In this section
Rituximab is a murine- human chimaeric monoclonal antibody (CD20) used for depletion of B cells in a variety of neoplastic and immune-mediated diseases. It is becoming increasingly applied to a diverse range of conditions traditionally requiring heavy immunosuppression and has demonstrated a fairly safe side effect profile compared to standard therapies. However, long-term side effects have not been fully examined and this must be considered when instituting rituximab therapy in conditions lacking published outcomes. Rituximab was first reported to treat a child with nephrotic syndrome in 20041. Since that time numerous reports and case series have been published, supporting the efficacy of rituximab in nephrotic syndrome. In this difficult group of steroid-dependent or resistant cases, partial or complete remission rates of 70-85% are reported, with many patients able to cease other immunosuppressive medications2. This document serves as a medical protocol for the prescription, monitoring and dose-adjustment of rituximab in paediatric nephrotic syndrome. Two additional documents should be referred to in the prescription of rituximab:
The standard rituximab dose has been extrapolated from its widespread use in the treatment of lymphoma- consisting of 375mg/m2 weekly for 4 weeks. Assessment of rituximab's efficacy is based on measurement of circulating B cells. This does not evaluate the extra-vascular B cell population, which may be considerable. Emerging evidence suggests that circulating B cell depletion is possible in most patients with fewer than 4 doses and often with a single dose. While it is unclear of any additional clinical benefit from doses beyond those achieving depletion of circulating B cells, the current protocol favours use of the minimal initial dosage to deplete circulating B cells, in order to minimise total exposure in the event repeat doses are required to maintain prolonged B cell depletion in the future. It does appear that rituximab's efficacy is optimised by ensuring a patient is in remission at the time of dosing. The literature does not demonstrate any clear benefit of reduced relapses or more prolonged depletion with greater doses at induction and single doses are increasingly being used3-5.
Rituximab induced B cell depletion has a variable duration from as little as 3 mth to as long as 2 yr. It is unclear how immunosuppressive this period of B cell depletion is for patients, but it seems prudent to assume this to be significant for the first 6 months, especially if the patient has been on concurrent immunosuppressive medications. Appropriate precautions and Bactrim prophylaxis for PCP are therefore recommended during this period6. For the purpose of defining the optimal time to assess the result of Rituximab's effect on B cells, it would appear that if a dose successfully depletes B cells, this is evident within 24 hours of the dose in >99% cases (Rituximab product information).
The following protocol outlines the approach to management of rituximab in nephrotic syndrome, including a guide to weaning a typical patient with SDNS on prednisolone, mycophemolate mofetil and cyclosporine. The goal is to achieve B cell depletion and maintain this for the first 12mth. A retrospective study recently reported sustained remission with rituximab in SDNS, but the relapse-free period was increased from 9mth without retreatment to 24.5mth in those retreated at the time of B cell recovery7. With such promising reports, we believe pre-emptive therapy to maintain remission for the first 12mth is justified. However, without randomised trial data or quantified long-term risks of therapy, an individualised approach must be taken after this period in order to balance the benefits of sustained remission on therapy, the possibility of spontaneous remission as the child ages and the risks of repeated doses of rituximab in childhood.
Rituximab should not be considered as a first line treatment for a patient with nephrotic syndrome. However, it does appear to have a definite role in patients failing to achieve satisfactory responses with standard therapies, such as steroids, calcineurin inhibitors, levamisole and mycophenolate mofetil. The primary indications include:
All patients undergoing this treatment should be registered on the Rituximab database, stored on the Nephrology Dept drive. For access, contact: Kerrie Scott, Dept Nephrology, ext 55054, email email@example.com
A review of the protocol outcomes will be performed 2 years after implementation- August 2015
1. Benz K, Dotsch J, Rascher W, Stachel D. Change of the course of steroid-dependent nephrotic syndrome after rituximab therapy. Pediatr Nephrol 2004;19:794-7.
2. Tullus K, Marks SD. Indications for use and safety of rituximab in childhood renal diseases. Pediatr Nephrol 2013;28:1001-9.
3. Ito S, Kamei K, Ogura M, et al. Survey of rituximab treatment for childhood-onset refractory nephrotic syndrome. Pediatr Nephrol 2013;28:257-64.
4. Sinha A, Bagga A. Rituximab therapy in nephrotic syndrome: implications for patients' management. Nat Rev Nephrol 2013;9:154-69.
5. Kemper MJ, Gellermann J, Habbig S, et al. Long-term follow-up after rituximab for steroid-dependent idiopathic nephrotic syndrome. Nephrol Dial Transplant 2012;27:1910-5.
6. Sato M, Ito S, Ogura M, et al. Atypical Pneumocystis jiroveci pneumonia with multiple nodular granulomas after rituximab for refractory nephrotic syndrome. Pediatr Nephrol 2013;28:145-9.
7. Tellier S, Brochard K, Garnier A, et al. Long-term outcome of children treated with rituximab for idiopathic nephrotic syndrome. Pediatr Nephrol 2013;28:911-8.
Dr. Joshua Kausman