Chronic spontaneous urticaria (CSU) is a multifaceted, heterogeneous dermatological disorder characterized by the spontaneous and recurrent appearance of wheals (hives), angioedema, or both, persisting for a minimum of six weeks in the absence of identifiable external triggers [1, 2]. The condition represents a significant public health burden due to its high prevalence and its marked impact on patients’ quality of life [3]. Patients frequently experience intense pruritus, disfiguring skin changes, and unpredictable symptom recurrence, which can lead to sleep disturbance, emotional distress, impaired work productivity, and social withdrawal [4, 5].

Angioedema, defined as sudden, pronounced [6] and transient swelling of the deep dermis, mucosa, or subcutaneous tissues, most frequently involves the lips, eyelids, face, extremities, and, in some cases, the upper airway [6, 7]. It is observed in 29.4–44.5% of patients with CSU, with approximately 5–10% presenting with angioedema in the absence of wheals [7–9]. These episodes can be particularly distressing due to their disfiguring nature and their unpredictable onset [9, 10].

The underlying pathophysiology involves activation and degranulation of cutaneous mast cells and basophils, leading to the release of histamine and other proinflammatory mediators [9]. Angioedema, when present in CSU, reflects deeper dermal and submucosal vascular leakage, primarily mediated by histamine, though additional pathways such as bradykinin and complement activation may contribute in some cases [8–10]. The coexistence of urticaria and angioedema likely represents overlapping but distinct pathogenic mechanisms, differing in mediator profile, vascular involvement, and tissue depth [9, 10].

Multiple studies have indicated that CSU with concomitant angioedema is associated with greater disease severity, longer disease duration, and poorer treatment responsiveness [7–9, 11]. Furthermore, CSU demonstrates a highly variable duration, ranging from several months to many years, with angioedema frequently emerging as a potential marker for prolonged disease course [9–11].

A growing availability of evidence suggests that autoimmunity—specifically the presence of circulating autoantibodies in approximately 40–50% of patients plays a key role in the pathogenesis of CSU [12]. Several reports have shown higher autologous serum skin test (ASST) positivity among CSU patients with angioedema, indicating that angioedema may serve as a clinical marker of autoimmunity in CSU [13–17], though this association requires further investigation. Angioedema may serve as a surrogate clinical marker pointing to the potential underlying autoimmune mechanisms, but its particular role remains to be clarified in future studies [18–24].

The present study provides robust evidence that angioedema in CSU is not merely a co-occurring symptom but a clinically meaningful marker associated with increased disease severity, an autoimmune predisposition, and prolonged disease persistence. In contrast, its frequency appears largely independent of patient responsiveness to H1-antihistamines or ASST reactivity, underscoring the need for clinicians to treat angioedema as a distinct, prognostically relevant domain of CSU. By contextualizing our findings against established literature, we highlight converging evidence from multiple independent cohorts and identify critical areas where existing data remain inconclusive.

In our cohort, angioedema was present in 82.02% of patients with severe CSU activity, markedly higher than in those with moderate (65.38%, p = 0.026), mild (65.96%, p = 0.036), or well-controlled disease (45.45%, p = 0.0004). This strong gradient across severity levels, with an estimated odds ratio (OR) of ~5.48 for severe versus well-controlled disease, parallels findings from Sussman et al. [17] and Örnek Özdemir et al. [10], both of whom reported prevalence rates of high prevalence rates in severe CSU. Our data reinforce these reports, extending their implications by demonstrating that angioedema frequency scales proportionally with disease activity even within stratified severity categories. This consistency across studies supports angioedema’s role as a high-value clinical marker for identifying patients with a more aggressive CSU phenotype.

Strikingly, even among patients in clinical remission—defined by the absence of active wheals—more than half reported previous or intermittent episodes of angioedema. This mirrors the longitudinal observations of several studies [7–9], which documented that angioedema can recur or persist independently of urticarial wheals, sometimes becoming the sole clinical manifestation in quiescent phases of disease. Our findings, therefore, underscore that disease control, as traditionally measured by UAS7, may underestimate the ongoing morbidity in patients with a history of angioedema. This has direct clinical implications: patients achieving wheal suppression should still be monitored specifically for angioedema recurrence, as its presence may signal persistent subclinical inflammatory activity.

When comparing antihistamine responders and non-responders, the rates of angioedema were statistically indistinguishable (71.17% vs. 67.16%, p = 0.55). This aligns with Kaplan’s conclusions [26] that standard-dose and even up-dosed second-generation H1-antihistamines often fail to control angioedema effectively, despite reducing pruritus and wheal formation. Our results, together with Kaplan’s, suggest that histamine-mediated pathways may not be the sole drivers of angioedema in CSU. Instead, alternative mediators—such as bradykinin, platelet-activating factor, or complement-derived anaphylatoxins—may play a larger role, thereby justifying early consideration of biologic therapies like omalizumab or emerging agents targeting IgE, IL-4Rα, or Siglec-8 [11].

The presence of autoimmunity—defined by positive anti-TPO, ANA, or RF serology or confirmed autoimmune disease—was associated with a significantly higher angioedema prevalence (75.17% vs. 61.18%, p = 0.025; RR ≈ 1.23). This finding resonates with Kolkhir et al. [30] and Kocatürk et al. [13], who reported that autoimmune CSU subtypes typically exhibit greater symptom burden, higher recurrence rates, and more prolonged disease courses. Our study not only corroborates these associations but also quantifies the relative risk specific to angioedema, strengthening the hypothesis that immune dysregulation underpins both superficial wheal formation and deeper dermal or submucosal swelling. The autoimmune link suggests that immune-modifying treatments—rather than purely symptomatic regimens—may be particularly warranted in this subgroup.

Although angioedema was numerically more frequent among ASST-positive patients (72.14%) than ASST-negative ones (66.67%), the difference was not statistically significant (OR: 1.30, p = 0.34). These results reflect the mixed evidence reported in prior studies: while some investigators have identified ASST positivity as a marker of more severe or treatment-resistant disease [34–39], others have failed to find consistent predictive value [12]. The absence of statistical significance in our analysis may reflect limited power for this endpoint or heterogeneity in the underlying pathomechanisms of ASST reactivity. Nevertheless, the numerical trend warrants further investigation in larger, multi-center cohorts.

Perhaps the most clinically consequential observation is the strong association between angioedema and prolonged disease duration. Patients with a history of angioedema experienced CSU for an average of 61.7 ± 46.2 months (median 54 months), compared to 35.4 ± 39.2 months (median 17 months) in those without angioedema (p = 0.000012; Cohen’s d ≈ 0.59). This corresponds closely to the ~2-year increase in disease persistence reported by different authors [6, 38, 39]. Our regression analysis further confirmed angioedema as an independent predictor of disease duration (β = 0.34, p < 0.001), suggesting it may serve as an early prognostic indicator for identifying patients at risk for chronicity. From a management perspective, such patients may benefit from earlier escalation of therapy and more intensive long-term follow-up.

In conclusion, although this study was designed to investigate CSU as a whole, with angioedema included as one of its parameters, our findings—when considered alongside existing evidence—reinforce angioedema’s role as a marker of severe, autoimmune-associated, and persistent CSU. Unlike wheals, its occurrence appears largely resistant to conventional antihistamine therapy, underscoring an unmet therapeutic need. Future research should aim to elucidate the molecular mediators specific to angioedema and develop targeted interventions to mitigate its clinical and prognostic impact.