Basophil FCER1A and PTAFR Gene Expression Profiles Correlate With Disease Severity in Chronic Spontaneous Urticaria.

Basophil CD63 expression in chronic spontaneous urticaria: correlation with allergic sensitization, serum autoreactivity and basophil reactivity.

Background: For the majority of chronic spontaneous urticaria (CSU) sufferers, nocturnal itch has a profound effect on quality of life (QoL), as it leads to sleep disturbances. To ensure good sleep quality (SQ), the body must produce an adequate amount of melatonin, which regulates the sleep cycle. Methods: This study examines the levels of salivary melatonin in 38 CSU patients and 38 healthy controls, as well as the relationship between CSU severity, QoL and SQ. The Enzyme-Linked Immunosorbent Assay (ELISA), Dermatology Quality of Life Index (DLQI), and Pittsburgh Sleep Quality Index (PSQI) were used to determine salivary melatonin levels, QoL, and SQ. In addition, the CSU participants were given the Urticaria Activity Score (UAS) and the Urticaria Control Test. Results: The median value of salivary melatonin in CSU patients was lower than that in healthy individuals (0.2 vs. 15.985 pg/mL; p < 0.001). A decreased melatonin level was seen in 90% of CSU patients and 18% of healthy individuals. Individuals with lower melatonin levels were significantly more likely to have CSU compared with those with higher melatonin levels (OR = 37.6; 95% CI 10.0-141.1). Melatonin was linearly related to QoL and sleep quality in the whole sample (r = -0.606 and -0.536; p < 0.001) but not in CSU patients. Impaired QoL in patients correlated with itch intensity and the number of hives (r = 0.740 and 0.646). The severity and activity of CSU are linearly related to impaired QoL and sleep quality (r = -0.606 and -0.536; p < 0.001). Sleep quality acts as the mediator of the association between QoL and salivary melatonin, when controlling for the effect of age and gender (B = -0.347; 95% CI = -0.679 to -0.080). Conclusions: The data suggest that melatonin may be more a non-specific marker of sleep disturbance than the severity of CSU. Sleep quality may act as a mediator linking dermatology-related QoL, circadian dysregulation and reduced melatonin secretion.

BackgroundThe pathophysiology of urticaria is still poorly understood. Recent studies demonstrate that the activation of coagulation is correlated with the clinical activity of Chronic Spontaneous Urticaria. Coagulation and inflammation are strongly linked. ObjectivesTo correlate the severity and activity of Chronic Spontaneous Urticaria with the levels of D-dimer, C-reactive protein, and autologous serum test in patients with Chronic Spontaneous Urticaria. MethodsThe study included 55 patients diagnosed with chronic spontaneous urticaria. D-dimer levels were measured using enzyme-linked fluorescent assay and C-reactive protein levels were measured using the nephelometric method; autologous serum testing was performed on patients who discontinued antihistamine therapy. The severity of the disease was assessed using the urticaria activity score. Resultspatients with severe, spontaneous, and difficult-to-control chronic urticaria had elevated serum levels of D-dimer, as well as a positive autologous serum test. Little correlation was demonstrated between the severity of chronic spontaneous urticaria and the levels of C-reactive protein. ConclusionThe authors concluded that patients with severe Chronic Spontaneous Urticaria showed signs of activated fibrinolysis. Most patients with high clinical scores had high D-dimer values. Patients with positive results for the autologous serum test also had more severe Chronic Spontaneous Urticaria and needed more drugs to control the disease. Finally, little correlation was found between C-reactive protein levels and disease severity. Study limitationsThe main limitation was the small sample of patients. In the present patients, it was demonstrated that serum D-dimer levels and the autologous serum test can act as predictive markers of severity and activity of Chronic Spontaneous Urticaria.

Chronic spontaneous urticaria (CSU) is a condition characterized by the development of itchy wheals (hives), angioedema, or both, with reoccurring symptoms for more than 6 weeks. CSU is often fluctuating and unpredictable in its course,1 which is a great burden to the patients, especially when no underlying causes are found. Psychosomatic and psychiatric comorbidities are often reported and an association between CSU and stress was proposed, in which psychosocial strain may initiate a vicious cycle of stress-induced worsening of the disease causing a higher psychosocial burden, which in turn amplifies the stress influence on the disease.2-5 At present, systematic studies in support of a stress- and disease-relationship in CSU are largely missing, rendering the stress-contribution to CSU unclear. Comprehensive studies of the association between stress and urticaria are needed to answers to the following questions: Do CSU patients report relevant stress levels? Are stress levels higher when no underlying cause can be identified (CSU‒ CSU+ patients)? Do CSU‒ patients suffer from higher disease activity compared to CSU+ patients? And finally, are stress levels in CSU‒ and CSU+ patients linked to disease activity? To address these knowledge gaps, we studied stress perception and resilience and their association with disease severity, assessed by use of the urticaria activity score (UAS7) in an explorative manner. In addition, selected routinely assessed immune outcomes that have been discussed to play a role in stress effects in urticaria (IgE, basophils, eosinophils) were studied. The exploratory study was approved by ethics committee of the Charité - Universitätsmedizin Berlin, Germany. A total of 303 CSU patients that provided informed written consent were assessed for mental distress, resilience, and immune outcomes (ELISA, complete blood count), and then, for potentially relevant underlying conditions, the results of which were disclosed to the patient after completion of the comprehensive workup of the etiologic tests by a team of experienced dermatologists (EMP, MM, MM). The scales "worries," "tension," "and "demands" of the Perceived Stress Questionnaire (PSQ) were used to assess stress perception, "joy" and the Self-efficacy, Optimism and Pessimism (SWOP) questionnaire to assess resilience to stress.6, 7 PSQ "summary score" values above 50 are one SD (=17) higher, values below 16 are one SD lower than the mean (=33) in a German reference population,6 and were set as cutoffs for severe, medium and low stress, respectively. Additional data obtained included age, sex, body mass index, previous steroid- and anti-histamine intake. Investigated potentially relevant underlying clinical and laboratory conditions included autoreactivity, chronic viral, bacterial, fungal, and parasitic infections, intolerance to food components, intolerance to physical provocation and chronic inflammatory diseases including autoimmune disorders and allergies. In 249 CSU patients, potentially relevant underlying conditions were identified (CSU+) as opposed to 54 patients without potentially relevant underlying conditions (CSU‒). Only a minority received oral medication prior to the assessment (antihistamines 20%, steroids 6%) and no medication or demographic differences were found between CSU+ and CSU‒ patients (Table S1). Levels of self-reported stress perception and resilience in CSU patients showed a wide range of mental distress levels, with low, moderate, and high PSQ scores in 21%, 64%, and 15% of patients, respectively. The mean PSQ "summary score" in women (32.05 ± 17.04, 72% of all patients) was slightly but not significantly higher than in men (29.82 ± 15.06). Patients younger than 45 years (55% of all patients) had slightly but not significantly higher PSQ "summary score" levels (33.12 ± 16.20) than older patients (29.55 ± 16.73). Chronic spontaneous urticaria‒ patients had significantly higher disease activity than CSU+ patients (Figure 1A). In CSU‒ patients, 52.6%, 31.6%, and 15.8% had UAS7 levels indicative of mild, moderate, and severe CSU, respectively, as compared to 64.2%, 25.8%, and 10% in CSU+ patients. CSU‒ patients reported higher PSQ "worries," "tension," and "demands," with statistically increased values for the scale "tension" (Figure 1B,C, Table S2). In contrast, stress resilience in CSU‒ and CSU+ patients was similar. No group differences with respect to selected immunological measures such as total serum IgE, blood basophil and eosinophil counts were found (Table S3). Correlation analyses revealed that in CSU‒ patients, UAS7 scores showed a moderate positive correlation with the results of the PSQ-scales "demands" (r = .362; P = .028) and a trend for "tension" (r = .292; P = .0791) (Table 1). A regression analysis (including the confounders age, gender, and body mass index) confirmed these links in CSU‒ patients (adjusted R2 "demands" = 0.195; F(1/35) = 9.746; P = .004, Figure 1D; adjusted R2 "tension" = 0.082; F(1/35) = 4.218; P = .048, Figure 1E). The explained variance of 19.5% expresses a medium effect of f2 = 0.24 and of 8.2% a low effect of f2 = 0.09, respectively. By contrast, the common confounders age, gender, and body mass index were not significant predictors of the UAS7 in this group. Our comprehensive analyses of stress in patients with CSU are the first to demonstrate that most CSU patients report stress, but also that mean levels of mental distress are comparable to the general population.8 More importantly, our findings confirm that in CSU‒ perceived stress and disease activity are linked in the absence of demographic group differences and even before CSU‒ patients know that no underlying cause for their urticaria will be found. These observations are relevant and may help to destigmatize CSU patients, who often feel that their doctors and peers do not take their disease-burden seriously and attribute their suffering to the seemingly minor mental problem of having too much stress. In conclusion, our findings suggest a possible causal link between CSU and mental distress and encourage further research to confirm whether the increased levels of stress in the CSU‒ subpopulation are the reason or the result of their high disease levels. Clearly, in some CSU patients, the signs and symptoms of urticaria and stress are linked, which confirms the need to assess both the clinical symptoms and stress, ideally by daily diary-assessments and during patient visits, and also to address both by therapy and research, for example by the implementation of psychological interventions. The authors declare that they have no conflicts of interest. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Introduction: Allergen-specific IgE (sIgE) sensitization exists in a considerable fraction of chronic spontaneous urticaria (CSU) patients. Basophils have been implicated in the pathogenesis of CSU. This paper aimed to explore the relationship between allergic sensitization and basophil reactivity in CSU and the possible underlying mechanism. Methods: Basophil-enriched leukocytes were isolated from the peripheral blood of 76 CSU patients and 9 healthy controls. Basophil CD63 and FcεRIα (the alpha subunit of the high-affinity IgE receptor) expression in the blood samples with various house dust mite (HDM)-sIgE levels were determined by flow cytometry. Basophil reactivity and SHIP-1 (a molecule related to the IgE/FcεRI signaling pathway) expression were analyzed after stimulation with an HDM allergen or other stimuli. Results: HDM-sIgEstrong positive (≥3.5 kU/L) CSU patients had a significantly higher mean percentage of basophil CD63 and higher baseline levels of FcεRIα expressed by basophils than HDM-sIgEnormal (<0.35 kU/L) CSU patients and healthy controls; the same went for total serum IgE. After stimulation with Dermatophagoides pteronyssinus peptidase 1 (Derp1) alone or together with Derp1-sIgE, the stimulation index of CD63 and levels of FcεRIα expressed by basophils in HDM-sIgEstrong positive CSU patients were significantly higher than those in HDM-sIgEnormal CSU patients and healthy controls. Significantly more SHIP-1 mRNA expression in HDM-sIgEstrong positive CSU patients was induced after the combined stimulation in comparison to other subjects. Conclusion: CSU patients with higher HDM-sIgE levels (≥3.5 kU/L) may have higher CD63 and FcεRIα expression on peripheral blood basophils. Peripheral blood basophils in these CSU patients are more responsive to HDM allergen stimulation. Higher HDM-sIgE levels among CSU patients may implicate higher basophil reactivity.

Translationally controlled tumor protein (TCTP) is also known as histamine releasing factor as it has the ability to activate mast cells. To investigate the role of TCTP in the pathogenesis of chronic spontaneous urticaria (CSU), we evaluated serum level of TCTP and effect of TCTP on basophil and mast cell degranulation. TCTP levels in the sera from 116 CSU patients and 70 normal healthy controls (NCs) were measured by ELISA. CD203c expression on basophils from CSU patients and β-hexosaminidase release from Laboratory of Allergic Disease 2 mast cells were measured upon stimulation monomeric and dimeric TCTP. Non-reducing Western blot analysis was used for detecting dimeric TCTP. No difference was observed in serum TCTP levels between CSU patients and NCs (p=0.676). However, dimeric TCTP intensity on Western blot was stronger in CSU patients than in NCs. TCTP levels were higher in patients with severe CSU (p=0.049) and with IgG positivity to FcɛRIα (p=0.038). A significant positive correlation was observed between TCTP and eosinophil cationic protein levels (Spearman's rho=0.341; p=0.001). Both basophil and mast cell degranulation were significantly increased after stimulation with dimeric TCTP, but not with monomic TCTP. The ability of TCTP to activate basophil and mast cells is dependent on dimerization, suggesting that the inhibition of TCTP dimerization can be a therapeutic option for CSU. Association between TCTP levels and the presence of IgG to high affinity Fc epsilon receptor I alpha subunit in CSU patients indicates that autoimmune mechanisms may be involved in the dimerization of TCTP.

Chronic spontaneous urticaria (CSU) is considered in a subset of patients to be an autoimmune disorder. Interleukin(IL)-17, IL-31, and IL-33 are involved in some immune response. The aim of this study was to quantify plasma IL-17, IL-31, and IL-33 levels in CSU patients and to examine their relationships with disease severity. Plasma IL-17, IL-31, and IL-33 concentration were measured in 51 CSU patients and 20 healthy subjects (HCs). Plasma IL-17 (P < 0.001), IL-31 (P < 0.001), and IL-33 (P < 0.001) concentrations were significantly higher in CSU patients when compared with those of HCs. Concerning UAS7, severe group of CSU patients had significantly higher IL-17 levels than the moderate and mild groups (P = 0.028 and 0.007, respectively), and significantly higher IL-33 concentrations than the mild group (P = 0.026). Regarding only pruritus, severe group of patients had significantly higher IL-31 levels than the mild group (P = 0.003). The IL-33 levels in the total IgE positive group were significantly higher than that of negative group (P = 0.010). Our results showed higher plasma levels of IL-17, IL-31, and IL-33 among CSU patients which may highlight a functional role of these cytokines in the pathogenesis of CSU.

Studies establish a link between autoimmune factors and chronic spontaneous urticaria (CSU). T cells are crucial in immune-mediated diseases like CSU, and T-cell receptor (TCR) diversity could be pivotal in autoimmune responses. The clinical relevance of TCR variations in CSU is unknown, but understanding them may offer insights into CSU's pathogenesis and treatment. This cross-sectional study included 132 chronic urticaria (CU) patients versus 100 age-matched healthy donors (HD), with subgroup analyses on CU type, angioedema, allergic comorbidities, and anti-IgE therapy efficacy. Peripheral TCRβ repertoires were analyzed by high-throughput sequencing. CSU patients showed reduced TCR diversity (lower D50) and increased large clone proportions than HD. Moreover, TCR diversity in CSU patients was significantly lower than in those with Chronic Inducible Urticaria (ClndU). There were also differences in variable (V) and joining (J) gene usage between CU and HD groups as well as CSU and ClndU groups. However, in subgroup analyses regarding angioedema, allergic comorbidities, and the efficacy of anti-IgE treatment, no significant differences were found in TCR diversity or large TCRβ clones. Notably, patients with treatment relapse or poor response to anti-IgE therapy had a higher proportion of positively charged CDR3. Additionally, age affected TCR diversity, but TIgE value, EOS counts, CU duration, and UAS7 score did not associate significantly with D50. CSU patients exhibit reduced TCR diversity and increased large clone proportions, indicating abnormal T cell activation. The TCR diversity differences and distinct V and J gene usage between CSU and ClndU may indicate different mechanisms in T lymphocyte-associated immune responses for these two subtypes of CU. The higher positive charge in CDR3 of relapsed or poorly responsive patients to anti-IGE treatment may indicate more antigen charge involvement. These findings provide new insights into the pathogenesis of CSU and potential future treatments.

Introduction: Chronic urticaria (CU) is a common skin condition that can be divided into chronic spontaneous urticaria (CSU) and chronic inducible urticaria (CIndU). Omalizumab is one treatment option for CU, but currently there are limited clinical studies of omalizumab’s efficacy for treating CU in Chinese patients. This study sought to investigate the efficacy and safety of omalizumab treatment for CU patients in a Chinese patient population. Specifically, we aimed to compare the differential efficacy of omalizumab for CSU and CIndU patients and predict risk factors for recurrence. Methods: We completed a retrospective clinical data review of 130 CU patients who received omalizumab treatment from August 2020 to May 2022, with a maximum follow-up period of 18 months. Results: A total of 108 CSU patients and 22 CIndU patients were included in the study. After treatment with omalizumab, the response rate in the CSU group was higher than that in the CIndU group (93.5% vs. 68.2%), and CSU patients accounted for a higher proportion of responders and early responders (responders: 87.1% vs. 12.9%, p < 0.001; early responders: 95.7% vs. 4.3%, p = 0.001). Nonresponders had lower total immunoglobulin E (IgE) levels (75.0 vs. 167.5 IU/mL, p = 0.046) and a relatively shorter duration of treatment (1.0 vs. 3.0 months, p = 0.009) compared to responders. Early responders had shorter disease duration (1.0 vs. 3.0 years, p = 0.028), higher baseline UCT (4.0 vs. 2.0, p = 0.034), lower baseline DLQI (18.0 vs. 18.5, p = 0.026), and shorter total treatment time (2.0 vs. 4.0 months, p < 0.001) compared to late responders. All adverse events reported during treatment were mild. Seventy-four patients with CU discontinued the drug after achieving complete disease control, of which 26 (35.1%) relapsed for 2.0 months (interquartile range: 1.0–3.0 months). Compared with nonrelapsed patients, relapsed patients often had other allergic diseases (42.3% vs. 18.8%, p = 0.029), higher basal levels of total IgE (263.0 vs. 140.0 IU/mL, p = 0.033), and longer disease duration (4.2 vs. 1.0 years, p = 0.002). Relapsed patients could still achieve good disease control after restarting omalizumab therapy. Conclusion: Omalizumab was effective and safe for CSU and CIndU patients. Patients with CSU responded more quickly to omalizumab and showed a relatively better treatment effect. However, there was a possibility of relapse after discontinuation of omalizumab after complete control of CU, and in these cases, restarting omalizumab treatment after relapse was effective.

Chronic spontaneous urticaria (CSU) is defined as the spontaneously appearing weals and/or angioedema for more than 6weeks. Dietary habits can modulate the pathogenesis of CSU. However, dietary intakes of nutrients or food in CSU patients, compared with healthy controls, have not been examined in quality and quantity. We evaluated dietary habits in adult Japanese patients with chronic spontaneous urticaria using a validated, brief-type self-administered diet history questionnaire and compared the results to those of age- and sex-matched healthy controls. The severity of CSU was evaluated using the Urticaria Control Test. Japanese CSU patients showed higher body mass indices, higher intakes of eggs, vegetables other than green/yellow vegetables/mushrooms/algae, cholesterol, folic acid, dietary fibres, vitamin D, vitamin K, Cu, Fe, Pi, Ca, Mg, Na and salt, and lower intake of alcohol, compared to controls. The logistic regression analysis showed that CSU was associated with high body mass index and high intake of eggs. The intake of beverages was higher in uncontrolled CSU patients (Urticaria Control Test ≦11 points) than in controlled patients. The logistic regression analysis showed that uncontrolled CSU was associated with high intake of beverages. The intake of coffee, caffeine-rich and non-alcohol beverage, in uncontrolled CSU patients was higher than that in controlled patients. Chronic spontaneous urticaria was associated with high body mass index and high intake of eggs. Uncontrolled CSU was associated with high intake of beverages. Further studies should elucidate the relationships of these results with the development or exacerbation of CSU.

Mas-related G-protein coupled receptor-X2 (MRGPRX2), a receptor on mast cells, basophils, and eosinophils associated with immunoglobulin E (IgE)-independent degranulation, has been reported to be highly expressed on cutaneous mast cells in patients with severe chronic spontaneous urticaria (CSU). We sought to investigate whether MRGPRX2 levels in the sera from CSU patients differ from those in healthy control subjects and to evaluate the clinical utility of MRGPRX2 levels in CSU patients. Severe CSU was defined as urticaria activity score over 7 days (UAS7) ≥ 28. Serum samples from 116 (73 severe and 43 non-severe) CSU patients and 50 healthy subjects were screened for MRGPRX2 using enzyme-linked immunosorbent assay. Serum MRGPRX2 levels were significantly higher in patients with severe CSU (median [interquartile range], 16.5 [10.8–24.8]) than in healthy controls (11.7 [6.5–21.2], P = 0.036) and in non-severe CSU patients (8.7 [4.5–18.8], P = 0.002), although they did not differ between healthy subjects and non-severe CSU patients. Serum MRGPRX2 levels in CSU patients showed positive correlations with UAS7 and specific IgE against Dermatophagoides farinae in CSU subjects, whereas no correlations were observed for age, sex, urticaria duration, atopy, combined angioedema, autologous serum skin test positivity, or total IgE levels. Logistic regression analysis identified serum MRGPRX2 ≥ 12 ng/mL (odds ratio, 6.421; P = 0.002) as an independent risk factor for severe CSU, along with increased serum total IgE levels, peripheral basophil percentage, and angioedema. In conclusion, we suggest that serum MRGPRX2 could help indicate severe CSU.

Aims: Chronic spontaneous urticaria (CSU) is one of the most prevalent skin disorders. Helicobacter pylori (HP) infection has been linked to CSU, and HP eradication therapy has been questioned as a viable treatment option. However, studies have produced contradictory results. In addition, recent studies suggest that gastritis, rather than HP bacteria, may be responsible for CSU symptoms. Herein, we aimed to ascertain the prevalence of HP infection in CSU, explore associations between HP infection, gastritis, and CSU severity or treatment response in CSU, and investigate the impact of HP eradication therapy on the CSU course. Methods: We retrospectively analyzed CSU patients who were investigated for HP infection. Patient characteristics, in-clinic urticaria activity scores (ic-UAS) and urticaria control test (UCT) scores, and CSU treatment responses were compared across different patient groups. Results: The study included 325 CSU patients, of whom 57.2% were HP-positive and 60.9% had gastritis. The mean baseline ic-UAS showed no difference between HP-positive and HP-negative patients (2.55±2 vs 2.45±1.98, p&gt;0.05) or between patients with and without gastritis (2.33±2 vs 2.51±2, p&gt;0.05). HP-positive patients had higher rates of elevated CRP levels (45% vs 29.9%, p=0.023) and ASST positivity (54.8% vs 29.8%, p0.05). Conclusion: Over half of CSU patients have been found to be infected with HP. However, the HP bacterium itself, the eradication of HP, or gastritis have no significant effect on CSU severity or treatment response.

Different expression patterns of plasma Th1-, Th2-, Th17- and Th22-related cytokines correlate with serum autoreactivity and allergen sensitivity in chronic spontaneous urticaria.

Background: Chronic urticaria (CU) is characterized by recurrent wheals and/or angioedema persisting for more than six weeks. While disease triggers are often unidentified, seasonal and environmental factors may modulate disease activity; however, evidence regarding their clinical impact remains limited. Objective: This study aimed to evaluate the effects of seasonal, meteorological, and pollutant-specific environmental factors on urticaria control using the Urticaria Control Test (UCT), and to compare these effects between chronic spontaneous urticaria (CSU) and chronic inducible urticaria (CIU) in relation to inflammatory serum biomarkers. Materials and Methods: This prospective observational study was conducted at the Allergy and Clinical Immunology outpatient clinic of Kirikkale University Faculty of Medicine between 1 June 2023 and 1 April 2024. Patients with CU were classified as CSU or CIU according to international guidelines. Each participant was evaluated during summer and winter seasons. Area-level air pollution data and meteorological parameters were obtained from national monitoring systems. Disease control was assessed using the UCT, and inflammatory biomarkers were analyzed. Results: Urticaria control showed significant seasonal variation, with lower UCT scores during summer and higher scores during winter in both CSU and CIU patients. Among environmental factors, ozone (O3) was the only pollutant consistently associated with poorer urticaria control, whereas particulate matter and traffic-related pollutants, despite being higher in winter, showed no clinically relevant association. Summer months were characterized by increased inflammatory activity, including elevated leukocyte counts, neutrophil-to-lymphocyte ratio (NLR), C-reactive protein (CRP), and D-dimer levels, particularly in CSU patients. D-dimer emerged as an independent marker associated with poor disease control during summer. Conclusions: CU demonstrates marked seasonal variation, with disease worsening during summer months. Pollutant-specific effects, particularly O3 exposure, rather than overall air pollution burden, appear to be clinically relevant in urticaria control. Inflammatory and coagulation-related biomarkers may provide additional insight into disease activity. These findings support a season-aware and individualized management approach and highlight the need for future studies incorporating individual-level exposure assessment and biomarker-guided strategies.

Chronic spontaneous urticaria (CSU) is a common dermatological condition presenting with wheals and/or angioedema for more than 6 weeks. The role of autoimmunity and inflammation in the pathogenesis of CSU have been studied, but the precise mechanism remains unknown. Association with coagulation cascade has been suggested based on the observations of increased coagulation indicators such as serum D-dimer levels. We report an omalizumab refractory case of severe CSU with high D-Dimer levels that declined only after disease remission with cyclosporine treatment but not with anticoagulation. Activation of coagulation cascade occurs secondary to the pro-inflammatory state in CSU patients and the correlation between D-dimer levels and disease activity may indicate the need for more studies to better understand the relationship of D-dimer levels and Omalizumab resistance. Clinicians should consider this relationship in CSU patients with significant D-dimer levels before considering treatment with anticoagulants.