Chronic urticaria – What does the new guideline tell us?

Patients with chronic urticaria experience significant impairment, and require an effective treatment. Such treatment is preceded by a thorough diagnostic workup and measurement of disease activity, disease burden and disease control using well‐­established tools. Treatment is subsequently adjusted according to patient needs and therapeutic response, based on the tenet “as much as necessary, as little as possible” (in that order). Once disease control has been achieved, it is recommended that intermittent attempts at medication withdrawal be made in order to identify spontaneous disease remission. Chronic urticaria should be treated until spontaneous remission occurs.     

Serial D‐dimer plasma levels in a patient with chronic spontaneous urticaria developing resistance to omalizumab

Chronic spontaneous urticaria (CSU) is a condition presenting as the spontaneous occurrence of itchy weals with or without angio‐oedema for > 6 weeks. A patient with severe chronic spontaneous urticaria who developed resistance to omalizumab is described. The patient's D‐dimer plasma levels strictly paralleled the disease activity despite the administration of anti‐IgE therapy.     

D-dimer as a potential blood biomarker for disease activity and treatment response in chronic urticaria: a focused review

Chronic urticaria is an itchy skin disease, which is treated with antihistamines; however, a large group of patients are unresponsive to antihistamines alone and are thus treated with omalizumab, although a small fraction of these patients have particularly recalcitrant disease. Currently, there are no reliable biomarkers available to assess disease activity/severity and treatment response in chronic urticaria patients. However, it has been reported that high levels of D-dimer are observed during disease activity and are significantly reduced during periods of remission. We present a focused overview of studies investigating plasma d-dimer level as a biomarker for disease activity and treatment response in patients with chronic urticaria.     

Evaluation of serum levels of C-reactive protein,D-Dimer and Autologous Serum Skin Test in patients with Chronic Spontaneous Urticaria in a Brazilian tertiary center : a cross-sectional study

BackgroundThe pathophysiology of urticaria is still poorly understood. Recent studies demonstrate that the activation of coagulation is correlated with the clinical activity of Chronic Spontaneous Urticaria. Coagulation and inflammation are strongly linked.ObjectivesTo correlate the severity and activity of Chronic Spontaneous Urticaria with the levels of D-dimer, C-reactive protein, and autologous serum test in patients with Chronic Spontaneous Urticaria.MethodsThe study included 55 patients diagnosed with chronic spontaneous urticaria. D-dimer levels were measured using enzyme-linked fluorescent assay and C-reactive protein levels were measured using the nephelometric method; autologous serum testing was performed on patients who discontinued antihistamine therapy. The severity of the disease was assessed using the urticaria activity score.Resultspatients with severe, spontaneous, and difficult-to-control chronic urticaria had elevated serum levels of D-dimer, as well as a positive autologous serum test. Little correlation was demonstrated between the severity of chronic spontaneous urticaria and the levels of C-reactive protein.ConclusionThe authors concluded that patients with severe Chronic Spontaneous Urticaria showed signs of activated fibrinolysis. Most patients with high clinical scores had high D-dimer values. Patients with positive results for the autologous serum test also had more severe Chronic Spontaneous Urticaria and needed more drugs to control the disease. Finally, little correlation was found between C-reactive protein levels and disease severity.Study limitationsThe main limitation was the small sample of patients. In the present patients, it was demonstrated that serum D-dimer levels and the autologous serum test can act as predictive markers of severity and activity of Chronic Spontaneous Urticaria.     

Vitamin D as a Marker for Disease Severity in Chronic Urticaria and Its Possible Role in Pathogenesis

Background

Chronic urticaria is defined as repeated episodes of wheals lasting for 6 weeks or longer. Nowadays, the role of vitamin D in various chronic diseases is a matter of great interest, but limited data is available on the vitamin D status in patients with chronic urticaria.

Objective

The goal of this study was to investigate the relationship between vitamin D status and clinical characteristics of chronic urticaria.

Methods

The clinical records of 72 patients with chronic urticaria, 26 with acute urticaria and 26 with atopic dermatitis, along with 72 healthy controls, were retrospectively reviewed.

Results

The serum 25-(OH)D₃ level was found to be significantly reduced in patients with chronic urticaria compared to those in the other groups. In particular, the proportion of patients with critically low vitamin D levels (<10 ng/ml) was significantly higher in the chronic urticaria group than in the other groups. The serum vitamin D levels showed significant negative associations with urticaria activity score and disease duration. In addition, serum vitamin D levels were significantly lower in subjects with a positive autologous serum skin test than in subjects with a negative result.

Conclusion

In conclusion, the serum vitamin D level was more likely to be critically low in patients with chronic urticaria, and an inverse relationship with disease severity and disease duration was observed. These findings may open up the possibility of the clinical use of vitamin D as a contributing factor in the pathogenesis of chronic urticaria and a predictive marker for disease activity in chronic urticaria.     

Evidence for methotrexate as a useful treatment for steroid-dependent chronic urticaria

Chronic urticaria is a relatively common disorder that can be severe and may impair quality of life. The management of recalcitrant chronic urticaria that is not responding to histamine antagonists includes short-term systemic corticosteroids, anti-inflammatory drugs (colchicine, dapsone and sulfasalazine) and immunomodulatory agents, such as cyclosporine, methotrexate, plasmapheresis and intravenous immunoglobulin. We report here our retrospective experience with the use of methotrexate in 8 patients (2 males and 6 females) with recalcitrant chronic urticaria who were not responding to high-dose first- and second-generation antihistamines. The mean duration of the disease prior to methotrexate treatment was 12 ± 8 months. Patients were treated for a mean duration of 4.5 months with a mean dose of 15 mg methotrexate/week. A complete response was achieved in 7 out of 8 patients (87%). Five out of the 7 patients were disease-free during a period of 1-10 months follow-up after discontinuing methotrexate and prednisone therapy. No serious adverse effects were reported. Methotrexate is an effective and safe treatment for chronic urticaria in patients who are not responsive to conventional therapy.     

慢性自发性荨麻疹的临床评估体系

【摘要】 慢性自发性荨麻疹（CSU）严重影响患者的生活质量,目前尚缺乏敏感且检测方便的生物标志物来评估CSU的严重程度以及药物疗效。在CSU日常管理中选择具有良好信度、效度的患者报告结局评估工具格外重要,如荨麻疹活动度评分、荨麻疹疾病控制评分和慢性荨麻疹患者生活质量评分等。本文梳理了已有的CSU评估工具,分析其优点、局限性和在临床上的应用,旨在构建CSU临床评估体系,为制定个性化的治疗方案和疗效评估提供参考。     

Turkish version of the chronic urticaria quality of life questionnaire: cultural adaptation, assessment of reliability and validity

Chronic spontaneous urticaria has a substantial impact on patients' quality of life. The first disease-specific tool to assess quality of life impairment in this condition, the Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL), was developed recently. The aim of this study was to adapt the original Italian version to the Turkish language and to evaluate its reliability, validity, and sensitivity to change. The Turkish version was developed by performing forward- and back-translation. It was then applied to 140 consecutive patients with chronic spontaneous urticaria, along with the Dermatology Life Quality Index and the Skindex-29. Disease activity was assessed using the Urticaria Activity Score. Sensitivity to change was measured in 101 patients, who completed the instruments twice at intervals of 4 weeks. Confirmatory factor analysis demonstrated that the six-scale structure of the original Italian version ("pruritus", "swelling", "impact on life activities", "sleep problems", "limits", "looks") can be retained in the Turkish instrument. Analysis regarding convergent validity showed good correlations of the Turkish CU-Q2oL with the other instruments. In addition, it was found to discriminate well between patients with different levels of urticaria activity, and to be sensitive to change. In conclusion, the Turkish version of CU-Q2oL is a reliable, valid, and sensitive instrument, which will help to characterize better the clinical impact of chronic spontaneous urticaria and treatment outcomes in Turkish patients. Its identical scale structure to that of other CU-Q2oL instruments makes it ideal for cross-cultural comparisons and for its application in future national and multinational studies.     

Chronic urticaria

Chronic urticaria has a spectrum of clinical presentations and causes. About 50% of patients with "idiopathic" disease have histamine-releasing autoantibodies in their blood. The term autoimmune urticaria is increasingly being accepted for this subgroup of patients, in whom immunosuppressive therapies may be appropriate if conventional approaches to management are unsuccessful. This article reviews the classification, causes, and management of chronic urticaria in light of recent advances in the understanding of its etiology. LEARNING OBJECTIVE: At the conclusion of this learning activity, participants should have up-to-date knowledge of the classification, assessment, and management of chronic urticaria and understand where the concept of autoimmune urticaria fits into existing frameworks.     

CC型趋化因子与慢性荨麻疹

CC型趋化因子是嗜酸粒细胞和T淋巴细胞等炎症细胞的选择性趋化剂,与变态反应密切相关。慢性荨麻疹是一种常见的变态反应性皮肤病,其发病机制除了Ⅰ型变态反应的速发相之外,还涉及到以嗜酸粒细胞浸润为特征的迟发相。CC型趋化因子在迟发相变态反应的发生、发展过程中起着重要的作用。     

Treatment of Refractory Chronic Urticaria: Current and Future Therapeutic Options

Chronic urticaria is a distressing disease that affects up to 1 % of the general population at a time point in life and may severely worsen the quality of life. First-line treatment has been based on antihistamines, and presently relies on the use of non-sedating, second-generation antihistamines; following the recommendations of the recent international guidelines, in patients who do not respond to antihistamines at licensed doses, the daily dosage of these drugs can be increased up to fourfold. Nonetheless, a significant proportion of patients with chronic urticaria remain poorly controlled; in these cases, alternative therapeutic approaches have to be considered. This article critically reviews all of the third- and fourth-line treatment options suggested for patients whose disease is refractory to antihistamines, including systemic corticosteroids, leukotriene receptor antagonists, several different anti-inflammatory drugs (dapsone, sulfasalazine, hydroxychloroquine), various immunosuppressive drugs (calcineurin inhibitors, methotrexate, cyclophosphamide, azathioprine, mycophenolate mofetil), intravenous immunoglobulin, and newer treatment options, such as omalizumab and other biologic drugs. In addition, the article examines possible future treatment options based on recent findings about pathogenic mechanisms, and considers the treatment of antihistamine-unresponsive urticaria in special conditions such as children and pregnancy/lactation. The evidence supporting the use of several of the discussed drugs is presently limited and thus insufficient to recommend their routine use; as a consequence, such compounds should be considered only in specific cases and in adequate settings.     

特异性免疫治疗对慢性荨麻疹患者临床及外周血IL-4和sVCAM-1水平的影响

目的探讨特异性免疫治疗对慢性荨麻疹患者的疗效和作用机理。方法对30例吸入组皮肤试验阳性的慢性荨麻疹患者进行特异性免疫治疗并观察疗效,用ELISA法检测患者治疗前后及健康对照组IL-4和sVCAM-1的血清水平。结果病例组经特异性免疫治疗3个疗程,有效率83.33%。病例组治疗前IL-4和sVCAM-1血清浓度明显高于对照组(P<0.05和0.01),经特异性免疫治疗后浓度下降,较治疗前均有显著差异(P<0.01和0.001)。sVCAM-1与IL-4血清浓度无直线相关关系(r=0.0268,P>0.05)。结论特异性免疫治疗对慢性荨麻疹患者安全有效。IL-4和sV-CAM-1可作为监测慢性荨麻疹病情变化指标之一。特异性免疫治疗可能是通过免疫调节达到其治疗作用。     

Levocetirizine in the treatment of chronic idiopathic urticaria: a randomized, double-blind, placebo-controlled study

BACKGROUND: Chronic urticaria is a common skin condition. It is frequently a disabling disease because of the persistence of clinical symptoms, the unpredictable course and its negative influence on the quality of life. OBJECTIVES: To determine whether levocetirizine is efficacious in the treatment of chronic idiopathic urticaria. METHODS: A randomized, double-blind, placebo-controlled study was conducted in 106 patients with a diagnosis of chronic idiopathic urticaria. A 1-week single blind placebo run-in period (baseline) was followed by a 6-week double blind active treatment period. The patients were randomized to receive one of the following treatments once daily: (a) oral levocetirizine 5 mg, or (b) oral placebo. The study ended after another 1-week single blind placebo washout period. RESULTS: The evaluable population consisted of 100 patients. Levocetirizine administered once daily is effective and well tolerated in the treatment of the symptoms of chronic idiopathic urticaria and in improving the patient's quality of life. Levocetirizine was superior to placebo in reducing the mean total symptoms score as well as individual symptoms, the number of daily episodes and the number of weals, the overall severity of symptoms and the quality of life. The significant beneficial effects of levocetirizine lasted only during the active trial, while at follow-up there was a significant worsening of all the variables evaluated in this study, after the end of the active trial (week 7). CONCLUSIONS: A global assessment indicates that levocetirizine 5 mg once daily is an effective agent in patients with chronic idiopathic urticaria, as its action provides a rapid and satisfactory control of the symptoms and measures of subjective disease, although this is limited to the duration of treatment.     

Actualización en el tratamiento de la urticaria crónica

Chronic spontaneous urticaria, also known as chronic idiopathic urticaria or simply chronic urticaria, is a common disorder that has a prevalence in the general population that ranges between 0.5% and 1%. This condition negatively affects the patient's quality of life and has considerable impact on direct and indirect health-related costs. Chronic urticaria is difficult to manage. Nonsedating H₁ antihistamines are the first line of therapy, but fewer than 50% of patients experience relief at recommended dosages. Although guidelines call for increasing the dosage when response is inadequate, some patients still do not achieve adequate control of symptoms. New treatment alternatives, with proven efficacy under the standards of evidence-based medical practice, must therefore be developed.     

Kostenintensiv,zeitaufwendig, problematisch? – Die Betreuung von Urtikariapatienten aus der Perspektive niedergelassener Årzte

Background: Urticaria is a common and frequently debilitating disease. Nevertheless, there are only few studies examining the situation of urticaria patient care. Patients and Methods: In this cross‐sectional study, we surveyed dermatologists, pediatricians and general practitioners in the practice setting regarding the epidemiology, situation of care as well as the perception of their patients with chronic spontaneous urticaria. Results: 776 data sets were available. The results show a high frequency of consultations due to chronic spontaneous urticaria. Most of the patients were reported to suffer moderately to severely and to have had history of disease of well over one year. The pediatricians indicated fewer diseases and shorter courses. The majority of participants stated that the time and cost spent on care, as well as the frequency of follow‐up visits, are above average. In addition, chronic spontaneous urticaria patients were reported to be a group with a strong emotional burden and high expectations as well as a group that is difficult to satisfy and hard to guide. Only a small minority of physicians rated patient satisfaction with current treatment options and therapy success as high. Conclusions: Chronic spontaneous urticaria plays an important role in daily practice. Problems are reported on various areas of care. Resolving these problems presents a major challenge and is crucial for improving the quality of patient care.     

Chronic urticaria: a role for newer immunomodulatory drugs?

Chronic urticaria is now recognized as an autoreactive disorder in a substantial fraction of patients. A serologic mediator of whealing has been demonstrated in 50-60% of patients with chronic urticaria, and autoantibodies against the high affinity IgE receptor or IgE have been detected in about half of these patients. The demonstration that chronic urticaria is frequently autoimmune has encouraged a more aggressive therapeutic approach, with the use of immunomodulatory drugs.A step-by-step approach to the management of chronic urticaria is proposed, based on our personal experience and review of current medical literature, identified through Medline research and hand searching in medical journals. The non- or low-sedating H(1) receptor antagonists (antihistamines), such as cetirizine, fexofenadine, loratadine, mizolastine and, more recently, levocetirizine, desloratadine and ebastine, represent the basic therapy for all chronic urticaria patients. Older sedating antihistamines, such as hydroxyzine and diphenhydramine, may be indicated if symptoms are severe, are associated with angioedema, and if the patient is anxious and disturbed at night.Corticosteroid therapy with prednisone or methylprednisolone can be administered for a few days (7-14) if urticarial symptoms are not controlled by antihistamines and a rapid clinical response is needed. In cases of relapse after corticosteroid suspension, leukotriene receptor antagonists, such as montelukast and zafirlukast, should be tried. In our experience, remission of urticarial symptoms can be achieved in 20-50% of chronic urticaria patients unresponsive to antihistamines alone. When urticaria is unremitting and is not controlled by combined therapy with antihistamines and leukotriene receptor antagonists, prolonged corticosteroid therapy may be needed. Long-term corticosteroid therapy should be administered at the lowest dose able to control urticarial symptoms, in order to minimize adverse effects. In a few patients, however, high-dose corticosteroid therapy may have to be administered for long periods. In these patients, immunosuppressive treatment with low-dose cyclosporine can be started. This type of treatment has a corticosteroid-sparing effect and is also generally effective in patients with severe, unremitting urticaria, but requires careful monitoring of cyclosporine plasma concentration and possible adverse effects. Other immunomodulating drugs that have been tried in chronic urticaria patients include hydroxychloroquine, dapsone, sulfasalazine and methotrexate, but their efficacy has not been proven in large controlled studies. Warfarin therapy may also be considered in some patients with chronic urticaria and angioedema unresponsive to antihistamines.     

抗IgE疗法——奥马珠单抗治疗慢性荨麻疹专家共识

【摘要】 慢性荨麻疹是一种常见的免疫相关性皮肤病，具有反复发作、迁延不愈等特点，部分患者对常规抗组胺药物治疗效果不佳，生活质量受到严重影响。目前，国内外多项研究证实，一类以新型生物制剂为主的抗IgE疗法能够较为有效和安全地应用于慢性荨麻疹等疾病的治疗。为规范并促进临床医生对抗IgE疗法的应用和认识，基于国外指南及近年相关研究报道，中华医学会皮肤性病学分会荨麻疹研究中心组织有关专家制订本共识，以奥马珠单抗为代表，详细介绍抗IgE疗法治疗慢性荨麻疹的具体机制、应用方案和注意事项，为皮肤科医务工作者提供相关的理论依据和用药指导。     

CHRONIC AUTOIMMUNE URTICARIA: WHERE WE STAND?

It is well-recognized that 30-40% of chronic idiopathic urticaria is autoimmune in nature. Chronic autoimmune urticaria is caused by anti-FcεRI and less frequently, by anti-IgE autoantibodies that lead to mast cell and basophil activation, thereby giving rise to the release of histamine and other proinflammatory mediators. Activation of the classical complement pathway and formation of C5a are important in dermal mast cell activation. C5a is also a neutrophil and eosinophil chemoattractant. Chronic autoimmune urticaria has been found to be associated with autoimmune thyroid disease. The autologous serum skin test is used as a screening test for chronic autoimmune urticaria and has a sensitivity and specificity of about 70 and 80%, respectively. The current gold standard diagnostic test is the basophil histamine release assay. The treatment of chronic autoimmune urticaria, as in chronic idiopathic urticaria, is with H1 antihistamines. Oral corticosteroids may be used during acute flares. Refractory cases have been shown to respond to cyclosporine and other immunomodulators. The prevalence of chronic autoimmune urticaria in Singapore is similar to that reported in Western countries at about 42%. The presence of thyroid autoimmunity appears to be higher than reported, with 22.5% of patients with chronic idiopathic urticaria here, exhibiting presence of thyroid autoantibodies.     

Therapeutische Alternativen bei Antihistamintherapie-refraktärer Urtikaria

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

The extent and nature of disability in different urticarial conditions

Chronic forms of urticaria are common, often adversely impacting on quality of life. No formal studies have assessed the extent and nature of disability in different types of urticaria. The Dermatology Life Quality Index (DLQI) is a simple and validated 10-item questionnaire designed to measure and compare disability in different skin conditions. In this study, we aimed to assess the disability in different urticarial groups using the DLQI, allowing comparison with previously published DLQI scores in common skin diseases. The DLQI was administered to 170 consecutive patients attending a specialist urticaria clinic over a 4-month period. Consistent with previous studies using the DLQI, mean scores were not influenced by gender or age. Patients with chronic idiopathic urticaria without a concurrent physical urticaria (n = 47) suffered moderate quality of life impairment (mean +/- SD DLQI 25 +/- 24%). In comparison, patients with chronic idiopathic urticaria with concurrent delayed pressure urticaria (DPU) (n = 26) suffered significantly higher quality of life impairment (mean +/- SD DLQI 43 +/- 23%, 95% confidence interval for difference 7-29%). Disability in this group was greatest in the dimensions of work/study, symptoms/feelings and leisure. Subjects with another form of physical urticaria, cholinergic urticaria, also endured high levels of disability (n = 9, mean +/- SD DLQI 50 +/- 34%). From our urticaria study group, we have shown that subjects with DPU and cholinergic urticaria endure the most quality of life impairment. The mean DLQI scores demonstrated in these groups are comparable with those previously seen in severe atopic dermatitis out-patients (60%) and higher than those seen in out-patients with psoriasis (29.7%), acne (24.3%) and vitiligo (16.1%).