DISCUSSION
This is the first prospective trial describing the successful use of
rhC1-INH as prophylactic treatment in one out of six patients with
InH-AAE (patient 1). Restart resulted in an equally fast and beneficial
response. pdC1-INH also appeared to be effective. We hypothesize that
the bradykinin route is pathomechanistically involved although we found
no formal proof after biomarker investigations. Post-trial, patients 1,
2, 5 and 6 received omalizumab treatment. Patients 2 and 6 experienced a
good, and a near complete response respectively. Patients 1 and 5
reported no clinical effect of omalizumab.
We observed an almost complete and fast improvement of AE activity in
patient 1, with only 3 mild attacks in the treatment period versus 19
attacks in the observation period. Equal effectiveness was found during
post-trial follow-up upon restart of rhC1-INH treatment on two different
treatment periods with a similarly fast and near complete response. This
was unlikely a placebo effect, since post-trial follow-up data showed a
similar response to pdC1-INH, whereas treatment with omalizumab had no
effect and resulted in an increased attack rate. The effect of rhC1-INH
was in line with that in HAE, in which a sustained effect of 72 hours or
longer was observed in 93% of HAE patients despite the short half-life
of approximately 3 hours.23 Clinical response to
recombinant (r)hC1-INH in patients with InH-AAE was not published
before. Three previous case reports describe successful use of plasma
derived (p)dC1-INH prophylaxis in four patients with
InH-AAE.16-18 However, from these reports, it is not
clear to what extent the observed responses were due to a placebo
effect, and what proportion of patients may respond to such therapy. Our
data show that only a proportion of the patients with InH-AAE may
respond to C1-INH treatment. Failure of efficacy of rhC1-INH in the
other 5 InH-AAE patients may suggest that bradykinin is not involved in
generating attacks in these patients. However, we favour another
explanation. A dose of 50 IU rhC1-INH per kg increases circulating
C1-INH levels by approximately 2-fold. This increase may have been too
low, especially since factor XIIa bound to an activator is less well
inhibited by C1-INH.24
None of the biomarkers of the bradykinin route (C1-INH, FXII, PK, HK)
differentiated the responding patient from the others. Moreover, none of
these biomarkers pointed to an increased activation of the contact
system. One may argue that levels of bradykinin could provide a better
biomarker for such activation. This is supported by the finding of
elevated bradykinin levels in InH-AAE patients at the time of AE
attacks.10 Considering the technical issues, such as
processing of plasma samples, we did not assess bradykinin levels in the
patients described here.
After the study period, treatment of patient 1 with both rhC1-INH and
pdC1-INH resulted in an immediate effect, though the effective treatment
interval appeared to be 3-4 days for pdC1-INH versus 5-6 days for
rhC1-INH. Previous studies show that there is no fundamental difference
in efficacy between pdC1-INH and rhC1-INH in patients with HAE, when
similar doses, expressed as IU, are given.34 However,
doses given to patient 1, who had a body weight of 100 kg, were
different, 4200 IU of rhC1-INH versus 1000 IU of pdC1-INH per
administration. Thus, the increase of C1-INH activity, which was
approximately 1 U per ml in case of rhC1-was considerably lower, about
0.25 IU, when pdC1-INH was administered. Therefore, C1-INH levels may
have decreased below a critical level more rapidly in cases of pdC1-INH
administration, in spite of its longer half-life.
The restart of C1-INH treatment in patient 1 resulted in an immediate
effect with a clear difference of the effective treatment interval of
3-4 days for pdC1-INH versus 5-6 days for rhC1-INH. Previous studies
show that there is no fundamental difference in efficacy between
pdC1-INH and rhC1-INH in patients with HAE.25 The
observed difference in treatment interval is therefore most likely
explained by dosage inequivalence since rhC1-INH is dosed at 50IU/kg
with a maximum of 4200IU and pdC1-INH at a fixed dose of
1000IU.26, 27 In our patient with body weight 100kg,
1000IU pdC1-INH might have been relatively under dosed compared to
4200IU rhC1-INH resulting in lower effectivity and the need for shorter
treatment intervals.28
C1-INH treatment is generally well tolerated, though recent studies
suggest a small risk of trombotic events upon treatment with rhC1-INH
and pdC1-INH in HAE patients.29, 30 We did not observe
thrombotic or any other adverse events in the patients studied, even
though we supplemented C1-INH in patients with normal levels.
A review of omalizumab for InH-AAE in six small case series, reports a
complete response in all 20 patients, with time to response ranging from
one day to 16 weeks.31 Four patients with InH-AAE who
did not respond to rhC1-INH treatment, were subsequently treated with
omalizumab. Two patients responded to this therapy. Patient 1 and 5 did
not show any benefit from three months omalizumab treatment, although
the possibility that the treatment period with omalizumab was too short
cannot be excluded.32 Prospective evaluation in an
unselected population is needed to gain insight about the real
percentage of responders. Response to omalizumab may be interpreted as
evidence for histamine as the main mediator of AE in these
patients.32 One should be careful about making this
conclusion, as marked activation of FXII, PK, and kininogen has
previously been found during anaphylaxis, indicating bradykinin cannot
be ruled out as the main mediator of AE even in conditions commonly
associated with mast cell activation.33
In conclusion, rhC1-INH treatment was effective in 1 of 6 InH-AAE
patients. Response to omalizumab and tranexamic acid during follow-up in
some of the other patients points to a heterogeneous pathogenesis of
this disease and, as a consequence, the need for a personalised
treatment approach.