Key messages list:
- A minimum of 3 years AIT treatment is required to obtain a sustained
long-term effectiveness.
- Dpg-pol HDM is able to remove allergic rhinitis and asthma symptoms
completely.
- 3-year treatment with dpg-pol HDM is able to maintain effectiveness 10
years after treatment.
MANUSCRIPT:
Introduction:
Allergen immunotherapy (AIT) is an effective treatment for allergic
rhinitis (AR) and allergic asthma (AA), which involves the repeated
administration of an allergen extract. An important question is whether
allergen immunotherapy provides a sustained clinical effect after
treatment cessation. Clinical studies suggest that a minimum of 3 years
of AIT treatment results in sustainable clinical benefit and
immunological changes with allergen specific tolerance [1,2]. AIT
guidelines recommend 3-5 years of treatment, and it seems that the
number of years of AIT treatment is determinant to obtain these results
[3]. Long-term benefit is an important consideration for the
recommendation of immunotherapy over standard pharmacotherapy. In
general, long-term studies evaluate efficacy of AIT treatment within 5
years after treatment discontinuation, and longer observational periods
are very scarce. Long term treatment efficacy has been defined by the
European Academy of Allergy & Clinical Immunology (EAACI) as sustained
clinical benefit that lasts for at least 1 year after immunotherapy
discontinuation and short-term treatment efficacy as the clinical
benefit to the patient while they are receiving immunotherapy [4,5].
Methods:
We present data from an observational, single-centre study conducted at
Hospital Universitario Ntra. Sra. de La Candelaria (Santa Cruz de
Tenerife, Spain) for a 10-year follow-up (10y-FU) of adult patients, who
initially participated in a double-blind placebo-controlled clinical
trial (DBPCT) and received subcutaneous immunotherapy (SCIT) treatment
with a depigmented,polymerized house dust mite (dpg-pol HDM) allergen
extract or placebo during a 54 week-period. Data from those patients who
agreed to continue with dpg-pol HDM SCIT (following real life routine
clinical practice) for a further period after the completion of the
DBPCT, were the objective of this study and the results are presented in
this article (Figure 1).
The initial DBPCT included patients diagnosed with mild/moderate asthma
with/without rhinoconjunctivitis due to HDM. Patients (N=54) were
divided in two groups; the active group (N=27) received a
depigmented-polymerized mixture (Depigoid® 100 DPP/mL)
of 50% Dermatophagoides pteronyssinus and 50%Dermatophagoides farinae (for the rest of the article referred as
dpg-pol HDM ), whilst the control group (N=27) received placebo,
monthly, over 54 weeks. The results of this clinical trial showed
statistically significant improvement in the active group compared to
placebo control group. All the information regarding the design and
results of this clinical trial can be found in a previous publication
[6].
Once the DBPCT was completed, patients from both groups were invited to
receive dpg-pol HDM under routine clinical practice. This
non-interventional retrospective study was designed to assess the
long-term effectiveness for AR and asthma of dpg-pol HDM in a 10y-FU
visit. Changes in the Total Symptom Score (TSS) and Medication Score
(MS) were the primary objectives. Visual Analogue Scale (VAS), Asthma
Control Test (ACT), and the degree of disease control assessed by the
physician were the secondary objectives. Data were analyzed at 3
different time-points: baseline (before dpg-pol HDM ), end of dpg-pol
HDM SCIT and 10y-FU visit (Figure 1). All patients signed informed
consent and this retrospective study was approved by the corresponding
ethics committee.
Results:
Data from 31 patients were available at the 10y-FU visit (Table 1):
median age was 38 years (range 29, 53), all patients 31/31 (100%) had
AA and 29/31(93.5%) had AR. Median dpg-pol HDM treatment duration was 4
years (range 2, 5). Twenty-three patients (74.2%) received dpg-pol HDM
for ≥ 3 years and 8 (25.8%) < 3 years, showing a good
persistence for this SCIT.
The primary objective results showed a significant reduction in TSS
(mean decrease [SD] -21.00 [16.56], p<0.0001) and MS
(mean decrease [SD]-9.3 [36.6], p=0.0003) at 10y-FU compared to
baseline. This significant reduction in TSS was also observed at end of
dpg-pol HDM treatment compared to baseline and no significant
differences were observed in TSS at 10y-FU compared to end of dpg-pol
HDM. This significant reduction in TSS was observed irrespective of
treatment duration.
Only those patients who received treatment for ≥ 3 years experienced a
significant reduction in the MS at 10y-FU compared to baseline (mean
reduction [SD] -12.8 [16.9], p=0.0004)(Table 1). All 31 patients
(100%) at baseline required inhaled steroids, however this number was
reduced to only 10 (32%) patients at 10y-FU visit. Moreover, 10
patients (32%) didn´t require any type of rescue medication at 10y-FU
and all 10 had been treated for ≥ 3 years with dpg-pol HDM.
A significant reduction in the number of patients with specific symptoms
was observed between baseline and: a) end of dpg-pol HDM i) for rhinitis
(p <0.001), ii) conjunctivitis
(p <0.0001), and iii) asthma (p <0.0001)
and b) 10y-FU visit for i) rhinitis (p =0.0129), ii)
conjunctivitis (p <0.0001), and iii) asthma
(p =0.0001). However, when analyzed by treatment duration, this
reduction in the number of patients with specific symptoms was only
observed if treated for ≥ 3 years, between baseline and a) end of
dpg-pol HDM for i) rhinitis (p =0.0001), ii) conjunctivitis
(p <0.0001), and iii) asthma
(p <0.0001), and b) 10y-FU for i) rhinitis
(p =0.0117), ii) conjunctivitis (p <0.0001), and
iii) asthma (p =0.0005). In the group treated < 3 years,
only a significant reduction in the number of patients with
conjunctivitis (p =0.0156) was observed at 10y-FU compared to
baseline (Figure 2 ).
Seventeen (54.8%) patients were asymptomatic at end of dpg-pol HDM, of
which 52.9% (9/17) remained asymptomatic at 10y-FU (Figure 3).
Significantly, all 9 asymptomatic patients at 10y-FU received treatment
for ≥ 3 years (p=0.0078).
Regarding the secondary objectives, VAS score at 10y-FU visit assessed
by patients was median 85 (range 75, 95), and likewise median 85 (range
80, 100) when assessed by investigator. No significant differences were
observed between VAS at end of dpg-pol HDM treatment compared to VAS at
10y-FU. ACT showed a good control of asthma (ACT>20) among
allergic asthmatic patients at 10y-FU; median 23.5 (range 22, 25) with
no differences depending on dpg-pol HDM treatment duration (Table 1).
The degree of disease control was assessed by physicians and considered
it controlled in 19/31 (61.3%) patients at 10y-FU, of which 16 were
treated with dpg-pol HDM for ≥ 3 years and 3 for < 3 years.
No adverse reactions were reported during the study period.
Conclusions:
Several clinical trials and observational studies have proven that SCIT
with Depigoid® HDM extract is safe and efficacious
[7-10], but little data is available regarding long-term
effectiveness [3] and asthmatic´s response. The results from this
study prove that Depigoid® HDM is an effective
treatment for AA and AR not only at the end of SCIT treatment, but also
10 years after AIT termination. Rhinitis, conjunctivitis and, more
importantly, asthma symptoms and medication scores remain significantly
favorable compared to baseline time-point between the end of dpg-pol HDM
and 10 years later, demonstrating long-term effectiveness, only when
dpg-pol HDM treatment is maintained for at least 3 years. Thirty-nine
percent and 43% of patients treated for at least 3 years were
asymptomatic and didn´t require any rescue medication, respectively, 10
years after dpg-pol HDM termination, reinforcing the importance of
treatment duration [3]. EAACI guidelines consider sustained
long-term a clinical effectiveness that lasts at least 1 year after AIT
discontinuation. In this study we proof that with dpg-pol HDM for at
least 3 years sustained clinical effectiveness is maintained at least 10
years after AIT discontinuation. Sustained effectiveness in real life
during routine clinical practice is relevant given that allergic
diseases have a great socio-economic impact. In Spain, the total mean
cost per patient year of allergic rhinitis (AR) is 2326\euro [11]
and for asthma is 1726\euro [12].
This study has some limitations, such as the number of patients, which
is especially small when splitting between 2 treatment groups; however,
the level of significance is very high and therefore we believe these
findings are robust. Given the retrospective study design, some
variables were not consistent between the initial clinical trial and the
current retrospective study; however, symptom and medication scores,
commonly used to measure efficacy in clinical trials, have been
evaluated in both studies. We do believe that better designed long-term
prospective studies are required to confirm these findings.
In general, these results suggest that AIT treatment duration of ≥ 3
years is cost-effective as an important percent of patients remain
asymptomatic and don´t require rescue medication including asthma
treatment, although specific studies are needed.
Given that long-term studies (observation period after more than 5 years
of AIT treatment discontinuation) are very scarce, these results help to
support the international guidelines recommendation that a minimum of 3
years of AIT treatment is required for a sustained long- term effect.
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Figure 1: Study design.
Figure 2 : Reduction in the number of patients with allergic symptoms
over time.
Figure 3:Evolution of percentage of asymptomatic patients.