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.