A randomised placebo-controlled trial investigating efficacy and mechanisms of low-dose intradermal allergen immunotherapy in treatment of seasonal allergic rhinitis

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Author(s)
Slovick, Anna
Douiri, Abdel
Muir, Rachel
Guerra, Andrea
Tsioulos, Konstantinos
Haye, Evie
Lam, Emily PS
Kelly, Joanna
Peacock, Janet L
Ying, Sun
Shamji, Mohamed H
Cousins, David J
Durham, Stephen R
Till, Stephen J
Griffith University Author(s)
Year published
2016
Metadata
Show full item recordAbstract
Background
We previously reported that repeated low-dose grass pollen intradermal allergen injection suppresses allergen-induced cutaneous late-phase responses, comparable with conventional high-dose subcutaneous and sublingual immunotherapy.
Objective
To evaluate the efficacy and mechanism of grass pollen intradermal immunotherapy for treatment of allergic rhinitis.
Design
A Phase II, double-blind, randomised controlled parallel-group trial.
Setting
Single-centre UK study.
Participants
Adults aged 18–65 years, with grass pollen-induced allergic rhinoconjunctivitis.
Interventions
Seven 2-weekly intradermal injections ...
View more >Background We previously reported that repeated low-dose grass pollen intradermal allergen injection suppresses allergen-induced cutaneous late-phase responses, comparable with conventional high-dose subcutaneous and sublingual immunotherapy. Objective To evaluate the efficacy and mechanism of grass pollen intradermal immunotherapy for treatment of allergic rhinitis. Design A Phase II, double-blind, randomised controlled parallel-group trial. Setting Single-centre UK study. Participants Adults aged 18–65 years, with grass pollen-induced allergic rhinoconjunctivitis. Interventions Seven 2-weekly intradermal injections were given into the forearm, containing either Phleum pratense soluble grass pollen extract (7 ng of the major allergen Phl p 5) or histamine control. Main outcome measures The primary outcome was a combined symptom and medication score (CSMS) during the 2013 grass pollen season. Secondary clinical outcomes were overall symptom scores; individual symptoms scores for nose, mouth, eyes and lungs; overall medication scores; CSMSs during the peak season; visual analogue scale (VAS) scores for nose and eye symptoms; Mini Rhinitis Quality of Life Questionnaire scores; health-related quality-of-life scores (European Quality of Life-5 Dimensions, 5-levels); a global evaluation of symptoms, number of symptom-free and medication-free days; number of days when prednisolone was used; and adverse events. Mechanistic studies included measurement of late-phase skin response sizes, allergen-specific antibody titres, analysis of skin biopsies and basophil activation tests. Results There was no significant difference in CSMSs between treatment arms [difference in median area under curve (AUC) 14, 95% confidence interval (CI) –172.5 to 215.1; p = 0.80]. Paradoxically, among the secondary outcomes, nasal symptoms measured with daily scores were higher in the active arm (difference in median AUC 35, 95% CI 4.0 to 67.5; p = 0.03), with a trend for higher nasal symptoms measured by VASs (difference in median AUC 53, 95% CI –11.6 to 125.2; p = 0.05). No differences were seen in other clinical outcomes in the main intention-to-treat analysis. In mechanistic studies, active treatment increased P. pratense-, Phl p 1- and Phl p 5-specific immunoglobulin E (all p = 0.001) compared with the control. T cells cultured from skin biopsies of active intradermal immunotherapy subjects showed higher T helper type 2 cell (Th2) marker CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) expression (p < 0.05) and lower T helper type 1 cell marker CXCR3 [chemokine (C-X-C Motif) receptor 3] expression (p < 0.05), respectively. Interleukin 5 messenger ribonucleic acid, measured by microarray, was more highly expressed by cultured skin T cells in the active arm (p < 0.05). Late-phase skin responses to grass pollen were still inhibited up to 7 months after intradermal immunotherapy (p = 0.03), but not at 10–13 months’ time points. Limitations Grass pollen doses were not increased during the course, as our proof-of-concept trial showed that repeating the same doses was sufficient to achieve almost complete late-response suppression. Injections were not continued throughout the season, as previous subcutaneous grass pollen immunotherapy trials have demonstrated preseasonal regimen efficacy. Conclusions Intradermal immunotherapy suppressed late-phase skin responses to allergen, but was not clinically effective. The intervention appeared to have an immunological priming effect and exacerbated certain seasonal symptoms, notably in the nose. Future work Further studies on low-dose intradermal grass pollen immunotherapy are not recommended because of our demonstrated worsening of allergic rhinitis symptoms and immunological priming. The findings are of great significance for other novel immunotherapies targeting the skin, such as epicutaneous techniques. Trial registration
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View more >Background We previously reported that repeated low-dose grass pollen intradermal allergen injection suppresses allergen-induced cutaneous late-phase responses, comparable with conventional high-dose subcutaneous and sublingual immunotherapy. Objective To evaluate the efficacy and mechanism of grass pollen intradermal immunotherapy for treatment of allergic rhinitis. Design A Phase II, double-blind, randomised controlled parallel-group trial. Setting Single-centre UK study. Participants Adults aged 18–65 years, with grass pollen-induced allergic rhinoconjunctivitis. Interventions Seven 2-weekly intradermal injections were given into the forearm, containing either Phleum pratense soluble grass pollen extract (7 ng of the major allergen Phl p 5) or histamine control. Main outcome measures The primary outcome was a combined symptom and medication score (CSMS) during the 2013 grass pollen season. Secondary clinical outcomes were overall symptom scores; individual symptoms scores for nose, mouth, eyes and lungs; overall medication scores; CSMSs during the peak season; visual analogue scale (VAS) scores for nose and eye symptoms; Mini Rhinitis Quality of Life Questionnaire scores; health-related quality-of-life scores (European Quality of Life-5 Dimensions, 5-levels); a global evaluation of symptoms, number of symptom-free and medication-free days; number of days when prednisolone was used; and adverse events. Mechanistic studies included measurement of late-phase skin response sizes, allergen-specific antibody titres, analysis of skin biopsies and basophil activation tests. Results There was no significant difference in CSMSs between treatment arms [difference in median area under curve (AUC) 14, 95% confidence interval (CI) –172.5 to 215.1; p = 0.80]. Paradoxically, among the secondary outcomes, nasal symptoms measured with daily scores were higher in the active arm (difference in median AUC 35, 95% CI 4.0 to 67.5; p = 0.03), with a trend for higher nasal symptoms measured by VASs (difference in median AUC 53, 95% CI –11.6 to 125.2; p = 0.05). No differences were seen in other clinical outcomes in the main intention-to-treat analysis. In mechanistic studies, active treatment increased P. pratense-, Phl p 1- and Phl p 5-specific immunoglobulin E (all p = 0.001) compared with the control. T cells cultured from skin biopsies of active intradermal immunotherapy subjects showed higher T helper type 2 cell (Th2) marker CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) expression (p < 0.05) and lower T helper type 1 cell marker CXCR3 [chemokine (C-X-C Motif) receptor 3] expression (p < 0.05), respectively. Interleukin 5 messenger ribonucleic acid, measured by microarray, was more highly expressed by cultured skin T cells in the active arm (p < 0.05). Late-phase skin responses to grass pollen were still inhibited up to 7 months after intradermal immunotherapy (p = 0.03), but not at 10–13 months’ time points. Limitations Grass pollen doses were not increased during the course, as our proof-of-concept trial showed that repeating the same doses was sufficient to achieve almost complete late-response suppression. Injections were not continued throughout the season, as previous subcutaneous grass pollen immunotherapy trials have demonstrated preseasonal regimen efficacy. Conclusions Intradermal immunotherapy suppressed late-phase skin responses to allergen, but was not clinically effective. The intervention appeared to have an immunological priming effect and exacerbated certain seasonal symptoms, notably in the nose. Future work Further studies on low-dose intradermal grass pollen immunotherapy are not recommended because of our demonstrated worsening of allergic rhinitis symptoms and immunological priming. The findings are of great significance for other novel immunotherapies targeting the skin, such as epicutaneous techniques. Trial registration
View less >
Journal Title
Efficacy and Mechanism Evaluation
Volume
3
Issue
10
Copyright Statement
© Queen’s Printer and Controller of HMSO 2016. This work was produced by Slovick et al. under the terms of a commissioning
contract issued by the Secretary of State for Health. This issue may be freely reproduced for the purposes of private research and
study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement
is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be
addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre,
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Subject
Immunology
Allergy
Applied immunology (incl. antibody engineering, xenotransplantation and t-cell therapies)