Abstract

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.

Wk: 245 (250)

Introduction

Allergy immunotherapy (AIT) is the only treatment for allergic rhinitis (AR) that is both symptom ameliorating and changes the course of the disease, although rarely eliminates the symptoms totally (1 ). It is usually given as subcutaneous immunotherapy (SCIT) with repeated injections at hospital or as sublingual immunotherapy (SLIT) with daily administrations at home (1, 2 ). Both routes involve treatment during at least three years and problems with side effects (3 ) and adherence (4 ) limit the use.
More than ten years ago, intralymphatic injections were proposed as a new route for AIT, based on a trial of three low dose (1000 SQ-U) grass allergen injections given in lymph nodes in the groin (5 ), and the concept of intralymphatic immunotherapy (ILIT) was born. Since then, several studies have evaluated the same or equivalent doses. The extracts used have included a recombinant cat dander allergen (6 ), house dust mite allergen (7 ), cedar pollens (8, 9 ), grass pollen (10-13 ), and in our own research group combinations of grass and/or birch pollens (14-17 ). Different up-titration schedules have been applied with grass allergen (18 ) and a combination of house dust mite, dog and cat allergens (19, 20 ). Most trials, but not all (10 ), have indicated improvement of allergen triggered symptoms and have had few and mild side effects.
The efficacy of AIT usually corresponds to a high allergen dose (21 ). What often limits the level of the maintenance doses is the risk of allergic side reactions (22 ). Based on the good safety profile of previous ILIT studies, a dose-escalation seemed to be the next step to develop ILIT. The two studies presented in this article are the first randomized double-blind placebo-controlled (RDBPC) trials that explore ILIT with ALK Alutard 5-grasses® in up-dosing schedules. The overall aim was to investigate if the dose increase 1000- 3000- 10 000 SQ-U could be used safely and to evaluate the potentially additional clinical improvement. Firstly, in “ILIT after SCIT- 10 000”, we investigated whether the schedule was safe among patients that had recently been treated with SCIT and presumably had a tolerance to the allergen. In the second study, “ILIT de novo- 3000”, the up-dosing schedule was attempted in patients without preceding SCIT. However, the first two patients had anaphylactic reactions at 5000 SQ-U. Therefore, the up-dosing protocol 1000- 3000- 3000 SQ-U was used. To track immunological changes following the treatment, we measured IgE and IgG4 antibody levels as well as the activation of T-cells in blood and dendritic cells (DCs) in the lymph nodes. See Figure 1 and the supplementary section for a description of the study outline and the methods used.