Comparative efficacy and tolerance of intralymphatic, subcutaneous and sublingual immunotherapy for pollen-induced allergic rhinitis: a network meta-analysis

Review question / Objective: What is the effect of intralymphatic, subcutaneous and sublingual immunotherapy for pollen-induced allergic rhinitis. Condition being studied: Immunotherapy is the classic treatment for allergic rhinitis. Intralymphatic immunotherapy is a new type of treatment. Currently, no studies have compared subcutaneous, sublingual and intralymphatic sublingual immunotherapy. At present, there is no review to compare the efficacy of intralymphatic, subcutaneous and sublingual immunotherapy for pollen-induced allergic rhinitis.

Intralymphatic immunotherapy for allergic rhinitis: A systematic review and meta-analysis

Background: Only a fraction of patients with allergic rhinitis receive allergen-specific immunotherapy (AIT). AIT is most commonly delivered subcutaneously in a series of injections over 3‐5 years. Common obstacles to completing this therapy include cost and inconvenience. Intralymphatic immunotherapy (ILIT) has been proposed as a faster alternative, which requires as few as three injections spaced 4 weeks apart. Objective: This systematic review and meta-analysis evaluated the current evidence that supports the use of ILIT for allergic rhinitis. Methods: Clinical trials were identified in the published literature by using an electronic search strategy and were evaluated by using a risk of bias tool. Treatment outcome (symptom scores, medication scores, and combined symptom and medication scores) and provocation testing results (nasal provocation and skin-prick testing) were included in a meta-analysis of standardized mean difference with subgrouping by using a random-effects model. Overall adverse event rates were tabulated, and overall risk ratios were calculated by using a random-effects model. Results: We identified 17 clinical trials that met eligibility criteria. The standardized mean difference of ILIT on the symptom and medication score was ‐0.72 (95% confidence interval [CI], ‐0.98 to ‐0.46; p < 0.0001) (n = 10). The standardized mean difference of ILIT on nasal provocation and skin-prick testing was ‐1.00 (95% CI, ‐1.38 to ‐0.61; p < 0.0001) (n = 7) and ‐0.73 (95% CI, ‐0.99 to ‐0.47; p < 0.0001) (n = 7), respectively. No statistically significant heterogeneity was detected. The overall adverse event rate was 39.5% for ILIT and 23.5% for placebo. Also, 98.4% of adverse events were mild. Conclusion: Our meta-analysis demonstrated that ILIT was safe, conferred desensitization to seasonal and nonseasonal allergens, alleviated allergic rhinitis symptoms, and reduced medication use. A larger randomized, double-blind, placebo controlled trial will be necessary for wider adaptation of this form of AIT.

High dose pollen intralymphatic immunotherapy: two RDBPC trials question the benefit of dose increase

Background The same dosing schedule, 1000 SQ-U times three, with one-month intervals, have been evaluated in most trials of intralymphatic immunotherapy (ILIT) for the treatment of allergic rhinitis (AR). The present studies evaluated if a dose escalation in ILIT can enhance the clinical and immunological effects, without compromising safety. Methods Two randomized double-blind placebo-controlled trials of ILIT for grass pollen induced AR were performed. The first included 29 patients that had recently ended 3 years of SCIT and the second contained 39 not previously vaccinated patients. An up-dosage of 1000-3000-10 000 (5000 + 5000 with 30 minutes apart) SQ-U with one month in between was evaluated. Results Doses up to 10 000 SQ-U was safe after recent SCIT. The combined symptom-medication scores (CSMS) were reduced by 31% and the grass specific IgG4 levels in blood were doubled. In ILIT de novo, the two first patients that received active treatment developed serious adverse reactions at 5000 SQ-U. A modified up-dosing schedule; 1000-3000-3000 SQ-U appeared to be safe but failed to improve the CSMS. Flow cytometry analyses showed increased activation of lymph node derived dendritic but not T-cells. Quality of life and nasal provocation response did not improve in any study. Conclusion ILIT in high doses after SCIT appears to further reduce grass pollen induced seasonal symptoms and may be considered as an add-on treatment for patients that do not reach full symptom control after SCIT. Up-dosing schedules de novo with three monthly injections that exceeds 3 000 SQ-U should be avoided.

Intralymphatic immunotherapy for allergic rhinoconjunctivitis: a systematic review and meta-analysis

BACKGROUND: Intralymphatic immunotherapy (ILIT) is a new route of allergen-specific immunotherapy. Data confirming its effect is restricted to a small number of studies. METHODOLOGY: A systematic review with meta-analysis was conducted. The short-term (less than 24 weeks), medium-term (24-52 weeks), and long-term (more than 52 weeks) effects of ILIT in patients with allergic rhinoconjunctivitis (ARC) were assessed. The outcomes were combined symptom and medication scores (CSMS), symptoms visual analog scale (VAS), disease-specific quality of life (QOL), specific IgG4 level, specific IgE level, and adverse events. RESULTS: Eleven randomized controlled trials and 2 cohorts (483 participants) were included. Compared with placebo, short term benefits of ILIT for seasonal ARC improved CSMS, improved VAS and increased specific IgG4 level but did not change QOL or specific IgE level. Medium-term effect improved VAS. Data on the long-term benefit of ILIT remain unavailable and require longer term follow-up studies. There were no clinical benefits of ILIT for perennial ARC. ILIT was safe and well-tolerated. CONCLUSION: ILIT showed short-term benefits for seasonal ARC. The sustained effects of ILIT were inconclusive. It was well tolerated.

High dose pollen intralymphatic immunotherapy: two RDBPC trials question the benefit of dose increase

Background The same dosing schedule, 1000 SQ-U times three, with one-month intervals, have been evaluated in most trials of intralymphatic immunotherapy (ILIT) for the treatment of allergic rhinitis (AR). The present studies aimed to evaluate if a dose escalation in ILIT can enhance the clinical and immunological effects, without compromising safety. Methods Two randomized double-blind placebo-controlled trials of ILIT for grass pollen induced AR were performed. The first included 29 patients that had recently ended 3 years of SCIT and the second contained 39 not previously vaccinated patients. An up-dosage of 1000-3000-10 000 SQ-U with one month in between was evaluated. Results ILIT in doses up to 10 000 SQ-U was safe after recent SCIT. The combined symptom-medication scores (CSMS) were reduced by 31% and the grass specific IgG4 levels in blood were doubled. In ILIT de novo, the two first patients that received active treatment developed serious adverse reactions at 5000 SQ-U. A modified up-dosing schedule; 1000-3000-3000 SQ-U appeared to be safe but failed to improve the CSMS, quality of life and nasal provocation response. Flow cytometry analyses could not detect any T-cell changes, while lymph node derived dendritic cells showed increased activation. Conclusion ILIT in high doses after SCIT appears to further reduce grass pollen induced seasonal symptoms and may be considered as an add-on treatment for patients that do not reach full symptom control after SCIT. Up-dosing schedules de novo with three monthly injections that exceeds 3 000 SQ-U should be avoided.

How Intralymphatic Immunotherapy Can Affect Quality of Life and Symptoms in Patients With Permanent Seasonal Allergic Rhinitis, a Quasi-Experimental Design

BackgroundAllergen-specific immunotherapy is known as the only disease-modifying treatment for IgE-mediated allergic disorders. Intra lymphatic immunotherapy (ILIT) is a safe, effective, and time-saving alternative to subcutaneous immunotherapy (SCIT). This study aimed to evaluate the effects and safety of ILIT in patients with moderate to severe allergic rhinitis. MethodsIn this clinical trial, fifteen patients with moderate to severe allergic rhinitis between 18-65 years old received monthly intralymphatic inguinal injections of an active allergen (1000 SQ-U Salsola kali pollen). Clinical effects were assessed before and 4 weeks after treatment and at two consecutive pollination seasons and following non-pollination season in April.ResultsNo moderate or severe reactions were recorded following the ILIT treatment. Lymph node enlargement, local itching/erythema were seen in 6.7%, 13.3% of total respectively one day after injection. Patients who received ILIT experienced a significant clinical improvement in self-recorded seasonal allergic symptoms after treatment, as compared to themselves before ILIT. Quality of life significantly got better based on the Mini RQLQ questionnaire.ConclusionAlthough this study is based on a limited number of patients, ILIT with Salsola-pollen extract appears to decrease symptoms of allergic rhinitis without causing any crucial complications.This clinical trial study was recorded in the Iran Registry of Clinical Trials (IRCT20161206031256N2).

Intralymphatic Immunotherapy: A 3-year Randomized, Double-blind Study in 72 Patients With Allergic Rhinitis Due to Birch and Grass

Background: There is need for a fast, efficient, and safe way to induce tolerance in patients with severe allergic rhinitis.Methods: Patients with severe birch and timothy allergy were randomized and received three doses of 0.1 ml of birch and 5-grass allergen extracts (10,000 SQ units/ml, ALK-Abelló), or birch and placebo or 5-grass and placebo by ultrasound-guided injections into inguinal lymph nodes at monthly intervals. We have no clean placebo group but the pollen seasons are mostly divided by time. Rhinoconjunctivitis Total Symptom Score, Medication Score and Rhinoconjunctivitis Quality of Life Questionnaire were evaluated before treatment and after each birch and grass pollen season during three subsequent years. Circulating proportions of T helper subsets and allergen-induced cytokine and chemokine production were analyzed by flow cytometry and Luminex.Results: The three groups reported fewer symptoms, lower use of medication and improved quality of life during the birch and grass pollen seasons each year after treatment at an almost similar rate independently of treatment. Mild local pain was the most common adverse event. IgE levels to birch decreased, whereas birch-induced IL-10 secretion increased in all three groups. IgG4 levels to birch and timothy and skin prick test reactivity remained mainly unchanged. Conjunctival challenge tests with timothy extract showed a higher threshold for allergen. In all three groups, regulatory T cell frequencies were increased three years after treatment.Conclusion: Intralymphatic immunotherapy against grass and birch pollen allergy was safe, seemed to be effective, and to be associated with bystander immune modulatory responses.Trial registration: EudraCT (2013-004726-28). Registered 14 January 2014https://www.clinicaltrialsregister.eu/ctr-search/search?query=2013-004726-28