To the Editor: Symptomatic dermographism (SDerm) is the most common form of physical urticaria with a prevalence of up to 5%.1 SDerm is characterized by itchy wheals that occur in response to ...friction, for example, after rubbing or scratching of the skin, and usually last for 1 to 2 hours.2 SDerm commonly lasts for years and significantly impairs quality of life (QOL).2 The underlying cause of SDerm is unknown, and the trigger is difficult, if not impossible, to avoid. ...symptomatic treatment with antihistamines is the first-choice treatment. ...omalizumab in doses of 150 and 300 mg resulted in a high rate of complete and partial responders in patients with SDerm and a pronounced overall reduction in disease activity and QOL impairment in these patients. There were no evident differences between omalizumab and placebo, other than their viscosity. Because of this, a separate and independent unblinded study team prepared and injected the study medication. Statistical analysis The UFO study is the first clinical trial of the efficacy and safety of omalizumab in SDerm. ...no pretrial sample size calculation was performed.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background
Autoimmune chronic spontaneous urticaria (aiCSU) is an important subtype of chronic spontaneous urticaria (CSU) in which functional IgG autoantibodies to IgE or its high‐affinity receptor ...(FcεRI) induces mast cell degranulation and subsequent symptom development. However, it has not been tightly characterized. This study aimed to better define the clinical and immunological features and to explore potential biomarkers of aiCSU.
Methods
This was a multinational, multicenter study of 182 CSU patients. The clinical features studied included: urticaria activity and impact (UAS7 and quality of life); autologous serum skin test (ASST); IgG anti‐FcεRI and IgG anti‐IgE; IgG‐anti‐thyroperoxidase (IgG anti‐TPO); total serum IgE; and basophil reactivity (BASO) using the basophil activation test (BAT) and basophil histamine release assay (BHRA).
Results
Of the 182 patients, 107 (59%) were ASST+, 46 (25%) were BASO+, and 105 (58%) were IgG anti‐FcεRI+/IgE+. Fifteen patients (8%) fulfilled all three criteria of aiCSU. aiCSU patients appeared more severe (UAS7 21 vs 9 P < 0.016) but showed no other clinical or demographic differences from non‐aiCSU patients. aiCSU patients also had markedly lower total IgE levels (P < 0.0001) and higher IgG anti‐TPO levels (P < 0.001). Of biomarkers, positive BAT and BHRA tests were 69% and 88% predictive of aiCSU, respectively.
Conclusions
aiCSU is a relatively small but immunologically distinct subtype of CSU that cannot be identified by routine clinical parameters. Inclusion of BHRA or BAT in the diagnostic workup of CSU patients may aid identification of aiCSU patients, who may have a different prognosis and benefit from specific management.
Autoimmune chronic spontaneous urticaria (aiCSU) is defined by IgG anti‐IgE or FcεRI, a positive basophil activation test (BAT) and a positive autologous serum skin test (ASST). 14% of ASST+ patients have aiCSU with low IgE levels and elevated levels of anti‐thyroperoxidase. Positive BAT and basophil histamine release assays (BHRA) were 69% and 88% predictive of aiCSU and, therefore, are biomarkers.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Background Patients with chronic idiopathic urticaria/chronic spontaneous urticaria (CIU/CSU) often continue to experience symptoms despite receiving standard-of-care therapy with H1 -antihistamines ...along with 1 or more add-on therapies. Objectives We sought to evaluate the safety and efficacy of 24 weeks of treatment with omalizumab in patients with persistent CIU/CSU despite treatment with H1 -antihistamines at up to 4 times the approved dose plus H2 -antihistamines, leukotriene receptor antagonists, or both. Methods In this phase III study patients were randomized to receive 6 subcutaneous injections at 4-week intervals of either 300 mg of omalizumab or placebo, followed by a 16-week observation period. The primary objective of the study was to evaluate the overall safety of omalizumab compared with placebo. Efficacy (itch severity, hive, and urticaria activity scores) was evaluated at weeks 12 and 24. Results The overall incidence and severity of adverse events and serious adverse events were similar between omalizumab and placebo recipients; the safety profile was consistent with omalizumab in patients with allergic asthma. At week 12, the mean change from baseline in weekly itch severity score was −8.6 (95% CI, −9.3 to −7.8) in the omalizumab group compared with −4.0 (95% CI, −5.3 to −2.7) in the placebo group ( P < .001). Significant improvements were seen for additional efficacy end points at week 12; these benefits were sustained to week 24. Conclusion Omalizumab was well tolerated and reduced the signs and symptoms of CIU/CSU in patients who remained symptomatic despite the use of H1 -antihistamines (up to 4 times the approved dose) plus H2 -antihistamines, leukotriene receptor antagonists, or both.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
This update on chronic urticaria (CU) focuses on the prevalence and pathogenesis of chronic spontaneous urticaria (CSU), the expanding spectrum of patient-reported outcome measures (PROMs) for ...assessing CU disease activity, impact, and control, as well as future treatment options for CU. This update is needed, as several recently reported findings have led to significant advances in these areas. Some of these key discoveries were first presented at past meetings of the Collegium Internationale Allergologicum (CIA). New evidence shows that the prevalence of CSU is geographically heterogeneous, high in all age groups, and increasing. Several recent reports have helped to better characterize two endotypes of CSU: type I autoimmune (or autoallergic) CSU, driven by IgE to autoallergens, and type IIb autoimmune CSU, which is due to mast cell (MC)-targeted autoantibodies. The aim of treatment in CU is complete disease control with absence of signs and symptoms as well as normalization of quality of life (QoL). This is best monitored by the use of an expanding set of PROMs, to which the Angioedema Control Test, the Cholinergic Urticaria Quality of Life Questionnaire, and the Cholinergic Urticaria Activity Score have recently been added. Current treatment approaches for CU under development include drugs that inhibit the effects of signals that drive MC activation and accumulation, drugs that inhibit intracellular pathways of MC activation and degranulation, and drugs that silence MCs by binding to inhibitory receptors. The understanding, knowledge, and management of CU are rapidly increasing. The aim of this review is to provide physicians who treat CU patients with an update on where we stand and where we will go. Many questions and unmet needs remain to be addressed, such as the development of routine diagnostic tests for type I and type IIb autoimmune CSU, the global dissemination and consistent use of PROMs to assess disease activity, impact, and control, and the development of more effective and well-tolerated long-term treatments for all forms of CU.
Background Detection of IgE to recombinant Hymenoptera venom allergens has been suggested to improve the diagnostic precision in Hymenoptera venom allergy. However, the frequency of sensitization to ...the only available recombinant honeybee venom (HBV) allergen, rApi m 1, in patients with HBV allergy is limited, suggesting that additional HBV allergens might be of relevance. Objective We performed an analysis of sensitization profiles of patients with HBV allergy to a panel of HBV allergens. Methods Diagnosis of HBV allergy (n = 144) was based on history, skin test results, and allergen-specific IgE levels to HBV. IgE reactivity to 6 HBV allergens devoid of cross-reactive carbohydrate determinants (CCD) was analyzed by ImmunoCAP. Results IgE reactivity to rApi m 1, rApi m 2, rApi m 3, nApi m 4, rApi m 5, and rApi m 10 was detected in 72.2%, 47.9%, 50.0%, 22.9%, 58.3%, and 61.8% of the patients with HBV allergy, respectively. Positive results to at least 1 HBV allergen were detected in 94.4%. IgE reactivity to Api m 3, Api m 10, or both was detected in 68.0% and represented the only HBV allergen–specific IgE in 5% of the patients. Limited inhibition of IgE binding by therapeutic HBV and limited induction of Api m 3– and Api m 10–specific IgG4 in patients obtaining immunotherapy supports recent reports on the underrepresentation of these allergens in therapeutic HBV preparations. Conclusion Analysis of a panel of CCD-free HBV allergens improved diagnostic sensitivity compared with use of rApi m 1 alone, identified additional major allergens, and revealed sensitizations to allergens that have been reported to be absent or underrepresented in therapeutic HBV preparations.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Allergic contact dermatitis and its animal model, contact hypersensitivity (CHS), are T cell-mediated inflammatory skin diseases induced by contact allergens. Though numerous cellular and molecular ...players are known, the mechanism of chemical-induced sensitization remains poorly understood. Here, we identify neutrophils as crucial players in the sensitization phase of CHS. Genetic deficiency of neutrophils caused by myeloid-specific deletion of Mcl-1 or antibody-mediated depletion of neutrophils before sensitization abrogated the CHS response. Neutrophil deficiency reduced contact allergen-induced cytokine production, gelatinase release, and reactive oxygen species production in naive mice. Mast cell deficiency inhibited neutrophil accumulation at the site of sensitization. In turn, neutrophils were required for contact allergen-induced release of further neutrophil-attracting chemokines, migration of DCs to the draining lymph nodes, and priming of allergen-specific T cells. Lymph node cells from mice sensitized in the absence of neutrophils failed to transfer sensitization to naive recipients. Furthermore, no CHS response could be induced when neutrophils were depleted before elicitation or when normally sensitized lymph node cells were transferred to neutrophil-deficient recipients, indicating an additional role for neutrophils in the elicitation phase. Collectively, our data identify neutrophils to be critically involved in both the sensitization and elicitation phase of CHS.
Determinants of allergenicity Traidl-Hoffmann, Claudia, MD; Jakob, Thilo, MD; Behrendt, Heidrun, MD
Journal of allergy and clinical immunology,
03/2009, Volume:
123, Issue:
3
Journal Article
Peer reviewed
Open access
The question “What makes an allergen an allergen?” has puzzled generations of researchers, and we still do not have a conclusive answer. Despite increasing knowledge about the molecular and ...functional characteristics of allergens that have been identified, we still do not fully understand why some proteins are clinically relevant allergens and most are not. Different approaches have been taken to identify the structural and functional features of allergens, aiming at developing methods to predict allergenicity and thus to identify allergens. However, none of these methods has allowed a reliable discrimination between allergenic and nonallergenic compounds on its own. This review sums up diverse determinants that contribute to the phenomenon of allergenicity and outlines that in addition to the structure and function of the allergen, factors derived from allergen carriers, the environment, and the susceptible individual are of importance.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background Component resolution recently identified distinct sensitization profiles in honey bee venom (HBV) allergy, some of which were dominated by specific IgE to Api m 3 and/or Api m 10, which ...have been reported to be underrepresented in therapeutic HBV preparations. Objective We performed a retrospective analysis of component-resolved sensitization profiles in HBV-allergic patients and association with treatment outcome. Methods HBV-allergic patients who had undergone controlled honey bee sting challenge after at least 6 months of HBV immunotherapy (n = 115) were included and classified as responder (n = 79) or treatment failure (n = 36) on the basis of absence or presence of systemic allergic reactions upon sting challenge. IgE reactivity to a panel of HBV allergens was analyzed in sera obtained before immunotherapy and before sting challenge. Results No differences were observed between responders and nonresponders regarding levels of IgE sensitization to Api m 1, Api m 2, Api m 3, and Api m 5. In contrast, Api m 10 specific IgE was moderately but significantly increased in nonresponders. Predominant Api m 10 sensitization (>50% of specific IgE to HBV) was the best discriminator (specificity, 95%; sensitivity, 25%) with an odds ratio of 8.444 (2.127-33.53; P = .0013) for treatment failure. Some but not all therapeutic HBV preparations displayed a lack of Api m 10, whereas Api m 1 and Api m 3 immunoreactivity was comparable to that of crude HBV. In line with this, significant Api m 10 sIgG4 induction was observed only in those patients who were treated with HBV in which Api m 10 was detectable. Conclusions Component-resolved sensitization profiles in HBV allergy suggest predominant IgE sensitization to Api m 10 as a risk factor for treatment failure in HBV immunotherapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Because a similar sIgE/tIgE discordance has already been reported for 5 different allergens (Bet v 1, Can f 1, Der p 2, Fel d 1, and Gal d 1),5-7 it is likely to apply also to the Hymenoptera venom ...allergens discussed here and explain the seemingly more sensitive detection of sIgE to rApi m 1 and rVes v 5 reported by Schrautzer et al.1 In line with this is the observation by Selb et al2 that positive values of rApi m 1 and rVes v 5 were, on average, 2.7 and 2.3 times higher with the Immulite than with the ImmunoCAP system.2 Unfortunately, Schrautzer et al1 did not provide data on the actual sIgE levels obtained, preventing a corresponding evaluation of their results.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Purpose of Review
In Hymenoptera venom allergy, the research focus has moved from whole venoms to individual allergenic molecules. Api m 10 (icarapin) has been described as a major allergen of ...honeybee venom (HBV) with potentially high relevance for diagnostics and therapy of venom allergy. Here, we review recent studies on Api m 10 characteristics as well as its role in component-resolved diagnostics and potential implications for venom-specific immunotherapy (VIT).
Recent Findings
Api m 10 is a major allergen of low abundance in HBV. It is an obviously unstable protein of unknown function that exhibits homologs in other insect species. Despite its low abundance in HBV, 35 to 72% of HBV-allergic patients show relevant sensitization to this allergen. Api m 10 is a marker allergen for HBV sensitization, which in many cases can help to identify primary sensitization to HBV and, hence, to discriminate between genuine sensitization and cross-reactivity. Moreover, Api m 10 might support personalized risk stratification in VIT, as dominant sensitization to Api m 10 has been identified as risk factor for treatment failure. This might be of particular importance since Api m 10 is strongly underrepresented in some therapeutic preparations commonly used for VIT.
Summary
Although the role of Api m 10 in HBV allergy and tolerance induction during VIT is not fully understood, it certainly is a useful tool to unravel primary sensitization and individual sensitization profiles in component-resolved diagnostics (CRD). Moreover, a potential of Api m 10 to contribute to personalized treatment strategies in HBV allergy is emerging.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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