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