Table 3 Potential explanations for the apparent discrepancy in clinical response reportedin clinical experience and DBRCTs
| Â | Clinical experience | Randomised controlled trials |
|---|---|---|
Disease activity | Refractory to conventional immunosuppressants | Rituximab was used as an add-on therapy to background immunosuppressants |
| Â | 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 |
| Â | 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 |
| Â | 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 |