INTRODUCTION: In patients with Hereditary Angioedema (HAE) related to primary C1 inhibitor deficiency (C1INH), the defective clearance of immune complexes and apoptotic materials along with impairment of normal humoral response potentially leads to autoimmunity. Few studies report evidence on autoimmune diseases in C1INH-HAE, but no large population studies focus on rare connective tissue diseases (RCTDs). We aim at evaluating for the first time prevalence and distribution of RCTDs - Systemic Lupus Erytematosus (SLE), primary Sjogren Syndrome (SjS), primary antiphospholipid syndrome (APS), Systemic Sclerosis (SSc), and mixed connective tissue diseases (MCTD) in a large Italian cohort of C1INH-HAE patients.
METHODS: A multicenter observational study includes C1INH-HAE patients from ITACA Centers throughout Italy (time frame Sept 2023-March 2024). Inclusion criteria are i. a defined diagnosis of type I or type II C1INH-HAE; ii. age ≥15 years (puberty already occurred); iii. enrollment in the ITACA Registry. The diagnosis of SLE, primary SjS, primary APS, SSc, and MCTD are made in accordance with international classification criteria.
RESULTS: Data are collected from a total of 855 C1INH-HAE patients referring to 15 ITACA Centers. Patients with concomitant RCTDs were 18/855 (2.1%) with F:M ratio 3.5 and a prevalent type I C1INH-HAE diagnosis (87.2%). A diagnosis of SLE results in 44.5% of cases (n=8) while the remaining diagnoses are primary SjS (22.2%, n=4), primary APS (16.6%, n=3), SSc (11.2%, n=2), and a single case of MCTD (5.5%). The female gender is prevalent in all the RCTDs. Patients on long term prophylaxis (LTP) are significantly prevalent in RCTDs group than in the whole C1INH-HAE population (p<0.01).
CONCLUSIONS: A relevant prevalence of RCTDs is documented in C1INH-HAE patients, mainly SLE. Patients with RCTDs are on LTP in a significant proportion supporting the idea of a bidirectional link between C1INH-HAE and autoimmunity.
A diagnosis of RCTDs occurs in 2.1% of the study cohort (n=18)
direct registry numerator and denominator, tempered by missing-data exclusions and only 18 identified cases
SLE is the prevalent diagnosis (44.5%, n=8)
direct subtype count within the cohort, though based on only eight SLE cases
Patients on LTP are significantly prevalent in RCTDs group than in the whole study population
unadjusted cross-sectional comparison with inconsistent small-subgroup reporting and no regression analysis
the prevalence of RCTDs - SLE, APS, and SSc - is approximately 5 to 10 times higher in C1INH-HAE patients compared to the general population
literature-only comparison without matched populations or standardized ascertainment
Derived from the full evaluation — not a separate score.
Strengths
The analysis includes 855 C1INH-HAE patients from 15 ITACA centers, providing substantial cohort coverage for a rare disorder and a defined denominator for prevalence description.
↳ Results, opening paragraph and Table 1
RCTD diagnoses were made by expert immunologists or rheumatologists using international classification criteria for SLE, SjS, APS, SSc, and MCTD.
↳ Patients and Methods
The Discussion compares the findings with earlier broad autoimmune cohorts, lupus reports, and general-population prevalence estimates while acknowledging heterogeneity between sources.
↳ Discussion, opening and disease-specific comparison paragraphs
Limitations
Type-I disease is reported as both 87.2% and 83.3% among RCTD cases, 2 of 3 APS patients are labeled 75%, and the LTP timing analysis uses an unexplained 7/12 denominator. These inconsistencies affect interpretation of a subgroup containing only 18 patients.
↳ Abstract, Results; Results, C1INH-HAE Patients with Concomitant RCTDs; APS paragraph
The LTP comparison uses unadjusted categorical tests, and the paper acknowledges that regression was not performed. The resulting association cannot establish that HAE activity and autoimmunity have a bidirectional or reciprocal relationship.
↳ Statistical Analysis; Discussion, LTP and regression-analysis paragraphs; Abstract, Conclusions
The 5-to-10-fold comparison relies on heterogeneous literature estimates without a matched or standardized comparator, despite the article's own warning about population and data-source differences.
↳ Discussion, concluding paragraph
The central descriptive result, 18 RCTD diagnoses among 855 registry participants, is directly supported and constitutes a useful disease-specific estimate. Methodological confidence falls sharply for the LTP analysis because it is unadjusted, regression was not performed, and the cross-sectional design cannot establish reciprocity between HAE activity and autoimmunity. The Discussion's 5-to-10-fold comparison also exceeds what heterogeneous external prevalence estimates can establish. Numerical discrepancies in the Abstract and Results require correction before the small-subgroup findings can be relied upon.
Nabu’s assessment, alongside the field’s view.
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Limited2.6
Confidence highThe study supplies disease-specific prevalence and subtype data from 855 C1INH-HAE patients across 15 Italian centers, extending prior reports that combined broader autoimmune diagnoses. Its contribution remains narrow because only 18 RCTD cases were identified, including subtypes represented by one or two patients.
A diagnosis of RCTDs occurs in 2.1% of the study cohort (n=18)
Validated classification criteria and a multicenter registry are suitable for cohort-specific prevalence description, but the LTP comparison is unadjusted and the article acknowledges that regression was not performed. Cross-sectional timing and confounding therefore cannot support the proposed bidirectional or reciprocal relationship.
A limitation of the study is represented by the lack of a regression analysis
The article follows a clear Introduction–Methods–Results–Discussion structure and presents subtype findings systematically. The abstract and conclusion nevertheless imply a bidirectional relationship from an unadjusted association, leading readers beyond what the design establishes.
supporting the idea of a bidirectional link between C1INH-HAE and autoimmunity
The Discussion engages prior HAE-autoimmunity studies and general-population prevalence estimates for each RCTD. Its quantitative 5-to-10-fold conclusion conflicts with the same paragraph's acknowledgment that comparisons across populations, data sources, and healthcare settings are challenging.
making adequate comparisons is challenging
Lower confidence on Contribution — domain match limited.
Concerns4 of 4 checks
Several subgroup percentages and denominators conflict within the article. Although the 18/855 prevalence count is unaffected, the inconsistencies materially reduce confidence in characterization of the small RCTD subgroup and its LTP findings.
Registry ethics approval and written consent procedures, including parental consent for minors, are declared. The generic data-availability statement is not independently verifiable but does not itself establish a conduct concern.
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 work is an initial observational prevalence signal rather than a validated risk model, intervention, or surveillance protocol. Substantial comparative and longitudinal work would be required before practice implementation.
regression analysis had not been done because of the small sample size
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