Guidelines
`
`Allergic Rhinitis and its Impact on Asthma (ARIA)
`guidelines—2016 revision
`
`Jan L. Bro _zek, MD, PhD,a,b Jean Bousquet, MD, PhD,c Ioana Agache, MD, PhD,d Arnav Agarwal, BHSc,a,e
`Claus Bachert, MD, PhD,f Sinthia Bosnic-Anticevich, BPharm, PhD,g Romina Brignardello-Petersen, DDS, MSc, PhD,a
`G. Walter Canonica, MD,h Thomas Casale, MD,i Niels H. Chavannes, MD, PhD,j Jaime Correia de Sousa, MD, PhD,k
`Alvaro A. Cruz, MD, PhD,l Carlos A. Cuello-Garcia, MD,a Pascal Demoly, MD, PhD,m Mark Dykewicz, MD,n
`Itziar Etxeandia-Ikobaltzeta, PhD,a,o Ivan D. Florez, MD, MSc,a,p Wytske Fokkens, MD, PhD,q Joao Fonseca, MD, PhD,r
`Peter W. Hellings, MD, PhD,s Ludger Klimek, MD, PhD,t Sergio Kowalski, MD,a Piotr Kuna, MD, PhD,u
`Kaja-Triin Laisaar, MD, MPH,v Desiree E. Larenas-Linnemann, MD,w Karin C. Lødrup Carlsen, MD, PhD,x
`Peter J. Manning, MD,y Eli Meltzer, MD,z Joaquim Mullol, MD, PhD,aa Antonella Muraro, MD, PhD,bb
`Robyn O’Hehir, PhD,cc Ken Ohta, MD, PhD,dd Petr Panzner, MD, PhD,ee Nikolaos Papadopoulos, MD, PhD,ff,gg
`Hae-Sim Park, MD, PhD,hh Gianni Passalacqua, MD,ii Ruby Pawankar, MD, PhD,jj David Price, MD,kk
`John J. Riva, DC, MSc,a,ll Yetiani Roldan, MD,a Dermot Ryan, MD,mm Behnam Sadeghirad, PharmD, MPH,nn
`Boleslaw Samolinski, MD, PhD,oo Peter Schmid-Grendelmeier, MD,pp Aziz Sheikh, MD, MSc,qq Alkis Togias, MD,rr
`Antonio Valero, MD, PhD,ss Arunas Valiulis, MD, PhD,tt Erkka Valovirta, MD, PhD,uu Matthew Ventresca, MSc,a
`Dana Wallace, MD,vv Susan Waserman, MD, MSc,b Magnus Wickman, MD,ww Wojtek Wiercioch, MSc,a
`Juan Jose Yepes-Nu~nez, MD, MSc,a,xx Luo Zhang, MD,yy Yuan Zhang, MPH,a Mihaela Zidarn, MD, MSc,zz
`Torsten Zuberbier, MD,aaa and Holger J. Sch€unemann, MD, PhD, MSca,bbb
`Hamilton and Toronto,
`Ontario, Canada; Montpellier and Paris, France; Brasov, Romania; Ghent and Brussels, Belgium; Sydney and Melbourne, Australia; Milan,
`Padua, and Genoa, Italy; Tampa and Fort Lauderdale, Fla; Leiden and Amsterdam, The Netherlands; Braga/Guimar~aes and Porto, Portugal;
`Salvador, Brazil; Vitoria-Gasteiz and Barcelona, Spain; St Louis, Mo; Medellin, Colombia; Wiesbaden and Berlin, Germany; Lodz, Poland;
`Tartu, Estonia; Mexico City, Mexico; Oslo, Norway; Dublin, Ireland; San Diego, Calif; Tokyo, Japan; Prague, Czech Republic; Athens,
`Greece; Manchester, Aberdeen, and Edinburgh, United Kingdom; Suwon, Korea; Kerman, Iran; Warsaw, Poland; Davos, Switzerland;
`Bethesda, Md; Vilnius, Lithuania; Turku, Finland; Stockholm, Sweden; Beijing, China; and Golnik, Slovenia
`
`From athe Department of Clinical Epidemiology and Biostatistics, and bthe Division of
`Clinical Immunology and Allergy, Department of Medicine, McMaster University,
`Hamilton; cUniversity Hospital, Montpellier; dthe Faculty of Medicine, Transylvania
`University, Brasov; ethe School of Medicine, University of Toronto; fthe Upper Air-
`ways Research Laboratory, Ghent University Hospital; gthe Woolcock Institute, Uni-
`versity of Sydney; hthe Asthma & Allergy Clinic, Humanitas University, Rozzano,
`Milan; ithe Division of Allergy and Immunology, University of South Florida, Tampa;
`jthe Department of Public Health and Primary Care, Leiden University Medical Center;
`kthe Life and Health Sciences Research Institute (ICVS), School of Health Sciences,
`University of Minho, Braga, and ICVS/3B’s–PT Government Associate Laboratory,
`Braga/Guimar~aes; lProAR–Center of Excellence for Asthma, Federal University of Ba-
`hia, Salvador; mUniversity Hospital of Montpellier, Montpellier, and Sorbonne Uni-
`versites, UPMC Paris 06, UMR-S 1136, IPLESP, Equipe EPAR, Paris; nthe Section
`of Allergy and Immunology, Department of Internal Medicine, Saint Louis University
`School of Medicine; oDireccion de Investigacion e Innovacion Sanitaria, Departamento
`de Salud, Gobierno Vasco-Eusko Jaurlaritza, Vitoria-Gasteiz; pthe Department of Pe-
`diatrics, University of Antioquia, Medellin; qthe Department of Otorhinolaryngology,
`Academic Medical Centre, Amsterdam; rCINTESIS–Center for Health Technology
`and Services Research, Faculdade de Medicina, Universidade do Porto & Allergy,
`CUF Porto Hospital and Instituto, Porto; sthe Department of Otorhinolaryngology, Uni-
`versity Hospitals Leuven, and the Department of Otorhinolaryngology, Academic
`Medical Center (AMC), Amsterdam; tthe Center of Rhinology and Allergology, Wies-
`baden; uthe Division of Internal Medicine Asthma and Allergy, Faculty of Medicine,
`Medical University of Lodz; vthe Institute of Family Medicine and Public Health, Uni-
`versity of Tartu; wHospital Medica Sur, Mexico City; xthe Department of Paediatrics,
`Oslo University Hospital, University of Oslo; ythe Department of Medicine, Royal Col-
`lege of Surgeons in Ireland Medical School, Dublin; zthe Department of Pediatrics, Di-
`vision of Allergy & Immunology, University of California, San Diego; aaUnitat de
`Rinologia i Clınica de l’Olfacte, Servei d’ORL, Hospital Clınic, Clinical & Experi-
`mental Respiratory Immunoallergy, IDIBAPS, Barcelona; bbthe Department of Women
`and Child Health & Food Allergy Referral Centre Veneto Region, University of Padua;
`ccAlfred Hospital and Monash University, Melbourne;
`ddNational Hospital
`
`950
`
`Organization Tokyo National Hospital, Kiyose-city, Tokyo; eethe Department of Immu-
`nology and Allergology, Faculty of Medicine in Pilsen, Charles University in Prague;
`ffthe Allergy Department, 2nd Pediatric Clinic, University of Athens; ggthe Division of
`Infection, Immunity & Respiratory Medicine, University of Manchester; hhthe Depart-
`ment of Allergy and Rheumatology, Ajou University School of Medicine, Suwon; iiAl-
`lergy and Respiratory Diseases, IRCCS San Martino, IST, University of Genoa; jjthe
`Department of Pediatrics, Nippon Medical School, Tokyo; kkthe University of Aber-
`deen; llthe Department of Family Medicine, McMaster University, Hamilton; mmthe Al-
`lergy and Respiratory Research Group, Usher Institute of Population Health Sciences
`and Informatics, University of Edinburgh; nnthe HIV/STI Surveillance Research Cen-
`ter, and World Health Organization Collaborating Center for HIV Surveillance, Insti-
`tute for Futures Studies in Health, Kerman University of Medical Sciences; oothe
`Department of Prevention of Environmental Hazards and Allergology, Medical Univer-
`sity of Warsaw; ppthe Allergy Unit, Department of Dermatology, University Hospital of
`Z€urich and Christine K€uhne Center for Allergy Research and Education CK-CARE,
`Davos; qqAsthma UK Centre for Applied Research, Usher Institute of Population
`Health Sciences and Informatics, University of Edinburgh; rrAsthma and Inflammation,
`National Institute of Allergy and Infectious Diseases, National Institutes of Health, Be-
`thesda; ssthe Department of Pneumology and Allergy, Immunoallergia Respiratoria
`Clınica I Experimental (IDIBAPS), Centro de Investigaciones Biomedicas en Red de
`Enfermedades Respiratorias (CIBERES), Barcelona; ttVilnius University Clinic of
`Children’s Diseases and Public Health Institute, Vilnius, and the European Academy
`of Paediatrics (EAP/UEMS-SP), Brussels; uuthe Department of Lung Diseases and
`Clinical Immunology, University of Turku and Allergy Clinic Terveystalo Turku;
`vvNova Southeastern University, Fort Lauderdale; wwthe Department of Pediatrics,
`Sachs’ Children’s Hospital, South General Hospital and Institute of Environmental
`Medicine, Karolinska Institutet, Stockholm; xxthe School of Medicine, University of
`Antioquia, Medellın; yythe Department of Otolaryngology Head and Neck Surgery,
`Beijing TongRen Hospital and Beijing Institute of Otolaryngology; zzUniversity Clinic
`of Pulmonary and Allergic Diseases Golnik; aaathe Department of Dermatology and Al-
`lergy, Charite–Universit€atsmedizin Berlin; and bbbthe Division of General Internal
`Medicine, Department of Medicine, McMaster University.
`
`Exhibit 1072
`IPR2017-00807
`ARGENTUM
`
`000001
`
`

`

`J ALLERGY CLIN IMMUNOL
`VOLUME 140, NUMBER 4
`
`BRO _ZEK ET AL 951
`
`Background: Allergic rhinitis (AR) affects 10% to 40% of the
`population. It reduces quality of life and school and work
`performance and is a frequent reason for office visits in general
`practice. Medical costs are large, but avoidable costs associated
`with lost work productivity are even larger than those incurred
`
`by asthma. New evidence has accumulated since the last revision
`of the Allergic Rhinitis and its Impact on Asthma (ARIA)
`guidelines in 2010, prompting its update.
`Objective: We sought to provide a targeted update of the ARIA
`guidelines.
`
`Disclosure of potential conflict of interest: J. L. Bro_zek has received support for the
`development of systematic reviews in these guidelines from the ARIA Initiative. J.
`Bousquet has received personal fees from Almirall, Meda, Merck, MSD, Novartis,
`Sanofi-Aventis, Takeda, Teva, Uriach, Chiesi, GlaxoSmithKline, and Menarini. S.
`Bosnic-Anticevich is on the advisory board for TEVA; has consultant arrangements
`with MEDA and GlaxoSmithKline; has received grants from TEVA; has received
`payment for lectures from TEVA, GlaxoSmithKline, and AstraZeneca; has received
`payment for manuscript preparation from MEDA; and has received payment for
`development of educational presentations from GlaxoSmithKline. T. Casale is the
`executive vice president of the American Academy of Allergy, Asthma & Immu-
`nology. J. Correia de Sousa has board memberships with Boehringer Ingelheim and
`Novartis, has received payment for lectures from Boehringer Ingelheim, and has
`received payment for development of educational presentations from Boehringer
`Ingelheim. A. A. Cruz has board memberships with Novartis, Boehringer Ingelheim,
`AstraZeneca, MEDA Pharma, and GlaxoSmithKline; has consultant arrangements
`with Boehringer Ingelheim; has provided expert testimony for Boehringer Ingelheim;
`has received grants from GlaxoSmithKline; and has received payment for lectures
`from Eurofarma, Chiesi, MEDA Pharma, and Hypermarcas-Ache. C. A. Cuello-Garcia
`has consultant arrangements with and has received payment
`for manuscript
`preparation and travel support from the World Allergy Organization. P. Demoly has
`received consulting fees from ALK-Abello, Stallergenes Greer, Thermo Fisher
`Scientific, MEDA, Chiesi, and Ysslab and has received grants from AstraZeneca. M.
`Dykewicz has consultant arrangements with Alcon and Merck and is the Workgroup
`Char for the Rhinitis Practice Parameter Update of the American Academy of Allergy,
`Asthma & Immunology/American College of Allergy, Asthma & Immunology
`ACAAI Joint Task Force on Practice Parameters. I. Etxeandia-Ikobaltzeta has received
`a consulting fee or honorarium from MacGRADE Centre. W. Fokkens has consultant
`arrangements with MEDA/Mylan; has
`received grants
`from MEDA/Mylan,
`GlaxoSmithKline, MAPI S.A.S.-RWE, Allakos, and Sanofi; and has received payment
`for lectures from MEDA/Mylan. J. Fonseca has received payment for lectures from A.
`Menarini and FAES Farma (Lab. Vitoria) and has received payment for development of
`educational presentations and travel support from A. Menarini. L. Klimek has board
`memberships with MEDA and Novartis; has consultant arrangments with
`ALK-Abello, MEDA, Novartis, Allergopharma, Bionorica, Boehringer Ingelheim,
`GlaxoSmithKline, and Lofarma; has received grants from ALK-Abello, Novartis,
`Allergopharma, Bionorica, GlaxoSmithKline, Lofarma, Biomay, HAL, LETI, Roxall,
`and Bencard; has received payment for lectures from ALK-Abello, MEDA, Novartis,
`Allergopharma, Bionorica, Boehringer Ingelheim, GlaxoSmithKline, and Lofarma;
`has received payment for manuscript preparation from Bionorica; and has received
`payment for performing a clinical trial from ALK-Abello. S. Kowalski is employed by
`Universidade Federal do Parana. P. Kuna has board memberships with Boehringer
`Ingelheim, ALK-Abello, FAES, Sandoz, Teva, Polpharma, Novartis, Allergopharma,
`and Celon Pharma; received payment for lectures from Adamed, Allergopharma,
`ALK-Abello, AstraZeneca, Bayer, Berlin Chemie, Boehringer Ingelheim, Chiesi,
`Faes, HAL Allergy, Lekam, Novartis, Polharma, Pfizer, Sandoz, and Teva; and has
`received travel support from Novartis, Berlin Chemie, and Boehringer Ingelheim. D. E.
`Larenas-Linnemann has consultant arrangements with MEDA, Boehringer Ingelheim,
`and Mitfarma; has received grants from AstraZeneca, TEVA, Boehringer Ingelheim,
`Novartis, GlaxoSmithKline, and MEDA; has received payment for lectures from
`AstraZeneca, MEDA, Novartis, UCB, Boehringer Ingelheim, MSD, Pfizer, Grunen-
`thal, Siegfried, and Armstrong; has received payment for development of educational
`presentations from Grunenthal; and is on the safety board for DBV. K. C. Lodrup-
`Carlsen has received travel support from the European Respiratory Society. E. Meltzer
`has consultant arrangements with Allergan, AstraZeneca, Boehringer Ingelheim,
`GlaxoSmithKline, Greer, Merck, Mylan, Regeneron-Sanofi, and Teva and has received
`payment for lectures from GlaxoSmithKline, Greer, Merck, Mylan, and Teva. J. Mullol
`has board memberships with Uriach, FAES, ALK-Abello, Sanofi, Genentech, and
`MEDA; has received grants from Meda, FAES, Uriach, GlaxoSmithKline, MSD; and
`has received payment for lectures from Uriach, Sanofi, MSD, Novartis, Menarini,
`MEDA, and UCB. A. Muraro has consultant arrangements with MEDA, Novartis, and
`Menarini; is employed by Padua University Hospital; and has received payment for
`lectures from MEDA and Menarini. K. Ohta has received payment for lectures from
`Kyorin, AstraZeneca, Astellas, and Boehringer Ingelheim. P. Panzner has board
`memberships with Allergy Therapeutics, Teva, and Novartis; has consultant arrange-
`ments with ALK-Abello, ASIT Biotech, and AstraZeneca; and has received payment
`for lectures from Shire and Stallergenes. N. Papadopoulos is on advisory boards for
`
`Novartis, Faes Farma, BIOMAY, HAL, and Nutricia Research; has consultant
`arrangements with Menarini, ALK-Abello, Novartis, MEDA, and Chiesi; has received
`grants from NESTEC and Menarini; and has received payment for lectures from
`Stallergenes, AbbVie, Novartis, MEDA, MSD, Omega Pharma, and Danone. R.
`Pawankar is employed by Nippon Medical School and has received a grant from the
`Japanese Ministry of Education. D. Price has board memberships with Aerocrine,
`Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, Meda, Mundipharma, Napp,
`Novartis, and Teva; has consultant arrangements with Almirall, Amgen, AstraZeneca,
`Boehringer
`Ingelheim, Chiesi, GlaxoSmithKline, Meda, Mundipharma, Napp,
`Novartis, Pfizer, Teva, and Theravance; has received grants from Aerocrine, AKL
`Research and Development, AstraZeneca, Boehringer Ingelheim, British Lung
`Foundation, Chiesi, Meda, Mundipharma, Napp, Novartis, Pfizer, Respiratory
`Effectiveness Group, Takeda, Teva Pharmaceuticals, Theravance, UK National Health
`Service, and Zentiva; has received payment for lectures from Almirall, AstraZeneca,
`Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Kyorin, Meda, Merck,
`Mundipharma, Novartis, Pfizer, Skyepharma, Takeda, and Teva Pharmaceuticals;
`has received payment for manuscript preparation from Mundipharma and Teva; has
`received payment for development of education presentations from Mundipharma and
`Novartis; owns shares in AKL Research and Development; has received travel support
`from Aerocrine, AstraZeneca, Boehringer Ingelheim, Mundipharma, Napp, Novartis,
`and Teva Pharmaceuticals; has received funding for patient enrollment or completion
`of research from Chiesi, Novartis, Teva Pharmaceuticals, and Zentiva; has served as a
`peer
`reviewer
`for grant committees for Efficacy and Mechanism Evaluation
`programme, Health Technology Assessment, and Medical Research Council; and
`owns 74% of Optimum Patient Care and 74% of Observational and Pragmatic
`Research Institute Pte. D. Ryan is on advisory panels for Uriah and Stallergenes; has
`received payment for lectures and payment for development of education presentations
`from MEDA; has board memberships with Stallergenes; has had consultant
`arrangements with Uriach; and is director of Respiratory Effectiveness Group. B.
`Samolinski has received travel support from Meda; has received grants from the
`National Science Center and the Ministry of Health; has received payment for lectures
`from Polfarma, Adamed, Teva, and Meda; has received payment for manuscript
`preparation from Adamed, Teva, Meda; has received payment for development of
`educational presentations from Teva and Adamed; and has received travel support
`from Meda and Adamed. P. Schmid-Grendelmeier has consultant arrangements with
`Novartis Pharma and Meda Pharma, has received grants from Novartis, and has
`received payment for lectures from Novartis. A. Sheikh has received payment to
`develop guidelines on allergen immunotherapy from the European Academy of
`Allergy and Clinical Immunology. D. Wallace has consultant arrangements with
`MEDA and has received payment for lectures from MEDA and Mylan. S. Waserman
`has consultant arrangements with Merck, GlaxoSmithKline, Novartis, CSL Behring,
`Shire, Sanofi Canada, Aralez, Pediapharm, Mylan, and Meda; is employed by
`McMaster University; has received grants from Pfizer Canada; has received payment
`for lectures from Merck, CSL Behring, Shire, AstraZeneca, Pfizer, Sanofi, Pedia-
`pharm, and Aralez; has received payment for development of educational pre-
`sentations from Merck; and has received travel support from Pediapharm. M.
`Wickman has consultant arrangements from Meda. T. Zuberbier has received
`institutional funding for research and/or honoraria for lectures and/or consulting
`from AstraZeneca, AbbVie, ALK-Abello, Almirall, Astellas, Bayer Health Care,
`Bencard, Berlin Chemie, FAES, HAL, Henkel, Kryolan, Leti, L’Oreal, Meda,
`Menarini, Merck, MSD, Novartis, Pfizer, Sanofi, Stallergenes, Takeda, Teva and
`UCB and is a member of ARIA/World Health Organization, DGAKI, ECARF,
`GA2LEN and WAO. H. J. Sch€unemann has received partial support for developing sys-
`tematic reviews for these guidelines from the ARIA Initiative. The rest of the authors
`declare that they have no relevant conflicts of interest.
`Received for publication October 3, 2016; revised February 12, 2017; accepted for pub-
`lication March 15, 2017.
`Available online June 8, 2017.
`Corresponding author: Jan L. Bro_zek, MD, PhD, McMaster University, Department of
`Clinical Epidemiology and Biostatistics, Hamilton, Ontario L8S 4K1, Canada.
`E-mail: jan.l.brozek@gmail.com.
`The CrossMark symbol notifies online readers when updates have been made to the
`article such as errata or minor corrections
`0091-6749/$36.00
`Ó 2017 American Academy of Allergy, Asthma & Immunology
`http://dx.doi.org/10.1016/j.jaci.2017.03.050
`
`000002
`
`

`

`952 BRO _ZEK ET AL
`
`J ALLERGY CLIN IMMUNOL
`OCTOBER 2017
`
`Methods: The ARIA guideline panel identified new clinical
`questions and selected questions requiring an update. We
`performed systematic reviews of health effects and the evidence
`about patients’ values and preferences and resource
`requirements (up to June 2016). We followed the Grading of
`Recommendations Assessment, Development, and Evaluation
`(GRADE) evidence-to-decision frameworks to develop
`recommendations.
`Results: The 2016 revision of the ARIA guidelines provides both
`updated and new recommendations about the pharmacologic
`treatment of AR. Specifically, it addresses the relative merits of
`using oral H1-antihistamines, intranasal H1-antihistamines,
`intranasal corticosteroids, and leukotriene receptor antagonists
`either alone or in combination. The ARIA guideline panel
`provides specific recommendations for the choice of treatment
`and the rationale for the choice and discusses specific
`considerations that clinicians and patients might want to review
`to choose the management most appropriate for an individual
`patient.
`Conclusions: Appropriate treatment of AR might improve
`patients’ quality of life and school and work productivity. ARIA
`recommendations support patients, their caregivers, and health
`care providers in choosing the optimal treatment. (J Allergy
`Clin Immunol 2017;140:950-8.)
`
`Key words: Allergic rhinitis, practice guideline
`
`Allergic rhinitis (AR) is among the most common diseases
`globally and usually persists throughout life.1 The prevalence of
`self-reported AR has been estimated to be approximately 2% to
`25% in children2 and 1% to greater than 40% in adults.1,3 The
`prevalence of confirmed AR in adults in Europe ranged from
`17% to 28.5%. Recent studies show that the prevalence of AR
`has increased in particular in countries with initial low prevalence
`(for a discussion of prevalence of AR, see section 5.1-5.2 in
`Allergic Rhinitis and its Impact on Asthma [ARIA] 2008 Up-
`date1). Classical symptoms of AR are nasal itching, sneezing, rhi-
`norrhea, and nasal congestion. Ocular symptoms are also
`frequent; allergic rhinoconjunctivitis is associated with itching
`and redness of the eyes and tearing. Other symptoms include itch-
`ing of the palate, postnasal drip, and cough.
`AR is also frequently associated with asthma, which is found in
`15% to 38% of patients with AR,4,5 and nasal symptoms are pre-
`sent in 6% to 85% patients with asthma.6-9 In addition, AR is a
`risk factor for asthma,4,9 and uncontrolled moderate-to-severe
`AR affects asthma control.10,11
`Compared with other medical conditions, AR might not appear
`to be serious because it is not associated with severe morbidity
`and mortality. However, the burden and costs are substantial.12
`AR reduces the quality of life of many patients, impairing sleep
`quality and cognitive function and causing irritability and fatigue.
`AR is associated with decreased school and work performance,
`especially during the peak pollen season.1 AR is a frequent reason
`for general practice office visits. Annual direct medical costs of
`AR are substantial, but indirect costs associated with lost work
`productivity are greater than those incurred by asthma.13-15
`Appropriate treatment of AR improves symptoms, quality of
`life, and work and school performance.
`Clinical practice guidelines for AR management were devel-
`oped over the past 20 years16 and have improved the care of
`
`Abbreviations used
`AR: Allergic rhinitis
`ARIA: Allergic Rhinitis and its Impact on Asthma
`EtD: Evidence to decision
`GRADE: Grades of Recommendation, Assessment, Development,
`and Evaluation
`ICP: Integrated care pathway
`PAR: Perennial allergic rhinitis
`SAR: Seasonal allergic rhinitis
`SMD: Standardized mean difference
`
`patients with AR.17 However, transparent reporting of guidelines
`to facilitate understanding and acceptance are needed. The ARIA
`initiative was initiated during a World Health Organization work-
`shop in 199918 and updated in 2008.1 The ARIA 2010 revision
`was the first evidence-based guideline in allergy to follow the
`Grading of Recommendations, Assessment, Development, and
`Evaluation (GRADE) approach19 with no influence of for-profit
`organizations and an explicit declaration and management of po-
`tential competing interests of panel members.20 It summarized the
`potential benefits and harms underlying the recommendations, as
`well as assumptions around values and preferences that influ-
`enced the strength and direction of the recommendations. In
`2014, the ARIA revision was found to rank first in the rigor of
`development and quality of reporting of guidelines about the
`management of AR,16 although recent guidelines published later
`were not considered.21
`
`CLINICAL QUESTIONS
`Since the last revision of the ARIA guidelines in 2010,20 new
`treatments have become available, and new evidence has accumu-
`lated about selected other treatments. By using a modified Delphi
`process, the ARIA guideline panel selected new questions that
`required answering with recommendations or the existing recom-
`mendations that required an updated review of the evidence and
`potentially updating the recommendations themselves. Therefore
`this revision of the ARIA guidelines is limited in scope and ad-
`dresses 6 questions about the treatment of AR:
`1. Should a combination of oral H1-antihistamine and intra-
`nasal corticosteroid versus intranasal corticosteroid alone
`be used for treatment of AR?
`2. Should a combination of intranasal H1-antihistamine and
`intranasal corticosteroid versus intranasal corticosteroid
`alone be used for treatment of AR?
`3. Should a combination of an intranasal H1-antihistamine
`and an intranasal corticosteroid versus intranasal H1-anti-
`histamine alone be used for treatment of AR?
`4. Should a leukotriene receptor antagonist versus an oral H1-
`antihistamine be used for treatment of AR?
`5. Should an intranasal H1-antihistamine versus an intranasal
`corticosteroid be used for treatment of AR?
`6. Should an intranasal H1-antihistamine versus an oral H1-
`antihistamine be used for treatment of AR?
`
`The target audience of these guidelines is primary care
`clinicians, school nurses, pharmacists, specialists in allergy and
`clinical immunology, general internists managing patients with
`AR, and pediatricians. Ear-nose-throat specialists, other health
`
`000003
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`

`

`J ALLERGY CLIN IMMUNOL
`VOLUME 140, NUMBER 4
`
`BRO _ZEK ET AL 953
`
`care professionals, and health care policy makers can also benefit
`from these guidelines.
`
`CLASSIFICATION OF AR
`The classification of AR was revised by ARIA in 2001. A major
`change was the introduction of the terms ‘‘intermittent’’ and
`‘‘persistent.’’18 Before then, AR was classified, based on the time
`and type of exposure and symptoms, into seasonal allergic rhinitis
`(SAR; most often caused by outdoor allergens, such as pollens or
`molds), perennial allergic rhinitis (PAR; most
`frequently,
`although not necessarily, caused by indoor allergens such as
`house dust mites, molds, cockroaches, and animal dander), and
`occupational allergic rhinitis.22,23 With very few exceptions, pub-
`lished studies refer to SAR and PAR and enroll patients based on
`the offending allergen (pollen, house dust mites, or both), and we
`retained the terms SAR and PAR to enable the interpretation of
`published evidence.
`The recommendations in the ARIA 2016 update apply directly
`to patients with moderate-to-severe AR. They might be less
`applicable to treatment of patients with mild AR who frequently
`do not seek medical help and manage their symptoms themselves
`with medications available other the counter.
`
`RECOMMENDATIONS FOR CHILDREN
`Almost all studies used to answer the questions in this update of
`the ARIA guidelines included exclusively adult patients. How-
`ever, careful extrapolation to the pediatric population can be
`attempted. One can assume that the relative effects of treatment of
`AR are likely similar among adults and children, but adverse
`effects might be more or less frequent, and their perception and
`importance might be different (eg, bitter taste). Values and
`preferences for specific outcomes and treatments can also vary
`between adults and children.
`
`METHODOLOGY
`The full description of methods used to develop recommenda-
`tions in these guidelines is described in the Methods section of the
`full version of the guideline document (see Online Repository
`item E1 in this article’s Online Repository at www.jacionline.
`org). Here we describe briefly the methodology to facilitate the
`interpretation of the guidelines.
`
`Questions and outcomes of interest
`The scope and questions for this update of the ARIA guidelines
`were identified by the ARIA guideline panel members. The
`guideline panel deemed the following outcomes to be important
`to patients: nasal and ocular symptoms, quality of life, work/
`school performance, and adverse effects. As for the previous
`revision of the ARIA guidelines, we did not formally assess the
`relative importance of each outcome of interest (ie, which
`outcomes are more and which are less important) but rather
`adopted the rating agreed upon by the guideline panel according
`to the structured discussion.24 In general, combined nasal symp-
`toms, ocular symptoms, quality of life, work/school performance,
`and serious adverse effects were considered critical to the deci-
`sion, and individual symptoms, a composite outcome of any
`adverse effects and adverse effects that were not serious or did
`
`not lead to discontinuation of treatment, were considered impor-
`tant but not critical (see evidence profiles in Online Repository
`item E2 in this article’s Online Repository at www.jacionline.
`org).
`
`Evidence review and development of clinical
`recommendations
`For each question, the methodology group performed a full
`systematic review of the literature to identify and summarize
`evidence about the effects of interventions on the outcomes of
`interest. We also searched systematically for information about
`patients’ values and preferences and resource use (cost). We
`systematically searched the Medline, Embase, and Cochrane
`CENTRAL electronic databases. Titles and abstracts and subse-
`quently full-text articles were screened in duplicate to assess
`eligibility according to prespecified criteria. Panel members were
`contacted to confirm completeness of the body of evidence and
`suggest additional articles that might have been missed in
`electronic searches.
`To obtain the estimates of effects on each outcome of interest,
`we performed meta-analyses using the Cochrane Collaboration
`Review Manager Software, version 5.3.5.25 We prepared evi-
`dence summaries (see Online Repository item E2) for each ques-
`tion according to the GRADE approach19 by using the
`GRADEpro Guideline Development Tool online application
`(www.gradepro.org).
`When continuous outcomes (eg, symptom scores or quality of
`life) are measured by using different scales, the results can only be
`combined in meta-analysis by using the standardized mean
`difference (SMD), which is expressed in SD units.26 Results ex-
`pressed as an SMD are challenging to interpret. To facilitate un-
`derstanding, we used interpretation of the effect size according
`to Cohen conventional criteria27: an SMD of around 0.2 is consid-
`ered a small effect, an SMD of around 0.5 is considered a moder-
`ate effect, and an SMD of around 0.8 or higher is considered a
`large effect. We used this interpretation throughout this document
`when we referred to effects of interventions as small, moderate, or
`large.
`We assessed the risk of bias at the outcome level by using the
`Cochrane Collaboration’s risk of bias tool.28 Subsequently, we as-
`sessed the certainty of the body of evidence (ie, confidence in the
`estimated effects, which is also known as ‘‘quality of the evi-
`dence’’) for each of the outcomes of interest according to the
`GRADE approach29 based on the following criteria: risk of
`bias, precision, consistency and magnitude of the estimates of ef-
`fects, directness of the evidence, risk of publication bias, presence
`of a dose-effect relationship, and assessment of the effect of resid-
`ual opposing confounding. Certainty of the evidence was catego-
`rized into 4 levels: high, moderate, low, and very low.
`For each question, we summarized all information in evidence-
`to-decision (EtD) frameworks (see Online Repository item E2)
`that included concise description of desirable and undesirable
`health effects, certainty of the evidence about those effects, evi-
`dence and assumptions about patients’ values and preferences,
`required resources and cost-effectiveness, potential influence on
`health equity, acceptability of the intervention to various stake-
`holders, and feasibility of implementation.30 Judgments about
`all these factors and suggested recommendations in EtD frame-
`works were drafted by J.L.B., who was also a clinical expert.
`
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`954 BRO _ZEK ET AL
`
`J ALLERGY CLIN IMMUNOL
`OCTOBER 2017
`
`EtDs for all questions were reviewed by the ARIA guideline
`panel members, who provided feedback by means of electronic
`communication and during a face-to-face meeting of Integrated
`Care Pathways for Airway Diseases (AIRWAYS ICPs)31,32 and
`Frailty European Innovation Partnership on Active and Healthy
`Ageing Reference Sites in Lisbon, Portugal on July 1, 2015.33
`All comments were addressed, and the frameworks were modi-
`fied accordingly. Modified EtD frameworks that included judg-
`ments about the research evidence, additional considerations of
`ARIA panel members, and draft recommendations were sent to
`all ARIA panel members for review and approval or disapproval
`and comments by using the online SurveyMonkey software
`(www.surveymonkey.com). We recorded and addressed all
`agreements/disagreements, comments, and suggestions
`for
`changes. We present
`the final EtD frameworks in Online
`Repository item E2.
`strength were decided by
`Recommendations and their
`consensus. The ARIA guideline panel agreed on the final wording
`of recommendations and remarks with further qualifications for
`each recommendation. The final document, including the recom-
`mendations, was reviewed and approved by all members of the
`guideline panel.
`According to the GRADE approach, the recommendations can
`be either ‘‘strong’’ or ‘‘conditional’’ depending on the guideline
`panel’s confidence