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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

Inflamacion

Celsus: The four cardinal symptoms of inflammation


Cellular communication is mediated through cytokines

receptor

C

signal

C

endocrine response

para- or autocrine response


Cytokines can activate their target cells differently target cell C

production of mediators

C

proliferation / cell division

C

differentiation / maturation

ZC

migration (mediators: chemokines)


Cytokines can activate their target cells differently target cell C

C

Z

but most often cytokines exert an anti-apoptic action

apoptosis


The correct response of the target cell to cytokines is crucial magnitude of respone

too strong too long normal response

too short too weak signal

C

C

C

C

C C

excessive production C of mediators C

duration of response

new signal

C

C

target cell

C

C

too many receptors

overshooting response of the target cell

C C

C C

inefficient shut-down of the signal cascade

mediator-independent activation (mutations)

ďƒ  possible disease development


Evolution of Biotechnology DNA double helix structure revealed

Recombinant human insulin approved Biologicals approved for clinical use DNA cloned

Monoclonal antibodies produced First human protein synthesized (growth hormone)

Genetic code elucidated

1953

1961-1965

(1962)–Medicine Watson, Crick, Wilkins

1973

(1968)–Medicine Holley, Khorana, Nirenberg

1975

(1980)–Chemistry Berg, Gilbert, Sanger

1977

(1984)–Medicine Jerne, Köhler, Milstein

Polymerase chain reactions First therapeutic MAb approved (muromonab)

1982

1983

1986

(1993)–Chemistry Mullis

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

Human genome mapped

2000+

Nobel Prizes (Year Awarded)


• • • •

INFLIXIMAB RITUXIMAB ETANERCEPT ADALIMUMAB


TNFα Plays a Central Role in I.M.I.D.s Crohn’s Disease Rheumatoid Arthritis

Ankylosing Spondylitis

Psoriasis

TNFα

Uveitis

Psoriatic Arthritis


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


I.M.I.D.s: Patogenesis. CD3

IL-5 IL-13

IL-4 TNFα

TH2

TP

CD3

Neutrophil

TREG

Ig

TC MCP-1

IL-6 IL-23 IL-12

Sensitization

Asthma Allergy

B Mast/Basophil Macrophage

CD3

APC

Neutrophil

IgE

IL-8

TNFα IL-18 IL-1

Eosinophil

CD3

B Monocyte

IL-21

TH1

Pathogenic T Cell Development Imbalance

Neutrophil Local Tissue Inflammation

RA Type I DM UC Crohn’s MS Psoriasis COPD Uveitis Sarcoidosis Osteoarthritis Graft Rejection Tissue damage Fibrosis


Agentes anti-TNFÎą Infliximab

Etanercept

Adalimumab

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.


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


Infliximab en LUPUS

Terapia de inducciòn a corto plazo


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 citokinas pro-inflamatorias • Presentación de Antigeno • Activación Cel. T • Producción de Auto-anticuerpos y su perpetuación

IL-6

TNFα

IL-10

Edwards 1999, Gause 2001, Zhang 1986, Takemura 2001, Dörner 2003, Shaw 2003

cell T

Cell Plasmática

R F

R FR F

R F

R F

Fija complemento

IL-1

• Señal Intracelular

Dendritic cell

TNF-α

Macrofago

IL-6

Cell B

Cell B

Cell B

TNF-α

IL-10

Daño inflamatorio

Pérdida de cartilago

Sinovia inflamada


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 Inducci贸n de remisi贸n en pacientes con LES, bajo el tratamiento de Rituximab en dosis 500x2.


ENSAYO PILOTO CON DOS PAUTAS TERAPEUTICAS Parametros

RTX1000

RTX500

p

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

Edad (SD)

Все пациенты получали унифицированную терапию БПВП:

Глюкокортикостероиды + Микофенолата мофетил + Гидроксихлорохин


RTX 1000X2 VS RTX 500 X 2 14

14

12,7

12

12 10

8,3

8 5,4

6

Баллы

10

Баллы

13,1

8 6

4

4

2

2

0

0

Исходно

3 мес

6 мес

Режим дозирования 1000*2

RTX1000

8,9

4,5

Исходно

3 мес

6 мес

Режим дозирования 500*2

RTX500


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 placentario 14-08-08 Hematoma retrocorial de 22 x 6 mm agudo


28-08-2008 Hematoma retrocorial con disminuci贸n de tama帽o a 17 mm.


17-10-2008 Reabsorci贸n de hematoma, con placenta de caracter铆sticas normales.


11 02 2009 Embarazo de 36 semanas de gestaci贸n promedio, crecimiento normal.


D.A. Clark / Journal of Reproductive Immunology 85 (2010) 15â&#x20AC;&#x201C;24


ADALIMUMAB

• EN ARTRITIS TEMPRANA 40 MG AL MES


Do Conventional Methods Give Us What We Need? Baseline

-Gd

+Gd

-Gd

+Gd

-Gd

+Gd

STIR

X-ray at month 9

9 months later

-Gd

+Gd

STIR

Ă&#x2DC;stergaard, et al. Ann Rheum Dis 2005; 64: 1503-1506


Maximum joints affected %

Joint Erosions Occur Early in RA 30

Up to 93% of patients with RA of <2 years may have radiographic abnormalities

20

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

10

MTP All Hand

0 0

1

2

3

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


TIGHT CONTROL


Toda verdad pasa por tres fases: - Primera, es ridiculizada. - Segunda, es combatida violentamente. - Tercera, es aceptada como evidente por sĂ­ misma Arthur Schopenhauer


Educacion en ARTRITIS

PREMIO ILAR 2011 www.educ-ar.com/


REAL • • • •

Red Excelencia Artritis Latinoamerica



Posibles indicaciones y estrategias para el manejo "off label" de los biologico Dr. Claudio Galarza