Dahdah, Lamia

Fiocchi, Alessandro

Mennini, Maurizio

English

MENNINI, MAURIZIO

Archivio della ricerca- Università di Roma La Sapienza

T h e  n e w  e ngl a nd  j o u r na l  o f  m e dic i n en engl j med 376;11 nejm.org March 16, 20171090Two Phase 3 Trials of Dupilumab versus Placebo in Atopic DermatitisTo the Editor: The conclusions of Simpson and colleagues (Dec. 15 issue)1 regarding the effec-tiveness and quality-of-life–enhancing capacity of dupilumab in patients with atopic dermatitis open new perspectives in the strategies of treat-ment of allergic diseases, because interleukin-4 and interleukin-13 are “type 2 inflammatory cyto-kines that may be important drivers of atopic or allergic diseases.” Given the good results in pa-tients with asthma2 or nasal polyposis,3 we as pediatricians look with interest to the possibili-ties arising from these studies involving adults. However, the higher rate of allergic conjunctivitis in the dupilumab-treated population than in the placebo group in this trial runs against these wishes. Although we agree with the authors that “further studies on the causes of conjunctivitis are warranted,” could these be cases of atopic keratoconjunctivitis rather than simple allergic conjunctivitis? This condition is often linked to atopic dermatitis.4 If so, could it be hypothe-sized that the blockage of interleukin-4 and inter-leukin-13 increases the activity of the specific ligands involved in atopic keratoconjunctivitis (e.g., the OX40 ligand) in the eye, an immuno-logically privileged area?5 This would limit the potential uses of dupilumab in the allergy field.Maurizio Mennini, M.D. Lamia Dahdah, M.D. Alessandro Fiocchi, M.D.Bambino Gesù Children’s Research Hospital Rome, Italy maurizio . mennini@ gmail . comNo potential conflict of interest relevant to this letter was re-ported.1. Simpson EL, Bieber T, Guttman-Yassky E, et al. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. N Engl J Med 2016; 375: 2335-48.2. Sy H, Bielory L. Atopic keratoconjunctivitis. Allergy Asthma Proc 2013; 34: 33-41.3. Bachert C, Mannent L, Naclerio RM, et al. Effect of subcuta-neous dupilumab on nasal polyp burden in patients with chronic sinusitis and nasal polyposis: a randomized clinical trial. JAMA 2016; 315: 469-79.4. Wenzel S, Ford L, Pearlman D, et al. Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med 2013; 368: 2455-66.5. Masli S, Vega JL. Ocular immune privilege sites. Methods Mol Biol 2011; 677: 449-58.DOI: 10.1056/NEJMc1700366The authors reply: In trials of dupilumab in-volving patients with atopic dermatitis, conjunc-tivitis occurred more often in patients who had severe atopic dermatitis or coexisting allergic conjunctivitis (>25% of the enrolled patients). More than 90% of the adverse events of conjunctivitis were mild or moderate in severity, and more than 75% resolved or were resolving during study treatment. In the SOLO trials, 1 of 920 patients who were treated with dupilumab discontinued study treatment because of conjunctivitis. Dupilu-mab was not associated with a higher rate of ad-verse events of conjunctivitis than placebo in trials involving patients with asthma or nasal polypo-sis,1,2 which suggests an atopic dermatitis–specific mechanism, not an inherent effect of dupilumab.The cause is unclear. Not all cases were diag-nosed by ophthalmologists. Findings did not typi-cally suggest atopic keratoconjunctivitis. Two clinical phenotypes were noted: blepharoconjunc-tivitis that was consistent with atopic dermatitis in the eyelids and periorbital area, and conjunc-tivitis with limbal accentuation. The incidence of atopic keratoconjunctivitis was less than 0.5% across all groups and was not higher in the dupi-lumab group than in the placebo group. Although the cornea is immune-privileged, the rest of the ocular surface, eyelids, and periorbital skin are not.There is an inverse relationship between se-rum concentrations of dupilumab and conjuncti-vitis, which suggests that local undertreatment, possibly due to higher target burden or lower tissue distribution, may play a role. In our trials and others,1,2 dupilumab effectively inhibited the inflammation of type 2 helper T (Th2) cells in patients with atopic dermatitis, asthma, or nasal polyposis. Similar Th2-cell inflammatory path-ways are involved in atopic keratoconjunctivitis.Eric L. Simpson, M.D.Oregon Health and Science University Portland, OR simpsone@ ohsu . eduBolanle Akinlade, M.D. Marius Ardeleanu, M.D.Regeneron Pharmaceuticals Tarrytown, NYSince publication of their article, the authors report no further potential conflict of interest.The New England Journal of Medicine Downloaded from nejm.org at IRCCS Pediatrico Bambino Gesu - Roma on December 17, 2019. For personal use only. No other uses without permission.  Copyright © 2017 Massachusetts Medical Society. All rights reserved. Correspondencen engl j med 376;11 nejm.org March 16, 2017 10911. Wenzel S, Castro M, Corren J, et al. Dupilumab efficacy and safety in adults with uncontrolled persistent asthma de-spite use of medium-to-high-dose inhaled corticosteroids plus a long-acting beta-agonist: a pivotal dose-ranging study. Lan-cet 2016; 388: 31-44.2. Bachert C, Mannent L, Naclerio RM, et al. Effect of subcuta-neous dupilumab on nasal polyp burden in patients with chron-ic sinusitis and nasal polyposis: a randomized clinical trial. JAMA 2016; 315: 469-79.DOI: 10.1056/NEJMc1700366Short-Term versus Long-Term Blood StorageTo the Editor: In the Informing Fresh versus Old Red Cell Management (INFORM) study, Heddle et al. (Nov. 17 issue)1 suggest that the debate over red-cell storage and outcome after transfusion is now closed. According to the ac-companying editorial,2 there may no longer be an issue regarding the freshness of red cells for transfusion. Although we admire the quality of all five recent, large cited studies on this topic2 (which have covered such diverse topics as the relationship between the age of blood and type of processing to patients’ outcomes), we consider this conclusion to be questionable.Previous studies have stressed the safety and survival benefit of a restrictive policy versus a liberal policy for red-cell transfusion, which sug-gests a downside to such transfusion.3 Red-cell storage lesions may explain this observation. Stored red cells have both reversible and irre-versible lesions; the latter occur from the second week onward.4 However, recent studies have com-pared red cells that were stored for 7 to 10 days with those that were stored for 15 to 20 days — in other words, comparing old red cells with older red cells. Other studies have suggested that the transfusion of blood from donors who have characteristics associated with storage problems (so-called bad donors)5 has resulted in poor out-comes among the recipients, an effect that was not analyzed in the current trials. We thus en-courage the continuation of trials of really fresh versus stored red cells and the identification of donor characteristics associated with good recipi-ent outcomes.Olivier Garraud, M.D., Ph.D.Institut National de la Transfusion Sanguine Paris, France ogarraud@ ints . frJean-Daniel Tissot, M.D., Ph.D.Transfusion Interrégionale Croix Rouge Suisse Epalinges, SwitzerlandAlexander P. Vlaar, M.D., Ph.D.Academic Medical Center Amsterdam, the NetherlandsNo potential conflict of interest relevant to this letter was re-ported.1. Heddle NM, Cook RJ, Arnold DM, et al. Effect of short-term vs. long-term blood storage on mortality after transfusion. N Engl J Med 2016; 375: 1937-45.2. Tobian AA, Ness PM. Red cells — aging gracefully in the blood bank. N Engl J Med 2016; 375: 1995-7.3. Holst LB, Petersen MW, Haase N, Perner A, Wetterslev J. Restrictive versus liberal transfusion strategy for red blood cell transfusion: systematic review of randomised trials with meta-analysis and trial sequential analysis. BMJ 2015; 350: h1354.4. Prudent M, Tissot JD, Lion N. In vitro assays and clinical trials in red blood cell aging: lost in translation. Transfus Apher Sci 2015; 52: 270-6.5. Chassé M, McIntyre L, English SW, et al. Effect of blood donor characteristics on transfusion outcomes: a systematic re-view and meta-analysis. Transfus Med Rev 2016; 30: 69-80.DOI: 10.1056/NEJMc1700464To the Editor: The study by Heddle and col-leagues is limited in what it actually addresses by design, since it specifically shows only that the length of red-cell storage is immaterial to mor-tality in the context of the current practice of red-cell transfusion aggregated across diverse clinical settings. Given that design, the study does not address whether any of the transfusions were essential, since most of the patients at high-est risk were excluded. Therefore, it is uncertain whether a between-group difference could have been detected. Without knowing whether the study design could have detected a true differ-ence, it remains possible that an important as-sociation between storage length and outcomes exists.There remains much controversy as to when and in which clinical settings transfusions are clearly beneficial to mortality,1,2 with wide vari-ability in transfusion practice3 and, arguably, still much overuse. This study leaves unaddressed important questions — notably, whether storage The New England Journal of Medicine Downloaded from nejm.org at IRCCS Pediatrico Bambino Gesu - Roma on December 17, 2019. For personal use only. No other uses without permission.  Copyright © 2017 Massachusetts Medical Society. All rights reserved. 

Two phase 3 trials of Dupilumab versus placebo in atopic dermatitis

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Two phase 3 trials of Dupilumab versus placebo in atopic dermatitis

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