Omalizumab is effective and safe in chronic inducible urticaria (CIndU): Real-world data from a large multi-national UCARE study.

BACKGROUND: Long-term data on the effectiveness and safety of omalizumab for chronic inducible urticaria (CIndU) in large populations are lacking. OBJECTIVE: To evaluate the effectiveness, safety, estimated omalizumab treatment duration and its predictors, as well as differences between CIndU subtypes, in a large long-term CIndU cohort. METHODS: A multinational multicenter study was conducted at 14 specialized urticaria centres (UCAREs), including all CIndU patients ever treated with omalizumab from 2009 until July 2022. Kaplan-Meier survival and regression analyses were performed. RESULTS: Across 234 CIndU patients (55% female; mean age 37 years), 76% (n = 178) had standalone CIndU and 24% (n = 56) had predominant CIndU plus minor CSU, with an observation period up to 13 years. Most CIndU patients (73%, n = 145/200 with available data on response) had complete/good response to omalizumab treatment, without significant differences between CIndU subtypes. Sixty-two (26%) patients discontinued omalizumab; due to well-controlled disease (47%, n = 29), ineffectiveness (34%, n = 21), side effects (3%, n = 2), combination of ineffectiveness and side effects (3%, n = 2) and other reasons (13%, n = 8). The median estimated omalizumab treatment duration exceeded 5 years (54% drug survival at 5 years) and was mostly determined by well-controlled disease. Higher age predicted a lower chance to discontinue omalizumab due to well-controlled disease (HR 0.969, 95%CI 0.945-0.995). CIndU subtype and presence of minor CSU were not related to response and time until omalizumab discontinuation for any reason. CONCLUSION: Omalizumab is highly effective and safe in CIndU patients, with long estimated treatment duration mainly reflecting long disease duration. Our data show omalizumab's high potential as treatment in any subtype of CIndU and support its clinical use for these patients.

A comparative analysis of chronic inducible urticaria in 423 patients: Clinical and laboratory features and comorbid conditions.

BACKGROUND: Chronic inducible urticaria (CIndU) is a subtype of chronic urticaria (CU) which require specific physical or non-physical triggers to occur. They may be isolated or may coexist with chronic spontaneous urticaria (CSU). Despite their frequent appearance in dermatology clinics, there is scarce information on the distinguishing features among the most common subtypes of CIndU as well as isolated CIndU versus CSU plus CIndU. OBJECTIVES: To compare clinical and laboratory characteristics, and comorbid conditions among the most common CIndU types and isolated CIndU versus CSU plus CIndU. METHODS: We retrospectively analysed CIndU patients and compared patients' demographic, clinical and laboratory characteristics across isolated CIndU, CSU plus CIndU, symptomatic dermographism (SD), cold urticaria (ColdU) and cholinergic urticaria (ChoU). RESULTS: A total of 423 patients (~70% isolated CIndU, ~30% CSU plus CIndU, ~5% mixed CIndU subtypes) were included in the study. The most frequent CIndU subtypes were SD (68.6%; 290/423), ColdU (11.4%; 48/423) and ChoU (10.9%; 46/423). Isolated CIndU patients were younger than CSU plus CIndU (33.74 ± 12.72 vs. 37.06 ± 11.84, p = 0.010). Angioedema, emergency referrals, need for systemic steroids, comorbid systemic disorders were more frequent and baseline urticaria control test scores were lower in CSU plus CIndU patients (vs. CIndU, p < 0.001, p = 0.008, p < 0.001, p = 0.031, p = 0.036, respectively). Among CIndU subtypes, ChoU patients were younger (24.9 ± 12.2 vs. 34.47 ± 12.12 vs. 31.38 ± 14.95; p < 0.001) and had male predominance (p < 0.001) while SD patients had no angioedema (p < 0.001) and had higher frequency of increased total IgE levels (p = 0.006). CONCLUSIONS: Isolated CIndU and CSU plus CIndU seems to be different endotypes of CU where CSU plus CIndU presents a more severe and refractory course. There are distinctive features of each CIndU subtype. These suggest involvement of different pathomechanistic pathways in these subtypes that need to be clarified in future studies.

Quality of life measurement in urticaria: Position statement of the European Academy of Dermatology and Venereology Task Forces on Quality of Life and Patient-Oriented Outcomes and Urticaria and Angioedema.

The European Academy of Dermatology and Venereology (EADV) Task Forces on quality of life (QoL) and patient-oriented outcomes and on urticaria and angioedema recommendations for the assessment of Health-related (HR) QoL in all patients with urticaria in research and practice are as follows: to use the DLQI for adults and the CDLQI for children as dermatology-specific and the CU-Q2oL as a disease-specific HRQoL instruments in urticaria; to use generic instruments to provide comparison of data on urticaria with non-dermatologic diseases, or to compare with healthy volunteers or the general population; to select validated HRQoL instruments with appropriate age limits; to present exact numeric data for HRQoL results; correct title of any HRQoL instrument should be used, along with its correct abbreviation and the reference to its original publication, where possible. The EADV TFs discourage the use of non-validated HRQoL instruments and modified HRQoL instruments that have not undergone standard validation.

D-dimer levels decline after immunosuppressive treatment rather than anticoagulant treatment in severe autoimmune chronic spontaneous urticaria.

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

The global burden of chronic urticaria for the patient and society.

Chronic urticaria (CU) affects about 1% of the world population of all ages, mostly young and middle-aged women. It usually lasts for several years (> 1 year in 25-75% of patients) and often takes > 1 year before effective management is implemented. It presents as chronic spontaneous urticaria (CSU), chronic inducible urticaria (CIndU) or both in the same person. More than 25% of cases are resistant to H1 -antihistamines, even at higher doses, and third- and fourth-line therapies (omalizumab and ciclosporin) control the disease only in two-thirds of H1 -antihistamine-resistant patients. Here we review the impact of CU on different aspects of patients' quality of life and the burden of this chronic disease for the patient and society. CU may have a strong impact on health-related quality of life (HRQoL), particularly when CSU is associated with angio-oedema and/or CIndU (Dermatology Life Quality Index > 10 in 30% of patients). Comorbidities, such as anxiety and depression, which are present in more than 30% of patients with CSU, compound HRQoL impairment. Severe pruritus and the unpredictable occurrence of weals and angio-oedema are responsible for sleep disorders; sexual dysfunction; limitations on daily life, work and sports activities; interfering with life within the family and in society; and patients' performance at school and work (6% absenteeism and 25% presenteeism). Apart from treatment costs, with annual values between 900 and 2400 purchasing power parity dollars (PPP$) in Europe and the USA, CU is associated with a high consumption of medical resources and other indirect costs, which may reach a total annual cost of PPP$ 15 550.

25-hydroxyvitamin D levels are low but not associated with disease activity in chronic spontaneous urticaria and depression.

AIM: To evaluate vitamin D levels in patients with chronic spontaneous urticaria (CSU), depression and both of them, thus to find out whether vitamin D may be a common causative factor of CSU and depression. METHODS: Thirty patients with CSU, 30 patients with depression, 30 patients with both CSU and depression and 30 healthy volunteers as control group were involved in the study. Serum 25-hydroxyvitamin D (25(OH)D) levels of these groups were measured and compared. Correlations between 25(OH)D levels and the activity of CSU and depression were analyzed. RESULTS: Healthy controls' 25(OH)D levels (17.2±8.8 ng/mL) were higher than patients with CSU (9.1±5.1 ng/mL), depression (8.9±6.1 ng/mL) and CSU with depression (7.7±4.7 ng/mL) (p<0.001, p<0.001 and p<0.001, respectively). There were no differences in 25(OH)D levels between CSU patients with and without depression, between depression patients and CSU patients with and without depression (p=0.43, p=0.82 and p=0.92, respectively). There were no correlations between 25(OH)D levels and the activity of CSU or depression (p=0.99 and p=0.76, respectively). CONCLUSION: Lower 25(OH)D levels in CSU and/or depression may appear as a secondary phenomenon, which means being result of these diseases rather than the cause (Tab. 1, Fig. 2, Ref. 41). Text in PDFwww.elis.sk Keywords: vitamin D, vitamin D deficiency, chronic urticaria, depression.

Immunological effects and potential mechanisms of action of autologous serum therapy in chronic spontaneous urticaria.

BACKGROUND: Autoimmune processes are considered to play a major role in the pathogenesis of chronic spontaneous urticaria (CSU). Very recently, interleukin 24 (IL-24) has been identified as an immunoglobulin E (IgE) autoantigen in CSU. Some studies revealed that notably autologous serum skin test (ASST)-positive CSU patients may benefit from autohemotherapy; however, the mechanisms of action remain unknown. We aimed to investigate the immunological effects of autologous serum injections in ASST-positive CSU patients. METHODS: Sixty-six ASST-positive CSU patients were treated with weekly intramuscular autologous serum injections for 8 weeks and followed up for 12 weeks. Urticaria activity score (UAS7) and Dermatology Life Quality Index (DLQI) were assessed. The ASST was done at baseline, week 9 and week 21. Serum samples (baseline, weeks 9, 13 and/or 21) were analysed for the levels of IgE-anti-IL-24 and immunoglobulin G (IgG)-anti-IL-24 via ELISA and their ability to release histamine in basophils [basophil histamine release assay (BHRA)]. RESULTS: Autologous serum therapy resulted in a substantial improvement in disease activity and quality of life after 8 and 20 weeks. Twenty-eight percent and 34% of patients turned ASST-negative in weeks 9 and 21, respectively, but there was no link between their response to treatment and changes of ASST results. Also, no significant or relevant changes in BHRA were observed. In contrast, autologous serum therapy significantly decreased IgE-anti-IL-24 serum levels, but not IgG-anti-IL-24 serum levels, in responders but not in non-responders. CONCLUSIONS: Our findings suggest that the immunological effects of autologous serum therapy include a reduction in IgE-anti-IL24 autoantibodies, which may contribute to the pathogenesis of CSU.

The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria.

This evidence- and consensus-based guideline was developed following the methods recommended by Cochrane and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group. The conference was held on 1 December 2016. It is a joint initiative of the Dermatology Section of the European Academy of Allergology and Clinical Immunology (EAACI), the EU-founded network of excellence, the Global Allergy and Asthma European Network (GA²LEN), the European Dermatology Forum (EDF) and the World Allergy Organization (WAO) with the participation of 48 delegates of 42 national and international societies. This guideline was acknowledged and accepted by the European Union of Medical Specialists (UEMS). Urticaria is a frequent, mast cell-driven disease, presenting with wheals, angioedema, or both. The lifetime prevalence for acute urticaria is approximately 20%. Chronic spontaneous urticaria and other chronic forms of urticaria are disabling, impair quality of life and affect performance at work and school. This guideline covers the definition and classification of urticaria, taking into account the recent progress in identifying its causes, eliciting factors and pathomechanisms. In addition, it outlines evidence-based diagnostic and therapeutic approaches for the different subtypes of urticaria.

Brooke-Spiegler syndrome: focus on reflectance confocal microscopy findings of trichoepithelioma and flat cylindroma.

Brooke-Spiegler syndrome (BSS) is a rare, autosomal dominant disorder characterized by multiple adnexal tumours, especially trichoepitheliomas, cylindromas and occasionally spiradenomas. These lesions usually begin to appear in the second or third decade of life. Malignant transformation of pre-existing tumours may occur. In vivo reflectance-mode confocal microscopy (RCM) is a noninvasive method that can be used to visualize the epidermis and the upper dermis at almost histological resolution. It has been used to evaluate several skin conditions, especially malignant lesions, and has been reported to be useful for differentiating between malignant and benign skin tumours. Only a few studies have reported on the use of confocal microscopy to characterize the features of benign adnexal neoplasms. We present a patient with BSS who presented to our clinic with multiple skin tumours. The possible utility of RCM for identifying adnexal neoplasms is emphasized in this report, which also describes the observed microscopic features.

Definition, aims, and implementation of GA(2) LEN Urticaria Centers of Reference and Excellence.

BACKGROUND: GA²LEN, the Global Allergy and Asthma European Network, has recently launched a program for the development, interaction, and accreditation of centers of reference and excellence in special areas of allergy embedded in its overall quality management of allergy centers of excellence. The first area chosen is urticaria. Urticaria is a common and debilitating condition and can be a challenge for both patients and treating physicians, especially when chronic. Centers of reference and excellence in urticaria (UCAREs) can help to improve the management of hard-to-treat conditions such as urticaria. AIMS: Here, we describe the aims, the requirements and deliverables, the application process, and the audit and accreditation protocol for GA²LEN UCAREs. RESULTS: The main aims of GA²LEN UCAREs are to provide excellence in urticaria management, to increase the knowledge of urticaria by research and education, and to promote the awareness of urticaria by advocacy activities. To become a certified GA²LEN UCARE, urticaria centers have to apply and fulfill 32 requirements, defined by specific deliverables that are assessed during an audit visit. DISCUSSION AND CONCLUSION: The GA²LEN UCARE program will result in a strong network of urticaria specialists, promote urticaria research, and harmonize and improve urticaria management globally.

Recommendations for assessing patient-reported outcomes and health-related quality of life in patients with urticaria: a GA(2) LEN taskforce position paper.

The aim of this Global Allergy and Asthma European Network (GA(2)LEN) consensus report is to provide recommendations and suggestions for assessing patient-reported outcomes (PROs) including health-related quality of life in patients with urticaria. We recommend that PROs should be used both in clinical trials and routine practice for the evaluation of urticaria patients. We suggest that PROs should be considered as the primary outcome of future clinical trials. Two validated and disease-specific instruments for assessing PROs are available, the urticaria activity score (for symptoms) and the chronic urticaria questionnaire on quality of life CU-Q(2)oL. This latter tool, CU-Q(2)oL, is available in many languages and should be preferred, where available, over more generic instruments for assessing urticaria-specific effects on quality of life. CU-Q(2)oL is only suited for the investigation of patients with chronic spontaneous urticaria. Similar instruments for other forms of urticaria have yet to be developed and validated. Also, tools for assessing other chronic spontaneous urticaria PROs besides quality of life and symptoms are needed.

Ear, nose and throat involvement in patients with pemphigus vulgaris: correlation with severity, phenotype and disease activity.

BACKGROUND: Pemphigus vulgaris (PV) is the most common clinical form of pemphigus that is characterized by easily ruptured or loose bulla formation on skin and/or mucosa. The frequency of the ear, nose and throat involvement of PV is not clearly defined. OBJECTIVES: To evaluate the frequency of ear, nose and throat (ENT) involvement in patients suffering from PV who had been recently diagnosed or exacerbated under follow up and to determine the association with ENT symptoms, clinical involvement, severity and duration of pemphigus vulgaris. MATERIALS AND METHODS: The study group included a total of 38 PV patients comprising 24 new patients and 14 patients who showed exacerbations while on complete remission or under treatment. All patients were asked about ENT symptoms and endoscopic examination were performed to evaluate the presence of nasal, pharynx, larynx and ear involvement. RESULTS: Of the 38 patients, 33 (87%) had active PV lesions on endoscopic evaluation. Twenty-five patients (66%) had lesions on pharynx, twenty-one (55%) on larynx, twenty-nine (76%) on nasal mucosa and four (10%) on the ear mucosa. ENT involvement was not associated with the severity and the clinical involvement of the disease. Pharyngeal and nasal involvement was significantly associated with symptoms, while laryngeal and ear involvement was not found to be significantly associated with symptoms. Nasal and ear involvement was not associated with the duration of the disease while pharyngeal and laryngeal involvement favored newly diagnosed patients. CONCLUSIONS: Our results revealed that high number of patients with PV may present with active ENT lesions, furthermore patients with ear, nose and throat involvement may be asymptomatic and active lesions may be found in patients without any ENT symptoms. Therefore it should be considered that to understand the real extent of PV involvement, endoscopic ENT evaluation should be performed in patients with or without symptoms.

Microalbuminuria as an early marker of renal involvement in Behcet's disease: it is associated with neurological involvement and duration of the disease.

BACKGROUND: Despite its nature as a systemic vasculitis, renal involvement is known to occur infrequently in Behçet's Disease (BD). OBJECTIVES: Our aim was to investigate proteinuria, microhematuria and microalbuminuria in 24-h urine and evaluate subclinical or symptomatic renal involvement in BD patients. METHODS: Two hundred and eleven patients who fulfilled the International Behçet's Disease criteria were included in the study. After urine analysis, five of 12 patients who were found to have proteinuria underwent renal biopsy, while 199 patients without proteinuria were investigated for microalbuminuria (MA). RESULTS: A total of 34 (16.1%) patients were found to have renal involvement including 22 (11.1%) with MA and 12 with proteinuria (5.6%). Renal biopsies resulted as focal glomerulosclerosis in three, membranous glomerulosclerosis in one and secondary amyloidosis in two patients. Neurological involvement was found to be significantly more prevalent in patients with MA (P < 0.01). Neurological involvement and duration of disease (> or = 10 years) was found to increase the risk for MA by 21.75-fold and 5.03-fold, respectively. Though age over 40 years, thrombophlebitis, HLA B51 haplotype and ophthalmological involvement were not found to be significantly associated with MA; these parameters increased the risk for MA. CONCLUSIONS: Renal involvement may be more prevalent in BD than it has been recognized; it usually presents with asymptomatic microhematuria, proteinuria and/or microalbuminuria; therefore clinicians must check 24-h urine for the presence of proteinuria, microhematuria and microalbuminuria; especially in patients who are aged over 40 years, have a longer duration of the disease and multisystem involvement.

Adaptation and initial results of the Polish version of the GA(2)LEN chronic urticaria quality of life questionnaire (CU-Q(2)oL).

BACKGROUND: Strong negative influence upon the quality of life in chronic urticaria is well proved. Before the GA(2)LEN Chronic Urticaria Quality of Life Questionnaire (CU-Q(2)oL) was introduced, the quality of life in chronic urticaria had been measured with general or dermatology specific questionnaires. CU-Q(2)oL was initially developed in Italy and consisted of 23 items divided into 6 quality of life dimensions. OBJECTIVE: The aim of our study was to adapt the Polish version of CU-Q(2)oL and to provide initial results from the Polish sample. METHODS: To prepare the Polish version forward and back translation was prepared. After cognitive debriefing, we collected a group of 126 chronic urticaria patients who completed Polish CU-Q(2)oL, Dermatology Life Quality Index (DLQI) and Skindex-29 questionnaire. Disease severity was assessed with Urticaria Activity Score (UAS). We performed the factorial analysis to identify CU-Q(2)oL subscales in our study, internal consistency and convergent validity assessment as well as factors driving the results. Moreover, we analysed tool's reproducibility and responsiveness. RESULTS: The factor analysis resulted in six subscales of Polish CU-Q(2)oL version with satisfying face validity: Itching, Swelling/Mental status, Functioning, Sleep, Eating/Limits, Embarrassment. All subscales presented recommended internal consistency and convergent validity. Disease severity was the only factor predicting results of all the subscales. Polish CU-Q(2)oL version was reproducible and sensitive to change. We noticed the highest quality of life impairment in Itching and Embarrassment subscales whereas Eating/Limits was the least affected. CONCLUSIONS: Our study supports reliability, responsiveness and validity of the Polish version of CU-Q(2)oL - easy in use, non time-consuming instrument to be used in research, clinical management and treatment outcome assessment and is one more step to confirm quality of life impairment in chronic urticaria.