BACKGROUND: Hereditary angioedema (HAE) in patients with normal C1 inhibitor (C1-INH) and the c.988A > G (p.Lys330Glu; p.K330E) variant in the plasminogen gene (HAE-PLG) is associated with skin swellings, abdominal pain attacks, and the risk of asphyxiation due to upper airway obstruction. Aim of this observational, retrospective study is to report about the efficacy of various treatments for acute attacks and long-term prophylaxis.
RESULTS: The study included 111 patients with HAE-PLG. Thirteen patients were treated with icatibant for 201 acute swelling attacks. The mean duration of the treated attacks (mean 4.3 h; standard deviation [SD] 2.6 h) was significantly shorter than that of the previous 149 untreated attacks (mean 44.7 h; SD 28.6 h, p < 0.0001). Twelve patients were treated with plasma-derived C1-INH for 74 acute swelling attacks. The duration of the treated attacks (mean 31.5 h; SD 18.6 h) was significantly shorter than that of the previous 129 untreated in the same patients (mean 48.2 h; SD 32.5 h, p < 0.0001). Corticosteroids alone showed good response in 61/268 attacks (8 patients), low response in 82/268 attacks (7 patients), and no response in 125/268 attacks (26 patients). Corticosteroids combined with antihistamines showed good response in 13/309 attacks (4 patients), low response in 150/309 attacks (7 patients), and no response in 146/309 attacks (17 patients). Antihistamines alone were ineffective in all 37 attacks of 5 patients. In 2 patients with imminent asphyxiation due to tongue swelling and partial obstruction of the upper airways fresh frozen plasma was used without clinical response. The mean reduction in attack frequency was 46.3% under progestins (6 patients), 93.9% under tranexamic acid (3 patients) and 83.3% under danazol (3 patients).
CONCLUSIONS: For patients with HAE-PLG various treatment options are available, which completely or at least partially reduce attack duration or attack frequency.
our results support the use if icatibant as first line treatment for acute attacks, followed by pdC1-INH concentrate
first-line ranking is not identified by physician-selected, uncontrolled historical comparisons
The mean duration of the treated attacks (mean 4.3 h; SD 2.6 h) was significantly shorter than that of the previous 149 untreated attacks (mean 44.7 h; SD 28.6 h, p < 0.0001)
large diary-recorded difference, though historical controls and unmodelled within-patient clustering limit inference
The mean reduction in attack frequency was 46.3% under progestins (6 patients), 93.9% under tranexamic acid (3 patients) and 83.3% under danazol (3 patients)
descriptive before-during reductions rely on very small uncontrolled prophylaxis groups
Derived from the full evaluation — not a separate score.
Strengths
The cohort includes 111 symptomatic carriers from 22 families, providing a substantial genotype-specific clinical record for HAE-PLG. The study reports both acute-treatment and prophylaxis experience.
↳ Results, opening paragraph; Tables 2–5
Tables 3 and 4 present attack duration and response information by patient and attack location for icatibant and pdC1-INH. Negative and mixed responses to other treatments are also reported rather than omitted.
↳ Results, Treatment for Acute Attacks; Tables 3–4; Figures 1–2
The paper addresses acute management and long-term prophylaxis for a condition associated with potentially fatal upper-airway obstruction. The intended clinical pathway and specialist audience are readily identifiable.
↳ Background, final paragraph; Discussion, opening paragraph
Limitations
Treatment was selected solely at physician discretion, and treated attacks were compared with prior untreated attacks without adjustment for severity, indication, time trends, or regression to the mean. These comparisons cannot establish a first-line hierarchy.
↳ Methods, Study Design; Conclusions
The reported t-tests and chi-square tests do not describe adjustment for multiple attacks contributed by the same patients. Treating those observations as independent can overstate the precision of per-attack comparisons.
↳ Methods, Laboratory and Statistical Methods; Tables 3–4
The Discussion acknowledges retrospective, non-random allocation, but the Conclusions still recommend first-line acute and prophylactic treatments. The TXA recommendation rests on only three patients.
↳ Discussion, final paragraph; Conclusions; Table 5
The study adds a sizeable genotype-defined cohort to a sparse HAE-PLG literature and reports treatment experience in unusually granular tables. Its strongest descriptive evidence is the diary-recorded shortening of attacks after icatibant and pdC1-INH. Treatment assignment was nevertheless discretionary, controls were historical, repeated attacks were not modelled as clustered observations, and ascertainment differed across treatment groups. Those design features support descriptive clinical orientation but not the comparative first-line hierarchy stated in the Conclusions.
Nabu’s assessment, alongside the field’s view.
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Limited2.7
Confidence mediumThe study materially enlarges the treatment-response evidence for a recently characterised, ultra-rare HAE genotype through 111 symptomatic patients from 22 families. Treatment-specific samples remain small, particularly for prophylaxis, but the advance over the sparse prior evidence is clear.
The total cohort consisted of 111 symptomatic individuals coming from 22 families
Within-patient historical comparisons and diary records provide useful descriptive evidence, but treatment assignment was discretionary and no analysis addressed confounding, selection, repeated-attack clustering, or differential ascertainment. First-line recommendations therefore exceed what the design can identify.
The choice of treatment had been based solely at the physician’s discretion
The treatment-specific Results structure and detailed Tables 3–5 make the observed data followable. The Conclusions nevertheless communicate a first-line hierarchy more decisively than the observational evidence warrants.
our results support the use if icatibant as first line treatment
The Discussion engages the sparse HAE-PLG literature, contrasts findings with other HAE types, and explicitly states the retrospective, non-randomised design limitation. That limitation is not carried through to the certainty of the first-line recommendations, especially for TXA based on three patients.
The main limitation of our study is that it is a retrospective observational study
Caveats4 of 4 checks
Reported treatment differences remain descriptively visible, but dependence among repeated attacks and heterogeneous outcome ascertainment limit the precision and comparability of the statistical claims. The overlapping response-category patient counts are clarified in Figure 1 but are not self-explanatory in the Abstract.
Ethics approval and informed consent are declared, and data are offered on reasonable request. The absent conflict-of-interest, registration, and code statements do not establish a conduct concern for this retrospective clinical series.
Flags: 2 declared / 5 total
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No retraction or expression of concern found in Crossref (includes Retraction Watch).
Sources: Crossref (incl. Retraction Watch) ✓
Where this paper’s evidence sits on the path from initial observation to real-world use.
The treatments were administered in routine clinical care over two decades, so the observations arise from real-world use. Readiness into comparative guidance remains preliminary because allocation was uncontrolled and no prospective implementation protocol was tested.
no specific treatment algorithm was applied
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