Introduction
Urticaria is characterized by transient pruritic wheals with or without angioedema, and if urticaria plaques persist for more than six weeks, it is defined as chronic urticaria (CU) (1). Although CU symptoms are related to activated skin mast cell mediators such as histamine, the underlying mechanism of mast cell activation is still unknown (1). CU is more common in females than in males. Usually, CU can be self-limited. However, it can persist for years in 20% of patients (2). More than 50 million patients could have been affected by CU in their lifetime and it deteriorates patients’ quality of life (QoL) and social activities (3). According to the International EAACI/GA2LEN/WAO, CU is divided into two groups: (a) chronic spontaneous urticaria (CSU), which has no identified eliciting factors, and (b) chronic inducible urticaria, which has a specific stimulation to occur, such as cold, heat, pressure, or vibration (1). Although CSU has no trigger for the symptoms, some specific factors can exacerbate the urticaria plaques like drugs (e.g. non-steroidal anti-inflammatory drugs), infections, emotional stress, or some foods (e.g. species) (1,4). In the recent urticaria guidelines, CSU is classified as type 1 [autoallergic, related to immunoglobulin E (IgE) to self-antigens] and type IIb (autoimmune, related to mast-cell activating autoantibodies) (1).
Using a standard dose of second-generation H1 antihistamines is suggested as the first-line therapy for CSU (1,4). Up-dosing to fourfold antihistamine can be used as a second-line therapy if CSU persists in the patients (1,4). Nevertheless, if the CSU persists under the four-dose H1 antihistamine therapy, omalizumab treatment, which is an anti-IgE monoclonal antibody, could be suggested to control refractory CSU (1,4). However, it is still unclear to predict in which patients do not respond to antihistamine therapy.
Although it is well known that patients’ diets, conditions, and abdominal obesity (AO), which is related to anthropometric parameters including body mass index (BMI), waist circumference (WC), or hip circumference, can affect some disease development such as diabetes, cardiovascular diseases, or thyroid autoimmunity (5-8). In the literature, there is no data on the anthropometric parameters’ impact on the development of refractory CSU. Additionally, to date, there is limited data on which patients with CSU could have refractory disease and are unresponsive to antihistamine therapy. Therefore, in this study, we aimed to evaluate the impact of AO on the course of the presence of refractory CSU. Additionally, we aimed to determine the possible risk factors for having refractory CSU.
Materials and Methods
Compliance with Ethical Standards
This study was approved by the University of Health Sciences Turkey, Derince Training and Research Hospital’s Ethics Committee (date: 12.05.2022, approval number: 2022-40) and written informed consent was obtained from all included patients.
Patient Selection and Study Design
This study was designed as a retrospective study, and data was collected from January 2021 to April 2022. A hundred and seventy CSU patients who were more than 18 years old and were followed at the Adult Immunology and Allergic Diseases outpatient clinic were included in this retrospective study. CSU was diagnosed according to the International EAACI/GA2LEN/WAO and Turkish National Society Urticaria guidelines, and refractory CSU was defined as patients who did not respond to four-fold antihistamine therapy for one month (1,4). Patients with known autoimmune diseases, accompanying physical urticaria, and those using omalizumab treatment were excluded from the study. To determine the differences between refractory or non-refractory CSU, patients were divided into two main groups as Group 1, which had refractory CSU under four-fold antihistamine treatment for one month (n=87, 51.2%), and Group 2, which had well-controlled CSU under the antihistamine treatment for one month (n=83, 48.8%).
Clinical Data Collection
Demographics and clinical features of the patients, including age, gender, smoking and alcohol habits, disease duration time, presence of angioedema accompanying CSU or other disease history, triggers (food, drugs, infection or stress) for CSU, and used antihistamine doses were collected from the patients records. To evaluate the AO impact on the development of refractory CSU, anthropometric measurements including weight, height, BMI, and WC were collected from patients’ records, retrospectively. To determine the AO, the waist-to-height ratio (WHtR) was used (9), and it was calculated by the physicians, retrospectively. According to the literature, a WHtR>0.5 was considered as having AO (9).
Data for the standard diagnostic evaluation of the patients, baseline laboratory testing including neutrophil, lymphocyte, basophil, eosinophil count, fasting blood glucose, LDL cholesterol, triglyceride, anti-thyroid peroxidase, and C-reactive protein (CRP) were recorded from patients’ medical files. The neutrophil/lymphocyte ratio (N/Lr) was calculated retrospectively. Turkish validated seven-day urticaria activity score (UAS7) was used for evaluating the disease activity before and 1 month after the antihistamine treatment (1). Accordingly, the UAS7=28-42, UAS7=16-27, UAS7s=7-15, and UAS7≤6 are considered as severe, moderate, mild, and well-controlled, respectively (1). Stress level was collected from patients' records which was evaluated with visual analogue scale (VAS)" if VAS was >5, it was considered as having high stress level (3).
Statistical Analysis
The Statistical Package for Social Sciences version 25.0 (SPSS Inc., Armonk, NY, USA) was used to analyze the data, and GraphPad Prism software (San Diego, CA, USA) was used for graphics.The patients’ descriptive characteristics are presented as mean standard deviation, median, and interquartile range (IQR) percentile of 25-75. A Kolmogorov-Smirnov test was conducted to evaluate the normality of data. The chi-square test and Mann-Whitney U test were used to compare categorical and continuous variables, respectively. A binary logistic regression test was used for the analysis of risk factors for having refractory CSU. A p-value of 0.05 or lower is generally considered statistically significant.
Results
Results of Demographics and Clinical Characteristics, and Laboratory Findings of the Patients
While the mean age of the patients was 38.95±13.08 years, the median (IQR) CSU duration time was 24 (8.5-48) months. One hundred and twenty-two (71.8%) patients were female and less than half of the patients had smoking habits (n=72, 42.4%). Whilst the number of patients accompanying angioedema history was 110 (64.7%), 114 (67.1%) patients had AO. Before the antihistamine treatment, the mean UAS7 was 34.91±5.81. Stress was the most common trigger for exacerbation of urticaria plaques in the patients (n=114, 67.1%) (Figure 1A). Before the antihistamine treatment, 160 (94.1%) patients had severe CSU and 10 (5.9%) patients had moderate CSU. While the mean BMI of the patients was 26.42±5.10 kg/m2, the mean WC and WHtR of the patients were 90.08±13.83 cm and 0.83±0.09, respectively. One hundred and fourteen (67.1%) patients had a WHtR of more than 0.5. Baseline demographics, clinical characteristics, and laboratory findings of the patients are summarized in Table 1.
Comparison Analysis Between Refractory and Non-refractory CSU Patients
The mean ages were 40.41±13.03 years and 37.43±13.04 years in Group 1 and Group 2, respectively (p>0.05). More than half of the patients were female in both groups [n=61 (70.1%) vs n=61 (73.5%), p>0.05]. The number of patients with angioedema accompanying CSU was significantly higher in Group 1 than in Group 2 [65 (74.7%) vs 45 (54.2%), p=0.005]. Exacerbation of urticaria plaques with stress was more common in Group 1 than in Group 2 (p=0.030) (Figure 1B). BM, WC, and WHtR were similar in both groups (p>0.05 for each). While 56 (64.4%) patients had AO in Group 1, 58 (59.9%) patients had AO in Group 2 (p>0.05). Group 1 had significantly higher CRP and neutrophil counts (p=0.008 and p=0.024, respectively). The comparison analysis between Group 1 and Group 2 is summarized in Table 2.
Analysis of Associated Possible Risk Factors for Having Refractory CSU
The regression analysis, which was performed to determine associated risk factors for refractory CSU, showed that having stress and accompanying angioedema were associated risk factors for refractory CSU [odds ratio (OR)=2.05, (95% confidence interval (CI) 1.06-3.93), p=0.031 and OR=2.49, (95% CI 1.30-4.77), p=0.006, respectively]. Furthermore, higher CRP levels and neutrophil counts were associated with the presence of refractory CSU (Table 3).
Discussion
This study demonstrated that having stress and angioedema accompanying CSU are related to having refractory to antihistamine treatment in patients with CSU in the Turkish population. Furthermore, higher blood neutrophil counts and CRP levels have been linked to refractory CSU. Additionally, our current study showed, for the first time, that there is no significant relationship between having AO and having refractory CSU.
In recent years, it has been frequently reported that AO has increased and become a global problem with the changes in food consumption habits (10-13). Moreover, it is well-known that AO can play a role in the development of severe diseases, including cardiovascular disease, diabetes, musculoskeletal disorders, or autoimmune diseases such as autoimmune thyroiditis (8,11,14-17). Normally, in healthy fit people, visceral adipose tissue is important for the immune system due to the metabolism of adipocytes, which regulate immune cell function and produce antibacterial peptides or proinflammatory cytokines (8). However, the uncontrolled increase in visceral adipose tissue (such as AO) may trigger autoimmune diseases by causing an excessive increase in proinflammatory cytokines (18). In our study, in which we investigated the possible impact of AO on refractory CSU, contrary to expectations, we did not observe a difference in terms of AO in patients with and without refractory CSU. However, when we evaluated the all-study population, we observed that more than half of the patients (114) had AO before the antihistamine therapy. Therefore, we may not have been able to show the effect of AO on refractory CSU since most of the patients already had AO. Further studies with a control group without AO and larger numbers of CSU patients are needed to demonstrate the real AO impact on the refractory CSU.
Previously, in the literature, Alen Coutinho et al. (19) characterized the phenotypes of CU refractory to antihistamine treatment and they observed that angioedema accompanying CSU and higher baseline UAS7 are possible predictors of poor control of CSU and treatment should be chosen crucially in the Portugal study. In another study, Sussman et al. (20) reported that angioedema accompanying CSU has a negative effect on QoL. Similar to the literature, in our study, we determined that angioedema accompanying CSU is an associated risk factor for having refractory antihistamine therapy in CSU patients. CSU is a mast-cell related disease, furthermore, mast cells can play a role in the development of angioedema (1,21). In line with this knowledge, we may speculate that in the presence of angioedema accompanying CSU, standard and four-fold antihistamine therapy may not be sufficient for symptom control, since the mast cell load will be higher compared to the presence of both diseases alone. In contrast to Alen Coutinho et al.’s (19) study, we did not observe any relationship between baseline UAS7 and poor control of CSU. The reason for this difference between our and Alen Coutinho et al.’s (19) study may be that most patients who applied to us had severe CSU (n=160, 94.1%) than in their study.
Psychological stress stimulates corticotropin releasing hormone (CRH). Furthermore, mast cells can synthesize CRH and express CRH receptors. Thus, psychological stress can cause mast cell degranulation (22,23). Previously, the relationship between psychological stress and increased symptoms in urticaria and mastocytosis was shown in Turkish patients (24,25). Although we collected the stress history from the anamnesis, we observed that stress is a possible associated risk factor for developing refractory CSU similar to the study. In line with this finding, we may think that stress-reducing psychological support may be needed to control refractory CSU and that multidisciplinary approaches to the CSU patients can improve the patients’ QoL and control the disease activity.
Although autoimmunity, which is a result of exacerbated systemic inflammatory response, can be a reason for CU (19,26), there is limited data about the impact of autoimmunity on the control of refractory CSU in the Turkish population. In the past, it was reported that high CRP is related to poor disease control in CU (19,27). Similar to the literature, in our study, refractory CSU was associated with a higher CRP level. Although CRP has proinflammatory and anti-inflammatory features, it can be pathogenic when it is activated by autoantibodies in autoimmunity (28). CRP can also rise during an infection or an autoimmune disease (28). Blood neutrophil count can rise in infections, urticaria, and autoimmune diseases, just like CRP (29-31). Furthermore, a high blood neutrophil count may indicate the presence of urticarial syndromes such as urticarial vasculitis (UV) or cryopyrin-associated periodic syndromes (CAPS). If patients with CU undergo antihistamine treatment and have special symptoms for UV or CAPS, urticaria plaque biopsy should be performed (1,31). In our study, we observed a higher baseline neutrophil count in refractory CSU. In line with this information and our findings, we may think that in CSU patients in whom other autoimmune diseases have been excluded, those with a high baseline CRP level and a high blood neutrophil count may be predictors of the antihistamine refractory CSU, and these patients should be followed up more closely.
Study Limitations
Although this study demonstrated the possible risk factors for antihistamine refractor CSU in the Turkish population, we had some limitations. As a first limitation, we could not use a validated stress scale for evaluating the stress level. We could collect the stress history from patients’ anamnesis and VAS. We believe that it will be important to conduct further larger studies, including more patients with validated scales, to support our findings. Secondly, we did not have a control group to compare the anthropometric parameters with healthy and CSU patients in the Turkish population. Therefore, we could not comment on the course of anthropometric measurement on the development of CSU; we could just comment on the AO impact on refractory CSU. Another limitation of our study was the lack of an autologous serum skin test, which is a clue for autoimmunity in CSU patients. But we think that CRP and blood neutrophil counts are good predictors of biomarkers for autoimmunity and the autologous serum skin test.
Conclusion
AO may not have an impact on the presence of antihistamine refractory CSU. However, high baseline CRP and blood neutrophil count, stress and angioedema accompanying CSU are the associated risks of refractory CSU in the Turkish population. Multidisciplinary approaches, including psychiatric evaluation, should be required in refractory CSU. While investigating CSU, accompanying angioedema should be questioned in all patients. Further studies with a larger number of patients are needed to support our findings.
Ethics
Ethics Committee Approval: This study was approved by the University of Health Sciences Turkey, Derince Training and Research Hospital’s Ethics Committee (date: 12.05.2022, approval number: 2022-40).
Informed Consent: Written informed consent was obtained from all included patients.
Peer-reviewed: Externally peer-reviewed.
Authorship Contributions
Concept: S.B., N.O., Design: S.B., N.O., Data Collection, or Processing: C.O., Analysis, or Interpretation: N.O., Literature Research: N.O., Writing: N.O.
Conflict of Interest: No conflict of interest was declared by the authors.
Financial Disclosure: The authors declare that this study received no financial support.