Allergic rhinitis

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Definition, etiology, pathogenesis, clinical manifestation, co-morbidity, diagnosis, management

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  • In addition to histamine, mast cells are also a major source of inflammatory mediators; the release of these inflammatory mediators may exacerbate allergic reactions induced primarily by histamine1 Inflammatory mediators released by mast cells include interleukins, tumor necrosis factor alpha (TNF α ), prostaglandins, and leukotrienes2 These inflammatory mediators promote endothelial cell activation, vasodilation, and movement of inflammatory cells from the circulation into tissues (extravasation)3 Illustration courtesy of Prof. M. Maurer. Kovarova and Rivera. Curr Med Chem. 2004;11:2083. Monroe et al. J Allergy Clin Immunol . 1997;99:S798-S806. Piconi et al. Int Arch Allergy Immunol . 2002;128:59.
  • The mechanism of nasal obstruction involves the action of a number of mediators, cytokines, and inflammatory cells involved in the allergic cascade, as shown in this slide. The pathophysiology of the early-phase response is primarily driven by preformed mediators (eg, histamine, tryptase, bradykinin), which contribute to airway oedema and subsequent symptoms of congestion and rhinorrhoea.[1] Histamine induces local nociceptive type C neurons by binding to neuronal H 1 receptors, which are found in the epithelium and submucosal regions.[1,2] Nerve endings release substance P and various peptides (eg, vasoactive intestinal polypeptide [VIP] and calcitonin gene-related peptide [CGRP]). Typical symptoms of the early-phase response are rhinorrhoea, sneezing, and itching, but nasal obstruction also has its origins at this stage. Pearlman DS. Pathophysiology of the inflammatory response. J Allergy Clin Immunol. 1999;104:S132-S137. Baraniuk JN. Pathogenesis of allergic rhinitis. J Allergy Clin Immunol. 1997;99:S763-S772.
  • Changes in nasal airflow and/or nasal architectural dynamics take place when allergic inflammation occurs in the nasal mucosa, but this is due to a combination of inflammation, increased vascular permeability, and congestion.[1] Release of certain early-phase mediators (eg, histamine, leukotrienes, kinins) causes increased vascular permeability and vasodilation in the nasal mucosa, resulting in mucosal oedema.[1] Vasodilation/vascular congestion is an important component of nasal obstruction, and it is quickly ameliorated in the short term with decongestants (ie, this is how decongestants are effective in nasal obstruction).[1] Release of allergic inflammatory mediators (ie, cytokines, chemokines, and adhesion molecules) associated with the late phase perpetuates the inflammatory response, of which nasal obstruction is the predominant symptom.[1] Nayak AS, Schenkel E. Desloratadine reduces nasal congestion in patients with intermittent allergic rhinitis. Allergy. 2001;56:1077-80.
  • Treatment options for nasal obstruction are limited to the H 1 -receptor antagonists, oral or topical decongestants, and topical nasal corticosteroids. We will discuss the advantages (pros) and disadvantages (cons) of each class of agents. Nayak AS, Schenkel E. Desloratadine reduces nasal congestion in patients with intermittent allergic rhinitis. Allergy. 2001;56:1077-80.
  • In this study, Horak and colleagues compared the effects of desloratadine and placebo on nasal airflow and SAR symptoms in response to grass pollen.[1] This graph demonstrates that the mean change from baseline in nasal obstruction scores was significantly reduced at 30 minutes with desloratadine therapy, an effect that persisted until the final measurement at 6 hours. Mean AUC for nasal obstruction scores for the desloratadine treatment group was also significantly lower than for the placebo group. Thus, nasal obstruction scores increased in response to allergen exposure, but this effect was blunted by desloratadine. The mean AUC for nasal symptom scores of rhinorrhoea and sneezing and for total nasal symptom scores during allergen exposure were significantly lower for desloratadine compared with placebo in both studies ( P < 0.001). Additionally, mean AUC for nasal secretion weights were significantly lower for desloratadine-treated patients compared with those receiving placebo. Desloratadine demonstrated a placebo-like safety profile. Horak F, Stubner UP, Zieglmayer R, Harris AG. Effect of desloratadine versus placebo on nasal airflow and subjective measures of nasal obstruction in subjects with grass pollen-induced allergic rhinitis in an allergen-exposure unit. J Allergy Clin Immunol . 2002;109:956-61.
  • In vitro data demonstrate that desloratadine inhibits allergic inflammatory mediators and reduces nasal obstruction symptoms in well-designed clinical studies. As demonstrated in these clinical studies, there is a consistent benefit on symptoms of nasal obstruction, which correlates with an improvement in nasal airflow.
  • Di dalam menginhibisi pelepasan cytokine mast cell, Aerius menunjukkan kemampuan inhibisi yang lebih besar dibandingkan dengan Cetirizine
  • Konsentrasi Aerius pada plasma darah adalah tidak dipengaruhi oleh makanan. Hal tersebut dibuktikan oleh penelitan yang dilakukan oleh Gupta dan kawan-kawan dimana pasien yang mendapatkan Aerius 7,5mg setelah puasa 10 jam memiliki konsentrasi Aerius pada plasma darah yang tidak berbeda dengan pasien yang mendapatkan Aerius 7,5 mg setelah mengkonsumsi makanan tinggi lemak dan tinggi kalori
  • Dari penelitian Banfield, menunjukkan bahwa konsentrasi Aerius pada plasma darah pasien yang meminum Aerius dengan juice grapefruit adalah sama dengan pasien yang meminum Aerius tanpa juice fruit. Beda dengan fexofenadine yang konsentrasi obat di plasma darah menurun apabila diminum bersama juice grapefruit
  • Konsentrasi Aerius pada plasma darah jika diminum bersama obat yang lain seperti Erythromycin adalah tidak berbeda signifikan secara klinis.
  • Pada Pemberian Aerius sampai 9 kali dari dosis yang dianjurkan atau 45 mg per hari selama 10 hari tidak ditemukan adanya QT prolongation
  • NASONEX Slide Update 5th proof 12/06/00 Slide # Efficacy of Mometasone Furoate Nasal Spray (MFNS, NASONEX ® ) in Pediatric Patients With Perennial Allergic Rhinitis (PAR) In a 4-week, double-blind study evaluating the effectiveness of NASONEX in the treatment of PAR, 381 children 3 to 11 years of age were assessed for symptom relief and overall response to treatment following treatment with NASONEX 100 mcg qd or placebo. At the end of 4 weeks, 357 patients continued in a 26-week, open-label extension. All received NASONEX 100 mcg qd during the extension. Schering-Plough Corporation. Data on file
  • NASONEX Slide Update 5th proof 12/06/00 Slide # Clinical Experience With Mometasone Furoate Nasal Spray (MFNS, NASONEX ® ) in Children: Conclusions In summary, NASONEX 100 mcg once daily has been demonstrated to be effective and well tolerated for the treatment of children with allergic rhinitis. A dose of 100 mcg once daily was determined to be the optimum pediatric dose and is as effective as beclomethasone dipropionate (BDP) 84 mcg twice daily. Several studies support the excellent safety profile of NASONEX in children. No evidence of growth suppression was detected in either a knemometry study or a 1-year statural growth study. In addition, no evidence of hypothalamic-pituitary-adrenal (HPA) axis suppression has been found in children treated with NASONEX, and plasma concentrations of NASONEX in children have been too low to formally calculate its bioavailability. Finally, NASONEX 100 mcg once daily has been found to be well tolerated in children, with incidences of adverse events comparable to placebo.
  • NASONEX Slide Update 5th proof 12/06/00 Slide # Long-Term Effects of Mometasone Furoate Nasal Spray (MFNS, NASONEX ® ) on Nasal Mucosa Because prolonged dermal application of topical corticosteroids has been reported to cause thinning of the epithelium, concerns have been raised about the safety of the nasal mucosa during prolonged intranasal corticosteroid use. Therefore, a year-long local safety study was conducted to determine the long-term effects of NASONEX on the nasal mucosa. Sixty-nine patients with perennial allergic rhinitis were treated over a 12-month period with NASONEX 200 mcg once daily. Nasal biopsies were performed before and after treatment, and in healthy subjects as a control. Figures A and B show before-and-after biopsies of a representative patient who was treated with NASONEX. Before treatment (Figure A), the epithelium is disturbed and heavy subepithelial inflammatory infiltration is present, particularly with eosinophils. Following 12 months of treatment (Figure B), the epithelium is pseudostratified, ciliated, and columnar, with no signs of atrophy. The subepithelial inflammatory infiltrate is significantly decreased with an absence of eosinophils. This local safety study also found that NASONEX did not cause atrophy of the nasal epithelium. Following 12 months of treatment, the percentage of intact, ciliated epithelium actually increased from 59% to 71% in patients who received NASONEX. Infiltration of inflammatory cells, particularly eosinophils, was significantly reduced by NASONEX. Minshall E, Ghaffar O, Cameron L, et al. Assessment by nasal biopsy of long-term use of mometasone furoate aqueous nasal spray (NASONEX) in the treatment of perennial rhinitis. Otolaryngol Head Neck Surg. 1998;118(5):648-654
  • Allergic rhinitis

    1. 1. Prof DR Dr Ariyanto Harsono SpA(K)
    2. 2. Definition: Impaired function of the nose after allergen exposure through IgE-mediated allergic inflammation Prevalence: 10-25% Impacts  Social  Quality of life  Performance Schools  Cost 2Prof DR Dr Ariyanto Harsono SpAK
    3. 3. 1. Allergen 2.Aspirin 3.Polution 3Prof DR Dr Ariyanto Harsono SpAK
    4. 4. 1. Allergen:-Inhalant House dust Polen Bulu hewan Tungau -Foods 4Prof DR Dr Ariyanto Harsono SpAK
    5. 5. Arachidonic Acid Phospholiphase A Cyccloxygenase Lipoxygenase Prostaglandine TXA Prostacyclin Leukotriene A Leukotriene B Leukotriene C Aspirin 2. Aspirin HETE,5-HETE, PAF 5Prof DR Dr Ariyanto Harsono SpAK
    6. 6. P Bacterial/ viral infection CytokinesStress P P P C C N C C C NN I-κB p50 ATP ADP I-κB kinase PhosphoryIation of I-κB kinase NF-κB Degradation of I-κB in proteosome Ubiquitination of I-κB Nucleus NF-κB - responsive gene (Ub) n (Ub) n Polution 3. Polution
    7. 7. Sel Epitel Makrofag Sel T Sel B Sel Mast Eosinofil Gejala Sitokin/Kemokin IL-4, IL-5, IL-13, IL-10, IL-3 GM-CSF,Eotaxin RANTES,TGF-α, TGF-β Mediator Histamin, Prostaglandin Leukotrien Bersin, Buntu, Rinorea Gatal Infiltrasi Sel Eosinofil Inflamasi Alergi Ko-morbid 7Prof DR Dr Ariyanto Harsono SpAK
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    12. 12. Mast Cell Preformed Mediator: Histamin, TNF-α, Protease,Kinin, ECF New Generated Mediator: PGD, Leukotriene 12 Prof DR Dr Ariyanto Harsono SpAK
    13. 13. Mast Cells Mediate Allergic and Inflammatory ReactionsIL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, IL-13, TNFα, MIPs, IFNγ, GM-CSF, TGFβ, bFGF, VPF/VEGF, PGD2, LTB4, LTC4, PAF, Serotonin, Heparin, Chondroitin- sulfate, Chymase, Tryptase, Cathepsin G Recruitment Extravasation Vasodilation Activation MC Graphics courtesy of Prof. M. Maurer. 13 Prof DR Dr Ariyanto Harsono SpAK
    14. 14. Granule contents: Histamine,TNF-α Proteases, Heparin Lipid mediators: Prostaglandins Leukotrienes Cytokine production: Specifically IL-4, IL-13 14Prof DR Dr Ariyanto Harsono SpAK
    15. 15. Eosinofil Mediator: MBP,ECP,EDN, Protease, Peroksidase Sitokin: TGF-α, TGF-β 15Prof DR Dr Ariyanto Harsono SpAK
    16. 16. Eosinophil activated and prolonged life-span by IL-5 16Prof DR Dr Ariyanto Harsono SpAK
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    18. 18. 18Prof DR Dr Ariyanto Harsono SpAK
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    22. 22. Keluhan Utama:-Rhinorrea -Itchy nose -Sneezing -Congestion Gejala minor: Rabbit Nose Allergic Salute Nasal crease Allergic Shiner Toothy mouth (Adenoid Face) 22Prof DR Dr Ariyanto Harsono SpAK
    23. 23. LeukotrieN C4 Prostaglandin D2 Tryptase HISTAMIN CYTOKINE IL-1 IL-3 IL-4 IL-5 IL-6 IL-13 TNF-α Kemokin IL-8 Eotaxin RANTES Adhesion Molecules P-selectin ICAM Early phaseResponse • Sneezing • Itchy, watery eyes • Runny nose • Congestion • Itchy nose Rapid phase Inflammatory Response Overview: Symptoms of Allergic Rhinitis Early phase Mediator 23Prof DR Dr Ariyanto Harsono SpAK
    24. 24. IncreaseVaskularPermebility /secretion Vascular obstruction Mucosal Inflammation Nasal obstruction Rapid phase Mediators Vasodilatation Mediators of allergic inflammation Etiologic Factors of Congestion 24Prof DR Dr Ariyanto Harsono SpAK
    25. 25. 25Prof DR Dr Ariyanto Harsono SpAK
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    33. 33. 33Prof DR Dr Ariyanto Harsono SpAK
    34. 34. Allergic Rhinitis and co-morbid conditions Allergic rhinitis Nasal polyps Sleep disturbance, including sleep- disordered breathing Rhinosinusitis (acute and chronic) Asthma with AR Congestion Inflammation Common cold 34Prof DR Dr Ariyanto Harsono SpAK
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    44. 44. •anamnesis •physical examination •Total IgE / Specific •Nasal mucosa smear eosinophils •Skin test •Nasal mucosa provocation test 44Prof DR Dr Ariyanto Harsono SpAK
    45. 45. •avoidance of allergens •education •pharmacotherapy •immunotherapy 45Prof DR Dr Ariyanto Harsono SpAK
    46. 46. ARIA = Allergic Rhinitis and its Impact on Asthma. Bousquet et al. J Allergy Clin Immunol. 2001;108 (5 suppl):S147. ARIA Guidelines: Recommendations for Management of Allergic Rhinitis Mild intermittent Moderate severe intermittent Mild persistent Moderate severe persistent Immunotherapy Allergen and irritant avoidance Intranasal decongestant (<10 days) or oral decongestant Second-generation nonsedating H1 antihistamine Leukotriene receptor antagonists Local cromone Intra-nasal steroid 46Prof DR Dr Ariyanto Harsono SpAK
    47. 47. Jenis obat bersin rinorea Buntu Gatal hidung Keluhan mata Antihistamin H1 Oral Intranasal Intraokuler ++ ++ 0 ++ ++ 0 + + 0 +++ ++ 0 ++ 0 +++ Kortikosteroid intranasal +++ +++ +++ ++ ++ Kromolin Intranasal Intraokuler + 0 + 0 + 0 + 0 0 ++ Dekongestan Intranasal Oral 0 0 0 0 +++ + 0 0 0 0 Antikolinergik 0 ++ 0 0 0 Antilekotrien 0 + ++ 0 ++ Gejala 47 Prof DR Dr Ariyanto Harsono SpAK
    48. 48. Jenis obat bersin rinorea Buntu Gatal hidung Keluhan mata Antihistamin H1 Oral Intranasal Intraokuler ++ ++ 0 ++ ++ 0 + + 0 +++ ++ 0 ++ 0 +++ Kortikosteroid intranasal +++ +++ +++ ++ ++ Kromolin Intranasal Intraokuler + 0 + 0 + 0 + 0 0 ++ Dekongestan Intranasal Oral 0 0 0 0 +++ + 0 0 0 0 Antikolinergik 0 ++ 0 0 0 Antilekotrien 0 + ++ 0 ++ Gejala 48Prof DR Dr Ariyanto Harsono SpAK
    49. 49. Drugs Choice for nasal congestion • Antagonist reseptor H1 • Dekongestan oral & topical – pseudoefedrin – fenilefrin • Topical nasal Cortikosteroid Nayak AS et al. Allergy. 2001;56:1077-80. 49Prof DR Dr Ariyanto Harsono SpAK
    50. 50. Desloratadin reduces nasal congestion Score *P = 0.005 †P = 0.01 ‡P = 0.001 dibanding plasebo 15 Waktu Terpapar Alergen (menit) 0 0.6 1.2 1.6 2.0 1.8 1.4 1 0.8 0.4 0.2 45 75 105 135 165 195 225 255 285 315 345 † * * † * † † † † * † † * † * † * ‡ ‡ ‡ ‡ ‡ ‡ Sumbatan Reduced Desloratadin Plasebo RerataperubahanSkor SumbatanHidung Horak F et al. J Allergy Clin Immunol. 2002;109:956-61. 50Prof DR Dr Ariyanto Harsono SpAK
    51. 51. Treatment with desloratadine: • Inhibition of allergic inflammatory mediators • Reduces symptoms of nasal obstruction in the well-designed studies • Improve nasal airflow, an objective measurement of the nasal obstruction 51Prof DR Dr Ariyanto Harsono SpAK
    52. 52. 0 10 20 30 40 50 60 70 IL-6 IL-8 IL-3 GM-CSF AERIUS Cetirizine Lippert U, et al. Exp Dermatol. 2000;9:118-124. Percentinhibition Desloratadine: Inhibition of Allergic Inflammation TNF-α Greater inhibition than Cetirizine Inhibition of Mast Cell Cytokine Release 52Prof DR Dr Ariyanto Harsono SpAK
    53. 53. Food Does Not Alter the Oral Bioavailability of Desloratadine Desloratadine 7.5 mg* after high-fat, high-calorie meal Desloratadine 7.5 mg* after 10-hour fast MeanDesloratadine PlasmaConcentration(µg/L) 0 4 8 12 16 20 24 0 1 2 3 4 Hour Randomised, open-label, single-dose, 2-way crossover study (n = 18) *The recommended daily dose for desloratadine is 5 mg. Gupta S et al. Clin Pharmacokinet. 2002;41(Suppl 1):7-12. 53Prof DR Dr Ariyanto Harsono SpAK
    54. 54. 0 6 12 18 24 0 50 100 150 200 0 1 2 3 4 0 6 12 18 24 (µg/LPlasma) Hours FexofenadineDesloratadine (ng/mLPlasma) Banfield C et al. Clin Pharmacokinet. 2002:41:311-8. Effect of Grapefruit Juice of Desloratadine and Fexofenadine Hours With Grapefruit Juice Without Grapefruit Juice 54Prof DR Dr Ariyanto Harsono SpAK
    55. 55. 0 4 8 12 16 20 24 0 1 2 3 4 5 6 Hour DL 7.5 mg/d* + placebo DL 7.5 mg/d* + erythromycin 500 mg TDS7 8 MeanDesloratadinePlasma Concentration(µg/L)onDay10 DL, desloratadine; TDS, three times daily. *The recommended daily dose for desloratadine is 5 mg. Banfield C et al. Clin Pharmacokinet. 2002;41:29-35. • Changes in AUC not clinically significant • Steady-state levels of DL achieved by day 10 after both treatments Desloratadine/Erythromycin Drug-Coadministration 55Prof DR Dr Ariyanto Harsono SpAK
    56. 56. ECG Pharmacodynamic Effects of Desloratadine • Desloratadine 45 mg* single daily doses for 10 days; placebo crossover design – No statistically significant differences in QTc observed • No clinically relevant adverse events reported *Nine times the recommended daily dose. ECG, electrocardiogram. Bousquet J, et al.Allergy 2004;59 (suppl.77):4-16 56Prof DR Dr Ariyanto Harsono SpAK
    57. 57. Desloratadine and EAACI/ARIA Criteria for Antihistamines in Allergic Rhinitis • AERIUS meets all EAACI-ARIA criteria for antihistamines required for the treatment of allergic rhinitis – Efficacy • Effective in the treatment of intermittent and persistent rhinitis • Effective for all nasal symptoms including nasal obstruction • Improvement of eye symptoms • Improvement in asthma symptoms • Efficacy in pediatric and elderly patients 57Prof DR Dr Ariyanto Harsono SpAK
    58. 58. Desloratadine and EAACI/ARIA Criteria for Antihistamines in Allergic Rhinitis - Safety and tolerability/side effects • No sedation or cognitive or psychomotor impairment • No anti-cholinergic effects • No weight gain • No cardiac side effects • Studies should be carried out in young children and elderly patients to assess safety • Prospective postmarketing safety analysis should be conducted 58Prof DR Dr Ariyanto Harsono SpAK
    59. 59. Jenis obat bersin rinorea Buntu Gatal hidung Keluhan mata Antihistamin H1 Oral Intranasal Intraokuler ++ ++ 0 ++ ++ 0 + + 0 +++ ++ 0 ++ 0 +++ Kortikosteroid intranasal +++ +++ +++ ++ ++ Kromolin Intranasal Intraokuler + 0 + 0 + 0 + 0 0 ++ Dekongestan Intranasal Oral 0 0 0 0 +++ + 0 0 0 0 Antikolinergik 0 ++ 0 0 0 Antilekotrien 0 + ++ 0 ++ Gejala 59Prof DR Dr Ariyanto Harsono SpAK
    60. 60. Efficacy NASONEX in Pediatric Patients with Perennial Allergic Rhinitis • 4-week, double-blind study (double blind) • With the extension of the 26-week, open- label • Children 3-11 years • MFNS 100 mcg qd or placebo 60Prof DR Dr Ariyanto Harsono SpAK
    61. 61. Results Clinical Experience NASONEX in Children • Mometasone furoate nasal spray (MFNS) 100 mcg qd is the optimal dose in children over 2 years • Low potential for systemic effects • There is no short-term growth disorders • There is no evidence of HPA axis suppression • Well tolerated • Incidence of adverse events similar placebo 61Prof DR Dr Ariyanto Harsono SpAK
    62. 62. Efek Jangka Panjang Nasonex thd Mukosa Hidung AA BB Before MFNS TreatmentBefore MFNS Treatment After 12 Months of TreatmentAfter 12 Months of Treatment With MFNSWith MFNS Minshall E, et al.Minshall E, et al. Otolaryngol Head Neck Surg.Otolaryngol Head Neck Surg. 1998;118(5):6481998;118(5):648 62Prof DR Dr Ariyanto Harsono SpAK
    63. 63. 63Prof DR Dr Ariyanto Harsono SpAK

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