Recomendaciones sobrela duracin

optima del tratamiento con

corticoesteroides tpicos intranasales:
Revisin de la evidencia
Presentacin y debate

Jorge F Mspero
Buenos Aires
Argentina

Rinitis Alrgica

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

Hiptesis higinica?
Aumento de la polucin?

Frecuentemente co mrbida

Allergic rhinitis: common, costly, and

neglected
Lancet 2008;371

Costos en salud de la Rinitis Alrgica

U$d 1.000.000.000 en 2005 (Agency for Healthcare

Research Quality, USA, 2005)
1/3 honorarios mdicos (22.000.000 consultas)
Promedio anual de u$d 520/persona

Afectacin personal y social

Gran impacto en la calidad de vida

Efectos en la escolaridad
Ausentismo laboral

1.906 MAP
14.703 pacientes encuestados y 4.335 a-q
Frecuencia de RA en asmticos 55,2%
RA
Intermitente 66,5%
Persistente 33,5%
81,2% tratados
34,1% con AH
14,2% con ICS

Cohorte de 453 individuos con AR (SFARq)

Evalu 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 medicacin que le haban indicado previamente
20 % consulta a un profesional de la salud
59% MAP
26% farmacutico
13% especialista
Seguimiento slo en el 42% de los pacientes, principalmente por
MAP

Prevalencia de los distintos

tipos
rinitis
(RA)
Prevalenciade
global
de la rinitis alrgica
alrgica
persistente

Europa 1

Amrica Latina *2
* Venezuela, Ecuador, Panam, Mxico, Per (n = 455)

29%

33%
67%

71%
Intermitente
Persistente
1 Bauchau y Durham. Eur Respir J. 2004;24:758.
2.Tassinari, AAAAI Annual Meeting, Presented as poster 2007

Presencia de sntomas
durante el ao completo en
pacientes con RAP
El 50% de los pacientes
presentan sntomas al menos
durante 4 meses en el ao
El 20% de los pacientes
presentan sntomas al menos
durante 9 meses en el ao.

Blaiss M. Costs of allergic rhinitis. In: Kaliner MA, ed. Current Review of Rhinitis. Philadelphia:
Current Medicine, 2002

Encuesta

Enfermedades alrgicas crnica ms frecuentes

en su consulta?

RA
AB
DA
U
Otra

35%
24%
17%
9%
15%

60% < 18 aos

RA Sntoma ms difcil de tratar

Congestin
Goteo post nasal

(2007/ 200 MAP y pediatras de Argentina, Brasil, Venezuela y Mxico)

Encuesta

(cont.)

El 74% de los encuestados dijo que 5 de

cada 10 pacientes que diagnostican sufren
sntomas persistentes

El 75% de los encuestados dijo que 5 de

cada 10 pacientes que diagnostican sufren
RA moderada/severa

El 52% utiliza ICS <30 das en promedio en

pacientes con RA moderada severa
(2007/ 200 MAP y pediatras de Argentina, Brasil, Venezuela y Mxico)

En la encuesta a mdicos
de atencin primaria en
Latinoamrica
ms del 75%
de los encuestados

respondieron que en sus consultas:

50% o ms de los pacientes son del tipo
persistente-moderado-severo cuando se
aplican los criterios de clasificacin de ARIA
Pero no usan el tratamiento sugerido por
ARIA ms de 30 das-ao
No hay estudios de largo plazo que evalen
las ventajas del tratamiento continuo vs
intermitente de la rinitis persistente

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- 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

Tratamiento de largo plazo con

esteroides nasales

Quin trata la rinitis?

Manejan el
71% del mercado de
antihistamnicos
82% del mercado de
antihistamnico + desc
38%
33%
29%

Otros
* Fuente INTE2007

Pediatr
as

MAP

El 50% del mercado de

corticoides tpicos

Argentina, Brasil, Venezuela, Mxico

Uso de las guas ARIA

EP3OS

Qu son las guas?

No las conoce
Las conoce

Las aplica
No las aplica 40%

64%
36%
60%

Slo el 22% las conoce y las

aplica

Cmo tratan la rinitis

alrgica?
PERMANENTE O
79% AH
slo o
combinados

A
ICS
14%

DEMANDA?
AH + ICS
7%

21% ICS
slo o
combinados

AH + DC
26%

AH
46%

Existen recursos
suficientes?
En Argentina hay 10.000.000 pacientes con rinitis
Especialistas

3.000
Clnicos y pediatras

Enfermeras

Asistentes en salud

40.500

29.000

60.300

Modificado de PAHO-WHO Argentine Representative 2001

Conclusiones iniciales
1.

Los MAP y pediatras son los que mayor nmero

de pacientes con RA atienden

2.

Estn pobremente entrenados en el diagnstico

y tratamiento de sta enfermedad

3.

Existen varias guas de tratamiento, pero

ninguna que permitan identificar fcil y
rpidamente a los pacientes que se
beneficiaran con una intervencin prolongada o
intermitente.

Cmo evaluar el tratamiento de

la rinitis alrgica persistente a
largo plazo ?
Diferencia con tratamiento intermitente?
Impacto en las Complicaciones ?
Tratamiento
continuo
de la Rinitis
Alrgica

Calidad de vida?
Influencia en Comorbilidades?
Impacto econmico beneficioso ?

Duracin optima del tratamiento con

corticoesteroides tpicos intranasales:
1.

Mantener la terapia an en ausencia de sntomas ?

(atacar la inflamacin mnima persistente)

2.

Buscar el control de los sintomas y luego usar la

menor dosis o uso p.r.n?

3.

Considerar rapidez de accin , costo directo

compliance y aceptacin por el paciente vs evolucin

a largo plazo , complicaciones y costos indirectos

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

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, even when
they are symptom-free:

MPI

MINIMAL PERSISTENT INFLAMMATION-

Ciprandi et al. JACI 1995

HDM (g/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. J Allergy Clin Immunol. 1995;96:971.

Der p I (low)

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. J Allergy Clin Immunol. 2000;105(1 Pt 1):54.

1
4
Weeks

Symptoms

The concept of

Minimal
Persistent
Inflammation
Symptom
threshold

INFLAMMATION
stimulus

Submucosa

*
Pre

Post

*
Pre

Post

Mast cells per field (0.202 mm2)

Eosinophils per field (0.202 mm2)

Epithelium

Epithelium

Submucosa

*
*
Pre

Post

*P<0.001
Minshall et al. Otolaryngol Head Neck Surg. 1998;118:648.

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

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. 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;118:648-654.

Persistent Inflammation in
Allergic Rhinitis: Summary

In patients with seasonal allergic rhinitis,

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 ,if any, the clinical advantages of long
term treatment?

Cuan persistente es la rinitis

persistente?

Calculation of the normal

range of nasal symptom scores.

Why did you take your

medication?,

could answer either:

1. To prevent symptoms;
2. As needed because of present symptoms;
3. Doctors orders;
4. A habit;
5. Other reason.

Conclusions

persistent nasal symptoms over a previously unstudied

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

 Prophylactic

use of
intranasal steroids in
seasonal allergic rhinitis

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 g qd (n=114)

BDP 168 g 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).

P<0.01 vs placebo.

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. J Allergy Clin Immunol. 1996;98:724.

Long-term use of intranasal

steroids in perennial allergic
rhinitis
Long-term use in adults
Long-term use in children

MFNS and Fluticasone Propionate (FP)

for Long-Term Treatment of Patients
With PAR: Study Design

A 3-month, randomised, double-blind, double dummy,

parallel-group study in 474 adolescent and adult
patients (age 12-77) with perennial allergic rhinitis

Treatment for 3 months

MFNS 200 g od (n=166)

Fluticasone propionate (FP) 200 g 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. Ann Allergy Asthma Immunol. 1997;79:370.

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 g od (n=183)
MFNS 200 g od (n=181)

Baseline

1-15

16-30

31-45

46-60

61-75

76-90

Endpoint

Days
*Secondary endpoint; P0.01 vs placebo.
Baseline congestion scores were 2.0 in all 3 groups (rated on a scale from 0 = none to 3 = severe).
Adapted from Mandl et al. Ann Allergy Asthma Immunol. 1997;79:370.

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<0.01 vs placebo.
Mandl et al. Ann Allergy Asthma Immunol. 1997;79:370.

Placebo (n=146)

FUROATO DE MOMETASONA: CAMBIO PORCENTUAL EN LA

CONGESTIN NASAL DE MODERADA A SEVERA EN LA
RINITIS ALRGICA PERENE
Mejora en la Congestin Nasal a las 12 semanas/final

Mejora media % de la congestin

nasal vs placebo en segn los
diarios del paciente

Mometasona 200 g
OD (n=154)

Fluticasona 200 g
OD (n=156)

Placebo (n=148)

-31%

-54%

*
*P=0.01
*P=0.01 vs placebo.

-51%

Puntaje de la congestin basal fue de 2.0 en los 3 grupos (mometasona, Fluticasona y placebo).
Mandl et al. Ann Allergy Asthma Immunol.
Immunol. 1997;79:370.
Data on file, Schering Corporation, Kenilworth, NJ. Protocol No. I94-079.

4 week DBPC treatment -6 month open follow up

Patel P.
Ann Allergy Asthma Immunol. 2008;100. Abstract P249.

MFNS in Children With PAR:

Design:1-Month Double-Blind and 6-Month OpenLabel Study

A multicentre, double-blind, randomised study in 381

children aged 3 to 11 years with at least 1-year history
of symptoms of PAR
Treatment
381

MFNS 100 g/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, TSS, and individual symptoms
Physician- and patient-rated overall condition of PAR
Patel et al. Ann Allergy Asthma Immunol. 2008;100. Abstract P249.

Mean change from baseline

MFNS in Children With PAR:

TNSS Evaluated
by
Baseline scores: 6.8 in both groups
Physicians
Day 8

Day 15

Day 29

-1.6 (-22%)
-2.2 (-32%)

-2.4* (-32%)

-2.5 (-37%)
-2.8 (-39%)

-3.4* (-46%)

*P0.01; P=0.02.
Patel et al. Ann Allergy Asthma Immunol. 2008;100. Abstract P249.

MFNS 100 g od (n=186)

Placebo (n=190)

Mean change from baseline

MFNS in Children With PAR:

TNSS Baseline
Evaluated
by
Patients
scores: 5.9 with MFNS; 6.0 with placebo
Days 1-15

Days 16-29

-1.1 (-18%)
-1.7* (-28%)

-1.8 (-28%)
-2.4* (-38%)

*P0.01.
Patel et al. Ann Allergy Asthma Immunol. 2008;100. Abstract P249.

MFNS 100 g od (n=187)

Placebo (n=189)

Mean change from baseline

MFNS in Children With PAR:

Overall Condition of PAR
Baseline score: 2.1 in both groups
Evaluated by Physicians
Day 8

Day 15

Day 29

-15%
-19%

-20%
-26%

-28%*
-34%

*P0.01; P=0.02.
Patel et al. Ann Allergy Asthma Immunol. 2008;100. Abstract P249.

MFNS 100 g od (n=186)

Placebo (n=190)

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. 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. Ann Allergy Asthma Immunol. 2008;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 g od

Placebo

Patel et al. Ann Allergy Asthma Immunol. 2008;100.

Abstract 249.

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

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, 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. Ann Allergy Asthma Immunol. 1997;79:370.
Patel et al. Ann Allergy Asthma Immunol. 2008;100. Abstract
249.

Intranasal
Steroids
Onset of
Action

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

*P0.028.
Kaiser et al. J Allergy Clin Immunol. 2007;119(Suppl):S232. Abstract 910.

Ciclesonide in PAR: Onset of Action After

the First Dose
Change from baseline in
instantaneous TNSS

Change in Instantaneous TNSS After First Dose

*P=0.03 vs placebo.

Hours

Meltzer et al. Ann Allergy Asthma Immunol. 2007;98:175-181.

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

*
*

*P0.04 vs placebo.
Berkowitz et al. Allergy Asthma Proc. 1999;20:167.
Data on file, Schering Corporation, Kenilworth, NJ. Protocol No. P97-019.

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

*
*

*P0.02 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

Major Symptom Score

MFNS 200 ug
twice daily
provided
significant
benefit
from day one vs.
placebo
(P0.037)

MFNS 200 g x 2 daily (n=234)

Amoxicillin 0.5 g x 3 daily (n=249)

Placebo (n=247)

3
2

*P0.037 vs. placebo

P0.012 vs. amoxicillin 0.5 g TID

* *

11

12

* *

* *

0
0

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 years treatment with
budesonide or cetirizine

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

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, which suggests that
antiinflammatory treatment has a prolonged effect.
Furthermore,periodic treatment with budesonide may
be a promising treatment strategy in perennial rhinitis.
(J Allergy Clin Immunol 2002;109:426-32.)

The diagnosis and management of

rhinitis: An updated practice
parameter(
Aug 2008)
Use of certain JACI
agentsthat
is, 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. B
However,as-needed use may not be as effective
as continuous use of intranasal corticosteroids. D

Consideration of using a Rhinitis Action Plan

JACI SUPLEMENT AUGUST 2008

Propuestas

Estudio de vida real sobre la actividad de la

rinitis persistente e impacto del tratamiento
en LA
Comparacin del tratamiento permanente vs
a demanda en rinitis persistente
Poblacin a definir:
Endpoints: TNSS, QOL,Congestion Screener,
Complicaciones y
comorbilidades( OME,olfato,sinusitis ,AOS
,asma,etc) productividad , costos , etc?