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Recomendaciones sobre la duración
optima del tratamiento con
corticoesteroides tópicos intranasales:
Revisión de la evidencia –
Presentación y debate

Jorge F Máspero
Buenos Aires
Argentina

Rinitis Alérgica

Prevalencia elevada


600.000.000 en el mundo
(1/3 con asma)

Prevalencia en aumento
Causas del aumento de la prevalencia

Cambios en el medioambiente sin dudas

Hipótesis higiénica?
Aumento de la polución?

Frecuentemente co mórbida

371  Costos en salud de la Rinitis Alérgica  U$d 1. costly. USA.000. and neglected Lancet 2008.000.Allergic rhinitis: common.000.000 consultas)  Promedio anual de u$d 520/persona  Afectación personal y social    Gran impacto en la calidad de vida Efectos en la escolaridad Ausentismo laboral .000 en 2005 (Agency for Healthcare Research Quality. 2005)  1/3 honorarios médicos (22.

703 pacientes encuestados y 4.     1.2% con ICS .335 a-q Frecuencia de RA en asmáticos 55.1% con AH  14.2% tratados  34.5% 81.906 MAP 14.5%  Persistente 33.2% RA  Intermitente 66.

principalmente por MAP .    Cohorte de 453 individuos con AR (SFARq) Evaluó el nivel de conocimiento de la enfermedad y su tratamiento Frente a un episodio de RA  49% espera a que se le pasa sin tratamiento  31% toma una medicación que le habían indicado previamente  20 % consulta a un profesional de la salud  59% MAP  26% farmacéutico  13% especialista Seguimiento sólo en el 42% de los pacientes.

2004. 2. AAAAI Annual Meeting.Tassinari.Prevalencia de los distintos tipos rinitis (RA) Prevalenciade global de la rinitis alérgica alérgica persistente Europa 1 América Latina *2 * Venezuela.24:758. Ecuador. México. Perú (n = 455) 29% 33% 67% 71% Intermitente Persistente 1 Bauchau y Durham. Presented as poster 2007 . Eur Respir J. Panamá.

Costs of allergic rhinitis. ed. Philadelphia: Current Medicine. 2002 .Presencia de síntomas durante el año completo en pacientes con RAP El 50% de los pacientes presentan síntomas al menos durante 4 meses en el año  El 20% de los pacientes presentan síntomas al menos durante 9 meses en el año.  Blaiss M. In: Kaliner MA. Current Review of Rhinitis.

Encuesta  Enfermedades alérgicas crónica más frecuentes en su consulta?       RA AB DA U Otra 35% 24% 17% 9% 15% 60% < 18 años RA – Síntoma más difícil de tratar   Congestión Goteo post nasal (2007/ 200 MAP y pediatras de Argentina. Brasil. Venezuela y México) .

Brasil.Encuesta (cont. Venezuela y México) .)  El 74% de los encuestados dijo que 5 de cada 10 pacientes que diagnostican sufren síntomas persistentes  El 75% de los encuestados dijo que 5 de cada 10 pacientes que diagnostican sufren RA moderada/severa  El 52% utiliza ICS <30 días en promedio en pacientes con RA moderada severa (2007/ 200 MAP y pediatras de Argentina.

    En la encuesta a médicos de atención primaria en Latinoamérica más del 75% de los encuestados respondieron que en sus consultas: 50% o más de los pacientes son del tipo persistente-moderado-severo cuando se aplican los criterios de clasificación de ARIA Pero no usan el tratamiento sugerido por ARIA más de 30 días-año No hay estudios de largo plazo que evalúen las ventajas del tratamiento continuo vs intermitente de la rinitis persistente .

Mild severe Moderatesevere Not in preferred order oral H1 blocker or intranasal H1-blocker and/or decongestant or intranasal CS or LTRA* (or chromone) In preferred order intranasal CS H1 blocker or LTRA* Review the patient after 2-4 wks Improved In persistent rhinitis review the patient after 2-4 wks If failure: step-up If improved: continue for 1 month Step-down and continue treatment for > 1 month Failure Review diagnosis Review compliance Query infections or other causes Blockage Add or increase add Rhinorrhea intranasal CS decongestant add ipratropium dose or oral CS (short term) Failure referral to specialist Allergen and irritant avoidance may be appropriate If conjunctivitis Add oral H1-blocker or intraocular H1-blocker or intraocular cromone (or saline) Consider specific immunotherapy .Check for asthma especially in patients with severe and/or persistent rhinitis Diagnosis of allergic rhinitis Intermittent symptoms Mild Not in preferred order oral H1 blocker or intranasal H1-blocker and/or decongestant or LTRA* Persistent symptoms Moderate.

Tratamiento de largo plazo con esteroides nasales .

México . Brasil. Venezuela.Quién trata la rinitis? Manejan el •71% del mercado de antihistamínicos •82% del mercado de antihistamínico + desc 38% 33% 29% Otros * Fuente INTE2007 Pediatr as MAP •El 50% del mercado de corticoides tópicos  Argentina.

Uso de las guías ARIA – EP3OS  Qué son las guías?   No las conoce Las conoce    Las aplica No las aplica 40% 64% 36% 60% Sólo el 22% las conoce y las aplica .

¿Cómo tratan la rinitis alérgica? ¿PERMANENTE O 79% AH sólo o combinados A ICS 14% DEMANDA? AH + ICS 7% 21% ICS sólo o combinados AH + DC 26% AH 46% .

000.300 Modificado de PAHO-WHO Argentine Representative ‘2001 .¿Existen recursos suficientes? En Argentina hay 10.500 29.000 Clínicos y pediatras Enfermeras Asistentes en salud 40.000 pacientes con rinitis Especialistas 3.000 60.

. Están pobremente entrenados en el diagnóstico y tratamiento de ésta enfermedad 3. pero ninguna que permitan identificar fácil y rápidamente a los pacientes que se beneficiarían con una intervención prolongada o intermitente. Existen varias guías de tratamiento.Conclusiones iniciales 1. Los MAP y pediatras son los que mayor número de pacientes con RA atienden 2.

¿Cómo evaluar el tratamiento de la rinitis alérgica persistente a largo plazo ? Diferencia con tratamiento intermitente? ¿Impacto en las Complicaciones ? Tratamiento continuo de la Rinitis Alérgica ¿Calidad de vida? ¿Influencia en Comorbilidades? Impacto económico beneficioso ? .

Buscar el control de los sintomas y luego usar la menor dosis o uso p.n? 3. complicaciones y costos indirectos . Considerar rapidez de acción . Mantener la terapia aún en ausencia de síntomas ? (atacar la inflamación mínima persistente) 2. compliance y aceptación por el paciente vs evolución a largo plazo .r. costo directo .Duración optima del tratamiento con corticoesteroides tópicos intranasales: 1.

Persistent inflammation in allergic rhinitis  Prophylactic use of intranasal steroids in seasonal allergic rhinitis  Long-term use of intranasal steroids in perennial allergic rhinitis  Long-term use in adults  Long-term use in children  .

JACI 1995 . even when they are symptom-free: MPI MINIMAL PERSISTENT INFLAMMATION- Ciprandi et al.GP722000 EXPERIMENTAL EVIDENCE PROVIDED BY THE NASAL MODEL Symptomfree patients sensitized and exposed to perennial allergens have always a weak inflammatory infiltrate and a weak ICAM-1 expression.

96:971. J Allergy Clin Immunol. 1995. Der p I (low) .HDM (µg/g of dust) Minimal Persistent Inflammation Der p I (low) Der p I (high) Threshold of symptoms Months Symptoms Minimal persistent inflammation Inflammation Ciprandi et al.

Evidence of Significant Inflammation During the Days with Low Pollen Count and Low or Absent Symptoms Eosinophil and Neutrophil Counts in Nasal Scrapings and ICAM1 Positivity in Nasal Epithelial Cells ICAM-1 Cell numbers Eosinophils Neutrophils ICAM-1 Days Ricca et al. 2000.105(1 Pt 1):54. 1 4 Weeks . J Allergy Clin Immunol.

Symptoms The concept of Minimal Persistent Inflammation Symptom  threshold INFLAMMATION stimulus .

Pre Post Mast cells per field (0.202 mm2) MFNS: Anti-Inflammatory Effect of Mast Cells Epithelial and SubmucosalTreatment Eosinophils Epithelial and 12-Month inSubmucosal Patients With PAR .202 mm2) Eosinophils per field (0.118:648. 1998.202 mm2) Epithelium Epithelium Submucosa * * Pre Post *P<0.Submucosa * Pre Post * Pre Post Mast cells per field (0. Otolaryngol Head Neck Surg.001 Minshall et al.

. Assessment by nasal biopsy of long-term use of mometasone furoate aqueous nasal spray (NASONEX) in the treatment of perennial rhinitis.Impact on the Nasal Mucosa Documented reduction of Unretouched Nasal Biopsy Pictures inflammation Before MFNS treatment After 12 months’ MFNS treatment Note: The clinical relevance of these data in the treatment of allergic rhinitis is not known. Minshall E. et al. 1998. Otolaryngol Head Neck Surg.118:648-654.

if any. inflammation is present both before and during the season Patients with perennial allergic rhinitis have persistent inflammation Intranasal steroids are effective antiinflammatory agents What are .Persistent Inflammation in Allergic Rhinitis: Summary     In patients with seasonal allergic rhinitis. the clinical advantages of long term treatment? .

¿Cuan persistente es la rinitis persistente? .

Calculation of the ‘normal range’ of nasal symptom scores. .

5. As needed because of present symptoms. 2. 4. 3. .      ‘could answer either: 1.Why did you take your medication?’. To prevent symptoms. A habit. Other reason. Doctor’s orders.

.

These findings suggest that. despite continued high allergen exposure. intermittently Increasing nasal symptom scores were a predictor for the use of nasal medications. time The majority of persistent rhinitic subjects used nasal medication intermittently.Conclusions     persistent nasal symptoms over a previously unstudied period of 12 months in persistent rhinitic subjects. subjects with persistent rhinitis experience some variation in symptom intensity and are able to respond to these changes by taking medication. . with pathologically high nasal symptom scores for 65% of the time.

 Prophylactic use of intranasal steroids in seasonal allergic rhinitis .

. ‡ The onset of the pollen season for all centres occurred an average of 26 days (range 16 to 30 days) after the start of treatment. Adapted from Graft et al. † P<0.01 vs placebo.98:724.MFNS and BDP in Prophylaxis of Nasal Symptoms of SAR: Primary Endpoint— Proportion Minimal Symptom Days Proportion of of Minimal Symptom Days* (Patient-Reported) % of days with minimal symptoms MFNS 200 μg qd (n=114) BDP 168 µg bid (n=112) Placebo (n=104) † Prior to pollen season‡ † † Pollen season‡ † Entire study * Primary endpoint is the proportion of minimal symptom days from the start of ragweed season to study completion (28 days). J Allergy Clin Immunol. 1996.

Long-term use of intranasal steroids in perennial allergic rhinitis •Long-term use in adults •Long-term use in children .

79:370.MFNS and Fluticasone Propionate (FP) for Long-Term Treatment of Patients With PAR: Study Design  A 3-month. double-blind. randomised. . Ann Allergy Asthma Immunol. double dummy. parallel-group study in 474 adolescent and adult patients (age 12-77) with perennial allergic rhinitis  Treatment for 3 months     MFNS 200 µg od (n=166) Fluticasone propionate (FP) 200 µg od (n=162) Placebo (n=146) 474 pts Primary efficacy variable  Change from baseline in total AM plus PM diary nasal symptom score over the first 15 days of treatment Mandl et al. 1997.

1997. .0 in all 3 groups (rated on a scale from 0 = none to 3 = severe).MFNS and FP in Adolescents and Adults With Moderate-to-Severe PAR: Percent Change in Patient-Rated Nasal Congestion Mean change in patient-reported nasal congestion score from baseline (%) Percent Change in Patient-Rated Congestion* From Baseline Placebo (n=184) FP 200 µg od (n=183) MFNS 200 µg od (n=181) † † † † Baseline 1-15 16-30 † † † † 31-45 † † 46-60 61-75 † † † 76-90 † Endpoint Days *Secondary endpoint.01 vs placebo. Ann Allergy Asthma Immunol.79:370. Adapted from Mandl et al. Baseline congestion scores were 2. †P≤0.

MFNS and FP in Adolescents and Adults With Moderate to Severe PAR: Percent Change in Patient-Rated Individual Symptom Scores Mean change from baseline (%) Reductions in Individual Symptom Scores at Days 76-90 (Patient-reported) Discharge Congestion Sneezing Itching -24% -39% -57% -57% * * -38% -40% -55% -56% * * -67% -66% * * -71% * -67% * MFNS (n=166) FP (n=162) * P<0. Placebo (n=146) . Mandl et al. 1997.01 vs placebo.79:370. Ann Allergy Asthma Immunol.

.01 vs placebo.01 *P=0. NJ. Ann Allergy Asthma Immunol. Schering Corporation.79:370. Fluticasona y placebo). Data on file. Mandl et al. 1997. Immunol. Kenilworth.FUROATO DE MOMETASONA: CAMBIO PORCENTUAL EN LA CONGESTIÓN NASAL DE MODERADA A SEVERA EN LA RINITIS ALÉRGICA PERENE Mejoría en la Congestión Nasal a las 12 semanas/final Mejoría media % de la congestión nasal vs placebo en según los diarios del paciente Mometasona 200 µg OD (n=154) Fluticasona 200 µg OD (n=156) Placebo (n=148) -31% -54% * *P=0. I94-079. Protocol No. -51% * Puntaje de la congestión basal fue de 2.0 en los 3 grupos (mometasona.

Abstract P249. . 2008.4 week DBPC treatment -6 month open follow up Patel P.100. Ann Allergy Asthma Immunol.

TSS. 2008. .and patient-rated overall condition of PAR Patel et al.MFNS in Children With PAR: Design:1-Month Double-Blind and 6-Month OpenLabel Study   A multicentre. and individual symptoms Physician.100. double-blind. Abstract P249. randomised study in 381 children aged 3 to 11 years with at least 1-year history of symptoms of PAR Treatment 381     MFNS 100 µg/day for 4 weeks (n=190) pts Placebo for 4 weeks (n=191) All subjects continued in open-label safety period with MFNS for up to 6 months Efficacy variables    Improvement from baseline in the physician-rated TNSS Patient-rated TNSS. Ann Allergy Asthma Immunol.

4* (-46%) *P≤0.2 (-32%) -2. 2008.Mean change from baseline MFNS in Children With PAR: TNSS Evaluated by Baseline scores: 6. †P=0. Abstract P249.8 (-39%) † -3.4* (-32%) -2.5 (-37%) -2.8 in both groups Physicians Day 8 Day 15 Day 29 -1. Ann Allergy Asthma Immunol.100.6 (-22%) -2.01.02. Patel et al. MFNS 100 µg od (n=186) Placebo (n=190) .

7* (-28%) -1.8 (-28%) -2. Abstract P249.0 with placebo Days 1-15 Days 16-29 -1.100. Patel et al. 6.01. 2008.1 (-18%) -1.4* (-38%) *P≤0.Mean change from baseline MFNS in Children With PAR: TNSS Baseline Evaluated by Patients scores: 5. Ann Allergy Asthma Immunol. MFNS 100 µg od (n=187) Placebo (n=189) .9 with MFNS.

100. Patel et al. 2008.1 in both groups Evaluated by Physicians Day 8 Day 15 Day 29 -15% -19% -20% -26% -28%* -34%† *P≤0. †P=0. MFNS 100 µg od (n=186) Placebo (n=190) .Mean change from baseline MFNS in Children With PAR: Overall Condition of PAR Baseline score: 2.02.01. Ann Allergy Asthma Immunol. Abstract P249.

MFNS in Children With PAR: Efficacy in 6-Month Open-Label Study Summary  After 4 weeks of double-blind treatment   Mean score of overall condition in patients treated with MFNS was better than in patients treated with placebo At week 30 after open-label treatment with MFNS  49% reduction of symptoms vs baseline in patients initially treated with placebo and switched to MFNS Patel et al.100. Ann Allergy Asthma Immunol. 2008. Abstract 249. .

Ann Allergy Asthma Immunol. 2008. .100. Abstract 249.MFNS Treatment for up to 6 Months Was Well Tolerated in Children With PAR  5 patients discontinued treatment during the double-blind period    2 in the MFNS group (both unrelated to treatment) 3 in the placebo group (2 unrelated to treatment) Treatment-related adverse events (AEs)   15% during the double-blind period (16% in the placebo group) 17% during the open-label period Patel et al.

100. Abstract 249.Epistaxis during both periods (% of patients) MFNS Treatment for up to 6 Months Was Well Tolerated in Children With PAR Epistaxis was the most frequently reported AE in the 6-month study 10% 4% MFNS 100 µg od Placebo Patel et al. Ann Allergy Asthma Immunol. 2008. .

PAR treatment during 12 months .

PAR treatment during 12 months .

PAR treatment during 12 months: Mometasone in pediatric PAR . 52 weeks Ratner et al in press .

Long-Term Use of Intranasal Steroids in Perennial Allergic Rhinitis: Summary  Persistent inflammation is a hallmark of AR   INS are potent anti-inflammatory agents INS are effective in the prophylaxis of seasonal allergic rhinitis both before and during the allergen season  Significantly more days with minimal or no symptoms  Significantly reduced symptom burden .

Ann Allergy Asthma Immunol. 2008. Abstract 249. 1997.Long-Term Use of Intranasal Steroids in Perennial Allergic Rhinitis: Summary  In adult and paediatric patients with PAR. longterm use of INS is associated with a significant reduction in      Total nasal symptom scores Individual nasal symptom scores. Patel et al. Ann Allergy Asthma Immunol.79:370. including congestion scores Overall condition of PAR Long-term use of INS is well tolerated in both adult and paediatric patients with PAR Therapeutic implications:  Consider long-term therapy with INS in patients with PAR Mandl et al.100. .

Intranasal Steroids Onset of Action .

Abstract 910. J Allergy Clin Immunol. Kaiser et al. .028.119(Suppl):S232.FF in SAR: Onset of Action-Change in iTNSS After First Dose Significant Difference in iTNSS after First Dose at 8 and 10 Hours Not Sustained at 12 Hours * * *P≤0. 2007.

98:175-181.Ciclesonide in PAR: Onset of Action After the First Dose Change from baseline in instantaneous TNSS Change in Instantaneous TNSS After First Dose * *P=0. . Ann Allergy Asthma Immunol. Hours Meltzer et al.03 vs placebo. 2007.

Kenilworth. Berkowitz et al.04 vs placebo. * * * * . Data on file. Schering Corporation.Percent change from baseline in total symptom score NASONEX® Onset of Action: Percent Change in (Park Total Percent Change in Total Symptom Score Study) After Single Dose Symptom Score Hours After Single Dose * * * * *P≤0. NJ. P97-019. Protocol No.20:167. 1999. Allergy Asthma Proc.

NASONEX® Onset of Action: Percent
Change in Total Nasal Symptom
Percent Change in Total Nasal Symptom Score (Park Study) After Single Dose
Score After Single Dose
Percent change from baseline
in total nasal symptom score

Hours

*
*

*P≤0.02 vs placebo.
Berkowitz et al. Allergy Asthma Proc. 1999;20:167.
Data on file, Schering Corporation, Kenilworth, NJ. Protocol No. P97-019.

*

*

*

*

MFNS Provided Significant Relief of
Acute Rhinosinusitis Symptoms on
Onset and Duration of Effect
Day One
on Major Symptoms Score vs. Placebo

*Meltzer et al. JACI,
2005;116:1298-95.

Baseline

9

Major Symptom Score

• MFNS 200 ug
twice daily
provided
significant
benefit
from day one vs.
placebo
(P≤0.037)

8

MFNS 200 µg x 2 daily (n=234)

7

Amoxicillin 0.5 g x 3 daily (n=249)
Placebo (n=247)

6

*

5

*

4

*

3
2

*

*

*

*

*P≤0.037 vs. placebo

P≤0.012 vs. amoxicillin 0.5 g TID

1

* *

9

11

12

*

* *

* *

0
0

1

2

3

4

5

6

7

8

Days

10

13

14

15

(J Allergy Clin Immunol 2002;109:426-32.)

Mean nPEF throughout the study with 12 months treatment both groups received 14day courses of budesonide when needed .

Proportion of patients free from relapses during the second year of the study after discontinuation of 1 year’s treatment with budesonide or cetirizine .

budesonide better prevents relapses for 1 to 2 months compared with cetirizine. (J Allergy Clin Immunol 2002.) .Conclusions: •Budesonide is significantly more effective than cetirizine in controlling perennial rhinitis. • After stopping treatment. • Periodic therapy with budesonide may be sufficient to control symptoms in most patients who have relapses.109:426-32.

) . • Furthermore. which suggests that antiinflammatory treatment has a prolonged effect.109:426-32. (J Allergy Clin Immunol 2002.periodic treatment with budesonide may be a promising treatment strategy in perennial rhinitis.Conclusions: •Although neither treatment significantly affected the long-term outcome of the condition •the time to relapse after discontinuation of therapy was longer with budesonide.

The diagnosis and management of rhinitis: An updated practice parameter( Aug 2008)  Use of certain JACI agents—that is. B However. intranasal corticosteroids— on an as-needed basis    Intranasal corticosteroids may provide significant relief of symptoms of seasonal allergic rhinitis when used not only on a regular basis but also on an as-needed basis. D Consideration of using a Rhinitis Action Plan .as-needed use may not be as effective as continuous use of intranasal corticosteroids.

JACI SUPLEMENT AUGUST 2008 .

.

Propuestas     Estudio de vida real sobre la actividad de la rinitis persistente e impacto del tratamiento en LA Comparación del tratamiento permanente vs a demanda en rinitis persistente Población a definir: Endpoints: TNSS. QOL.Congestion Screener.asma.AOS .olfato.sinusitis . costos .etc) productividad . Complicaciones y comorbilidades( OME. etc? .