# Rare connective tissue diseases in patients with C1-inhibitor deficiency hereditary angioedema: first evidence on prevalence and distribution from a large Italian cohort study.

- **DOI:** [10.3389/fimmu.2024.1461407](https://doi.org/10.3389/fimmu.2024.1461407)
- **Rating:** Limited (2.6 out of 5)
- **Verdict:** A useful disease-specific prevalence study whose unadjusted cross-sectional evidence cannot support its proposed reciprocal relationship between HAE activity and autoimmunity.
- **Framework version:** v5.9
- **Pipeline version:** v0.4
- **Evaluation date:** 2026-09-18
- **Evaluation page:** https://www.nabu.science/paper/10.3389%2Ffimmu.2024.1461407

## Key claims

1. A diagnosis of RCTDs occurs in 2.1% of the study cohort (n=18)
   - Support: Supported
   - Type: Primary finding
   - Basis: direct registry numerator and denominator, tempered by missing-data exclusions and only 18 identified cases
   - Location: Results, C1INH-HAE Patients with Concomitant RCTDs
2. SLE is the prevalent diagnosis (44.5%, n=8)
   - Support: Supported
   - Type: Secondary
   - Basis: direct subtype count within the cohort, though based on only eight SLE cases
   - Location: Results, Prevalence and Distribution of RCTDs
3. Patients on LTP are significantly prevalent in RCTDs group than in the whole study population
   - Support: Tentative
   - Type: Secondary
   - Basis: unadjusted cross-sectional comparison with inconsistent small-subgroup reporting and no regression analysis
   - Location: Results, C1INH-HAE Patients with Concomitant RCTDs; Figure 2
4. the prevalence of RCTDs - SLE, APS, and SSc - is approximately 5 to 10 times higher in C1INH-HAE patients compared to the general population
   - Support: Tentative
   - Type: Secondary
   - Basis: literature-only comparison without matched populations or standardized ascertainment
   - Location: Discussion, concluding paragraph

## Strengths

- **Large disease-specific registry cohort** 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.
  - Dimension: contribution
  - Location: Results, opening paragraph and Table 1
- **Standardized specialist diagnostic classification** RCTD diagnoses were made by expert immunologists or rheumatologists using international classification criteria for SLE, SjS, APS, SSc, and MCTD.
  - Dimension: methodological rigour
  - Location: Patients and Methods
- **Direct engagement with prior estimates** The Discussion compares the findings with earlier broad autoimmune cohorts, lupus reports, and general-population prevalence estimates while acknowledging heterogeneity between sources.
  - Dimension: positioning
  - Location: Discussion, opening and disease-specific comparison paragraphs

## Limitations

- **Subgroup numbers conflict across sections** 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.
  - Dimension: methodological rigour
  - Location: Abstract, Results; Results, C1INH-HAE Patients with Concomitant RCTDs; APS paragraph
- **Unadjusted association receives causal framing** 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.
  - Dimension: methodological rigour
  - Location: Statistical Analysis; Discussion, LTP and regression-analysis paragraphs; Abstract, Conclusions
- **External prevalence multiplier lacks comparability** 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.
  - Dimension: positioning
  - Location: Discussion, concluding paragraph

## Reliability checks

Concerns (4 of 4 checks).

- **Internal coherence:** Concern. 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.
- **Research conduct:** Clean. 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.
- **Reference integrity:** Clean. 52 of 52 checkable references verified
  - 52 references in manuscript
  - References not verified automatically are resolved manually within 24 hours.

## Post-publication record

- **Status:** Clean
- **Summary:** No retraction or expression of concern found in Crossref (includes Retraction Watch).
- **Last checked:** 2026-10-17