Lack of biomarkers predicting treatment response
Levels of C1-INH, HK, PK and FXII during treatment did not differ from
those during the observation periods (Figure 2). These levels were all
normal except for PK levels in patient 3, which were decreased but did
not change during rhC1-INH treatment.
All measured % cHK levels were within the normal range with little
variation throughout the study in all patients (upper normal limit cHK
<20%; mean levels in patient 1 15± 4 (SD)%; patient 2 3±
2%; patient 3 2± 1%; patient 4 15± 4%; patient 5 7± 1%; patient 6 4±
3%) (Supplemental Figure 2A).
Mean D-dimer levels were slightly elevated compared to the reference
range (<0.50 mg/L) in patient 1 (0.54 ± 0.06 mg/L), patient 3
(1.42 ± 0.15) and patient 4 (1.62 ± 0.94,), whereas they were normal in
patients 2, 5 and 6. None of the patients had an attack when blood
samples were collected (Supplemental Figure 2B).
CRP and leukocyte counts in patients were within, or slightly above the
normal range (Supplemental figure 2C&2D).
Post-trial follow-up reveals a heterogeneous treatment
response Patient 1 restarted rhC1-INH treatment after the second
observation period initially with a standard treatment interval of 3-4
days achieving again rapid and complete remission (table 3). This was
maintained when extending the treatment interval to 5 days. After seven
months, due to health insurance limitations, treatment was switched to
omalizumab 300mg/4wks and tranexamic acid 1000mg twice daily for three
months, resulting in frequent and severe AE with 15 (AAS28:87) and 11
(AAS28: 101) attacks in the first two months and also in month 3, of
which detailed data are missing. In this period, admission to emergency
room or intensive care was required seven times. Treatment of attacks
with 1000 IU pdC1INH was effective. Subsequently, health insurance
approval was granted and prophylactic treatment with 1000 IU pdC1-INH
every 3-4 days was initiated, which again led to immediate symptom
control. After one year, treatment was switched to 4200IE rhC1-INH since
herewith, remission could be achieved with longer intervals of 5-6 days.
After one year, treatment was switched to 4200 IU rhC1-INH every 5-6
days, which successfully prevented the development of attacks.
Additional genetic analysis supported the InH-AAE diagnosis (see
supplemental table 1).
Patient 2 initiated omalizumab after the study and reported
partial response after six months of treatment. Consequently, the
treatment dose was increased incrementally to 600mg/3wks, which resulted
in a good treatment response after 28 doses.
Patient 3 wished for no further treatment additional to
antihistamines and accepted symptoms with no further follow-up.
Patient 4 started post-trial tranexamic acid three times daily
500mg alongside desloratadin 5 mg four times daily, resulting in a
decrease in frequency and severity.
Patient 5 started icatibant as attack medication during a
two-month period. Due to ineffectiveness, icatibant was ceased and the
patient recently started omalizumab treatment. The first three doses did
not yet result in improvement.
Patient 6 showed an immediate near complete response after the
first dose of omalizumab with an AAS28 score of 5 after the first
omalizumab dose compared to a mean AAS28 score of 32 in the six weeks
before omalizumab treatment.