IgM and IgA in addition to IgG autoantibodies against FcɛRIα are frequent and associated with disease markers of chronic spontaneous urticaria

Background IgG autoantibodies against the high-affinity IgE receptor, FcɛRIα, contribute the pathogenesis of autoimmune chronic spontaneous urticaria (CSU). However, it is not known whether such patients also exhibit IgM or IgA autoantibodies against FcɛRIα. To address this question we developed an ELISA to assess serum levels of IgG, IgM, and IgA autoantibodies against FcɛRIα 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 FcɛRIα. Results One in four CSU patients (8/35, 24%) had elevated serum levels of IgG-anti-FcɛRIα 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-FcɛRIα, but not of IgG or IgA against FcɛRIα, were linked to low blood basophil (r = .414,P = .021) and eosinophil (r = .623,P < .001) counts. Conclusions Increased serum levels of IgM-anti-FcɛRIα are common in patients with CSU and linked to features of autoimmune CSU. The role and relevance of autoantibodies to FcɛRIα in CSU can and should be further characterized in future studies, and our novel assay can help with this

Sensitization against skin resident fungi is associated with atopy in cholinergic urticaria patients

Background: Cholinergic urticaria (CholU) is a common type of chronic inducible urticaria, characterized by small itchy wheals that appear upon physical exercise or passive warming. Malassezia globosa, a skin resident fungus, has been identified as an antigen that induces mast cell/basophil degranulation and wheal formation through specific IgE, in Japanese patients with atopic dermatitis and CholU. In this study we aimed in assessing the rate of IgE sensitizations against skin resident fungi in European CholU patients. Methods: We assessed serum IgE levels to Malassezia furfur, Candida albicans and Trichophyton mentagrophytes using routine lab testing and Malassezia globosa using a newly established ELISA. We correlated the results to wheal formation and other clinical features. Results: Four patients (of 30 tested) had elevated levels of IgE against Malassezia furfur and Candida albicans and two had elevated levels of IgE against Trichophyton mentagrophytes. Four sera (of 25 tested) had elevated levels of IgE to the Malassezia globosa antigen supMGL_1304. Sensitization to one skin fungus was highly correlated with sensitization to the other tested fungi. We saw highly significant correlations of sensitization to supMGL_1304 with wheal size in the autologous sweat skin test (rs = 0.7, P = 0.002, n = 19), the Erlangen atopy score (rs = 0.5, P = 0.03, n = 19), total IgE serum levels (rs = 0.5, P = 0.04, n = 19) and a positive screen for IgE against common airborne/inhalant allergens s (sx1; rs = 0.54, P = 0.02, n = 19). Conclusions: Sensitization to skin resident fungi including Malassezia globosa is uncommon in European CholU patients, but is associated with atopy and pronounced wheal formation upon dermal contact with their own sweat.Trial registration German Clinical Trials Registry DRKS-ID: DRKS00004277

Impaired sweating in patients with cholinergic urticaria is linked to low expression of acetylcholine receptor CHRM3 and acetylcholine esterase in sweat glands

BackgroundCholinergic urticaria (CholU), a frequent form of chronic inducible urticaria, is characterized by itchy wheals and angioedema in response to sweating. As of now, the rate and pathophysiological relevance of impaired sweating in patients with CholU are ill-defined.AimTo assess in CholU patients the rate and extent of impaired sweating and its links to clinical and pathophysiological features of CholU.Patients and methodsWe assessed sweating in patients with CholU (n = 13) subjected to pulse-controlled ergometry (PCE) provocation testing. Pre- and post-PCE biopsies of lesional (L) and non-lesional (NL) skin were analyzed for the expression of acetylcholine receptor M3 (CHRM3) and acetylcholine esterase (ACh-E) by quantitative histomorphometry and compared to those of healthy control subjects (HCs). CholU patients were assessed for disease duration and severity as well as other clinical features.ResultsOf the 13 patients with CholU, 10 showed reduced sweating in response to PCE provocation, and 3 had severely reduced sweating. Reduced sweating was linked to long disease duration and high disease severity. CholU patients with impaired sweating responses showed reduced sweat gland epithelial expression of CHRM3 and ACh-E.ConclusionReduced sweating is common in CholU patients, especially in those with long-standing and severe disease, and it can be severe. Reduced expression of CHRM3 and ACh-E may be the cause or consequence of CholU in patients with impaired sweating, and this should be explored by further studies

Autologous serum skin test reactions in chronic spontaneous urticaria differ from heterologous cell reactions

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

What Basophil Testing Tells Us About CSU Patients – Results of the CORSA Study

Basophil testing is the most effective single approach for diagnosing type-IIb autoimmune chronic spontaneous urticaria (TIIbaiCSU). A positive basophil test has been linked to long disease duration, higher disease activity, a poor response to antihistamines and omalizumab, and a better response to cyclosporine and fenebrutinib. As of now it is unclear what other features are connected to a positive basophil test in chronic spontaneous urticaria (CSU). We aimed to identify features of basophil test-positive CSU patients. We performed a cross-sectional study of 85 CSU patients. Basophil testing was done with the basophil activation test (BAT) and the basophil histamine release assay (BHRA). Data were analysed using SPSS: Student's t-test, Chi-square test, Odds Ratio, Spearman's correlation test. Of 85 CSU patients, 44% and 28% tested positive with the BAT and BHRA, respectively. These patients showed higher disease activity and impact, lower levels of disease control and total serum IgE, as well as higher rates of having a positive autologous serum skin test (ASST), angioedema, nocturnal symptoms, symptoms for >5 days/week, and thyroid autoantibodies. The ASST, by itself, was not a good predictor of basophil test results, but it predicted a positive basophil test in up to 100% of cases when combined with angioedema, thyroid autoantibodies or low IgE. In conclusion, a positive basophil test is linked to known features of TIIbaiCSU and novel characteristics including nocturnal symptoms. Further studies on basophil test-positive and -negative CSU patients can help to better understand CSU endotypes and to develop better management approaches

IgE Mediated Autoallergy against Thyroid Peroxidase – A Novel Pathomechanism of Chronic Spontaneous Urticaria?

Chronic spontaneous urticaria (csU), which is characterized by recurrent episodes of mast cell-driven wheal and flare-type skin reactions, is often associated with elevated total IgE levels and thyroid autoimmunity. We speculate that some csU patients express IgE autoantibodies against thyroid antigens such as thyroid peroxidase (TPO), which could bind to skin mast cells and induce their activation.We developed and used a site-directed human IgE capture ELISA to quantify IgE-anti-TPO. We used this assay and investigated csU patients (n = 478) and healthy control subjects (n = 127) for IgE-anti-TPO and then assessed IgE-anti-TPO-positive and -negative csU patients for clinical and serological differences. ( = 61%, IgE-anti-TPO: median 6.67, interquartile range 5.39–8.24). IgE-anti-TPO-positive and -negative csU patients had very similar distributions of age and gender as well as disease activity and duration. IgE-anti-TPO-positive csU patients exhibited significantly higher IgG-anti-TPO levels and lymphocyte counts as well as decreased C4 complement levels.Our findings show that a sizeable subgroup of csU patients expresses IgE antibodies against thyroid peroxidase. These autoantibodies could cause “autoallergic” mast cell activation, a novel pathomechanism of chronic spontaneous urticaria

Risk factors for systemic reactions in typical cold urticaria: Results from the COLD‐CE study

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® 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

The global impact of the COVID-19 pandemic on the management and course of chronic urticaria

Introduction: The COVID-19 pandemic dramatically disrupts health care around the globe. The impact of the pandemic on chronic urticaria (CU) and its management are largely unknown. Aim: To understand how CU patients are affected by the COVID-19 pandemic; how specialists alter CU patient management; and the course of CU in patients with COVID-19. Materials and Methods: Our cross-sectional, international, questionnaire-based, multicenter UCARE COVID-CU study assessed the impact of the pandemic on patient consultations, remote treatment, changes in medications, and clinical consequences. Results: The COVID-19 pandemic severely impairs CU patient care, with less than 50% of the weekly numbers of patients treated as compared to before the pandemic. Reduced patient referrals and clinic hours were the major reasons. Almost half of responding UCARE physicians were involved in COVID-19 patient care, which negatively impacted on the care of urticaria patients. The rate of face-to-face consultations decreased by 62%, from 90% to less than half, whereas the rate of remote consultations increased by more than 600%, from one in 10 to more than two thirds. Cyclosporine and systemic corticosteroids, but not antihistamines or omalizumab, are used less during the pandemic. CU does not affect the course of COVID-19, but COVID-19 results in CU exacerbation in one of three patients, with higher rates in patients with severe COVID-19. Conclusions: The COVID-19 pandemic brings major changes and challenges for CU patients and their physicians. The long-term consequences of these changes, especially the increased use of remote consultations, require careful evaluation

Monitoring of interleukin-31 in chronic spontaneous urticaria patients during the treatment with Omalizumab

Die chronische spontane Urtikaria (CSU) ist eine der häufigsten dermatologischen Erkrankungen. Sie ist durch die klinischen Symptome wiederkehrende juckende Quaddeln und Angioödeme gekennzeichnet. Die vorliegende Arbeit hatte zum Ziel, Interleukin-31 (IL-31) als therapeutischen Biomarker für die Therapie mit Omalizumab in Patienten mit CSU zu untersuchen. Hierfür wurden drei unabhängige Studien durchgeführt. Zunächst wurde die Wirksamkeit der Therapie mit Omalizumab bei CSU Patienten im Rahmen einer placebokontrollierten Studie klinisch monitoriert, aus der sich die Fragestellung nach objektivierbaren Biomarkern für das Therapieansprechend ergab. In der zweiten Studie wurde untersucht, ob IL-31 als Biomarker in Frage kommt und die biologische Relevanz von IL-31 im Prick-Test untersucht und die resultierende Hautreaktion und der Juckreiz erfasst. In der letzten Studie wurde IL-31 als therapeutischer Biomarker retrospektiv in der erstgenannten Studie untersucht. Hier wurde die Veränderung der IL-31 Spiegel in den Seren der Omalizumab- oder placebobehandelten CSU Patienten monitoriert, mit den klinischen Daten korreliert und die Eignung von IL-31 als therapeutischer Biomarker untersucht. Zusammengefasst zeigte die erste Studie, dass es bei CSU Patienten durch Omalizumab, jedoch nicht durch Placebo, zu einem statistisch signifikanten (p=0,0089) Rückgang des Beschwerdescores UAS7 (-17,8) kam. Zwei Drittel der Patienten waren sogar komplett frei von Hauterscheinungen. In der zweiten Studie konnte erstmalig gezeigt werden, dass IL-31 beim Menschen mit einer zeitlichen Verzögerung von durchschnittlich 143 Minuten Juckreiz induziert und somit als biologisch relevanter Biomarker in Frage kommt. In der letzten Studie konnte schlussendlich gezeigt werden, dass das klinische Ansprechen auf Omalizumab in der ersten Studie mit einer statistisch signifikanten Reduktion der IL-31 Serumspiegel (-48%; p=0,004) einherging. Insgesamt zeigt die vorliegende Arbeit, dass IL-31 ein geeigneter Biomarker für das Monitoring des therapeutischen Ansprechens auf Omalizumab ist. Außerdem zeigt IL-31 einen interessanten Angriffspunkt in der Pathogenese der CSU auf, der sowohl für das Verständnis der Pathogenese der CSU und hier im Besonderen des Juckreizes wichtig ist, als auch als möglicher therapeutischer Angriffspunkt bei der CSU und anderen juckenden Hauterkrankungen dienen könnte.Chronic spontaneous urticaria (CSU) is among the most frequent dermatological diseases. It is characterized by recurrent itchy wheal and flare type skin reactions and angioedema. The overall aim was to investigate interleukin-31 (IL-31) as therapeutic biomarker during the treatment of CSU patients with Omalizumab. To achieve this goal, three independent studies were performed. In the first study, CSU patients were treated with Omalizumab, a therapeutic anti-IgE antibody, and the clinical improvement was monitored. This study raised the question for an objective therapeutic biomarker. In the second study, IL-31, a potential biomarker for CSU, was investigated for its biologic activity and relevance regarding itch induction and sustainment. In the last retrospective study, the potential suitability of IL-31 as a therapeutic biomarker in CSU was investigated. Here, IL-31 was retrospectively analyzed from serum samples of CSU patients of the first study and correlated with their clinical data. In brief, the first study showed that Omalizumab, but not placebo, significantly (p=0.0089) reduced the urticaria symptom score UAS7 (-17.8). Two thirds of the CSU patients were even completely free of symptoms. The second study demonstrated for the first time that IL-31 induces a delayed itch after 143 minutes in humans. The last study exhibited that the improvement of the clinical scores in the first study was linked to a significant reduction (-48%; p=0.004) of IL-31 levels in the serum. Non- responder or placebo treated patients had no changes of their IL-31 levels. In summary, IL-31 may be an appropriate therapeutic biomarker for the monitoring of the therapeutic response of CSU patients to Omalizumab. Furthermore, IL-31 could play an important role in the pathophysiology of CSU and appears to be an interesting target for new therapeutic treatment options