Monday, April 7, 2014

The use of Rituximab in Kidney Disease

Rituximab, the monoclonal chimeric anti-CD20 antibody, is an effective B-Cell depleting agent and continues to gather data for its use in a wide range of conditions relevant for the Nephrologist. It was also a pre-season favourite in the recent NephMadness event run by our friends at eAJKD, so I figured a quick recap was timely. As the literature is vast and grows by the week, I will only give a brief review of the current data, much of which is weak consisting of small observational reports.

Lupus Nephritis
The jury is still out. The LUNAR study randomized 144 patients with proliferative LN to Rituximab 1g x 4 or placebo with both groups receiving MMF & steroids. The experimental group had a decrease in anti-dsDNA and complement levels. Remission rates were numerically, but not statistically, better with add-on Rituximab (57% V 46%). While a lack of benefit with additional use of Rituximab was demonstrated, whether it could be an alternative to MMF is not known. In cases of resistant LN, we again have multiple favourable case series but no hard evidence.

Steroid-Resistant Nephrotic Syndrome (SRNS)
Evidence suggests Rituximab may be effective in steroid-dependent or calcineurin inhibitor-dependent patients, allowing withdrawal of one/both agents. An open-label RCT in 54 children with SRNS examined standard therapy (with steroids & calcineurin inhibitors) to Rituximab with lowering doses of usual therapy. The experimental arm had lower proteinuria, less relapse and was more likely to be drug free at 3 months. However, relapse did occur in 18.5% of Rituximab treated patients at the time of recovery of the B-Cell population.
The data does not all demonstrate a benefit however, which brings us to a recent small case series in the NEJM. Another anti-CD20 monoclonal antibody, this time the humanized preparation Ofatumumab, was reported to be an effective treatment in 5 cases of SRNS refractory to Rituximab. Although both are anti-CD20 antibodies, they have different epitope specificities which may explain the outcome in this small series. This reinforces the idea that B-Cell depletion is more complex than some may presume.

Minimal Change Disease
No RCT data exists but observational series suggest a benefit in steroid-dependent, but not resistant cases. A new case series in NDT reports on 16 adult patients with MCD who were steroid-dependent (n=12) or resistant and given 2-4 doses of Rituximab. Overall, 13 had a complete and 2 a partial remission with one non-responder. No serious adverse events were reported but 7 relapsed after 9–28 months.

Membranous Nephropathy (MN)
Guess what? No RCT data exists but limited data suggests it may be a useful agent. (See Nate’s previous post). The largest observational study I could find included 100 patients, 32 of whom had disease resistant to other immunosuppressive agents. Baseline proteinuria of 9g/day had been present for a mean of 2 years. Complete/partial/no remission was achieved in 27/38/35 patients respectively, remissions after a mean of 7 months. Prior immunosuppressant use did not appear to alter outcome. Other smaller studies also report that patients, including those with resistant disease, may respond.
There is evidence that Rituximab may cause a decrease in Anti-M-type Phospholipase A2 Receptor (PLA2R) antibodies. In this study, 25/35 patients with idiopathic MN had Anti-PLA2R antibodies, and these autoantibodies declined or disappeared in 17 (68%) of these patients within 1 year of rituximab treatment. The patients who demonstrated antibody response had much improved rates of complete and partial remission in this small study. Perhaps these autoantibodies may prove to be a useful biomarker for treatment response in MN.

ANCA associated vasculitis (AAV)
As per the RAVE study (& RITUXIVAS), there is now robust evidence that a 4 week course of rituximab is non-inferior to cyclophosphamide in the treatment of AAV, including a finding that it may be superior to conventional immunosuppression in relapsing patients. Note that only 2/3 of patients had renal impairment in RAVE with creatinine clearances of 54-69mls/min in the 2 groups. See my previous post for more detail.

FSGS
Limited evidence suggests it may be beneficial in steroid-dependent but not steroid-resistant cases. We must be wary of publication bias from early series which reported  positive findings, especially as they have often failed to be replicated. It has been used with some success for recurrent FSGS post-transplantation, often together with plasma exchange. There is growing evidence for a direct effect on the podocyte, as well as its known anti-B Cell effect, possibly via binding of podocyte proteins such as SMPDL-3b.

Transplantation
It is beyond the scope of this post to delve into the use of Rituximab in transplantation. It can be used in desensitization protocols, PTLD and treatment of acute antibody-mediated rejection (AMR) as adjuncts to IVIG and plasma exchange (trial data awaited regarding allograft outcome). There is no clear evidence for its use in chronic AMR, which tends to have little response to any agent.

Another indication is essential mixed cryoglobulinemia. Here, Rituximab has been reported to be beneficial in cases usually associated with Hepatitis C infection. See Gearoid’s previous post.
Overall, B-Cell depletion in general is an exciting treatment strategy for many of the disease processes we deal with. Like much in Nephrology, we lack strong data for if, when and how to use it. We also lack thorough knowledge as to its precise mechanism of action. Suggestions of a direct podocyte effect in glomerular disease and different mechanistic effects of alternate anti-CD20 preparations illustrate how much we have to learn.

4 comments:

Richard McCrory said...

Excellent summary guys. Rituximab's patent expires in 2015. Not sure if that will mean it becomes easier to fund trials of it's use in proteinuric kidney disease. And then there's the long term data in relation to infection and malignancy risk in the nephrology cohort. Anyone aware of any data out there looking at this? R

Paul Phelan said...

Hi Richard, thanks for the comment. Certainly my take on adverse events data for Rituximab is disappointingly similar to traditional agents (even CyP in RAVE & RITUXIVAS) for all cause and serious infectious events. This is surprising to me (and others) who consider Rituximab a 'clean' agent. Also a suggestion of more malignancy but I don't think the longterm data is there yet. See review ahead of print in CJASN which mentions some of this http://m.cjasn.asnjournals.org/content/early/2014/05/14/CJN.01600214

Anonymous said...

Hi I have recently been diagnosed with the above mentioned FSGS. Recent medications have not been working and doctors are possibly thinking on Rituximab. With side effects and openness to infection unknown I am rather worried. Is there really that little study into this drug and how it works?

Anonymous said...

Also to add to the previous comment, I am steroid dependant and have had very little success with treatment without steroids. This may be a positive as it has worked in steroid dependant patients before. Thanks.