Subcutaneous immunotherapy and pharmacotherapy in seasonal allergic rhinitis: a comparison based on meta-analyses.

BACKGROUND: Allergen-specific subcutaneous immunotherapy (SCIT) of seasonal allergic rhinitis (SAR) is usually considered a "second-line," slow-acting, disease-modifying treatment. OBJECTIVE: We sought to test whether SCIT is as effective as antisymptomatic treatment in the control of symptoms in patients with SAR in the first year of treatment. METHODS: We reviewed meta-analyses with 5 or more randomized, double-blind, placebo-controlled trials of SCIT or antisymptomatic treatment in patients with SAR. We then selected trials measuring the total nasal symptom score (TNSS), the total symptom score (TSS), or both during the first pollen season after treatment initiation. Efficacy was determined as the percentage reduction in TSSs and TNSSs obtained with active treatment compared with placebo (relative clinical impact [RCI]) and the standardized mean difference (SMD) of treatment verses placebo (effect size [ES]). RESULTS: The weighted mean RCI of SCIT on TNSSs (-34.7% ± 6.8%) was higher than those of mometasone (-31.7% ± 16.7%, P < .00001) and montelukast (-6.3% ± 3.0%, P < .00001). The weighted mean RCI of SCIT on TSSs (-32.9% ± 12.7%) was higher than that of desloratadine (-12.0% ± 5.1%, P < .00001). The overall ES of SCIT in terms of TNSSs (SMD, -0.94; 95% CI, -1.45 to -0.43) was similar to that of mometasone (SMD, -0.47; 95% CI, -0.63 to -0.32; P > .05) and higher than that of montelukast (SMD, -0.24; 95% CI, -0.33 to -0.16; P < .05). The overall ES of SCIT in terms of TSSs (SMD, -0.86; 95% CI, -1.17 to -0.55) was comparable with that of desloratadine (SMD, -1.00; 95% CI, -1.68 to -0.32; P > .05). CONCLUSIONS: Our data provide indirect but consistent evidence that SCIT is at least as potent as pharmacotherapy in controlling the symptoms of SAR as early as the first season of treatment.

Strategies for recombinant allergen vaccines and fruitful results from first clinical studies.

Recombinant DNA technology has delivered the prospect of a new generation of preparations for allergen-specific immunotherapy. The first clinical studies with recombinant allergens have yielded encouraging results, suggesting that there is a good chance that such preparations will become available for use in the routine management of allergic disease.

Allergy immunotherapy with a hypoallergenic recombinant birch pollen allergen rBet v 1-FV in a randomized controlled trial.

BACKGROUND: Pollen extracts and chemically modified allergoids are used successfully in allergen immunotherapy (AIT). Recombinant extracts offer potential advantages with respect to pharmaceutical quality, standardization and dosing. A hypoallergenic recombinant folding variant of the major birch pollen allergen (rBet v 1-FV) was compared with an established native birch preparation. A pre-seasonal, randomized, actively controlled phase II study was performed in birch pollen allergic rhino-conjunctivitis with or without asthma, GINA I/ II. 51 patients (24 rBet v 1-FV, 27 native extract) started therapy with subcutaneous allergen immunotherapy (SCIT). Primary end-point was a combined symptom medication score (SMS), changes in nasal provocation test, visual rating score and specific antibody responses secondary end-points. FINDINGS: After one pre-seasonal treatment course the combined SMS was 5.86 (median; IQR: 14.02) for the rBet v 1-FV group versus 12.40 (median; IQR: 9.32) for the comparator during the three weeks pollen season (p = 0.330). After treatment in the second year, scores were 3.00 (median; IQR: 6.50) and 2.93 (4.86) respectively. Allergen tolerance in a nasal provocation test improved to a comparable extent in both groups. Significant increases in birch pollen-specific IgG1 and IgG4 were observed in both treatment groups following the first treatment phase and remained significantly raised until the end of the study. CONCLUSION: In this first in man, proof of concept phase II trial no statistical difference between rBet v 1-FV and an established natural pollen extract could be observed. rBet v 1-FV could be administered in higher doses than the native protein with no increase in adverse effects. TRIAL REGISTRATION: The study was registered in clinicalTrials.gov (NCT00266526).

Allergen specific immunotherapy has no influence on standard chemistry and hematology laboratory parameters in clinical studies.

BACKGROUND: A set of standard clinical chemistry and hematology parameters are usually measured during clinical studies. The major outcome of these standard tests is to control that the drug investigated does not lead to pathophysiological changes in respective organs or blood. In some cases based on scientific rationale such tests may not be needed. In this paper we report on a standard set of clinical chemistry and hematology laboratory parameters measured before and after treatment in three different immunotherapy studies, representing different routes of administration and different formulations. METHODS: Thirteen hematological laboratory parameters and eight clinical chemistry parameters were evaluated from three double-blind, placebo-controlled, randomized, multi-centre, phase III studies. The three studies include one with sublingual immunotherapy (n = 185), one subcutaneous immunotherapy trial with an aluminium hydroxide-adsorbed recombinant hypoallergenic Bet v1-FV (n = 211) and one with pre-seasonal subcutaneous immunotherapy with a 6-grass pollen allergoid (n = 154). RESULTS: Allergen specific immunotherapy with both administration forms and formulations respectively did not show any influence on any of the 21 laboratory parameters analyzed. Few patients had a change in laboratory parameters from within normal range at baseline to either below or above at end-of-treatment. No differences between active and placebo were seen with respect to number of patients with such a change. CONCLUSIONS: This study with different preparations and routes of application indicates that the value of repeated measurements of standard clinical chemistry and hematology parameters during allergen immunotherapy should be discussed further.

The placebo effect in allergen-specific immunotherapy trials.

BACKGROUND: Double-blind, placebo-controlled (DBPC) trials are the gold standard for demonstrating clinical efficacy and tolerability. The placebo effect, although an important feature in placebo-controlled studies, has never been systematically investigated in allergen-specific immunotherapy (SIT) studies. This study was performed to examine the placebo response in SIT trials that employed a baseline observational period and two treatment years using a symptom-medication-score (SMS) as the primary endpoint. METHODS: The placebo effect was evaluated in six DBPC SIT studies (five studies using subcutaneous SIT (SCIT) and one sublingual (SLIT)), two grass, two birch and two house dust mite (HDM) SIT, including a total of 472 adult patients treated with a placebo. The results were reported as changes from baseline of the SMS area under the curve after two years of perennial placebo therapy during the respective evaluation periods. Pollen counts and IgG4 levels were additionally analysed. RESULTS: Subcutaneously treated placebo patients displayed a marked decrease in the SMS. The mean placebo effect in the SCIT trials with comparable allergen exposure was up to 41% in the second treatment year and, in contrast, reached only 1% in the SLIT trial. Allergen exposure had an inverse influence on the placebo effect. No changes from baseline in allergen specific IgG4 antibodies were observed in the placebo-treated patients. CONCLUSIONS: SIT studies display a significant placebo effect, mainly observed in subcutaneous immunotherapy, with high variability depending on the route of application and allergen exposure. Our findings indicate the differential role of the placebo effect in SIT efficacy depending on the route of administration and pollen exposure.

Prospective validation of the "rhino conjunctivitis allergy-control-SCORE©" (RC-ACS©).

BACKGROUND: Recently we reported the validation of the "Allergy-Control-SCORE© (ACS)" which assesses symptom severity as well as medication use on three dimensions lung, nose and eyes. The aim of this study was to test the validity of the score for eyes and nose. METHODS: One-hundred-twenty-one consenting subjects (age 19-65y), including 81 patients with allergic rhino-conjunctivitis (RC) and 40 healthy controls, participated in the study. Patients rated daily nasal and eye symptoms using a 4-point scale (none, mild, moderate, and severe) and their use of anti-symptomatic medication. Validation criteria were pollen counts in the course of the study period. Discrimination capacity was analyzed by comparing the rhino-conjunctivitis Allergy-Control-SCORE© (RC-ACS©) values of allergic patients and healthy controls. Convergent reliability was assessed by correlating RC-ACS© values with the global severity of allergy, the quality of life, and the allergy-related medical consultations. Retest reliability was assessed by the correlation of the repeated measured RC-ACS© scores during each of two consecutive weeks. RESULTS: Convergent reliability analysis indicated a significant correlation between RC-Allergy-Control-SCORE© and global severity of allergy (r = 0.691; p < 0.0001), quality of life (r = 0.757; p < 0.0001) and allergy-related medical consultations (r = 0.329; p = 0.0019). RC-Allergy-Control-SCORE© showed a good retest reliability (r = 0.813; p < 0.001) and discriminated extremely well between allergic patients and healthy controls (Median: 3.7 range: 0; 14.1 vs. Median: 0 range: 0; 2.9; p < 0.001), with a sensitivity of 93.8% and a specificity of 92.5% at a score value of 0.786. CONCLUSIONS: The RC-ACS© can be considered as valid and reliable to assess the severity of rhino-conjunctivitis severity in clinical trials and observational studies.