The efficacy and safety of rituximab in treating childhood nephrotic syndrome: an Italian perspective
© The Author(s). 2016
Received: 30 March 2016
Accepted: 17 June 2016
Published: 12 July 2016
Nephrotic syndrome is a disorder characterized by proteinuria, hypoalbuminemia and dyslipidemia. Low-dose alternate-day steroid regimen is the standard of care. In case of relapse or significant adverse events, steroid-sparing agents may be used. This analysis was aimed at assessing the efficacy and safety of rituximab for the treatment of children with nephrotic syndrome.
Four studies were included in the final meta-analysis. The end-point of our analysis was the percentage of patients in remission at 6 months. Pooled data from the four studies favours the use of rituximab (RR 5.25, 95 % CI: 3.05–9.06; p < 0.0001). As regards the safety data, rituximab has a limited number of adverse effects, the most common of which occur during the infusions.
In Italy, the off-label use of drugs is regulated by Law 648/96. In our opinion, there are three scientific requirements to merit a conditional national reimbursement for rituximab in nephrotic syndrome: 1. favourable clinical efficacy and safety data; 2. no available alternatives; 3. outcome data collecting by AIFA through prescribers. In conclusion, our results report a significant incremental benefit of adding rituximab to corticosteroid and/or calcineurin inhibitors for the treatment of nephrotic syndrome.
KeywordsRituximab Nephrotic syndrome 648/96 law Off label Reimbursement
Nephrotic syndrome (NS) is a disorder characterized by heavy proteinuria, hypoalbuminemia (serum albumin <2.5 g/dl), often associated with dyslipidemia and hypercoagulability (Ravani et al. 2015). The most recent update of the NS clinical guidelines suggests a low-dose alternate-day steroid regimen as first-line treatment for the management of children who develop frequently-relapsing (FRNS) or steroid-dependent nephrotic syndrome (SDNS) .
However, when there is a failure to maintain remission or significant adverse events occur with corticosteroid therapy, clinicians have the option of using a number of steroid-sparing agents such as cyclophosphamide and calcineurin inhibitors (CIs, e.g., cyclosporin, tacrolimus, mycophenolate mofetil) or levamisole. Some of these immunosuppressant agents may cause serious adverse events such as nephrotoxicity, hyperglycemia, headaches and dyslipidemia . Therefore, new drugs are needed to address this problem. Several reports and guidelines have proposed rituximab as a novel agent for the treatment of children with FRNS/SDNS [1–4].
During an evaluation of the off-label prescription of drugs in our hospital, we encountered many prescriptions for rituximab for the treatment of children with NS. Thus, the aim of this analysis was to assess the efficacy and safety data of the use of rituximab for the treatment of children with FRNS/SDNS, in whom the corticosteroid therapy is not sufficient to manage the disease, and to provide these quantitative results as meta-analytical data.
Efficacy and safety data
Basic characteristics of included studies. The intervention group comprised patients treated with rituximab plus prednisone and/or CIs, while the control group contained patients on prednisone and/or CIs. The end-point of our meta-analysis was the percentage of patients in remission at 6 months
First author, year (Reference)
Intervention group (n)
Control group (n)
Age intervention group/age control group, yr, mean
Male/Female patients, n/n
Ravani et al. 2015 .
Corticosteroid therapy (15)
All patients were maintained in remission with high prednisone doses (>0.7 mg/kg per day)
- RTX (one infusion of 375 mg/m2)
- prednisone was tapered off by 0.3 mg/kg per week if proteinuria was <1 g/d.
- prednisone (mean dose 49 mg/m2 per day)
Ravani et al. 2011 
Corticosteroid + CIs therapy (27)
- RTX (one or two infusion of 375 mg/m2)
- chlorfenamine maleate
- methyl prednisolone
- prednisone was tapered off by 0.3 mg/kg per week if proteinuria was <1 g/d.
- prednisone and CIs (tapered off by 0.3 mg/kg per week if proteinuria was <1 g/d.)
Iijima et al. 2014 
Corticosteroid therapy (24)
- RTX an intravenous dose of 375 mg/m2 (maximum
500 mg) once weekly for 4 weeks.
- d-chlorpheniramine maleate
- prednisolone (60 mg/m2 orally three times a day (maximum of 80 mg per day) for 4 weeks, and then tapered over 6 weeks.
Ahn et al. 2013 
Corticosteroid + CIs therapy (18)
- single dose of intravenous RTX (375 mg/m2)
- corticosteroid therapy
As regards the safety data, rituximab has a limited number of adverse effects, the most common of which occur during the infusions [5, 6]. In the study by Iijima et al. 2014, most adverse events for rituximab were mild, and no patient died during the trial. Although more patients in the rituximab group had serious adverse events compared to controls, the difference was not significant (p = 0.36). The most common grade 3–4 adverse events in the rituximab group were hypoproteinemia, lymphocytopenia and neutropenia.
Both studies by Ravani et al. report similar safety data, the most common adverse events being bronchospasm, hypotension (at the second rituximab infusion), skin rash, acute arthritis at the hip joint after 2 and 6 days from the infusion (resolution was rapidly and completely achieved within 24 to 48 h with non-steroidal anti-inflammatory medications). In the study by Ahn et al. 2014, 24 of the 54 treated patients (44 %) experienced mild and transient infusion reactions, however, no serious side effects were observed.
In Italy, the off-label use of drugs is currently regulated by Law 648/96. According to this regulation, medicines can be used off-label at NHS expense, once the Italian Medicine Agency (Agenzia Italiana del Farmaco, AIFA ) has authorised their inclusion on a specific list. The inclusion on this list requires the coexistence of three elements: favourable clinical efficacy and safety data; no or scant alternatives for treating the disease; outcome data collection by AIFA through prescribers. In our opinion, all the above mentioned requirements are met to merit a conditional national reimbursement for rituximab in NS through the law 648/96. However, the third requirement (e.g., collection of outcome data) should be made more stringent by AIFA and, in this case, it would allow for a pharmaco-epidemiological description of the treatments performed nationwide, compared to the current situation in which each individual hospital manages and analyses its own small pool of patients. The cost of one infusion of rituximab (375 mg/m2) is 1,943 euros/patient (this cost does not take into account any eventual nationally-negotiated procurement discount).
A new humanized anti-CD20 antibody - ofatumumab - has been developed and is currently being tested in two clinical trials: 1. Ofatumumab vs rituximab for children with SDNS (trial identifier NCT02394106 ); 2. ofatumumab vs placebo for children with FRNS (Basu 2014; Bonanni et al. 2015; trial identifier NCT02394119 [11–13]). The results are expected in the coming years; therefore, to date, rituximab is the best available alternative therapy to corticosteroids and/or CIs. The cost for one infusion of ofatumumab (1500 mg/m2) is 6,268 euros/patient (this cost does not take into account any eventual nationally-negotiated procurement discount).
The important aspects related to the price and the costs of these two monoclonal antibodies need to be taken into consideration. On one hand, rituximab is a well-known monoclonal antibody that became off-patent in Europe in November 2013 , although it is not yet marketed as such; on the other hand, ofatumumab is a new monoclonal antibody with a hypothetical future conditional approval for the treatment of children with NS, which costs more and, up to now, has less evidence supporting its use than rituximab does. In other words, to date, the reimbursement of rituximab under Law 648/96 might represent a cost-saving opportunity for the NHS to provide a treatment option for children with complicated FRNS/SDNS, in spite of the limited favourable supporting evidence available, at a lower price than ofatumumab, in case both drugs are included on the 648/96 list.
The results of our updated meta-analysis report a significant incremental benefit of adding rituximab to corticosteroids and/or CIs when treating children with complicated FRNS/SDNS.
The authors would like to acknowledge Dr. Roberto Draghi for his contribution to the data analysis.
FV, DM: conception and design of the article. MB, MGC: conducted the literature search, determined studies for exclusion and inclusion, extracted data from retrieved studies. DM, FV: performed the meta-analysis and drafted the manuscript. GM: provided comments on the clinical data. All authors reviewed the paper and approved the final manuscript.
The authors declare that they have no competing interests.
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