Search

Cholinergic urticaria (CholU) is characterized by the occurrence of itchy wheals induced by sweating. Intradermal injections of acetylcholine (ACh) have been proposed to help with diagnosing CholU and subgrouping of patients, but controlled studies are largely missing.To compare the rates of positive ACh test results in well characterized CholU patients and controls and to identify clinical features of CholU linked to ACh reactivity.Acetylcholine was injected intradermally into 38 CholU patients and 73 matched healthy controls. Wheal and flare skin responses were assessed after 15 and 30 min and correlated with clinical features of CholU.At 15 min after intradermal injections of ACh, wheal and flare responses were significantly more frequent in CholU patients than healthy controls, wheals: 34 % vs.15% (P = 0.028); flares: 50 % vs.18 % (P0.001). Also, wheals were 37 % and flares 172 % larger and of longer duration in CholU patients than in healthy controls (both P0.01). CholU patients with ACh-induced wheals (AChIntradermal ACh testing does not allow for the identification of CholU patients due to its low sensitivity. ACh-induced wheals, in patients with CholU, is linked to sweating and longer lasting symptoms. Intradermal ACh testing is an interesting tool for mechanistic studies in CholU.

Background In chronic spontaneous urticaria (CSU), the guidelines recommend very limited diagnostic procedures during the routine workup, although additional investigations might be indicated in some patients with CSU. For physicians treating patients with CSU, it is often difficult to decide which diagnostic tests are useful. Objective To provide recommendations on what diagnostic tests should be performed on which patients with CSU. Methods We performed an extensive literature search on the respective topics and identified relevant questions that should prompt diagnostic procedures based on the published evidence and expert consensus among all authors. Results We provide questions, diagnostic testing, where appropriate, and recommendation that should be included when assessing the history of a patient with CSU, to explore and rule out differential diagnoses, to assess patients for underlying causes and modifying conditions, to explore patients for comorbid diseases and consequences of having CSU, and to assess patients for CSU components that can help to predict their disease course and response to treatment. Conclusions Here, we provide physicians treating patients with CSU with information about which clues should lead to which tests and why.

Background Pruritus often accompanies chronic skin diseases, exerting considerable burden on many areas of patient functioning; this burden and the features of pruritus remain insufficiently characterized. Objective To investigate characteristics, including localization patterns, and burden of pruritus in patients with chronic dermatoses. Methods We recruited 800 patients with active chronic skin diseases. We assessed pruritus intensity, localization, and further characteristics. We used validated questionnaires to assess quality of life, work productivity and activity impairment, anxiety, depression, and sleep quality. Results Nine out of every 10 patients had experienced pruritus throughout their disease and 73% in the last 7 days. Pruritus often affected the entire body and was not restricted to skin lesions. Patients with moderate to severe pruritus reported significantly more impairment to their sleep quality and work productivity, and they were more depressed and anxious than control individuals and patients with mild or no pruritus. Suicidal ideations were highly prevalent in patients with chronic pruritus (18.5%) and atopic dermatitis (11.8%). Conclusions Pruritus prevalence and intensity are very high across all dermatoses studied; intensity is linked to impairment in many areas of daily functioning. Effective treatment strategies are urgently required to treat pruritus and the underlying skin disease.

Chronic spontaneous urticaria (CSU) is considered to be primarily a mast cell–driven disease. However, recent evidence suggests that eosinophils may also have an axial role in symptomology. Histologic studies have demonstrated the presence of both eosinophils and eosinophil granules, indicative of activation, in CSU lesions. Although many allergic and inflammatory conditions are associated with a peripheral blood eosinophilia, the converse appears to be the case in CSU, with a peripheral blood eosinopenia being observed in many patients. Possible mechanisms include the depletion of blood eosinophils by recruitment into the skin during active disease and immunologic destruction in the blood. We also address in some detail the interactions between eosinophils and mast cells, particularly the cytokine cross-talk of these cells and mediator release possibly leading to clinical symptoms. Also, activation by eosinophil proteins of the coagulation pathway leads to the generation of thrombin and increased mast cell degranulation. Finally, treatments aimed at reducing eosinophil accumulation and activation, such as the anti–IL-5 antibodies mepolizumab, reslizumab, and benralizumab, have been reported to reduce CSU symptoms. Clearly, a new picture of an important role of eosinophils in the pathogenesis of CSU is emerging.

Background Recurrent angioedema (AE) is an important clinical problem in the context of chronic urticaria (mast cell mediator-induced), ACE-inhibitor intake and hereditary angioedema (both bradykinin-mediated). To help patients obtain control of their recurrent AE is a major treatment goal. However, a tool to assess control of recurrent AE is not yet available. This prompted us to develop such a tool, the Angioedema Control Test (AECT). Methods After a conceptional framework was developed for the AECT, a list of potential AECT items was generated by a combined approach of patient interviews, literature review and expert input. Subsequent item reduction was based on impact analysis, inter-item correlation, additional predefined criteria for item performance, and a review of the item selection process for content validity. Finally, an instruction section was generated, and an US-American-English version was developed by a structured translation process. Results A 4-item AECT with recall periods of 4 weeks and 3 months was developed based on 106 potential items tested in 97 patients with mast cell mediator-induced (n = 49) or bradykinin-mediated recurrent AE (n = 48). Eighty-four items were excluded based on impact analysis. The remaining 22 items could be further reduced by a method-mix of inter-item correlation, additional predefined criteria for item performance and review for content validity. Conclusions The AECT is the first tool to assess disease control in recurrent AE patients. Its retrospective approach, its brevity and its simple scoring make the AECT ideally suited for clinical practice and trials. Its validity and reliability need to be determined in future independent studies.

Objective Chronic urticaria (CU) is a common, heterogeneous, and debilitating disease. Antihistamines and omalizumab are the mainstay therapies of CU. Additional treatment options are needed. Here, we review the off and beyond label use of licensed drugs, novel treatments that are currently under development, and promising new targets. Data Sources MEDLINE was searched for recent reports of the successful use of treatments in CU and promising targets for the development of novel treatment options. We also searched ClinicalTrials.gov for recent and ongoing randomized clinical trials in CU. Study Selections Relevant articles were selected and reviewed. Results Omalizumab, the treatment of choice in patients with antihistamine-resistant chronic spontaneous urticaria (CSU), should be explored for use in chronic inducible urticaria in children younger than 12 years with CSU and at higher doses. The off-label use of dupilumab, reslizumab, mepolizumab, and benralizumab can be effective in CU. Ligelizumab and UB-221, 2 novel anti-IgE monoclonal antibodies, are in clinical trials for CU. Other promising drugs that are currently under development for CU are a chemoattractant receptor–homologous molecule expressed on TH2 cell antagonist, a monoclonal antibody to Siglec-8 (AK002), Bruton tyrosine kinase inhibitors (fenebrutinib and Lou064), a spleen tyrosine kinase inhibitor, and dupilumab. Promising targets of future therapies include the Mas-related G-protein–coupled receptor X2; the histamine4 receptor; C5a and its receptor; inhibitory mast cell receptors other than Siglec-8; interleukin 33, interleukin 25, and thymic stromal lymphopoietin, and stem cell factor. Conclusion Novel and better treatments for CU are very much needed. Some agents are in clinical trials already (eg, ligelizumab), and additional ones should be developed, making use of the many promising targets recently identified and characterized.

Background Cholinergic urticaria (CholU) is a frequent type of chronic inducible urticaria. Symptomatic treatment with second-generation antihistamines (sgAH) is recommended by current guidelines as first-line therapy, but little is known about how patients with CholU are treated in real life and how they respond to treatment. Aim To assess real-life treatment of CholU in German-speaking countries. Methods Patients with CholU (n = 111) took part in an online survey study that assessed their treatments and their treatment responses. Results Virtually all patients (97 %) had used antihistamines, 87 % of them sgAH; 23 % had also taken first-generation antihistamines (fgAH). The proportion of patients who benefited from standard-dosed antihistamine treatment was low (sgAH: 32 % vs. fgAH: 16 %), and side effects of sgAH and fgAH were comparable. Updosing of antihistamines had been tried by 66 patients (59 %) (most commonly [98 %, n = 65] with sgAH) and resulted in marginally better responses (sgAH: 38 % vs. fgAH: 32 %). Only very few patients had used other treatments, mostly corticosteroids (30 %) and omalizumab (5 %). Conclusions SgAH were commonly used, but insufficient in about two thirds of CholU patients. Accordingly, improved use of third-line and fourth-line treatment options and development of better therapies for patients with CholU are needed.

Background: cold urticaria (ColdU), that is, the occurrence of wheals or angioedema in response to cold exposure, is classified into typical and atypical forms. The diagnosis of typical ColdU relies on whealing in response to local cold stimulation testing (CST). It can also manifest with cold-induced anaphylaxis (ColdA). We aimed to determine risk factors for ColdA in typical ColdU. Methods: an international, cross-sectional study COLD-CE was carried out at 32 urticaria centers of reference and excellence (UCAREs). Detailed history was taken and CST with an ice cube and/or TempTest(R) performed. ColdA was defined as an acute cold-induced involvement of the skin and/or visible mucosal tissue and at least one of: cardiovascular manifestations, difficulty breathing, or gastrointestinal symptoms. Results: of 551 ColdU patients, 75% (n = 412) had a positive CST and ColdA occurred in 37% (n = 151) of the latter. Cold-induced generalized wheals, angioedema, acral swelling, oropharyngeal/laryngeal symptoms, and itch of earlobes were identified as signs/symptoms of severe disease. ColdA was most commonly provoked by complete cold water immersion and ColdA caused by cold air was more common in countries with a warmer climate. Ten percent (n = 40) of typical ColdU patients had a concomitant chronic spontaneous urticaria (CSU). They had a lower frequency of ColdA than those without CSU (4% vs. 39%, p = .003). We identified the following risk factors for cardiovascular manifestations: previous systemic reaction to a Hymenoptera sting, angioedema, oropharyngeal/laryngeal symptoms, and itchy earlobes. Conclusion: coldA is common in typical ColdU. High-risk patients require education about their condition and how to use an adrenaline autoinjector., GA(2)LEN UCARE Network

BACKGROUND In skin diseases and experimental models of pruritus, pure itch is accompanied by additional sensations that are poorly characterized. OBJECTIVES This study compared the sensory qualities evoked by different models of experimentally induced pruritus including skin prick testing (SPT) with histamine or capsaicin and application of cowhage spicules. SPT as a method of capsaicin application was validated for this purpose. METHODS Two pilot experiments were performed in eight healthy volunteers. First, a concentration of 8% capsaicin was identified as evoking a reproducible itch using SPT. Further, a list of the seven most frequently reported sensations was chosen after SPT with 10 mg/mL histamine, 8% capsaicin and application of 40-45 cowhage spicules. Finally, 31 subjects were challenged with the same itch-inducers. Wheal and flare were measured at 10, 20, 40, 60 and 90 min, itch intensity every minute for 30 min, and the overall evaluation of sensory descriptors were recorded on a 100-mm visual analogue scale once itching had subsided. RESULTS Skin prick testing with histamine and capsaicin resulted in flare reactions, which were 23% smaller for capsaicin (P

Background Along with the newly approved vaccines against coronavirus disease 2019 (COVID-19), first reports of allergic or intolerance reactions were published. Subsequently, questions arose whether these vaccines pose an increased risk for intolerance reactions and whether allergic patients may be at higher risk for this. Results Allergic reactions following COVID-19 vaccinations have been reported, but mostly of mild severity and at normal (Moderna®) or only slightly increased frequency (BioNTech/Pfizer®) compared to established conventional vaccines. The risk of allergic reaction to the newly licensed vector vaccines (AstraZeneca®, Johnson&Johnson®) cannot be conclusively assessed yet, but also appears to be low. There is currently no evidence that patients with allergic diseases (atopic patients) react more frequently or more severely to these vaccines. It is currently assumed that intolerance reactions of the immediate-type are either type I allergic (IgE-mediated) reactions or occur via complement activation (CARPA, “complement activation-related pseudoallergy”). Polyethylene glycol (PEG) or polysorbate, which are present as stabilizers in the vaccines, are suspected as triggers for this. Conclusion The data available so far do not show a significantly increased risk of immediate-type allergic reactions in atopic persons. In almost all cases, atopic patients can be vaccinated without problems. Standardized follow-up tests after suspected allergic reactions or CARPA-mediated reactions are currently limited.

Background: Autoimmune chronic spontaneous urticaria (CSU) is due to mast cell (MC)-activating autoantibodies, which are screened for by the autologous serum skin test (ASST) and basophil tests (BTs). Many CSU patients are positive in only one of these tests. How often this occurs and why is currently unknown. Objectives: To characterize the prevalence of mismatched ASST and BTs in CSU patients, and to investigate possible reasons for these mismatches. Methods: We determined the rates of ASST+/BT− and ASST−/BT+ mismatches in published CSU studies. We assessed sera from 48 CSU patients by ASST, two BTs (basophil histamine release assay, BHRA; basophil activation test, BAT), a MC histamine release assay (MCHRA) and by ex vivo skin microdialysis (SMD). Results: The ASST/BT mismatch rate in published CSU studies was 31% (ASST+/BT−: 22%, ASST−/BT+: 9%). In our patients, the ASST/BHRA and ASST/BAT mismatch rate was 35.4% (ASST+/BHRA−: 18.8% and ASST−/BHRA+: 16.7%) and 31.3% (ASST+/BAT−: 6.3% and ASST−/BAT+: 25.0%), respectively, and the two BTs were significantly correlated (P = 0.0002). The use of heterologous MCs, in vitro and in situ, instead of basophils produced similar results (MCHRA mismatch: 47.9%, ASST+/MCHRA−: 18.8%, ASST−/MCHRA+: 29.2%; SMD mismatch: 40.0%, ASST+/SMD−: 10.0% and ASST−/SMD+: 30.0%), and the MCHRA was highly correlated with SMD results (P = 0.0002). Conclusions: The ASST and BTs show divergent results in a third of CSU patients. Mismatches cannot be explained by the choice of basophil assay, the type of heterologous cells exposed to CSU serum in vitro (basophils vs. mast cells), nor the experimental setting of heterologous skin mast cells (in vitro vs. in situ). Thus, serum-induced whealing, in CSU patients, seems to involve autologous skin signals modulating MC degranulation.

Chronic inducible urticaria (CIndU) is characterized by wheals, angioedema or both in response to specific and definite triggers[1] . Half of CIndU patients are refractory to H1 -antihistamine treatment even at higher doses[2] . Multiple studies have proven the benefits of omalizumab in chronic spontaneous urticaria[3] . Real life data on the efficacy and safety of omalizumab treatment in CIndU are limited[4, 5] .

Objective Immunoglobulin E (IgE) and its receptor, FcɛRI, importantly contribute to the pathophysiology of chronic spontaneous urticaria (CSU). Recent findings point to a possible role of total IgE as a marker of CSU disease activity, endotypes, and responses to treatment. The evidence in support of total IgE included in the diagnostic workup of patients with CSU has not yet been reviewed. Methods Publications were searched via PubMed. The search terms used were "chronic urticaria" and "total IgE." Studies were screened by titles and abstracts, and 141 were used in the review. Results CSU patients frequently had elevated total IgE serum levels (up to 50%), but normal or very low total IgE levels also occurred. High total IgE may represent high disease activity, longer disease duration, high chance of responding to omalizumab treatment, quick relapse after stopping omalizumab, and lower chance of responding to cyclosporine. Low IgE, in contrast, may suggest Type IIb autoimmune CSU, poor response to treatment with omalizumab and a better chance to benefits from cyclosporine treatment. Furthermore, IgE in different CSU cohorts may have different physicochemical properties that could explain differences in treatment responses to IgE-directed therapies. Conclusion The results of our review suggest that total IgE is a valuable marker for CSU, and we recommend its assessment in the routine diagnostic workup of CSU patients.

SummaryBackground Cholinergic urticaria (CholU), a common form of chronic inducible urticaria, is characterized by itchy weals that occur in response to physical exercise or passive warming. CholU patients frequently exhibit a high burden of disease. As of yet, no specific instrument is available to assess their disease-related quality-of-life (QoL) impairment. Objective The aim of this study was to develop and validate the first disease-specific QoL instrument for CholU patients, the Cholinergic Urticaria Quality-of-Life Questionnaire (CholU-QoL). Methods Using a combined approach of the literature search, semistructured patient interviews and expert opinion, we developed 96 potential CholU-QoL items. Subsequent item selection was performed by means of impact analysis complemented by an expert review for face validity. The resulting final CholU-QoL was then tested for levels of validity, reliability and influence factors in 88 CholU patients. In parallel, an US American-Canadian English version of the CholU-QoL was developed. Results The final 28-item CholU-QoL was found to have a 5-domain structure (“symptoms,” “functional life,” “social interaction,” “therapy,” “emotions”) with excellent internal consistency. The CholU-QoL also showed a valid total score, and good levels of convergent validity, known-groups validity, as well as test-retest reliability. Multiple regression analysis found no significant drivers of the CholU-QoL total score. Conclusions and Clinical Relevance The CholU-QoL is the first disease-specific QoL instrument for CholU and also the first specific QoL measure in the field of chronic inducible urticarias. It may serve as a valuable tool for clinical trials and improve routine patient management.

The use of standardized, valid, and reliable clinical measures is an important element in modern patient management, particularly in diseases that are not objectively assessable and are associated with a high disease burden. Chronic urticaria is such a disorder for which several new and well-developed clinical measures became available. These measures comprise tools to assess disease activity, disease control, and health-related quality-of-life impairment. This review provides an overview of the currently available clinical measures for chronic urticaria. In addition, it provides information on their strengths and limitations and how to best use them and evaluate their results.

Background IgG autoantibodies against the high-affinity IgE receptor, Fc��RI��, contribute the pathogenesis of autoimmune chronic spontaneous urticaria (CSU). However, it is not known whether such patients also exhibit IgM or IgA autoantibodies against Fc��RI��. To address this question we developed an ELISA to assess serum levels of IgG, IgM, and IgA autoantibodies against Fc��RI�� and investigated whether their presence is linked to clinical features of CSU including the response to autologous serum skin testing (ASST). Methods Serum samples of 35 CSU patients (25 ASST-positive) and 52 healthy control individuals were analyzed using a newly developed competitive ELISA for IgG, IgM, and IgA autoantibodies to Fc��RI��. Results One in four CSU patients (8/35, 24%) had elevated serum levels of IgG-anti-Fc��RI�� compared with (3/52, 6%) healthy controls. More than half of patients had IgM (21/35, 60%) and IgA (20/35, 57%) vs (3/52, 5%) each in healthy controls. Elevated IgM, but not IgG or IgA, autoantibodies were significantly more frequent in ASST-positive CSU patients (18/25, 72%) compared with ASSTnegative patients (3/10, 33%,P = .022). Also, elevated levels of IgM-anti-Fc��RI��, but not of IgG or IgA against Fc��RI��, were linked to low blood basophil (r = .414,P = .021) and eosinophil (r = .623,P < .001) counts. Conclusions Increased serum levels of IgM-anti-Fc��RI�� are common in patients with CSU and linked to features of autoimmune CSU. The role and relevance of autoantibodies to Fc��RI�� in CSU can and should be further characterized in future studies, and our novel assay can help with this.

Background Cholinergic urticaria (CholU) is a frequent chronic urticaria disorder with itchy weal and flare-type skin reactions in response to physical exercise or passive warming. A higher frequency of atopy among CholU patients has been reported, but the significance of this observation is unclear. Objective To assess the prevalence and relevance of atopy in CholU patients. Materials and Methods Thirty CholU patients were assessed for atopic skin diathesis (atopic predisposition) by use of the Erlangen Atopy Score and divided into atopic and non-atopic predisposed CholU individuals. Both groups were assessed for disease severity (CholUSI) and activity (CholUAS7), quality of life impairment [Dermatology Life Quality Index (DLQI) and CU-Q2OL], seasonal exacerbation, total and specific serum IgE and comorbidities. Results CholU patients were found to exhibit high rates of atopic predisposition (57%), with higher prevalence and scores in female than in male patients. High Erlangen Atopy Scores were linked to high CholU severity, activity and impact on QoL. Atopic predisposed CholU patients show different seasonal exacerbation patterns, IgE specificity and comorbidity profiles as compared to non-atopic CholU patients. Conclusion Atopic predisposition and cholinergic urticaria appear to be linked more closely than previously thought, which suggests shared pathogenetic mechanisms. Atopic patients with cholinergic urticaria have more severe disease and poorer quality of life than those who do not. Thus, all cholinergic urticaria patients should be assessed for atopic predisposition.

Background Recurrent angioedema (RA) is an important clinical problem in routine care and emergency medicine. As of recently, the only validated tools to specifically assess disease status in patients with RA were diary-type activity assessments and angioedema-related quality-of-life questionnaires. Although these tools are particularly helpful in clinical studies, they were not designed to determine disease control or to guide treatment decisions. To close this gap, the Angioedema Control Test (AECT) was published recently. Objective To test the AECT for its validity and reliability, and to identify a cutoff value to aid treatment decisions. Methods Two AECT versions with a recall period of 4 weeks (AECT-4wk) and 3 months (AECT-3mo) were tested for their internal consistency and test-retest reliability, convergent and known-groups validity as well as screening accuracy in 81 patients with RA with bradykinin-mediated angioedema, mast cell mediator-mediated angioedema, or idiopathic angioedema. Results Both AECT versions showed excellent internal consistency reliability with a Cronbach alpha value of more than 0.85 and test-retest reliability with an intraclass correlation coefficient greater than 0.9. The convergent validity of both AECT versions was high. Both tools showed strong correlations with anchors of disease control, angioedema frequency, and health-related quality of life. A stratification of AECT scores into different levels of disease control together with a receiver-operating characteristic curve analysis suggested a cutoff value of 10 or more points to identify patients with well-controlled RA versus less than 10 points to identify patients with poorly controlled disease for both AECT versions. Conclusions The AECT is the first valid and reliable patient-reported outcome measure to assess disease control in patients with RA.

Background: Chronic spontaneous urticaria (CSU) is characterized by the degranulation of skin mast cells and the influx of basophils and eosinophils to affected skin sites. Blood basopenia has been linked to severe antihistamine-resistant CSU and type IIb autoimmunity, whereas the role of eosinophils in CSU is largely unknown. Objective: To analyze data from 1613 patients with CSU from 2 centers to study the prevalence, role, and relevance of eosinopenia in CSU. Methods: Peripheral blood eosinophil and basophil counts were measured by automated hematology analyzers. Patient files were screened for clinical characteristics, results of laboratory tests, the autologous serum skin test, the serum-induced basophil histamine release assay, and response to second-generation H1-antihistamines and omalizumab. Results: Ten percent of patients with CSU had eosinopenia. Eosinopenia was associated with the female sex, high disease activity, autologous serum skin test and basophil histamine release assay positivity, low total IgE, and high levels of C-reactive protein and IgG-antithyroperoxidase (P ≤ .007). Nonresponders to second-generation H1-antihistamines or omalizumab had significantly lower eosinophils as compared with responders (P < .05 and P < .01, respectively). Blood eosinophil counts correlated with basophil counts (r = 0.396; P < .001), and 81% of patients with CSU with undetectable eosinophils had basopenia. The combination of eosinopenia and basopenia is a better predictor of nonresponse to second-generation H1-antihistamines than eosinopenia alone (odds ratio of 9.5 vs 4.8). Conclusions: Eosinopenia in patients with CSU is associated with type IIb autoimmunity, high disease activity, and poor response to treatment. Eosinophils should be explored as biomarkers and investigated for their contribution to the pathogenesis of CSU.

BACKGROUND Elevated levels of C-reactive protein (CRP), a sensitive marker of inflammation, have been consistently reported in chronic spontaneous urticaria (CSU). Here, we retrospectively analyzed data from 1253 CSU patients from 2 centers to answer the following questions: (i) What is the prevalence of elevated levels of CRP in CSU? (ii) Why do CSU patients show elevated levels of CRP? (iii) Are elevated CRP levels relevant? METHODS Serum levels of CRP were measured by the nephelometric method. We collected information regarding various laboratory tests including ESR, CBC with differential, D-dimer, fibrinogen, C3, C4, IL-6, etc. For most patients, we also collected data on age, gender, duration of CSU, presence of angioedema, activity (UAS at the time of blood sampling and for 7 days), quality of life (CU-Q2oL and/or DLQI), comorbidities and possible causes of CSU, and autologous serum skin test (ASST) response. The efficacy of second-generation antihistamines was evaluated on the day of blood collecting. RESULTS One-third of CSU patients had elevated levels of CRP. Higher levels of CRP were associated with ASST positivity (P = .009) and arterial hypertension (P = .005), but not with other possible causes or comorbidities of CSU. C-reactive protein correlated with urticaria activity (P < .001), quality of life impairment (P = .026), and inflammatory and coagulation markers (P < .001). C-reactive protein levels were significantly higher in nonresponders to antihistamines as compared to responders (P < .001). CONCLUSION Elevated levels of CRP are common and relevant in CSU patients. The assessment of CRP levels may help to optimize the management of patients with CSU.

Background Cholinergic Urticaria (CholU) is a common skin disease characterized by the development of pinpoint sized wheals and severe itch upon physical exercise. Little is known about the epidemiology of CholU. CholU can occur at any age and has the highest prevalence among young adults. As of now, it is unclear if patients of different age show differences in the clinical manifestation of CholU, duration of disease, comorbidities or response to treatment. Methods Here, we analysed the demographic data and clinical characteristics including disease duration and comorbidities of 200 CholU patients, 12 to 76 years of age. Results We identified two distinct types of CholU, one with early onset (EO, 71%) and one with late onset (LO, 29%). EO and LO CholU patients markedly differ in key characteristics: EO patients, who had a disease onset before the age of 36, showed no gender preponderance, and had a significantly higher rate of concomitant atopic dermatitis (16.9 vs. 5.2%; p= 0.028) and higher IgE-Levels (295.5 vs. 267.1 IU/ml; p= 0.020) as compared to LO patients, who were mainly female (69%), had a shorter duration of disease (33.3 vs. 63.7 months; p= 0.005), a higher rate of concomitant other forms of urticaria (48.3 vs. 33.1%; p=0.044), and a higher rate of psychiatric comorbidities (12.1 vs 1.4%; p= 0.001).. Conclusion There are two subtypes of CholU patients with different gender ratios, disease duration, and comorbidities. These findings suggest that two distinct underlying pathogenetic pathways are relevant in these two subgroups of CholU patients. This article is protected by copyright. All rights reserved.

Patients with chronic spontaneous urticaria (CSU) are widely held to often have other autoimmune disorders, including autoimmune thyroid disease. Here, we systematically evaluated the literature on the prevalence of thyroid autoimmunity in CSU and vice versa. There is a strong link between CSU and elevated levels of IgG antithyroid autoantibodies (AAbs), with most of a large number of studies reporting rates of ≥10%. Levels of IgG against thyroid peroxidase (TPO) are more often elevated in CSU than those of other IgG antithyroid AAbs (strong evidence). Levels of IgG antithyroid AAbs are more often elevated in adult patients with CSU than in children (strong evidence). Patients with CSU exhibit significantly higher levels of IgG antithyroid AAbs (strong evidence) and IgE-anti-TPO (weak evidence) than controls. Elevated IgG antithyroid AAbs in CSU are linked to the use of glucocorticoids (weak evidence) but not to disease duration or severity/activity, gender, age, or ASST response (inconsistent evidence). Thyroid dysfunction rates are increased in patients with CSU (strong evidence). Hypothyroidism and Hashimoto's thyroiditis are more common than hyperthyroidism and Graves' disease (strong evidence). Thyroid dysfunction is more common in adult patients with CSU than in children (strong evidence) and in female than in male patients with CSU (weak evidence). Urticaria including CSU is more prevalent in patients with thyroid autoimmunity than in controls (weak evidence). CSU can improve in response to treatment with levothyroxine or other thyroid drugs (strong evidence). Pathogenic mechanisms in CSU patients with thyroid autoimmunity may include IgE against autoantigens, immune complexes, and complement.

Cholinergic urticaria (CholU) is a common condition in which active or passive warming leads to development of pinpoint wheals, flares and itch.To develop a standardized protocol for diagnosing CholU and measuring trigger thresholds, independent of patients' fitness levels.Ten CholU patients and matched healthy controls underwent pulse-controlled incremental ergometry for 30 min (stationary bicycle) increasing their pulse rate by 15 beats every 5 min. Non-invasive, heat-flux double-sensor and conventional electronic thermometers measured core and skin surface temperatures from which mean body temperature (MBT) was calculated. The time of onset of sweating (starch-iodine test) and symptoms (whealing) were recorded.All individuals completed the ergometry protocol without difficulty. All CholU patients but no controls developed wheals. The time to whealing correlated inversely with disease severity. In four patients MBT increased0.5°C and in two whealing occurred at a temperature lower than at the start of exercise. Onset of symptoms correlated with the time of sweating.Pulse-controlled ergometry is sensitive and specific for diagnosing CholU and investigating trigger thresholds and disease mechanisms. Our results refute the hypothesis that a rise in MBT is the critical trigger for CholU while sweating appears to have the central role.

Background Cholinergic urticaria (CholU), a frequent type of chronic inducible urticaria, presents with small itchy wheals upon physical exercise or passive warming. Omalizumab has been shown to be very effective in patients with chronic spontaneous urticaria. Whether or not omalizumab is also effective in CholU is largely unknown. Aim To assess the effectiveness of omalizumab treatment in CholU Method We assessed the effects of real life omalizumab treatment at standard and higher than standard doses in CholU patients including their time to response, the effects on concomitant urticaria forms and links to clinical features. Results Of 16 CholU patients treated with omalizumab, 11 (68%) reported a major or complete response, 2 patients reported a minor effect (13 %) and 3 patients (19%) showed no benefit. Omalizumab updosing led to complete response in 4 of 6 patients, who did not achieve controlled disease on standard dosed omalizumab therapy, i.e. 300 mg/4wks. Time to onset of benefit was fast, and concomitant urticaria forms showed similar response patterns. Treatment effects were linked to patient gender, with better responses in female patients (p Conclusion Omalizumab treatment is effective in the majority of CholU patients, especially in female patients. Most non-responders to standard-dosed omalizumab benefit from updosing. Our findings call for controlled clinical trials of omalizumab and other IgE-targeted treatments in CholU.

Cholinergic urticaria (CholU) is a frequent and often hard to treat disorder characterized by wheal and flare type reactions that occur in response to exercise and passive warming. Antihistamines are the first-line treatment, but are often not effective. Here, we report a 33-year-old male CholU patient who was able to engage in physical activities without suffering any symptoms for several hours following the intake of methantheliniumbromide, an anticholinergic agent that suppresses sweating. We confirmed this therapeutic response by pulse-controlled ergometry testing, which showed delayed sweating and markedly delayed and reduced whealing after methantheliniumbromide treatment. Our findings suggest that CholU patients may benefit from methantheliniumbromide treatment.

Background Atopic dermatitis (AD) is a common skin disorder. Its diagnosis relies on clinical judgment. Mild and untypical manifestations may cause diagnostic difficulties. Biomarkers for the differential diagnostic workup of AD are needed. Objective To test whether the results of skin provocation with cowhage, an established model of histamine-independent pruritus, and histamine are different in AD patients and healthy subjects and whether these tests may be used as diagnostic markers of AD. Methods Twenty-two AD patients and 18 healthy controls were subjected to topical cowhage provocation and skin prick testing with histamine and assessed for differences in the quality, intensity, and persistence of itch, for wheal diameter, volume, and flare size and intensity. Results Patients with AD, compared with healthy controls, exhibited significantly smaller histamine-induced flares (P < 0.01) and markedly longer itch persistence after provocation with cowhage (P < 0.01). Both parameters showed good diagnostic properties for AD (area under the receiver operating characteristic (ROC) curve 0.78 and 0.80, respectively). The persistence of cowhage-induced itch for at least 30 min and a histamine-induced flare of less than 2 cm in diameter were reliable thresholds for the diagnosis of AD. If combinations of the results of both tests were used, their sensitivity and specificity of diagnosing AD were up to 91% and 94%, respectively. Conclusion The clinical benefit of cowhage and histamine skin provocation tests should be investigated in further studies. Long persistence of cowhage-induced itch and diminished histamine-induced flare in nonlesional skin may support diagnosis of AD.

These recommendations for the definition, diagnosis and management of chronic inducible urticaria (CIndU) extend, revise and update our previous consensus report on physical urticarias and cholinergic urticaria (Allergy, 2009). The aim of these recommendations is to improve the diagnosis and management of patients with CIndU. Our recommendations acknowledge the latest changes in our understanding of CIndU, and the available therapeutic options, as well as the development of novel diagnostic tools. Dr. Borzova reports a sponsorship by Glaxo Smith Cline for the research in chronic spontaneous urticaria, outside the submitted work. Dr. Gim enez-Arnau reports grants and personal fees from Uriach Pharma, grants and personal fees from Novartis Pharma, grants from Intendis Bayer, personal fees and other from GSK, personal fees and other from Leo Pharma, grants and personal fees from Almirall, personal fees from Menarini, outside the submitted work. Dr. Grattan reports personal fees from Novartis, outside the submitted work. Dr. Magerl reports personal fees from Novartis, outside the submitted work, and is a scientific advisor of MOXIE GmbH. Dr. Maurer reports grants and personal fees from Novartis/Genentech, grants and personal fees from Uriach, grants and personal fees from FAES/Menarini, from Moxie, personal fees from MSD, outside the submitted work. Dr. Meshkova reports support for travel to meetings from Novartis Russia. Dr. Metz reports personal fees from Bayer, personal fees from Dr. R. Pfleger, personal fees from GSK, personal fees from Moxie, personal fees from Nerre, personal fees from Novartis, personal fees from Roche, personal fees from Sanofi, outside the submitted work. Dr. Zuberbier is consulting with the following companies: AnseIl, Bayer Schering, DST, FAES, Fujisawa, HAL, Henkel, Kryolan, Leti, Menarini, Merck, MSD, Novartis, Procter and Gamble, Ranbaxy, Sanofi-Aventis, Schering Plough, Stallergenes, Takeda, UCB.

Chronic urticaria (CU) is a group of common and debilitating conditions containing both chronic spontaneous urticaria (CSU) and chronic inducible urticarias (CIndU) including cold urticaria (ColdU) [1]. While antihistamines and omalizumab are effective treatments for both CSU and ColdU [2], many patients show insufficient response to either or both of these treatments [3], and additional and better therapies are needed [4]. This article is protected by copyright. All rights reserved.

Background Cold- and heat-induced urticaria are chronic physical urticaria conditions in which wheals, angioedema or both are evoked by skin exposure to cold and heat respectively. The diagnostic work up of both conditions should include skin provocation tests and accurate determination of critical temperature thresholds (CTT) for producing symptoms in order to be able to predict the potential risk that each individual patient faces and how this may be ameliorated by therapy. Objective To develop and validate TempTest® 4, a simple and relatively inexpensive instrument for the accurate determination of CTT which may be used in clinical practice. Methods TempTest® 4 has a single 2 mm wide 350 mm U-shaped Peltier element generating a temperature gradient from 4 °C to 44 °C along its length. Using a clear plastic guide placed over the skin after provocation, CTT values may be determined with an accuracy of ±1 °C. Here, TempTest® 4 was compared with its much more expensive predecessor, TempTest® 3, in inducing wheals in 30 cold urticaria patients. Results Both TempTest® 4 and TempTest® 3 induced wheals in all 30 patients between 8 ° and 28 °C. There was a highly significant (P

In physical urticaria, exogenous physical factors such as thermal triggers, solar radiation and mechanic triggers including friction or pressure are responsible for the elicitation of symptoms in the skin of patients. Avoidance of the respective stimulus is usually difficult or impossible, and many patients are not sufficiently treated with standard antihistamines. We report that treatment with omalizumab (Xolair®) of 7 patients with physical urticarias [solar urticaria (n = 2), urticaria factitia/symptomatic dermographism (n = 2), cold urticaria, delayed pressure urticaria and localized heat urticaria] resulted in complete symptom control within days after the first injection in 5 patients. In 1 patient, symptoms improved after increasing the dose of omalizumab, and 1 patient with localized heat urticaria did not respond significantly to treatment. Before anti-immunoglobulin E treatment, all patients had suffered from their physical urticaria for years and had had numerous unsuccessful therapies. The overall excellent responses to omalizumab treatment reported here indicate that anti-immunoglobulin E is a safe and effective treatment for recalcitrant physical urticarias.

Patients with chronic spontaneous urticaria, the most frequent non-acute form of urticaria, generally exhibit a clinical picture of persistent disease, a high degree of disease activity, considerable impairment of quality of life, and poor response to treatment. More than half of the patients continue to develop symptoms despite standard therapy with non-sedating antihistamines. In these cases, the antihistamine dose should be increased (up to four times the daily dose). If this approach also does not result in symptom control, the high-dose antihistamine should be combined with a leukotriene antagonist and if necessary an H2 blocker. If the patient does not respond to this combination therapy, cyclosporin A, dapsone, or omalizumab should be administered.

The onset of wheals and/or angioedema following the exposure to cold may be associated with a number of different diseases. Most frequently this occurs in cold contact urticaria, a type of physical urticaria, which is characterized by a positive cold stimulation test. The clinical symptoms are based on cold-dependent mast cell activation with subsequent release of proinflammatory mediators. In cases of negative or atypical reaction to cold stimulation testing rare acquired atypical or familiar cold urticaria forms may be suspected. Strict avoidance of cold should be recommended as far as possible. As the underlying causes of cold contact urticaria are widely unknown, the symptomatic use of non-sedating antihistamines is the treatment of first choice. The very rare familiar cold auto-inflammatory syndrome (FCAS) is based on CIAS1/NLRP3 mutations and may be treated effectively by neutralization of pathogenic interleukin 1β.

Chronic urticaria (CU) is one of the most frequent diseases in the field of dermatology. Recent studies have shown a point prevalence between 0.5 and 1% in the total population with a predominance of females. In general, all age groups and all classes of the population can be affected. An incidence peak has been found in the third and fourth decades. According to the current guidelines, CU is characterized by the spontaneous occurrence of wheals and/or angioedema for more than 6 weeks. However, epidemiological studies have revealed that the majority of patients suffer for several months, or frequently years. Disease duration is likely to be longer in case of angioedema, a combination with physical urticaria, positivity in the autologous serum skin test (autoreactivity) and a high disease severity. Studies on the impairment of quality of life have been shown that many CU patients suffer as strong from their disease as patients with coronary artery disease. Apart from pure physical symptoms, patients experience restrictions in daily life activities and social life. In addition, sleep disturbances are common and CU patients frequently exhibit psychiatric comorbidities. To avoid frustration in care, it is important to perceive all different dimensions of CU that impact the patient's life and to take the patients and their disease seriously. The aim of therapy should be to obtain total symptom control.

1. The antiarthritic and anti-inflammatory efficacy of N -acetyl- L -cysteine (NAC) was tested in male DBA/1 hybrid mice suffering from type II collagen–induced arthritis. Parameters including the arthritis index and the phagocytic responses recorded by chemiluminescence in unseparated blood were used for the assessment of disease activity. 2. Mice were immunized by subdermal injection of bovine type II collagen in Freund's complete adjuvant. The treatment with NAC started at day 42 after immunization and was continued over a period of six weeks: in doses ranging up to 50 mg/kg, a dose-dependent suppression of arthritis was noted; between 50 and 200 mg/kg, the inhibition curve had a plateau [ED 50 =50 mg/(kg × day)]. 3. The arthritis index correlated positively with the generation of chemiluminescence by reactive oxygen species (ROS) produced in neutrophils and monocytes activated by 12- O -tetradecanoylphorbol 13-acetate. 4. After treatment with 100 mg/kg of NAC from day 42 after immunization over a period of six weeks, the ROS production was reduced to levels occurring in whole blood of healthy animals. 5. It is concluded that low-molecular–weight antioxidants such as NAC may be adequate for controlling oxidative stress–derived damage in rheumatic diseases by modulation of ROS-dependent signal transduction pathways.

Background The most intriguing function attributed to interleukin-31 (IL-31) is its ability to induce pruritus in pathologic conditions, such as atopic dermatitis (AD). As of today, this feature of IL-31 was tested in vivo only in animal models. Methods Ten patients with AD and 10 healthy controls were challenged with IL-31 and NaCl (negative control) by skin prick testing. Twenty additional healthy controls were subjected to skin prick testing with histamine. Itch and local inflammatory responses of the skin were assessed for up to 72 h. Results All of the histamine-challenged subjects developed immediate pruritus (i.e. within the first 5 min). In contrast, only one IL-31- and two of the NaCl-challenged subjects reported immediate itch at the provocation site (short lasting, for 2–6 min). Nine subjects (five patients with AD) reported late itch responses to IL-31 challenges with a mean delay of 143 min. No subject reported late itch responses to histamine or NaCl testing. There was no significant difference in IL-31-induced itch start time, duration and intensity between patients with AD and healthy volunteers. Conclusion IL-31 does not induce immediate itch responses in humans. The late onset of IL-31-induced itch supports the notion that IL-31 exerts its pruritic effect indirectly via keratinocytes and secondary mediators, rather than through its receptors on cutaneous nerves.