Norbert Reider

Predictors of severe systemic anaphylactic reactions in patients with Hymenoptera venom allergy: Importance of baseline serum tryptase—a study of the European Academy of Allergology and Clinical Immunology Interest Group on Insect Venom Hypersensitivity

BACKGROUND Severe anaphylaxis to honeybee or vespid stings is associated with a variety of risk factors, which are poorly defined. OBJECTIVE Our aim was to evaluate the association of baseline serum tryptase concentrations and other variables routinely recorded during patient evaluation with the frequency of past severe anaphylaxis after a field sting. METHODS In this observational multicenter study, we enrolled 962 patients with established bee or vespid venom allergy who had a systemic reaction after a field sting. Data were collected on tryptase concentration, age, sex, culprit insect, cardiovascular medication, and the number of preceding minor systemic reactions before the index field sting. A severe reaction was defined as anaphylactic shock, loss of consciousness, or cardiopulmonary arrest. The index sting was defined as the hitherto first, most severe systemic field-sting reaction. Relative rates were calculated with generalized additive models. RESULTS Two hundred six (21.4%) patients had a severe anaphylactic reaction after a field sting. The frequency of this event increased significantly with higher tryptase concentrations (nonlinear association). Other factors significantly associated with severe reactions after a field sting were vespid venom allergy, older age, male sex, angiotensin-converting enzyme inhibitor medication, and 1 or more preceding field stings with a less severe systemic reaction. CONCLUSION In patients with honeybee or vespid venom allergy, baseline serum tryptase concentrations are associated with the risk for severe anaphylactic reactions. Preventive measures should include substitution of angiotensin-converting enzyme inhibitors.

Predictors of side effects during the buildup phase of venom immunotherapy for Hymenoptera venom allergy: the importance of baseline serum tryptase.

BACKGROUND Severe side effects during venom immunotherapy (VIT) are associated with a variety of risk factors. OBJECTIVE Our aim was to evaluate the association of baseline serum tryptase concentration (BTC) and of other parameters, which are routinely recorded during patient evaluation, with the frequency of severe reactions requiring an emergency intervention during the buildup phase of VIT. METHODS In this observational prospective multicenter study, we enrolled 680 patients with established honeybee or vespid venom allergy who underwent VIT. Data were collected on tryptase concentration, age, sex, culprit insect, cardiovascular medication, degree of preceding sting reaction, preventive antiallergic medication before therapy, time between last preceding sting reaction and VIT, venom specific IgE concentration, and type of buildup procedure. Relative rates were calculated with generalized additive models. RESULTS Fifty-seven patients (8.4%) required an emergency intervention during buildup because of a severe systemic reaction. The frequency of interventions increased significantly with higher BTC (log-linear association; adjusted odds ratio, 1.56; 95% CI, 1.15-2.11; P < .005). The predictive power of BTC was markedly greater when VIT was performed for vespid venom allergy than for bee venom (for bee VIT, no significant association; for vespid VIT, log-linear association; adjusted odds ratio, 2.33; 95% CI, 1.28-4.26; P = .005). The most important other factor significantly associated with severe reactions during the buildup phase of VIT was bee venom allergy. CONCLUSION Before vespid VIT, measurement of baseline serum tryptase concentration should be used to identify patients with a high risk for side effects. Patients with bee venom allergy require a particularly high degree of surveillance during VIT.

Effect of the dual endothelin receptor antagonist bosentan on Raynaud’s phenomenon secondary to systemic sclerosis: a double-blind prospective, randomized, placebo-controlled pilot study

OBJECTIVE To investigate the efficacy of the endothelin receptor antagonist, bosentan, in patients with RP secondary to SSc without pre-existing digital ulcers. METHODS Single-centre, randomized, prospective, double-blinded comparison of bosentan and placebo. Patients received either 62.5 mg bosentan twice daily for 4 weeks, followed by 125 mg twice daily for 12 weeks or matching doses of placebo. RESULTS Of the 17 patients enrolled, 16 completed the study and 1 withdrew from the study due to the reversible development of peripheral oedema. Compared with placebo, bosentan did not improve the frequency, duration, pain or severity of RP attacks. However, in contrast to placebo, bosentan significantly improved the functional scores. With respect to baseline, the scleroderma HAQ disability index changes were in favour of bosentan at Weeks 12 (P = 0.03) and 20 (P = 0.01), and the United Kingdom functional score changes at Weeks 8 (P = 0.038) and 16 (P = 0.039). CONCLUSIONS Bosentan is not effective in SSc-related RP without pre-existing digital ulcers, but it might benefit functional impairment in those patients. TRIAL REGISTRATION European Union Drug Regulating Authorities Clinical Trials, https://eudract.emea.europa.eu, EudraCT-Nr 2004-002686-21.

Analysis of Epitope-Specific Immune Responses Induced by Vaccination with Structurally Folded and Unfolded Recombinant Bet v 1 Allergen Derivatives in Man

Previously, we have constructed recombinant derivatives of the major birch pollen allergen, Bet v 1, with a more than 100-fold reduced ability to induce IgE-mediated allergic reactions. These derivatives differed from each other because the two recombinant Bet v 1 fragments represented unfolded molecules whereas the recombinant trimer resembled most of the structural fold of the Bet v 1 allergen. In this study, we analyzed the Ab (IgE, IgG subclass, IgA, IgM) response to Bet v 1, recombinant and synthetic Bet v 1-derived peptides in birch pollen allergic patients who had been vaccinated with the derivatives or adjuvant alone. Furthermore, we studied the induction of IgE-mediated skin responses in these patients using Bet v 1 and Bet v 1 fragments. Both types of vaccines induced a comparable IgG1 and IgG4 response against new sequential epitopes which overlap with the conformational IgE epitopes of Bet v 1. This response was 4- to 5-fold higher than that induced by immunotherapy with birch pollen extract. Trimer more than fragments induced also IgE responses against new epitopes and a transient increase in skin sensitivity to the fragments at the beginning of therapy. However, skin reactions to Bet v 1 tended to decrease one year after treatment in both actively treated groups. We demonstrate that vaccination with folded and unfolded recombinant allergen derivatives induces IgG Abs against new epitopes. These data may be important for the development of therapeutic as well as prophylactic vaccines based on recombinant allergens.

Recommendations for the Long-Term Treatment of Psoriasis with Infliximab: A Dermatology Expert Group Consensus

Background/Aims: Infliximab has been approved for the treatment of chronic plaque psoriasis for only a few years. As physicians gain confidence in initiating and maintaining this therapy, guidance on the management of patients beyond several months or years is needed. To date, there is little or no information about the long-term management in clinical trials or guidelines. Methods: Here we report on the key aspects related to the use of infliximab for the treatment of psoriasis. The data presented here were derived using a modified Delphi survey to obtain a consensus opinion of 11 dermatologists from Europe and Canada experienced in long-term therapy with infliximab. Results/Conclusion: The Delphi participants reviewed several important topics related to biological therapy and infliximab. This paper is not intended to provide a recommendation on all practical aspects related to biological therapy; it has rather been written to provide useful and practical information on the ‘best practice’ use of infliximab.

Clinical effectiveness of hymenoptera venom immunotherapy: a prospective observational multicenter study of the European academy of allergology and clinical immunology interest group on insect venom hypersensitivity

Background Treatment failure during venom immunotherapy (VIT) may be associated with a variety of risk factors. Objective Our aim was to evaluate the association of baseline serum tryptase concentration (BTC) and of other parameters with the frequency of VIT failure during the maintenance phase. Methods In this observational prospective multicenter study, we followed 357 patients with established honey bee or vespid venom allergy after the maintenance dose of VIT had been reached. In all patients, VIT effectiveness was either verified by sting challenge (n = 154) or patient self-reporting of the outcome of a field sting (n = 203). Data were collected on BTC, age, gender, preventive use of anti-allergic drugs (oral antihistamines and/or corticosteroids) right after a field sting, venom dose, antihypertensive medication, type of venom, side effects during VIT, severity of index sting reaction preceding VIT, and duration of VIT. Relative rates were calculated with generalized additive models. Results 22 patients (6.2%) developed generalized symptoms during sting challenge or after a field sting. A strong association between the frequency of VIT failure and BTC could be excluded. Due to wide confidence bands, however, weaker effects (odds ratios <3) of BTC were still possible, and were also suggested by a selective analysis of patients who had a sting challenge. The most important factor associated with VIT failure was a honey bee venom allergy. Preventive use of anti-allergic drugs may be associated with a higher protection rate. Interpretation It is unlikely that an elevated BTC has a strong negative effect on the rate of treatment failures. The magnitude of the latter, however, may depend on the method of effectiveness assessment. Failure rate is higher in patients suffering from bee venom allergy.

Histamine intolerance: lack of reproducibility of single symptoms by oral provocation with histamine: A randomised, double-blind, placebo-controlled cross-over study

ZusammenfassungHINTERGRUND: Der Terminus Histamin-Intoleranz steht für eine ganze Reihe von Symptomen an unterschiedlichen Effektororganen, die nach dem Genuss Histamin-reicher Nahrung auftreten. Das Studienziel war, Histamin-assoziierte Beschwerden durch die Provokation mit einer standardisierten Menge an Histamin zu objektivieren und zu quantifizieren und zu prüfen, ob oral verabreichte Diaminoxidase (DAO) das Beschwerdeausmaß beeinflusst. PATIENTEN UND METHODEN: Vier Institutionen in Österreich nahmen teil. Es wurden Patienten rekrutiert, die den Verdacht auf Histamin-Intoleranz äußerten. Zunächst erfolgte eine offene orale Provokation mit 75 mg Histamin in Tee. Alle Probanden, die dabei Beschwerden entwickelten, wurden in den verblindeten Teil der Studie eingeschlossen und erhielten in drei weiteren verblindeten, einem crossover Design folgenden Provokationsschritten Kombinationen aus Histamin-freiem und Histamin-hältigem Tee mit Diaminoxidase- und Placebo-Kapseln. Es wurden Haupt- und Nebensymptome (stärkste und weniger starke Beschwerden an den einzelnen Effektororganen auf einer 10-Punkte-Skala) definiert, die Reproduzierbarkeit dieser Beschwerden in Bezug auf die jeweiligen Effektororgane geprüft, die Beschwerden weiters in ihrer Gesamtheit (Summe der Beschwerdepunkte aller Effektororgane) erfasst und Veränderungen nach Supplementation von DAO beurteilt. ERGEBNISSE: 39 von 56 Patienten reagierten in der offenen Provokation und wurden in den verblindeten Studienabschnitt eingeschlossen. Haupt- und Nebensymptome waren dabei nicht zu reproduzieren, die Probanden reagierten quasi zufällig. Allerdings brachte die Einnahme von DAO eine statistisch signifikante Reduktion von Beschwerden (definiert durch den Rückgang der aufsummierten Gesamtpunkte) im Vergleich zur Placebo-Gruppe. SCHLUSSFOLGERUNG: Die Ergebnisse erscheinen kontrovers. Möglicherweise reagieren Histamin-intolerante Personen zu unterschiedlichen Zeiten mit unterschiedlichen Symptomen. Die Reproduzierbarkeit definierter Symptome allein würde dann nicht genügen, um eine Histamin-Intoleranz zu bestätigen. Am Kollektiv zeigte sich weiters, dass die Einnahme von DAO-Kapseln im Vergleich mit Placebo-Kapseln zu einer statistisch signifikanten Abschwächung von Beschwerden nach Histamin-Provokation führte.SummaryOBJECTIVES: The term histamine intolerance stands for a range of symptoms involving various effector organs after the consumption of histamine-rich food. Our intention was to objectify and quantify histamine-associated symptoms and to analyse whether oral administration of the histamine-degrading enzyme diamine oxidase (DAO) caused a reduction of symptoms. PATIENTS AND METHODS: Four Austrian centres participated. Patients suspected to be histamine intolerant were recruited. The first step consisted in the open oral provocation of these patients with 75 mg of liquid histamine. Patients who developed symptoms were tested in a randomised double blind crossover provocation protocol using histamine-containing and histamine-free tea in combination with DAO capsules or placebo. Main and secondary symptoms (strongest and weaker symptoms based on a ten-point scale) were defined, the grand total of all symptoms of the individual provocation steps was determined and changes in symptoms after administration of DAO were measured. RESULTS: Thirty nine patients reacted to the open histamine provocation and were enrolled in the blinded part. Here, both the main and secondary symptoms were not reproducible. Subjects reacted sometimes unexpectedly and randomly. Regarding the total symptom scores, the differences between the three treatment groups were statistically significant. The intake of DAO demonstrated a statistically significant reduction of histamine-associated symptoms compared to placebo (P = 0.014). CONCLUSIONS: Oral provocation with 75 mg of liquid histamine failed to reproduce histamine-associated single symptoms in many patients. One may suggest that histamine-intolerant subjects reacted with different organs on different occasions. As a consequence, reproducibility of single symptoms alone may not be appropriate to diagnose histamine-intolerance whereas a global symptom score could be more appropriate. The fact, that the intake of DAO capsules compared to placebo led to a statistically significant reduction of total symptom scores, may indirectly point in the same direction.

Analysis of the Antibody Responses Induced by Subcutaneous Injection Immunotherapy with Birch and Fagales Pollen Extracts Adsorbed onto Aluminum Hydroxide

Background: Allergen-specific subcutaneous immunotherapy (SCIT) is an antigen-specific therapy of IgE-mediated allergies. In the present study, we analyze the epitope specificities of antibody responses induced by SCIT with allergen extracts from pollen of trees belonging to the order Fagales (birch, alder, hazel) adsorbed onto aluminum hydroxide. Methods: The IgE, IgG1–4 and IgA responses to defined recombinant allergens (birch pollen: Bet v 1; alder pollen: Aln g 1; hazel pollen: Cor a 1; apple: Mal d 1) as well as to Bet v 1-derived recombinant fragments and synthetic peptides were analyzed in sera from patients who had undergone SCIT for different periods of time. Results: Long-term SCIT (>1 year; cumulative dose >1,000,000 SQ units) induced more pronounced IgG1, IgG2 and IgG4 responses to Bet v 1 and Bet v 1-related allergens according to the degree of sequence homology (Bet v 1>Aln g 1>Cor a 1>Mal d 1) than short-term SCIT (<1 year; cumulative dose <1,000,000 SQ units). In contrast to patients treated for <1 year, patients treated for >1 year mounted distinct IgG1, IgG2 and IgG4 responses against sequential Bet v 1 epitopes. No relevant allergen-specific IgA or IgG3 responses were induced by short- or long-term SCIT. Using a competitive ELISA assay, it could be shown that serum IgG from patients undergoing long-term SCIT inhibited IgE reactivity to Bet v 1 better than IgG from patients undergoing short-term SCIT. Conclusion: SCIT with allergen extracts adsorbed onto aluminum hydroxide induces IgG responses against new epitopes that block IgE binding and cross-react with structurally related allergens depending, among other factors, on duration of treatment and cumulative injected dose.

A marriage of two "Methusalem" drugs for the treatment of psoriasis?: Arguments for a pilot trial with metformin as add-on for methotrexate.

In this article we present arguments that the “antidiabetic” drug metformin could be useful as an add-on therapy to methotrexate for the treatment of psoriasis and, perhaps, for rheumatoid arthritis as well. Biochemical data suggest that both drugs may share a common cellular target, the AMP-activated protein kinase (AMPK). This enzyme is a master regulator of metabolism and controls a number of downstream targets, e.g., important for cellular growth or function in many tissues including T-lymphocytes. Clinical observations as well as experimental results argue for anti-inflammatory, antineoplastic and antiproliferative activities of metformin and a case-control study suggests that the drug reduces the risk for psoriasis. Patients with psoriasis have higher risk of metabolic syndrome, type 2 diabetes and cardiovascular mortality. Metformin has proven efficacy in the treatment of prediabetes and leads to a pronounced and sustained weight loss in overweight individuals. We expect that addition of metformin to methotrexate can lead to positive effects with respect to the PASI score, reduction of the weekly methotrexate dose and of elevated cardiovascular risk factors in patients with metabolic syndrome and psoriasis. For reasons explained later we suggest that only male, overweight patients are to be included in a pilot trial. On the other side of the coin are concerns that the gastrointestinal side effects of metformin are intolerable for patients under low dose, intermittent methotrexate therapy. Metformin has another side effect, namely interference with vitamin B12 and folate metabolism, leading to elevated homocysteine serum levels. As patients must receive folate supplementation and will be controlled with respect to their B12 status increased hematological toxicity is unlikely to result.

Sublingual Immunotherapy for Allergic Rhinoconjunctivitis – The Seeming and the Real

Background: Subcutaneous specific immunotherapy (SIT) has been shown to be a causal treatment with long-term efficacy for allergic rhinoconjunctivitis and asthma, and a preventive measure against the development of asthma and new sensitizations. As it is associated with several inconveniences and serious side effects, sublingual immunotherapy (SLIT) has been developed to evade these problems. Methods: The present review of previously published studies on allergic rhinoconjunctivitis aimed to determine the efficacy of SLIT in comparison with subcutaneous treatment and to summarize long-term results of immunotherapy and its effects on the prevention and treatment of asthma and the prevention of new sensitizations. Results: The effect of SLIT on allergic rhinoconjunctivitis is low to moderate, depends on the allergen used and is more pronounced in adults than in children, in whom a consistent effect has not been demonstrated. Direct comparison with SIT shows conflicting and inconsistent results. Detailed studies on the prevention of asthma and new sensitizations are not available. Consistent effects of asthma treatment on both symptom and medication scores and lung function have not been reported. A quantitative evaluation is not possible due to indistinct inclusion criteria and different outcome criteria. In summary, currently SLIT plays no significant role in the treatment of asthma, apart from children monosensitized to house dust mites in whom it may have low-moderate effects. Only one study deals with the long-term efficacy of SLIT, which demonstrated a persistent positive effect on asthma, whereas data on rhinoconjunctivitis are completely lacking. Conclusions: Primary and secondary targets of specific immunotherapy have not been answered satisfactorily for the sublingual route. To date, SLIT cannot be recommended as an adequate alternative to the subcutaneous form. Questions regarding the cumulative dose, duration of therapy and immunological mechanisms have also not been answered. The indication should thus be limited to adult patients with pollen-induced rhinoconjunctivitis being unable to perform SIT, e.g. due to significant side effects.