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

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

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

18. Neumonitis lupica aguda

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.

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

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

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

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

44. ETANERCEPT SINDROME ANTIFOSFOLIPIDICO OBSTETRICO GOTA

45. SÍNDROME ANTIFOSFOLIPÍDICO Y EMBARAZO Pérdidas fetales Prematuridad Retraso del crecimiento intrauterino Pre-eclampsia

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.

56. D.A. Clark / Journal of Reproductive Immunology 85 (2010) 15–24

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

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 yearsMaximum 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

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

69. Educacionen ARTRITIS PREMIO ILAR 2011 www.educ-ar.com/

70. REAL Red Excelencia Artritis Latinoamerica