Comparative analysis of the phototoxicity induced by BRAF inhibitors and alleviation through antioxidants.

BACKGROUND: Small molecules tackling mutated BRAF (BRAFi) are an important mainstay of targeted therapy in a variety of cancers including melanoma. Albeit commonly reported as side effect, the phototoxic potential of many BRAFi is poorly characterized. In this study, we evaluated the phototoxicity of 17 distinct agents and investigated whether BRAFi-induced phototoxicity can be alleviated by antioxidants. METHODS: The ultraviolet (UV) light absorbance of 17 BRAFi was determined. Their phototoxic potential was investigated independently with a reactive oxygen species (ROS) and the 3T3 neutral red uptake (NRU) assay in vitro. To test for a possible phototoxicity alleviation by antioxidants, vitamin C, vitamin E phosphate, trolox, and glutathione (GSH) were added to the 3T3 assay of selected inhibitors. RESULTS: The highest cumulative absorbance for both UVA and UVB was detected for vemurafenib. The formation of ROS was more pronounced for all compounds after irradiation with UVA than with UVB. In the 3T3 NRU assay, 8 agents were classified as phototoxic, including vemurafenib, dabrafenib, and encorafenib. There was a significant correlation between the formation of singlet oxygen (P = .026) and superoxide anion (P < .001) and the phototoxicity observed in the 3T3 NRU assay. The phototoxicity of vemurafenib was fully rescued in the 3T3 NRU assay after GSH was added at different concentrations. CONCLUSION: Our study confirms that most of the BRAF inhibitors exhibited a considerable phototoxic potential, predominantly after exposure to UVA. GSH may help treat and prevent the phototoxicity induced by vemurafenib.

S2k guideline on diagnosis and treatment of atopic dermatitis - short version.

Atopic dermatitis (AD) represents a pruritic, non-contagious, chronic or chronically relapsing, inflammatory skin disease. The course of the disease may be complicated by bacterial or viral superinfections. The first manifestation of the disease and further flare-ups are due to genetic predisposition and also to a variety of further trigger factors. The therapy regimen should be adapted to disease symptoms that are actually present and consider individual features of the disease as reported by the patients or their parents. This short version of the German guideline on AD provides an overview of evidence-based diagnostic and treatment options. All recommendations made here are the result of a consensus of the scientific medical societies, working groups and support groups based on scientific data published to date. Abstracts and details of the studies cited are provided in the long version of this guideline (see: www.awmf.org).

S2k guideline on diagnosis and treatment of atopic dermatitis--short version.

Atopic dermatitis (AD) represents a pruritic, non-contagious, chronic or chronically relapsing, inflammatory skin disease. The course of the disease may be complicated by bacterial or viral superinfections. The first manifestation of the disease and further flare-ups are due to genetic predisposition and also to a variety of further trigger factors. The therapy regimen should be adapted to disease symptoms that are actually present and consider individual features of the disease as reported by the patients or their parents. This short version of the German guideline on AD provides an overview of evidence-based diagnostic and treatment options. All recommendations made here are the result of a consensus of the scientific medical societies, working groups and support groups based on scientific data published to date. Abstracts and details of the studies cited are provided in the long version of this guideline (see: www.awmf.org).

Guideline for the diagnosis of drug hypersensitivity reactions: S2K-Guideline of the German Society for Allergology and Clinical Immunology (DGAKI) and the German Dermatological Society (DDG) in collaboration with the Association of German Allergologists (AeDA), the German Society for Pediatric Allergology and Environmental Medicine (GPA), the German Contact Dermatitis Research Group (DKG), the Swiss Society for Allergy and Immunology (SGAI), the Austrian Society for Allergology and Immunology (ÖGAI), the German Academy of Allergology and Environmental Medicine (DAAU), the German Center for Documentation of Severe Skin Reactions and the German Federal Institute for Drugs and Medical Products (BfArM).

Drug hypersensitivity reactions are unpredictable adverse drug reactions. They manifest either within 1-6 h following drug intake (immediate reactions) with mild to life-threatening symptoms of anaphylaxis, or several hours to days later (delayed reactions), primarily as exanthematous eruptions. It is not always possible to detect involvement of the immune system (allergy). Waiving diagnostic tests can result in severe reactions on renewed exposure on the one hand, and to unjustified treatment restrictions on the other. With this guideline, experts from various specialist societies and institutions have formulated recommendations and an algorithm for the diagnosis of allergies. The key principles of diagnosing allergic/hypersensitivity drug reactions are presented. Where possible, the objective is to perform allergy diagnostics within 4 weeks-6 months following the reaction. A clinical classification of symptoms based on the morphology and time course of the reaction is required in order to plan a diagnostic work-up. In the case of typical symptoms of a drug hypersensitivity reaction and unequivocal findings from validated skin and/or laboratory tests, a reaction can be attributed to a trigger with sufficient confidence. However, skin and laboratory tests are often negative or insufficiently reliable. In such cases, controlled provocation testing is required to clarify drug reactions. This method is reliable and safe when attention is paid to indications and contraindications and performed under appropriate medical supervision. The results of the overall assessment are discussed with the patient and documented in an "allergy passport" in order to ensure targeted avoidance in the future and allow the use of alternative drugs where possible.

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.

Photosensitizing properties of compounds related to benzophenone.

Benzophenone is a phototoxic compound with absorption maxima in the ultraviolet A (UVA) and ultraviolet B (UVB) range. Many benzophenone derivatives are known to be photosensitizing. On the other hand, 2-hydroxy-4-methoxybenzophenone is used as a photoprotective agent. The aim of the present study was to analyse a range of benzophenone derivatives and thus examine the effects of molecular changes in the benzophenone molecule on phototoxic behaviour. Phototoxicity was tested by an in vitro photohaemolysis test. The tested compounds were benzophenone itself and the derivatives 2-hydroxybenzophenone, 2-aminobenzophenone, 2-benzoylbenzoic acid, 3-hydroxybenzophenone, and 4-hydroxybenzo-phenone, as well as the structurally similar compounds 9-fluorenone, 9-fluorenone-2-carboxylic acid, cyclohexyl phenyl ketone, and 1,4-naphtho-quinone. It was shown that minor changes in molecular structure can result in highly different phototoxic characteristics.

Sensitization to common ragweed in southern Bavaria: clinical and geographical risk factors in atopic patients.

BACKGROUND: Sensitization to common ragweed (Ambrosia artemisiifolia) is associated with a variety of risk factors, which are incompletely defined. Our aim was to evaluate the association of a variety of clinical, geographical and demographical variables with ragweed sensitization and also to determine its frequency in southern Bavaria. METHODS: In this cross-sectional multicentre study, we enrolled 977 patients with a documented or suspected atopic disease or food allergy. Data were collected on aeroallergen sensitization, age, sex, type and history of allergic disease, place of residence and potential local ragweed exposure. For this last variable, county ragweed cover was taken as a surrogate variable. Relative rates were calculated with multiple additive logistic regression models. Randomly selected patients with ragweed sensitization had a conjunctival provocation test. RESULTS: According to skin prick tests, 190 patients (19.5%) were sensitized to ragweed. The frequency of this finding increased significantly with a rising number of additional sensitizations. Other less important predictors for a ragweed sensitization were male gender, mugwort sensitization, food allergy and a maximum of complaints in September or October. County of residence, extent of local ragweed cover or type of residential area were without relevance. Of 48 sensitized patients, 26 (54.2%) had a positive conjunctival provocation test. DISCUSSION: Patients with multiple sensitizations may be more readily sensitized to a new aeroallergen. Local geographic or environmental conditions are presumably of minor importance for becoming sensitized to ragweed. The frequency of ragweed allergy among sensitized patients might be high.

Insect stings: clinical features and management.

BACKGROUND: In human beings, local and systemic reactions can be caused both by blood-sucking insects and by venomous insect stings. In Central Europe, the insects that most commonly cause such reactions are honeybees, certain social wasps, mosquitoes, and flies. METHODS: This article is based on a selective literature review, including guidelines from Germany and abroad. RESULTS: Insect venom induces a toxic reaction at the site of the sting. Large local reactions are due to allergy and occur in up to 25% of the population; as many as 3.5% develop IgE-mediated, potentially life-threatening anaphylaxis, of which about 20 people die in Germany each year. Mastocytosis is found in 3% to 5% of patients with sting anaphylaxis, rendering these patients prone to very severe reactions. Blood-sucking by hematophagous insects can elicit a local allergic reaction, presenting as a wheal or papule, in at least 75% of the population. Large local reactions may ensue, but other diseases are rare. The acute symptoms of an insect sting are treated symptomatically. Patients who have had a systemic reaction or a large local reaction due to insect allergy must take permanent measures to avoid further allergen contact, and to make sure they can treat themselves adequately if stung again. Most patients with systemic anaphylactic reactions to bee or wasp stings need specific immunotherapy. CONCLUSION: Insect stings can cause severe disease. Anaphylaxis due to bee or wasp stings is not a rare event; specific immunotherapy protects susceptible persons from further, potentially life-threatening reactions.

Management of occupational Hymenoptera allergy.

PURPOSE OF REVIEW: Certain outdoor activities show a particularly high risk for being stung by Hymenoptera species. Avoidance of such stings is preferable for preventing unwanted local or systemic sting reactions. The purpose of this review is to evaluate the current knowledge on risk factors and management of Hymenoptera venom allergy. We will specifically focus on patients with an intense occupational exposure to Hymenoptera venom. RECENT FINDINGS: Repeated stings were found to increase the risk for subsequent severe anaphylactic sting reactions. The male preponderance for severe anaphylactic sting reactions probably reflects in part a sex-specific occupational exposure being higher in males. When selecting a specific venom for therapy, current knowledge of cross-reactivity between venoms of various species should be considered. If available, venom immunotherapy should be performed using the venom of the culprit insect. Recently, a pilot study also showed the efficacy of venom immunotherapy when treating large local reactions. SUMMARY: If an intensely exposed patient presents with a systemic anaphylactic sting reaction, efficacy of venom immunotherapy should be demonstrated by a tolerated sting challenge before allowing this patient to return to his/her occupation. Patients with bee venom allergy and an intense exposure should be treated with an increased maintenance dose of 200 µg bee venom. Patients with a history of large local reactions should be provided with an emergency kit, which should contain oral antihistamines and corticosteroids. In patients in whom local sting reactions induce symptoms of high clinical significance, an off-label use of venom immunotherapy may be discussed.

Release of mast cell tryptase into saliva: a tool to diagnose food allergy by a mucosal challenge test?

BACKGROUND: Our aim was to examine whether measurement of the saliva mast cell tryptase (MCT) concentrations before and after a mucosal challenge test with the offending food would be helpful in diagnosing food allergy. METHODS: We performed a retrospective analysis of 44 food challenge tests performed in 38 patients between 2006 and 2009. Patients with a suspected history of food allergy chewed the food until they developed symptoms or until the amount of time known from the patients' history to usually be required for the provocation of symptoms had passed. In 5 patients, saliva samples for the measurement of MCT were collected at minutes 0, 1, 4, 8, 11, and 16 after the first onset of symptoms. The remainder of the patients only had samples taken before chewing and 4 min after the end of the test period. RESULTS: During repeated measurements, MCT peaked about 4 min after the onset of symptoms (p = 0.028). During 33 of the 44 tests (75.0%), we observed oral symptoms during testing; after 25 of the 33 (75.8%) tests evoking symptoms, the saliva MCT concentration increased. The MCT increase was negative in all other tests where no oral symptoms could be provoked. CONCLUSIONS: The measurement of saliva MCT 4 min after the onset of symptoms may be helpful to diagnose food allergy. Because of numerous confounding variables, however, a negative saliva MCT increase does not exclude food allergy.

Immediate-type hypersensitivity to succinylated corticosteroids.

BACKGROUND: Despite their frequent use, systemic corticosteroids have rarely elicited immediate-type reactions. OBJECTIVE: We report two male patients, aged 26 and 70 years, respectively, with severe immediate-type hypersensitivity secondary to the administration of corticosteroids esterified with succinate. METHODS: Skin tests, basophil activation tests and challenge tests were performed for diagnostic evaluation. RESULTS: In both patients, immediate-type skin test reactions were found to methylprednisolone sodium hemisuccinate (MSH) and prednisolone sodium hemisuccinate (PSH). In contrast, nonsuccinylated corticosteroids (including methylprednisolone and prednisolone in one patient) yielded no test reactions. Basophils from one patient exhibited a stimulated expression of the activation marker CD63 upon in vitro incubation with PSH or hydrocortisone sodium succinate, but not with hydrocortisone. Skin tests and basophil activation tests were negative in controls. One patient was challenged with the incriminated drugs. He developed flush, conjunctivitis, tachycardia and dyspnea 2 min after injection of MSH, and dyspnea shortly after intravenous administration of PSH. Oral and intravenous challenge tests with nonsuccinylated corticosteroids were tolerated well by both patients. CONCLUSIONS: These case reports should alert clinicians to rare, but severe immediate-type reactions to corticosteroids, related to the succinate moiety in our patients. In case of allergic reactions to corticosteroids, it is mandatory to identify the causative agent and find safe alternatives.

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.

Hymenoptera venom allergy.

Allergic reactions to Hymenoptera stings usually present as large local reactions or systemic reactions with symptoms of immediate type allergy (anaphylaxis). In Central Europe they are predominantly elicited by stings of the honeybee or Vespula spp. Acute reactions are managed by symptomatic treatment. Long-term care includes patient education (allergen avoidance, course of action at re-sting) and prescription of an emergency kit for self-treatment. Venom immunotherapy is established as specific treatment for Hymenoptera venom allergic patients. Diagnosis of Hymenoptera venom anaphylaxis is based on history, skin tests and measurement of venom-specific serum IgE antibodies. "False negative" or "false positive" results are possible with all test methods. If standard tests are negative, additional tests using the patient's peripheral blood leucocytes can be useful. Venom immunotherapy is usually well tolerated. After reaching the maintenance dose, therapeutic efficacy should be assessed by a sting challenge test. If the patient again develops a systemic reaction, an increase of the maintenance dose (usually 200 microg are sufficient) nearly always induces protection. In most patients venom immunotherapy can be stopped after (3 to) 5 years. However, if there is an increased risk of sting anaphylaxis due to intense allergen exposure (e.g. in beekeepers) or if there are individual risk factors for particularly severe reactions (especially mastocytosis and/or elevated baseline serum tryptase concentration, severe cardiovascular disease), modifications of the standard venom immunotherapy are necessary.

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.