History
It is not known when
rheumatoid arthritis
first developed. There is
controversy as to
whether this disease is
a modern illness (i.e.
16th century onwards)
or whether it predates
this
Auguste Renoir
Christian Barnard
RA
Risk factors:
Genetic factors:
Twin studies show the disease to have a heritability of 60%;
Genes encoding human leukocyte antigen (HLA-DR) molecules have an important
contribution to this genetic risk
Gender:
F/M = 2-3/1
Hormonal and reproductive factors contribute to the female excess and parity,
breast-feeding and exogenous hormones have been implicated in determining
susceptibility
Infectious agents
Smoking
Genetic factors
AUTOANTIBODIES
AUTOANTIBODIES
Unknown Ag
Soluble mediator
production: citokines,
adhesion molecules,
chemokines
LT
CPA
TNF-
TNF-
IL1
IL1
TNF-
IL6
Cell migration/proliferation
Bone/cartilage breakdown
LT
Mf
Mf
LT
Mf
Mf
Fb
Fb
Matur
Osteoclast
PGE2
LT
Mf
Fb Fb
RANK/RANKL/OPG
LT
LT
Bone
Fb
Cartilage
CD11a,b,c
CD54
CD58
CD54
LFA1
CD2
Anergy
APC
MHC AgTCR
CD80,
86
LT
CD28
Costimmulation
Apoptosis
Clonal expansion
cell activation
Synovial tissue
FR
Yu
Endothelial cells
Plasmacell
DC
Mph
MHC II
Fibroblasts
TNF-
IL-1
IL-6
IL-17
B cell
Th cell
PANUS
Cartilage
Osteoclast
Osteoblastes
MMP
Condrocytes
OS
Bone
A disequilibrium between pro- and anti-inflammatory cytokines within the joints of patients with RA
exists. Both types of cytokines are up-regulated, however the balance is in favor of the
proinflammatory cytokines. Some of these cytokines play a prominent role in the pathogenesis of RA.
Proinflammatory cytokines such as TNFa, IL-6 and IL-1 induce inflammatory mediators like
prostaglandins, reactive oxygen species, and nitric oxide. They are also important in the connective
tissue breakdown of cartilage, inhibition of matrix synthesis, and within bone via effects on osteoclasts
and osteoblasts. Anti-inflammatory mediators such as IL-10, IL-1ra (IL-1 receptor antagonist) and sTNFR (soluble TNF receptor) also exist and may play pro- and anti-inflammatory roles.
citokines,
chemokines
Mf
HLA
inflammation
Mf
MA, VEGF
Cel. endot.
procoagulant
TNF-
Acute fase-reactants
angiogenesis
cellular infiltration
cellular
infiltration
CRP
Hepatocit
MMP
Condrocit
Cartilage
destruction
PG, RANKL
Bone destruction
Osteoclast
TNF-
TNF-
Normal synovium
Sin=with, Ovium=eggs
<1/10.000 G
Histopathologic examination of
normal adult synovium usually
reveals a relatively acellular structure
with two distinct layers.
synovial lining or the intima, is in direct
contact with the intra-articular cavity. The
lining is a loosely organized, avascular
layer of cells that is only one or two cells
deep.
Exudative Synovitis
Exudative Synovitis
Proliferative Synovitis
Synovial lining hyperplasia
becomes quite prominent,
sometimes extending to a
depth of more than 10
cells. Although the
increase is due to greater
numbers of both type A
and type B cells, most of
the expansion occurs in
the former. It is not
certain whether this is
caused by in situ
replication or by
migration of new cells
into the lining
PANNUS
Cartilage Destruction
BONE INVOLVEMENT
Bone erosions
Osteopenia
Osteoporosis
RANK/OPG/RANKL
IL-6
T Cell
Osteoclaste
Macrofag
Osteoclaste
OPG
TNF-, IL-1, IL-17
Fibroblaste
RANK Ligand
PGE2
RANK
Osteoblaste
BONE
Mature Osteoclaste
CLINICAL FEATURES
Inflammation
Dolor,
tumor, calor,
functio lesa
Simetric
Chronic
Distructive,
deformity
Extra-articular involvement
organ systems
Subcutaneous Nodules
Subcutaneous nodules occur in 20% of RA
patients with positive tests for RF and rarely in
seronegative patients
Nodules develop most commonly on
pressure areas, including the elbows, finger
joints, ischial and sacral prominences,
Vasculitis
A small-vessel vasculitis is intimately
associated with many of the clinical
manifestations seen in RA
infarcts of the fingertips
sensorimotor neuropathy
vasculitis may extend to involve
mesenteric, coronary and cerebral
arteries
Pulmonary fibrosis
Pulmonary hypertension
The
Iridociclitis
Sjogren Syndrom
Drugs
Mesenteric vasculitis
nodular, deforming RA
LAB TESTS
HEMATOLOGY
IMMUNOLOGY
Anemia
RF (75-80%)
Leucocitosis / leucopenia
ANA (10-15%)
Trombocitosis
Complement
Anti CCP Ab
BIOCHEMISTRY
2 globuline
Fb
CRP
Complement
ESR
Glucose
RF +
SYNOVIAL FLUID
DAS
Joint involvement
Serology
Duration of symptoms
Acute-phase reactants
CRITERIA
SCORE
1 large joint
High-positive RF or high-positive
ACPA (>3xN)
< 6 weeks
6 weeks
Classification of functional
capacity
1.
2.
3.
4.
Totally dependent
number of self-report
questionnaires, such as
the Stanford HAQ,
Functional Disability
Index, Arthritis Impact
Measurement Scales and
modifications thereof,
have been developed for
the evaluation of patients
with RA!
DIFFERENTIAL DIAGNOSIS
SLE
Osteoarthritis
Vasculitis
Gout
DIFFERENTIAL DIAGNOSIS
DM
Psoriatic Arthritis
Scleroderma
MANAGEMENT
TREATMENT PURPOSES
The
Early
NSAIDs
Non-steroidal
anti-inflammatory drugs
CORTICOSTEROIDS IN RA
INDICATIONS
Rheumatoid vasculitis or
CONTRAINDICATIONS
ABSOLUTE
Acute Phychosis
Severe Infections
severe pain)
Vaccinations
Diseminate Micozis
Acute flare
Bridge-therapy
Drug toxicity
Oligo-arthritis
RELATIVE
TBC
Peptic Ulcer
Diabetes
Glaucoma
Throbosis
Heart failure
CORTICOSTEROIDS IN RA
DOSE
INDICATIONS
1-2 mg/kg/day
Rheumatoid vasculitis
Systemic involvement
15-40 mg/day
5-7.5 mg/day
Long therapy+DMARD+/NSAIDs
Pulse-therapy
1 g/day 3 days
250 mg/day 5 days
Severe flares of RA
DMARD
The term DMARD is currently used to denote a
Cells activation
LT
Mf
Cell Migration/proliferation
Mf
LT
Mf
Mf
Fb
Mf
Fb
LT
LT
LT
Cytokines production
TNF-
TNF-
TNF-
CLASICAL DMARDs
-Anti-proliferative:
-MTX, LF, CFX, AZT
-Other DMARDs:
-SSZ, gold, HQ, ciclosporine
IL1
IL1
IL1
Cartilage/bone destruction
Os
RANK/RANKL/OPG
Cartilage
H 2N
CONH
CO2H
CH2
CH2
CH
CO2H
CONH
CO2H
CH2
CH2
CH
CO2H
NH
NH2
H 2N
CONH
CO2H
CH2
CH2
CH
CO2H
NH
HO
H2N
MTX
CH3
FOLIC ACIDE
MTX
LEUCOVORINE
NH
HO
N
CHO
MTX
MTX
MTX
MTX
DH-folat
MTX-poli-glutamat
Homocisteina
DH-folat reductaza
-CH3
Metil TH-folat
TH-folat
Methionina
Purinic Synthesis
Proteic Synthesis
MTX
FR
APC
MHC II
Plasmocit
Proliferation LT,B
IL-2
LTh
Fibroblasts TNF-
PANUS
LB
IL-1
Cartilage
Osteoclastes
Osteoblastes
MMP
Condrocytes
OS
BONE
MTX
LF
inhibits
DHODH
LT
Mf
APC
(DC, Mf)
LF
FR
APC
MHC II
Plasmocit
Proliferation LT,B
IL-2
LTh
Fibroblasts TNF-
PANUS
LB
IL-1
Cartilage
Osteoclasts
Osteoblastes
MMP
Condrocytes
OS
BONE
LF
SSZ
FR
CPA
MHC II
Plasmocit
IL-2
LTh
Fibroblasti
PANUS
TNF-
LB
IL-1
Cartilaj
Osteoclast
Osteoblaste
MMP
Condrocite
OS
Os
SSZ
Gastrointestinal symptoms
Anemia, thrombocytopenia, leucopenia
A proportion of males develop a reversible decline in sperm
count: females who wish to conceive may remain on SSZ.
Gold
FR
CPA
MHC II
Plasmocit
IL-2
LTh
Fibroblasti
PANUS
TNF-
LB
IL-1
Cartilaj
Osteoclast
Osteoblaste
MMP
Condrocite
OS
Os
GOLD
Skin rash
Mouth ulcers
Diarrhea
Nitritoid reaction
Proteinuria
Marrow suppression (leukopenia,
thrombocytopenia)
HQ
FR
CPA
MHC II
Plasmocit
IL-2
LTh
Fibroblasti
PANUS
TNF-
LB
IL-1
Cartilaj
Osteoclast
Osteoblaste
MMP
Condrocite
OS
Os
HQ
Organ
Side effect
Skin
Rash,
depigmentation
Eye
Blurring of vision,
rarely retinopathy
Central nervous
system
Tinnitus, headache
Muscle
Myopathy
Pregnancy
Crosses placenta
and risk of fetal
abnormalities
BIOLOGICAL AGENTS IN RA
CYTOKINES BLOCKADE
Normal
Cytokines Blockade
Proinflammatory
Citokine
MAB
Receptor
Soluble
Receptor
Inflammatory
signal
No signal
anti-inflamm.
Receptors blockade
Anti-receptor
MAB
Receptor
Antagonist
No signal
cytokines
Anti-inflamm.
cytokines
No signal
Proinflammatory
signal
Anti-TNF-
MAB
Soluble
Receptor
No signal
sReceptor
MAB
Ac monoclonal
Anti-Cytokine
anti-receptor
Cytokine
MAB
Ac monoclonal
Anti-Receptor
anti-receptor
Receptor antagonist
Cytokine Receptor
Target cell
Inflammatory
signal
BLOCKED
ETANERCEPT
p75 TNF
receptor
uman
S S
SS
Regiunea
constanta
a lantului
greu
S S
Regiunea
balamalei
Regiunea de legare a
complementului
341
S S
446
Fc
ETANERCEPT
Soluble TNF-
TNF-
Membrane TNF-
TNF- Receptor
Target Cell
ETANERCEPT
II Chimeric
I Murine
Uman
(fara proteina de soarece)
10% proteina de soarece
Infliximab
CDP870
Adalimumab
(D2E7)
SS
SS
ADALIMUMAB
TNF-
SS
SS
TNF- solubil
TNF- membranar
SS
SS
Receptor TNF-
INFLIXIMAB
Target Cell
Infliximab
Infliximab is a chimeric
anti-TNF human IgG1k
engrafted to the murine Fv
region of a high-affinity
neutralizing murine antiHuTNF- antibody.
One potential
disadvantage to this
molecule is that the human
body may see the mouse
protein as foreign and
mount an immune
response to it. This is
Human
referred to as being
Mouse
antigenic or
immunogenic.
INFLIXIMAB
Fab
S S
S S
Fc
COO
446
INFLIXIMAB
sTNF-
mTNF-
ADALIMUMAB
Fa
b
S S
S S
235
341
Secventa umana
*van de Putte, et al. Ann Rheum Dis, 2004;63:508-16
COO
446
Regiunea de
legare a
complementului
Fc
FR
APC
MHC II
Plasmocit
IL-2
LTh
Fibroblasti
PANUS
TNF-
IL-1
LB
CD20
Cartilaj
Osteoclast
Osteoblaste
MMP
Condrocite
OS
BONE
RITUXIMAB
CD20
CD20
CD20
CD20
LB
Ag
APC
APC
ABATACEPT
LT
T cell activation
T cell inhibition
LT
CD80/86 CD28
Costimmulation
Is blocked
Tcell activation
IL-6
IL-6
IL-6
sIL-6R
mIL-6R
gp130
Semnal transmembranar
gp130
Semnal de transductie
TOCILIZUMAB
MAB anti IL-6R
IL-6
sIL-6R
mIL-6R
gp130
gp130
NON-PHARMACOLOGICAL
TREATMENT
Surgery
Synovectomy
Surgery
Total
joint prothesys
Thank you!