Uso de la terapia biológica en indicaciones no “aprobadas”<br />Claudio Galarza Maldonado MD PhD<br />UNERA<br />Cuenca, E...
Insidious Consequences of“evidence-based medicine” based only on randomized clinical trials <br />Implicit goal to rely on...
Acute exsudative inflammatory reaction<br />I n f l a m a c i o n<br />Celsus: The four cardinal symptoms of inflammation<...
endocrine response<br />para- or autocrine response<br />Cellular communication is mediated through cytokines<br />recepto...
C<br />Cytokines can activate their target cells differently<br />target cell<br />production of mediators<br />C<br />pro...
Cytokines can activate their target cells differently<br />target cell<br />but most often cytokines exert <br />an anti-a...
The correct response of the target cell to cytokines  is crucial<br />magnitude <br />of respone<br />too strong<br />too ...
Evolution of Biotechnology<br />Monoclonalantibodiesproduced<br />Recombinanthuman insulin approved<br />DNA double helix ...
INFLIXIMAB<br />RITUXIMAB<br />ETANERCEPT<br />ADALIMUMAB<br />
TNF Plays a Central Role in I.M.I.D.s<br />Crohn’s Disease<br />Rheumatoid Arthritis<br />Ankylosing <br />Spondylitis<br...
I.M.I.D.s: Cytokines and Disease Phenotype<br />
Asthma<br />Allergy<br />CD3<br />Neutrophil<br />IL-13<br />IL-5<br />IL-4<br />IgE<br />TNFa<br />IL-8<br />TH2<br />Mas...
Agentes anti-TNFα<br />Infliximab <br />Adalimumab<br />Etanercept <br />Murine (mouse) Fab <br />TNF binding region<br />...
INFLIXIMAB<br />LUPUS<br />SINDROME ANTIFOSFOLIPIDICO<br />VASCULITIS<br />
Autoimmun REV2011 May 18. <br />Therapeutic blockade of TNF in patients with SLE-Promising or crazy?<br />Aringer M, Smole...
Neumonitis lupica aguda<br />
Terapia de inducciòn a cortoplazo<br />Infliximab en LUPUS<br />
RITUXIMAB<br />EN DOSIS MENORES A LAS APROBADAS EN ARTRITIS REUMATOIDE.<br />EN LUPUS, DOSIS DE 500X2.<br />
Alcanzar la remisión y si esto no es posible,<br />lograr la mínima actividad de la enfermedad.<br />Evitar la perdida de ...
RolPotencial de lasCélula B en la Immunopatogénesis de la AR<br />Secreción de citokinaspro-inflamatorias<br />Presentació...
Some Pragmatic Limitations of Randomized Controlled Clinical Trials in Chronic DiseasesJ ClinEpidemiol  41:1037,1988; Arth...
HIPOTESIS<br />Inducción de remisión en pacientes con LES, bajo el tratamiento de Rituximab en dosis 500x2.<br />
ENSAYO PILOTO CON DOS PAUTAS TERAPEUTICAS<br />Все пациенты получали унифицированную терапию БПВП: <br />Глюкокортикостеро...
RTX 1000X2 VS RTX 500 X 2<br />RTX1000<br />RTX500<br />
NO MAME GALLO !!!<br />
Mario  Cardiel MD MSc<br />Jefe de la Unidad de Investigación “Dr. Mario Alvizouri<br />Muñoz” del Hospital General “Dr. M...
ETANERCEPT<br />SINDROME ANTIFOSFOLIPIDICO OBSTETRICO<br />GOTA<br />
SÍNDROME ANTIFOSFOLIPÍDICO Y EMBARAZO<br />Pérdidas fetales<br />Prematuridad<br />Retraso del crecimiento intrauterino<br...
Desprendimiento laminar placentario14-08-08 Hematoma retrocorial de 22 x 6 mm agudo<br />
28-08-2008 Hematoma retrocorial con disminución de tamaño a 17 mm.<br />
17-10-2008 Reabsorción de hematoma, con placenta de características normales.<br />
11 02 2009Embarazo de 36 semanas de gestación promedio, crecimiento normal.  <br />
D.A. Clark / Journal of Reproductive Immunology 85 (2010) 15–24<br />
ADALIMUMAB<br />EN ARTRITIS TEMPRANA 40 MG AL MES<br />
Do Conventional Methods Give Us What We Need? <br />X-ray at month 9<br />-Gd<br />+Gd<br />-Gd<br />+Gd<br />STIR<br />Ba...
Joint Erosions Occur Early in RA<br />MTP<br />Hand <br />All<br /><ul><li>Up to 93% of patients withRA of <2 years may ha...
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</li></ul>Max...
TIGHT CONTROL<br />
Toda verdad pasa por tres fases:- Primera,  es ridiculizada.- Segunda, es combatida violentamente. - Tercera, es aceptada ...
Educacionen ARTRITIS<br />PREMIO ILAR 2011<br />www.educ-ar.com/<br />
REAL<br />Red<br />Excelencia<br />Artritis<br />Latinoamerica<br />
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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)
XIII Congreso Colombiano de Reumatologia 2011 Barranquilla

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

  1. 1. Uso de la terapia biológica en indicaciones no “aprobadas”<br />Claudio Galarza Maldonado MD PhD<br />UNERA<br />Cuenca, Ecuador<br />
  2. 2. Insidious Consequences of“evidence-based medicine” based only on randomized clinical trials <br />Implicit goal to rely on data from randomized clinical trials as the primary source for all clinical knowledge<br />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. <br />Virtual abandonment by most clinicians of careful observation of their own clinical experience. <br />Theodore Pincus, M.D.<br />
  3. 3. Acute exsudative inflammatory reaction<br />I n f l a m a c i o n<br />Celsus: The four cardinal symptoms of inflammation<br />
  4. 4.
  5. 5. endocrine response<br />para- or autocrine response<br />Cellular communication is mediated through cytokines<br />receptor<br />C<br />signal<br />C<br />C<br />
  6. 6. C<br />Cytokines can activate their target cells differently<br />target cell<br />production of mediators<br />C<br />proliferation / cell division<br />C<br />differentiation / maturation<br />C<br />migration<br />Z<br />C<br />(mediators: chemokines)<br />
  7. 7. Cytokines can activate their target cells differently<br />target cell<br />but most often cytokines exert <br />an anti-apoptic action<br />C<br />apoptosis<br />C<br />Z<br />
  8. 8. The correct response of the target cell to cytokines is crucial<br />magnitude <br />of respone<br />too strong<br />too long <br />normal response <br />too short<br />too weak<br />duration of response<br />signal <br />new signal <br />C<br />excessive <br /> production<br /> of<br /> mediators<br />C<br />C<br />C<br />C<br />C<br />C<br />C<br />C<br />C<br />C<br />C<br />C<br />C<br />C<br />C<br />target cell<br />mediator-independent<br />activation (mutations)<br />inefficient shut-down<br />of the signal cascade<br />too many<br />receptors<br /> possible disease development<br />overshooting response of the target cell <br />
  9. 9. Evolution of Biotechnology<br />Monoclonalantibodiesproduced<br />Recombinanthuman insulin approved<br />DNA double helix structure<br />revealed<br />Biologicals approved for clinical use<br />DNAcloned<br />Polymerase chain reactions<br />Genetic codeelucidated<br />First therapeutic MAb approved (muromonab)<br />Human genome mapped<br />First human protein synthesized (growth hormone)<br />2000+<br />1953<br />1961-1965<br />1973<br />1975<br />1977<br />1982<br />1986<br />1983<br />(1962)–MedicineWatson, Crick,Wilkins<br />(1968)–MedicineHolley, Khorana,Nirenberg<br />(1980)–ChemistryBerg, Gilbert,Sanger<br />(1984)–MedicineJerne, Köhler,Milstein<br />(1993)–ChemistryMullis<br />Nobel Prizes<br />(Year Awarded)<br />Historical Events in Biotechnology. Available at: www.biotechinstitute.org/what_is/timeline.html. Accessed August 10, 2007.<br />All Nobel Laureates. Available at: www./nobelprize.org. Accessed August 10, 2007<br />
  10. 10. INFLIXIMAB<br />RITUXIMAB<br />ETANERCEPT<br />ADALIMUMAB<br />
  11. 11. TNF Plays a Central Role in I.M.I.D.s<br />Crohn’s Disease<br />Rheumatoid Arthritis<br />Ankylosing <br />Spondylitis<br />Psoriasis<br />TNF<br />Uveitis<br />Psoriatic Arthritis<br />
  12. 12. I.M.I.D.s: Cytokines and Disease Phenotype<br />
  13. 13. Asthma<br />Allergy<br />CD3<br />Neutrophil<br />IL-13<br />IL-5<br />IL-4<br />IgE<br />TNFa<br />IL-8<br />TH2<br />Mast/Basophil<br />B<br />TH1<br />Eosinophil<br />Macrophage<br />CD3<br />APC<br />RA Type I DM<br />UC<br />Crohn’s MS<br />Psoriasis COPD Uveitis<br />Sarcoidosis<br />Osteoarthritis<br />Graft Rejection<br />TP<br />CD3<br />Neutrophil<br />TREG<br />Ig<br />TC<br />TNFa<br />CD3<br />MCP-1<br />IL-18<br />IL-1<br />Monocyte<br />IL-6<br />IL-23<br />IL-21<br />B<br />IL-12<br />Neutrophil<br />Pathogenic T Cell Development<br />Imbalance <br />Local Tissue<br />Inflammation <br />Tissue damage<br />Fibrosis<br />Sensitization <br />I.M.I.D.s: Patogenesis.<br />
  14. 14. Agentes anti-TNFα<br />Infliximab <br />Adalimumab<br />Etanercept <br />Murine (mouse) Fab <br />TNF binding region<br />Extracellular domain of <br />Human p75 TNF receptor<br />Human Fab <br />TNF binding region<br />Human Fc region<br />Human Fc region <br />Human Fc region <br />Mikuls TR, et al. Curr Rheumatol Rep. 2003,5:270.<br />
  15. 15. INFLIXIMAB<br />LUPUS<br />SINDROME ANTIFOSFOLIPIDICO<br />VASCULITIS<br />
  16. 16. Autoimmun REV2011 May 18. <br />Therapeutic blockade of TNF in patients with SLE-Promising or crazy?<br />Aringer M, Smolen JS<br />
  17. 17.
  18. 18. Neumonitis lupica aguda<br />
  19. 19.
  20. 20.
  21. 21.
  22. 22.
  23. 23. Terapia de inducciòn a cortoplazo<br />Infliximab en LUPUS<br />
  24. 24. RITUXIMAB<br />EN DOSIS MENORES A LAS APROBADAS EN ARTRITIS REUMATOIDE.<br />EN LUPUS, DOSIS DE 500X2.<br />
  25. 25.
  26. 26. Alcanzar la remisión y si esto no es posible,<br />lograr la mínima actividad de la enfermedad.<br />Evitar la perdida de la capacidad funcional<br />Controlar la inflamación<br />Evitar la progresión radiológica<br />Mejorar la calidad de vida<br />
  27. 27. RolPotencial de lasCélula B en la Immunopatogénesis de la AR<br />Secreción de citokinaspro-inflamatorias<br />Presentaciónde Antigeno<br />ActivaciónCel. T<br />Producción deAuto-anticuerpos y superpetuación<br />SeñalIntracelular<br />Cell B<br />Cell B<br />Cell B<br />Dendritic cell<br />CellPlasmática<br />cell T <br />IL-6<br />IL-10<br />TNF-<br />RF<br />TNF-<br />RF<br />RF<br />Macrofago<br />RF<br />RF<br />Fija complemento<br />IL-1<br />IL-10<br />TNF-<br />Daño inflamatorio<br />IL-6<br />Sinoviainflamada<br />Pérdida de cartilago<br />Edwards 1999, Gause 2001, Zhang 1986, Takemura 2001, Dörner 2003, Shaw 2003<br />
  28. 28.
  29. 29.
  30. 30. Some Pragmatic Limitations of Randomized Controlled Clinical Trials in Chronic DiseasesJ ClinEpidemiol 41:1037,1988; Arthritis Rheum 48:313, 2003 <br />Statistically significant results not necessarily clinically important, and vice versa<br />Tuulikki Sokka, Theodore Pincus<br />
  31. 31.
  32. 32.
  33. 33.
  34. 34. HIPOTESIS<br />Inducción de remisión en pacientes con LES, bajo el tratamiento de Rituximab en dosis 500x2.<br />
  35. 35. ENSAYO PILOTO CON DOS PAUTAS TERAPEUTICAS<br />Все пациенты получали унифицированную терапию БПВП: <br />Глюкокортикостероиды + Микофенолата мофетил + Гидроксихлорохин<br />
  36. 36. RTX 1000X2 VS RTX 500 X 2<br />RTX1000<br />RTX500<br />
  37. 37.
  38. 38.
  39. 39. NO MAME GALLO !!!<br />
  40. 40. Mario Cardiel MD MSc<br />Jefe de la Unidad de Investigación “Dr. Mario Alvizouri<br />Muñoz” del Hospital General “Dr. Miguel Silva” de la Secretaría de Salud del Estado de Michoacán <br />Julio Molineros, Ph.D.<br />Associate Research Scientist<br />Arthritis & Clinical Immunology Research ProgramOklahoma Medical Research Foundation<br />
  41. 41.
  42. 42.
  43. 43.
  44. 44. ETANERCEPT<br />SINDROME ANTIFOSFOLIPIDICO OBSTETRICO<br />GOTA<br />
  45. 45. SÍNDROME ANTIFOSFOLIPÍDICO Y EMBARAZO<br />Pérdidas fetales<br />Prematuridad<br />Retraso del crecimiento intrauterino<br />Pre-eclampsia<br />
  46. 46.
  47. 47.
  48. 48. Desprendimiento laminar placentario14-08-08 Hematoma retrocorial de 22 x 6 mm agudo<br />
  49. 49. 28-08-2008 Hematoma retrocorial con disminución de tamaño a 17 mm.<br />
  50. 50. 17-10-2008 Reabsorción de hematoma, con placenta de características normales.<br />
  51. 51. 11 02 2009Embarazo de 36 semanas de gestación promedio, crecimiento normal.  <br />
  52. 52.
  53. 53.
  54. 54.
  55. 55.
  56. 56. D.A. Clark / Journal of Reproductive Immunology 85 (2010) 15–24<br />
  57. 57.
  58. 58. ADALIMUMAB<br />EN ARTRITIS TEMPRANA 40 MG AL MES<br />
  59. 59. Do Conventional Methods Give Us What We Need? <br />X-ray at month 9<br />-Gd<br />+Gd<br />-Gd<br />+Gd<br />STIR<br />Baseline<br />-Gd<br />+Gd<br />-Gd<br />+Gd<br />STIR<br />9 months later<br />Østergaard, et al. Ann Rheum Dis 2005; 64: 1503-1506<br />
  60. 60. Joint Erosions Occur Early in RA<br />MTP<br />Hand <br />All<br /><ul><li>Up to 93% of patients withRA of <2 years may have radiographic abnormalities
  61. 61. Erosions can be detected by MRI within 4 months of RA onset
  62. 62. Rate of progression is significantly (p<0.05) more rapid in the first year than in the second and third years</li></ul>Maximum joints affected % <br />Year<br />Fuchs, et al. J Rheumatol 1989;16:585–591<br />McQueen, et al. Ann Rheum Dis 1998;57:350–356<br />van der Heijde, et al. J Rheumatol 1995;22:1792–1796<br />
  63. 63.
  64. 64.
  65. 65.
  66. 66. TIGHT CONTROL<br />
  67. 67. Toda verdad pasa por tres fases:- Primera, es ridiculizada.- Segunda, es combatida violentamente. - Tercera, es aceptada como evidente por sí misma Arthur Schopenhauer <br />
  68. 68.
  69. 69. Educacionen ARTRITIS<br />PREMIO ILAR 2011<br />www.educ-ar.com/<br />
  70. 70. REAL<br />Red<br />Excelencia<br />Artritis<br />Latinoamerica<br />

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