Efficacy and safety of garadacimab, a factor XIIa inhibitor for hereditary angioedema prevention (VANGUARD): a global, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Hereditary angioedema is a rare and potentially life-threatening genetic disease that is associated with kallikrein-kinin system dysregulation. Garadacimab (CSL312), a novel, fully-human monoclonal antibody that inhibits activated factor XII (FXIIa), is being studied for the prevention of hereditary angioedema attacks. The aim of this study was to evaluate the efficacy and safety of once-monthly subcutaneous administrations of garadacimab as prophylaxis for hereditary angioedema. METHODS: VANGUARD was a pivotal, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial that recruited patients (aged ≥12 years) with type I or type II hereditary angioedema across seven countries (Canada, Germany, Hungary, Israel, Japan, the Netherlands, and the USA). Eligible patients were randomly assigned (3:2) to receive garadacimab or placebo for 6 months (182 days) by an interactive response technology (IRT) system. Randomisation was stratified by age (≤17 years vs >17 years) and baseline attack rate (1 to <3 attacks per month vs ≥3 attacks per month) for the adult group. The randomisation list and code were kept by the IRT provider during the study, with no access by site staff and funding representatives. All patients and investigational site staff, and representatives from the funder (or their delegates) with direct interaction with the study sites or patients, were masked to treatment assignment in a double-blind fashion. Randomly assigned patients received a 400-mg loading dose of subcutaneous garadacimab as two 200-mg injections or volume-matched placebo on day 1 of the treatment period, followed by five additional self-administered (or caregiver-administered) monthly doses of 200-mg subcutaneous garadacimab or volume-matched placebo. The primary endpoint was the investigator-assessed time-normalised number of hereditary angioedema attacks (number of hereditary angioedema attacks per month) during the 6-month treatment period (day 1 to day 182). Safety was evaluated in patients who received at least one dose of garadacimab or placebo. The study is registered with the EU Clinical Trials Register, 2020-000570-25 and ClinicalTrials.gov, NCT04656418. FINDINGS: Between Jan 27, 2021, and June 7, 2022, we screened 80 patients, 76 of whom were eligible to enter the run-in period of the study. Of 65 eligible patients with type I or type II hereditary angioedema, 39 were randomly assigned to garadacimab and 26 to placebo. One patient was randomly assigned in error and did not enter the treatment period (no dose of study drug received), resulting in 39 patients assigned to garadacimab and 25 patients assigned to placebo being included. 38 (59%) of 64 participants were female and 26 (41%) were male. 55 (86%) of 64 participants were White, six (9%) were Asian (Japanese), one (2%) was Black or African American, one (2%) was Native Hawaiian or Other Pacific Islander, and one (2%) was listed as other. During the 6-month treatment period (day 1 to day 182), the mean number of investigator-confirmed hereditary angioedema attacks per month was significantly lower in the garadacimab group (0·27, 95% CI 0·05 to 0·49) than in the placebo group (2·01, 1·44 to 2·57; p<0·0001), corresponding to a percentage difference in means of -87% (95% CI -96 to -58; p<0·0001). The median number of hereditary angioedema attacks per month was 0 (IQR 0·00-0·31) for garadacimab and 1·35 (1·00-3·20) for placebo. The most common treatment-emergent adverse events were upper-respiratory tract infections, nasopharyngitis, and headaches. FXIIa inhibition was not associated with an increased risk of bleeding or thromboembolic events. INTERPRETATION: Monthly garadacimab administration significantly reduced hereditary angioedema attacks in patients aged 12 years and older compared with placebo and had a favourable safety profile. Our results support the use of garadacimab as a potential prophylactic therapy for the treatment of hereditary angioedema in adolescents and adults. FUNDING: CSL Behring.

Prevention of Hereditary Angioedema Attacks with a Subcutaneous C1 Inhibitor.

BACKGROUND: Hereditary angioedema is a disabling, potentially fatal condition caused by deficiency (type I) or dysfunction (type II) of the C1 inhibitor protein. In a phase 2 trial, the use of CSL830, a nanofiltered C1 inhibitor preparation that is suitable for subcutaneous injection, resulted in functional levels of C1 inhibitor activity that would be expected to provide effective prophylaxis of attacks. METHODS: We conducted an international, prospective, multicenter, randomized, double-blind, placebo-controlled, dose-ranging, phase 3 trial to evaluate the efficacy and safety of self-administered subcutaneous CSL830 in patients with type I or type II hereditary angioedema who had had four or more attacks in a consecutive 2-month period within 3 months before screening. We randomly assigned the patients to one of four treatment sequences in a crossover design, each involving two 16-week treatment periods: either 40 IU or 60 IU of CSL830 per kilogram of body weight twice weekly followed by placebo, or vice versa. The primary efficacy end point was the number of attacks of angioedema. Secondary efficacy end points were the proportion of patients who had a response (≥50% reduction in the number of attacks with CSL830 as compared with placebo) and the number of times that rescue medication was used. RESULTS: Of the 90 patients who underwent randomization, 79 completed the trial. Both doses of CSL830, as compared with placebo, reduced the rate of attacks of hereditary angioedema (mean difference with 40 IU, -2.42 attacks per month; 95% confidence interval [CI], -3.38 to -1.46; and mean difference with 60 IU, -3.51 attacks per month; 95% CI, -4.21 to -2.81; P<0.001 for both comparisons). Response rates were 76% (95% CI, 62 to 87) in the 40-IU group and 90% (95% CI, 77 to 96) in the 60-IU group. The need for rescue medication was reduced from 5.55 uses per month in the placebo group to 1.13 uses per month in the 40-IU group and from 3.89 uses in the placebo group to 0.32 uses per month in the 60-IU group. Adverse events (most commonly mild and transient local site reactions) occurred in similar proportions of patients who received CSL830 and those who received placebo. CONCLUSIONS: In patients with hereditary angioedema, the prophylactic use of a subcutaneous C1 inhibitor twice weekly significantly reduced the frequency of acute attacks. (Funded by CSL Behring; COMPACT EudraCT number, 2013-000916-10 , and ClinicalTrials.gov number, NCT01912456 .).

SQ house dust mite sublingual immunotherapy tablet subgroup efficacy and local application site reaction duration.

BACKGROUND: Allergic rhinitis with or without conjunctivitis (AR/C) is common, necessitating evaluation of SQ house dust mite (HDM) sublingual immunotherapy (SLIT)-tablet efficacy in various subgroups. OBJECTIVE: To evaluate 12 SQ-HDM efficacy and safety across subgroups, and the onset, duration, and recurrence of local application site reactions. METHODS: Subgroup (age, sex, race, asthma status, and allergen sensitization) efficacy was assessed using pooled data from 2 previously described trials of daily 12 SQ-HDM vs placebo for AR/C (n = 2,138). Efficacy was measured by average total combined rhinitis score (TCRS; rhinitis daily symptom plus medication score) during the last 8 weeks of treatment. Safety in subgroups and local application site reaction onset, duration, and recurrence were evaluated using pooled data from 5 previously described trials of SQ HDM SLIT-tablet (n = 2,923). RESULTS: Significant (based on 95% confidence intervals [CIs]) reduction in TCRS was seen with 12 SQ-HDM relative to placebo across all subgroups, with TCRS improvements ranging from 15% to 25%. The AE profile was generally similar within subgroups. Approximately 95% of local application site reactions were mild to moderate in severity. Median duration on day 1 of treatment for the most common local application site reactions (throat irritation, oral pruritus, ear pruritus, and lip swelling) ranged from 30 to 60 minutes; median first day of onset ranged from days 1 to 4 of treatment; median days that reactions recurred ranged from 3 to 12 days. CONCLUSION: Treatment with 12 SQ-HDM consistently improved symptoms and was well tolerated in relevant subgroups of subjects with HDM AR/C. Local application site reactions to 12 SQ-HDM were typically mild to moderate and transient.

Efficacy of house dust mite sublingual immunotherapy tablet in North American adolescents and adults in a randomized, placebo-controlled trial.

BACKGROUND: The house dust mite (HDM) sublingual immunotherapy (SLIT) tablet (MK-8237; Merck & Co, Kenilworth, NJ/ALK-Abelló, Hørsholm, Denmark) has demonstrated beneficial effects on allergic rhinoconjunctivitis and asthma outcomes in European trials. OBJECTIVE: This is the first trial to assess the efficacy/safety of HDM SLIT-tablets in North American subjects with HDM-induced allergic rhinitis with or without conjunctivitis (AR/C). METHODS: In this double-blind, multicenter trial (NCT01700192) 1482 subjects (aged ≥12 years) with HDM-induced AR/C with or without asthma were randomized to a daily SQ HDM SLIT-tablet (12 SQ-HDM dose) or placebo for up to approximately 52 weeks. A rhinitis daily symptom score (DSS; 4 nasal symptoms, maximum score = 12) of 6 or greater, or 5 or greater with 1 symptom being severe, on 5 of 7 consecutive days before randomization was required. The primary end point was the average total combined rhinitis score, which was defined as the rhinitis DSS plus rhinitis daily medication score (DMS), during the last 8 treatment weeks. RESULTS: Treatment with 12 SQ-HDM improved the total combined rhinitis score by 17% (95% CI, 10% to 25%) versus placebo. Improvements versus placebo in the secondary end points of average rhinitis DSS, rhinitis DMS, total combined rhinoconjunctivitis score, and visual analog scale-assessed AR/C symptoms were 16%, 18%, 17%, and 16%, respectively. All nominal P values were less than .001 versus placebo, except rhinitis DMS (P = 0.15). No treatment-related adverse events meeting the International Council on Harmonization definition of a serious adverse event were reported; 1 nonserious treatment-related systemic allergic reaction occurred (assessed as moderate intensity) at first administration under medical supervision and was treated with epinephrine. CONCLUSIONS: In the first North American trial of use of a SLIT-tablet for HDM allergy, 12 SQ-HDM was well tolerated and improved HDM-induced rhinitis symptoms in adults and adolescents.

Effect of Varying Doses of Epicutaneous Immunotherapy vs Placebo on Reaction to Peanut Protein Exposure Among Patients With Peanut Sensitivity: A Randomized Clinical Trial.

Importance: Epicutaneous immunotherapy may have potential for treating peanut allergy but has been assessed only in preclinical and early human trials. Objective: To determine the optimal dose, adverse events (AEs), and efficacy of a peanut patch for peanut allergy treatment. Design, Setting, and Participants: Phase 2b double-blind, placebo-controlled, dose-ranging trial of a peanut patch in peanut-allergic patients (6-55 years) from 22 centers, with a 2-year, open-label extension (July 31, 2012-July 31, 2014; extension completed September 29, 2016). Patients (n = 221) had peanut sensitivity and positive double-blind, placebo-controlled food challenges to an eliciting dose of 300 mg or less of peanut protein. Interventions: Randomly assigned patients (1:1:1:1) received an epicutaneous peanut patch containing 50 µg (n = 53), 100 µg (n = 56), or 250 µg (n = 56) of peanut protein or a placebo patch (n = 56). Following daily patch application for 12 months, patients underwent a double-blind, placebo-controlled food challenge to establish changes in eliciting dose. Main Outcomes and Measures: The primary efficacy end point was percentage of treatment responders (eliciting dose: ≥10-times increase and/or reaching ≥1000 mg of peanut protein) in each group vs placebo patch after 12 months. Secondary end points included percentage of responders by age strata and treatment-emergent adverse events (TEAEs). Results: Of 221 patients randomized (median age, 11 years [quartile 1, quartile 3: 8, 16]; 37.6% female), 93.7% completed the trial. A significant absolute difference in response rates was observed at month 12 between the 250-µg (n = 28; 50.0%) and placebo (n = 14; 25.0%) patches (difference, 25.0%; 95% CI, 7.7%-42.3%; P = .01). No significant difference was seen between the placebo patch vs the 100-µg patch. Because of statistical testing hierarchical rules, the 50-µg patch was not compared with placebo. Interaction by age group was only significant for the 250-µg patch (P = .04). In the 6- to 11-year stratum, the response rate difference between the 250-µg (n = 15; 53.6%) and placebo (n = 6; 19.4%) patches was 34.2% (95% CI, 11.1%-57.3%; P = .008); adolescents/adults showed no difference between the 250-µg (n = 13; 46.4%) and placebo (n = 8; 32.0%) patches: 14.4% (95% CI, -11.6% to 40.4%; P = .40). No dose-related serious AEs were observed. The percentage of patients with 1 or more TEAEs (largely local skin reactions) was similar across all groups in year 1: 50-µg patch = 100%, 100-µg patch = 98.2%, 250-µg patch = 100%, and placebo patch = 92.9%. The overall median adherence was 97.6% after 1 year; the dropout rate for treatment-related AEs was 0.9%. Conclusions and Relevance: In this dose-ranging trial of peanut-allergic patients, the 250-µg peanut patch resulted in significant treatment response vs placebo patch following 12 months of therapy. These findings warrant a phase 3 trial. Trial Registration: clinicaltrials.gov Identifier: NCT01675882.

Varying Doses of Epicutaneous Immunotherapy With Viaskin Milk vs Placebo in Children With Cow's Milk Allergy: A Randomized Clinical Trial.

Importance: No approved treatment exists for allergen-specific immunoglobulin E (IgE)-mediated cow's milk allergy (CMA), a common childhood food allergy. Objective: To assess dose, efficacy, and safety of epicutaneous immunotherapy with Viaskin milk in children with IgE-mediated CMA. Design, Setting, and Participants: A phase 1/2, 2-part, randomized, double-blind, placebo-controlled dose-ranging clinical trial in children aged 2 to 17 years with IgE-mediated CMA was conducted between November 2014 through December 2017. It took place at 17 trial sites in the US and Canada. Current CMA was confirmed by double-blind, placebo-controlled food challenge at study entry. Part A assessed the short-term safety of 150 µg, 300 µg, or 500 µg of Viaskin milk; part B evaluated the efficacy and safety of the 3 doses vs placebo over 12 months of treatment. Of the 308 screened participants with physician-diagnosed CMA, 198 met eligibility criteria (including an eliciting dose 300 mg or less) and were randomized. Intervention: Safety of Viaskin milk (150-µg, 300-µg, or 500-µg doses) was evaluated over a 3-week period (part A). In part B, 180 additional participants were randomized to receive Viaskin milk at doses of 150 µg, 300 µg, or 500 µg or placebo (1:1:1:1) for 12 months. Main Outcomes and Measures: The primary outcome was the proportion of treatment responders, defined as a 10-fold or more increase in the cumulative reactive dose of cow's milk protein (reaching at least 144 mg) or a cumulative reactive dose of cow's milk protein at 1444 mg or more at the month 12 double-blind, placebo-controlled food challenge. Results: A total of 95.5% of the randomized participants (mean [SD] age, 8 [4.17] years; 124 of 198 were male [62.6%]) completed treatment. The highest response rate was observed in participants who received Viaskin milk at the 300-µg dose with 24 of 49 responders (49.0%) overall vs 16 of 53 responders (30.2%) in the placebo group (odds ratio, 2.19; 95% CI, 0.91-5.41; P = .09), highest in the 2 to 11 years age group (22 of 38 [57.9%] vs 13 of 40 [32.5%]; P = .04). Most treatment-emergent adverse events were mild or moderate application-site reactions. One participant in the 500-µg Viaskin milk dose group experienced treatment-related anaphylaxis. Conclusions and Relevance: In this randomized clinical trial, 12 months of daily epicutaneous immunotherapy with a dose of Viaskin milk at 300 µg was associated with a statistically significant treatment response in 2- to 11-year-old children with IgE-mediated CMA. Treatment-related anaphylaxis and treatment-related discontinuation rates were low. Further research is needed to explore Viaskin milk as a viable treatment option for children with IgE-mediated CMA. Trial Registration: ClinicalTrials.gov Identifier: NCT02223182.

Long-term efficacy of fixed-dose omalizumab for patients with severe chronic spontaneous urticaria.

BACKGROUND: Treatment of chronic urticaria is challenging because many patients are refractory to or experience adverse effects with conventional therapy. Recently, short-term efficacy of omalizumab has been demonstrated. OBJECTIVE: To determine both the short- and long-term efficacy of omalizumab in the treatment of chronic urticaria. METHODS: Sixteen patients with severe chronic spontaneous urticaria at our center received omalizumab, 150 mg every 2 to 4 weeks, between 2010 and 2011. Disease severity was measured by urticaria activity scores before the first injection, during treatment, and at most recent follow-up, ranging from 9 to 24 months. Duration of therapy was determined individually for each patient. In this retrospective analysis, outcome measures include number of treatments required to induce remission and long-term remission sustainability. RESULTS: Ten patients had remission of urticaria after their first injection (62%). Four patients required 2 to 6 treatments to achieve remission. Two patients discontinued treatment after 2 injections. Of the 14 patients who initially benefited (88%), 4 remain in remission more than 9 months after their last treatments. Seven patients continue to achieve remission with maintenance omalizumab, dosed at intervals appropriate for individual remission duration. Three patients became refractory and discontinued treatment (19%). CONCLUSION: Omalizumab is an effective treatment for inducing and maintaining long-term remission for patients with severe chronic urticaria. Onset of remission is rapid, although duration is variable, with some patients requiring maintenance treatment. Large-scale randomized trials are necessary to confirm our findings that support the long-term efficacy of anti-IgE therapy for the treatment of this disease.

Pathophysiology of bradykinin and histamine mediated angioedema.

Angioedema is characterized by swelling localized to the subcutaneous and submucosal tissues. This review provides an overview of angioedema, including the different types, triggers, and underlying pathophysiologic mechanisms. Hereditary and acquired angioedema are caused by dysregulation of the complement and kinin pathways. In contrast, drug-induced and allergic angioedema involve the activation of the immune system and release of vasoactive mediators. Recent advances in the understanding of the pathophysiology of angioedema have led to the development of targeted therapies, such as monoclonal antibodies, bradykinin receptor antagonists, and complement inhibitors, which promise to improve clinical outcomes in patients with this challenging condition. To accurately diagnose and manage angioedema, an understanding of this condition's complex and varied pathophysiology is both necessary and critical.

Diphenhydramine: Time to Move on?

Diphenhydramine is one of the most widely available, longest-used antihistamine medications but has many side effects including sedation and risk of toxicity in overdose including cardiac toxicity. It is frequently inappropriately used when newer, more favorable antihistamine medications are available. Second-generation antihistamines are also widely available and affordable, with many of the same desired effects as diphenhydramine and fewer, if any, of the undesirable side effects. Because of the negative side effects and wide availability of alternative antihistamine medications, it is definitively time to move on from diphenhydramine.

Cannabis: An Emerging Occupational Allergen?

Cannabis is the most commonly used psychoactive drug. In recent years, Cannabis access has expanded for both medicinal and non-medicinal has grown. This is also marked with an increasing number of individuals gaining employment in this emerging industry. In this article, we briefly discuss the health hazards associated with Cannabis exposure with an emphasis on the potential for allergic reactions in workers who handle and process Cannabis plant.

Occupational Allergies to Cannabis.

Within the last decade there has been a significant expansion in access to cannabis for medicinal and adult nonmedical use in the United States and abroad. This has resulted in a rapidly growing and diverse workforce that is involved with the growth, cultivation, handling, and dispensing of the cannabis plant and its products. The objective of this review was to educate physicians on the complexities associated with the health effects of cannabis exposure, the nature of these exposures, and the future practical challenges of managing these in the context of allergic disease. We will detail the biological hazards related to typical modern cannabis industry operations that may potentially drive allergic sensitization in workers. We will highlight the limitations that have hindered the development of objective diagnostic measures that are essential in separating "true" cannabis allergies from nonspecific reactions/irritations that "mimic" allergy-like symptoms. Finally, we will discuss recent advances in the basic and translational scientific research that will aid the development of diagnostic tools and therapeutic standards to serve optimal management of cannabis allergies across the occupational spectrum.

Impact of Adverse Event Solicitation on the Safety Profile of SQ House Dust Mite Sublingual Immunotherapy Tablet.

BACKGROUND: It has been recommended that sublingual immunotherapy (SLIT) safety be assessed using solicited adverse event (AE) collection methods. OBJECTIVES: The objectives of this study were to describe the impact on the safety profile of SQ house dust mite (HDM) SLIT-tablet (12 SQ-HDM dose) when prespecified local application site reactions were solicited versus unsolicited, and discuss ramifications of AE solicitation. METHODS: Subjects were randomized to daily 12 SQ-HDM or placebo for up to 52 weeks in 4 double-blinded, multicenter trials. In one trial (NCT01700192; N = 1272), subjects documented daily the presence or absence of 15 World Allergy Organization-defined local application site reactions using a structured questionnaire of closed-ended questions (solicited AEs). Subjects in the other trials were not asked about specific AEs (unsolicited AEs), and AE data were pooled (N = 1287). Analysis was limited to adults aged 18 to 65 years. RESULTS: Whether AEs were solicited or unsolicited, the most common AEs leading to study discontinuation with 12 SQ-HDM were throat irritation and oral pruritus. Approximately 95% of treatment-related AEs were mild to moderate. Placebo-subtracted frequencies of local application site reactions associated with 12 SQ-HDM were higher when solicited versus unsolicited (ie, throat irritation, 46% vs 13%, respectively; oral pruritus, 47% vs 17%; ear pruritus, 40% vs 4%; mouth swelling, 8% vs 2%; tongue ulceration, 10% vs 0%; mouth ulceration, 7% vs <1%). CONCLUSIONS: Qualitatively, the safety profile of 12 SQ-HDM was similar when AEs were solicited versus unsolicited; hence, solicitation did not alter the safety profile. Higher observed frequencies of local application site reactions with AE solicitation may be partly due to suggestive reporting bias, as observed in placebo-treated subjects.

Anaphylaxis following a transvaginal ultrasound.

Polyethylene glycol is a ubiquitous, water-soluble, organic compound found in a wide variety of commercially available products. While generally a benign substance, in rare instances, it can induce hypersensitivity reactions. Herein, we describe a case of anaphylaxis to polyethylene glycol-containing lubricating gel used for a transvaginal ultrasound. This case highlights the importance of early recognition of a rare cause of anaphylaxis that may occur in the health-care setting. It is of particular importance given the widespread use of similar lubricating materials in multiple practice settings for the use of internal examinations and ultrasonography.

Specific IgE response to purified and recombinant allergens in latex allergy.

BACKGROUND: In recent years, allergy to natural rubber latex has emerged as a major allergy among certain occupational groups and patients with underlying diseases. The sensitization and development of latex allergy has been attributed to exposure to products containing residual latex proteins. Although improved manufacturing procedures resulted in a considerable reduction of new cases, the potential risk for some patient groups is still great. In addition the prevalent cross-reactivity of latex proteins with other food allergens poses a major concern. A number of purified allergens and a few commercial kits are currently available, but no concerted effort was undertaken to evaluate them. METHODS: We studied 11 purified latex allergens, Hev b 1 to Hev b 10, and Hev b 13 along with several crude allergen extracts and two commercial ImmunoCAP assays to evaluate specific IgE antibody in the sera from latex allergic patients and controls. Health care workers and spina bifida patients with clinical symptoms of latex allergy, spina bifida patients without latex allergy, and non-atopic health care workers have been studied. RESULTS: The results suggest that Hev b 2, 5, 6, and 13 together identified over 80 percent health care workers with latex allergy, while Hev b 6 along with Hev b 1 or 3 detected specific IgE antibody in all sera studied from patients with spina bifida and latex allergy. The ImmunoCAP results using both Hev b 5 amplified and non-amplified closely agreed with the clinical diagnosis of latex allergy in health care workers and in spina bifida. CONCLUSION: Although the purified allergens and crude extracts reacted diversely with IgE from different patient groups, the results indicated that use of certain combinations of purified recombinant antigens will be useful in commercial kits or in in-house assays for detecting specific IgE antibody in the sera. The results suggest that a combination of Hev b 2, 3, 5, 6, and 13 together detected specific IgE in 80% of the sera from latex allergic patients. Both ImmunoCAPs correctly identified over 95% of latex allergic patients, however, showed reactivity with a few normal control subjects.

Prolonged efficacy of the 300IR 5-grass pollen tablet up to 2 years after treatment cessation, as measured by a recommended daily combined score.

BACKGROUND: The 300IR (index of reactivity) 5-grass pollen tablet has favorable short-term and sustained clinical efficacy in patients with grass pollen-induced allergic rhinoconjunctivitis (ARC). Here, we report maintenance of efficacy and safety over 2 years following treatment discontinuation. METHODS: Randomized, double-blind, placebo-controlled, parallel-group, multicenter Phase 3 trial in patients aged 18-50 years with ARC. During study years 1-3, patients received a daily sublingual tablet containing either 300IR 5-grass pollen extract or placebo, according to a discontinuous pre- and coseasonal protocol. Study years 4 and 5 were treatment-free. In response to health authorities' recommendations, the daily combined score (DCS) was assessed in a post-hoc analysis as the efficacy endpoint. Components of the DCS were daily rhinoconjunctivitis total symptom score (DRTSS) and daily rescue medication score (DRMS). RESULTS: 633 patients with ARC were randomized to placebo (n = 219) or 300IR 5-grass pollen tablet, beginning 4 months (4 M, n = 207) or 2 months (2 M, n = 207) prior to the estimated start of the grass pollen season and continuing until season's end. During the first post-treatment year, a statistically significant difference versus placebo in least squares (LS) mean DCS was noted in patients previously receiving active treatment (300IR (2 M) point estimate: -0.16, 95% confidence interval (CI95%): [-0.26, -0.06], p = 0.0019; -31.1%; 300IR (4 M) point estimate: -0.13, CI95%: [-0.23, -0.03], p = 0.0103, -25.3%). During the second post-treatment year, patients in the 300IR (4 M) group, but not the 300IR (2 M) group, showed a statistically significant difference in LS mean DCS versus placebo (point estimate: -0.11, CI95%: [-0.21; 0.00], p = 0.0478, -28.1%). This significant efficacy seen during the post-treatment years in patients previously treated with 5-grass pollen tablet compared favorably with that during the 3 prior years of active treatment. A statistically significant difference versus placebo was also noted in secondary efficacy measures in both post-treatment years (except for DRTSS in year 5). In the absence of any active treatment, the safety profile was similar in the active groups versus placebo group during either post-treatment year. CONCLUSIONS: In adults with grass pollen-associated ARC, 5-grass pollen tablet therapy beginning 4 months before the pollen season and continuing to season's end demonstrated efficacy across all variables during active treatment, and this effect was prolonged for up to 2 years post-treatment. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00418379.

Evaluating chronic urticaria patients for allergies, infections, or autoimmune disorders.

Urticaria is a common disorder affecting one-fifth of the world's population. The pathophysiology is characterized by an increased propensity for mast cell degranulation with the release of potent mediators into the dermal and subdermal tissues with resulting vasoactive, chemotactic, and inflammatory effects. The final clinical manifestation of the typical urticarial lesion is the effect of several diverse effects and causes. The general classification is acute, chronic, and physical urticaria. In general, allergenic triggers can be identified in between 60-80% of acute urticarias. Physical urticarias are characterized by the onset after the specific inciting stimulus, which can reproduce the characteristic lesion which is usually of shorter duration (with the exception of delayed pressure urticaria). Chronic idiopathic urticaria is associated with thyroid autoimmunity and, more recently, anti-mast cell receptor antibodies. An extensive work-up is usually not indicated or helpful in identifying a cause. Food or other allergens are rare causes of this type of presentation. The evaluation and work-up is dependent on clues identified by history. The treatment is removal of specific and non-specific triggers and the use of symptomatic medications generally attenuating the mediator effects.