936 CORRESPONDENCE
J ALLERGY CLIN IMMUNOL MARCH 2014
5. Mirza FS, Padhi ID, Raisz LG, Lorenzo JA. Serum sclerostin levels negatively correlate with parathyroid hormone levels and free estrogen index in postmenopausal women. J Clin Endocrinol Metab 2010;95:1991-7. 6. Ardawi M-SM, Al-Kadi HA, Rouzi AA, Qari MH. Determinants of serum sclerostin in healthy pre- and postmenopausal women. J Bone Miner Res 2011; 26:2812-22. 7. Amrein K, Amrein S, Drexler C, Dimai HP, Dobnig H, Pfeifer K, et al. Sclerostin and its association with physical activity, age, gender, body composition, and bone mineral content in healthy adults. J Clin Endocrinol Metab 2012;97:148-54. Available online January 16, 2014. http://dx.doi.org/10.1016/j.jaci.2013.12.008
Why are direct comparisons of subcutaneous and sublingual immunotherapy so rare? To the Editor: A series of systematic reviews and meta-analyses on allergen immunotherapy has been conducted in recent years. However, the approach of Dretzke et al1 to compare subcutaneous immunotherapy (SCIT) with sublingual immunotherapy (SLIT) is innovative. Actually, the comparison could be made only indirectly because a single head-to-head trial was available. The results of the analysis led the authors to conclude that superiority of one route of administration over the other was not apparent through indirect comparison. However, the authors deplored the fact that trials of direct comparison are so rare, suggesting that the reasons might be a reluctance of manufacturers to perform such studies or the methodological aspects of double blinding. We offer possible issues to be argued for such reluctance. First, in the only double-blind study of direct comparison of SCIT and SLIT by Khinchi et al,2 patients were randomized to 3 groups, one treated by active SCIT and placebo SLIT, another with placebo SCIT and active SLIT, and the third with double placebo. The rate of dropouts in this study was 20.8% with active SCIT and 39.2% with active SLIT. This rate is much higher than commonly reported in trials based on only 1 active treatment. In particular, we calculated the mean rate of dropouts in the SLIT studies included in the analysis by Dretzke et al to be 18.6%. This
suggests that patients are less compliant to protocols including double treatments and makes understandable why such trials are not performed. Moreover, the recent development of SLIT toward drug-quality preparations in tablets has led to the performance of double-blind trials aimed at obtaining the registration of such products by the regulatory authorities,3-5 but the comparison with SCIT was not included in the aims. These issues make it unlikely that direct comparison of SCIT and SLIT will be the objective of trials in the next few years. Franco Frati, MDa Ilaria Dell’Albani, BSa Cristoforo Incorvaia, MDb From athe Scientific and Medical Department, Stallergenes, and bAllergy/Pulmonary Rehabilitation, ICP Hospital, Milan, Italy. E-mail: [email protected]. Disclosure of potential conflict of interest: F. Frati and I. Dell’Albani are employed by Stallergenes Italy. C. Incorvaia has consultant arrangements with Stallergenes Italy. Editor’s note: There is no accompanying reply to this correspondence. REFERENCES 1. Dretzke J, Meadows A, Novielli N, Huissoon A, Fry-Smith A, Meads C. Subcutaneous and sublingual immunotherapy for seasonal allergic rhinitis: a systematic review and indirect comparison. J Allergy Clin Immunol 2013;131:1361-6. 2. Khinchi MS, Poulsen LK, Carat F, Andre C, Hansen AB, Malling HJ. Clinical efficacy of sublingual and subcutaneous birch pollen allergen-specific immunotherapy: a randomized, placebo-controlled, double-blind, double-dummy study. Allergy 2004;59:45-53. 3. Didier A, Malling HJ, Worm M, Horak F, Jager S, Montagut A, et al. Optimal dose, efficacy, and safety of once daily sublingual immunotherapy with a 5-grass pollen tablet for seasonal allergic rhinitis. J Allergy Clin Immunol 2007;120:1338-45. 4. Wahn U, Tabar A, Kuna P, Halken S, Montagut A, de Beaumont O, et al. SLIT Study Group. Efficacy and safety of 5-grass pollen sublingual immunotherapy tablets in pediatric allergic rhinoconjunctivitis. J Allergy Clin Immunol 2009;123: 160-6. 5. Cox LS, Casale TB, Nayak AS, Bernstein DI, Creticos PS, Ambroisine L, et al. Clinical efficacy of 300IR 5-grass pollen sublingual tablet in a US study: the importance of allergen-specific serum IgE. J Allergy Clin Immunol 2012;130: 1327-34. Available online December 10, 2013. http://dx.doi.org/10.1016/j.jaci.2013.10.043
J ALLERGY CLIN IMMUNOL MARCH 2014
5. Mirza FS, Padhi ID, Raisz LG, Lorenzo JA. Serum sclerostin levels negatively correlate with parathyroid hormone levels and free estrogen index in postmenopausal women. J Clin Endocrinol Metab 2010;95:1991-7. 6. Ardawi M-SM, Al-Kadi HA, Rouzi AA, Qari MH. Determinants of serum sclerostin in healthy pre- and postmenopausal women. J Bone Miner Res 2011; 26:2812-22. 7. Amrein K, Amrein S, Drexler C, Dimai HP, Dobnig H, Pfeifer K, et al. Sclerostin and its association with physical activity, age, gender, body composition, and bone mineral content in healthy adults. J Clin Endocrinol Metab 2012;97:148-54. Available online January 16, 2014. http://dx.doi.org/10.1016/j.jaci.2013.12.008
Why are direct comparisons of subcutaneous and sublingual immunotherapy so rare? To the Editor: A series of systematic reviews and meta-analyses on allergen immunotherapy has been conducted in recent years. However, the approach of Dretzke et al1 to compare subcutaneous immunotherapy (SCIT) with sublingual immunotherapy (SLIT) is innovative. Actually, the comparison could be made only indirectly because a single head-to-head trial was available. The results of the analysis led the authors to conclude that superiority of one route of administration over the other was not apparent through indirect comparison. However, the authors deplored the fact that trials of direct comparison are so rare, suggesting that the reasons might be a reluctance of manufacturers to perform such studies or the methodological aspects of double blinding. We offer possible issues to be argued for such reluctance. First, in the only double-blind study of direct comparison of SCIT and SLIT by Khinchi et al,2 patients were randomized to 3 groups, one treated by active SCIT and placebo SLIT, another with placebo SCIT and active SLIT, and the third with double placebo. The rate of dropouts in this study was 20.8% with active SCIT and 39.2% with active SLIT. This rate is much higher than commonly reported in trials based on only 1 active treatment. In particular, we calculated the mean rate of dropouts in the SLIT studies included in the analysis by Dretzke et al to be 18.6%. This
suggests that patients are less compliant to protocols including double treatments and makes understandable why such trials are not performed. Moreover, the recent development of SLIT toward drug-quality preparations in tablets has led to the performance of double-blind trials aimed at obtaining the registration of such products by the regulatory authorities,3-5 but the comparison with SCIT was not included in the aims. These issues make it unlikely that direct comparison of SCIT and SLIT will be the objective of trials in the next few years. Franco Frati, MDa Ilaria Dell’Albani, BSa Cristoforo Incorvaia, MDb From athe Scientific and Medical Department, Stallergenes, and bAllergy/Pulmonary Rehabilitation, ICP Hospital, Milan, Italy. E-mail: [email protected]. Disclosure of potential conflict of interest: F. Frati and I. Dell’Albani are employed by Stallergenes Italy. C. Incorvaia has consultant arrangements with Stallergenes Italy. Editor’s note: There is no accompanying reply to this correspondence. REFERENCES 1. Dretzke J, Meadows A, Novielli N, Huissoon A, Fry-Smith A, Meads C. Subcutaneous and sublingual immunotherapy for seasonal allergic rhinitis: a systematic review and indirect comparison. J Allergy Clin Immunol 2013;131:1361-6. 2. Khinchi MS, Poulsen LK, Carat F, Andre C, Hansen AB, Malling HJ. Clinical efficacy of sublingual and subcutaneous birch pollen allergen-specific immunotherapy: a randomized, placebo-controlled, double-blind, double-dummy study. Allergy 2004;59:45-53. 3. Didier A, Malling HJ, Worm M, Horak F, Jager S, Montagut A, et al. Optimal dose, efficacy, and safety of once daily sublingual immunotherapy with a 5-grass pollen tablet for seasonal allergic rhinitis. J Allergy Clin Immunol 2007;120:1338-45. 4. Wahn U, Tabar A, Kuna P, Halken S, Montagut A, de Beaumont O, et al. SLIT Study Group. Efficacy and safety of 5-grass pollen sublingual immunotherapy tablets in pediatric allergic rhinoconjunctivitis. J Allergy Clin Immunol 2009;123: 160-6. 5. Cox LS, Casale TB, Nayak AS, Bernstein DI, Creticos PS, Ambroisine L, et al. Clinical efficacy of 300IR 5-grass pollen sublingual tablet in a US study: the importance of allergen-specific serum IgE. J Allergy Clin Immunol 2012;130: 1327-34. Available online December 10, 2013. http://dx.doi.org/10.1016/j.jaci.2013.10.043
