posibles indicaciones y estrategias para el manejo "off label" de los biologicos
TRANSCRIPT
Uso de la terapia biológica en indicaciones no “aprobadas”
Claudio Galarza Maldonado MD PhD
UNERA
Cuenca, Ecuador
Insidious Consequences of “evidence-based medicine” based only on randomized clinical trials
• Implicit goal to rely on data from randomized clinical trials as the primary source for all clinical knowledge
• Rheumatologists are frequent authors of manuscripts and presenters of lectures concerning clinical trials which they did not design or analyze, but rarely present data from their own clinical care.
• Virtual abandonment by most clinicians of careful observation of their own clinical experience.
Theodore Pincus, M.D.
Acute exsudative inflammatory reaction
Celsus: The four cardinal symptoms of inflammation
I n f l a m a c i o n
CC
C
endocrine response
para- or autocrine response
Cellular communication is mediated through cytokines
signal
receptor
CZ
C
Cytokines can activate their target cells differently
C
C
C
production of mediators
proliferation / cell division
differentiation / maturation
migration
target cell
(mediators: chemokines)
Z
Cytokines can activate their target cells differently
C apoptosis
target cell
C but most often cytokines exert an anti-apoptic action
The correct response of the target cell to cytokines is crucial
duration of response
normal response
C
magnitude of respone
signal new signal
too strong
too long
too weak
too short
C
C
C
CC
C
excessive production
ofmediators
target cell
CC C
C
too manyreceptors
C
C C
C
inefficient shut-downof the signal cascade
mediator-independentactivation (mutations)
overshooting response of the target cell possible disease development
C
Evolution of Biotechnology
Recombinant
human insulin approved
1953 1961-1965 1973 1975 1977 1982 1986 2000+1983
Nobel Prizes(Year Awarded)
Historical Events in Biotechnology. Available at: www.biotechinstitute.org/what_is/timeline.html. Accessed August 10, 2007.
All Nobel Laureates. Available at: www./nobelprize.org. Accessed August 10, 2007
Genetic code
elucidated
DNA
cloned
First human protein
synthesized (growth
hormone)
Polymerase
chain
reactions
Human
genome
mapped
DNA double
helix structure
revealed
Monoclonal
antibodies
produced
Biologicals
approved for
clinical use
First therapeutic
MAb approved
(muromonab)
(1962)–MedicineWatson, Crick,Wilkins
(1968)–MedicineHolley, Khorana,Nirenberg
(1980)–ChemistryBerg, Gilbert,Sanger
(1984)–MedicineJerne, Köhler,Milstein
(1993)–ChemistryMullis
• INFLIXIMAB
• RITUXIMAB
• ETANERCEPT
• ADALIMUMAB
TNF Plays a Central Role in I.M.I.D.s
Crohn’s Disease
Rheumatoid ArthritisAnkylosing
Spondylitis
Uveitis Psoriatic Arthritis
Psoriasis
TNF
I.M.I.D.s: Cytokines and Disease Phenotype
Condition Relative Overexpression of
Cytokines
Crohn’s disease TNF, IL-1, IL-2, IL-6, IL-8, IL-12, IFNg
Type 1 diabetes mellitus TNF, IL-1, IL-2, IL-12, IFNg
Multiple sclerosis TNF, IL-6, IL-12
Sarcoidosis TNF, IL-1, IL-6, TGFb
Psoriatic arthritis TNF, IL-1, IL-6, IL-8, IFNg
Psoriasis TNF
Ankylosing spondylitis TNF, IL-10
Rheumatoid arthritis TNF, IL-1, IL-6
Ulcerative colitits TNF, IL-1, IL-5, IL-6, IL-8
TREG
CD3
TP
APC
B
Ig
Neutrophil
Neutrophil
Monocyte
IgE
Eosinophil
Mast/BasophilB
Neutrophil
Macrophage
TH2
CD3IL-5
IL-8
TC
CD3
TH1
CD3MCP-1
Asthma
Allergy
RA Type I DM
UC
Crohn’s MS
Psoriasis COPD Uveitis
Sarcoidosis
Osteoarthritis
Graft Rejection
Sensitization Pathogenic T Cell Development
Imbalance
Local Tissue
Inflammation
Tissue damage
Fibrosis
I.M.I.D.s: Patogenesis.
Murine (mouse) Fab TNF binding region
Human Fc region
Infliximab
Agentes anti-TNFα
Adalimumab
Human Fc region
Human Fab TNF binding region
Etanercept
Human Fc region
Extracellular domain of Human p75 TNF receptor
Mikuls TR, et al. Curr Rheumatol Rep. 2003,5:270.
INFLIXIMAB
• LUPUS
• SINDROME ANTIFOSFOLIPIDICO
• VASCULITIS
Autoimmun REV 2011 May 18.
Therapeutic blockade of TNF in patients with SLE-Promising or crazy?Aringer M, Smolen JS
Neumonitis lupica aguda
Terapia de inducciòn a cortoplazo
Infliximab en LUPUS
RITUXIMAB
• EN DOSIS MENORES A LAS APROBADAS EN ARTRITIS REUMATOIDE.
• EN LUPUS, DOSIS DE 500X2.
Alcanzar la remisión y si esto no es posible,
lograr la mínima actividad de la enfermedad.
A. Evitar la perdida de la capacidad funcional
B. Controlar la inflamación
C. Evitar la progresión radiológica
D. Mejorar la calidad de vida
Rol Potencial de las Célula B en la Immunopatogénesis de la AR
• Secreción de citokinaspro-inflamatorias
• Presentaciónde Antigeno
• Activación Cel. T
• Producción deAuto-anticuerpos y su perpetuación
• Señal IntracelularSinovia
inflamada
Edwards 1999, Gause 2001, Zhang 1986, Takemura 2001, Dörner 2003, Shaw 2003
Pérdida de cartilago
IL-6
Cell B
cell T
Macrofago
Dendritic
cellIL-10TNF-
TNF-IL-10
R
F
Fija complemento
TNF-
Cell B
IL-6
Cell B
Cell
Plasmática
R
F
R
FR
F
R
F
IL-1
Some Pragmatic Limitations of Randomized Controlled Clinical Trials in Chronic Diseases
J Clin Epidemiol 41:1037,1988; Arthritis Rheum 48:313, 2003
• Statistically significant results not necessarily clinically important, and vice versa
Tuulikki Sokka, Theodore Pincus
HIPOTESIS
Inducción de remisión en pacientes con LES, bajo el
tratamiento de Rituximab en dosis 500x2.
ENSAYO PILOTO CON DOS PAUTAS TERAPEUTICAS
Parametros RTX1000 RTX500 p
Edad (SD) 37,8 (10,0) 38,1 (11,7) ns
Tiempo de la enfermedad,
Ме
6,3 6,1 ns
Actividad en MEXSLEDAI, Ме 12,5 13,0 ns
ACTIVIDAD II, n 3 2 ns
ACTIVIDAD III, n 7 8 ns
Dosis GC >20 мг/сут, n 5 6 ns
Dosis<20 мг/сут, n 5 4 ns
Все пациенты получали унифицированную терапию БПВП:
Глюкокортикостероиды + Микофенолата мофетил + Гидроксихлорохин
RTX 1000X2 VS RTX 500 X 2
8,3
5,4
12,7
0
2
4
6
8
10
12
14
Исходно 3 мес 6 мес
Режим дозирования 1000*2
Ба
лл
ы
13,1
8,9
4,5
0
2
4
6
8
10
12
14
Исходно 3 мес 6 мес
Режим дозирования 500*2
Ба
лл
ы
RTX1000 RTX500
0
10
20
30
40
50
60
baseline 3 meses 6 meses 12 meses 18 meses 24 meses
Remisión (0-1)
Muy intensa (14 o más)
Intensa (10-13)
NO MAME GALLO !!!
Julio Molineros, Ph.D.
Associate Research Scientist
Arthritis & Clinical Immunology Research Program
Oklahoma Medical Research Foundation
Mario Cardiel MD MSc
Jefe de la Unidad de Investigación “Dr.
Mario Alvizouri
Muñoz” del Hospital General “Dr. Miguel
Silva” de la Secretaría de Salud del
Estado de Michoacán
ETANERCEPT
• SINDROME ANTIFOSFOLIPIDICO OBSTETRICO
• GOTA
SÍNDROME ANTIFOSFOLIPÍDICO Y EMBARAZO
• Pérdidas fetales
• Prematuridad
• Retraso del crecimiento intrauterino
• Pre-eclampsia
Desprendimiento laminar placentario14-08-08
Hematoma retrocorial de 22 x 6 mm agudo
28-08-2008Hematoma retrocorial con disminución de tamaño a 17 mm.
17-10-2008Reabsorción de hematoma, con placenta de características
normales.
11 02 2009Embarazo de 36 semanas de gestación promedio, crecimiento
normal.
D.A. Clark / Journal of Reproductive Immunology 85 (2010) 15–24
ADALIMUMAB
• EN ARTRITIS TEMPRANA 40 MG AL MES
Baseline
9 months later
Do Conventional Methods Give Us What We Need?
-Gd +Gd -Gd +Gd STIR
-Gd +Gd -Gd +Gd STIR
X-ray at month 9
Østergaard, et al. Ann Rheum Dis 2005; 64: 1503-1506
Joint Erosions Occur Early in RA
0
10
20
30
0 1 2 3
Hand
MTP
All
Year
Ma
xim
um
jo
ints
aff
ec
ted
% • Up to 93% of patients with
RA of <2 years may have
radiographic abnormalities
• Erosions can be detected
by MRI within 4 months of
RA onset
• Rate of progression is
significantly (p<0.05) more
rapid in the first year than in
the second and third years
Fuchs, et al. J Rheumatol 1989;16:585–591McQueen, et al. Ann Rheum Dis 1998;57:350–356van der Heijde, et al. J Rheumatol 1995;22:1792–1796
0
1
2
3
4
5
6
7
8
9
10
DA
S28
PACIENTES
DAS28 en AR temprana. Adalimumab 40 mg/mes
TIGHT CONTROL
Toda verdad pasa por tres fases:- Primera, es ridiculizada.- Segunda, es combatida violentamente. - Tercera, es aceptada como evidente por sí misma
Arthur Schopenhauer
PREMIO ILAR 2011
Educacion en ARTRITIS
www.educ-ar.com/
REAL• Red
• Excelencia
• Artritis
• Latinoamerica