Ann Allergy Asthma Immunol 114 (2015) 173e174
Contents lists available at ScienceDirect
Year in review: allergen immunotherapy Giorgio Walter Canonica, MD; and Enrico Compalati, MD, PhD Allergy and Respiratory Diseases, Department of Internal Medicine, IRCCS S Martino, IST, University of Genoa, Genoa, Italy
A R T I C L E
I N F O
Article history: Received for publication November 10, 2014. Received in revised form December 15, 2014. Accepted for publication December 16, 2014.
This year-in-review article on allergen immunotherapy (AIT) is aimed at recalling the main findings of research published in the Annals of Allergy, Asthma, and Immunology during 2014. These articles were undertaken mainly to address the requirement for regulatory approval of sublingual immunotherapy (SLIT) of standardized allergen extracts in the United States and to explore the possibilities of improving adherence to AIT for the treatment of respiratory allergy. This last aspect is extremely important to therapeutic success but unfortunately remains a critical issue in many cases. Traditional subcutaneous immunotherapy (SCIT) for AIT is the most common in the United States, but it requires regular injections at a clinician’s office, typically for a long period, and entails the risk of potentially serious systemic allergic reactions (SRs). These 2 aspects can affect patients’ acceptance and adherence, although several factors can influence the decision to initiate and complete an AIT regimen. Because a treatment course of 3 to 5 years is desirable to achieve and sustain a clinical benefit after discontinuation, the decision to initiate requires a long-term commitment by patients. A retrospective review of electronic health records of patients with allergic rhinitis from January 2005 to June 2011, conducted in a large private allergy practice in Pennsylvania, showed that only a minority of patients initiated AIT, despite having documentation of an AIT prescription.1 In particular, of 8,790 patients advised to consider AIT, only 36.2% initiated it (57% of adults, 43% of children). Many more sensitivities were associated more significantly with choosing AIT, particularly off-label sublingual drops, suggesting that polysensitization can positively influence the choice of initiating a desensitization program. AIT targeting the causes of allergy is often considered complementary to pharmacologic treatment rather than as an add-on approach, but this survey showed that most patients were already receiving multiple
Reprints: Giorgio Walter Canonica, MD, Allergy and Respiratory Diseases, Department of Internal Medicine, IRCCS S Martino, IST, University of Genoa, Largo Rosanna Benzi 10, Genoa 16132, Italy; E-mail: [email protected]. Disclosure: Authors have nothing to disclose.
antiallergic medications at AIT initiation and had comorbidities, suggesting an advanced disease status. Interestingly, the choice of SCIT (78%) vs SLIT (22%) was significantly associated with older age, female sex, and more allergy medications at initiation. SLIT was preferred by pediatric patients (SLIT drops in 59.6% vs SCIT in 38.6%) when a comorbidity existed. Conversely, when the asthma population was stratified by age, SCIT (47.1%) was selected more often than SLIT (17.2%) by adults. Unfortunately, only a subset of those patients initiating AIT completed the treatment course, with 39.6% discontinuing before completion at 3 years and 49% before completion at 5 years. After 3 years, 35% and 23.7% of patients had completed SCIT and SLIT, respectively. The median course of treatment was longer for adults on SCIT than for those on SLIT (3 vs 1.6 years). Similar findings occurred in children, but they tended to remain longer on treatment (SCIT for 4.7 years vs SLIT for 3.5 years). Overall, these data confirm that treatment discontinuation represents a major problem in daily clinical practice because of lack of efficacy, financial burden, adverse events, and time consumption. However, in a vast majority of patients (SLIT in 69% vs 77% in SCIT), no specific reason was identified, suggesting that interventions, such as educational sessions, strict follow-up, regular contacts, and cost decreases (or covering by health insurance for SLIT), could improve persistence. The most recent approaches to developing clinical care guidelines have solicited explicit considerations of patients’ perspectives and resource use when recommending medical interventions, because these issues can influence patients’ compliance. For instance, patients can experience pain and discomfort from SCIT injections, thus impairing treatment acceptance or persistence and prompting physicians to limit the number of injections per visit, mainly in children. Therefore, it is desirable to include patients in these decisions. Surprisingly, a recent survey conducted in more than 300 patients 4 to 80 years old undergoing SCIT at the Wilford Hall Ambulatory Surgical Center Allergy Clinic showed that most patients consider the number of injections irrelevant as long as the treatment is effective.2 These findings come from a peculiar setting where patients, members of the military, paid no additional money
http://dx.doi.org/10.1016/j.anai.2014.12.024 1081-1206/Ó 2015 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
174
G.W. Canonica and E. Compalati / Ann Allergy Asthma Immunol 114 (2015) 173e174
to receive AIT, indicating that the cost of AIT could be a factor that limits patients’ preference when deciding to start or to receive multiple injections. The same consideration can be applied to another 10-year retrospective review at the West Los Angeles US Veterans Affairs Medical Center, in which adherence rates for low, medium, and high socioeconomic groups were quite similar (w65%) but surprisingly in line with studies in which patients paid for AIT.3 In that study, a statistically significant increase in adherence was found with age, likely because retired veterans do not have other time commitments, such as employment or school. The apparently paradoxical observation of a better adherence to AIT in patients with a diagnosis of psychiatric disorders supports the conviction that regular follow-up programs can positively influence treatment success. The occurrence of SRs can be regarded as a deterrent to initiate a SCIT course, but interesting findings resulted from a comprehensive investigation on the safety of the Joint Task Force on Practice Parameters 2007 recommendation to formulate more potent immunotherapy (1:1 concentrate dosing) compared with the previously used more diluted maintenance dosing.4 During 7 years in a large academic practice, the rate and grading severity of SRs according to the World Allergy Organization, which occurred with pre- and post-parameter dosing, were not substantial. In conclusion, provided there is an appropriate 30-minute wait time after injection and with the exception of patients being transitioned from an established regimen to a new one who appear more vulnerable to SRs, the 1:1 dosing should be as safe as more diluted dosing but would enhance the immunologic response, involving a decrease in mast cells and eosinophils, a decrease in basophil activation, an increase in IgG4, and a shift in the cytokine milieu because of the immunomodulation provided by peripherally derived CD4 T-regulatory cells.5 The recent approval of grass pollen SLIT tablets by the Food and Drug Administration to treat hay fever provides a standardized alternative to allergy shots in health care providers’ offices, with the advantage of home self-management after the first administration and no need for up-titration. This aspect might prove to be more convenient for patients wishing to decrease medical visits. In 2014 the largest randomized trial conducted in North America evaluated 1,501 patients (5e65 years old, 85% polysensitized, 25% with asthma) receiving a SLIT tablet (MK-7243) for timothy grass or placebo, with only the first dose under medical supervision without up-titration and adjustment for age or weight.6 SLIT vs placebo yielded improvement in up to 29% in the peak season according to combined symptoms and medication scores, with irrelevant differences between adults and children. The timothy grass extract was sufficient for treating patients with timothy and related grass sensitizations and when co-sensitization to other allergens existed. As expected, most adverse events were local, self-limiting, and of mild or moderate severity. Only 3 patients had moderate SRs, and epinephrine was used by 2 patients on active treatment for symptoms unrelated to AIT and in the absence of clear indications suggestive of acute anaphylaxis. Trials such as this require the involvement of hundreds of patients and large amounts of data collected to prove the efficacy of AIT, representing an expensive challenge to reach the end point, because of a substantial placebo effect associated with symptom scoring. Objectively measuring exhaled breath temperature, a putative marker of airway inflammation, with a dedicated instrument during an AIT course was recently proposed as an effective way of assessing treatment response, although this hypothesis requires further investigation.7
A pilot double-blinded, placebo-controlled study conducted in Sofia included 56 young adults sensitized to grass pollen and showed that the mean increase in exhaled breath temperature during the allergy season was significantly lower (by 59.1%) in the SLIT group than in the control group, permitting better discrimination between active and placebo treatments compared with a subjective assessment based on a visual analog scale. Grass seems to be the most diffuse sensitizing pollen in the United States, and 26% of the population appears to be sensitized to ragweed (up to 33% in Canada). Because there is limited safety experience with ragweed SLIT, new formulations in tablet form (MK-3641) for allergic rhinoconjunctivitis recently underwent clinical investigation in 4 large, multicenter, randomized, placebocontrolled phase II and III trials. Their subsequent post hoc pooled analysis provided a comprehensive assessment of the short-term and long-term safety profile.8 The adverse event rate in the 52week assessment was largely comparable to that based on the 28-day assessment, with mainly transient mild to moderate local reactions, suggesting that the safety profile at initiation might be representative of the long-term course. Four treatment-related SRs were treated with epinephrine, and 2% of patients developed SRs in the 28-day assessment, but it is not clear whether these rates are comparable to those in real-world clinical practice. Adverse events were comparable in incidence, features, and severity in patients with and without mild controlled asthma. In conclusion, these recent publications indicate that, although multiple factors, including tolerability and patient preference, affordable costs, adherence, and response to other medications, are worthy of consideration at its initiation, AIT remains an important option, particularly for patients seeking long-term relief, but appears frequently underused or discontinued. The SLIT administration of standardized high-quality extracts can be regarded as a new effective weapon in the allergist’s armamentarium, offering the possibility to overcome some limitations of the traditional injective approach, but patients’ involvement in decision making will be crucial for identification of the optimal treatment strategy. Future research is expected to demonstrate the convenience of different AIT approaches in various real-life scenarios and with the most relevant allergens.
References [1] Anolik R, Schwartz AM, Sajjan S, Allen-Ramey F. Patient initiation and persistence with allergen immunotherapy. Ann Allergy Asthma Immunol. 2014;113: 101e107. [2] Coop CA, Yip SK, Tankersley MS. Perceptions regarding injection number and technique. Ann Allergy Asthma Immunol. 2014;113:227e228. [3] Guenechea-Sola M, Hariri SR, Galoosian A, Yusin JS. A retrospective review of veterans’ adherence to allergen immunotherapy over 10 years. Ann Allergy Asthma Immunol. 2014;112:79e81. [4] Holland CL, Samuels KM, Baldwin JL, Greenhawt MJ. Systemic reactions to inhalant immunotherapy using 1:1 target dosing. Ann Allergy Asthma Immunol. 2014;112:453e458. [5] Steinke JW, Lawrence MG. T-cell biology in immunotherapy. Ann Allergy Asthma Immunol. 2014;112:195e199. [6] Maloney J, Bernstein DI, Nelson H, et al. Efficacy and safety of grass sublingual immunotherapy tablet, MK-7243: a large randomized controlled trial. Ann Allergy Asthma Immunol. 2014;112:146e153. [7] Kralimarkova TZ, Popov TA, Staevska M, et al. Objective approach for fending off the sublingual immunotherapy placebo effect in subjects with pollenosis: double-blinded, placebo-controlled trial. Ann Allergy Asthma Immunol. 2014; 113:108e113. [8] Nolte H, Amar N, Bernstein DI, et al. Safety and tolerability of a short ragweed sublingual immunotherapy tablet. Ann Allergy Asthma Immunol. 2014;113: 93e100.
Contents lists available at ScienceDirect
Year in review: allergen immunotherapy Giorgio Walter Canonica, MD; and Enrico Compalati, MD, PhD Allergy and Respiratory Diseases, Department of Internal Medicine, IRCCS S Martino, IST, University of Genoa, Genoa, Italy
A R T I C L E
I N F O
Article history: Received for publication November 10, 2014. Received in revised form December 15, 2014. Accepted for publication December 16, 2014.
This year-in-review article on allergen immunotherapy (AIT) is aimed at recalling the main findings of research published in the Annals of Allergy, Asthma, and Immunology during 2014. These articles were undertaken mainly to address the requirement for regulatory approval of sublingual immunotherapy (SLIT) of standardized allergen extracts in the United States and to explore the possibilities of improving adherence to AIT for the treatment of respiratory allergy. This last aspect is extremely important to therapeutic success but unfortunately remains a critical issue in many cases. Traditional subcutaneous immunotherapy (SCIT) for AIT is the most common in the United States, but it requires regular injections at a clinician’s office, typically for a long period, and entails the risk of potentially serious systemic allergic reactions (SRs). These 2 aspects can affect patients’ acceptance and adherence, although several factors can influence the decision to initiate and complete an AIT regimen. Because a treatment course of 3 to 5 years is desirable to achieve and sustain a clinical benefit after discontinuation, the decision to initiate requires a long-term commitment by patients. A retrospective review of electronic health records of patients with allergic rhinitis from January 2005 to June 2011, conducted in a large private allergy practice in Pennsylvania, showed that only a minority of patients initiated AIT, despite having documentation of an AIT prescription.1 In particular, of 8,790 patients advised to consider AIT, only 36.2% initiated it (57% of adults, 43% of children). Many more sensitivities were associated more significantly with choosing AIT, particularly off-label sublingual drops, suggesting that polysensitization can positively influence the choice of initiating a desensitization program. AIT targeting the causes of allergy is often considered complementary to pharmacologic treatment rather than as an add-on approach, but this survey showed that most patients were already receiving multiple
Reprints: Giorgio Walter Canonica, MD, Allergy and Respiratory Diseases, Department of Internal Medicine, IRCCS S Martino, IST, University of Genoa, Largo Rosanna Benzi 10, Genoa 16132, Italy; E-mail: [email protected]. Disclosure: Authors have nothing to disclose.
antiallergic medications at AIT initiation and had comorbidities, suggesting an advanced disease status. Interestingly, the choice of SCIT (78%) vs SLIT (22%) was significantly associated with older age, female sex, and more allergy medications at initiation. SLIT was preferred by pediatric patients (SLIT drops in 59.6% vs SCIT in 38.6%) when a comorbidity existed. Conversely, when the asthma population was stratified by age, SCIT (47.1%) was selected more often than SLIT (17.2%) by adults. Unfortunately, only a subset of those patients initiating AIT completed the treatment course, with 39.6% discontinuing before completion at 3 years and 49% before completion at 5 years. After 3 years, 35% and 23.7% of patients had completed SCIT and SLIT, respectively. The median course of treatment was longer for adults on SCIT than for those on SLIT (3 vs 1.6 years). Similar findings occurred in children, but they tended to remain longer on treatment (SCIT for 4.7 years vs SLIT for 3.5 years). Overall, these data confirm that treatment discontinuation represents a major problem in daily clinical practice because of lack of efficacy, financial burden, adverse events, and time consumption. However, in a vast majority of patients (SLIT in 69% vs 77% in SCIT), no specific reason was identified, suggesting that interventions, such as educational sessions, strict follow-up, regular contacts, and cost decreases (or covering by health insurance for SLIT), could improve persistence. The most recent approaches to developing clinical care guidelines have solicited explicit considerations of patients’ perspectives and resource use when recommending medical interventions, because these issues can influence patients’ compliance. For instance, patients can experience pain and discomfort from SCIT injections, thus impairing treatment acceptance or persistence and prompting physicians to limit the number of injections per visit, mainly in children. Therefore, it is desirable to include patients in these decisions. Surprisingly, a recent survey conducted in more than 300 patients 4 to 80 years old undergoing SCIT at the Wilford Hall Ambulatory Surgical Center Allergy Clinic showed that most patients consider the number of injections irrelevant as long as the treatment is effective.2 These findings come from a peculiar setting where patients, members of the military, paid no additional money
http://dx.doi.org/10.1016/j.anai.2014.12.024 1081-1206/Ó 2015 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
174
G.W. Canonica and E. Compalati / Ann Allergy Asthma Immunol 114 (2015) 173e174
to receive AIT, indicating that the cost of AIT could be a factor that limits patients’ preference when deciding to start or to receive multiple injections. The same consideration can be applied to another 10-year retrospective review at the West Los Angeles US Veterans Affairs Medical Center, in which adherence rates for low, medium, and high socioeconomic groups were quite similar (w65%) but surprisingly in line with studies in which patients paid for AIT.3 In that study, a statistically significant increase in adherence was found with age, likely because retired veterans do not have other time commitments, such as employment or school. The apparently paradoxical observation of a better adherence to AIT in patients with a diagnosis of psychiatric disorders supports the conviction that regular follow-up programs can positively influence treatment success. The occurrence of SRs can be regarded as a deterrent to initiate a SCIT course, but interesting findings resulted from a comprehensive investigation on the safety of the Joint Task Force on Practice Parameters 2007 recommendation to formulate more potent immunotherapy (1:1 concentrate dosing) compared with the previously used more diluted maintenance dosing.4 During 7 years in a large academic practice, the rate and grading severity of SRs according to the World Allergy Organization, which occurred with pre- and post-parameter dosing, were not substantial. In conclusion, provided there is an appropriate 30-minute wait time after injection and with the exception of patients being transitioned from an established regimen to a new one who appear more vulnerable to SRs, the 1:1 dosing should be as safe as more diluted dosing but would enhance the immunologic response, involving a decrease in mast cells and eosinophils, a decrease in basophil activation, an increase in IgG4, and a shift in the cytokine milieu because of the immunomodulation provided by peripherally derived CD4 T-regulatory cells.5 The recent approval of grass pollen SLIT tablets by the Food and Drug Administration to treat hay fever provides a standardized alternative to allergy shots in health care providers’ offices, with the advantage of home self-management after the first administration and no need for up-titration. This aspect might prove to be more convenient for patients wishing to decrease medical visits. In 2014 the largest randomized trial conducted in North America evaluated 1,501 patients (5e65 years old, 85% polysensitized, 25% with asthma) receiving a SLIT tablet (MK-7243) for timothy grass or placebo, with only the first dose under medical supervision without up-titration and adjustment for age or weight.6 SLIT vs placebo yielded improvement in up to 29% in the peak season according to combined symptoms and medication scores, with irrelevant differences between adults and children. The timothy grass extract was sufficient for treating patients with timothy and related grass sensitizations and when co-sensitization to other allergens existed. As expected, most adverse events were local, self-limiting, and of mild or moderate severity. Only 3 patients had moderate SRs, and epinephrine was used by 2 patients on active treatment for symptoms unrelated to AIT and in the absence of clear indications suggestive of acute anaphylaxis. Trials such as this require the involvement of hundreds of patients and large amounts of data collected to prove the efficacy of AIT, representing an expensive challenge to reach the end point, because of a substantial placebo effect associated with symptom scoring. Objectively measuring exhaled breath temperature, a putative marker of airway inflammation, with a dedicated instrument during an AIT course was recently proposed as an effective way of assessing treatment response, although this hypothesis requires further investigation.7
A pilot double-blinded, placebo-controlled study conducted in Sofia included 56 young adults sensitized to grass pollen and showed that the mean increase in exhaled breath temperature during the allergy season was significantly lower (by 59.1%) in the SLIT group than in the control group, permitting better discrimination between active and placebo treatments compared with a subjective assessment based on a visual analog scale. Grass seems to be the most diffuse sensitizing pollen in the United States, and 26% of the population appears to be sensitized to ragweed (up to 33% in Canada). Because there is limited safety experience with ragweed SLIT, new formulations in tablet form (MK-3641) for allergic rhinoconjunctivitis recently underwent clinical investigation in 4 large, multicenter, randomized, placebocontrolled phase II and III trials. Their subsequent post hoc pooled analysis provided a comprehensive assessment of the short-term and long-term safety profile.8 The adverse event rate in the 52week assessment was largely comparable to that based on the 28-day assessment, with mainly transient mild to moderate local reactions, suggesting that the safety profile at initiation might be representative of the long-term course. Four treatment-related SRs were treated with epinephrine, and 2% of patients developed SRs in the 28-day assessment, but it is not clear whether these rates are comparable to those in real-world clinical practice. Adverse events were comparable in incidence, features, and severity in patients with and without mild controlled asthma. In conclusion, these recent publications indicate that, although multiple factors, including tolerability and patient preference, affordable costs, adherence, and response to other medications, are worthy of consideration at its initiation, AIT remains an important option, particularly for patients seeking long-term relief, but appears frequently underused or discontinued. The SLIT administration of standardized high-quality extracts can be regarded as a new effective weapon in the allergist’s armamentarium, offering the possibility to overcome some limitations of the traditional injective approach, but patients’ involvement in decision making will be crucial for identification of the optimal treatment strategy. Future research is expected to demonstrate the convenience of different AIT approaches in various real-life scenarios and with the most relevant allergens.
References [1] Anolik R, Schwartz AM, Sajjan S, Allen-Ramey F. Patient initiation and persistence with allergen immunotherapy. Ann Allergy Asthma Immunol. 2014;113: 101e107. [2] Coop CA, Yip SK, Tankersley MS. Perceptions regarding injection number and technique. Ann Allergy Asthma Immunol. 2014;113:227e228. [3] Guenechea-Sola M, Hariri SR, Galoosian A, Yusin JS. A retrospective review of veterans’ adherence to allergen immunotherapy over 10 years. Ann Allergy Asthma Immunol. 2014;112:79e81. [4] Holland CL, Samuels KM, Baldwin JL, Greenhawt MJ. Systemic reactions to inhalant immunotherapy using 1:1 target dosing. Ann Allergy Asthma Immunol. 2014;112:453e458. [5] Steinke JW, Lawrence MG. T-cell biology in immunotherapy. Ann Allergy Asthma Immunol. 2014;112:195e199. [6] Maloney J, Bernstein DI, Nelson H, et al. Efficacy and safety of grass sublingual immunotherapy tablet, MK-7243: a large randomized controlled trial. Ann Allergy Asthma Immunol. 2014;112:146e153. [7] Kralimarkova TZ, Popov TA, Staevska M, et al. Objective approach for fending off the sublingual immunotherapy placebo effect in subjects with pollenosis: double-blinded, placebo-controlled trial. Ann Allergy Asthma Immunol. 2014; 113:108e113. [8] Nolte H, Amar N, Bernstein DI, et al. Safety and tolerability of a short ragweed sublingual immunotherapy tablet. Ann Allergy Asthma Immunol. 2014;113: 93e100.
