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Posibles indicaciones y estrategias para el manejo "off label" de los biologicos
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Posibles indicaciones y estrategias para el manejo "off label" de los biologicos

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Por: Dr. Claudio Galarza (ECU) …

Por: Dr. Claudio Galarza (ECU)
XIII Congreso Colombiano de Reumatologia 2011 Barranquilla

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  • 1. Uso de la terapia biológica en indicaciones no “aprobadas”
    Claudio Galarza Maldonado MD PhD
    UNERA
    Cuenca, Ecuador
  • 2. 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.
  • 3. Acute exsudative inflammatory reaction
    I n f l a m a c i o n
    Celsus: The four cardinal symptoms of inflammation
  • 4.
  • 5. endocrine response
    para- or autocrine response
    Cellular communication is mediated through cytokines
    receptor
    C
    signal
    C
    C
  • 6. C
    Cytokines can activate their target cells differently
    target cell
    production of mediators
    C
    proliferation / cell division
    C
    differentiation / maturation
    C
    migration
    Z
    C
    (mediators: chemokines)
  • 7. Cytokines can activate their target cells differently
    target cell
    but most often cytokines exert
    an anti-apoptic action
    C
    apoptosis
    C
    Z
  • 8. The correct response of the target cell to cytokines is crucial
    magnitude
    of respone
    too strong
    too long
    normal response
    too short
    too weak
    duration of response
    signal
    new signal
    C
    excessive
    production
    of
    mediators
    C
    C
    C
    C
    C
    C
    C
    C
    C
    C
    C
    C
    C
    C
    C
    target cell
    mediator-independent
    activation (mutations)
    inefficient shut-down
    of the signal cascade
    too many
    receptors
     possible disease development
    overshooting response of the target cell
  • 9. Evolution of Biotechnology
    Monoclonalantibodiesproduced
    Recombinanthuman insulin approved
    DNA double helix structure
    revealed
    Biologicals approved for clinical use
    DNAcloned
    Polymerase chain reactions
    Genetic codeelucidated
    First therapeutic MAb approved (muromonab)
    Human genome mapped
    First human protein synthesized (growth hormone)
    2000+
    1953
    1961-1965
    1973
    1975
    1977
    1982
    1986
    1983
    (1962)–MedicineWatson, Crick,Wilkins
    (1968)–MedicineHolley, Khorana,Nirenberg
    (1980)–ChemistryBerg, Gilbert,Sanger
    (1984)–MedicineJerne, Köhler,Milstein
    (1993)–ChemistryMullis
    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
  • 10. INFLIXIMAB
    RITUXIMAB
    ETANERCEPT
    ADALIMUMAB
  • 11. TNF Plays a Central Role in I.M.I.D.s
    Crohn’s Disease
    Rheumatoid Arthritis
    Ankylosing
    Spondylitis
    Psoriasis
    TNF
    Uveitis
    Psoriatic Arthritis
  • 12. I.M.I.D.s: Cytokines and Disease Phenotype
  • 13. Asthma
    Allergy
    CD3
    Neutrophil
    IL-13
    IL-5
    IL-4
    IgE
    TNFa
    IL-8
    TH2
    Mast/Basophil
    B
    TH1
    Eosinophil
    Macrophage
    CD3
    APC
    RA Type I DM
    UC
    Crohn’s MS
    Psoriasis COPD Uveitis
    Sarcoidosis
    Osteoarthritis
    Graft Rejection
    TP
    CD3
    Neutrophil
    TREG
    Ig
    TC
    TNFa
    CD3
    MCP-1
    IL-18
    IL-1
    Monocyte
    IL-6
    IL-23
    IL-21
    B
    IL-12
    Neutrophil
    Pathogenic T Cell Development
    Imbalance
    Local Tissue
    Inflammation
    Tissue damage
    Fibrosis
    Sensitization
    I.M.I.D.s: Patogenesis.
  • 14. Agentes anti-TNFα
    Infliximab
    Adalimumab
    Etanercept
    Murine (mouse) Fab
    TNF binding region
    Extracellular domain of
    Human p75 TNF receptor
    Human Fab
    TNF binding region
    Human Fc region
    Human Fc region
    Human Fc region
    Mikuls TR, et al. Curr Rheumatol Rep. 2003,5:270.
  • 15. INFLIXIMAB
    LUPUS
    SINDROME ANTIFOSFOLIPIDICO
    VASCULITIS
  • 16. Autoimmun REV2011 May 18.
    Therapeutic blockade of TNF in patients with SLE-Promising or crazy?
    Aringer M, Smolen JS
  • 17.
  • 18. Neumonitis lupica aguda
  • 19.
  • 20.
  • 21.
  • 22.
  • 23. Terapia de inducciòn a cortoplazo
    Infliximab en LUPUS
  • 24. RITUXIMAB
    EN DOSIS MENORES A LAS APROBADAS EN ARTRITIS REUMATOIDE.
    EN LUPUS, DOSIS DE 500X2.
  • 25.
  • 26. Alcanzar la remisión y si esto no es posible,
    lograr la mínima actividad de la enfermedad.
    Evitar la perdida de la capacidad funcional
    Controlar la inflamación
    Evitar la progresión radiológica
    Mejorar la calidad de vida
  • 27. RolPotencial de lasCélula B en la Immunopatogénesis de la AR
    Secreción de citokinaspro-inflamatorias
    Presentaciónde Antigeno
    ActivaciónCel. T
    Producción deAuto-anticuerpos y superpetuación
    SeñalIntracelular
    Cell B
    Cell B
    Cell B
    Dendritic cell
    CellPlasmática
    cell T
    IL-6
    IL-10
    TNF-
    RF
    TNF-
    RF
    RF
    Macrofago
    RF
    RF
    Fija complemento
    IL-1
    IL-10
    TNF-
    Daño inflamatorio
    IL-6
    Sinoviainflamada
    Pérdida de cartilago
    Edwards 1999, Gause 2001, Zhang 1986, Takemura 2001, Dörner 2003, Shaw 2003
  • 28.
  • 29.
  • 30. Some Pragmatic Limitations of Randomized Controlled Clinical Trials in Chronic DiseasesJ ClinEpidemiol 41:1037,1988; Arthritis Rheum 48:313, 2003
    Statistically significant results not necessarily clinically important, and vice versa
    Tuulikki Sokka, Theodore Pincus
  • 31.
  • 32.
  • 33.
  • 34. HIPOTESIS
    Inducción de remisión en pacientes con LES, bajo el tratamiento de Rituximab en dosis 500x2.
  • 35. ENSAYO PILOTO CON DOS PAUTAS TERAPEUTICAS
    Все пациенты получали унифицированную терапию БПВП:
    Глюкокортикостероиды + Микофенолата мофетил + Гидроксихлорохин
  • 36. RTX 1000X2 VS RTX 500 X 2
    RTX1000
    RTX500
  • 37.
  • 38.
  • 39. NO MAME GALLO !!!
  • 40. 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
    Julio Molineros, Ph.D.
    Associate Research Scientist
    Arthritis & Clinical Immunology Research ProgramOklahoma Medical Research Foundation
  • 41.
  • 42.
  • 43.
  • 44. ETANERCEPT
    SINDROME ANTIFOSFOLIPIDICO OBSTETRICO
    GOTA
  • 45. SÍNDROME ANTIFOSFOLIPÍDICO Y EMBARAZO
    Pérdidas fetales
    Prematuridad
    Retraso del crecimiento intrauterino
    Pre-eclampsia
  • 46.
  • 47.
  • 48. Desprendimiento laminar placentario14-08-08 Hematoma retrocorial de 22 x 6 mm agudo
  • 49. 28-08-2008 Hematoma retrocorial con disminución de tamaño a 17 mm.
  • 50. 17-10-2008 Reabsorción de hematoma, con placenta de características normales.
  • 51. 11 02 2009Embarazo de 36 semanas de gestación promedio, crecimiento normal.  
  • 52.
  • 53.
  • 54.
  • 55.
  • 56. D.A. Clark / Journal of Reproductive Immunology 85 (2010) 15–24
  • 57.
  • 58. ADALIMUMAB
    EN ARTRITIS TEMPRANA 40 MG AL MES
  • 59. Do Conventional Methods Give Us What We Need?
    X-ray at month 9
    -Gd
    +Gd
    -Gd
    +Gd
    STIR
    Baseline
    -Gd
    +Gd
    -Gd
    +Gd
    STIR
    9 months later
    Østergaard, et al. Ann Rheum Dis 2005; 64: 1503-1506
  • 60. Joint Erosions Occur Early in RA
    MTP
    Hand
    All
    • Up to 93% of patients withRA of <2 years may have radiographic abnormalities
    • 61. Erosions can be detected by MRI within 4 months of RA onset
    • 62. Rate of progression is significantly (p<0.05) more rapid in the first year than in the second and third years
    Maximum joints affected %
    Year
    Fuchs, et al. J Rheumatol 1989;16:585–591
    McQueen, et al. Ann Rheum Dis 1998;57:350–356
    van der Heijde, et al. J Rheumatol 1995;22:1792–1796
  • 63.
  • 64.
  • 65.
  • 66. TIGHT CONTROL
  • 67. Toda verdad pasa por tres fases:- Primera, es ridiculizada.- Segunda, es combatida violentamente. - Tercera, es aceptada como evidente por sí misma Arthur Schopenhauer
  • 68.
  • 69. Educacionen ARTRITIS
    PREMIO ILAR 2011
    www.educ-ar.com/
  • 70. REAL
    Red
    Excelencia
    Artritis
    Latinoamerica