BACKGROUND: Acquired angioedema due to C1-inhibitor (C1-INH) deficiency (AAE-C1-INH) is a serious condition that may result in life-threatening asphyxiation due to laryngeal edema. It is associated with malignant B-cell lymphoma and other disorders. The purpose of this study was to describe the characteristics and associated disorders of patients with AAE-C1-INH and assess the efficacy of plasma-derived C1-INH concentrate (pdC1-INH) in the treatment of AAE-C1-INH. Forty-four patients with AAE-C1-INH from the Angioedema Outpatient Service of Mainz were assessed for associated disorders. In 32 of these patients, the duration of swelling attacks was measured before and after treatment with pdC1-INH (Berinert® (CSL Behring, Marburg, Germany)). The time between injection and complete resolution of symptoms and treatment effectiveness was provided by the patients.
RESULTS: The following underlying disorders were present: monoclonal gammopathy of undetermined significance (47.7%), non-Hodgkin lymphoma (27.3%), anti-C1-INH autoantibodies alone (11.4%), and other conditions (4.5%). In 9.1% patients, no associated disorder could be found. AAE-C1-INH led to the detection of lymphoma in 75% of patients with the malignancy. Treatment with pdC1-INH shortened attacks by an average (SD) 54.4 (± 32.8) hours (P < 0.0001). The earlier the attack was treated, the shorter the time between injection and resolution of symptoms (P = 0.0149). A total of 3553 (97.7%) of the 3636 attacks were effectively treated with pdC1-INH as assessed by the patient. The mean (SD) dose per-attack was 787 (± 442) U. pdC1-INH was effective in 1246 (93.8%) of 1329 attacks in 8 patients with anti-C1-INH autoantibodies and in 344 (99.4%) of 346 attacks in 6 patients without autoantibodies. The average (SD) dose per effectively treated attack was 1238.4 (± 578.2) U in patients with anti-C1-INH autoantibodies and 510.2 (± 69.1) U in patients without autoantibodies.
CONCLUSIONS: pdC1-INH is highly effective in treating AAE-C1-INH patients and is also effective in the vast majority of attacks in patients with anti-C1-INH autoantibodies. It is fast-acting and reduces attack duration.
Treatment with pdC1-INH shortened attacks by an average (SD) 54.4 (± 32.8) hours (P < 0.0001).
historical within-patient comparison with severity-based treatment selection and patient-reported durations
pdC1-INH is highly effective in treating AAE-C1-INH patients and is also effective in the vast majority of attacks in patients with anti-C1-INH autoantibodies.
subjective response assessments from an uncontrolled series with incomplete antibody testing
In 9 (75.0%) of 12 patients, the associated malignant lymphoma was detected following diagnosis of AAE-C1-INH.
directly documented chronology in all twelve lymphoma cases
Derived from the full evaluation — not a separate score.
Strengths
The study follows 44 patients and reports treatment experience in 32 patients across 3,636 stated attacks, providing an unusually extensive dataset for AAE-C1-INH.
↳ Results, Patient Characteristics and Plasma-derived C1-inhibitor concentrate treatment
Attack duration, time to relief, time to resolution, dose, and patient-assessed response are reported on per-patient and per-attack bases, with a sensitivity analysis for injection timing.
↳ Results, Efficacy, Effect of Time to Injection, and Tables 3–5
The Discussion contrasts the observed antibody-positive response rate with earlier reports of partial or complete resistance and identifies higher dose requirements in some patients.
↳ Discussion, autoantibody treatment paragraphs
Limitations
Untreated attacks occurred before pdC1-INH use, while mild attacks were specifically not treated and other therapies continued during the treatment period. These features leave severity selection, temporal change, and concomitant treatment as alternative explanations for part of the observed difference.
↳ Methods, Study Design and Treatment; Results, Prior and Concomitant Treatment
Attack duration and effectiveness were obtained through questionnaires, interviews, or diaries without blinded or objective outcome confirmation. The Discussion acknowledges possible bias but the Conclusions retain definitive efficacy wording.
↳ Methods, Study Design; Discussion, final paragraph; Conclusions
Table 2 location counts total 4,493 while the paper states that 3,636 attacks were treated, without explaining overlapping categories. The efficacy narrative also reports 88 non-effective attacks where the reported totals and Tables 4–5 imply 83.
↳ Results, Table 2 and Efficacy of pdC1-INH concentrate treatment; Tables 4–5
The paper’s main value is the scale and detail of its accumulated experience in a rare condition, including dose, timing, and autoantibody-stratified analyses. The primary efficacy comparison nevertheless contrasts historical untreated attacks with selectively treated later attacks, while concomitant therapies and patient-reported outcomes remain unresolved sources of uncertainty. The Discussion engages relevant prior series and acknowledges retrospective bias, but the final causal wording is more definitive than that design supports. Numerical discrepancies in Tables 1–2 and the non-response count also require correction before the descriptive findings can be relied upon.
Nabu’s assessment, alongside the field’s view.
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Limited2.7
Confidence mediumThe series adds a comparatively large AAE-C1-INH cohort, extensive accumulated treatment experience, and antibody-stratified results to a sparse evidence base. Its advance is meaningful but remains observational rather than comparative.
published information on the efficacy and safety of AAE-C1-INH treatments is limited
The study supplies detailed timelines, dosing data, within-patient comparisons, and a sensitivity analysis, but untreated attacks are historical and treatment selection depends on severity. Patient-reported outcomes, incomplete antibody testing, and concomitant treatments leave substantial uncontrolled uncertainty.
Patients were counseled that mild skin swellings should not be treated.
The progression from cohort description to treatment and subgroup analyses is readily followable, with definitions and numerical outcomes presented in the Methods and Results. Definitive phrases such as “reduces attack duration” are stronger than the historical, patient-assessed comparison warrants.
It is fast-acting and reduces attack duration.
The Discussion compares the cohort with earlier AAE and HAE series and addresses previous reports of autoantibody-associated resistance. It acknowledges retrospective patient-report bias and incomplete testing but does not fully translate those limitations into reduced certainty in the conclusion.
which may have resulted in some bias
Concerns4 of 4 checks
Several tabulated or narrative counts are internally inconsistent. The most material discrepancy concerns the attack-location denominator in Table 2, while other errors appear to be isolated reporting or formatting problems.
Ethics approval, informed consent, and a reasonable-request data statement are reported. No funding or conflict-of-interest disclosure appears in the supplied article despite repeated identification of a single commercial product.
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.
pdC1-INH was already being administered by patients, general practitioners, hospitals, and the specialist department, demonstrating use in operational care. Retrospective assessment without a contemporaneous comparator limits validation for broader implementation.
either self-injected or administered by the patient’s general practitioner
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