Angioedema (AE), transient localized swelling due to extravasated fluid, is commonly classified as mast cell mediator-induced, bradykinin-mediated or of unknown cause. AE often occurs more than once, ...and it is these recurrent forms of AE that are challenging for patients and physicians, and they are the ones we focus on and refer to as AE in this review. Since effective treatment depends on the causative mediator, reliable and early diagnosis is essential. Although their clinical presentations bear similarities, many forms of angioedema exhibit specific patterns of clinical appearance or disease history that may aid in diagnosis. Here, we describe the most common differences and similarities in the mechanisms and clinical features of bradykinin-mediated and mast cell mediator-induced types of angioedema. We first provide an overview of the diseases that manifest with mast cell mediator-induced versus bradykinin-mediated angioedema as well as their respective underlying pathogenesis. We then compare these diseases for key clinical features, including angioedema location, course and duration of swelling, attack frequency, prevalence and relevance of prodromal signs and symptoms, triggers of angioedema attacks, and other signs and symptoms including wheals, age of onset, and duration. Our review and comparison of the clinical profiles of different types of angioedema incorporate our own clinical experience as well as published information. Our aim is to highlight that mast cell mediator-induced and bradykinin-mediated angioedema types share common features but are different in many aspects. Knowledge of the differences in underlying pathomechanisms and clinical profiles between different types of angioedema can help with the diagnostic approach in affected patients and facilitate targeted and effective treatment.
The current therapeutic algorithm for chronic spontaneous urticaria (CSU), endorsed by the international guideline, entails treatment escalation from second‐generation H1‐antihistamines (sgAHs) to ...omalizumab and cyclosporine until complete response is achieved. Recently, several predictors of response to these treatment options have been described. Here, we discuss the most promising predictors of response and nonresponse to these treatments in CSU. A systematic search was performed by two independent researchers using the MEDLINE/PubMed database with specific keywords and 73 studies included in the review. Levels of evidence were categorized as strong (robust predictors), weak (emerging predictors) or no association, based on the outcome and number of studies available. High disease activity, high levels of C‐reactive protein and D‐dimer are robust predictors for a poor or no response to sgAHs. Poor or no response to omalizumab is robustly predicted by low serum levels of total IgE. A good response to cyclosporine is robustly predicted by a positive basophil histamine release assay, whereas low total IgE is an emerging predictor. The response to treatment with sgAHs, omalizumab and cyclosporine can be predicted by the use of markers that are readily available in routine clinical practice. Further studies are needed to confirm these predictors.
Summary
This review presents evidence that the skin mast cell, in particular the MCTC subtype, is the primary effector cell in urticaria. Mast cells are located in the upper dermis, the ideal ...situation for wheal formation and sensory nerve stimulation. Increased numbers of mast cells are found in both lesional and non‐lesional skin in CSU and inducible urticaria. Mast cell degranulation in the area of wheals has been demonstrated repeatedly by light and electron microscopy. Histamine, PGD2 and tryptase are found in the venous blood draining wheal formation. The last 2 are specific for mast cells rather than basophils. Mast cell reactivity is increased in active urticaria by local inflammatory cytokines and neuropeptides. Mast cell cytokines and neuropeptides, particularly nerve growth factor, induce a Th2 type inflammation that is particularly obvious at the sites of whealing. In conclusion, autoimmunity, either of Type 1 viz. IgE antibodies to local autoallergens, or Type 2b, viz. IgG autoantibodies to IgE or its receptor, are considered to be the most frequent causes of CSU. In both cases, the mast cell is likely to be the axial cell in producing the wheals.
Abstract Background Omalizumab (anti-IgE) therapy is effective and safe in chronic urticaria (CU) in placebo-controlled clinical trials but real life clinical data are scarce. Objective To better ...understand the effects of omalizumab in CU patients treated outside of clinical trials. Methods In this retrospective clinical analysis, we assessed responder rates, optimal dosage, response to up-/downdosing, time to relief of symptoms, rates of return and time of relapse after omalizumab administration, and safety in 51 CU patients, 20 with chronic spontaneous urticaria (CSU) alone, 21 with different forms of chronic inducible urticaria (CindU) and 10 with both. Results Omalizumab treatment led to complete remission in 83% of CSU and 70% of CindU patients. When starting with 150 mg omalizumab 4 weekly, only 2/15 CSU and 7/17 CindU patients required updosing to achieve complete remission. In CSU, 57% of complete responses occurred within week one, all on the first day. Relapses were 2–8 weeks in all but six patients, where they were <4 months. Omalizumab was safe. Efficacy was not correlated to baseline IgE levels. Conclusion Clinical experience from more than 1250 injections in 51 patients over four years indicates that omalizumab is a rapidly acting, highly effective and safe drug in CSU and CindU patients. Our observations in a real life clinical setting support the recommendation of current EAACI/GA2 LEN/EDF/WAO guideline for the management of urticaria to use omalizumab to treat urticaria patients.
Background Chronic spontaneous urticaria (CSU) is defined by itchy hives, angioedema, or both for at least 6 weeks. Omalizumab, an anti-IgE antibody that affects mast cell and basophil function, is a ...promising new treatment option. As of now, however, the efficacy and safety of different doses of omalizumab used in clinical trials for CSU have not been systematically analyzed and summarized. Objective We sought to assess the efficacy and safety of different doses of omalizumab for the treatment of CSU in a meta-analysis of clinical trial results. Methods Suitable trials were identified by searching PubMed, Medline, Embase, and Web of Science databases and with the help of omalizumab's manufacturers. Only double-blind, randomized, placebo-controlled studies with omalizumab-treated versus placebo-treated patients with CSU were included in this analysis. Results We identified 7 randomized, placebo-controlled studies with 1312 patients with CSU. Patients treated with omalizumab (75-600 mg every 4 weeks) had significantly reduced weekly itch and weekly wheal scores compared with the placebo group. Omalizumab's effects were dose dependent, with the strongest reduction in weekly itch and weekly wheal scores observed with 300 mg. Rates of complete response were significantly higher in the omalizumab group (relative risk, 4.55; P < .00001) and dose dependent, with the highest rates in the 300-mg group. Rates of patients with adverse events were similar in the omalizumab and placebo groups. Conclusion This meta-analysis provides high-quality evidence for the efficacy and safety of omalizumab in patients with CSU and for treating these patients with 300 mg of omalizumab every 4 weeks.
The cutoff time of 8 days between fast and slow responders was chosen because it corresponds with the peak plasma level of omalizumab after its initial injection.3 We hypothesized that a slow ...response to omalizumab occurs in patients with CSU in whom IgG antibodies to unoccupied IgE receptors (FcepsilonRI) activate mast cell mediator release to cause wheal and angioedema formation.4 This hypothesis is based on the knowledge that omalizumab first complexes soluble IgE then sequesters IgE released from mast cells, thus uncovering membrane FcepsilonRI, which subsequently decays slowly over several weeks.5 To test this, the basophil histamine release assay (BHRA) was used. Quantification of free serum IgE, IgE neutralization, and omalizumab concentrations A commercially available recoveryELISA kit was used for the quantification of free IgE, IgE neutralization rates, and omalizumab levels in patient serum (BioTeZ Berlin Buch GmbH, Berlin, Germany) as described previously.E4 Characteristic All complete responders (n = 56) Complete response within 8 d Complete response after 8 d P value Age (y) 48 (33-60) 49 (37-58) 42 (31-63) .544 Sex Female 40 (71.4%) 28 (71.8%) 12 (70.6%) .583 Male 16 (28.6%) 11 (28.2%) 5 (29.4%) BMI 27.3 ± 4.8 27.9 ± 4.9 26.1 ± 4.6 .192 UAS7low * 24.0 ± 9.7 23.0 ± 9.3 26.5 ± 4.6 .215 Disease durationlow * 36 (16-102) 40 (18-103) 24 (14-85) .240 ASST+low * 23 of 46 (50.0%) 12 of 33 (36.4%) 11 of 13 (84.6%) <.01 BHRA+low * 9 of 55 (16.4%) 1 of 38 (2.6%) 8 of 17 (47.1%) <.001 Anti-FcepsilonRI+low * 5 of 44 (11.4%) 4 of 30 (13.3%) 1 of 14 (7.1%) .485 Anti-IgE+low * 1 of 44 (2.3%) 1 of 30 (3.3%) 0 of 14 (0.0%) .682 Total IgElow * 205.4 ± 229.6 239.2 ± 250.6 130.0 ± 155.0 .104 Free IgE after omalizumabdagger 31.8 ± 47.7 31.2 ± 39.6 33.2 ± 64.7 .893 % IgE neutralizationdagger 94.7 ± 13.4 96.7 ± 2.2 90.0 ± 24.5 .106 Omalizumab (μg/mL)dagger 16.2 ± 7.8 16.6 ± 7.2 15.2 ± 9.2 .557 Table I CSU responders to omalizumab:
Treatment of urticarial vasculitis: A systematic review Kolkhir, Pavel; Grakhova, Maria; Bonnekoh, Hanna ...
Journal of allergy and clinical immunology,
February 2019, 2019-02-00, 20190201, Letnik:
143, Številka:
2
Journal Article
Recenzirano
Urticarial vasculitis (UV) is a difficult-to-treat condition characterized by long-lasting urticarial rashes and histopathologic findings of leukocytoclastic vasculitis. Treatment is dictated by the ...severity of skin and systemic involvement and the underlying systemic disease. This is a comprehensive systematic review of the efficacy of current UV treatment options. We searched for relevant studies in 7 databases, including MEDLINE, Scopus, and Web of Science. In total, 261 eligible studies and 789 unique patients with UV were included in the systematic review. Most patients with UV are adult women with chronic (≥6 weeks) and systemic disease. UV is mostly idiopathic but can be associated with drugs, malignancy, autoimmunity, and infections. It usually resolves with their withdrawal or cure. Corticosteroids are effective for the treatment of skin symptoms in more than 80% of patients with UV. However, their long-term administration can lead to potentially serious adverse effects. The addition of immunomodulatory or immunosuppressive agents often allows corticosteroid tapering and improves the efficacy of therapy. Biologicals, including omalizumab, as well as corticosteroids, cyclophosphamide, dapsone, mycophenolate mofetil, plasmapheresis, colchicine, hydroxychloroquine, intravenous immunoglobulin, nonsteroidal anti-inflammatory drugs, and cyclosporine, can be effective for both skin and systemic symptoms in patients with UV. H1-antihistamines, montelukast, danazol, H2-antihistamines, pentoxifylline, doxepin, and tranexamic acid are not effective in most patients with UV. As of yet, no drugs have been approved for UV, and management recommendations are based mostly on case reports and retrospective studies. Prospective studies investigating the effects of treatment on the signs and symptoms of UV are needed.
Background Chronic urticaria is a frequent and debilitating skin disease. Its symptoms commonly fluctuate considerably from day to day. As of yet, the only reliable tool to assess disease activity is ...the Urticaria Activity Score, which prospectively documents the signs and symptoms of urticaria for several days. Objective We sought to develop and validate a novel patient-reported outcome instrument to retrospectively assess urticaria control, the Urticaria Control Test (UCT). Methods Potential UCT items were developed by using established methods (literature research and expert and patient involvement). Subsequently, item reduction was performed by using a combined approach, applying impact and regression analysis. The resulting UCT instrument was then tested for its validity, reliability, and screening accuracy. Results A 4-item UCT with a recall period of 4 weeks was developed based on 25 potential UCT items tested in 508 patients with chronic urticaria. A subsequent validation study with the 4-item UCT in 120 patients with chronic urticaria demonstrated that this new tool exhibits good convergent and known-groups validity, as well as excellent test-retest reliability. In addition, the screening accuracy to identify patients with urticaria with insufficiently controlled disease was found to be high. Conclusions The UCT is the first valid and reliable tool to assess disease control in patients with chronic urticaria (spontaneous and inducible). Its retrospective approach and simple scoring system make it an ideal instrument for the management of patients with chronic urticaria in clinical practice.
This update and revision of the international guideline for urticaria was developed following the methods recommended by Cochrane and the Grading of Recommendations Assessment, Development and ...Evaluation (GRADE) working group. It is a joint initiative of the Dermatology Section of the European Academy of Allergology and Clinical Immunology (EAACI), the Global Allergy and Asthma European Network (GA²LEN) and its Urticaria and Angioedema Centers of Reference and Excellence (UCAREs and ACAREs), the European Dermatology Forum (EDF; EuroGuiDerm), and the Asia Pacific Association of Allergy, Asthma and Clinical Immunology with the participation of 64 delegates of 50 national and international societies and from 31 countries. The consensus conference was held on 3 December 2020. This guideline was acknowledged and accepted by the European Union of Medical Specialists (UEMS). Urticaria is a frequent, mast cell–driven disease that presents with wheals, angioedema, or both. The lifetime prevalence for acute urticaria is approximately 20%. Chronic spontaneous or inducible urticaria is disabling, impairs quality of life, and affects performance at work and school. This updated version of the international guideline for urticaria covers the definition and classification of urticaria and outlines expert‐guided and evidence‐based diagnostic and therapeutic approaches for the different subtypes of urticaria.
Bradykinin-mediated angioedema (Bk-AE) can be life-threatening and requires specific targeted therapies. Knowledge of its epidemiology may help optimize its management.
We systematically searched the ...medical literature to identify abstracts of interest indexed between 1948 and March, 2016. We used published national survey data on the proportion of the population treated with angiotensin-converting enzyme inhibitors (ACEI) to derive estimates of the population prevalence of ACEI-AE in the USA, Germany and France. For hereditary angioedema (C1-INH-HAE) and C1-inhibitor related acquired angioedema (C1-INH-AAE), publications had to contain original epidemiologic data collection within a defined geographical area. Hereditary angioedema with normal C1-INH was not included in the analysis due to lack of clearly defined criteria.
We identified 4 relevant publications on the prevalence of ACEI-AE, 6 on the prevalence of C1-INH-HAE, and 1 on the prevalence of C1-INH-AAE. The 1st year cumulative incidence of ACEI-AE was estimated to vary between 0.12 (population-based analyses) and 0.30 (meta-analyses of clinical trials) per 100 patient-years. The population prevalence of ACEI-AE was modeled to vary between 7 and 26 in 100,000. The prevalence of C1-INH-HAE was estimated to vary between 1.1 and 1.6 per 100,000. The prevalence of C1-INH-AAE was estimated to be 0.15 per 100,000 in one epidemiological investigation of AAE in Denmark.
Epidemiological evidence on Bk-AE is limited to North America and Europe. ACEI-AE is more common than C1-INH-HAE (~ 10:1), which is more common than C1-INH-AAE (~ 10:1). More studies are needed to comprehensively assess the epidemiological burden of Bk-AE.
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