addition of rituximab to a standard immunosuppressive regimen did not increase the overall response rate among patients with lupus nephritis, a randomized trial found.
At 1 year, the rates of combined complete and partial response among patients receiving rituximab (Rituxan) and those given placebo were 56.9% and 45.8%, respectively (P=0.18), according to Dr. Brad Rovin of Ohio State University in Columbus, and colleagues.
Most of the difference between the rituximab and placebo groups was in partial response rates, which were 30.6% and 15.3%, respectively, the investigators reported in the April edition of Arthritis & Rheumatism. Up to half of patients with systemic lupus erythematosus develop nephritis, and available treatments have proven inadequate.
"Renal response rates, especially complete remissions, continue to be unacceptably low despite the use of aggressive initial therapies," Rovin and colleagues wrote.
Because B cells appear to contribute to renal injury in these patients, and some uncontrolled studies have hinted at a benefit for the B-cell depleting agent rituximab, the investigators conducted a multinational trial to explore a possible therapeutic role for the agent.
They enrolled 144 patients with class 3 or 4 nephritis, randomizing them to mycophenolate mofetil (CellCept) in doses up to 3 g/day, plus oral prednisone, for 1 year. The prednisone was given in doses up to 60 mg per day (0.75 mg/kg/day) for the first 16 days, and then tapered below 10 mg per day by week 16.
Patients randomized to rituximab received 1 g intravenously on days 1 and 15, and then at weeks 24 and 26. A second assessment was done 6 months later, at week 78, to examine post-treatment effects.
The composite endpoints of complete and partial response reflected serum creatinine levels, urinary sediment, and urine protein-to-creatinine ratios. Mean age was 31, most patients were women, and slightly more than half had no prior history of nephritis. After 52 weeks of treatment, complete response rates were seen in 30.6% of the placebo group and 26.4% of the rituximab group.
No response was seen in 54.2% and 43.1% of the two groups, respectively. Among the partial responders, seven patients receiving rituximab but only one receiving placebo had complete resolution of proteinuria. Responses on secondary clinical endpoints at 1 year also were generally similar between the groups.
For instance, the median number of months until complete response did not differ significantly, being 11.99 in the rituximab group and 12.12 in the placebo group (P=0.63). However, a complete or partial response in proteinuria was seen in 66.7% of the rituximab group and 56.9% of placebo patients at one year.
Six months later, the proteinuria response rate rose to 73.6% of the rituximab group but remained at the same level in the placebo patients, allowing for a statistically significant difference ( P=0.04).
This finding suggested that "a longer duration of observation may be necessary to understand the full impact of rituximab therapy," the researchers observed. The change on the Short Form 36 physical function score was a mean of 4.8 points in the active treatment group and 5.7 points in the placebo group (P=0.59).
However, more patients in the placebo group needed rescue therapy with cyclophosphamide (8 versus zero, P=0.006) by 1 year. A prespecified subgroup analysis of African-American patients found a 70% response rate at week 52 with rituximab treatment compared with a 45% rate without add-on rituximab (P=0.20).
Although that difference was not statistically significant, black patients often have more severe disease, and the possibility of improved renal outcomes in this group may warrant a randomized study of rituximab in these patients, according to the researchers. Significant differences were seen in serologic measures with rituximab treatment, including reductions in the levels of anti-double-stranded DNA (P=0.007) and increased serum complement C3 (P=0.03).
Adverse event rates overall were similar in the rituximab and placebo groups, although patients receiving rituximab experienced more hypotension, neutropenia, and leukopenia. Serious adverse events were more frequent in the placebo group, at 74.3 per 100 patient-years compared with 42.9 in the rituximab group.
Two deaths occurred in rituximab-treated patients, neither of which was considered treatment related. The researchers concluded that their findings, in conjunction with positive results seen in earlier open studies of treatment-refractory patients, "indicate a need to further examine the potential role for rituximab in certain subsets of patients with [lupus nephritis]."
In an editorial accompanying the study, Dr. Liz Lightstone, of Imperial College London, explained that her group had performed an observational study in which rituximab and mycophenolate mofetil were given in combination but without oral prednisone.
She noted that much of the greatly increased risk of cardiovascular disease and mortality among patients with lupus can be attributed to long-term steroid use, and that clinicians are often unwilling to taper steroids whenever proteinuria is present.
"What is needed are not agents that can be added to steroids but rather agents that allow us to take the bold step of getting rid of steroids -- perhaps the real holy grail of lupus treatment," she wrote.
She called for a randomized trial similar to her observational study, which could be "a game-changing trial that might rid at least some patients from the drugs that have perhaps plagued us the most for the last 60 years while at the same time demonstrating the true worth of rituximab."
Source: B. Rovin, et al "Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the lupus nephritis assessment with rituximab study," Arthritis & Rheumatism 2012; 64: 1215-1226. MedPage Today