In our study, similar to previous reports, we noted higher IL-6 levels in AU [5] and CU [6] patients. This increase was previously found in patients with antihistamine-resistant urticaria [9] and in severe CU compared to patients with mild CU [16]. We did not confirm the correlation of IL-6 levels with disease activity; however, this correlation has been documented in previous work [16–18]. We noted a correlation between IL-6 levels and CRP for AU and CU and IL-6 levels and duration of hospitalization in AU. In addition, we confirmed that IL-6 concentration correlates with WBC, NLR, and neutrophil count. ROC analysis showed that IL-6 has high sensitivity and specificity as a predictor of urticaria occurence.
IL-6 is an acute phase protein closely related to the production of CRP and fibrinogen [3], whose levels are elevated during urticaria exacerbations [6, 19]. It stimulates the production of tissue factor linking coagulation and inflammation [6]. The expression of IL-6 is dependent on many factors such as coexisting chronic diseases, stress factors, trauma or infections [9], its concentration is also subject to circadian fluctuations [17].
We demonstrated significantly higher levels of IL-17A in patients with AU and CU compared to CG. In predicting the occurrence of skin lesions, this index with a relatively high specificity showed a lower sensitivity than most of the cytokines tested (88% and 78%, respectively, cut-off point 38.2). So far, most reports, like our work have shown higher IL-17 levels in CU patients [3, 9] compared to CG. Additionally, this increase was found in patients with CU and a positive autologous serum skin test (ASST) [20]. Atwa et al. reported a correlation between IL-17 levels and urticaria severity [21], which was not confirmed by Chen et al. [4]. Contrary to previous work [7], we confirmed a positive correlation between IL-17A levels and CRP in all patients with urticaria. We also found a correlation between IL-17A and D-dimer levels in patients with CU.
IL-17A stimulates the production of proinflammatory cytokines like IL-1 and IL-6 and adhesion molecules [7]. It plays a role in recruitment of neutrophils present in urticarial infiltrate [8, 22]. Together with IL-23, it is involved in the development of autoimmune mechanisms, which is of particular importance for CU [7, 21]. IL-23 directs the early immune response and influences T-cell differentiation toward Th17 [8].
Our analysis showed significantly lower IL-23 levels in AU and CU patients with respect to CG. Different results were obtained in several papers on CU [3, 4, 20], where additionally a correlation between IL-23 levels and CU severity was shown [4]. On the other hand, Degirmenci et al. reported lower levels of IL-17 and IL-23 in patients with CU, which was explained by the effect of cytokine consumption during the ongoing inflammatory process [8]. This parameter showed relatively high sensitivity and specificity in predicting the development of urticarial lesions (86% and 98%, respectively; cut-off point 481.0).
In this study, we found significantly lower IL-18 levels in AU and CU patients compared with CG. ROC curve analysis showed that IL-18 as a marker of urticaria occurrence had the lowest sensitivity and specificity among the parameters studied (70% and 75%, respectively; cut-off point 123.9). Previous studies have shown elevated IL-18 levels in children with a single episode of AU compared to patients with recurrent urticaria and healthy volunteers [11]. Two papers reported higher IL-18 levels in adults with CU [23, 24], while other studies did not confirm such an increase or the relationship between IL-18 levels and positive ASST and urticaria activity [3, 25].
IL-18 is responsible for the regulation of Th1, Th2, and Th17 responses, stimulates mast cell degranulation, and affects the recruitment of neutrophils and eosinophils to the site of inflammation [11, 23]. It is involved in the development of many diseases including CU and autoinflammatory syndromes (cryopyrin-associated periodic syndrome - CAPS and Schnitzler syndrome) [10].
Our analysis showed lower serum levels of RANTES and IP-10 in patients with AU and CU. In the ROC curve evaluation, IP-10 proved to be a statistically valuable predictor of urticaria incidence, but no correlation with disease activity was demonstrated.
The relationship between RANTES and IP-10 has been investigated in a small number of papers finding higher levels in CU patients [15, 26], but the data are inconclusive. Puxeddu et al. showed no correlation of RANTES with disease activity [15], while Caproni et al. found no difference in IP-10 concentrations in CU patients regardless of ASST score [27].
RANTES induces histamine release from basophils and promotes differentiation and activation of mast cell progenitor cells [3, 15]. Both IP-10 and RANTES have been shown to play an important role in Th1 lymphocyte recruitment [14, 15]. IL-17 decreases lymphocyte recruitment by reducing RANTES production [28], which could indirectly explain the higher IL-17 concentrations we found with concomitantly lower RANTES levels in patients with urticaria.
The presented study is characterized by several limitations. These include the single-center, retrospective nature of the study, the limited size of the groups, and the lack of prospective determinations during the remission or convalescence phase. Urticaria activity in all patients was assessed according to the TSS scale, which does not provide more information about the patients' quality of life relevant to the overall evaluation. Cut-off points were self-selected to qualify for a group with specific urticaria severity, which may affect the interpretation of the results.