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Mechanistic correlates of clinical responses to omalizumab in the setting of oral immunotherapy for milk allergy.

ABSTRACT: BACKGROUND:In our recent clinical trial, the addition of omalizumab to oral immunotherapy (OIT) for milk allergy improved safety, but no significant clinical benefit was detected. OBJECTIVE:We sought to investigate mechanisms by which omalizumab modulates immunity in the context of OIT and to identify baseline biomarkers that predict subgroups of patients most likely to benefit from omalizumab. METHODS:Blood was obtained at baseline and multiple time points during a placebo-controlled trial of OIT for milk allergy in which subjects were randomized to receive omalizumab or placebo. Immunologic outcomes included measurement of basophil CD63 expression and histamine release and casein-specific CD4+ regulatory T-cell proliferation. Biomarkers were analyzed in relationship to measurements of safety and efficacy. RESULTS:Milk-induced basophil CD63 expression was transiently reduced in whole blood samples from both omalizumab- and placebo-treated subjects. However, IgE-dependent histamine release increased in washed cell preparations from omalizumab- but not placebo-treated subjects. No increase in regulatory T-cell frequency was evident in either group. Subjects with lower rates of adverse reactions, regardless of arm, experienced better clinical outcomes. Pre-OIT basophil reactivity positively associated with occurrence of symptoms during OIT, whereas the baseline milk IgE/total IgE ratio correlated with the likelihood of achieving sustained unresponsiveness. A combination of baseline basophil and serologic biomarkers defined a subset of patients in which adjunctive therapy with omalizumab was associated with attainment of sustained unresponsiveness and a reduction in adverse reactions. CONCLUSIONS:Combining omalizumab therapy with milk OIT led to distinct alterations in basophil reactivity but not T-cell responses. Baseline biomarkers can identify subjects most likely to benefit from adjunctive therapy with omalizumab.

SUBMITTER: Frischmeyer-Guerrerio PA

PROVIDER: S-EPMC5632581 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Mechanistic correlates of clinical responses to omalizumab in the setting of oral immunotherapy for milk allergy.

Frischmeyer-Guerrerio Pamela A PA Masilamani Madhan M Gu Wenjuan W Brittain Erica E Wood Robert R Kim Jennifer J Nadeau Kari K Jarvinen Kirsi M KM Grishin Alexander A Lindblad Robert R Sampson Hugh A HA

The Journal of allergy and clinical immunology 20170413 4

<h4>Background</h4>In our recent clinical trial, the addition of omalizumab to oral immunotherapy (OIT) for milk allergy improved safety, but no significant clinical benefit was detected.<h4>Objective</h4>We sought to investigate mechanisms by which omalizumab modulates immunity in the context of OIT and to identify baseline biomarkers that predict subgroups of patients most likely to benefit from omalizumab.<h4>Methods</h4>Blood was obtained at baseline and multiple time points during a placebo ...[more]

PMID: 28414061

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Project description:BackgroundOral immunotherapy (OIT) and sublingual immunotherapy (SLIT) are potential therapies for food allergy, but the optimal method of administration, mechanism of action, and duration of response remain unknown.ObjectiveWe sought to explore the safety and efficacy of OIT and SLIT for the treatment of cow's milk (CM) allergy.MethodsWe randomized children with CM allergy to SLIT alone or SLIT followed by OIT. After screening double-blind, placebo-controlled food challenges and initial SLIT escalation, subjects either continued SLIT escalation to 7 mg daily or began OIT to either 1000 mg (the OITB group) or 2000 mg (the OITA group) of milk protein. They were challenged with 8 g of milk protein after 12 and 60 weeks of maintenance. If they passed the 60-week challenge, therapy was withdrawn, with challenges repeated 1 and 6 weeks later. Mechanistic correlates included end point titration skin prick testing and measurement of CM-specific IgE and IgG(4) levels, basophil histamine release, constitutive CD63 expression, CD203c expression, and intracellular spleen tyrosine kinase levels.ResultsThirty subjects with CM allergy aged 6 to 17 years were enrolled. After therapy, 1 of 10 subjects in the SLIT group, 6 of 10 subjects in the SLIT/OITB group, and 8 of 10 subjects in the OITA group passed the 8-g challenge (P = .002, SLIT vs OIT). After avoidance, 6 of 15 subjects (3 of 6 subjects in the OITB group and 3 of 8 subjects in the OITA group) regained reactivity, 2 after only 1 week. Although the overall reaction rate was similar, systemic reactions were more common during OIT than during SLIT. By the end of therapy, titrated CM skin prick test results and CD63 and CD203c expression decreased and CM-specific IgG(4) levels increased in all groups, whereas CM-specific IgE and spontaneous histamine release values decreased in only the OIT group.ConclusionOIT was more efficacious for desensitization to CM than SLIT alone but was accompanied by more systemic side effects. Clinical desensitization was lost in some cases within 1 week off therapy.

Project description:Abstract Background There are no universally accepted criteria for discontinuing milk oral immunotherapy (MOIT) in patients with persistent cow milk allergy (CMA) and little data are available on predictive risk factors for dropping out from oral immunotherapy (OIT), due to allergic reactions or other reasons. Methods We retrospectively reviewed clinical records of patients with persistent severe CMA undergoing MOIT in a tertiary care center hospital to investigate risk factors associated with discontinuation of OIT. Persistent and severe allergy was defined as the history of systemic reactions and any milk protein‐specific IgE level >85 kU/ml. All patients were first admitted for an in‐hospital rush phase eventually followed by an at‐home dose increase. We evaluated the effect of various factors on two primary outcomes: the highest dose of milk ingested during the in‐hospital rush phase and during the home OIT phase. Results We identified 391 patients, of whom 131 met the inclusion criteria for the retrospective study, 54 females and 77 males. Data of the home OIT phase were available for 104 patients (27%). Regarding the home OIT outcome, an association for having a cow milk avoiding diet was found with reaching a dose below 10 ml during the in‐hospital rush phase (relative risks [RR]: 2.33, confidence interval [CI]: 0.85; 6.42), an age above than 10 years from the time of admission (RR: 3.29, CI: 0.85; 12.73), and a higher total number of reactions occurred during the hospitalization (RR: 1.54, CI: 1.02; 2.32), whereas the presence of respiratory reactions with wheezing (RR: 1.93, CI: 0.49; 7.61) and an IM adrenaline use was related to a higher risk of having an OIT still in progress (RR: 5.47, CI: 0.33; 7.73). Conclusions In this cohort of children with persistent CMA undergoing OIT who presented with respiratory reactions with wheezing, the development of anaphylaxis with the need for IM adrenaline, and age above 10 years were predictors of poor long‐term outcome. Key Messages This study shows that wheezing reactions during the in‐hospital phase admission, discharge with a dose below 10 ml, use of IM epinephrine, and older age (over 10 years) were all risk factors for OIT discontinuation. The provided phenotype of patients with a severe milk allergy who are more likely to fail OIT can help pediatricians to provide to their parents the elements to properly decide the most appropriate approach. Risk factors for discontinuing oral immunotherapy.

Dataset Information

Mechanistic correlates of clinical responses to omalizumab in the setting of oral immunotherapy for milk allergy.

Publications

Mechanistic correlates of clinical responses to omalizumab in the setting of oral immunotherapy for milk allergy.

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