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2014; Elsevier BV; Volume: 133; Issue: 3 Linguagem: Inglês
10.1016/j.jaci.2013.11.037
ISSN1097-6825
AutoresHans‐Jørgen Malling, Marianne Witten, Lars K. Poulsen,
Tópico(s)Asthma and respiratory diseases
ResumoWe appreciate the interesting comments by Kündig et al.1Kündig T.M. Johansen P. Bachmann M.F. Cardell L.O. Senti G. Intralymphatic immunotherapy: time interval between injections is essential.J Allergy Clin Immunol. 2014; 133: 930-931Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar They argue that the total lack of clinical efficacy of intralymphatic immunotherapy (ILIT) as recently published by Witten et al2Witten M. Malling H.J. Blom L. Poulsen B.C. Poulsen L.K. Is intralymphatic immunotherapy ready for clinical use in patients with grass pollen allergy?.J Allergy Clin Immunol. 2013; 132: 1248-1252.e5Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar is caused by the latter group using 2-week intervals in contrast to the “recommended” 4-week intervals claimed to be optimal for ILIT. In their commentary, Kündig et al1Kündig T.M. Johansen P. Bachmann M.F. Cardell L.O. Senti G. Intralymphatic immunotherapy: time interval between injections is essential.J Allergy Clin Immunol. 2014; 133: 930-931Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar base their arguments on conventional vaccinology recommendations for preventive vaccines,3General recommendation on immunization. Recommendations of the Advisory Committee on Immunization Practices (ACIP). 2011. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/rr6002a1.htm. Accessed January 2, 2014.Google Scholar but it should be noted that allergen-specific immunotherapy—by some called allergy vaccination—is not even mentioned in the recommendations because they are therapeutic vaccines, where an immune deviation is aimed for. Thus, the design of our study with either 3 or 6 injections every second week was based on the present use of injection immunotherapy in the field of allergy. Kündig et al1Kündig T.M. Johansen P. Bachmann M.F. Cardell L.O. Senti G. Intralymphatic immunotherapy: time interval between injections is essential.J Allergy Clin Immunol. 2014; 133: 930-931Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar claim that if the interval between vaccine injections is less than 4 weeks, the dose given within 4 weeks is “invalid.” If this had any relation to the lack of clinical efficacy observed in our study,2Witten M. Malling H.J. Blom L. Poulsen B.C. Poulsen L.K. Is intralymphatic immunotherapy ready for clinical use in patients with grass pollen allergy?.J Allergy Clin Immunol. 2013; 132: 1248-1252.e5Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar it might explain the missing clinical efficacy in the x3 group (received 3 injections with 2-week intervals followed by 3 placebo injections). It does not, however, explain the identical missing clinical efficacy in the x6 group. If injections given with less than a 4-week interval were “invalid,” as suggested by Kündig et al,1Kündig T.M. Johansen P. Bachmann M.F. Cardell L.O. Senti G. Intralymphatic immunotherapy: time interval between injections is essential.J Allergy Clin Immunol. 2014; 133: 930-931Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar the x6 group in our design would actually constitute an exact copy of the 3 studies of ILIT claiming clinical efficacy.4Senti G. Prinz Vavricka B.M. Erdmann I. Diaz M.I. Markus R. McCormack S.J. et al.Intralymphatic allergen administration renders specific immunotherapy faster and safer: a randomized controlled trial.Proc Natl Acad Sci U S A. 2008; 105: 17908-17912Crossref PubMed Scopus (297) Google Scholar, 5Senti G. Crameri R. Kuster D. Johansen P. Martinez-Gomez J.M. Graf N. et al.Intralymphatic immunotherapy for cat allergy induces tolerance after only 3 injections.J Allergy Clin Immunol. 2012; 29: 1290-1296Abstract Full Text Full Text PDF Scopus (219) Google Scholar, 6Hylander T. Latif L. Petersson-Westin U. Cardell L.O. Intralymphatic allergen-specific immunotherapy: an effective and safe alternative treatment route for pollen-induced allergic rhinitis.J Allergy Clin Immunol. 2013; 131: 412-420Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar Thus, assuming that every second injection is “invalid,” the allergen dosages in the x6 group are administered with a 4-week interval as in the studies by Senti et al4Senti G. Prinz Vavricka B.M. Erdmann I. Diaz M.I. Markus R. McCormack S.J. et al.Intralymphatic allergen administration renders specific immunotherapy faster and safer: a randomized controlled trial.Proc Natl Acad Sci U S A. 2008; 105: 17908-17912Crossref PubMed Scopus (297) Google Scholar, 5Senti G. Crameri R. Kuster D. Johansen P. Martinez-Gomez J.M. Graf N. et al.Intralymphatic immunotherapy for cat allergy induces tolerance after only 3 injections.J Allergy Clin Immunol. 2012; 29: 1290-1296Abstract Full Text Full Text PDF Scopus (219) Google Scholar and Hylander et al6Hylander T. Latif L. Petersson-Westin U. Cardell L.O. Intralymphatic allergen-specific immunotherapy: an effective and safe alternative treatment route for pollen-induced allergic rhinitis.J Allergy Clin Immunol. 2013; 131: 412-420Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar and furthermore using identical allergen dosage (1000 SQ-U4Senti G. Prinz Vavricka B.M. Erdmann I. Diaz M.I. Markus R. McCormack S.J. et al.Intralymphatic allergen administration renders specific immunotherapy faster and safer: a randomized controlled trial.Proc Natl Acad Sci U S A. 2008; 105: 17908-17912Crossref PubMed Scopus (297) Google Scholar, 6Hylander T. Latif L. Petersson-Westin U. Cardell L.O. Intralymphatic allergen-specific immunotherapy: an effective and safe alternative treatment route for pollen-induced allergic rhinitis.J Allergy Clin Immunol. 2013; 131: 412-420Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar). This indicates that the lack of clinical efficacy was not caused by discrepancies in injection intervals. We would like to emphasize that a major difference between our study2Witten M. Malling H.J. Blom L. Poulsen B.C. Poulsen L.K. Is intralymphatic immunotherapy ready for clinical use in patients with grass pollen allergy?.J Allergy Clin Immunol. 2013; 132: 1248-1252.e5Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar and the above-mentioned studies is the way clinical efficacy was estimated. According to the European Medicine Agency,7Commitee for medicinal products for human use (CHMP). Guideline on the clinical development of products for specific immunotherapy for the treatment of allergic diseases. CHMP/EWP/18504/2006. London: European Medicines Agency; 2008.Google Scholar the primary outcome in confirmatory studies should “reflect both symptom severity as well as the intake of rescue medication.” It is furthermore suggested to “combine both scores by a weighted sum of the symptom and medication score respectively.” Already in 2000, the US Department of Health and Human Services Food and Drug Administration8Guidance for Industry. Allergic rhinitis: Clinical development programs for drug products. Draft guidance. U.S. Department of Health and Human Serviced, FDA Food and Drug Adminstration, Center for Drug Evaluation and Research (CDER). Rockville, MD: 2000.Google Scholar proposed the same rating system. The World Allergy Organization9Canonica G.W. Baena-Cagnani C.E. Bousquet J. Bousquet P.J. Lockey R.F. Malling H.J. et al.Recommendations for standardization of clinical trials with Allergen Specific Immunotherapy for respiratory allergy. A statement of a World Allergy Organization (WAO) taskforce.Allergy. 2007; 62: 317-324Crossref PubMed Scopus (388) Google Scholar likewise clearly indicates that the only parameter reflecting clinical efficacy is a measure of clinical symptoms in different treatment arms and the intake of rescue medication relative to placebo treated patients and the paper goes on to state: “Symptoms and medication usage are strictly interdependent, thus a combined score is more appropriate to evaluate global efficacy.” The studies claiming clinical efficacy4Senti G. Prinz Vavricka B.M. Erdmann I. Diaz M.I. Markus R. McCormack S.J. et al.Intralymphatic allergen administration renders specific immunotherapy faster and safer: a randomized controlled trial.Proc Natl Acad Sci U S A. 2008; 105: 17908-17912Crossref PubMed Scopus (297) Google Scholar, 5Senti G. Crameri R. Kuster D. Johansen P. Martinez-Gomez J.M. Graf N. et al.Intralymphatic immunotherapy for cat allergy induces tolerance after only 3 injections.J Allergy Clin Immunol. 2012; 29: 1290-1296Abstract Full Text Full Text PDF Scopus (219) Google Scholar, 6Hylander T. Latif L. Petersson-Westin U. Cardell L.O. Intralymphatic allergen-specific immunotherapy: an effective and safe alternative treatment route for pollen-induced allergic rhinitis.J Allergy Clin Immunol. 2013; 131: 412-420Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar rely on nasal challenge test as the outcome. However, in the World Allergy Organization recommendations,9Canonica G.W. Baena-Cagnani C.E. Bousquet J. Bousquet P.J. Lockey R.F. Malling H.J. et al.Recommendations for standardization of clinical trials with Allergen Specific Immunotherapy for respiratory allergy. A statement of a World Allergy Organization (WAO) taskforce.Allergy. 2007; 62: 317-324Crossref PubMed Scopus (388) Google Scholar challenge in a relevant shock organ (nose or eyes in patients with hay fever) is not even considered as a secondary efficacy parameter but ranked as a surrogate marker for efficacy. Kündig et al1Kündig T.M. Johansen P. Bachmann M.F. Cardell L.O. Senti G. Intralymphatic immunotherapy: time interval between injections is essential.J Allergy Clin Immunol. 2014; 133: 930-931Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar speculate that the frequency of side effects in our study was related to the injection interval. Because the 3 systemic reactions in our study occurred at the first injection, these cannot be attributed to this. However, when comparing local side effects, the frequency in our study is indeed higher (see below). We do not at this stage have data to suggest whether it relates only to the larger number of injections given in our study or whether the injection interval caused an increased frequency of local side effects. It is still early days for ILIT and the 3 placebo-controlled studies that have been conducted so far (Table I) have not had a strong power with only 12,5Senti G. Crameri R. Kuster D. Johansen P. Martinez-Gomez J.M. Graf N. et al.Intralymphatic immunotherapy for cat allergy induces tolerance after only 3 injections.J Allergy Clin Immunol. 2012; 29: 1290-1296Abstract Full Text Full Text PDF Scopus (219) Google Scholar 7,6Hylander T. Latif L. Petersson-Westin U. Cardell L.O. Intralymphatic allergen-specific immunotherapy: an effective and safe alternative treatment route for pollen-induced allergic rhinitis.J Allergy Clin Immunol. 2013; 131: 412-420Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar and 252Witten M. Malling H.J. Blom L. Poulsen B.C. Poulsen L.K. Is intralymphatic immunotherapy ready for clinical use in patients with grass pollen allergy?.J Allergy Clin Immunol. 2013; 132: 1248-1252.e5Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar patients being treated with active immunotherapy. We completely agree with Kündig et al1Kündig T.M. Johansen P. Bachmann M.F. Cardell L.O. Senti G. Intralymphatic immunotherapy: time interval between injections is essential.J Allergy Clin Immunol. 2014; 133: 930-931Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar that more properly designed and powered studies are needed to define the magnitude of clinical efficacy of ILIT. We would, however, suggest to focus on phase 2 proof-of-concept studies clearly documenting a statistically significant and clinically relevant reduction in disease severity evaluated by a combined symptom/medication score. This is critical before testing the concept in other diseases and in children.Table IComparison of published studies of intralymphatic immunotherapySenti et al4Senti G. Prinz Vavricka B.M. Erdmann I. Diaz M.I. Markus R. McCormack S.J. et al.Intralymphatic allergen administration renders specific immunotherapy faster and safer: a randomized controlled trial.Proc Natl Acad Sci U S A. 2008; 105: 17908-17912Crossref PubMed Scopus (297) Google ScholarSenti et al5Senti G. Crameri R. Kuster D. Johansen P. Martinez-Gomez J.M. Graf N. et al.Intralymphatic immunotherapy for cat allergy induces tolerance after only 3 injections.J Allergy Clin Immunol. 2012; 29: 1290-1296Abstract Full Text Full Text PDF Scopus (219) Google ScholarHylander et al6Hylander T. Latif L. Petersson-Westin U. Cardell L.O. Intralymphatic allergen-specific immunotherapy: an effective and safe alternative treatment route for pollen-induced allergic rhinitis.J Allergy Clin Immunol. 2013; 131: 412-420Abstract Full Text Full Text PDF PubMed Scopus (115) Google ScholarWitten et al2Witten M. Malling H.J. Blom L. Poulsen B.C. Poulsen L.K. Is intralymphatic immunotherapy ready for clinical use in patients with grass pollen allergy?.J Allergy Clin Immunol. 2013; 132: 1248-1252.e5Abstract Full Text Full Text PDF PubMed Scopus (84) Google ScholarNumber of injections per patient3336Systemic side effects (treated)10% (6 of 58 patients)25% (3 episodes of 12 patients)14% (1 of 7 patients)9% (3 of 33∗Including an initial safety study. patients)Local side effects (treated)Not described33% (4 episodes of 12 patients)43% (3 of 7 patients)75% (25 of 33∗Including an initial safety study. patients)∗ Including an initial safety study. Open table in a new tab Intralymphatic immunotherapy: Time interval between injections is essentialJournal of Allergy and Clinical ImmunologyVol. 133Issue 3PreviewWitten et al1 recently published an extensive Letter to the Editor in the Journal of Allergy and Clinical Immunology questioning that intralymphatic immunotherapy (ILIT) with grass pollen, at the present state of knowledge, is ready for clinical use. The results of their double-blind placebo-controlled clinical trial in 38 adult patients with hay fever revealed that 3 or 6 intralymphatic injections with grass pollen allergen extract induced some promising immunological changes, such as a regulatory T-cell response and elevated IgG4 levels. Full-Text PDF
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