Elevated serum B-cell activating factor in patients with chronic urticaria

The B and T cells abnormalities that have been described among CU patients, lend support to its regard as an autoimmune disease. In this study we compared serum B-cell activation factor (BAFF) levels in 46 CU patients to 24 healthy controls and evaluated a possible association between elevated serum BAFF in CU patients and the presence of autologous serum skin test, anti-thyroid antibodies, antinuclear antibodies, high total IGE levels, and urticaria disease severity. We found that serum BAFF levels is elevated statistically significant in CU patients compared to healthy control (1228±342 pg/ml vs. 758±313 pg/ml, P<0.0001). CU patients with severe disease activity had significantly higher serum BAFF levels compared to patients with mild CU (1394.6±299.6 vs. 1097.6±221.3, P=0.0008). No association was found between the presence of positive autologous serum skin test, anti-thyroid antibodies or antinuclear antibodies or high levels of total IgE and serum BAFF levels in CU Patients. We conclude that CU patients have higher levels of serum BAFF which associate with disease severity.     

Serum-induced basophil CD63 expression by means of a tricolour flow cytometric method for the in vitro diagnosis of chronic urticaria

BACKGROUND: Functional autoantibodies against the alpha-chain of the high-affinity IgE receptor (FcepsilonRIalpha) identify a subset of patients with chronic urticaria (CU) due to autoreactivity, as assessed by an in vivo positive response to autologous serum skin test (ASST). We performed a study to standardize the serum-induced basophil activation assay by flow cytometry (FCM) using a new tricolour method, assessing the diagnostic performance of this test in discriminating between ASST+ and ASST- CU patients. METHODS: Sera of 64 CU patients (22 ASST+ CU and 42 ASST- CU) and 10 healthy subjects were tested for their ability to induce basophil CD63 expression when incubated with whole blood of both atopic (DA) and non-atopic donors (DNA). Using a triple-labelled strategy with anti-CD123, anti-HLA-DR and anti-CD63 antibodies, CD63+ basophils were identified on a selected population of CD123+ HLA-DR- cells. In 3 ASST+ CU patients who underwent cyclosporine therapy, the assay was performed before and after treatment. RESULTS: The ASST+ CU sera resulted in a significant higher induction of basophil CD63 expression compared with ASST- CU and healthy donors sera; when whole blood from DA was used, sensitivity and specificity of the assay were 95.5% and 90.5% respectively. ASST+ CU serum activity was significantly decreased during cyclosporine A treatment, in parallel with clinical remission. CONCLUSIONS: Chronic urticaria serum-induced CD63 expression assay performed on DA whole blood by means of our tricolour FCM method could be the most useful tool for identification of a subset of patients with autoimmune CU and may become a promising tool also for monitoring treatment efficacy.     

Plasma of patients with chronic urticaria shows signs of thrombin generation, and its intradermal injection causes wheal-and-flare reactions much more frequently than autologous serum

BACKGROUND: Several aspects of the pathogenesis of chronic urticaria (CU) remain contradictory. Autologous serum skin tests (ASSTs) and in vitro histamine release assays seem to look into distinct aspects of the disease, and the specificity of ASST has been questioned. OBJECTIVE: We compared the autologous plasma skin test (APST) with ASST to detect autoreactivity in patients with CU. The clotting process was investigated as well by measuring in vivo thrombin generation. METHODS: A total of 96 adults with CU underwent ASST; 71 of them underwent APST with Na citrate-anticoagulated plasma. Prothrombin fragment 1+2 plasma levels were measured by a sandwich ELISA in Na citrate-anticoagulated plasmas from 28 patients and 27 controls. RESULTS: Fifty-one of 96 (53%) patients scored positive on ASST, whereas 61 of 71 (86%) patients scored positive on APST (21/30 [70%] ASST-negative and 40/41 [98%] ASST-positive). Plasma prothrombin fragment 1+2 was higher in patients than controls (3.06 [SD 3.36] vs 0.80 [0.34]; P < .001) and in ASST-positive/APST-positive than in ASST-negative/APST-positive patients (3.89 [SD 3.68] vs 1.33 [1.64]; P = 0.058) and was directly related to urticaria severity (r = 0.37; P < .05). CONCLUSION: Most patients with CU are positive on APST-Na citrate. CU is associated with the generation of thrombin, a serine protease able to activate mast cells and to cause relevant increase in permeability of endothelium. APST and ASST only partially depend on the presence of circulating antibodies to FcepsilonRI or to IgE. CLINICAL IMPLICATIONS: These findings provide new insights into the pathogenesis of CU and suggest new therapeutic opportunities for treating this disease.     

Association of specific IgE to staphylococcal superantigens with the phenotype of chronic urticaria

It has been well established that bacterial superantigens lead to the induction and aggravation of chronic inflammatory skin diseases. We investigated the clinical significance of serum specific immunoglobulin E (lgE) to the staphylococcal superantigens staphylococcal enterotoxin A (SEA), staphylococcal enterotoxin B (SEB), and toxic shock syndrome toxin (TSST)-1 in patients with chronic urticaria (CU), focusing on the differences in these prevalences between aspirin-intolerant CU (AICU) and aspirin-tolerant CU (ATCU) patients. Aspirin sensitivity was confirmed by oral aspirin provocation test. There were 66 patients AICU and 117 patients ATCU in the study. Serum IgE antibodies specific for SEA, SEB, and TSST-1 were measured by the ImmunoCAP test and the patients were compared with 93 normal controls (NC). The prevalences of serum specific IgE to staphylococcal superantigens were significantly higher in CU than in NC patients (IgE to SEA, 13.7% vs. 5.4%; IgE to SEB, 12.0% vs. 4.3%; IgE to TSST-1, 18.0% vs. 6.5%; p<0.05, respectively). The patients with specific IgE to SEA, SEB, and TSST-1 had higher serum total IgE levels and higher rates of atopy. Significant associations were noted between the prevalence of specific IgE to SEA and SEB and the HLA DQB1*0609 and DRB1*1302 alleles in the AICU group. We confirmed that a sub-population of patients with CU possesses serum IgE antibodies to SEA, SEB, and TSST- 1. Particularly, the IgE immune response to TSST-1 is associated with aspirin sensitivity in CU patients.     

EAACI/GA2LEN task force consensus report: the autologous serum skin test in urticaria

Injection of autologous serum collected during disease activity from some patients with chronic spontaneous urticaria (CU) into clinically normal skin elicits an immediate weal and flare response. This observation provides a convincing demonstration of a circulating factor or factors that may be relevant to the understanding of the pathogenesis and management of the disease. This test has become known as the autologous serum skin test (ASST) and is now widely practised despite incomplete agreement about its value and meaning, the methodology and the definition of a positive response. It should be regarded as a test for autoreactivity rather than a specific test for autoimmune urticaria. It has only moderate specificity as a marker for functional autoantibodies against IgE or the high affinity IgE receptor (FcεRI), detected by the basophil histamine release assay, but high negative predictive value for CU patients without them. It is usually negative in other patterns of CU, including those that are physically induced. Positive ASSTs have been reported in some subjects without CU, including those with multiple drug intolerance, patients with respiratory allergy and healthy controls, although the clinical implications of this are uncertain. It is essential that failsafe precautions are taken to ensure that the patient's own serum is used for skin testing and aseptic procedures are followed for sample preparation and handling. CU patients with a positive ASST (ASST⁺) are more likely to be associated with HLADR4, to have autoimmune thyroid disease, a more prolonged disease course and may be less responsive to H1-antihistamine treatment than those with a negative ASST (ASST⁻) although more evidence is needed to confirm these observations conclusively.     

Natural History and Influencing Factors of Chronic Urticaria in Children

PurposeChronic urticaria (CU) can reduce the quality of life of children and their parents, but there are only a few studies on the course of CU in children. This study aimed to investigate the natural course of CU in children and identify the factors that influence its prognosis.MethodsWe evaluated 77 children diagnosed with CU, who were monitored for at least 48 months. Subjects were classified as either chronic spontaneous urticaria (CSU) or other CU, and the clinical features were compared. Remission was defined as having no symptoms without treatment for more than 1 year. The remission rate was analyzed, and the factors influencing the prognosis were investigated.ResultsThe average age of the study population was 5.96 ± 4.06 years, and 64 (83.1%) patients had CSU. The remission rates at 6 months, 1 year, 2 years, 3 years, and 4 years after symptom onset were 22.1%, 40.3%, 52.0%, 63.7%, and 70.2%, respectively, for children with CU. For children with CSU, these values were 23.4%, 43.7%, 56.2%, 68.7%, and 75.0%, respectively. The total serum immunoglobulin E (IgE) levels were positively correlated with disease duration (r = 0.262, P = 0.021); no other factors were associated with the duration of the disease.ConclusionsA high proportion of children with CU were classified as CSU. No indicators, except for total IgE were found to predict the timing of spontaneous remission. The CU remission rate identified in this study is expected to be used as one of the reference data for the progress of CU in patients.     

Correlation between T-cell and mast cell activity in patients with chronic urticaria

BACKGROUND: The presence of autoantibodies reacting with the high affinity IgE receptor (FcepsilonRIalpha) usually indicates a more severe form of chronic urticaria (CU). Previously, we showed an increased lymphocyte reactivity in CU patients; however, the relation between enhanced cellular immunity and the presence of anti-FcepsilonRIalpha-specific autoantibodies has not been investigated. METHODS: Cellular and humoral immune reactivity of 50 CU patients and 28 healthy controls was studied.Serum sIL-2R, neopterin, and tryptase levels were measured to assess T-cell, monocyte/macrophage and mast cell activity, respectively. Helicobacter pylori (HP)-specific IgG antibody, and IgE levels were also tested. Anti-FcepsilonRIalpha-specific autoantibody was determined by Western blotting. In vivo histamine-releasing activity of patients' sera was assessed by the autologous serum skin test (AST). RESULTS: 17/50 CU patients, who both had IgG-type anti-FcepsilonRIalpha-antibodies by Western blotting and a positive AST response, were classified as autoimmune CU. All patients with CU had significantly higher serum sIL-2R and tryptase levels than healthy controls (p = 0.000257, p = 0.000166, respectively), indicating T-cell and mast cell activation. Patients with higher sIL-2R levels also had higher tryptase levels; the strongest correlation was shown in the autoimmune subgroup of patients (rho = 0.688, p = 0.002). There was a tendency towards higher tryptase levels in the autoimmune subgroup, as compared to the nonautoimmune CU patients. While the serum IgE was significantly lower in autoimmune than in nonautoimmune CU (p = 0.000836), there was no significant difference in their sIL-2R, neopterin and HP-specific IgG antibody levels. CU patients with a positive AST response (38/50) had significantly higher tryptase levels (p = 0.0107) when compared to the negative skin test group. CONCLUSIONS: The significant correlation between sIL-2R and tryptase levels in patients with CU indicates that T cell activation is proportional to mast cell degranulation in these patients. The increased level of tryptase in autoimmune CU may suggest more severe disease.     

High prevalence of autoimmune urticaria in children with chronic urticaria

BACKGROUND: The etiology of chronic urticaria (CU) in childhood often remains unrecognized. Recently, in adults it has been shown that approximately 40% of patients with CU have autoimmune urticaria (AU); however, no data are available in children. OBJECTIVE: To determine the prevalence and possible risk factors for AU in children with CU. METHODS: Ninety-three consecutive children (52 male; median age, 7.8 years) with CU were evaluated for AU by means of autologous serum skin test (ASST) in all and serum-induced basophil histamine release (HR-urticaria test) in 52. All other known causes of CU were excluded as appropriate. RESULTS: A cause for CU was identified in 44 children (47%), whereas 49 (53%) remained idiopathic. ASST and HR-urticaria test had positive results in 22 of 49 (45%) and in 16 of 31 (52%) children with idiopathic CU compared with 1 of 44 (2%) and 5 of 21 (24%) with CU of a known cause, respectively ( P <.00001; P=.09). Sensitivity, specificity, and positive and negative predictive values of the ASST for diagnosing AU are 78%, 85%, 74%, and 88%. The prevalence of AU in childhood is 31% (15/52; 95% CI, 24%-51%). None of the variables studied were predictive for development of AU. CONCLUSION: Our results demonstrate for the first time that children have the same ability as adults to produce functionally active autoantibodies directed against IgE or IgE receptor and that AU occurs in children in as many as 30% of cases. The addition of screening for AU dramatically decreases the rate of the idiopathic form from 52% to 20%.     

Validation of basophil histamine release against the autologous serum skin test and outcome of serum-induced basophil histamine release studies in a large population of chronic urticaria patients

BACKGROUND: Endogenous histamine-releasing factors (HRFs) are involved in 30-60% of patients with chronic urticaria (CU). Evidence for their existence comes from in vivo studies of autoreactivity with the autologous serum skin test (ASST), in vitro immunoassays demonstrating autoantibodies against the immunoglobulin E (IgE) or the high affinity IgE receptor (FcepsilonRI) and serum-induced histamine release (HR) from basophils and mast cells. We have examined the correlation between the ASST and a new basophil histamine-releasing assay (the HR-Urtikaria test) in a group of well-characterized CU patients and subsequently determined the frequency of HR-Urticaria-positive sera from a larger population of CU patients. SUBJECTS: Group 1 consisted of 28 patients with CU (16 were ASST-positive) 20 patients with atopic dermatitis, 24 patients with allergy to birch and nine healthy controls. Group 2 consisted of 873 unselected CU patients. METHODS: White blood cells containing 1-2% basophils from a healthy nonatopic donor were incubated with patients sera in the presence of interleukin (IL)-3. Histamine was measured by the glass fibre method. RESULTS: Using the ASST as the true outcome, the HR-Urticaria test showed a sensitivity and specificity of 75% in group 1 using a cut-off value for HR of >16.5%. None of the controls was positive in the HR-Urticaria test. In group 2, we found no difference in the frequency of positives between male (34.6%, n = 254) and female adults (35.1%, n = 576) but twice as many females as males were tested. CONCLUSIONS: Our studies have shown that the HR-Urticaria test has a good sensitivity and specificity for endogenous HRFs demonstrated by the ASST in patients with CU and that about one-third of unselected patients with CU have a positive result.     

Autoantibodies in chronic idiopathic urticaria and nonurticarial systemic autoimmune disorders

BackgroundChronic idiopathic urticaria (CU) has been associated with other autoimmune diseases and basophil-activating autoantibodies to FcεRI or IgE. It is unknown whether patients with systemicautoimmune diseases have a similar prevalence of these autoantibodies.ObjectiveTo compare the prevalences of basophil-activating autoantibodies (elevated CU Index) in patients with CU, rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE). Clinical characteristics and laboratory studies were examined for an association with the CU Index.MethodsAdult patients, 27 with CU, 27 with RA, and 26 with SLE, and 20 healthy controls were compared on the basis of the CU Index panel, anti-IgE, and antithyroid antibodies.ResultsThe CU Index values were significantly higher in the CU group when compared with the RA group but not when compared with the SLE group. 33% of CU, 23% of SLE, 3.7% of RA, and 15% of controls had apositive CU Index. Elevated antithyroid antibody levels did not correlate with a positive CU Index in any of the groups. An elevated CU Index in the SLE group was not associated with age, sex, ethnicity, disease severity, or history of atopy.ConclusionThe CU Index values were elevated in patients with CU and SLE. The presence of these autoantibodies did not correlate with disease activity or presence of thyroid antibodies. Functional autoantibodies may not be specific for chronic idiopathic urticaria, and their role in nonurticarial systemic autoimmune diseases requires further investigation.     

Chronic urticaria: a disease at a crossroad between autoimmunity and coagulation

Chronic urticaria (CU), defined as recurrence of wheals with or without angioedema for more than 6 weeks, is a quite common disease that may severely worsen the quality of life. Studies carried out during the last 2 decades have demonstrated an autoimmune pathogenesis mediated by functionally active autoantibodies to the high affinity IgE receptor (FcepsilonRI) or to IgE which are able to induce histamine release from basophils and mast cells. However, such mechanism can be detected in less than 50% of patients only. The present article reviews recent findings showing an additional pathogenic mechanisms in CU patients: activation of the coagulation cascade resulting in thrombin production. Thrombin is a serine protease which may play a key role in urticaria, being able to induce edema through an increase in vascular permeability, mast cell activation and degranulation, and to induce the production of the anaphylotoxin C5a. Such mechanism seems to be active in the majority of CU patients, however their relationship with anti-FcepsilonRI or anti-IgE autoantibodies is still matter of research.     

Detection of basophil-activating IgG autoantibodies in chronic idiopathic urticaria by induction of CD 63

BACKGROUND: Approximately 40% to 50% of patients with chronic idiopathic urticaria (CIU) have functional IgG autoantibodies against FcepsilonRIalpha or IgE, which induce histamine release from basophils and cutaneous mast cells. A positive autologous serum skin test response is believed to reflect the presence of these autoantibodies. OBJECTIVE: We sought to further define the functional properties of and develop a sensitive functional assay for detection of autoantibodies in patients with CIU. METHODS: Sera from patients with CIU (n=61) and sera from healthy control subjects (n=23) were incubated with donor basophils. Activation of basophils was determined on the basis of CD 63 surface expression, as analyzed on a FACScan flow cytometer. RESULTS: A positive basophil activation test result was found in 51% of patients with CIU, and basophil-activating properties were present in the IgG fractions of sera. When both the in vitro test and the autologous serum skin test were considered, basophil/mast cell-activating autoantibodies were present in 62% of the patients. Patients with a positive basophil activation test result had a significantly higher prevalence of other autoantibodies, had more severe urticaria, and were more likely to have angioedema. CONCLUSION: The results demonstrate the presence of basophil-activating autoantibodies in about 50% of patients with CIU. The data support the autoimmune cause of the disease and provide a simple test for detection of these autoantibodies.     

Assessment of circulating FCεRIa in Chronic Spontaneous Urticaria patients and its correlation with clinical and immunological variables

Chronic spontaneous urticaria (CSU) is a chronic type characterized by episodes of wheals with or without angioedema. Autoantibody against the alpha subunit of Fc epsilon receptor (FcεRIa) was detected in CSU patients' sera. The study aims to evaluate the clinical utility of skin tests in CSU patients. In addition, it assesses the presence of circulating FcεRIa in CSU patients and their correlation with other clinical and immunological variables. The study includes 40 healthy controls and 40 CSU patients who had urticaria symptoms for at least 8 weeks. All subjects underwent the following tests: autologous serum skin test (ASST), autologous plasma skin test (APST), immunoglobulin E (IgE), antinuclear antibodies (ANA), antithyroid antibodies (ATA). An in-house enzyme-linked immunosorbent assay was used for FcεRIa detection. The prevalence of ANA and ATA in CSU was 7.5% and 20% respectively. Total IgE was significantly higher in CSU than in controls (p?<?0.0001). The study detected circulating antibody to FcεRIα in 2.5% of controls and 52.5% of CSU patients (p?<?0.0001). The prevalence of antibody to FcεRIa was 27.3% and 83.3% of ASST negative and positive patients respectively (p?=?0.0004). But the prevalence was 17.6% and 78.3% of APST negative and positive patients respectively (p?=?0.0002). In conclusion, Circulating antibody to FcεRIa has a role in the pathogenic mechanisms of CSU.     

Circulating level of the platelet-derived CXC chemokine platelet factor 4 in chronic urticaria patients with or without coexistent euthyroid Hashimoto's thyroiditis

The concept of autoimmune aetiology of some cases of chronic urticaria (CU) has been supported by several observation including wheal-and-flare reaction induced by intradermal injection of autologous serum as well as association with other autoimmune diseases, in particular Hashimoto's thyroiditis (HT). It is known that activated platelets may actively participate in immune-inflammatory processes. Therefore, we assessed whether autoimmune phenomenon associated with CU influence the systemic platelet activity measured by circulating level of platelet factor 4 (PF-4). Plasma level of PF-4 was analysed using enzyme-linked immunosorbent assay in twelve women with strong positive response to autologous serum skin test (ASST) suffering from CU, twelve female patients with strong positive ASST suffering from both CU and untreated, HT as well as sixteen healthy women. All the subjects were clinically and biochemically euthyroid. There were no statistically significant differences between the CU patients with or without euthyroid HT and plasma PF-4 level in healthy controls. In patients with both CU and thyroiditis, plasma level of PF-4 did not correlate significantly with the level of antibodies against thyroperoxidase. It seems that circulating level of the platelet-derived chemokine is not increased in CU patients with positive response to ASST, regardless the occurrence of euthyroid HT.     

Helicobacter pylori infection: prevalence in chronic urticaria patients and incidence of autoimmune urticaria (study in Dr. Cipto Mangunkusumo Hospital, Jakarta)

AIM: To determine the prevalence of Hp infection in patients with chronic urticaria (CU) and to evaluate the result of autologous serum skin test (ASST) in CU patients with Hp infections. METHODS: In this cross-sectional study, 16 patients with chronic urticaria and 16 non-urticaria volunteers were investigated (matched for age and sex). All subjects were examined for Hp infection with the 13C-urea breath test. Autologous serum skin test was performed in patients with proven Hp infection. RESULTS: Helicobacter pylori was detected in 12.5% of patients and 0% of the control group. There was no significant difference between the two groups (p = 0.484 using Fisher exact test). Autologous serum skin test was positive in 1 of 2 CU patients with Hp infection. CONCLUSION: In this study, there was no significant difference in the seroprevalence of Hp infection between CU patients and controls. Autologous serum skin test was positive in 1 of 2 CU patients with Hp infection.     

Clinical significance of IgG4 antibody determination in children against egg white, milk, soybean and Dermatophagoides farinae]

The measurement of IgE and IgG4 antibodies against egg white, milk, soybean and Dermatophagoides farinae was performed by FAST (fluorescence allergosorbent test) using 21 serum samples obtained from non-allergic children and 160 serum samples from atopic children with bronchial asthma and/or atopic dermatitis. Their antibody levels were evaluated for any association with disease severity and for clinical significance in establishing diagnosis. It was found that children with bronchial asthma showed lower levels of IgE antibodies against egg white, milk and soybean and higher levels of IgE antibodies against Dermatophagoides farinae compared with those of children with atopic dermatitis, while both groups showed higher levels of egg white and milk-specific IgG4 antibodies compared with non-allergic children. These IgE and IgG4 antibody levels revealed a tendency to correlate with disease severity in patients with atopic dermatitis, while this was not observed in patients with bronchial asthma. The contribution percentages of IgG4 antibody determination, together with IgE antibody determination, in retrieving causal allergens were 71% for egg white, 70% for milk and 48% for soybean allergy, implying their diagnostic value in establishing clinical diagnosis.     

Autoantibodies to the high-affinity IgE receptor in children with chronic urticaria.

BACKGROUND: Chronic urticaria (CU) in childhood remains a challenge for investigation, and its etiology is largely unknown. Autoantibodies to the high-affinity IgE receptor (FcepsilonRI) are believed to play a role in the pathogenesis of this disease in adults. OBJECTIVE: To determine the prevalence of autoantibodies to FcepsilonRIalpha on basophils in children with CU vs atopic eczema dermatitis syndrome (AEDS). METHODS: Eighty children with CU were compared with 38 children with AEDS. In addition to complete blood cell counts and total IgE measurements, CAP-RASTs to egg, codfish, soy, milk, and peanut were performed. Stool samples were examined for parasites, and autologous serum skin testing and a functional anti-FcepsilonRIalpha assay were conducted to detect autoantibodies. RESULTS: No significant differences were observed between children with CU and controls in mean basophil or eosinophil counts. Twenty (26%) of 77 children with CU and 31 (82%) of 38 with AEDS had positive CAP-RAST results (P < .001). Only 2.5% of the children with CU and 0% with AEDS had stool samples positive for parasites (P = .005). Anti-FcepsilonRIalpha autoantibodies were positive in 37 (47%) of 78 children with CU and in none of 33 with AEDS. Non-IgG histamine-releasing factors were found in 10 (13%) of 78 children with CU. CONCLUSIONS: Children have a similar prevalence of autoantibodies to the FcepsilonRIalpha as has been previously published for adults. Few have type I allergies, and parasite infestation is also uncommon. Further studies are required to investigate the predictive value of the autoantibodies in these children with respect to clinical profile, requirements for medications other than antihistamines, and remission rates.     

Plasma levels of matrix metalloproteinase‐9 in chronic urticaria patients correlate with disease severity and C‐reactive protein but not with circulating histamine‐releasing factors

Background Matrix metalloproteinase‐9 (MMP‐9) is an endopeptidase produced by many inflammatory cells that has been found in increased amounts in plasma from patients with chronic urticaria (CU). Objective To evaluate plasma levels of MMP‐9 and its tissue inhibitor of metalloproteinase‐1 (TIMP‐1) in CU patients in relation with disease severity, C‐reactive protein (CRP) and circulating histamine‐releasing factors. Methods Fifty‐two consecutive CU patients were included in the study and disease activity was graded from 0 to 3. Plasma MMP‐9, TIMP‐1 and CRP levels were measured by enzyme immunoassays. Circulating histamine‐releasing factors were assessed using in vivo (autologous serum skin test) and in vitro (basophil histamine release) tests. Seven CU patients were studied both during active disease and during remission. Thirty healthy subjects were used as normal controls. Results Plasma levels of MMP‐9, TIMP‐1 and CRP were significantly higher in CU patients than in healthy controls (P=0.0001, 0.003 and 0.005, respectively) and a trend towards a higher MMP‐9/TIMP‐1 molar ratio was found (P=0.051). A significant correlation was found between plasma MMP‐9 levels and urticaria severity score (r=0.48, P<0.0001). CRP levels correlated with MMP‐9 levels (r=0.37, P=0.008) and CU severity score (r=0.52, P=0.0001), but not with TIMP‐1 (r=0.13) concentrations. MMP‐9, TIMP‐1 and CRP plasma levels and MMP‐9/TIMP‐1 molar ratio did not differ in patients either with or without an evidence of circulating histamine‐releasing factors. Seven patients evaluated during remission showed a significant reduction of MMP‐9 and CRP plasma levels. Conclusion Plasma levels of MMP‐9 and its inhibitor TIMP‐1 are increased in CU patients. MMP‐9 levels are associated with disease severity and CRP levels, but not with skin reactivity to autologous serum and with circulating histamine‐releasing factors. These findings suggest that in CU there is an ongoing inflammatory process independent of the presence of circulating histamine‐releasing factors.     

Unmet clinical needs in chronic spontaneous urticaria. A GA²LEN task force report

Chronic spontaneous urticaria, formerly also known as chronic idiopathic urticaria and chronic urticaria (CU), is more common than previously thought. At any time, 0.5-1% of the population suffers from the disease (point prevalence). Although all age groups can be affected, the peak incidence is seen between 20 and 40 years of age. The duration of the disease is generally 1-5 years but is likely to be longer in more severe cases, cases with concurrent angioedema, in combination with physical urticaria or with a positive autologous serum skin test (autoreactivity). Chronic spontaneous urticaria has major detrimental effects on quality of life, with sleep deprivation and psychiatric comorbidity being frequent. It also has a large impact on society in terms of direct and indirect health care costs as well as reduced performance at work and in private life. In the majority of patients, an underlying cause cannot be identified making a causal and/or curative treatment difficult. Nonsedating H?-antihistamines are the mainstay of symptomatic therapy, but treatment with licensed doses relieves symptoms effectively in < 50% of patients. Although guideline-recommended updosing up to fourfold increases symptom control in many patients, a substantial number of patients have only little benefit from H? -antihistamines. Consequently, there is a great need for new therapeutic strategies.     

Elevated MRGPRX2 Levels Related to Disease Severity in Patients With Chronic Spontaneous Urticaria

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.