ricardo del olmo becario hospital clínic i provincial barcelona – españa hospital maría ferrer...
TRANSCRIPT
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Ricardo del Olmo
Becario Hospital Clínic i ProvincialBarcelona – España
Hospital María FerrerFundación CIDEA
Buenos Aires - Argentina
Asma Severo, Asma No Controlado, Asma de Difícil Control
¿Son lo mismo o diferentes?
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• Asma Severa: Definiciones, Pasado y Presente
– Definiciones previas (ATS y ERS): Altas dosis de tratamiento según consideración de guías internacionales
– Definición 2013 ATS-ERS: • Altas dosis de CI+LABA y/o corticoides sistémicos.
• Y simplifica criterios menores: Altas dosis de tratamiento para lograr el control, o control nunca alcanzado a pesar del tratamiento a dosis plenas
1° Paso Confirmación del diagnóstico2° Paso Asma Severa vs Leve-Moderada3° Paso Establecer si hay o no control
• Sin definiciones respecto a heterogeneidad, biomarcadores o patobiología
Asma Severo, Asma No Controlado, Asma de Difícil Control
¿Son lo mismo o diferentes?
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• Asma Severa: Difícil Control– Altas dosis de Corticoides Inhalados
(Fluticasona ± 1000 mcg o equivalente) – + 2° medicación de control (LABA)
(o uso de Corticoides Sistémicos) para lograrlo– o persistencia de “descontrol” a pesar de este tratamiento
• Pacientes bajo control pero que empeoran al reducir las dosis de medicación, también forman parte del grupo
Asma Severo, Asma No Controlado, Asma de Difícil Control
¿Son lo mismo o diferentes?
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• Control vs No control– Impacto en la calidad de vida: ACQ consistentemente > 1.5 o ACT < 20
durante evaluación de 3 meses– Exacerbaciones frecuentes: 2 o mas en el año previo, con uso de
corticoides sistémicos > 3 días en c/evento– Exacerbaciones graves: 1 hospitalización o Ingreso a UCI o Asistencia
Respiratoria en el último año– Deterioro funcional: VEF1 < 80% (con ↓VEF1/CVF) al disminuir
medicación
UNO de ellos significa Pérdida del Control
Asma Severo, Asma No Controlado, Asma de Difícil Control
¿Son lo mismo o diferentes?
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Asma sin Tratamiento de Control Adecuadovs
Asma de Difícil Controlen Hospital María Ferrer
• 147 pacientes, 164 internaciones consecutivas• 37 pacientes (25%) en grupo 1 (TRSA) (84% mujeres). • 110 pacientes (75%) grupo 2 (DTTSA) y ninguno grupo 3. • Diferencias estadísticamente significativas en
“Grupo 1 Refractaria” vs “Grupo 2 Acceso Inadecuado”– Edad (51.3±14.9 vs. 39.8±13,5 ys., P<0.0001), – Mas de 1 internación previa (54% vs 28%, P<0.05), – Tabaquismo activo (5.4% vs 20% P< 0.0001), – Sinusitis (40.5% vs 19.6% P<0.05), – Antecedentes de enfermedad psiquiátrica (40.5% vs 22%, P<0.05) and – Prevalencia de síntomas de RGE (63.9% vs 46% P<0.05). – Mujeres de grupo 1 (TRSA) con mayor edad (P<0.05) y IMC (P<0.05) que grupo 2 (DTTSA).
– Sin diferencias en nivel educativo, edad de inicio del asma, Rinitis Alérgica, , nivel de ac. Láctico o FeNO.
ERSCongress Barcelona 2013
Sin diferencias en VEF1 (%) al ingreso
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43,9% usan 400 dosis al mes
(13 disparos al día)
Uso de Salbutamol como Rescate
Menos de 15 días
15-30 días
1-2 meses
Más de 2 meses Sin datos
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Nunca
Control del Asma Visitas a guardia en el último año
1 vez
2 veces
Mas de 2 veces
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Resultados de Inflamación vs Celularidad Análisis de 65 pacientes
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IL8 Eosinofilicos Neutrofilicos Paucigranulociticos
Mean 481,6 931 121,1
Std. Error 85,24 128,1 38,74
0
250
500
750
1000
1250Eosinófilos (n=36)Neutrófilos (n=4)Paucigran.(n=10)
***
IL8
(pg
/mL
)
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Pacientes Eosinofílicos (n = 37, 5 ADC : 14 %)
Pacientes Neutrofílicos (n = 4, 3 ADC: 75 %)
Pacientes Paucigranulocíticos (n = 15, 1 ADC: 6.5%)
EOS NEUTROSNumber of values 36 36
Minimum 3 2Median 10 13
Maximum 29 36Mean 11,04 14,97
Std. Error 1,09 1,783
EOS NEUTROSNumber of values 5 5
Minimum 0 53Median 0 57,5
Maximum 0,97 92Mean 0,2425 65
Std. Error 0,2425 9,12
EOS NEUTROSNumber of values 10 10
Minimum 0 0Median 0 14
Maximum 1,96 33Mean 0,331 14,7
Std. Error 0,2253 3,6
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Pero entonces…¿Los pacientes con asma grave son o no diferentes?
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Las pruebas funcionales “inestables”…
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Las pruebas funcionales “inestables”… (19 pacientes con BC durante la espirometría)
• 13 pacientes (68%) sufrieron episodios de asma casi fatal
• 9 pacientes (47%) tenían VEF1 > 65% del predicho en la visita inicial
• 6 pacientes (32%) tuvieron una caída de su VEF1 >50%.
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¿Los pacientes con asma grave son o no diferentes?
• La gravedad es una situación que puede ser inherente a la enfermedad en sí, pero también un hecho puntual en la historia de un paciente en particular
• Un evento de riesgo vital se puede presentar inesperadamente en un paciente que por otros aspectos puede estar en control y poco/nada sintomático (inesperado)
• Existen enfermos con propensión a eventos críticos con riesgo vital a pesar del adecuado acceso al tratamiento (Fatality prone)
• El control o falta del mismo es una situación de necesaria evaluación retrospectiva o prospectiva, pero que implica concepto de tiempo e intensidad de la medicación de control usada
• El concepto de Difícil Control implica adecuada indicación de dosis máximas de los mejores controladores, tiempo suficiente de uso, adherencia total, y a pesar de ello no poder cumplir con las expectativas ideales del paciente y médico
• La mayoría de los pacientes pueden lograr un control adecuado si usan bien medicación controladora (esteroides inhalados)
• El uso del esputo inducido (eosinofilia), FeNO, Periostina, dosaje de IgE o eosinofilia en sangre periférica puede marcar perfil TH2 elevado. La ausencia de los mismos perfil TH2 bajo Entonces si… Son
diferentes
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En el árbol de decisión hay que buscarOpciones terapéuticas diferentes
Lo que puedo usar y lo que viene…
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Omalizumab: Anticuerpo monoclonal humanizado contra IgE
• 10 años desde su registro• Evaluación de seguridad: >9500 pacientes
en programas clínicos• > 400.000 pte/Tto/año post-market
• Omalizumab reduce el nivel de múltiples marcadores inflamatorios1–6
• Omalizumab reduce la respuesta temprana y tardía luego de exposición al antígeno 7,8
Eosinofilia periférica, en esputo y en submucosa
bronquial1
IL-2, IL-4,IL-5, IL-13
y GM-CSF1–4
T-lymphocytesy
B-lymphocytes5FeNO6
1. Noga O, et al. J Allergy Clin Immunol 2006;117:1493–9; 2. Holgate S, et al. Allergy 2009;64:1728‒36; 3. Simon HU, et al. Eur J Immunol 2003;33:834–9; 4. Corren J. Discov Med 2012;13:305‒12; 5. Djukanović R, et al. Am J Respir Crit Care Med 2004;170:583–93; 6. Hanania HA, et al. Am J Respir Crit Care Med 2013;Mar 7 [Epub ahead of print]; 7. Fahy J, et al. Am J Respir Crit Care Med 1997;155:1828‒34; 8. van Rensen ELJ, et al. Allergy 2009;64:72–80.
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Rabe KF, et al. Allergy 2011;66:1142–51;Galli SJ, Tsai M. Nat Med 2012;18:693–704.
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ERJ Express. Published on March 21, 2013 as doi: 10.1183/09031936.00149812
Add-on omalizumab in children with severe allergic asthma: a one year real life survey
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183 embarazadas enroladas29/9/2006 – 1/10/2012
161 embarazos de evolución conocida
12 en curso10 discontinuados
148 nacidos vivos de 152
infantes(4 sets de mellizos)
11 abortos espontáneos
1 muerte fetal antes de nacer
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Garcia, et al. Chest 144(2):411-419, 2013
Omalizumab en asma intríseca ?
Change in FEV1 (% pred.)
• FCεRI expression on dendritic cells
• FEV1
• Exacerbations
• Omalizumab • Placebo
16 weeks -1
1
3
5
7
9
Omalizumab Placebo
p=0.029
Exacerbations
• Omalizumab vs. placebo 0.8 vs. 1.4, p=0.278
41 patients with severe non-allergic asthma
55 yrs., IgE 155 IU/ml, FEV1 66%
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The EXCELS study: long-term use of omalizumabMalignancy rates – all malignancies
Omalizumabn=5,007
Non-omalizumabn=2,829
0.0
4.0
8.0
12.0
16.0
20.0
16
19.1
Ma
lign
an
cy r
ate
(a
ny
typ
e)
pe
r 1
,00
0 p
atie
nt-
yea
rs
Ratio of rates 0.84 (95% CI: 0.62, 1.13)
CI = confidence interval
(95% CI: 14.2, 17.9)
(95% CI: 16.5, 22.0)
†
†All non-omalizumab patients prior to any treatment with omalizumab
Difference in rates –3.06 (95% CI: –9.19, 2.03)
Long AA, et al. Am J Respir Crit Care Med 187;2013:A3869
295 events
190 events
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FDA Drug Safety Communication: FDA approves label changes for asthma drug Xolair (omalizumab), including describing slightly higher risk of heart and brain adverse eventsThis update is in follow-up to the Early Communication about an Ongoing Safety Review of Omalizumab (marketed as Xolair) issued on July 16, 2009.[9-26-2014]
Safety AnnouncementA U.S. Food and Drug Administration (FDA) review of safety studies suggests a slightly increased risk of problems involving the heart and blood vessels supplying the brain among patients being treated with the asthma drug Xolair (omalizumab) than in those who were not treated with Xolair. As a result, we have added information about these potential risks to the drug label. Patients taking Xolair should continue to take the medication as prescribed and discuss any questions or concerns with their health care professionals.
FDA approved Xolair in 2003 to treat patients 12 years and older with moderate to severe persistent asthma who have a positive skin or blood test to year-round allergens in the air and whose symptoms are not well-controlled by asthma medicines called inhaled corticosteroids. Xolair has been shown to decrease the number of asthma attacks in these patients.
Our review of a 5-year safety study found a slightly higher rate of heart and brain blood vessel problems occurred in patients being treated with Xolair compared to those patients not treated with Xolair. The heart and brain blood vessel problems included mini-strokes known as transient ischemic attacks or TIAs; heart attacks; sudden, unexpected chest pain; high blood pressure in the arteries of the lungs called pulmonary hypertension; and blood clots in the lungs and veins. Although the data are suggestive of a serious safety signal, due to weaknesses in how the safety study was designed and carried out, we are unable to definitively confirm or determine the exact increased level of these risks with Xolair.
Some previous clinical trials have shown slightly higher rates of various cancers in patients treated with Xolair compared with non-Xolair-treated patients. Our review of the 5-year safety study found no difference in the rates of cancer between those patients being treated with Xolair and those who were not being treated with Xolair. However, due to limitations in the 5-year study, we cannot rule out a potential risk of cancer with Xolair, so we have added this information to the Warnings and Precautions section of the drug label.
Our review of a 5-year safety study found a slightly higher rate of heart and brain blood vessel problems occurred in patients being treated with Xolair compared to those patients not treated with Xolair. The heart and brain blood vessel problems included mini-strokes known as transient ischemic attacks or TIAs; heart attacks; sudden, unexpected chest pain; high blood pressure in the arteries of the lungs called pulmonary hypertension; and blood clots in the lungs and veins. Although the data are suggestive of a serious safety signal, due to weaknesses in how the safety study was designed and carried out, we are unable to definitively confirm or determine the exact increased level of these risks with Xolair.
Some previous clinical trials have shown slightly higher rates of various cancers in patients treated with Xolair compared with non-Xolair-treated patients. Our review of the 5-year safety study found no difference in the rates of cancer between those patients being treated with Xolair and those who were not being treated with Xolair. However, due to limitations in the 5-year study, we cannot rule out a potential risk of cancer with Xolair, so we have added this information to the Warnings and Precautions section of the drug label.
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• Anti - IgE Omalizumab QGE031 Anticuerpo Anti-receptor-IgE
(anti-M1 prime)
Anti – IL-4
IL-4
Otros biológicos en Asma
• Anti - IL-5 Mepolizumab Reslizumab Benralizumab
(Anticuerpo Anti-receptor-IL-5)
• Anti - IL-13 Lebrikizumab Tralokinumab
• Anti - IL-4 Dupilumab
(Anticuerpo Anti-receptor-IL-4)
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QGE-031: Propiedades químicas y datos preclínicosEl próximo anti-IgE
• Licenciado por Tanox* in 2006• Propiedades Químicas
– Ac Monoclonal Humanizado IgG1k de alta afinidad IgE (Kd=130pM, omalizumab Kd=6.8nM)
– Diseñado para evitar anafilaxia– Formulación líquida con buena estabilidad (12 meses)
• Datos Pre-Clínicos– 54 veces mayor afinidad que Omalizumab a IgE– Bloqueo de la degranulación de basófilos y mastocitos mediada por IgE
(~50 veces superior a Omalizumab)– QGE031 no causa toxicidad en simios a dosis SC 150mg/kg– 773 pacientes en estudios Fase I-II
Mayor eficacia terapéutica?
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Pelaia, et al. Nat Rev Drug Discov 2012
Dupilumab
Otros biológicos en asma
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Dupilumab en asma eosinofílica
• Dupilumab(anti-IL-4 receptor)300 mg s.c./week
• Placebo
Wenzel, et al. N Engl J Med368(26):2455-2466, 2013
12 weeks
Exacerbaciones (% pacientes)Asthma patientson ICS + LABA
≥ 300 eos./µL bloodor ≥3% sputum eos.
- 87%p<0.001
[%]
Exacerbaciones
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Dupilumab en asma eosinofílica
Tiempo a la 1° exacerbación
Wenzel, et al. N Engl J Med368(26):2455-2466, 2013
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Basal
1° mes
2° mes
3° mes
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ESPUTO INDUCIDO
Esputo Inducido
Abrazando el futuro
Muchas Gracias
Augusto