Unveiling Treatment Response Predictors in Predominant Subtypes of Chronic Inducible Urticaria.

INTRODUCTION: Chronic inducible urticaria (CIndU) is a subtype of chronic urticaria (CU), which requires specific triggers to occur. Despite their common occurrence, treatment response rates and predictors of treatment responses are largely lacking in the literature. This study evaluates antihistamine (AH) and omalizumab response rates in the most common CIndU subtypes and examines whether certain features can predict treatment responses. METHODS: We retrospectively analyzed CU patients with at least one CIndU subtype and performed comparisons between subgroups, in a total of 423 patients (70% CIndU, 30% chronic spontaneous urticaria [CSU] plus CIndU). RESULTS: The treatment response rates in CIndU were 51.6%, 51.5%, and 86.5% with standard-dose second-generation H1-antihistamines (sgAHs), updosed/combined sgAH, and omalizumab, respectively. Overall AH response was higher in CIndU than CSU plus CIndU (78.3% vs. 62%, p = 0.002) and in symptomatic dermographism (SD) and cold urticaria (ColdU) than cholinergic urticaria (ChoU) (83.2% vs. 78.3 vs. 60.9%, p = 0.04). AH-refractory patients had a longer disease duration (45.2 ± 56.7 months vs. 37 ± 51.9 months, p = 0.04), more angioedema, accompanying CSU, mixed CIndU subtypes (37.5% vs. 21.1%, p = 0.003; 45.1% vs. 27.1%, p = 0.002; 8.8% vs. 2.4%, p = 0.014), and lower baseline urticaria control test scores (5.86 ± 3.3 vs. 8.6 ± 3.6, p < 0.001) than AH-responsive patients. CONCLUSION: CIndU exhibits a good response to both AHs and omalizumab. Notably, the response to AHs is more pronounced in SD and ColdU compared to ChoU. Disease duration, angioedema, accompanying CSU, mixed CIndU, and lower baseline UCT scores may be used to predict AH treatment outcome in CIndU.

Chronic Inducible Urticaria.

Chronic inducible urticaria (CIndU) is characterized by the appearance of hives (urticaria) and/or angioedema in response to specific triggers or stimuli. For accurate diagnosis, anamnesis-driven specific, and if available, standardized trigger testings, as well as patient reported outcomes, should be applied. The currently recommended treatment algorithm is the same as for chronic spontaneous urticaria but is largely off-label for CIndU. New, and possibly more disease-specific, treatment options are needed for CIndU patients, who are often severely impacted by their disease. Several clinical trials are currently ongoing.

Acetylcholinesterase is regulated by exposure of ultraviolet B in skin keratinocytes: A potential inducer of cholinergic urticaria.

Cholinergic urticaria is a dermatological disease characterized by the presence of large patches of red skin and transient hives triggered by factors, such as exercise, sweating, and psychological tension. This skin problem is hypothesized to be attributed to a reduced expression of acetylcholinesterase (AChE), an enzyme responsible for hydrolyzing acetylcholine (ACh). Consequently, ACh is thought to the leak from sympathetic nerves to skin epidermis. The redundant ACh stimulates the mast cells to release histamine, triggering immune responses in skin. Here, the exposure of ultraviolet B in skin suppressed the expression of AChE in keratinocytes, both in in vivo and in vitro models. The decrease of the enzyme was resulted from a declined transcription of ACHE gene mediated by micro-RNAs, that is, miR-132 and miR-212. The levels of miR-132 and miR-212 were markedly induced by exposure to ultraviolet B, which subsequently suppressed the transcriptional rate of ACHE. In the presence of low level of AChE, the overflow ACh caused the pro-inflammatory responses in skin epidermis, including increased secretion of cytokines and COX-2. These findings suggest that ultraviolet B exposure is one of the factors contributing to cholinergic urticaria in skin.

Altered Sweat Composition Due to Changes in Tight Junction Expression of Sweat Glands in Cholinergic Urticaria Patients.

In cholinergic urticaria (CholU), small, itchy wheals are induced by exercise or passive warming and reduced sweating has been reported. Despite the described reduced muscarinic receptor expression, sweat duct obstruction, or sweat allergy, the underlying pathomechanisms are not well understood. To gain further insights, we collected skin biopsies before and after pulse-controlled ergometry and sweat after sauna provocation from CholU patients as well as healthy controls. CholU patients displayed partially severely reduced local sweating, yet total sweat volume was unaltered. However, sweat electrolyte composition was altered, with increased K+ concentration in CholU patients. Formalin-fixed, paraffin-embedded biopsies were stained to explore sweat leakage and tight junction protein expression. Dermcidin staining was not found outside the sweat glands. In the secretory coils of sweat glands, the distribution of claudin-3 and -10b as well as occludin was altered, but the zonula occludens-1 location was unchanged. In all, dermcidin and tight junction protein staining suggests an intact barrier with reduced sweat production capability in CholU patients. For future studies, an ex vivo skin model for quantification of sweat secretion was established, in which sweat secretion could be pharmacologically stimulated or blocked. This ex vivo model will be used to further investigate sweat gland function in CholU patients and decipher the underlying pathomechanism(s).

General anesthetic management in two patients with an anaphylaxis history cholinergic urticaria.

BACKGROUND: Cholinergic urticaria is triggered by an increased body temperature after exercise, passive warming, or emotional stresses. The anesthetic management used for two patients with an anaphylaxis history after cholinergic urticaria is described. CASE PRESENTATION: Patient 1: A 34-year-old female was scheduled for a right-side thyroidectomy. At 27 years old, she experienced post-exercise anaphylaxis and repeated episodes of hives following exercise, sunbathing, mental stresses, and the consumption of spicy foods. Patient 2: A 35-year-old female was scheduled for a laparoscopic ovarian cystectomy. At 19 years old, she experienced anaphylaxis after a long bath and then hives after hot showers, bicycle riding, and long walks. For both patients, intraoperative passive warming was not performed to prevent excessive warming, and prophylactic antiemetics and multimodal analgesia were used to minimize their perioperative stresses. CONCLUSION: Careful anesthetic management is necessary to prevent anaphylaxis during anesthesia in a patient with a history of cholinergic urticaria.

Development and application of clinical assessment tools for cholinergic urticaria / 中华皮肤科杂志

This review comprehensively summarizes clinical assessment tools which have been developed and validated for cholinergic urticaria (CholU) , involving diagnosis and severity assessment of CholU, assessment of patients′ quality of life, and assessment of disease control. The application methods and status of relevant tools in clinical practice are introduced in detail.

Disease Impact, Diagnostic Delay, and Unmet Medical Needs of Patients With Cholinergic Urticaria in German-Speaking Countries.

Background: Cholinergic urticaria (CholU) is a common type of chronic inducible urticaria. Little is known about the burden of the disease and its unmet medical needs. Aim: To characterize the unmet medical needs of patients with CholU. Methods: Patients with CholU (n = 111) took part in a German online survey that assessed their symptoms, diagnostic delay, impact on daily life, quality of life (QoL), and their experience with physician care. Results: Virtually all patients reported typical signs and symptoms of CholU, i.e., whealing (93.7%) and itching (91.9%), in response to typical trigger situations, such as physical activity, passive warming, or stress. Despite this, patients reported a marked diagnostic delay of 30.2 months (range from 0 to 279 months). Only 38% of the patients received a blood examination, and only 16% underwent provocation testing for diagnosing CholU, as recommended by the international guidelines. Physician contacts were common, but patient satisfaction with their disease management was low. In total, 90.1% of the patients stated to have an uncontrolled disease, resulting in a strong impact on their everyday activities, sleep, and QoL. Conclusion: Patients with CholU exhibit many important unmet needs, and improvement in the diagnostic workup and patient care is needed, as are better treatment options.

Clinical and histological characterization of transient dermal pain triggered by sweating stimuli.

BACKGROUND: Tingling dermal pain triggered by sweating impairs the lives of patients with cholinergic urticaria and generalized anhidrosis. However, dermal pain evoked by sweating stimuli has been under investigated. METHODS: To clarify characteristics of tingling dermal pain on sweating, we retrospectively evaluated clinical and histopathological manifestations in 30 patients having the main problem of dermal pain on sweating, and the efficacy of treatments. RESULTS: Dermal pain upon sweating affected mostly young males. It accompanied eruptions upon sweating and/or hypohidrosis in 24 patients, while 6 patients had dermal pain independently of hypohidrosis or eruptions. Dermal pain appeared immediately upon exposure to sweating stimuli, and disappeared within mostly 30 or 10 min. Hypohidrosis was not necessarily generalized but localized or absent. Histological analysis revealed that dermal pain could occur even without morphological changes and inflammation of sweat glands. Hypersensitivity to sweat contents was found only in 26% of patients. Sweat histamine and increase of plasma histamine after thermal induction in patients were significantly higher than those in healthy subjects. Effectiveness of steroid pulse therapy was demonstrated for dermal pain with hypohidrosis. Medications acting on nervous systems and regular sweat-inducing activities for promoting perspiration were also effective. CONCLUSIONS: Short-lasting tingling dermal pain appears immediately upon exposure to sweating stimuli, regardless of developing eruptions and/or presence of hypohidrosis, but possibly in association with sweat and plasma histamine.

Anhidrosis accompanied by cholinergic urticaria-like rash and dermal pain in a patient with Sjögren's syndrome.

Cholinergic urticaria (CholU)-like rash and dermal pain on sweating occur in patients with acquired idiopathic generalized anhidrosis (AIGA). However, it is unclear whether these are symptoms specific to AIGA among the various types of acquired generalized anhidrosis/hypohidrosis (AGAH). Moreover, the pathogenesis underlying CholU-like rash and dermal pain observed with anhidrosis remains to be clarified. A 20-year-old Japanese man with Sjögren's syndrome (SS) presented with anhidrosis. Transient stinging pain on the skin and pinpoint wheals were observed when his body temperature increased. Thermoregulatory sweat testing revealed anhidrotic areas covering 69% of the body surface area with a symmetrical distribution. A high concentration of histamine was detected (506 ng/mL) in the sweat. A skin biopsy specimen from the anhidrotic area showed the inflamed secretory portion of eccrine glands. This suggested inflammation-mediated damage to sweat glands, consistent with AGAH related to SS. Furthermore, immunohistochemical analysis revealed an ectopic distribution of dermcidin, a sweat-specific peptide, in the dermal tissue surrounding the secretory portion of eccrine glands. The expression of claudin-3, a tight junction (TJ) component of sweat glands, decreased or distributed in a mottled manner in the secretory portion. No decreased expression of muscarinic cholinergic receptor M3 was detected. These results suggested that sweat had leaked into the dermis in association with impaired TJ in the secretory portion, along with the damage to inflamed sweat glands related to SS. Collectively, CholU-like rash and dermal pain on sweating were observed in an AGAH patient with SS. The sweat leakage into the dermis may contribute to the development of the rash and pain.

Cholinergic Urticaria, an Effective and Safe "Off Label" Use of Dupilumab: A Case Report with Literature Review.

Cholinergic Urticaria (CholU) is a form of generalized urticaria induced by an increase in core body temperature that activates the sweat reflex. Clinically it is characterized by localized and highly itchy wheals with surrounding erythema and can occur in response to exercise, hot baths and/or emotional stress. Dupilumab is a fully human monoclonal antibody specifically designed to simultaneously inhibit the activity of interleukin-4 (IL-4) and interleukin-13 (IL-13), which play a key role in the inflammation cascade of type 2. We report the case of a 26-year-old man suffering from CholU for 3 years, unresponsive to standard treatment in which off-label therapy was undertaken with Dupilumab, 600 mg subcutaneous as a loading dose and then 300 mg every 15 days. The daily Visual Analogue Scale (VAS) score was used to assess the efficacy of the therapy. Already after the first two administrations, the patient no longer had CholU episodes and resumed regular sporting activity, with a marked improvement in the quality of life. A possible mechanism of Dupilumab in reducing the manifestations of CholU is the blocking of the IL-4 pathway and the expression of the high-affinity IgE receptor (FcεR1) on B cells, mast cells (MCs) and basophils. By decreasing the production of FcεR1, the adhesion of IgE to the surface of MCs decreases with consequent reduction of MCs activation and histamine release. Further experience and large-scale studies may be needed to establish whether Dupilumab can be a therapeutic alternative in CholU, especially in patients who do not respond to standard treatment.

An open-label, proof-of-concept study of lirentelimab for antihistamine-resistant chronic spontaneous and inducible urticaria.

BACKGROUND: Chronic urticaria (CU) is a debilitating mast cell-driven disease, often refractory to standard therapy (ie, antihistamines). Lirentelimab, an anti-sialic acid-binding immunoglobulin-like lectin 8 mAb, selectively inhibits mast cells and depletes eosinophils. OBJECTIVE: We sought to determine safety and efficacy of lirentelimab in patients with CU. METHODS: This phase 2a study enrolled patients with CU refractory to up to 4-fold H1-antihistamine doses. Patients received 6 monthly intravenous doses of lirentelimab (0.3, 1, and up to 3 mg/kg). Primary efficacy end point was change in Urticaria Control Test score at week 22. Urticaria Activity Score weekly average (UAS7) was assessed in patients with chronic spontaneous urticaria (CSU), and Cholinergic UAS7 was used for patients with cholinergic urticaria (CholU). RESULTS: A total of 45 patients were enrolled in 4 cohorts (n = 13 omalizumab-naive CSU, n = 11 omalizumab-refractory CSU, n = 11 CholU, n = 10 symptomatic dermographism). Urticaria Control Test scores increased with lirentelimab across cohorts, with mean changes at week 22 of 11.1 ± 4.1, 4.8 ± 7.0, 6.5 ± 6.2, and 3.4 ± 4.1 and complete response rates (Urticaria Control Test score ≥ 12) of 92%, 36%, 82%, and 40%, respectively. In omalizumab-naive and omalizumab-refractory patients with CSU, disease activity decreased at week 22 (mean UAS7 change, -73% and -47%, respectively), with UAS7 response rates (≥50% reduction) of 77% and 45%, respectively. In patients with symptomatic dermographism, 50% (5 of 10) and 40% (4 of 10) had complete itch and hive resolution by FricTest, respectively, and 100% (7 of 7) evaluable patients with CholU had negative responses to Pulse-Controlled Ergometry exercise test. Most common adverse events included infusion-related reactions (43%; all mild/moderate and transient), nasopharyngitis (21%), and headache (19%). No treatment-related serious adverse events occurred. CONCLUSIONS: Lirentelimab demonstrated activity across 3 forms of antihistamine-refractory CU.

Acquired Idiopathic Generalized Anhidrosis (AIGA) and Its Complications: Implications for AIGA as an Autoimmune Disease.

Acquired idiopathic generalized anhidrosis (AIGA) is a rare disorder in which systemic anhidrosis/hypohidrosis occurs without causative dermatological, metabolic or neurological disorder. Most cases of AIGA have been reported in Asia, especially in Japan, but there have been only a few reports in Europe and the United States. Severe AIGA may result in heatstroke and can reduce quality of life due to restriction of exercise and outdoor works. AIGA is often accompanied by cholinergic urticaria (CholU), and it is thought that AIGA and CholU with anhidrosis/hypohidrosis belong to the same spectrum of the disease. However, the pathophysiology of AIGA has not yet been clarified. Decreased expression of cholinergic receptor M3 on the epithelial cells of eccrine sweat glands is often accompanied by T cell infiltration around eccrine apparatus, suggesting an immunological mechanism of disordered perspiration. AIGA is occasionally associated with various complications indicative of autoimmune disorders. The association of autoimmune complications further suggests that AIGA is an autoimmune disorder. Studies on complications may lead to a better understanding of the pathophysiology of AIGA.

Acetylcholine-induced whealing in cholinergic urticaria - What does it tell us?

BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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 % (P <0.001). Also, wheals were 37 % and flares 172 % larger and of longer duration in CholU patients than in healthy controls (both P < 0.01). CholU patients with ACh-induced wheals (ACh+) had larger flare but not wheal responses in response to histamine than those without (ACh-; P = 0.011). Also, ACh-induced wheal responses were significantly correlated with sweating (r = 0.54, P = 0.046) in CholU patients. Finally, wheal responses lasted longer in ACh+ than in ACh- patients (P = 0.03). CONCLUSION: Intradermal 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.

Sinovitis colinérgica: descripción de 4 casos / Cholinergic synovitis: Description of four cases

Presentamos los hallazgos clínicos y ecográficos de 4 pacientes con sinovitis moderada y lesiones cutáneas urticariales asociadas a la actividad deportiva en ambientes cálidos. Incluimos la evolución tras su tratamiento con hidroxicina. Sugerimos una relación causal similar a la urticaria colinérgica en la que la sinovia vecina responde con derrame que autolimita una vez suspendido el proceso desencadenante.(AU)

We present the clinical and ultrasound findings of four patients with moderate synovitis and urticarial skin lesions associated with sports activity in warm environments. We include progress after treatment with hydroxycin. We suggest a causal relationship similar to cholinergic urticaria where the neighbouring synovium responds with effusion that self-limits once the triggering process has been halted.(AU)

Direct and indirect action modes of acetylcholine in cholinergic urticaria.

Cholinergic urticaria (CholU) manifests small, itchy and/or painful wheals occurring upon perspiration and mechanically involving acetylcholine (Ach). Although a considerable number of studies have been conducted, the pathomechanisms underlying perspiration-associated release of histamine remain to be elucidated. We have proposed that CholU can be categorized into two major subtypes: Ach-indirectly induced, sweat allergic type and Ach-directly induced, depressed sweating type. In the former type, Ach evokes perspiration, and some sweat antigen(s) leaking from the sweat ducts to the dermis may stimulate mast cells to release histamine. In this scenario, the ducts might be damaged or obstructed for sweat leakage, and patients frequently exhibit positive autologous sweat skin test, representing "sweat allergy (hypersensitivity)". On the other hand, the latter Ach-mast cell directly interacting type, typically seen as "CholU with anhidrosis and/or hypohidrosis (CUAH)", eccrine sweat gland epithelial cells lack cholinergic receptor M3 expression. The expression of cholinergic receptors is completely absent in the anhidrotic areas and only slightly expressed in the hypohidrotic areas. In the hypohidrotic area, where pinpoint wheal occurs, it is hypothesized that released Ach cannot be completely trapped by cholinergic receptors of eccrine glands and overflows to the adjacent mast cells, leading to wheal formation. Thus, sweat allergy is not a requirement in this depressed sweating type. Although some additional complications, such as angioedema, anaphylaxis, and cold urticaria, have been documented, these two types represent the modes of action of Ach in this enigmatic urticaria.

Cholinergic synovitis: Description of four cases. / Sinovitis colinérgica: descripción de 4 casos.

We present the clinical and ultrasound findings of four patients with moderate synovitis and urticarial skin lesions associated with sports activity in warm environments. We include progress after treatment with hydroxycin. We suggest a causal relationship similar to cholinergic urticaria where the neighbouring synovium responds with effusion that self-limits once the triggering process has been halted.

[Treatment of simultaneously occurring urticaria and atopic dermatitis with dupilumab]. / Therapie von Urtikaria und atopischer Dermatitis bei einer Patientin mit Dupilumab.

Our 21-year-old woman presented with symptoms of chronic spontaneous urticaria with angioedema and of cholinergic urticaria as well as of atopic dermatitis. Treatment with the IgE antibody omalizumab resulted in an improvement of urticaria; however, relapses of the atopic dermatitis occurred. The use of the monoclonal IL-4/13 receptor antibody dupilumab resulted in complete healing of the atopic dermatitis, complete remission of the chronic spontaneous urticaria with angioedema, and the satisfactory control of cholinergic flare ups over a follow-up period of 26 weeks.