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.