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.