Characterization of oral immune cells in birch pollen-allergic patients: impact of the oral allergy syndrome and sublingual allergen immunotherapy on antigen-presenting cells.

BACKGROUND: A detailed characterization of human oral immune cells is needed to better understand local mechanisms associated with allergen capture following oral exposure. METHODS: Oral immune cells were characterized by immunohistology and immunofluorescence in biopsies obtained from three healthy individuals and 23 birch pollen-allergic patients with/without oral allergy syndrome (OAS), at baseline and after 5 months of sublingual allergen immunotherapy (AIT). RESULTS: Similar cell subsets (i.e., dendritic cells, mast cells, and T lymphocytes) were detected in oral tissues from healthy and birch pollen-allergic individuals. CD207+ Langerhans cells (LCs) and CD11c+ myeloid dendritic cells (DCs) were found in both the epithelium and the papillary layer of the Lamina propria (LP), whereas CD68+ macrophages, CD117+ mast cells, and CD4+ /CD8+ T cells were rather located in both the papillary and reticular layers of the LP. Patterns of oral immune cells were identical in patients with/without OAS, except lower numbers of CD207+ LCs found in oral tissues from patients with OAS, when compared to OAS- patients (P < 0.05). A 5-month sublingual AIT had a limited impact on oral immune cells, with only a significant increase in IgE+ cells in patients from the active group. Colocalization experiments confirmed that such IgE-expressing cells mostly encompass CD68+ macrophages located in the LP, and to a lesser extent CD207+ LCs in the epithelium. CONCLUSION: Two cell subsets contribute to antigen/allergen uptake in human oral tissues, including (i) CD207+ LCs possibly involved in the physiopathology of OAS and (ii) CD68+ macrophages likely critical in allergen capture via IgE-facilitated mechanisms during sublingual AIT.

Post-treatment efficacy of discontinuous treatment with 300IR 5-grass pollen sublingual tablet in adults with grass pollen-induced allergic rhinoconjunctivitis.

BACKGROUND: Sustained efficacy over three pollen seasons of pre- and co-seasonal treatment with 300IR 5-grass pollen sublingual tablet has been demonstrated in adults with moderate-severe grass pollen-associated allergic rhinoconjunctivitis. OBJECTIVE: To assess the efficacy of discontinuous treatment with 300IR 5-grass pollen sublingual tablet during the post-treatment pollen season of this long-term study. METHODS: Adults aged 18-50, sensitized to grass pollen, with a history of allergic rhinoconjunctivitis for more than two pollen seasons, and a retrospective rhinoconjunctivitis total symptom score ≥ 12 (0-18 scale), were randomized to receive Placebo or a 300IR tablet daily beginning either 4 months (4M) or 2 months (2M) prior to each pollen season and continuing for its duration for three consecutive years. They were followed over the subsequent immunotherapy-free pollen season. Post-treatment efficacy was evaluated using the Average Adjusted Symptom Score (AAdSS, adjusting the Rhinoconjunctivitis Total Symptom Score for rescue medication usage) during the post-treatment pollen period. Secondary endpoints included Average Rhinoconjunctivitis Total Symptom Score (ARTSS), Average Rescue Medication Score (ARMS), overall Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) score and safety evaluation. Efficacy variables were analysed using ancova. RESULTS: Overall, 435 patients contributed to the Year 4 efficacy analyses. The Least-Squares (LS) mean differences (95% confidence interval) in AAdSS between active treatment and Placebo over the fourth pollen period were -1.14 (-2.03; -0.26) (P = 0.0114) and -1.43 (-2.32; -0.53) (P = 0.0019) in the (4M) and (2M) groups, corresponding to -22.9% and -28.5% relative LS mean differences (vs. Placebo) respectively. The active groups also showed statistically significant differences compared to Placebo in ARTSS, ARMS and overall RQLQ score. No safety risk was identified during the post-treatment period. CONCLUSIONS AND CLINICAL RELEVANCE: Pre- and co-seasonal treatment with 300IR 5-grass pollen sublingual tablet administered discontinuously for three consecutive years is efficacious post-treatment, safe and well tolerated. Benefits of treatment were meaningful to patients.

Heterogeneity of antibody responses among clinical responders during grass pollen sublingual immunotherapy.

BACKGROUND: During allergen-specific sublingual immunotherapy (SLIT), the relevance of changes in specific IgE and IgG antibody titres to treatment efficacy remains to be evaluated at an individual patient level. OBJECTIVE: To investigate whether antibody responses can be used as biomarkers for SLIT efficacy. METHODS: Comprehensive quantitative, qualitative and functional analyses of allergen-specific IgA, IgE, IgG1-4 and IgM responses were performed using purified Phl p 1 to 12 allergens in sera, saliva and nasal secretions from 82 grass pollen allergic patients. These patients were enrolled in a randomized, double-blind placebo-controlled study and assessed in an allergen challenge chamber (ClinicalTrials.gov NCT00619827). Antibody responses were monitored in parallel to clinical responses before and after daily sublingual treatment for 4 months with either a grass pollen or a placebo tablet. RESULTS: A significant mean improvement (i.e. 33-40.6%) in rhinoconjunctivitis total symptom scores was observed in SLIT recipients, irrespective of their baseline patterns of IgE sensitization (i.e. narrow, intermediate, broad) to grass pollen allergens. SLIT did not induce any de novo IgE sensitization. Clinical responders encompassed both immunoreactive patients who exhibited strong increases in titres, affinity and/or blocking activity of grass-pollen-specific IgGs (representing 17% of treated patients), as well as patients with no detectable antibody responses distinguishing them from the placebo group. No significant changes were detected in antibody titres in saliva and nasal washes, even in clinical responders. CONCLUSIONS AND CLINICAL RELEVANCE: Sublingual immunotherapy with a grass pollen tablet is efficacious irrespective of the patients' baseline sensitization to either single or multiple grass pollen allergens. Seric IgG responses may contribute to SLIT-induced clinical tolerance in a fraction (i.e. 17%) of patients, but additional immune mechanisms are involved in most patients. Consequently, antibody responses cannot be used as a marker of SLIT efficacy at an individual patient level.

Safety and tolerability of NVA237, a once-daily long-acting muscarinic antagonist, in COPD patients.

NVA237 is a novel once-daily inhaled long-acting muscarinic antagonist administered via a dry powder inhaler. This randomized, double-blind, placebo-controlled study evaluated the safety, tolerability and bronchodilator efficacy of two doses of NVA237 (100 and 200 microg), versus placebo, in patients with moderate-to-severe COPD (forced expiratory volume in 1s [FEV(1)]>or=30% and <80% predicted and FEV(1)/forced vital capacity [FVC]<0.7, 30 min after inhalation of 80 microg ipratropium bromide). After appropriate washout periods, patients were randomized to treatment with NVA237 100 microg (n=92), NVA237 200 microg (n=98) or placebo (n=91) for 28 days. The primary objective was evaluation of safety, with efficacy measures included as secondary objectives. NVA237 was generally well tolerated and associated with a frequency and distribution of adverse events similar to placebo. Serious adverse events were uncommon and there was no evidence of adverse cardiovascular effects or unexpected events. Trough FEV(1) was significantly higher in those receiving NVA237 compared with placebo. For NVA237 100 microg the differences were 131 and 161 mL on Days 1 and 28, respectively (p<0.05), and for NVA237 200 microg the differences were 146 and 151 mL on Days 1 and 28, respectively (p<0.05). Peak FEV(1), FEV(1) at all timepoints up to 24h after dosing, and FEV(1) area under the curve during 5 min-5 h post-dosing were also significantly higher in both NVA237 groups, compared with placebo. Patients receiving NVA237 required fewer daily puffs of rescue medication and had a higher percentage of days on which rescue medication was not required. Overall, the present study provides further evidence of the safety, tolerability and bronchodilator efficacy of once-daily treatment with NVA237 100 and 200 microg in patients with moderate-to-severe COPD.

Caplacizumab reduces the frequency of major thromboembolic events, exacerbations and death in patients with acquired thrombotic thrombocytopenic purpura.

Essentials Acquired thrombotic thrombocytopenic purpura (aTTP) is linked with significant morbidity/mortality. Caplacizumab's effect on major thromboembolic (TE) events, exacerbations and death was studied. Fewer caplacizumab-treated patients had a major TE event, an exacerbation, or died versus placebo. Caplacizumab has the potential to reduce the acute morbidity and mortality associated with aTTP. SUMMARY: Background Acquired thrombotic thrombocytopenic purpura (aTTP) is a life-threatening autoimmune thrombotic microangiopathy. In spite of treatment with plasma exchange and immunosuppression, patients remain at risk for thrombotic complications, exacerbations, and death. In the phase II TITAN study, treatment with caplacizumab, an anti-von Willebrand factor Nanobody® was shown to reduce the time to confirmed platelet count normalization and exacerbations during treatment. Objective The clinical benefit of caplacizumab was further investigated in a post hoc analysis of the incidence of major thromboembolic events and exacerbations during the study drug treatment period and thrombotic thrombocytopenic purpura-related death during the study. Methods The Standardized Medical Dictionary for Regulatory Activities (MedDRA) Query (SMQ) for 'embolic and thrombotic events' was run to investigate the occurrence of major thromboembolic events and exacerbations in the safety population of the TITAN study, which consisted of 72 patients, of whom 35 received caplacizumab and 37 received placebo. Results Four events (one pulmonary embolism and three aTTP exacerbations) were reported in four patients in the caplacizumab group, and 20 such events were reported in 14 patients in the placebo group (two acute myocardial infarctions, one ischemic stroke, one hemorrhagic stroke, one pulmonary embolism, one deep vein thrombosis, one venous thrombosis, and 13 aTTP exacerbations). Two of the placebo-treated patients died from aTTP during the study. Conclusion In total, 11.4% of caplacizumab-treated patients and 43.2% of placebo-treated patients experienced one or more major thromboembolic events, experienced an exacerbation, or died. This analysis shows the potential for caplacizumab to reduce the risk of major thromboembolic morbidities and mortality associated with aTTP.

Losartan versus valsartan in the treatment of patients with mild to moderate essential hypertension: data from a multicenter, randomized, double-blind, 12-week trial.

BACKGROUND: Losartan, the first of the angiotensin II receptor blockers (ARBs) to be introduced, has been studied extensively in comparison with other classes of antihypertensive agents. Less research has been conducted on the efficacy and tolerability of losartan compared with that of other ARBs. OBJECTIVE: This randomized, multicenter, double-blind, parallel-group equivalence study was conducted to compare the antihypertensive efficacy and tolerability of a once-daily regimen of losartan with that of valsartan. METHODS: Patients > or = 21 years of age with mild to moderate hypertension, defined as a trough sitting diastolic blood pressure (SiDBP) between 95 and 115 mm Hg, were randomized to receive once-daily losartan (50 mg) or valsartan (80 mg) for 12 weeks. At the end of the sixth treatment week, patients in both groups with trough SiDBP > or = 90 mm Hg had their dose doubled for the remainder of the treatment period. Analysis of variance was used to compare treatment groups with respect to change in mean trough SiDBP from baseline to week 12. Within-treatment changes were analyzed using the paired t test. With at least 220 patients per treatment group, the study had 90% power to place a 90% CI on the difference between losartan and valsartan in SiDBP within the equivalence interval of +/- 2.5 mm Hg. RESULTS: A total of 495 patients were randomized, 247 to the losartan group and 248 to the valsartan group: 456 patients completed the study. Adjusted mean change from baseline values for trough SiDBP atthe end of 12 weeks of treatment were significantly different (P < 0.001) from zero in both the losartan group (-9.9 mm Hg) and the valsartan group (-10.1 mm Hg). At week 12, losartan was as effective as valsartan in lowering SiDBP, with a between-group difference of 0.2 mm Hg (90% CI, -1.3 to 1.7; P = 0.827). At week 6, the difference in SiDBP between groups was -1.3 mm Hg (90% CI, -2.7 to 0.0; P = 0.106). A similar pattern of results was obtained at weeks 6 and 12 for sitting systolic blood pressure. The percentage of patients reaching the SiDBP goal at week 6 (46% [112/2411 losartan; 42% [103/245] valsartan) and week 12 (57% [139/243] losartan; 59% [145/245] valsartan) was not significantly different between the treatment groups. Both losartan and valsartan were similarly well tolerated. Over the 12 weeks, the laboratory profiles of the 2 drugs were similar except for serum uric acid levels, which decreased from 6.0 to 5.7 mg/dL in the losartan group and increased from 5.9 to 6.0 mg/dL in the valsartan group (P = 0.001 for between-treatment difference). CONCLUSIONS: At starting and titrated doses, losartan and valsartan are similarly effective in reducing blood pressure in patients with mild to moderate hypertension. Losartan, but not valsartan, was associated with a decrease in serum uric acid levels.

Rats acquire spatial learning sets.

This experiment was designed to examine the development of a spatial learning set in rats and some of the variables influencing the retention of individual problems. The apparatus was a plus maze. At the beginning of each test, the rat was put on two arms, each in a different place. Food was present in one of the arms, but not in the other. The rat was then given a choice between these two places; the correct response was to return to the place that previously contained food (win-stay, lose-shift, response-reinforcement contingency). Fifty different two-choice spatial discriminations were given, each in a different location. At the end of testing, the mean percentage of correct responding for the first choice between the two places was 83%. Control procedures showed that the discriminative stimuli were distal, extramaze spatial stimuli. Variations of the procedure examined the influence of proactive interference and temporal delay on the memory for each discrimination. These results demonstrate that rats can develop a spatial learning set and provide new information about the characteristics of the memory underlying learning sets.

Adding omalizumab to the therapy of adolescents with persistent uncontrolled moderate--severe allergic asthma.

OBJECTIVE: This study aimed to evaluate the effectiveness of omalizumab among adolescents with moderate-severe allergic asthma inadequately controlled with inhaled corticosteroids. PATIENTS AND METHODS: Data from patients 12 to 17 years of age were pooled from 5 placebo-controlled registration trials of omalizumab. Impact on asthma control was assessed by need for rescue bursts of oral corticosteroids, lung function, symptom scores, and unscheduled office visits. RESULTS: In adolescents (n = 146), addition of omalizumab decreased mean number of rescue bursts (0.3 vs 0.9) versus placebo; relative risk 0.47 (95% confidence interval [CI], 0.22-0.99; P = .047). At study conclusion, mean forced expiratory volume in 1 second increased 268 mL (13.8%) in omalizumab-treated subjects versus 98 mL (5.5%) for placebo (least squares mean treatment difference 146 mL [95% CI, 19.4-272.6; P = .024]). Omalizumab significantly improved asthma symptom scores and reduced unscheduled office visits. CONCLUSION: Omalizumab added to baseline therapy improves measures of asthma control in adolescents with persistent moderate-severe allergic asthma.