This is the first systematic review that summarizes the efficacy and safety of rituximab in children with ITP, and this review is very important at this time as rituximab has been widely used off-label for children with ITP. The treatment of rituximab achieved response in 68% and complete response in 39% of patients with primary ITP. According to studies reporting individual data, the median time to response was 3.0 weeks and the median response duration was 12.8 months. Studies with a small number of patients with secondary ITP reported that response rate to rituximab was from 64.7%~100%. Most adverse events were mild to moderate and no death was reported.
The response and complete response rate in children with primary ITP obtained in this review was 68% and 39%, respectively. It was similar to that reported in the previous systematic review on adults, which reported that overall response (platelet count >50×109
/L) and complete response (platelet count >150×109/
L) rate was 63% and 46% respectively 
. Although response criteria differ in these two reviews, it may suggest that rituximab results in a similar response in adults and children with primary ITP.
The frequently administrated dose of rituximab is 375 mg/m2
per week for 4 weeks for both children and adult with ITP 
, although this dose was developed and approved for the treatment of lymphoma 
. 1 study investigated the efficacy of a single dose of rituximab (375 mg/m2
) in children, and reported a similar response and complete response rate as 4 doses 
. 2 studies investigated a low dose rituximab of 100 mg/dose/week for 4 weeks in 18 children with primary ITP, which suggested that the lower dose of rituximab still reached a good response 
. Treatment of rituximab is still costly in the present time, and thus sometimes 4 doses of 375 mg/m2
are not affordable, especially for patients with poor accessibility to health resources. In addition, high dose and multiple dosing may increase risk of adverse events. Low dose of rituximab may be promising for patients with ITP, and more studies are needed to investigate that.
Most of adverse events associated with rituximab in children with ITP were mild to moderate infusional reactions. More severe adverse effects included serum sickness, common variable immunodeficiency, severe virus infection including enteroviral meningoencephalitis, and white matter changes. 2 children developed viral infection after rituximab treatment, but they were both previously treated with other immunosuppressive agents like steroids, vincristine, and cyclosporine A, it is difficult to establish a direct association with rituximab 
. In addition, a systematic review in cancer patients did not find any increase of infection caused by monoclonal antibodies 
. The case of common variable immunodeficiency in patients with ITP after rituximab treatment was reported in an 8-year-old child 
, however, it was not clear whether it was caused by rituximab, as ITP might be the first clinical manifestation before development of common variable immunodeficiency. 1 patient developed headache and MRI showing white matter changes 
, but without detailed information as published only in abstract, it is not clear whether the children developed progressive multifocal leukoencephalopathy, although it is reported that there was a potential of progressive multifocal leukoencephalopathy among rituximab-treated patients 
. No death was found in this review, but 9 cases of death (2.9%) were reported in studies on adults 
. The mortality reported in adults treated with rituximab might be overestimated and these cases might be explained by long courses of complex treatment regimens or the selection of patients with advanced disease.
All the studies eligible for efficacy analysis in this review failed to compare effect between rituximab with non-rituximab group. The response rate obtained may be influenced by many potential factors, such as treatments before and combined with rituximab, cause and development of ITP. Studies on this topic with better methodological design like randomized controlled studies are urgently needed. Consecutive enrolling of patients can help to reduce selection bias in prospective case series studies, unfortunately, few studies provided information on that, and this needs improvement in future studies.