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 Brad H. Rovin, MD, 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 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.
IMPORTANT SAFETY INFORMATION
RITUXAN can cause serious side effects that can lead to death, including: infusion reactions, tumor lysis syndrome (TLS; kidney failure due to fast breakdown of cancer cells), severe skin and mouth reactions, and progressive multifocal leukoencephalopathy (PML; a rare, serious brain infection).
RITUXAN has also been associated with serious and life-threatening side effects, including: the return of active hepatitis B virus infection with sudden and serious liver problems including liver failure, and death, other serious infections that can lead to death, heart problems, kidney problems, and stomach and serious bowel problems including blockage and tears in the bowel that can sometimes lead to death.
The most common side effects of RITUXAN seen in patients with non-Hodgkin’s lymphoma were infusion reactions, fever, chills, low white blood cells, infections, body aches, and tiredness. Before starting treatment with RITUXAN it is important to talk to your doctor about your medical history.
Tell your doctor about any side effect that bothers you or that does not go away. These are not all of the possible side effects with RITUXAN. For more information, ask your doctor
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.
Lupus nephritis, one of the most serious manifestations of systemic lupus erythematosus (SLE), usually arises within 5 years of diagnosis; however, renal failure rarely occurs before American College of Rheumatology criteria for classification are met.
Lupus nephritis is histologically evident in most patients with SLE, even those without clinical manifestations of renal disease. The symptoms of lupus nephritis are generally related to hypertension, proteinuria, and renal failure.
Evaluating renal function in patients with SLE to detect any renal involvement early is important because early detection and treatment can significantly improve renal outcome. Renal biopsy should be considered in any patient with SLE who has clinical or laboratory evidence of active nephritis, especially upon the first episode of nephritis.
The principal goal of therapy in lupus nephritis is to normalize renal function or, at least, to prevent the progressive loss of renal function. Therapy differs depending on the pathologic lesion. With the advent of more aggressive immunosuppressive and supportive therapy, rates of renal involvement and patient survival are improving.
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.
Rituximab injection is a monoclonal antibody. It is used to treat a type of cancer called non-Hodgkin’s lymphoma (NHL). It can be used alone or with other cancer medicines (chemotherapy). It is also used as a “maintenance” treatment for patients with advanced follicular lymphoma who responded to initial treatment with this medicine plus chemotherapy (induction treatment).
Rituximab is also used in combination with fludarabine and cyclophosphamide (FC) for the treatment of chronic lymphocytic leukemia (CLL).
Rituximab may also be used in combination with methotrexate to reduce the signs and symptoms of rheumatoid arthritis and help keep joint damage from getting worse after at least one other medicine (e.g., adalimumab, etanercept, infliximab) has been used and did not work well.
Rituximab is also used in combination with glucocorticoids to treat Wegener’s granulomatosis (WG) and microscopic polyangiitis (MPA).
This medicine is to be administered only by or under the immediate supervision of your doctor.
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.
Lupus nephritis Causes, incidence, and risk factors:
Systemic lupus erythematosus (SLE, or lupus) is an autoimmune disease. This means there is a problem with the body’s immune system.
Normally, the immune system helps protect the body from harmful substances. But in patients with an autoimmune disease, the immune system cannot tell the difference between harmful substances and healthy ones. As a result, the immune system attacks otherwise healthy cells and tissue.
SLE may damage different parts of the kidney, leading to interstitial nephritis, nephrotic syndrome, and membranous GN. It may reapidly worsen to kidney failure.
Lupus nephritis affects approximately 3 out of every 10,000 people. In children with SLE, about half will have some form or degree of kidney involvement.
More than half of patients have not had other symptoms of SLE when they are diagnosed with lupus nephritis.
SLE is most common in women ages 20 – 40. For more information, see: systemic lupus erythematosus.
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, Liz Lightstone, PhD, 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.
Rituximab treatment was not associated with a higher rate of complete or partial renal responses at the end of the study, with a 56.9% rate compared to 45.8% for placebo, the researchers reported online ahead of print in Arthritis & Rheumatism.
“At this time we cannot recommend the addition of rituximab to MMF for the initial therapy of proliferative lupus nephritis,” Dr. Rovin concluded. “We suspect that there are patients who may benefit from rituximab, but we still need to develop methods to identify who they are.”
“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.”
The study was supported by Genentech and Biogen Idec.
The lead author has received honoraria from Biogen Idec. His co-authors disclosed receiving fees and honoraria from various companies including Biogen Idec, Takeda, Savient, and Roche, and one holds a patent for rituximab in autoimmune disease.
Lightstone has received consulting fees, speaking fees, and/0r honoraria from Genentech, Biogen Idec, Aspreva, and GlaxoSmithKline.
Primary source: Arthritis & Rheumatism
Source reference: Rovin B, et al “Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the lupus nephritis assessment with rituximab study” Arthritis Rheum 2012; 64: 1215-1226.