INTRODUCTION
Chronic spontaneous urticaria (CSU) is characterized by the presence of wheals and/or angioedema that persists for over 6 weeks [1]. The pathogenesis of chronic spontaneous urticaria is not yet fully understood. It is believed that various mechanisms, including dysregulation of intracellular signaling pathways in mast cells and basophils, autoimmunity, inflammation, and coagulation may play a role [2, 3].
To establish personalized treatment approaches and predict disease activity, biomarkers needed. In recent years, there have been great efforts to find reliable biomarkers to predict disease activity and anti-histamine responsiveness in CSU [4]. Certain studies offer evidence on biomarkers reflecting urticaria disease activity. These include low basophil count, high C-reactive protein (CRP), D-dimer, low eosinophil count, and elevated eotaxin levels, elevated anti TPO IgG which serve as indicators of severe chronic spontaneous urticaria [4–7]. In some recent studies, interleukin-6 (IL-6) and CRP have been found to be elevated in patients with CSU, supporting the effect of inflammation [8, 9].
Recent studies have shown that various hematological parameters, which rise with inflammation, can be used as markers to monitor the severity of skin diseases. These include neutrophil/lymphocyte ratio (NLR), CRP, and mean platelet volume (MPV) [10]. In recent years, eosinophil cells have been shown to be associated with inflammation, and eosinophil/lymphocyte ratio (ELR) and eosinophil/neutrophil ratio (ENR) has been shown to be an indicator of inflammation in some diseases [11, 12].
CAR, which is calculated by dividing the positive acute-phase protein CRP by the negative acute-phase protein albumin, has gained recognition as an inflammatory marker in recent years. It is utilized to predict inflammation and also holds prognostic significance [13].
IgE is considered a key factor in the development of CSU for several reasons. Firstly, CSU patients tend to have elevated IgE levels [14]. Secondly, some individuals with CSU possess autoantibodies that activate mast cells against FceRI, and the expression of FceRI is influenced by IgE. Finally, many CSU patients have IgE directed against autoantigens, and this IgE is capable of stimulating mast cells to release histamine [15].
In CSU, fibrinogen/albumin ratio (FAR), D-dimer/albumin ratio (DAR) and uric acid/HDL ratio (UHR) have been analyzed for disease activity [4]. However, to our knowledge, the prognostic significance of CRP/albumin ratio (CAR) in patients with CSU has not been studied by now.
AIM
In this study, we aimed to investigate the potential of CAR, total IgE, NLR, ELR, ENR as a measure for assessing the severity of CSU and as a predictor of response anti-histamine treatment.
MATERIAL AND METHODS
STUDY POPULATION
We analyzed electronic or record-based medical data from 246 patients with CSU admitted to our Outpatient Clinic from August 2022 to August 2024. Exclusion criteria were: being under 18 years of age, isolated chronic inducible urticaria (CIndU), severe systemic and infectious disease, concomitant atopic dermatitis, neoplastic disease, pregnancy, cardiovascular disease, with acute infections, nutritional problems, malignancy, symptomatic gastrointestinal disorders, renal and hepatic diseases and those using any medications. The urticaria activity score-7 (UAS-7) score has been used to assess urticaria severity. An UAS-7 score of ≤ 6 is categorized as well-controlled, 7–15 as mild, 16–27 as moderate, and 28–42 as severe urticaria [15]. UAS-7 was measured at baseline and 1 month after the start of standard dose anti-histamine therapy (once a day) and this factor was used to classify patients into non-responders (UAS-7 reduction < 30%, compared to the baseline) and responders (UAS-7 reduction ≥ 30%, compared to the baseline) [16].
Participants were fully briefed on the experimental procedures and provided their informed consent. The study protocol was approved by our hospital Local Ethics Committee (with reference number: GOKAEK-2024-01-11) and was conducted in adherence to the standards of good clinical practice and the Declaration of Helsinki.
COLLECTED DATA
Clinical parameters such as age, gender, duration of disease, the presence of angioedema, drug allergy and laboratory tests such as CRP, albumin, total immunoglobulin E (IgE), erythrocyte sedimentation rate (ESR), leukocyte, neutrophil, basophil and eosinophil counts, MPV were collected from patient files, retrospectively. The CAR, NLR, ENR, ELR were estimated.
STATISTICAL ANALYSIS
Statistical analyses were done using SPSS software (version 21.0 for Windows; SPSS Inc., Chicago, IL, USA). Parametric variables were presented as means and standard deviations, non-parametric variables as medians and interquartile ranges (IQR) according to normal distribution. The number of cases and percentages were used for categorical variables. Whether the continuous variables were normally distributed or not was determined by Kolmogorov-Smirnov test. The χ2 or Fisher’s exact test was used in the analysis of categorical variables. In comparing numerical variables that did not show normal distribution, Mann-Whitney U and Kruskal-Wallis tests were used depending on the number of groups. The relationship between two numerical variables was evaluated with the Spearman test. All confidence intervals were 95%. A p-value of 0.05 or less was considered statistically significant.
RESULTS
Of the 246 patients included in the study, 174 (70.7%) were female and the median (IQR) age was 33 (27–43) years. The median time of disease duration was 6 (3–24) months. When urticaria was categorized according to severity, 13% of patients were in the mild group, 16% were in the moderate group and 71% were in the severe group. Baseline demographic characteristics and laboratory results are presented in Table 1.
Table 1
Baseline demographic, clinical, and laboratory features of patients (n = 246)
In the correlation analysis, no significant relationship was observed between urticaria activity score and CRP, albumin (p > 0.05). On the other hand, total IgE median levels in the severe group were higher than in the moderate group (181 vs. 119, p = 0.04). There was no statistically significant correlation between UAS-7 and CAR (p > 0.05). Moreover, there was no relationship between other ratios (NLR, ENR, ELR) and UAS-7 (p > 0.05).
In the non-responder group, total IgE levels, presence of angioedema and the duration of the disease were found higher than in the responder group (186 vs. 152, p = 0.008; 51% vs. 31%, p = 0.001; 11 vs. 6, p = 0.02, respectively). But CAR, NLR, ELR and ENR were not significantly associated with the response to treatment (Table 2).
Table 2
Comparison of characteristics between responders and non-responders to standard dose antihistamine treatment
DISCUSSION
In our study, we found that longer duration of the disease and presence of angioedema were associated with non-response to standard dose antihistamine treatment. While no relationship was observed between the severity of CSU and other inflammatory markers such as CAR, NLR, ELR and ENR, we found that total IgE levels in the severe group were higher than in the moderate group. In addition, total IgE levels also were higher in the non-responder group than in the responder group. But no significant difference was observed for CAR, NLR, ELR, ENR values in antihistamine responders compared to non-responders.
CSU is an immune-related inflammatory condition that can affect people of all ages. However, it typically presents between the ages of 20 and 40 and is more than twice as common in women [16]. In our trial, the median age of CSU patients was 33 years (ranging from 27 to 43), and 70.7% of those patients were female, aligning with findings reported in the existing literature [4].
Stepaniuk et al. reported that the presence of angioedema and disease duration were higher in the severe disease [17]. On the other hand, angioedema is frequent in H1-antihistamine-refractory CSU patients in the study by Maurer et al. [18]. Similarly, we also found that the presence of angioedema and long disease duration were higher in patients unresponsive to antihistamine treatment.
In patients with CSU, elevated serum CRP levels have been recognized as a marker of acute inflammation in earlier studies, with some suggesting a correlation between these levels and disease severity [8, 19, 20]. Albumin serves as a negative acute phase reactant, and recent studies highlight its roles in both procoagulant and anticoagulant processes [21, 22]. The observation that albumin levels are decreased in some CSU patients suggests that it may be involved in particular pathways of CSU pathogenesis, indicating its potential as a useful marker [23].
In the literature, it was observed that UAS was correlated with CRP, D-dimer and activated partial thromboplastin time (APTT) in urticaria patients [24]. Although the literature presents varied findings regarding the relationships between identified variables and UAS-7, it is important to highlight that none of the variables in our study showed a correlation with UAS-7. This lack of correlation may be partly due to the limited number of patients with moderate and severe CSU in our cohort. Therefore, future studies should explore the correlation of UAS-7 specifically in more severe cases of CSU.
Earlier research has shown that the CAR value can serve as a prognostic parameter in various inflammatory conditions, including sepsis, Behçet’s disease and alopecia areata [13, 25, 26]. Given that elevated interleukin-6 levels are linked to increased CRP and decreased albumin, the CAR value may hold prognostic importance in the inflammatory response related to these diseases. In our trial, although we did not find a statistically significant relationship between CAR and urticaria disease severity, and we did not find a statistically significant relationship between CAR and response of patients to antihistamines after initial presentation, we observed lower CAR in antihistamine responders compared to non-responders. This may be due to the fact that CRP and albumin acute phase reactants are in more constant value ranges in CSU compared to other diseases such as sepsis and Behçet’s disease.
The eosinophil, neutrophil, and lymphocyte counts in peripheral blood are typically reported as normal in patients with urticaria. However, the exact role of neutrophils and lymphocytes in the condition remains unclear [27]. In some diseases, markers such as ELR, ENR, and CRP have been identified as indicators of inflammation [11, 12]. Some researchers have previously suggested that the eosinophil/lymphocyte ratio (ELR) could be a predictor of oral corticosteroid dose reduction, improvements in quality of life, and better asthma control following biological treatment in patients with severe asthma [28]. These findings clearly indicate that identifying predictors of treatment response is both crucial and feasible. NLR is recognized as an inflammatory marker due to its accessibility and cost-effectiveness. Recent studies have identified NLR as a marker of systemic inflammation in various conditions, including atherosclerosis, psoriasis [29, 30]. Additionally, the activation of the coagulation cascade has been observed in patients with CSU, with a significant connection between coagulation and inflammation [31]. In the study conducted by Cosansu with a control group, it was found that NLR was significantly lower in patients with antihistamine response [32]. In our study, lower NLR was observed in the responder group, but it was not statistically significant. We think that the reason for this was the absence of a control group in our study.
In a meta-analysis of 73 studies looking at response to treatment in CSU, a variety of studies indicate that low total IgE levels can serve as a predictor of nonresponse or a poor response to omalizumab treatment [5, 33–36]. In a study by Marzano et al. that found low baseline IgE levels to be associated with nonresponse to omalizumab, the cut-off level for non-responders was set at 42 kUA/l [34]. Considering the ability to predict CSU severity and treatment response; the total IgE level was significantly higher in the nonresponder group compared to the responder group.
Serum inflammatory cytokines are part of the body’s defense mechanism, involved in immune cell regulation and inflammation control [37]. Studies have shown that levels of these cytokines are elevated in patients with CSU and are closely linked to disease severity [38–40]. The inflammatory response is considered a key factor in the development of CSU. Zeng et al. found that increased serum concentrations of IL-4, IL-17, and IL-31 in CSU patients were positively correlated with both disease severity and quality of life (QOL) scores [40]. Since these inflammatory markers cannot be examined in our clinic in Turkey, we searched for easy-to-access and easy-to-apply parameters that would determine the patient’s prognosis within routine laboratory tests and differently, we used the UAS-7 scoring system, which is a commonly used scoring system, instead of QOL.
Naturally, our study comes with some limitations beginning with its single-center and retrospective analysis. Secondly, the anti-histamines given in standard dose antihistamine treatment are not the same active substances. On the other hand, it has been observed that not all active substances are superior to each other in the treatment of CSU [1]. The urticaria control test and quality of life were not evaluated in the patients.
CONCLUSIONS
The pathophysiology of CSU still remains inadequately understood because of its complex underlying mechanisms. As a result, there are no well-established criteria for predicting severe disease and guiding treatment management. Consequently, it is crucial to use markers that are highly specific, sensitive, and involved in various pathways for effective disease management. In conclusion, we confirm that total IgE levels are significant in the management of CSU. The observation that elevated total IgE levels, presence of angioedema, and longer disease duration may predict inadequate responses to treatment with sgAHs may assist physicians in identifying patients who require a more rapid adjustment in their therapeutic approach, rather than continuing prolonged sgAH treatment that offers little or no benefit. Therefore, we believe that total IgE values could serve as a useful marker for assessing treatment approaches and follow-up strategies in CSU.
