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 Urticaria in Children: an Update on Diagnosis and Treatment.

PURPOSE OF REVIEW: Both adults and children are frequently affected by symptoms of itchy urticarial lesions that cause considerable distress and impact nearly all their daily activities. A comprehensive history is critical to identify the etiology in patients who have chronic spontaneous urticaria (CSU) (those with symptoms for > 6 weeks) and is more important than extensive laboratory serum tests. Unfortunately, most of the current treatment guidelines have been based on data from adult studies since there is rare data on children. These treatment algorithms have been subsequently used to extrapolate treatments for children. RECENT FINDINGS: Current treatment regiments do not achieve complete success in all patients, neither adults nor children. As the pathophysiology of chronic urticaria slowly becomes defined, novel therapies are being tested which target these individual molecular pathways to treat those that continue to experience symptoms. Future studies are required to establish the natural history, risks/benefits and efficacy of current medications, and biologics used to treat CSU in children.

Fric Test Revisited: A Suggestion for a New Scoring System and Its Correlation with Urticaria Control Test and Dermatology Life Quality Index.

BACKGROUND: Fric test is a useful tool for the diagnosis and threshold testing for symptomatic dermographism. When threshold testing is not available, Urticaria Control Test (UCT) and Dermatology Life Quality Index (DLQI) might be used to assess disease control and quality of life (QoL) impairment, respectively. OBJECTIVES: In this study, we aimed to describe a new scoring system for the Fric test and evaluate the correlations of Fric scores with UCT, DLQI, and other disease activity assessment scores. METHOD: Provocation test with Fric Test 4.0 was performed in all patients at referral and at the 4th week. We considered a 4-grade rating score for Fric Test (0-4) [Total Fric Score (TFS)]. A positive response with all of the four pins suggested severe dermographism (TFS = 4), while a wheal with only the largest pin (4.5 mm) was considered as milder disease (TFS = 1). Treatment responses were evaluated with Fric Test 4.0, UCT, patient's global assessment of disease severity (PatGA-VAS), the physician's global assessment of disease control (PhyGA-VAS), and DLQI at baseline and at the 4th week of treatment. The correlations of TFS with UCT, DLQI, PatGA-VAS, PhyGA-VAS at baseline as well as the changes in the mean scores after treatment (week 4) were performed. RESULTS: The mean UCT and DLQI scores were 8.69 ± 3.40 and 7.88 ± 6.02 at the first visit. At the second visit, TFS decreased from a mean of 2.79 ± 1.68 to 1.91 ± 1.85 (p < 0.001), and UCT scores and PhyGA-VAS were increased (p < 0.001), while DLQI scores, PatGA-VAS, and pruritus scores decreased significantly (p = 0.002; p = 0.001; p = 0.012). There was a positive correlation between TFS and pruritus scores (r = 0.378) and DLQI scores (r = 0.392). TFS was found to have a negative correlation with UCT score (r = -0.283) and PhyGA-VAS (r = -0.347). CONCLUSIONS: This new Fric scoring system allows comparison with other tools and shows moderate correlations with most of the tools. Using disease-specific tools is recommended since they provide a subjective evaluation of disease severity, QoL impairment, and disease control.

Omalizumab treatment in patients with chronic inducible urticaria: A systematic review of published evidence.

BACKGROUND: Omalizumab, a recombinant anti-IgE antibody, effectively treats chronic spontaneous urticaria. Evidence is lacking in patients with chronic inducible urticarias (CIndUs), which are frequently H1-antihistamine resistant. OBJECTIVE: From the current published literature, we aimed to determine the strength of evidence for omalizumab efficacy and safety in the treatment of CIndUs. METHODS: We performed a PubMed search to identify evidence on omalizumab use in the following 9 CIndU subtypes: symptomatic dermographism, cold urticaria, delayed-pressure urticaria, solar urticaria, heat urticaria, vibratory angioedema, cholinergic urticaria, contact urticaria, and aquagenic urticaria. RESULTS: Forty-three trials, case studies, case reports, and analyses were identified. Our review indicates that omalizumab has substantial benefits in patients with various CIndUs. The evidence is strongest for symptomatic dermographism, cold urticaria, and solar urticaria. Little/no evidence was available on vibratory angioedema and aquagenic and contact urticaria. Our review supports rapid onset of action demonstrated through early symptom control in most cases, sometimes within 24 hours. Many patients gained complete/partial symptom relief and substantially improved quality of life. Adverse events were generally low, with omalizumab being well tolerated by most patients, including children. CONCLUSIONS: A strong body of evidence supports the use of omalizumab in the treatment of patients with therapy-refractory CIndU. More data from randomized controlled studies are warranted.

Urticaria: A comprehensive review: Epidemiology, diagnosis, and work-up.

Urticaria is a common clinical condition presenting with wheals (hives), angioedema, or both. Urticaria has a complex pathogenesis, along with a high disease burden, a significant impact on quality of life, and high health care costs. The first article in this continuing medical education series covers the definition, classification, epidemiology, diagnosis, and work-up of urticaria, taking into account the recent literature and the best available evidence.

Clinical and photobiological response in eight patients with solar urticaria under treatment with omalizumab, and review of the literature.

BACKGROUND: Solar urticaria (SU) is a rare photodermatosis. Treatment is challenging, and outcomes are often disappointing. Omalizumab is an anti-IgE, currently approved for treatment of chronic spontaneous urticaria. We sought to evaluate therapy with omalizumab in refractory SU and describe predictive factors for response. MATERIALS/METHODS: Patients with refractory SU under treatment with omalizumab were included in this study. Clinical outcome was evaluated using the Urticaria Activity Score 7 (UAS7), Dermatology Life Quality Index (DLQI) and Pruritus Visual Analogue Scale (VAS). Complete clinical response (CCR) was defined as having an UAS7 = 0, DLQI <6 and VAS = 0. Phototesting was performed and compared to baseline. We performed a PubMed search to identify reported cases of SU in adults treated with omalizumab, analysing their characteristics in order to predict response to omalizumab. RESULTS: Eight patients were included. Median age was 45.5 years (range, 23-64). Light spectrum most commonly implicated was UV-A. Clinical outcomes: 89% (7/8) achieved CCR with omalizumab. Phototesting was normal in 42.8% (3/7) of them. In our review, we identified 38 patients (including the current case series), and 68.4% showed favourable outcomes with omalizumab. Median time since onset of SU was lower in responders. CONCLUSIONS: Omalizumab can be an effective treatment in refractory SU.

Review of Physical Urticarias and Testing Methods.

PURPOSE OF REVIEW: This review aims to update the information available on the prevalence, clinical picture, diagnostic methods, and treatment of urticarias induced by external physical stimuli. RECENT FINDINGS: Physical urticarias are present in up to 5% of the general population, and in 10 to 50% of patients with chronic urticaria. Recent investigations have provided evidence that the presence of physical urticaria alone or when comorbid with chronic spontaneous urticaria is associated with a worse prognosis and duration. Most frequent subtypes of physical urticaria are dermographism and delayed pressure urticaria. The diagnosis is established through specific provocation tests and the management encompasses avoidance measures, pharmacologic therapy with nonsedating antihistamines, and alternative medications in refractory cases.

Solar urticaria: Epidemiology and clinical phenotypes in a Spanish series of 224 patients. / Urticaria solar. Epidemiología y fenotipos clínicos en una serie española de 224 pacientes.

BACKGROUND: Solar urticaria is a chronic inducible urticaria also classified as an idiopathic dermatosis. The objective of this paper is to define the phenotypic characteristics of solar urticaria and to evaluate its incidence. MATERIAL AND METHOD: This was a retrospective multicenter study in which data were gathered on the epidemiology and clinical, photobiologic, laboratory, and therapeutic characteristics of solar urticaria. RESULTS: A total of 224 patients (141 women and 83 men) were included from 9 photobiology units. The mean age of the patients was 37.9 years (range, 3-73 years). A history of atopy was detected in 26.7%, and the most common presentation was allergic rhinitis (16.5%). Clinical signs were limited to sun-exposed areas in 75.9% of patients. The light spectrum most commonly implicated was visible light only (31.7%), and in 21% of cases it was only possible to trigger solar urticaria with natural light. The treatments most widely used by photobiology experts were oral antihistamines (65.46%), followed by different forms of phototherapy (34%). Complete resolution was observed most often in patients with solar urticaria triggered exclusively by visible or natural light, with statistically significant differences with respect to other wavelengths (P<.05). No increase in the annual incidence of solar urticaria was observed. CONCLUSIONS: We have presented the largest series of solar urticaria published to date. The epidemiological, clinical, and photobiologic findings confirm previously reported data, although there was a particularly high rate of negative phototests in our series. Reactivity exclusively to visible or natural light was associated with a higher probability of resolution. No increasing trend was observed in the annual incidence.

The definition, diagnostic testing, and management of chronic inducible urticarias - The EAACI/GA(2) LEN/EDF/UNEV consensus recommendations 2016 update and revision.

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.

Acquired cold urticaria: Clinical features, particular phenotypes, and disease course in a tertiary care center cohort.

BACKGROUND: Data about special phenotypes, natural course, and prognostic variables of patients with acquired cold urticaria (ACU) are scarce. OBJECTIVES: We sought to describe the clinical features and disease course of patients with ACU, with special attention paid to particular phenotypes, and to examine possible parameters that could predict the evolution of the disease. METHODS: This study was a retrospective chart review of 74 patients with ACU who visited a tertiary referral center of urticaria between 2005 and 2015. RESULTS: Fourteen patients (18.9%) presented with life-threatening reactions after cold exposure, and 21 (28.4%) showed negative results after cold stimulation tests (classified as atypical ACU). Nineteen patients (25.7%) achieved complete symptoms resolution at the end of the surveillance period and had no subsequent recurrences. Higher rates of atypical ACU along with a lower likelihood of achieving complete symptom resolution was observed in patients who had an onset of symptoms during childhood (P < .05). In patients with atypical ACU, shorter disease duration and lower doses of antihistamines required for achieving disease control were detected (P < .05). Age at disease onset, symptom severity, and cold urticaria threshold values were found to be related to disease evolution (P < .05). LIMITATIONS: This study was limited by its retrospective nature. CONCLUSIONS: The knowledge of the clinical predictors of the disease evolution along with the clinical features of ACU phenotypes would allow for the establishment of an early and proper therapeutic strategy.

Cold-Induced Urticaria in a Paediatric Patient: A Case Report and Literature Review.

Acquired cold-induced urticaria is a rare form of physical urticaria, especially in children. The variety of clinical presentations and the low estimated prevalence contribute to its underdiagnosis. Given the associated risk of anaphylaxis, it is crucial to alert clinicians to the different forms of presentation, diagnosis, and treatment. Starting with a case report of acquired cold-induced urticaria in a previously healthy nine-year-old boy, the authors then review the literature about acquired cold-induced urticaria and discuss the diagnostic exams and disease management.

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.

Prevalence, Management, and Anaphylaxis Risk of Cold Urticaria: A Systematic Review and Meta-Analysis.

BACKGROUND: Cold urticaria is a subtype of chronic inducible urticaria (CIndU) associated with significant morbidity and a risk for anaphylaxis. Few studies have assessed the prevalence, management, and prevalence of associated anaphylaxis of cold urticaria. OBJECTIVES: To evaluate the prevalence of cold urticaria among CIndU and chronic urticaria (CU) cases, to assess the management of cold urticaria, and to determine the prevalence of associated anaphylaxis. METHODS: We searched PubMed and EMBASE for studies pertaining to cold urticaria and/or CIndU published in the past 10 years. We conducted meta-analyses to evaluate the prevalence of cold urticaria among CIndU and CU cases, the management of cold urticaria with H1-antihistamines and omalizumab, and the prevalence of associated anaphylaxis. RESULTS: Twenty-two studies were included in the systematic review and 14 in the meta-analysis. The pooled prevalence of cold urticaria among patients with CU and CIndU was 7.62% (95% confidence interval [CI], 3.45% to 15.99%; I2 = 98%) and 26.10% (95% CI, 14.17% to 43.05%; I2 = 97%), respectively. Cold urticaria was managed by H1-antihistamines in 95.67% (95% CI, 92.47% to 97.54%; I2 = 38%) of patients and omalizumab in 5.95% (95% CI , 2.55% to 13.27%; I2 = 83%) of patients. The pooled prevalence of anaphylaxis among patients with cold urticaria was 21.49% (95% CI, 15.79% to 28.54%; I2 = 69%). CONCLUSIONS: Cold urticaria constitutes an appreciable proportion of CIndU and CU cases and is predominantly managed with H1-antihistamines; few patients receive omalizumab. Anaphylaxis is common, and an epinephrine autoinjector prescription may be considered.

Prevalence of Chronic Inducible Urticaria in Elderly Patients.

BACKGROUND: No data currently exist regarding the epidemiology of chronic inducible urticarias (CIndUs) in the ≥65-year-old population. OBJECTIVE: The study aimed to determine the prevalence of CIndUs among elderly patients affected by chronic urticaria (CU). METHODS: The medical records of all patients referred to us with a diagnosis of CU from January 2008 to September 2020 were retrospectively reviewed, and the patients with CIndUs were identified. The subjects aged 65 years or above were included in the study. RESULTS: The number of patients aged 65 years or above was 153 out of 1970 subjects affected by CU (7.77%; 92 females (60.13%); mean age 70.96 ± 4.22). Out of 153, 26 patients (16.99%; 20 females (76.9%); mean age 71.23 ± 2.6 years) were diagnosed with CIndUs. Most subjects (25/26; 96.15%) suffered from physical urticarias. Symptomatic dermographism was the most frequent, affecting 65.38% (17/26) of our patients, followed by cold urticaria (6/26 (23.08%) cases). CONCLUSION: Our data seem to indicate that CIndUs may also affect the elderly, although it occurs less frequently in aging patients than in lower age groups.

Cold Urticaria: Clinical Features and Natural Course in a Tropical Country.

PURPOSE: To review the clinical features and natural courses of cold urticaria (ColdU) in a tropical country. METHODS: A retrospective chart review was performed of patients who visited Siriraj Urticaria Clinic, Siriraj Hospital, Bangkok, Thailand, and were diagnosed with ColdU between 2007 and 2018. Data on provocation and threshold tests, clinical courses, and laboratory work-up were analyzed and compared with data reported by studies in temperate countries. RESULTS: Of 1,063 chronic urticaria patients, 27 (2.5%) were diagnosed with ColdU, with a mean age of symptom onset of 34.8 years. Half of the patients had a history of atopy, and 1 (3.7%) had a history of anaphylaxis. All patients were positive to 1 of 3 provocation tests: an ice cube test; TempTest 4.0; or a tray filled with ice, salt and water. Thirteen patients underwent the ice cube test, and all had positive results. TempTest was performed on 15 patients, 8 of whom had positive results, with a mean critical temperature threshold (CTT) of 21.0°C. All of the 7 patients who had a negative TempTest result later produced positive results to the immersion of their hand and forearm in a tray filled with ice, salt, and water. All patients were treated with H1-antihistamines, the vast majority (96.3%) being non-sedating H1-antihistamines. Some (14.8%) needed to be administered oral corticosteroids, ciclosporin, or omalizumab. Six patients (22.2%) were in remission. A Kaplan-Meier survival curve demonstrated 5-year and 10-year remission rates of 13.8% and 42.6%, respectively. CONCLUSIONS: The rate of anaphylaxis in patients with ColdU in a tropical country was lower than those reported by other studies conducted intemperate climates. On the other hand, the number of female patients, mean age at symptom onset, atopy rate, rate of concomitant chronic spontaneous urticaria and mean CTT were higher.

Acquired Cold-Induced Urticaria in Pediatric Patients: A 22-Year Experience in a Tertiary Care Center (1996-2017).

BACKGROUND: Acquired cold-induced urticaria (ACU) has not been well evaluated in pediatrics. OBJECTIVE: To further evaluate the presentation of ACU in children and associated risk of anaphylaxis. METHODS: A retrospective chart review was performed in children 18 years or younger diagnosed with ACU at Boston Children's Hospital (US, Northeast) from 1996 to 2017. RESULTS: A total of 415 patients with ACU were identified, aged 4 months to 18.3 years at the time of diagnosis, with similar male:female distribution. Most patients had a history of atopic disease (78.3%), and 25.8% had other urticaria. Around two-third of patients experienced only localized cold-induced symptoms (grade 1), whereas 14.0% had diffuse cutaneous symptoms (grade 2) as the most severe reaction, and 18.6% experienced anaphylaxis (grade 3). Swimming triggered 77.6% of grade 3 reactions, whereas the rest were secondary to ingestion of cold food or beverages, or cold air or cold water exposure. Seven percent of subjects had more than 1 episode of anaphylaxis. Cold stimulation test (CST) was performed in 61.7% of patients, and the result was positive in 69.9% of those tested. Positive CST result was significantly associated with increased risk of anaphylaxis. There was a 11.7% rate of anaphylaxis among patients with negative CST result. Disease resolution at any point in the study period was documented in 8.9% of patients and was associated with a negative history of anaphylaxis. CONCLUSIONS: In the largest study to date on ACU, grade 3 reactions occurred in about a fifth of patients. Positive CST result was associated with a higher risk for anaphylaxis from ACU. Epinephrine prescription and patient/family counseling about risk factors for grade 3 reactions are recommended.

Review of cold-induced urticaria characteristics, diagnosis and management in a Western Canadian allergy practice.

BACKGROUND: Cold-induced urticaria is a significant condition, especially among young females. Despite the morbidity of this disease, studies that fully characterize the disease are limited. METHODS: We analyzed the characteristics of patients diagnosed with cold-induced urticaria at a community-based allergy practice in Vancouver, BC, Canada between 2003 and 2016. Detailed patient history, diagnostic measures and treatment were evaluated. RESULTS: A total of 50 patients were found to have active cold-induced urticaria with a median age of 28.5 (range 2-67) years and 35 patients (70%) were female. 16 patients (32%) had co-occurring physical urticarias while 26 patients (52%) had secondary allergic diagnoses and 3 patients (6%) were thought to have a provoking factor. Of those with a clinical history of suspected cold-induced urticaria that were evaluated with ice cube testing, a positive test was obtained in 84.7% of patients. Treatment was largely with non-sedating antihistamines, with the majority of patients receiving this modality. CONCLUSIONS: Cold-induced urticaria is a complex disease with significant overlap with other chronic inducible urticarias and other allergic diseases. Diagnostic testing shows inconsistent results and the mainstay of treatment consists of non-sedating antihistamines, with other options available for those who do not respond.

Recurrence of Chronic Urticaria: Incidence and Associated Factors.

BACKGROUND: Chronic urticaria (CU) is urticaria that has been present continuously or intermittently for at least 6 weeks. Although the prevalence and characteristics of CU are well established, little is known about recurrent CU (RCU). OBJECTIVES: We sought to establish a definition, determine the frequency, and evaluate risk factors for RCU. METHODS: A retrospective chart review of adult patients with CU evaluated at the University of Texas Southwestern allergy and immunology clinic was performed. RCU was defined as CU recurring at least 6 months after cessation of controller therapy and resolution of prior CU symptoms. Charts were reviewed for symptom resolution and recurrence, subtypes of CU (idiopathic, physical, and urticarial vasculitis), and medication usage (first-line agents, alternative agents, and steroid dependence). RESULTS: Forty-five of 341 patients (13%) had RCU. The recurrence group had a higher frequency of alternative agent use at 57.8% (n = 26) compared with the nonrecurrence group at 34.8% (n = 103), which was statistically significant (P < .01). The rate of steroid dependence was similar in both groups (13.3% in the recurrence group vs 14.5%) and not statistically significant. Individuals exposed to anti-inflammatory agents, immunosuppressants, and omalizumab had a significantly higher relative risk of recurrence compared with those who only used first-line agents (relative risk [RR] 2.32, P < .01; RR 2.69, P < .01; and RR 2.18, P = .05, respectively). CONCLUSIONS: RCU occurs in approximately 13% of patients with CU in our clinic population. Alternative agent use and antihistamine refractoriness appear to place patients at increased risk for recurrence compared with first-line agent use alone.

Cold-induced Anaphylaxis: The Case of a 9-year-old Child and Review of the Literature.

BACKGROUND AND OBJECTIVE: The present review investigated cold-induced anaphylaxis, a potentially life-threatening condition that occurs after exposure to cold stimuli and is characterized by respiratory distress and/or hypotension. Anaphylaxis is rarely associated to cold-induced urticarial (CU), a particular form of physical urticaria that is difficult to diagnose and manage. The incidence of cold-induced urticaria has been estimated at about 0.05%, higher in colder regions and in women; its pathological mechanisms are still unknown. METHODS: The literature was searched via the Medline/PubMed database (http://www.ncbi.nlm.gov/ pubmed). RESULTS AND CONCLUSION: Patients affected by CU should be well-informed about the risk of anaphylaxis and preventive measures. The prevention of CU is based on the avoidance of cold exposure. The most effective treatment is antihistamines symptomatic therapy. Anyway, patients should also carry with them an emergency kit containing corticosteroids, antihistamines and an epinephrine injector. Future studies are necessary to determine the CU pathophysiology so to establish a more targeted management of this important and potentially life-threatening condition.