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Table 3 Potential explanations for the apparent discrepancy in clinical response reportedin clinical experience and DBRCTs

From: B-cell depletion in SLE: clinical and trial experience with rituximab and ocrelizumaband implications for study design

  Clinical experience Randomised controlled trials
Disease activity Refractory to conventional immunosuppressants Rituximab was used as an add-on therapy to background immunosuppressants
  Favourable response reported in life-threatening cases, often including arange of organ-system involvement such as CNS manifestations, cytopenias andothers Life-threatening cases and those with CNS manifestations were not evaluatedin controlled trials. This setting warrants a dedicated study
Clinical response No defined pretreatment, therefore complete and partial
responders might not be clearly distinguished
Predefined endpoints were stringent, perhaps driven by the impressiveresponses seen in clinical experience in an uncontrolled setting
  Improvement in one system alone might qualify for response, regardless of aflare or lack of response in another organ system Predefined and usually stringent. For example, despite clinical response andsteroid-sparing effect, a reduction in proteinuria that does not meet thepredefined threshold would not qualify as complete/partial response
Background immunosuppressants Flexibility in changes to background immunosuppressants including the doseof corticosteroids Changes to or deviation with predefined background therapy would qualify asnonresponder
  Concomitant use of large dose of steroids is uncommon Concomitant use of large dose of corticosteroids might have limited anybeneficial effects of rituximab, the extent of which may be more restrictedin such a setting than previously assumed
Rituximab dosing-regimen Variable between reports Predefined dosing regimen
Steroid tapering Steroid-sparing effect is not a requirement to define response and thereforefavourable response might be overestimated Steroid dosing effect was included in the definition of clinicalresponse
Adverse events No standardised reporting of adverse events. Therefore, the true incidenceof serious adverse events in clinical practice is not comparable with thatreported in other uncontrolled studies or controlled clinical trials Rituximab therapy appears to be safe as no there were no significantdifferences in serious adverse events when compared with standard-of-caretreatment
Follow-up period Not defined, therefore it is not known how many responders had sustainedresponse in the long term Predefined, therefore, unless long-term studies are undertaken, it would bedifficult to detect the importance of effects seen at relatively short-termfollow-up
  1. CNS, central nervous system.