Discussion
There are no clinical trials to validate the use of any second or third line therapies in steroid-refractory ES in children. More often, treating physicians are left to draw conclusions from anectodal or small series of cases. Steroids alone are seldom effective in providing sustained remission with significant long-term adverse effects; thus, are considered as an adjunct to other therapies. Rituxmab induces complete/partial remissions in approximately 60% of children with risk of infections, hypogammaglobeninema, and multifocal leukoencephalopathy. Other therapies such intravenous immunoglobulin, TRA, mycophenolate mofetil, siroliumus, cyclosporine, sand plenectomy have had variable success.
Heterogeneity of treatment responses reflects variations in the underlying mechanism in each case. Since ES is primarily mediated by autoantibodies, B cell-plasma cell (PC) pathway has been the target of several therapies. Inability of B cell-depleting rituximab in eliminating long-lived PC lacking CD20 could be the clue in its failure in some cases. Thus, aiming long-lived PC eradication is a reasonable approach in such cases, in light of successful outcomes of a proteasome inhibitor, bortezomib in multiple myeloma (MM) therapy targeting malignant PC4. Nevertheless, bortezomib has shown success in anectodal cases of refractory ITP and ES and in vitro evidence suggested elimination of long-lived PC by bortezomib3,5-6.
Two of three ES cases reviewed here showed quite a dramatic and long-lasting response to bortezomib therapy. We would like to stress three observations from our experience: 1. Initial response came rather fast raising the possibility of mechanisms involved beyond inhibition of autoantibody production through elimination of long-lived PC, since half-life of IgG is approximately 3 weeks and such autoantibodies tend to be high-affinity likely secondary to affinity maturation over time. This is a very interesting point requiring further research. 2. In line with the rapidity of response and furthermore, lasting recovery after a single dose of bortezomib following a flare in the first case, smaller and/or lesser doses could be sufficient to induce responses. 3. Bortezomib has been well-toleated without any evidence of peripheral neuropathy, the frequent side effect in patients with MM.
We think clinical trials integrating bortezomib in ES treatment even as a front line therapy option is justifiable and responsive cases may avoid several adverse effects of other interventions. Furthermore, biological correlates of responsive and refractory cases may help understand the variability of mechanism of ES.