204 IGE/IGG4 Ratio as a Possible Surrogate Marker of Clinical Efficacy During Allergen-Specific Immunotherapy with House Dust Mite Vaccines

BACKGROUND: Allergen immunotherapy (AIT) induces IgG4 antibodies with blocking effect, and long-term reduction of IgE. The problem of finding suitable surrogate paraclinical markers during AIT is currently very relevant. The aim was to evaluate the allergen-specific IgE/IgG4 ratio as an immunological correlate to clinical efficacy during AIT with House Dust Mite (HDM) allergen vaccines in Cuban asthmatic patients. METHODS: Three separate Double-Blind Placebo-Controlled clinical trials of AIT were performed using standardized registered allergen extracts of 3 HDM species: Dermatophagoides pteronyssinus, and the tropical species D. siboney and Blomia tropicalis. Each clinical trial included 40 asthmatic patients, totalling 120 individuals. Half of them received placebo. Allergen-specific IgE and IgG4 antibodies were measured by ELISA. Antibody titres were normalized and averaged between the 3 trials. Size effect was calculated as the Standard Mean Difference (SMD) between the active and placebo groups, using meta-analysis tools. RESULTS: There was a significant increase of IgG4 antibodies (P < 0.05) after 6 months of treatment. At 12 months, the IgG4 increase was even greater and the IgE decrease achieved also significance (P < 0.05). Thus, IgG4 induction appeared to precede IgE changes, in agreement with the possible role of the Treg/IL-10 response induction at the initial AIT phase. Moreover, 83% of patients showed a decrease of the IgE/IgG4 ratio in the active groups, whereas only 32% showed reduction in placebo groups. The IgE/IgG4 ratio was the immunological variable with the greatest size effect value (SMD = 0.81 95% CI, 0.71-0.91), as compared to changes in IgE or IgG4 levels, alone. The size effect value was close to the clinical effect (symptom-medication score SMD = 1.2 95% CI, 0.7-1.7). Per-patient changes in IgG4 levels, as well as, in the IgE/IgG4 ratio, were significantly correlated to the symptom-medication variable (r = 0.23, P = 0.04). CONCLUSIONS: These results support the use of the IgE/IgG4 ratio as an easily measurable marker for monitoring the allergen-specific immunity during AIT with HDM in asthmatic patients, and possibly, for predicting patient's clinical improvement after 1 year of treatment.