Blog entry by Arif Khwaja
Anyone who read my ASN blog will know that Remuzzi's group from Bergamo presented what appeared to be very positive data on the role of Rituximab in idiopathic membranous glomerulonephritis (IMN) at the ASN in 2011. Well the data has finally been published and serves as a salutory reminder to me that one always needs to see the final paper before being able to assess the impact on ones' practice. Remuzzi presents data on a 100 consecutive patient with IMN treated with Rituximab. The median duration of persistent proteinuria prior to rituximab therapy was over 2 years and follow up data was available for a median of 29 months. 27% achieved complete remission whilst 38% achieved partial remission (defined as less than 3g/24 hours and a 50% reduction in proteinuria from baseline). The authors suggest that 'Rituximab might be considered as first line therapy' for IMN. Does the data justify such a statement? Almost certainly not and its worth considering the following:
i) Given the very variable remission and progression rate with IMN, any therapeutic data without a control group is of limited value (some would say meaningless...). IMN runs a highly variable course with a high rate of spontaneous remission that occur can occur even quite late after presentation. This was observed not only by the GLOSEN group in Spain but by Remuzzi himself who when publishing in the NEJM on presumably another cohort of of 100 IMN patients found that 65% of patients went into complete or partial remission after 5 years of observation prompting him to note that 'Most untreated patients with idiopathic membranous nephropathy maintain renal function for prolonged periods and are likely to have spontaneous remission'......
ii) Following on from the above its worth noting that the serum creatinine and 24 hour urinary protein excretion was lower and the serum albumin was higher at baseline in the complete remission group versus the no remission group.. so the question arises did the complete remission group have milder disease that would just get better anyway. Of course unless you have a control you just dont know!
ii) Only 32 patients had recieved prior immunosuppression and of these only 24 had prior steroids in combination with an alkylating agent - this is currently the KDIGO recommended first line therapy as as Gerald Appel points out in an accompanying editorial, given the fact that we have placebo controlled RCTs with both CNIs and alkylating agents, but not with Rituximab, why should we use Rituximab as first line therapy?
iii) the authors cite safety concerns of cyclophosphamide although the cumulative dose of cyclophosphamide used in IMN is relatively low and the safety of Rituximab in auto-immune disease (in terms of side effects such as progressive multifocal leucoencepholopathy) maybe different than in those with lymphoma.
iv) Rituximab is expensive. The authors state that as they only use one dose (375mg/m2) costs are reduced though its worth noting that 18 patients with rituximab relapsed and required a second dose. The use of phospholipase A2 receptor antibodies as a guide to dosing schedule may make more sense.
Taking this work together with Fernando Fervenza's data from the Mayo Rituximab is probably better than placebo in IMN. Its expensive and until there is an RCT comparuing it with an alkylating agent or a CNI I would only use in those patients with progressive IMN who are refractory to (or have contraindications to) alkylating agents therapy and/or calcinuerin inhibitors.
1.Rituximab in Idiopathic Membranous Nephropathy. Piero Ruggenenti, Paolo Cravedi, Antonietta Chianca, Annalisa Perna, Barbara Ruggiero, Flavio Gaspari, Alessandro Rambaldi, Maddalena Marasà, and Giuseppe Remuzzi. J Am Soc Nephrol published 19 July 2012, 10.1681/ASN.2012020181
2. Prognosis of untreated patients with idiopathic membranous nephropathy. Schieppati A, Mosconi L, Perna A, Mecca G, Bertani T, Garattini S, Remuzzi G, N Engl J Med. 1993 Jul 8;329(2):85-9.
3. Spontaneous remission of nephrotic syndrome in membranous nephropathy with chronic renal impairment. Nephrol Dial Transplant 2012 Jan;27(1):231-4. Epub 2011 May 30. Polanco N, Gutiérrez E, Rivera F, Castellanos I, Baltar J, Lorenzo D, Praga M, Grupo de Estudio de las Enfermedades Glomerulares de la Sociedad Española de Nefrología (GLOSEN)
4. Rituximab therapy in idiopathic membranous nephropathy: a 2-year study. Fervenza FC, Abraham RS, Erickson SB, Irazabal MV, Eirin A, Specks U, Nachman PH, Bergstralh EJ, Leung N, Cosio FG, Hogan MC, Dillon JJ, Hickson LJ, Li X, Cattran DC; Mayo Nephrology Collaborative Group. . 2010 Dec;5(12):2188-98.