Key messages list:
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.
REFERENCES
  1. Bousquet J, Lockey R, Malling HJ. Allergen immunotherapy: therapeutic vaccines for allergic diseases. A WHO position paper. J Allergy Clin Immunol. 1998 Oct;102(4):558-62.
  2. Roberts G, Pfaar O, Akdis CA, Ansotegui IJ, Durham SR, Gerth van Wijk R, et al. EAACI Guidelines on Allergen Immunotherapy: Allergic rhinoconjunctivitis. Allergy. 2018 Apr;73(4):765-798.
  3. Penagos M, Eifan AO, Durham SR, Scadding GW. Duration of Allergen Immunotherapy for Long-Term Efficacy in Allergic Rhinoconjunctivitis. Curr Treat Options Allergy. 2018;5(3):275-290
  4. Roberts G, Pfaar O, Akdis CA, Ansotegui IJ, Durham SR, Gerth van Wijk R, et al. EAACI Guidelines on Allergen Immunotherapy: Allergic rhinoconjunctivitis. Allergy. 2018 Apr;73(4):765-798.
  5. Dhami S, Nurmatov U, Arasi S, Khan T, Asaria M, Zaman H, et al. Allergen immunotherapy for allergic rhinoconjunctivitis: A systematic review and meta-analysis. Allergy. 2017 Nov;72(11):1597-1631.
  6. García-Robaina JC, Sánchez I, de la Torre F, Fernández-Caldas E, Casanovas M. Successful management of mite-allergic asthma with modified extracts of Dermatophagoides pteronyssinus and Dermatophagoides farinae in a double-blind, placebo-controlled study. J Allergy Clin Immunol. 2006 Nov;118(5):1026-32.
  7. Mösges R, Valero Santiago A, Allekotte S, Jahed N, Astvatsatourov A, Sager A, et al. Subcutaneous immunotherapy with depigmented-polymerized allergen extracts: a systematic review and meta-analysis. Clin Transl Allergy. 2019 Jun 5;9:29.
  8. Ameal A, Vega-Chicote JM, Fernández S, Miranda A, Carmona MJ, Rondón MC, et al. Double-blind and placebo-controlled study to assess efficacy and safety of a modified allergen extract of Dermatophagoides pteronyssinus in allergic asthma. Allergy. 2005 Sep;60(9):1178-83.
  9. Ferrer A, García-Sellés J. Significant improvement in symptoms, skin test, and specific bronchial reactivity after 6 months of treatment with a depigmented, polymerized extract of Dermatophagoides pteronyssinus and D. farinae. J Investig Allergol Clin Immunol. 2003;13(4):244-51.
  10. Pfaar O, Sager A, Robinson DS. Safety and effect on reported symptoms of depigmented polymerized allergen immunotherapy: a retrospective study of 2927 paediatric patients. Pediatr Allergy Immunol. 2015 May;26(3):280-286
  11. Colás C, Brosa M, Antón E, Montoro J, Navarro A, Dordal MT, et al. Estimate of the total costs of allergic rhinitis in specialized care based on real-world data: the FERIN Study. Allergy. 2017 Jun;72(6):959-966.
  12. Martínez-Moragón E, Serra-Batllés J, De Diego A, Palop M, Casan P, Rubio-Terrés C, et al; por el Grupo de Investigadores del estudio AsmaCost. Coste económico del paciente asmático en España (estudio AsmaCost) [Economic cost of treating the patient with asthma in Spain: the AsmaCost study]. Arch Bronconeumol. 2009 Oct;45(10):481-6.
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.