Treatment of Sleep Associate disturbance in Allergy Diseases Timothy J. Craig Professor of Medicine and Pediatrics Distinguished Educator Penn State University

Presentation Overview Allergic Rhinitis and Sleep Disturbance Mechanisms of Sleep Disturbance in Allergic Rhinitis Impact of AR-associated Sleep Disturbances Effects of Allergic Rhinitis Therapies on Sleep and Quality of Life

conflicts of interest with this presentation Merck- speaker, researcher, consultant Astra-Zeneca- speaker Teva- speaker GSK- researcher

Allergic Rhinitis Adversely Impacts Sleep in Adults and Children/Adolescents N=476 Adults/Adolescents/ Children with AR N=221 Adolescents/ Children with AR Patients with Moderate or Severe Impact (%) Patients with Impact (%) School/ Work Performance Sleep Daily Activities School/ Work Performance Normal Activities Lifestyle Sleep O’Connor and Punekar. J Allergy Clin Immunol. 2006;117:S322. Abstract 1244. Scadding and Punekar. EAACI Abstract Book. 2006;211. Abstract 741.

Allergic Rhinitis Symptoms are Associated with Sleep Complaints Prevalence of Sleep Complaints in Patients with Allergic Rhinitis and Controls Subjects with complaint (%) Difficulty Falling Asleep Nocturnal Awakening Early Awakening Nonrestorative Sleep Feeling of Lack of Sleep Snoring ESS score >10 * * * * * * * *P<0.001 vs controls. Leger et al. Arch Intern Med. 2006;166:1744.

Allergic Rhinitis (AR) Symptoms are Associated with Sleep Disorders Prevalence of Sleep Disorders in Patients with Allergic Rhinitis and Controls Subjects with disorder (%) Insomnia Severe Insomnia Sleep Apnea Syndrome Hypersomnia * 7.6 fold increase of OSA in AR *P≤0.003 vs controls. Leger et al. Arch Intern Med. 2006;166:1744.

Allergic Patients Experience More Apnea/Hypopnea than Non-allergic Controls Allergic patients had more apnea/hypopnea episodes than non-allergic controls P<0.001 AHI=apnea/hypopnea index, determined as the total number of apnea and hypopnea episodes (assessed by polysomnography) divided by hours of sleep. Stuck et al. J Allergy Clin Immunol. 2004;113:663.

Allergic Rhinitis is Associated with Increased Microarousals Patients with rhinitis had 10 times more microarousals (average of 50) than controls (n=14) Lavie et al. Acta Otolaryngol. 1981;92;529.

Microarousals in Allergic Rhinitis Correlate with Impaired Breathing Microarousals Correlate with Impaired Breathing Lavie et al. Acta Otolaryngol. 1981;92;529.

Similarities between the two Obese man with severe OAS Increase in IL-1 Increase in TNF Increase in Il-6 Increase in T-helper 2 cytokines Decrease in T-helper 1 cytokines A young girl snoring and with rhinitis Increase in IL-1 Increase in TNF Increase in Il-6 Increase in T-helper 2 cytokines Decrease in T-helper 1 cytokines

What is the Mechanism of Sleep Disturbance in Allergic Rhinitis? Inflammatory components of the allergic response Symptoms of allergic rhinitis Nasal congestion All three Answer

Impact of Poor Sleep Delayed onset Sleep fragmentation Impaired Social Functioning: daytime fatigue/somnolence Impaired performance Impaired learning Emotional/behavioral impact Delayed onset Sleep fragmentation Arousals/microarousals Sleep Disordered Breathing Snoring Obstructive Sleep Apnea Associated Diseases: Hypertension Cardiovascular disease Stroke Diabetes Psychological disorders

Treatment Options

Treatment Options: Snoring Children

The approach to the child with concerns for having OSA

The affect of OSA and benefits of T+A on asthma

The affect of OSA and benefits of T+A on poorly controlled asthma

Sleep apnea in children treated with topical budesonide nasal spray Kheirandish-Gozal. Pediatrics 2008

Leukotrienes in tonsil tissue in children with sleep apnea (SA) and those with recurrent infection (RI) LTB-4 LTC-4

Adenoid reduction with 16 weeks of montelukast therapy

Montelukast affect on sleep in children with sleep apnea compared with those receiving no therapy

Treatment Options for Rhinitis Associated With Sleep disordered Breathing

Treatment Considerations in Allergic Rhinitis: ARIA Guidelines Congestion Rhinorrhea Itching/ Sneezing Sleep Intranasal steroids Oral antihistamines Intranasal antihistamines Oral decongestants Intranasal decongestants Intranasal cromones Anticholinergics Antileukotrienes Clinical Efficacy of Various Treatments for Allergic Rhinitis1,2 According to the US Allergy Report, “Corticosteroids are the most effective pharmacologic agents for treating allergic rhinitis.”1 Intranasal steroids are highly effective against all nasal symptoms, including nasal congestion, and have prolonged duration of action (up to 48 hours). Intranasal steroids exert only local anti-inflammatory effects and are considered safer than their systemic counterparts. 1. The Allergy Report. American Academy of Allergy, Asthma, and Immunology, Inc. 2000. 2. Van Cauwenberge et al. Allergy. 2000;55:116. Bousquet et al. Allergy. 2003;58:192. Bousquet et al. Allergy. 2002;57:841. Van Cauwenberge et al. Allergy. 2000;55:116.

Intranasal Steroid Therapy in Patients with PAR Improves Sleep* Change in Symptom Severity vs Baseline † † † Congestion Sleep Problems Daytime Sleepiness Daytime Fatigue *Improvement in scores vs baseline was determined using the 0 (none) to 4 (greatly) scoring system in patient questionnaires. †P≤0.05 vs placebo. Hughes et al. Allergy. 2003;58:380.

Intranasal Steroid Therapy in Patients with PAR Improves Sleep ‡ Symptom Score Congestion* Improved Sleep† Improved Daytime Sleepiness† Improved Daytime Fatigue† *Congestion scores were rated on the scale from 0=none to 4=severe. † Improvement in sleep, daytime sleepiness, and daily fatigue scores vs baseline was determined using the 0 (none) to 4 (greatly) scoring system in patient questionnaires. Craig et al. Allergy Asthma Proc. 2003;24:53. ‡P=0.04 vs placebo.

Intranasal Steroid Therapy in Patients with PAR Improves Congestion and Sleep* † † Improvement in symptoms per daily diary over 8 weeks *Improvement in congestion and sleep vs baseline was determined using the 0 (none) to 4 (greatly) scoring system in patient questionnaires. †P<0.05 vs placebo. Craig et al. J Allergy Clin Immunol. 1998;101:633.

Intranasal Steroid Therapy Improves Symptoms, Sleep, and Quality of Life in Children with Allergic Rhinitis Mansfield et al. Ann Allergy Asthma Immunol. 2004;92:240.

Intranasal Steroid Therapy Reduces Respiratory Disturbances in Children with Allergic Rhinitis Mansfield et al. Ann Allergy Asthma Immunol. 2004;92:240.

Improvement of Epworth Sleepiness Scale: Budesonide vs Placebo Difference=–3.85; P=0.02; SD=1.45.

Efficacy of Fluticasone Nasal Spray Compared With Placebo on AHI (Number Per Hour) 15 Fluticasone Placebo Mixed/obstructive apnea/ hypopnea index (number per hour) 10 5 Pretreatment Posttreatment Mixed/obstructive apnea/hypopnea index decreased from 10.7 ± 2.6 to 5.8 ± 2.2 (SE) in fluticasone group but increased from 10.9 ± 2.3 to 13.1 ± 3.6 in placebo group; P=0.4. AHI=apnea-hypopnea index. Brouillette RT, et al. J Pediatr. 2001;138:838-844.

MFNS-4 Pooled Phase III Trials in SAR*: Change in Ocular Symptoms Mean Change in Daily rTOSS Days Days 1-15 1-15 Patients with Moderate to Severe Ocular Symptoms at Baseline (TOSS≥4) All Patients P<0.001 Mean Change in daily rTOSS from Baseline Mean Change in daily rTNSS from Baseline P=0.002 NASONEX® 4 Pooled Phase III Trials in SAR: Change in Ocular Symptoms Total ocular symptom scores (TOSS) in phase III SAR studies with NASONEX® were evaluated on the 0-9 scale (0-3 scale for each of the 3 ocular symptoms: itching, redness, and tearing/watery eyes). In the pooled analysis of 4 independent phase III trials of NASONEX® in SAR, the differences in the mean change in daily reflective TOSS from baseline for days 1-15 between the NASONEX® and placebo groups were 0.4 points in all patients (P<0.001) and 0.46 points in patients with moderate to severe ocular symptoms at baseline (TOSS≥4; P=0.002). In the pooled analysis of 4 independent phase III trials of NASONEX® in SAR, daily reflective TOSS at days 1-15 in all patients were 1.33 points in the NASONEX® group and 0.93 points in the placebo group, whereas the corresponding values in patients with moderate to severe ocular symptoms at baseline (TOSS≥4) were 1.97 and 1.51 points for the NASONEX® and placebo groups. The magnitude of TOSS benefit with NASONEX® in the pooled analysis of phase III trials in SAR cannot be compared with fluticasone furoate, because no such analyses were reported for fluticasone furoate. Data on file, Schering Corporation, Kenilworth, NJ. Protocol No. C93-013, C93-184, C94-145, I94-001. MFNS 200 µg OD (n=490) Placebo (n=492) MFNS 200 µg OD (n=298) Placebo (n=307) *C93013, C93184, C94145, I94001 TOSS=total ocular symptom scores. Data on file, Schering Corporation, Kenilworth, NJ. Protocol No. C93-013, C93-184, C94-145, I94-001. Submitted for AAAAI 2007 and publication.

Fluticasone Propionate: Ocular Effects in Analysis of Pooled Trials in SAR Physician-Rated Ocular Symptoms at 14 Days* TOSS Itching Tearing Redness Puffing Mean change from baseline (points) † *Each of the 4 ocular symptoms was rated on a 1-100 visual analog scale (VAS). †P<0.001 vs placebo. DeWester et al. Allergy Asthma Proc. 2003;24:331.

Treatment Considerations in Allergic Rhinitis: ARIA Guidelines Congestion Rhinorrhea Itching/ Sneezing Sleep Intranasal steroids +++ ++/+++ ++++ Oral antihistamines Intranasal antihistamines Oral decongestants Intranasal decongestants Intranasal cromones Anticholinergics Antileukotrienes Clinical Efficacy of Various Treatments for Allergic Rhinitis1,2 According to the US Allergy Report, “Corticosteroids are the most effective pharmacologic agents for treating allergic rhinitis.”1 Intranasal steroids are highly effective against all nasal symptoms, including nasal congestion, and have prolonged duration of action (up to 48 hours). Intranasal steroids exert only local anti-inflammatory effects and are considered safer than their systemic counterparts. 1. The Allergy Report. American Academy of Allergy, Asthma, and Immunology, Inc. 2000. 2. Van Cauwenberge et al. Allergy. 2000;55:116. Bousquet et al. Allergy. 2003;58:192. Bousquet et al. Allergy. 2002;57:841. Van Cauwenberge et al. Allergy. 2000;55:116.

Oral Antihistamines Do Not Improve Sleep Latency and REM Sleep Duration Sleep Latency Immediately After Treatment REM Latency and Duration * * * Time (min) Sleep Onset Latency (min) Placebo Fexo Chlor *P≤0.05 vs placebo and fexofenadine. N=18 healthy Japanese volunteers. Boyle et al. Curr Med Res Opin. 2006;22:1343.

Desloratadine: Effect on Ocular Symptoms in Patients with SAR AM/PM Reflective Ocular Symptom Scores (2-Week Average) Redness of Eyes Tearing/ Watery Eyes Itching/ Burning Eyes Mean change from baseline * * * Desloratadine 5 mg OD (n=172) Placebo (n=174) *P<0.05 vs placebo. Meltzer et al. Clin Drug Invest. 2001;21:25. Data on File, Schering Corporation.

Treatment Considerations in Allergic Rhinitis: ARIA Guidelines Congestion Rhinorrhea Itching/ Sneezing Sleep Intranasal steroids +++ ++/+++ ++++ Oral antihistamines + ++ +++/++ Intranasal antihistamines Oral decongestants Intranasal decongestants Intranasal cromones Anticholinergics Antileukotrienes Clinical Efficacy of Various Treatments for Allergic Rhinitis1,2 According to the US Allergy Report, “Corticosteroids are the most effective pharmacologic agents for treating allergic rhinitis.”1 Intranasal steroids are highly effective against all nasal symptoms, including nasal congestion, and have prolonged duration of action (up to 48 hours). Intranasal steroids exert only local anti-inflammatory effects and are considered safer than their systemic counterparts. 1. The Allergy Report. American Academy of Allergy, Asthma, and Immunology, Inc. 2000. 2. Van Cauwenberge et al. Allergy. 2000;55:116. Bousquet et al. Allergy. 2003;58:192. Bousquet et al. Allergy. 2002;57:841. Van Cauwenberge et al. Allergy. 2000;55:116.

Intranasal Antihistamines: Effect on Congestion and Sleep † Improvement vs baseline over 8 weeks (score)* *Improvement was determined using the 0 (none) to 4 (greatly) scoring system in patient questionnaires. N=24 patients with perennial allergic rhinitis. †P=0.041 Golden et al. Ann Allergy Asthma Immunol. 2000;85:53.

Treatment Considerations in Allergic Rhinitis: ARIA Guidelines Congestion Rhinorrhea Itching/ Sneezing Sleep Intranasal steroids +++ ++/+++ ++++ Oral antihistamines + ++ +++/++ Intranasal antihistamines ++/++ tiredness Oral decongestants Intranasal decongestants Intranasal cromones Anticholinergics Antileukotrienes Clinical Efficacy of Various Treatments for Allergic Rhinitis1,2 According to the US Allergy Report, “Corticosteroids are the most effective pharmacologic agents for treating allergic rhinitis.”1 Intranasal steroids are highly effective against all nasal symptoms, including nasal congestion, and have prolonged duration of action (up to 48 hours). Intranasal steroids exert only local anti-inflammatory effects and are considered safer than their systemic counterparts. 1. The Allergy Report. American Academy of Allergy, Asthma, and Immunology, Inc. 2000. 2. Van Cauwenberge et al. Allergy. 2000;55:116. Bousquet et al. Allergy. 2003;58:192. Bousquet et al. Allergy. 2002;57:841. Van Cauwenberge et al. Allergy. 2000;55:116.

Oral decongestants compared to placebo and benefit on sleep and rhinitis

Oral decongestants compared to placebo and benefit on sleep and rhinitis

Treatment Considerations in Allergic Rhinitis: ARIA Guidelines Congestion Rhinorrhea Itching/ Sneezing Sleep Intranasal steroids +++ ++/+++ ++++ Oral antihistamines + ++ +++/++ Intranasal antihistamines ++/++ tried Oral decongestants - -/- Intranasal decongestants Intranasal cromones Anticholinergics Antileukotrienes Clinical Efficacy of Various Treatments for Allergic Rhinitis1,2 According to the US Allergy Report, “Corticosteroids are the most effective pharmacologic agents for treating allergic rhinitis.”1 Intranasal steroids are highly effective against all nasal symptoms, including nasal congestion, and have prolonged duration of action (up to 48 hours). Intranasal steroids exert only local anti-inflammatory effects and are considered safer than their systemic counterparts. 1. The Allergy Report. American Academy of Allergy, Asthma, and Immunology, Inc. 2000. 2. Van Cauwenberge et al. Allergy. 2000;55:116. Bousquet et al. Allergy. 2003;58:192. Bousquet et al. Allergy. 2002;57:841. Van Cauwenberge et al. Allergy. 2000;55:116.

Nasal Decongestant: Effect on Apnea-Hypopnea Index in Snorers * * Apnea-Hypopnea Index Control Nasal Decongestant Best Position Nasal Decongestant + Best Position N=20 asymptomatic male snorers. *P≤0.03 vs control. Braver and Block. Sleep. 1994;17:516.

Treatment Considerations in Allergic Rhinitis: ARIA Guidelines Congestion Rhinorrhea Itching/ Sneezing Sleep Intranasal steroids +++ ++/+++ ++++ Oral antihistamines + ++ +++/++ Intranasal antihistamines ++/++ tried Oral decongestants - -/- Intranasal decongestants Intranasal cromones Anticholinergics Antileukotrienes Clinical Efficacy of Various Treatments for Allergic Rhinitis1,2 According to the US Allergy Report, “Corticosteroids are the most effective pharmacologic agents for treating allergic rhinitis.”1 Intranasal steroids are highly effective against all nasal symptoms, including nasal congestion, and have prolonged duration of action (up to 48 hours). Intranasal steroids exert only local anti-inflammatory effects and are considered safer than their systemic counterparts. 1. The Allergy Report. American Academy of Allergy, Asthma, and Immunology, Inc. 2000. 2. Van Cauwenberge et al. Allergy. 2000;55:116. Bousquet et al. Allergy. 2003;58:192. Bousquet et al. Allergy. 2002;57:841. Van Cauwenberge et al. Allergy. 2000;55:116.

Treatment Considerations in Allergic Rhinitis: ARIA Guidelines Congestion Rhinorrhea Itching/ Sneezing Sleep Intranasal steroids +++ ++/+++ ++++ Oral antihistamines + ++ +++/++ Intranasal antihistamines ++/++ tried Oral decongestants - -/- Intranasal decongestants Intranasal cromones +/+ Anticholinergics Antileukotrienes Clinical Efficacy of Various Treatments for Allergic Rhinitis1,2 According to the US Allergy Report, “Corticosteroids are the most effective pharmacologic agents for treating allergic rhinitis.”1 Intranasal steroids are highly effective against all nasal symptoms, including nasal congestion, and have prolonged duration of action (up to 48 hours). Intranasal steroids exert only local anti-inflammatory effects and are considered safer than their systemic counterparts. 1. The Allergy Report. American Academy of Allergy, Asthma, and Immunology, Inc. 2000. 2. Van Cauwenberge et al. Allergy. 2000;55:116. Bousquet et al. Allergy. 2003;58:192. Bousquet et al. Allergy. 2002;57:841. Van Cauwenberge et al. Allergy. 2000;55:116.

Treatment Considerations in Allergic Rhinitis: ARIA Guidelines Congestion Rhinorrhea Itching/ Sneezing Sleep Intranasal steroids +++ ++/+++ ++++ Oral antihistamines + ++ +++/++ Intranasal antihistamines ++/++ tried Oral decongestants - -/- Intranasal decongestants Intranasal cromones +/+ Anticholinergics Antileukotrienes Clinical Efficacy of Various Treatments for Allergic Rhinitis1,2 According to the US Allergy Report, “Corticosteroids are the most effective pharmacologic agents for treating allergic rhinitis.”1 Intranasal steroids are highly effective against all nasal symptoms, including nasal congestion, and have prolonged duration of action (up to 48 hours). Intranasal steroids exert only local anti-inflammatory effects and are considered safer than their systemic counterparts. 1. The Allergy Report. American Academy of Allergy, Asthma, and Immunology, Inc. 2000. 2. Van Cauwenberge et al. Allergy. 2000;55:116. Bousquet et al. Allergy. 2003;58:192. Bousquet et al. Allergy. 2002;57:841. Van Cauwenberge et al. Allergy. 2000;55:116.

Leukotriene Receptor Antagonists: Effect on Congestion and Sleep in Patients with SAR Improvement in Total and Individual Nighttime Symptoms Over Placebo Total nighttime symptoms Difficulty going to sleep Nighttime awakenings Congestion on awakening * * Improvement over Placebo Loratadine 10 mg (n=602) Montelukast 10 mg (n=348) Percentage improvements over placebo were modest for both total and individual nighttime symptoms *P≤0.003 vs placebo. All symptoms were scored on a scale from 0 (best) to 3 (worst). Philip et al. Clin Exp Allergy. 2002;32:1020.

Leukotriene Receptor Antagonists: Ocular Effects in Patients with SAR Improvement in Total and Individual Daytime Eye Symptoms Over Placebo Total daytime eye symptoms Tearing Pruritus Redness * * Improvement over Placebo Loratadine 10 mg (n=602) Montelukast 10 mg (n=348) Percentage improvements over placebo for both total and individual daytime eye symptoms were greater with loratadine *P≤0.001 vs placebo. All symptoms were scored on a scale from 0 (best) to 3 (worst). Philip et al. Clin Exp Allergy. 2002;32:1020.

Montelukast for sleep disturbance associated with rhinitis Santos et al. Allergy and Asthma Proceedings

Treatment Considerations in Allergic Rhinitis: ARIA Guidelines Congestion Rhinorrhea Itching/ Sneezing Sleep Intranasal steroids +++ ++/+++ ++++ Oral antihistamines + ++ +++/++ Intranasal antihistamines ++/++ tried Oral decongestants - -/- Intranasal decongestants Intranasal cromones +/+ Anticholinergics Antileukotrienes Clinical Efficacy of Various Treatments for Allergic Rhinitis1,2 According to the US Allergy Report, “Corticosteroids are the most effective pharmacologic agents for treating allergic rhinitis.”1 Intranasal steroids are highly effective against all nasal symptoms, including nasal congestion, and have prolonged duration of action (up to 48 hours). Intranasal steroids exert only local anti-inflammatory effects and are considered safer than their systemic counterparts. 1. The Allergy Report. American Academy of Allergy, Asthma, and Immunology, Inc. 2000. 2. Van Cauwenberge et al. Allergy. 2000;55:116. Bousquet et al. Allergy. 2003;58:192. Bousquet et al. Allergy. 2002;57:841. Van Cauwenberge et al. Allergy. 2000;55:116.

Effect of Therapies for Allergic Rhinitis on Sleep and Quality of Life: Summary Intranasal steroids provide significant relief of congestion and ocular symptoms and improve sleep in patients with allergic rhinitis Non-sedating antihistamines and leukotriene receptor antagonists provide modest improvements in congestion, ocular, and nighttime symptoms Decongestants effectively reduce congestion, but have minimal affect on sleep-disordered breathing

Allergic rhinitis is associated with impaired sleep Adverse Impact of Allergic Rhinitis on the Patient Quality of Life-Focus on Sleep: Conclusions Allergic rhinitis is associated with impaired sleep Sleep impairment in allergic rhinitis can be caused by Inflammatory mediators Nasal symptoms, primarily congestion and rhinorrhea Ocular symptoms Impaired sleep adversely affects performance, productivity and social functioning, and increases the risk of associated diseases Intranasal steroids effectively target inflammation and relieve symptoms to provide improved sleep

Thank you Stephanie Teets Stan Golden Josh Berlin Sujani Kukumanu Katherine Hughs Casey Glass Joel Torretti Faina Gurevich Wenxin Wei Jeff McCann Chris Hanks Carah Santos Niti Sardana

Questions Have a great day.