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PRIORITY PRESS - Annual General Meeting of the Canadian Society of Nephrology

Montreal, Québec / April 24-28, 2013

Montreal - Treatment of glomerulonephritis has long been dependent on the use of steroids plus cytotoxic or antiproliferative drugs. With the success of therapeutic monoclonal agents in other autoimmune diseases, their use in immunologically-mediated glomerulonephritis has gained attention. The efficacy of treating anti-neutrophil cytoplasmic autoantibodies (ANCA)-associated vasculitis by depletion of B cells is well documented and B-cell depletion appears to have considerable potential in refractory forms of glomerulonephritis as well. Future studies will consolidate the role of therapeutic monoclonals in complex kidney diseases and results may lead to a new era of targeted therapy in the management of renal disease.

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

B-cell depletion is a new treatment strategy for ANCA-associated vasculitis (AAV) and a viable treatment option in several forms of glomerulonephritis when standard regimens fail, according to a leading expert on therapeutic monoclonals in glomerulonephritis, Dr. David Jayne, Lecturer in Medicine, Cambridge University, UK.

In an editorial, Dr. Jayne, noted that “Immunologically-mediated glomerulonephritis occurs as a primary disorder or in association with a multisystem disease such as lupus or vasculitis and is a potentially preventable cause of end-stage renal disease (ESRD),” (J Am Soc Nephrol 2010;21:14-17).

Vasculitis in turn usually suggests the presence of ANCA-associated necrotizing glomerulonephritis. “Rituximab or B-cell targeted therapy directly reduces the auto-antibody that contributes to both injury and T-cell activity,” Dr. Jayne explained in an interview here at the annual meeting of the Canadian Society of Nephrology. Cytotoxic-T cells also damage the kidney and blood vessels. Because T-cells require B-cell support, “if we take the B cells away, the T cells stop being autoreactive and go to sleep,” he added.

Response Rates

In two cohort studies carried out in refractory/relapsing AAV, “We saw high response rates of over 95% with rituximab with only 1 or 2 patients in each group failing,” Dr. Jayne observed. In the first study, 82% of 34 refractory/relapsing AAV patients achieved full remission; 15% achieved partial remission and only 3% failed treatment after a single course of anti-CD20 antibody treatment. In the second study, 93% of 72 refractory/relapsing AAV patients achieved full remission while 4% achieved partial remission after repeated doses of the same B-cell depletion therapy and 3% failed to respond to treatment—a clear signal that rituximab has a high level of efficacy in relapsing or refractory AAV, as Dr. Jayne remarked.

Two subsequent randomized controlled trials were carried out exploring the use of rituximab in induction therapy in newly diagnosed AAV patients. In the non-inferiority RAVE (Rituximab for ANCA-associated Vasculitis) study, rituximab was compared to oral cyclophosphamide (CYC) in severe AAV, the primary end point being percentage of patients in complete remission at 6 months (N Engl J Med 2010:363:221-32).

In RITUXVAS (Randomised Trial of Rituximab versus Cyclophosphamide for ANCA Associated Renal Vasculitis), IV rituximab 375 mg/m² every week for 4 weeks with IV CYC 15 mg/kg at first and third rituximab infusion was tested against IV CYC administered for 3 to 6 months in newly diagnosed AAV patients with active renal disease.

At 6 months, approximately 65% of RAVE patients treated with rituximab and 55% of patients receiving oral CYC were in complete remission. Although the difference between groups was not statistically significant, it was not expected in this non-inferiority trial. In RITUXVAS, the rituximab-based regimen was not superior to standard IV CYC for severe AAV, and sustained remission rates were high in both groups (N Engl J Med 2010;363:211-20).

Addressing Relapses

“The problem with rituximab is that it produces a relatively short response and then the B cells come back,” Dr. Jayne explained in an interview. After rituximab induction, physicians might consider going back to a conventional regimen consisting of azathioprine (AZA) plus methotrexate (MTX) ±steroids which Dr. Jayne does not consider particularly effective after anti-CD20 induction.

Physicians could also wait until patients flare again and then retreat them with anti-CD20 therapy or consider the approach that the Cambridge group has adopted i.e., a fixed-interval, repeat-dose regimen of a rituximab 2-g induction followed by 1 g q6 months to achieve B-cell depletion until such time as treatment is stopped at 2 years.

“This is not in new patients,” Dr. Jayne emphasized. “But we find that about 45% of our patients—and these are selected patients with difficult disease—remain really well with this maintenance regimen for at least 4 years after their treatment period which we think is as close to a cure as we can get.”

Varying Treatment Options

Following the diagnosis of AAV, treatment options vary depending on disease severity. As Dr. Jayne pointed out, CYC, MTX or mycophenolate mofetil (MMF) given with steroids leads to high and similar levels of clinical remission at 6 months—although the risk of relapse may be higher following MMF compared with CYC. For those with generalized disease, CYC, MMF or rituximab +steroids (possibly IV steroids) are all equally valid options. Patients with severe organ failure are best off receiving either CYC or rituximab with steroids (probably IV), with some favouring the use of plasma exchange for these patients, although plasma exchange has little mortality benefit.

After 3 to 6 months, patients in remission may be switched to either AZA, MTX or MMF plus steroids; if they relapse, the combination of anti-CD20 therapy plus steroids is indicated, as it is for patients who prove refractory to initial treatment. Complete therapeutic withdrawal, starting with steroids first, may be considered for patients who remain in remission at 2 to 3 years follow-up, Dr. Jayne observed.

For those with disease refractory or intolerant to rituximab at the same time point, second-line treatment with either CYC or novel agents such as gusperimus or alemtuzumab may be considered, all given together with steroids.

Other Forms Respond Well

If AAV offers the best pathogenic rationale for B-cell depletion therapy, it is not the only form of glomerulonephritis which appears to respond well to anti-CD20 treatment. For example, it is known that autoantibodies to phospholipase A₂ receptor (anti-PLA₂R) are sensitive and specific for primary membranous nephropathy (MN).

In one study by Beck et al., over 70% of serum samples in 35 MN patients contained anti-PLA₂R (J Am Soc Nephrol 2011;22:1543-50). After 12 months of anti-CD20 treatment, anti-PLA₂R levels declined or disappeared in over two-thirds of patients and this response correlated with a much improved clinical outcome compared with patients with persistent anti-PLA₂R levels. Only a minority of patients with primary MN respond fully to treatment, Dr. Jayne cautioned. Nevertheless, “I think that the data is fairly consistent from a number of groups that rituximab does have an effect on MN and we might be able to go in and use a safer biological here.”

A common problem in focal segmental glomerulosclerosis (FSGS) is that one of the structural cells in the kidney, the podocyte, may become dysfunctional. “Genetic abnormalities in podocytes cause some forms of FSGS,” as Dr. Jayne noted. A single study suggested that rituximab may have a direct effect on podocyte function, he added—a sign that anti-CD20 treatment may have another mode of action in the kidney in addition to B-cell depletion.

Over a decade of experience indicates that rituximab is useful as a second-line agent in patients with lupus nephritis who fail standard therapy. “I don’t think anyone is going to recommend rituximab up-front for lupus nephritis, but for the failing patient, I think it is a viable option.” Dr. Jayne stated. Indeed, experience indicates that approximately one-third of patients with refractory lupus nephritis do not respond to anti-CD20 treatment but that two-thirds do and in some of them, response is “quite remarkable,” as he observed.

Based on this experience, EULAR/ERA-EDTA now recommend that patients with lupus nephritis who fail MMF or CYC be switched from MMF to CYC or from CYC to MMF or to rituximab.

Summary

Over the past decade, the use of therapeutic monoclonals has become relatively routine in clinical practice in other areas of medicine but they are only now being introduced in the treatment of glomerulonephritis. For AAV, the emergence of rituximab as a key therapeutic option is an important and welcome advance. Better evidence is required to support monoclonal use in primary glomerulonephritis but experience thus far supports the use of rituximab in patients with lupus nephritis who have failed standard therapy.