How Infection and Vaccination Are Linked to Acute and Chronic Urticaria: A Special Focus on COVID-19.

Since more than a century ago, there has been awareness of the connection between viral infections and the onset and exacerbation of urticaria. Our knowledge about the role of viral infection and vaccination in acute and chronic urticaria improved as a result of the COVID-19 pandemic but it has also highlighted knowledge gaps. Viral infections, especially respiratory tract infections like COVID-19, can trigger the onset of acute urticaria (AU) and the exacerbation of chronic urticaria (CU). Less frequently, vaccination against viruses including SARS-CoV-2 can also lead to new onset urticaria as well as worsening of CU in minority. Here, with a particular focus on COVID-19, we review what is known about the role of viral infections and vaccinations as triggers and causes of acute and chronic urticaria. We also discuss possible mechanistic pathways and outline the unmet needs in our knowledge. Although the underlying mechanisms are not clearly understood, it is believed that viral signals, medications, and stress can activate skin mast cells (MCs). Further studies are needed to fully understand the relevance of viral infections and vaccinations in acute and chronic urticaria and to better clarify causal pathways.

Differences between adult and pediatric chronic spontaneous urticaria from a cohort of 751 patients: Clinical features, associated conditions and indicators of treatment response.

BACKGROUND: Chronic spontaneous urticaria (CSU) is a common disease both in the pediatric and in the adult population. However, there are differences between the two patient populations with respect to etiological factors, comorbidities, and treatment responses. Our aim was to determine differences between pediatric and adult CSU in terms of clinical characteristics, laboratory parameters, comorbidities, response to treatment, and indicators of response. METHODS: A retrospective analysis of CSU patients was performed. Data regarding differences between pediatric and adult CSU patients were analyzed. Indicators of treatment response were determined separately in both pediatric and adult patients. RESULTS: Of 751 CSU patients (162 pediatrics and 589 adults), female dominancy (48.8% vs. 69.6%) and rate of angioedema (19.1% vs. 59.8%) were lower, and disease duration (5 months vs. 12 months) was shorter in pediatric patients. Anti-TPO positivity (24.7% vs. 9%), elevated CRP (46.5% vs. 11.1%), eosinopenia (38.5% vs. 18.1%), and skin prick test positivity (39.3% vs. 28.8%) were significantly more frequent in adult patients. Response to antihistamines was higher in the pediatric group, and only 7% used omalizumab versus 20.8% in the adults. The comparisons were also performed between <12-year and ≥12-year patients and yielded similar results. CONCLUSION: Pediatric CSU shows distinct characteristics such as lower incidence of angioedema and antithyroid antibodies, and it responds better to antihistamines. These suggest that CSU becomes more severe and refractory in adolescents and adults. Adolescent CSU shows features similar to adult CSU rather than pediatric CSU.

Omalizumab versus cyclosporin-A for the treatment of chronic spontaneous urticaria: can we define better-responding endotypes?

Abstract Background: Chronic Spontaneous Urticaria (CSU) is characterized by recurrent wheals and/or angioedema for longer than 6-weeks. Guidelines recommend Omalizumab (Oma) as first-line and Cyclosporine-A (Cs-A) as second-line treatment in antihistamine resistant CSU. This step-wise algorithm might be time-consuming and costly. Objective: To determine indicators of response to Oma or Cs-A in CSU patients. Methods: We retrospectively analyzed data from seven centers in Turkey; the inclusion criteria for patients were to receive both Oma and Cs-A treatment (not concurrently) at some point in time during their follow-up. Clinical and laboratory features were compared between groups. Results: Among 110 CSU patients; 47 (42.7%) were Oma-responders, 15 (13.6%) were Cs-A-responders, and 24 (21.8%) were both Oma and Cs-A responders and 24 (21.8%) were non-responders to either drug. High CRP levels were more frequent in Cs-A-responders (72.7% vs. 40.3%; p = 0.055). Oma-responders had higher baseline UCT (Urticaria Control Test) scores (6 vs. 4.5; p = 0.045). Responders to both drugs had less angioedema and higher baseline UCT scores compared to other groups (33.3% vs. 62.8%; p = 0.01 and 8 vs. 5; p = 0.017). Non-responders to both drugs had an increased frequency in the female gender and lower baseline UCT scores compared to other groups (87.5% vs. 61.6%; p = 0.017 and 5 vs. 7; p = 0.06). Study Limitations: Retrospective nature, limited number of patients, no control group, the lack of the basophil activation (BAT) or BHRA (basophil histamine release assay) tests. Conclusions: Baseline disease activity assessment, which considers the presence of angioedema and disease activity scores, gender, and CRP levels might be helpful to predict treatment outcomes in CSU patients and to choose the right treatment for each patient. Categorizing patients into particular endotypes could provide treatment optimization and increase treatment success. © 2022 Published by Elsevier España, S.L.U. on behalf of Sociedade Brasileira de Dermatologia. This is an open access article under the CC BY license (https://creativecommons.org/licenses/by/4.0/).

Omalizumab versus cyclosporin-A for the treatment of chronic spontaneous urticaria: can we define better-responding endotypes?

BACKGROUND: Chronic Spontaneous Urticaria (CSU) is characterized by recurrent wheals and/or angioedema for longer than 6-weeks. Guidelines recommend Omalizumab (Oma) as first-line and Cyclosporine-A (Cs-A) as second-line treatment in antihistamine resistant CSU. This step-wise algorithm might be time-consuming and costly. OBJECTIVE: To determine indicators of response to Oma or Cs-A in CSU patients. METHODS: We retrospectively analyzed data from seven centers in Turkey; the inclusion criteria for patients were to receive both Oma and Cs-A treatment (not concurrently) at some point in time during their follow-up. Clinical and laboratory features were compared between groups. RESULTS: Among 110 CSU patients; 47 (42.7%) were Oma-responders, 15 (13.6%) were Cs-A-responders, and 24 (21.8%) were both Oma and Cs-A responders and 24 (21.8%) were non-responders to either drug. High CRP levels were more frequent in Cs-A-responders (72.7% vs. 40.3%; p = 0.055). Oma-responders had higher baseline UCT (Urticaria Control Test) scores (6 vs. 4.5; p = 0.045). Responders to both drugs had less angioedema and higher baseline UCT scores compared to other groups (33.3% vs. 62.8%; p = 0.01 and 8 vs. 5; p = 0.017). Non-responders to both drugs had an increased frequency in the female gender and lower baseline UCT scores compared to other groups (87.5% vs. 61.6%; p = 0.017 and 5 vs. 7; p = 0.06). STUDY LIMITATIONS: Retrospective nature, limited number of patients, no control group, the lack of the basophil activation (BAT) or BHRA (basophil histamine release assay) tests. CONCLUSIONS: Baseline disease activity assessment, which considers the presence of angioedema and disease activity scores, gender, and CRP levels might be helpful to predict treatment outcomes in CSU patients and to choose the right treatment for each patient. Categorizing patients into particular endotypes could provide treatment optimization and increase treatment success.

Assessment of disease activity and quality of life in patients with recurrent bradykinin-mediated versus mast cell-mediated angioedema.

OBJECTIVE: Recurrent Angioedema (RAE) is characterized by sudden swelling of mucosal surfaces or deep dermis and is either mast cell-(MMAE) or bradykinin-mediated (BMAE). How patients with BMAE and MMAE differ in terms of disease activity and impact remains largely unknown. Here, we determined validity, reliability, and sensitivity to change of Turkish versions of angioedema activity score (AAS) and quality of life questionnaire (AE-QoL) and used both instruments to investigate and compare patients with BMAE and MMAE. METHODS: Turkish versions of AAS28 and AE-QoL were applied to 94 patients with RAE (18-72 years). Patients' global self-assessment of QoL (PGA-QoL), disease activity (PGA-DA-VRS, PatGA-DA-VAS), and 12-Item-Short Form Survey were used at week 4 (visit 2), and week 8 (visit 3). Demographic characteristics, clinical features, and AAS28 and AE-QoL values were compared between 31 patients with BMAE and 63 patients with MMAE. RESULTS: Turkish AAS28 and AE-QoL showed excellent internal consistency, high reproducibility and known-groups validity. Compared to patients with MMAE, BMAE patients were younger (34.6 ± 10.7 vs. 40.7 ± 13.3 years), had longer disease duration (236 ± 178 vs. 51 ± 78 months), high prevalence of family history (63% vs 14%), longer duration of attacks (65 ± 20 vs. 40 ± 25 h), and they were more commonly affected by upper airway angioedema (70% vs 23%). Disease activity (AAS28) was lower (29.3 ± 24.6 vs 55.2 ± 52.9), but AE-QoL was higher (44.2 ± 16.1 vs 34.5 ± 22.5) in BMAE patients as compared to MMAE patients. CONCLUSIONS: Patients with BMAE and MMAE have distinct disease characteristics. Recurrent bradykinin-mediated angioedema impacts quality of life more than mast cell-mediated angioedema. The discriminating characteristics of patients with BMAE and MMAE may help to improve the diagnosis and management of patients with RAE.

Depression scores change significantly after omalizumab treatment in patients with chronic spontaneous urticaria.

BACKGROUND: Chronic spontaneous urticaria (CSU) is frequently associated with psychiatric comorbidities. OBJECTIVE: We aimed to determine if depressive symptoms were present in CSU patients who received omalizumab and if depression scores got better with omalizumab treatment and whether the presence of depressive symptoms impaired treatment responses. METHODS: CSU patients who received at least three injections of omalizumab were included in the study. Changes in Urticaria Activity Score (UAS), Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL), Beck Depression Inventory (Beck-D) and Urticaria Control Test (UCT) scores were compared before and after treatment. RESULTS: From 49 patients, 20 (40.8%) had depressive symptoms at baseline. After treatment, UAS7, CU-Q2oL, Beck-D scores decreased and UCT-scores increased significantly (p < 0.001, for all). UCT scores were lower at baseline and at 3rd month following treatment in patients with depressive symptoms compared to patients without (baseline median (interquartile range-IQR) 2.5 (1-5) vs 5 (2.5-6.5); p = 0.04 and 3rd month 12 (9-13) vs 14 (12-16); p = 0.006, respectively). Omalizumab non-responders had higher baseline Beck-D-scores [18.5 (15.2-22) vs 12 (6-22.5); p = 0.031]. The number of omalizumab non-responders were significantly higher among patients with depressive symptoms compared to patients without. (40% vs 13.8%; p = 0.048). Only 6 patients scored as having depressive symptoms after treatment; of these 6 patients only one was an omalizumab responder. CONCLUSIONS: Omalizumab not only provides symptom control for urticaria but also improves psychological conditions of the patients. Coexistent psychiatric comorbidities should be taken into account in CSU patients since these conditions might impair treatment response.

Effectiveness of as-needed antihistamines in chronic spontaneous urticaria patients under omalizumab treatment.

The question how second-generation antihistamines (sgAHs) should be used when chronic spontaneous urticaria (CSU) is under control with omalizumab is still unanswered. This study aimed to investigate the effectiveness of as-needed sgAHs in patients with well-controlled urticaria under omalizumab treatment. Patients from four different urticaria centers who were treated with omalizumab 300 mg/4 weeks for at least 3 months, had well-controlled urticaria (Urticaria Control Test: 16 > UCT≥12) and were using sgAHs only if needed, were included in this study. In order to assess effectiveness of sgAHs, change in the itch, hives, and total itch-hives scores before and after sgAHs were evaluated using modified urticaria activity score-twice daily. Fifty-three patients [38 female (71.7%)] with mean age 41.1 ± 11.4 years were included in this study. Median sgAH intake per patient throughout the 4 week-intervals was 3 (2-5) tablets. sgAH intake decreased itch, hives and total itch-hives scores 45.7% ± 52.9, 42.4% ± 39.1, and 50.2% ± 51.1, respectively (P < .001 for all). This decrease was similar in both isolated-urticaria and urticaria-and-angioedema phenotypes. Baseline IgE levels were positively correlated with the decrease of three symptom scores (r = 0.31, P = .05; r = 0.375, P = .017; r = 0.31, P = .05, respectively) that showed in patients with higher baseline total IgE levels, as needed sgAH intake decreased the symptom scores less. Our study showed that sgAHs may still be an effective option for the treatment of the intermittent symptoms in patients with well-controlled urticaria under omalizumab treatment. Baseline total IgE levels may be used as a potential biomarker for sgAH effectiveness in these patients.

Validation of the Turkish version of the Urticaria Control Test: Correlation with other tools and comparison between spontaneous and inducible chronic urticaria.

BACKGROUND: The urticaria control test (UCT) is a questionnaire designed to determine if chronic urticaria (CU) is controlled or not and to aid therapeutic decision-making. It collects retrospective information about the symptoms and quality of life impairment over the last 4 weeks. The current study aimed to investigate the validity, reliability and sensitivity to change of the Turkish version of the UCT. We also evaluated its correlation with other tools and compared the UCT results of patients with chronic spontaneous urticaria (CSU) and patients with chronic inducible urticaria (CINDU). METHODS: Following forward/backward translation and cognitive debriefing, the Turkish version of the UCT was used in 81 CSU and 78 CINDU patients. Dermatology life quality index (DLQI), Chronic urticaria quality of life questionnaire (CU-Q2oL), urticaria activity score (UAS), patients' and physicians' global assessment visual analog scores and Likert scales were used at baseline and after four weeks to assess quality of life impairment, disease activity and disease control. Statistical analysis to determine the validity and reliability of the Turkish version of the UCT as well as comparison between CINDU and CSU patients were performed. RESULTS: Duration of disease was longer, disease control was poorer and severe complaints were more frequent in CINDU patients (duration of disease: 36.3 (24) ± 49.1 vs 31.5 (9) ± 67.9, p = .007, UCT baseline: 8.4 (8) ± 3.4 vs 10.4 (11) ± 3.9, p = .001 and patient's global assessment Likert scale severe complaints: 6 vs 15, p < .001, respectively). The UCT showed excellent internal consistency for CSU and a minimally acceptable consistency for CINDU (Cronbach's α 0.89 for CSU versus 0.68 for CINDU). It showed strong correlation with CU-Q2oL but a moderate correlation with DLQI (r = -0.649, P < .001 and r = -0.545, P < .001, respectively). It was able to discriminate between patients with different disease control and was sensitive to detect changes in the disease control in both groups. The minimally important difference of the UCT was found to be 3. CONCLUSIONS: The Turkish version of the UCT is a valid and reliable tool for the management of CU patients and can be used both in CSU and CINDU patients to determine if the treatment is sufficient and if disease activity and quality of life impairment are under control or not.

Fric Test Revisited: A Suggestion for a New Scoring System and Its Correlation with Urticaria Control Test and Dermatology Life Quality Index.

BACKGROUND: Fric test is a useful tool for the diagnosis and threshold testing for symptomatic dermographism. When threshold testing is not available, Urticaria Control Test (UCT) and Dermatology Life Quality Index (DLQI) might be used to assess disease control and quality of life (QoL) impairment, respectively. OBJECTIVES: In this study, we aimed to describe a new scoring system for the Fric test and evaluate the correlations of Fric scores with UCT, DLQI, and other disease activity assessment scores. METHOD: Provocation test with Fric Test 4.0 was performed in all patients at referral and at the 4th week. We considered a 4-grade rating score for Fric Test (0-4) [Total Fric Score (TFS)]. A positive response with all of the four pins suggested severe dermographism (TFS = 4), while a wheal with only the largest pin (4.5 mm) was considered as milder disease (TFS = 1). Treatment responses were evaluated with Fric Test 4.0, UCT, patient's global assessment of disease severity (PatGA-VAS), the physician's global assessment of disease control (PhyGA-VAS), and DLQI at baseline and at the 4th week of treatment. The correlations of TFS with UCT, DLQI, PatGA-VAS, PhyGA-VAS at baseline as well as the changes in the mean scores after treatment (week 4) were performed. RESULTS: The mean UCT and DLQI scores were 8.69 ± 3.40 and 7.88 ± 6.02 at the first visit. At the second visit, TFS decreased from a mean of 2.79 ± 1.68 to 1.91 ± 1.85 (p < 0.001), and UCT scores and PhyGA-VAS were increased (p < 0.001), while DLQI scores, PatGA-VAS, and pruritus scores decreased significantly (p = 0.002; p = 0.001; p = 0.012). There was a positive correlation between TFS and pruritus scores (r = 0.378) and DLQI scores (r = 0.392). TFS was found to have a negative correlation with UCT score (r = -0.283) and PhyGA-VAS (r = -0.347). CONCLUSIONS: This new Fric scoring system allows comparison with other tools and shows moderate correlations with most of the tools. Using disease-specific tools is recommended since they provide a subjective evaluation of disease severity, QoL impairment, and disease control.

Management of chronic inducible urticaria according to the guidelines: A prospective controlled study.

BACKGROUND: The recommended treatment approach in chronic inducible urticarias (CIndU) is the same as that for chronic spontaneous urticaria (CSU). But there is a lack of controlled trials assessing efficacy of available treatment options. OBJECTIVE: We aimed to evaluate the efficacy of treatment algorithm recommended by the guidelines and comparison of treatment responses in CIndU vs CSU. METHODS: This prospective parallel group controlled study included 70 CIndU and 66 CSU patients. The same treatment algorithm recommended by the European Academy of Allergology and Clinical Immunology/Global Allergy and Asthma European Network/European Dermatology Forum/World Allergy Organization (EAACI/GA2LEN/EDF/WAO) was implemented to both CSU and CIndU patients. Treatment responses of the groups were evaluated with urticaria control test (UCT) and dermatology life quality questionnaire (DLQI) scores at the 0, 4, 8, 12 and 24th weeks for CIndU and 0, 4, 12 and 24 weeks for CSU. RESULTS: Fourteen patients (20,9%) with CIndU and 25 (37,9%) with CSU responded to standard doses of H1-AHs which was significantly higher in the CSU group (p=0,031, p<0,05). Patients with CIndU and CSU showed statistically similar responses to 2nd line treatments (combining or updosing AHs) (p=0,979; p>0,05). Twenty-seven (40,3%) of CIndU patients and 21 (31,8%) of CSU patients were diagnosed as AH-resistant urticaria. Omalizumab was administered to 15 CSU patients and 17 CIndU patients. Response rates to omalizumab were similar in both groups. Total response rates increased from 37,9% (n:25) to 68,2% (n:45) with the 2nd line treatments in CSU group while it increased from 20,9% (n:14) to 59,7% (n:40) in CIndU group. When omalizumab was introduced to AH-refractory cases as a 3rd line treatment, total response rates evaluated at the 12th week were 76,1% (n:51) in patients with CIndU and 83,3% (n:55) in CSU. Continuing omalizumab treatment for 24 weeks increased response rates in patients who were unresponsive at week 12. CONCLUSION: CIndU seem to be more resistant to standard doses of AHs and higher doses of AHs are required for the control of symptoms. The same guidelines for CSU may be implemented to patients with CIndU.

Evaluation of the Clinical and Sociodemographic Features of Turkish Patients with Vitiligo.

Vitiligo is an acquired, pigmentary skin disorder that affects about 0.1-4.0% of the population. In this study, we aimed to investigate the disease features such as age of onset, disease duration, clinical and sociodemographic characteristics, and laboratory parameters of patients with vitiligo. A hundred patients who were in follow-up for vitiligo between the period of June 2013 and May 2014 were included in the study. The clinical features and laboratory parameters were retrospectively obtained from the records of the patients. The mean age was 34.9±16.8 years. The most common clinical types were focal and acrofacial. Facial involvement was the most common localization. Forty-five (45%) patients had an associated systemic disease. Autoimmune thyroid disease, essential hypertension, and alopecia areata, which were observed in 28%, 8%, and 5% of patients, respectively, were the most common associated diseases. Twenty-one percent of the patients had low ferritin levels, 20% had low iron levels, 12% had low vitamin B12 levels, and 1% had low folic acid levels. The prevalence of anti-TG (anti-thyroglobulin) and anti-TPO (anti-thyroid peroxidase) antibodies were found 17% and 27% of the patients, respectively. We found that the clinical characteristics of vitiligo in our patients were similar to those in other studies. We observed laboratory abnormalities and accompanying diseases associated with vitiligo. Therefore we conclude that laboratory examinations including thyroid antibodies and regular follow-up of these patients are essential.

Pruritus in Systemic Diseases: A Review of Etiological Factors and New Treatment Modalities.

Pruritus is the most frequently described symptom in dermatology and can significantly impair the patient's quality of life. In 10-50% of adults with persistent pruritus, it can be an important dermatologic clue for the presence of a significant underlying systemic disease such as renal insufficiency, cholestasis, hematologic disorder, or malignancy (Etter and Myers, 2002; Zirwas and Seraly, 2001). This review describes the presence of pruritus in different systemic diseases. It is quite important to discover the cause of pruritus for providing relief for the patients experiencing substantial morbidity caused by this condition.