Three years of specific immunotherapy may be sufficient in house dust mite respiratory allergy

Transcription

1 Three years of specific immunotherapy may be sufficient in house dust mite respiratory allergy Ana I. Tabar, MD, PhD, a Esozia Arroabarren, MD, b Susana Echechipıa, MD, PhD, a Blanca E. Garcıa, MD, PhD, a Santiago Martin, MS, c and Marıa J. Alvarez-Puebla, MD, PhD a Pamplona, San Sebastian, and Madrid, Spain Background: Specific immunotherapy (SIT) duration for respiratory allergy is currently based on individual decisions. Objective: To evaluate the differences in clinical efficacy of SIT as a result of the duration between the current recommended limits (3-5 years). Methods: A 5-year prospective, controlled clinical trial of SIT blind until the first year and randomization to a 3-year (IT3) or 5-year (IT5) course was conducted. Of the 239 patients with respiratory allergy caused by D pteronyssinus initially included, 142 completed 3 years of SIT with good compliance. Twentyseven controls were included at the third year. Efficacy of SIT after 3 (T3) and 5 (T5) years was assessed by using clinical scores, visual analog scales (VASs), rhinitis (RQLQ) and asthma (AQLQ) quality of life questionnaires, skin tests, and serum immunoglobulins. Results: At T3, significant reductions were observed in rhinitis (44% in IT3 and 50% in IT5; P <.001), asthma (80.9 % in IT3 and 70.9% in IT5; P <.001) scores, VAS (P <.001 in both), RQLQ (P <.001 in both) and AQLQ (P <.001 in both). At T5, the clinical benefit was maintained in both groups, and IT5 patients presented additional decreases (19%; P 5.019) in rhinitis scores. At Tf, specific IgG 4 measurements were lower in IT3 (P 5.03) without detecting differences in IT5. An increase in asthma score of 133% was the only difference observed in controls. Conclusion: Clinical improvement is obtained with 3 years of D pteronyssinus SIT. Two additional years of SITadd clinical benefit in rhinitis only. (J Allergy Clin Immunol 2011;127:57-63.) Key words: Specific immunotherapy, duration, quality of life, asthma, rhinitis, house dust mite, clinical efficacy, compliance, children, immunotherapy relapses Since the first clinical trial with specific immunotherapy (SIT) was carried out by Noon, 1 its clinical efficacy has been demonstrated by means of several meta-analyses. 2-4 In addition, its preventive ability has been reinforced by several trials 5-7 as well as the maintenance of the clinical efficacy after its discontinuation However, the duration of treatment is still arbitrarily From a the Department of Allergy, Hospital Virgen del Camino, Pamplona; b the Department of Pediatrics, Hospital Universitario Donostia, San Sebastian; and c the Clinical Research Department, ALK-Abello, Madrid. Supported by a research grant from the Regional Government of Navarra. Disclosure of potential conflict of interest: S. Martin is an employee of ALK-Abello and helped in the design and analysis of the study. The rest of the authors have declared that they have no conflict of interest. Received for publication July 6, 2010; revised October 13, 2010; accepted for publication October 20, Reprint requests: Ana I. Tabar, MD, PhD, Department of Allergy, Hospital Virgen del Camino, CS Conde Oliveto, Plaza de la Paz s/n, Pamplona, Spain. ana.tabar.purroy@cfnavarra.es /$36.00 Ó 2010 American Academy of Allergy, Asthma & Immunology doi: /j.jaci Abbreviations used AQLQ: Asthma Quality of Life Questionnaire HDM: House dust mite IT3: Patients receiving SIT for 3 years IT5: Patients receiving SIT for 5 years RQLQ: Rhinoconjunctivitis Quality of Life Questionnaire SIT: Specific immunotherapy T0: Baseline evaluation T1: 1-year follow-up T3: 3-year follow-up T5: 5-year follow-up VAS: Visual analog scale decided. Being able to establish the adequate duration of inhalant SIT may have important clinical implications, because it may influence the patient s compliance, the efficacy of treatment, its safety, and expenses derived from treatment and the disease itself. 11 Current immunotherapy guidelines 12,13 recommend ceasing the treatment on individual basis. The usual duration ranges between 3 and 5 years, although it might be administered indefinitely for certain cases of Hymenoptera venom allergy. 14 Des Roches et al 15 observed a greater frequency of relapses related to shorter treatments. Most of the available information on when SIT should be discontinued is based on Hymenoptera venom trials. 14 In most of these patients, a 5-year course of SIT equals the risk of systemic reactions to the general population. 14 Regarding inhalants, we have indirect data from trials performed during variable periods, with different doses and allergens: pollen 8-10 and house dust mite (HDM). 16 These data suggest that SIT administration is effective in the treatment of respiratory allergy, and its efficacy continues after treatment discontinuation. However, no trial has been specifically designed to address the topic of optimal duration of SIT. Our objective was to evaluate the possible differences in the efficacy of HDM SIT in respiratory allergy as a result of the duration between the currently recommended limits. METHODS Study design This was a 5-year, phase IV, prospective study, double-blind for the first year, in which the initial phase (cluster or conventional) was blind. After the first year, half the patients were randomized 17 to 3 years (IT3) and the other half to 5 years of SIT (IT5). At the third year (T3), a control group receiving pharmacologic treatment exclusively was also included (Fig 1). Patients were evaluated at baseline (T0), after the first year (published data 18 ), and at the third year (T3) and the fifth year (T5). Patients At baseline, we invited patients age 5 to 45 years studied at our department during the previous year and diagnosed with moderate-severe rhinitis and/or asthma caused by sensitization to D pteronyssinus to participate. SIT was 57

2 58 TABAR ET AL J ALLERGY CLIN IMMUNOL JANUARY 2011 each dose. Doses administered were recorded in the Immunotherapy Unit Management software INMUNOWIN (ALK-Abello). FIG 1. Study design. T0 to T1: results published in Tabar AI, Echechipıa S, Garcıa BE, Olaguibel JM, Lizaso MT, Gomez B, et al. Double-blind comparative study of cluster and conventional immunotherapy schedules with Dermatophagoides pteronyssinus. J Allergy Clin Immunol 2005;116: Arrows, Randomization. Red triangle, STOP immunotherapy. indicated for all the patients according to the European Academy of Allergy and Clinical Immunology recommendations. 13 Diagnosis and pharmacologic treatment of rhinitis and asthma were based on the International Consensus Report on the Diagnosis and Management of Rhinitis 19 and National Institutes of Health, National Heart, Lung and Blood Institute, 20 respectively. All patients had to show positive results to D pteronyssinus in skin prick test (wheal diameter >_ 3 mm) and in serum specific IgE (>0.7 ku/l).the initial sample size was 239 patients. Once we completed the first year of SIT (T1) and determined the lack of differences regarding efficacy and safety between the schedules, 18 we performed a new randomization 17 : half of patients would receive a 3-year course and the rest a 5-year course of SIT. At T3, patients who had withdrawn from SITand those who had an irregular compliance (defined below) were excluded. At T3, we also recruited the control group among the patients who had come to our department for the first time by using a randomized sequence 17 and the same clinical criteria. All subjects were evaluated at T5. At each visit (baseline, T1, T3, and T5), patients underwent clinical assessment and physical evaluation by the physician, skin prick tests, and spirometry and fulfilled their analog scales and quality of life questionnaires. A venous blood sample was also obtained. Ethical issues This protocol was conducted in compliance with the principles established in the World Medical Association Declaration of Helsinki 21 and was approved by the Hospital Clinical Research Ethics Committee and the Spanish Drug Agency. All patients were provided with written information and signed an informed consent that was specific for minors. Allergen extract A biologically standardized D pteronyssinus extract quantified in micrograms of Der p 1 and Der p 2 (Pangramin Depot UM; ALK-Abello, Madrid, Spain) was used for treatment. During the maintenance phase, 0.8 ml containing 3.6 mg Der p 1 was administered monthly. Skin prick tests were made with 4 dilutions of the same D pteronyssinus extract in 50% glycerin (wt/vol) containing phenol 0.4% (wt/vol) and ClNa 0.9% (wt/vol), with a biological activity of 500 biological unit/ml (225 mg Der p 1), stored at 208C to keep its biological activity throughout the study. Administration of the immunotherapy During the initial phase, a cluster and a conventional initial schedule were used. 18 Patients were monitored for 30 minutes after the administration of Assessments Compliance. Compliance was assessed by reviewing the registries in the INMUNOWIN program. In addition, a physician performed a telephone survey of all patients who withdrew to ascertain reasons for withdrawal. An irregular compliance with frequent delays (>_ 3 consecutive doses) or administration delays in the maintenance phase longer than 16 weeks were considered noncompliance. Efficacy assessment. Clinical efficacy was assessed by using objective scales on symptoms and medication use, adding a lung function test (forced spirometry) in patients with asthma patients, previously used by our group. 18,22-24 Rhinitis severity was explored by combined scales for symptoms (0-12 points) and medication (0-2 points) published by Meltzer. 25 Asthma was evaluated by an asthma symptom scale modified from Aas 26 assessing symptoms (0-5 points), medication (0-5 points), and lung function tests (0-2 points). The extent of clinical efficacy was graded according to the parameters published by Malling 27 (see this article s Tables E1 and E2 in the Online Repository at Changes in quality of life were assessed by using the standardized Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) 28,29 and the Asthma Quality of Life Questionnaire (AQLQ) that patients themselves fulfilled. They assessed the 3 months before each visit, and their values ranged from 0 points (no impairment) to 6 points (greatest impairment) for rhinitis and from 7 points (no impairment) to 0 points (greatest impairment) for asthma. Patient-perceived severity was also measured by a visual analog scale (VAS) that explored the week before the visit and whose values ranged from 0 (very good) to 10 (very bad). 31 Pulmonary function tests. Patients with asthma underwent forced spirometry with bronchodilation test according to the American Thoracic Society guidelines. 32 We used a Jaeger spirometer (MasterScope, Jaeger Toennies; Erich Jaeger GMBH, Hoechberg, Germany). Asthma-free patients. Patients asymptomatic, with normal lung function, and without any pharmacologic treatment for at least the 3 months before the assessments were considered asthma-free patients. 15 Reactivity to D pteronyssinus. Skin prick tests. Immediate skin reactivity was assessed by prick test with D pteronyssinus extract, standardized in mass units to 225, 45, 9, and 1.8 mg of Der p 1 with histamine hydrochloride positive at 10 mg/ml and saline as positive and negative controls, respectively, according to the European Academy of Allergy and Clinical Immunology Subcommittee on Skin Tests recommendations. 33 The wheal diameter was measured by a scanner. Data were transformed logarithmically for analysis with parametric tests. In vitro testing. Serum levels of D pteronyssinus specific IgG, IgG 4, and IgE were determined by enzyme immunoassay following the CAP System RAST FEIA method (Phadia, Uppsala, Sweden). Measurements were made at the end of the study by using the same assay for each evaluated parameter. Statistical and computing methodology For statistical analysis, the statistical software SPSS 16.0 for Windows, BMDP Statistical Software release 7, Star Xact (Cytel Software Corp, Madrid, Spain), and the AIAS CRS-PLA software (ALK-Abello, Madrid, Spain) were used. The differences in efficacy between groups at each visit (asthma and rhinitis severity, VAS, and RQLQ and AQLQ scores) were assessed by repeated-measures ANOVA. Changes in skin reactivity were assessed by AIASA CRS-PLA software for individual data, estimating the differences in the skin tolerance rate on each time point. The evolution of both treatment groups was compared by a 1-way ANOVA (duration of treatment). In vitro endpoints were assessed at T5 versus T3 by using a 1-way ANOVA (duration of immunotherapy). All statistical tests had a significance level of.05.

3 J ALLERGY CLIN IMMUNOL VOLUME 127, NUMBER 1 TABAR ET AL 59 TABLE I. Patients baseline characteristics Patients characteristics All SIT patients IT-5 group IT-3 group Control group Age, <15/>15 y 81/158 39/31 29 /43 6/21 Age, median 18 (5,49) 12,5 (5,42) 19 (5,49) 24 (8,43) (interquartile) Sex, female/male 145/93 21/49 40/32 14/13 Monosensitized, 125/114 32/28 37/31 11/16 yes/no Diagnosis, asthma/ rhinitis/rhinitis and asthma 30/64/145 11/15/44 9/21/42 3/16/8 TABLE II. SIT safety Reactions IT5 group IT3 group Local reactions 1 Late local reaction (M) 1 Local reaction (I) 1 Nodes (M) 1 Local reaction (M) 1 Local reaction (M) 1 Local reaction (M) 1 Local reaction (l) 1 Local reaction (M) 1 Local reaction (M) Systemic reactions 1 Anaphylaxis (M) 1 Nonspecific RS symptoms (I) 1 Rhinoconjunctivitis (I) 1 Nonspecific RS symptoms (M) 1 Asthma* (M) 1 Nonspecific RS symptoms (M)* 1 Asthma (M) 1 Asthma (M) 1 Rhinoconjunctivitis (M) FIG 2. Patients flowchart throughout the study. RESULTS Two hundred thirty-nine patients initiated the study, and at T3, 142 of the 215 patients who completed the first year were still on treatment with good compliance. Seventy patients were told to continue SIT for 2 more years (IT5 group) and 72 were told to cease the treatment (IT3 group) according to a randomized sequence. At this time, the control group was recruited. Fortynine (IT5) and 62 (IT3) patients came to all scheduled visits. For analysis, we used data from patients who had complete baseline, T3, and T5 data (Fig 2). Patients baseline characteristics are detailed in Table I. Compliance Fifty-three dropouts and 18 withdrawals for noncompliance occurred between the first and third years of follow-up. The reasons for withdrawal and/or dropouts are summarized in Fig 2 (see detailed information in this article s Results section in the Online Repository at No differences in age, sex, or initial diagnosis were found between patients who complied with the 5-year follow-up and those who withdrew. Safety Safety data from baseline and first year of SIT have been already published. 18 During the 5-year follow-up, 9 systemic reactions (3 unspecific, 2 rhinoconjunctivitis, 3 asthma attacks, and 1 anaphylaxis; see detailed information in this article s Results I, Reactions during initiation phase; M, reactions during maintenance phase; RS, systemic reactions. * And correspond to reactions experienced by the same patient. section in the Online Repository) were recorded, involving 0.07% of doses and 5.6% of patients, among patients using SIT (Table II). Clinical efficacy Compared with baseline, we observed statistically significant decreases (P <.01) in rhinitis and asthma scores as well as in subjective endpoints (VAS scores and quality of life measurements) at T3 (Fig 3). Rhinitis score. Compared with baseline, IT5 group scores had a reduction of 50% (P <.001) at T3 and of 69.1% at T5 (P <.001). The difference between T3 and T5 scores was also significant (P 5.019). Alternatively, IT3 group scores decreased in 44% (P <.001) at T3 and in 48% (P <.001) at T5. When both groups global scores were compared at T5, we observed no significant difference (P 5.146). No difference was observed in rhinitis severity in the control group (Fig 3, A). Asthma score. Compared with baseline, IT5 group patients had a 70.9% (P <.001) reduction in the global asthma score at T3 that grew to 79.9% (P <.001) at T5. IT3 patients had an 80.9% (P <.001) reduction in global asthma scores at T3 that was maintained (80.9%; P <.001) at T5. When changes at T3 and at T5 were compared, we observed no significant difference either in the IT5 (P 5.729) or in the IT3 (P 5.302) groups. Neither were the differences were significant between IT3 and IT5 at T5 (P 5.330; Fig 3, B).

4 60 TABAR ET AL J ALLERGY CLIN IMMUNOL JANUARY 2011 FIG 3. A, Rhinitis severity (global score). B, Asthma severity (global score). C, VAS score. Mean values (black line) (SEs).*P <.001. CO, Control group. TABLE III. Symptom-free and asthma medication-free patients IT randomization 3-year SIT course N (%) 5-year SIT course N (%) Asthma-free T0 Asthma-free 0 0 Asthma Asthma-free T3 Asthma-free 32 (62.7) 47 (74.6) Asthma 18 (35.3) 16 (25.4) Asthma-free T5 Asthma-free 40 (64.5) 46 (74.1) Asthma 22 (35.5) 16 (25.9) In the control group, we observed significant changes (0.5 points) in the RQLQ domains concerning activity and emotions. Reactivity against D pteronyssinus Skin prick tests. No significant differences regarding HDM skin reactivity were seen in any group in the 3 assessment time points (P >.05). In vitro parameters. At T5, significant decreases in seric IgG (P 5.025) and sigg4 (P 5.003) measurements were observed among IT3 patients compared with the IT5 group. Control group measurements remained unchanged (Table IV). The asthma symptoms score increased in 133% from baseline in the control group. Asthma-free patients. All patients with asthma were symptomatic and required antiasthmatic treatment at baseline. At T3, 70% of SIT patients were symptom-free and out of treatment. At T5, neither apparent asthma relapses nor greater numbers of symptom-free patients were detected (Table III). VAS. Compared with baseline, the VAS scores decreased in the IT5 and IT3 groups at T3 (61.1% and 58.7%, respectively) and at T5 (67.6% and 64%, respectively). Differences seen in VAS scores between the third and fifth years of SIT were not significant in IT3 (P 5.256) or IT5 (P 5.283). The difference between VAS scores after 5 years between IT3 and IT5 were not significant either (P 5 1). The control group showed similar VAS scores throughout the study (P >.05; Fig 3, C). Quality of life. Compared with baseline, both groups showed significant changes in the domains explored by RQLQ (general, nasal, and ocular symptoms, practical issues, and emotional function) and AQLQ (symptoms, emotion, activity limitations, and environment). These changes had clinical relevance, 29,30 increases above 0.5 points for RQLQ and above 1.5 points for AQLQ. In none of the groups were differences observed when results at T3 and T5 were compared (Fig 4). DISCUSSION The recommended duration of SIT treatment relies on empiric data and is not well documented. In our opinion, an adequate SIT treatment should guarantee clinical efficacy with significant reduction of the symptoms and medication needs, a good safety profile without unpredictable systemic reactions, and a long-term therapeutic benefit after its completion. To date, few studies have addressed the identification of the proper duration of SIT treatment needed to fulfill those requirements. 34 Some trials have shown that the clinical benefit can be maintained up to 10 years after SIT is completed. 9,10 Nevertheless, trials 15,35 specifically assessing SIT duration observed a varying percentage of relapses in some cases, above 50% 2 years after stopping SIT. These data could be attributed at least in part to factors that were not directly considered in the results analysis such as the low numbers of patients included in these trials, the extracts and doses administered, and the study design. To our knowledge, with the exception of recently published trials with products under investigation performed with different aims, 36 this is the first trial that prospectively explores the currently recommended duration limits of SIT. We tried to control those factors other than treatment duration that might influence the efficacy, such as patient screening, the choice of the allergen, the quality and profile of the extract, and the patient s compliance, among others. Dermatophagoides mite

5 J ALLERGY CLIN IMMUNOL VOLUME 127, NUMBER 1 TABAR ET AL 61 FIG 4. RQLQ and AQLQ scores. A, IT5. B, IT3. C, Control group. Mean values (black line) (SEs). *P <.01. TABLE IV. Evolution of specific IgE (ku/l), IgG (ku/l), and IgG 4 (mcg/ml) levels against D pteronyssinus, median (interquartile) T0 T3 T5 IT5 IgEe 34.3 ( ) 31.8 ( ) ( ) IgGe 13.3 ( ) 20.7 ( ) 16.7 ( ) IgG 4 e ( ) 2650 ( ) 2625 ( ) IT3 IgEe 41.5 ( ) 30.9 ( ) 25.7 ( ) IgGe 14.1 ( ) 21.1 ( ) 13.7 ( ) IgG 4 e ( ) 2935 ( ) 1920 ( ) CO IgEe ( ) 9.06 ( ) IgGe 10.4 ( ) ( ) IgG 4 e 0.01 ( ) 0.01( ) is the main cause of respiratory allergy in our environment. During 1 year, we included the patients who had been consecutively diagnosed with HDM respiratory allergy and in whom SIT was indicated. Therefore, we are confident that demographic and diagnosis characteristics of our sample mirror the profile of patients who usually visit our department. We also had experience concerning optimal dose, efficacy, and safety of the treatment extract In addition, we knew the exact dose of the major allergen (in micrograms) received by our patients. This should also allow us to compare our results with other trials in which the composition is detailed. Because of the likelihood of disease progression, the long-term design of our trial did not advise including a control group at baseline. Therefore, and to avoid a possible limitation of the clinical benefit of a future SIT among these patients, the control group was added 4 years after the first vaccinated patients. Criteria for inclusion of controls were the same that had been followed with the treated patients. During data analysis, we could observe that both the percentage of asthma diagnosis and the severity of respiratory symptoms were lower among the control group. These differences may be attributed to the randomization itself but also to the calling effect of recent medical articles such as rhinitis guides 37 that highlight the clinical relevance of the disease, and trials demonstrating the prophylactic ability of SIT, previously mentioned. 9,10 All of them may have influenced both an earlier demand of specialized care by the patient and an earlier clinical indication of SIT therapy by the specialist, leading to the lack of comparability observed between the SIT and control groups. However, this fact has not influenced either the evolution of the vaccinated patients regarding their initial clinical status or the progression of the control group itself, as proven by the worsening of asthma symptoms. Although we used a per-protocol analysis, we tried to limit bias by randomization and by checks for comparability of baseline characteristics of completers and withdrawals.

6 62 TABAR ET AL J ALLERGY CLIN IMMUNOL JANUARY 2011 Compliance is a cornerstone for the efficacy of any medical treatment. As discussed, we excluded patients who had discontinued SIT but also those whose cumulative doses were too low and could potentially compromise the efficacy of SIT. At 3 years, we observed a compliance rate of 66%. This rate is consistent with the wide range of compliance rates reported among subjects following SIT, varying from 16% 38 to 80%. 39 According to the World Allergy Organization recommendations, 28 most of the parameters used to evaluate SIT efficacy were clinical. Evaluation at T3 showed significant improvements in all the treated patients before randomization. These changes were greater than those observed at T1 18 and consisted of reductions of rhinitis and asthma scores of 50% and 80%, respectively. Seventy percent of the patients with asthma were symptom-free without any antiasthmatic medication. At T5, we confirmed again that SIT had induced significant improvements in both treated groups. As detected at T3, improvements seemed to be more relevant in asthma (70% of the asthma patients remained symptom-free, and asthma score reductions remained unchanged), than in rhinitis (48% score reduction in IT3 and 69% in IT5). The magnitude of the improvement observed among patients with asthma at T3 had indeed left a small margin of benefit for the 2 additional years of SIT to make any difference. Both groups of patients had similar clinical status at T5 because we observed neither relapses in IT3 patients nor increases in the rate of IT5 asthma-free patients. However, rhinitis scores varied from 48% in IT3 to 69% in IT5 at T5. It seemed that among IT5 patients, 2 further years of SIT had added clinical benefit to rhinitis severity. These changes reached no statistical difference when comparing IT5 and IT3 scores, and were under the minimum rate of 30% proposed by Malling. 27 However, following the same author s criteria, the overall efficacy of SIT in the reduction of rhinitis severity increased from moderate at T3 (50%) to high at T5 (69.1%) among IT5 patients, whereas it was not modified among the IT3 group. Trials assessing SIT duration observed that most of relapses happened within the first 2 years after treatment discontinuation. According to that, our 2-year follow-up period should be appropriate to detect the relapses that may have occurred in our IT3 group. In the last few years, the patient s point of view has become more important both in clinical practice and in therapeutic evaluation. Accordingly, quality of life questionnaires were included as primary endpoints in the Cochrane meta-analysis testing SIT efficacy in rhinitis. 4 In our study, we included 2 subjective endpoints: VAS and quality of life questionnaires. To date, there are no standards to evaluate the modifications of VAS scores, but they offer us patients perceptions of their health status. We observed greater improvements in quality of life questionnaires among patients with asthma compared with those who had only rhinitis symptoms. Strikingly, we also observed that the improvement measured by the physician matched the patient s perception of health status. These observations are in keeping with the clinical observation regarding patients diagnosed with rhinitis and asthma who, after SIT treatment, become asymptomatic regarding asthma without needing of medication whereas they still have residual symptoms of rhinitis that require treatment. It is noteworthy that, in our study, 70% of the patients remained asthma-free after SIT, without relapses in those who had stopped 2 years before (IT3). To our knowledge, this is the first time these observations have been made. Des Roches et al 15 also described greater skin reactivity among patients who relapsed. We had observed changes in skin reactivity after a year of SIT 18 that were not maintained either at T3 or at T5. We attributed this fact to the irregular behavior of skin reactivity as an index to evaluate SIT efficacy 8,10 but also, although less likely, to the fact that tests were performed by different technicians at the different visits (baseline and T1 vs T3 and T5). Specific IgG 4 measurements increased significantly after 3 years of SIT. At T5, IgG 4 decreased significantly in IT3 but not in IT5 patients. We cannot check these data with literature because long-term efficacy trials 9 usually lack in vitro parameters. The significance is far from clear, although serum immunoglobulins provide information about the activity of regulatory T cells in SIT. 40 Therefore, it could be speculated that the relative decrease in IgG 4 levels among patients from the IT3 group might be related to a likely relapse of the disease. To date, these markers did not correlate with current clinical status, and only a longer followup should allow us to test that hypothesis. We conclude that 3 years of SIT is an adequate duration for the treatment of respiratory allergy caused by HDM because it induces a significant reduction in the severity of the disease, especially asthma, as well as significant changes in the patient s quality of life, that remain 2 years after SIT discontinuation. Two additional years of SIT seem to add benefit in rhinitis. Longer observation periods would be needed to assess whether a 5-year course might be related to a more prolonged efficacy. We thank Dr S. 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8 63.e1 TABAR ET AL J ALLERGY CLIN IMMUNOL JANUARY 2011 RESULTS Efficacy assessment See Tables E1 and E2. Compliance of SIT Four patients required changes on the adjuvant treatment or route of administration and were excluded. Four patients discontinued SIT because of nonimmunologic nonspecific reactions. Two patients discontinued SIT because of pregnancy, 5 because of subjective spontaneous improvement, 4 because of lack of clinical improvement, and 1 because of an asthma exacerbation unrelated to vaccination. Eighteen patients discontinued without a specific reason but without experiencing adverse events and 7 because they moved. Twelve patients could not be contacted. Safety of SIT A 31-year-old patient with asthma, monosensitized to D pteronyssinus, who was stable and on maintenance treatment for more than 3 years, without previous reactions, experienced an anaphylactic reaction 1 minute after the administration of the 61st dose of treatment. The reaction was rapidly resolved with subcutaneous epinephrine, intravenous methylprednisone, and nebulized salbutamol. It supposes 0.009% of the administered and 0.7% of the patients completing the follow-up. SIT was discontinued at that point. Four patients required changes in the adjuvant or route of administration because of local reactions and/or the presence of subcutaneous nodules.

9 J ALLERGY CLIN IMMUNOL VOLUME 127, NUMBER 1 TABAR ET AL 63.e2 TABLE E1. Rhinitis severity: symptoms and medication score Symptoms Sneezing AND/OR nose itching 0 Absent 1 Mild 2 Moderate 3 Severe Anterior rhinorrhea 0 Absent 1 Mild 2 Moderate 3 Severe Nose obstruction 0 Absent 1 Mild 2 Moderate 3 Severe Postnasal drip 0 Absent 1 Mild 2 Moderate 3 Severe Medication 0 No medication needed 1 Topical steroids OR oral antihistamines 2 Topical steroids AND oral antihistamines

10 63.e3 TABAR ET AL J ALLERGY CLIN IMMUNOL JANUARY 2011 TABLE E2. Asthma severity combined score: symptom score, medication score, and lung function Symptoms 0 No symptoms 1 Less than 5 short episodes (<7 d long) without any symptoms between crisis 2 Five to 10 short episodes (<7 d long) without symptoms between crisis or airflow obstruction less than 12 wk per year 3 More than 10 short episodes without symptoms between crises or airflow obstruction less than 12 wk per year 4 Frequent symptoms and airflow limitation for more than 6 mo in 1 year; 2 or 3 emergency department attendances 5 Incapacitating and chronic asthma with severe and frequent exacerbations despite optimal treatment; more than 3 emergency department attendances Medication 0 No treatment 1 Intermittent short-acting b 2 -agonists 2 Cromones 3 Inhaled steroids 4 Inhaled steroids plus sustained release theophylline or 1-3 oral short glucocorticosteroid treatments 5 Regular oral steroid treatment (lowest dose) or more than 4 oral steroid courses Lung function 0 Normal base spirometry (FEV 1 >80%) 1 Complete reversible airflow limitation after inhaled bronchodilator 2 Partial reversible airflow limitation after inhaled bronchodilator