Rheumatoid Arthritis

History
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

Artwork from the Flemish masters and other

European artists suggest the presence of
rheumatoid arthritis in the 16th century

The first detailed description of the

clinical picture of RA may be attributed
to Landr-Beauvais (August 1800); he
called the condition 'goutte asthnique
primitive'. His first patient was
suddenly afflicted by pain in the elbow,
the wrist, the knee and the feet, with
joint swelling and motility range
limitation; Landr-Beauvais also
pointed out the role of cold weather,
humid atmosphere, irregular
menstruations, and that the disease
starts in the fingers or the wrists, and
extends later to the other joints. He
established the picture of rheumatoid
arthritis and distinguished it from gout
and from the other rheumatic
conditions recognized in his time.
1857 Robert Adams - Medical Atlas
1959 Garrod RA

Auguste
Auguste Renoir
Renoir
Christian Barnard

Rheumatoid Arthritis (RA)

Rheumatoid arthritis (RA) is a chronic, systemic inflammatory

disease of unknown cause that may affect many tissues and
organs, but principally attacks synovial joints.
The hallmark feature of this condition is persistent symmetric
polyarthritis that affects many joints. Extra-articular involvement of
organs such as the skin, heart, lungs and eyes can be significant.

RA

RA has an annual incidence of approximately 0.2 per 1000 in males

and 0.4 per 1000 in females

A prevalence of 0.5-1% is reported in diverse populations worldwide

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

Autoimmunity: type II colagen, RF, ACPA

Smoking

Genetic factors

AUTOANTIBODIES

RA is an autoimmune disease but the role of

autoimmune reactions in the pathogenesis of RA is
still not fully understood

Autoantibodies to a variety of antigens commonly

occur in sera of patients with RA. Some of them may
be present already in the earliest disease stages and
even precede disease onset

Rheumatoid factors (RF) = autoantibodies to the Fc

portion of IgG

Although RF are not specific for RA, high titered RF are

associated with more severe RA and may therefore have
some prognostic value

AUTOANTIBODIES

Anti-CCP Ab (ACPA) = Ab to antigens containing the

amino acid citrulline (generated by post-translational
deimination of arginine residues) appear to be highly
specific for RA.

Apart from their diagnostic value, autoantibodies

may contribute to the pathophysiology of RA by
inducing, maintaining or modulating the disease
process. However, for none of the autoantibodies
identified so far a pathogenetic role has been clearly
proven and the primary (disease inducing)
autoimmune targets are presumably still unidentified

Unknown Ag

Genetic predisposition (HLA-DR4 cu shared epitope)

Immune cell activation

LT

CPA

Soluble mediator
production: citokines,
adhesion molecules,
chemokines
TNF-

TNF-

IL1
IL1

TNF-

Cell migration/proliferation

IL6

Bone/cartilage breakdown
LT

Mf
Mf

Mf

LT

Mf

Fb

Fb

Matur
Osteoclast

PGE2

LT

Mf
Fb Fb

RANK/RANKL/OPG

LT
Fb

LT

Bone
Cartilage

CD11a,b,c
CD54
CD58

CD54
LFA1
CD2
Anergy

APC

MHC AgTCR

CD80,
86

LT

CD28

Costimmulation

Apoptosis

Clonal expansion

cell activation

Pathologic and immunogenetic evidence strongly suggests

that a T lymphocyte-mediated immune response drives joint
inflammation in RA
It is unclear whether the critical immune response in RA is
directed against autoantigens or exogenous antigens. Arthritis
can be induced by T cell responses to ubiquitous antigens in
addition to those expressed only in the joint
Synovial T cells are enriched for memory cells and are
maintained in a highly differentiated state, reflecting
recruitment to the joint and factors in the local environment
The RA synovium is dominated by cytokine production, which
could be brought about by a combination of antigen-specific T
cells and cell-cell interactions between synoviocytes and nonspecifically activated T cells.

Synovial tissue

Yu

u
Y

Y FR

MH
M
HC
CI
III

Endothelial cells
Plasmacell

DC
Mph

MHC
MHC IIII

Fibroblasts

TNF-
IL-1
IL-6
IL-17

2
IL-

B cell

Th cell

PANUS
Cartilage
MMP

Osteoclast
Osteoblastes

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
sTNF-R (soluble TNF receptor) also exist and may play pro- and anti-inflammatory roles.

ANT
PROIN

ORY
T
A
M
F LA M

TNF-
IL-1
IL-6

IL-8
IFN-
SF
C
M
G

TORY
A
M
M
I-INFLA

IL-4
IL-10
TGF

R
sTNF
sIL-1R
a
IL-1R

citokines,
chemokines
Mf

HLA

inflammation

Mf

angiogenesis

MA, VEGF
Cel. endot.

procoagulant

cellular infiltration

Proliferation, AM, citokines

Sinoviocit A, B

TNF-

(GM-CSF, IL-6, IL-8)

Acute fase-reactants

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.

subsynovium, also called the

sublining or subintima. Normally,
this region is relatively acellular,
containing scattered blood
vessels, fat cells and fibroblasts

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

 There

are two basic histologic patterns of B

cell infiltration in the rheumatoid synovium:

First, aggregates of lymphocytes that contain up

to several hundred B cells collect in the sublining,
particularly near blood vessels.
A second pattern is a diffuse B cell infiltration
without obvious organization. In this case, the B
cells are usually located immediately below the
lining and extend 1-2 mm into the sublining
tissue.

PANNUS

Synovial cell hyperplasia, infiltration by plasma cells,

lymphocytes, macrophages and mast cells, and the
overgrowth of a fibrovascular granulation tissue =
pannus, which covers and erodes articular cartilage,
leading to irreversible joint destruction. As in the case of
tumors, angiogenesis is an important component of
pannus formation.

Cartilage
Cartilage D
Destruction
estruction

BONE
BONE INVOLVEMENT
INVOLVEMENT

Bone erosions

Osteopenia

Osteoporosis

RANK/OPG/RANKL
IL-6

Macrofag

T Cell

Osteoclaste
Osteoclaste
OPG

TNF-, IL-1, IL-17

Fibroblaste

RANK Ligand

PGE2

RANK

Osteoblaste

BONE

Mature Osteoclaste

CLINICAL FEATURES
Joint

involvement in RA is symmetric, and

whereas wrists, fingers, knees and feet are
the most commonly affected joints in early
disease
Progressive disease is also associated with
larger joints, such as the shoulders, elbows
and knees.
Articular indices weighted for size and
amount of synovium, have been found to
correlate better with the amount of
inflammation than do simple joint counts.

Inflammation
Dolor, tumor, calor,

functio lesa

Simetric

Chronic

Distructive,
deformity

Swelling of the MCP

and PIP joints. Fusiform
swelling of the PIP joints
is typical of RA and
associated with morning
stiffness, difficulty
making a fist, reduced
grip strength and
tenderness of the
affected joint

The space between the odontoid process and the

arch of the atlas normally measures 3 mm. If this
space exceeds 3 mm, the condition is defined as
atlantoaxial subluxation. Cervical subluxation at any
level is common in severe erosive RA and may be
found in 30% of patients in this category.

Baker's popliteal cyst. Posterior view showing

rheumatoid swelling behind the right knee.
Swelling of the lower limb was related to venous
compression by popliteal synovitis

Extra-articular
Extra-articular involvement
involvement
Extra-articular

involvement affects several

organ systems
Systemic

features may be associated with

a poor prognosis, especially vasculitis,

amyloidosis and pulmonary fibrosis.
The

major features reflecting systemic

involvement in rheumatoid arthritis include

fevers, malaise and weight loss.

Subcutaneous
Subcutaneous Nodules
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,
occipital scalp and Achillis tendon.
Rheumatoid nodules are firm and frequently
adherent to the underlying periosteum.
Histologically, there is a focal central fibrinoid
necrosis with surrounding fibroblasts. This is
believed to occur as a result of small vessel
vasculitis with fibrinoid necrosis and
surrounding fibroblastic proliferation
Lung, kidney, heart, eyes

Vasculitis
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 involvement is frequent, although the

clinical features may be subtle. Men are affected
more often than women.

Pleural disease is common and is usually

asymptomatic. Rheumatoid pleural effusions are
exudates with greater cell counts
(lymphocytes>granulocytes), high LDH
concentrations and high protein concentrations (>4
g/l). Glucose concentrations are < 25 mg/dl (1.4
mmol/l). The low glucose in rheumatoid pleural
effusions is a result of impaired transport across
an inflamed pleura. Concentrations of hemolytic
complement are low, RF may be present. Pleurisy
and pleural effusions may be bilateral in 25% of
patients.

Pulmonary fibrosis
Pulmonary hypertension

 The

acute and chronic

inflammatory disease of
RA may lead to cardiac
disease by mechanisms of
vasculitis, nodule
formation, amyloidosis,
serositis, valvulitis and
fibrosis
Abnormalities in the
conduction pathways
have also been described.
Endocardial involvement
may be diffuse, but it is
rarely clinically significant

Nerve compression is a common

cause of neurologic impairment in RA

Central nervous system disease may

manifest as stroke, seizure,
hemorrhage, encephalopathy and
meningitis as a result of cerebral
vasculitis, amyloidosis or rheumatoid
nodules, or both, in the dura and
choroid plexus of the brain. Most
patients have long-standing RA with
other extra-articular disease.

 The

kidneys are usually

spared in RA, although a
low-grade membranous
nephropathy, glomerulitis,
vasculitis and secondary
reactive amyloidosis have
all been described

Iridociclitis

Scleromalacia in a patient with RA.

Sjogren Syndrom

Drugs

Mesenteric vasculitis

Felty's syndrome is defined as RA

in combination with splenomegaly
and leukopenia. The syndrome
characteristically occurs in patients
with long-standing, seropositive,
nodular, deforming RA

LAB TESTS

HEMATOLOGY

IMMUNOLOGY

Anemia

RF (75-80%)

Leucocitosis / leucopenia

ANA (10-15%)

Trombocitosis

Complement

Anti CCP Ab

BIOCHEMISTRY

SYNOVIAL FLUID

2 globuline

Fb

50-60 000 cel/mm3 (75% PMN)

CRP

Complement

ESR

Glucose

RF +

DAS

DAS3v
28 = 0.56t28 + 0.28sw28 + 0.70Ln (ESR)1.08+ 0.16
3v
DAS4v
28 = 0.56 t28 + 0.28 (sw28) + 0.70Ln(ESR) + 0.014 PG
4v

DAS is used for both patient

monitoring and assessment.
Assessment = the capacity to
describe the patient's
condition at a single point in
time.

Van Riel, P. at. al. Ann Rheum Dis, 2000, 59:S28-31

Key radiographic findings in RA

Symmetric polyarticular disease of
synovial joints of the appendicular skeleton
Fusiform soft tissue swelling
Regional or periarticular osteoporosis
Marginal and central osseous erosions
and cysts
Diffuse loss of joint space

Pancompartmental wrist involvement with articular destruction, carpal

fusion and carpal collapse are seen. Note severe destruction of the distal
radius and ulna

EULAR/ACR Classification criteria for RA

DOMAINS

CRITERIA
1 large joint

Joint involvement

Serology

Duration of
symptoms
Acute-phase
reactants

SCOR
E
0

2-10 large joints

1-3 small joints

4-10 small joints

> 10 joints (at least 1 small)

Negative RF and negative ACPA

Low-positive RF or low-positive
ACPA (<3xN)

High-positive RF or high-positive
ACPA (>3xN)

< 6 weeks

6 weeks

Normal CRP and normal ESR

Abnormal CRP or abnormal ESR

6/10 is needed for classification of a patient as having definite RA)

Classification of functional
capacity
1.

Normal function without or

despite symptoms

2.

Some disability, but adequate for

normal activity without special
devices or assistance

3.

Activities restricted, requires

special devices or personal
assistance

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

D
M

Psoriatic Arthritis

Scleroderma

MANAGEMENT

TREATMENT PURPOSES
The

potential for joint damage is present

during the earliest phases of disease

Early

introduction of effective treatment to

maximally inhibit the inflammatory and
destructive mechanisms is recommended

NSAIDs
Non-steroidal

anti-inflammatory drugs

(NSAIDs) and low-dose corticosteroids can

often provide satisfactory rapid relief of pain
and stiffness
Cannot

prevent structural damage!

CORTICOSTEROIDS IN RA
INDICATIONS

Rheumatoid vasculitis or

CONTRAINDICATIONS

ABSOLUTE

other systemic involvements

Acute Phychosis

Severe clinical status (F,

Severe Infections

severe pain)

Vaccinations

Acute flare

Diseminate Micozis

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

Medium or severe disease

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

disease-modifying antirheumatic drug used in

the therapy of inflammatory joint diseases such
as RA, juvenile idiopathic arthritis, psoriatic
arthritis and ankylosing spondylitis. Criteria
used for classifying a drug as a DMARD are:

slow onset of action (usually more than 6 weeks)

an effect on the acute phase response with a fall

in the erythrocyte sedimentation rate and Creactive protein

an improvement in functional status as measured

by the Health Assessment Questionnaire

a slowing down of the rate of radiological

progression of the disease (in RA)

Cells activation
LT

Mf

Cell
Cell Migration/proliferation
Migration/proliferation
Mf

Mf
Mf
Fb
Fb

LT

Mf
Fb
Fb

LT
LT

LT

Cytokines production

TNF-

TNF-

TNF-

IL1
IL1
IL1
IL1
IL1
IL1

Cartilage/bone
Cartilage/bone destruction
destruction

Os
RANK/RANKL/OPG
RANK/RANKL/OPG

CLASICAL
CLASICAL DMARDs
DMARDs
-Anti-proliferative:
Anti-proliferative:
-MTX,
MTX, LF,
LF, CFX,
CFX, AZT
AZT
-Other
Other DMARDs:
DMARDs:
-SSZ,
SSZ, gold,
gold, HQ,
HQ, ciclosporine
ciclosporine
Anticytokines
Anticytokines biological
biological agents:
agents:
-Anti-TNFAnti-TNF-
:
-Infliximab,
Infliximab, Adalimumab,
Adalimumab,
Etanercept,
Etanercept, Golimumab,
Certolizumab
Certolizumab
-Anti-IL1:
Anti-IL1:
-Anakinra
Anakinra
-Anti-IL6:
Anti-IL6:
-Tocilizumab
Tocilizumab
Non-cytokines
Non-cytokines biological
biological agents:
-Anti-LB:
Anti-LB: Rituximab
Rituximab
-Anti-costimmulating
Anti-costimmulating molecules:
molecules:
Abatacept
Abatacept
Cartilage
Cartilage

H2N

CONH

CO2H
CH2
CH2
CH
CO2H

NH
NH22

H2N

CONH

CO2H
CH2
CH2
CH
CO2H

NH
HO

H2N

MTX

CH33

ACIDE

MTX

NH
HO

FOLIC

N
CHO

CONH

CO2H
CH2
CH2
CH
CO2H

LEUCOVORINE

MTX

MTX is ordinarily the first choice of most

rheumatologists.

The initial dose is usually 10-15 mg administered

orally either in a single dose or in divided doses on 1
day each week. The dose may be escalated until the
usual maintenance dose of 15-25 mg/week is
reached.

The therapeutic effect may be delayed for up to 4 - 8

weeks.

MTX
MTX

MTX

DH-folat
MTX-poli-glutamat
Homocisteina
DH-folat reductaza

-CH3
Metil TH-folat
TH-folat

Metil TH-folat reductaza

Methionina

Purinic Synthesis
Proteic Synthesis

MTX

MHC II

Plasmocit

M
MH
HC
C III
I

Proliferation LT,B

Y
IL-2

LTh

Fibroblas
Fibroblasts
ts TNF-

PANUS
MMP
MMP

LB

IL-1

Cartila
Cartilage
ge

Osteoclast
Osteoclastes
es
Osteoblaste
Osteoblastess

Condrocytes
Condrocytes

Y FR

MH
M
HC
CI
III

APC

OS

BONE
BONE

MTX
Careful

monitoring of MTX therapy is required,

although most adverse events are mild and do
not require discontinuation of the drug
MTX hepatotoxicity is most widely discussed,
The most common adverse effects include:
ulcerattive stomatitis, anemia, leucopenia,
predisposition to infection, nausea, abdominal
pain, fatigue, fever, and dizzine
MTX is a known teratogen and effective
contraception should be considered in women
with the potential for pregnancy

LF

inhibits DHODH
Leflunomide inhibits pyrimidine
synthesis, resulting in blockade of T-cell
proliferation

LT
Mf

TCR MHC II

APC
(DC,
(DC, Mf)
Mf)

LF

MHC II

Plasmocit

M
MH
HC
C III
I

Proliferation LT,B

Y
IL-2

LTh

Fibroblasts TNF-

PANUS
MMP

LB

IL-1

Cartilage

Osteoclasts
Osteoblastes

Condrocytes

Y FR

MH
M
HC
CI
III

APC

OS

BONE

LF

Leflunomide is used in patients with moderate to

severe active RA with early or late disease
Monotherapy with LF has been shown to be equally as
effective as MTX and SSZ in improving symptoms and
signs of RA
Leflunomide as monotherapy results in substantial
inhibition of joint damage, as assessed radiologically
The most common side effects of leflunomide are
gastrointestinal symptoms and hepatotoxicity
Combination of leflunomide with methotrexate results
in a significant increase in hepatotoxicity
Leflunomide is teratogenic and is therefore
contraindicated in women who may become pregnant

SSZ
CD
80
/86

MHC
MHC IIII

CD
40

Plasmocit

M
MH
HC
C III
I

CD
40
L

CD
4

TC
R/C
D3

IL-2

LTh

Fibroblasti
Fibroblasti

PANUS
MMP
MMP

TNFTNF-

LB

IL-1
IL-1

Cartilaj
Cartilaj

Osteoclast
Osteoclast
Osteoblaste
Osteoblaste

Condrocite
Condrocite

Y FR

MH
M
HC
CI
III

CPA

OS

Os
Os

SSZ

SSZ is a versatile effective DMARD

= sulfapyridine + 5-aminosalicylic acid
In clinical trials in RA, SSZ has equal effect to MTX,
leflunomide, intramuscular gold and D-penicillamine
Adverse drug reactions mostly occur early (in first 6
months) and are reversible
Practical prescribing: a gradual increase in dose (0.5
g weekly)
Adverse events:

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
CD
8

0/8

6 C
D4

MHC II

Plasmocit

M
MH
HC
C III
I

CD
4

CD
4

TC
R/C
D3

0L

IL-2

LTh

Fibroblasti

PANUS
MMP

TNF-

LB

IL-1

Cartilaj

Osteoclast
Osteoblaste

Condrocite

Y FR

MH
M
HC
CI
III

CPA

OS

Os

GOLD

Injectable gold compounds have

been shown to slow down the rate of
radiological progression of
rheumatoid arthritis.
Side effect (40-60%):
Skin rash
Mouth ulcers
Diarrhea
Nitritoid reaction
Proteinuria
Marrow suppression (leukopenia,
thrombocytopenia)

HQ
CD
8

0/8

6 C
D4

MHC II

Plasmocit

M
MH
HC
C III
I

CD
4

CD
4

TC
R/C
D3

0L

IL-2

LTh

Fibroblasti

PANUS
MMP

TNF-

LB

IL-1

Cartilaj

Osteoclast
Osteoblaste

Condrocite

Y FR

MH
M
HC
CI
III

CPA

OS

Os

HQ

200

400 mg/day

Organ

Side effect

Gastrointestinal tract Nausea, abdominal

discomfort,
diarrhea
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

Receptors blockade
Anti-receptor
MAB
Receptor
Antagonist
No signal

anti-inflamm.
cytokines

Anti-inflamm.
cytokines
No signal

To block the TNF actions on cells that cause

pathogenesis in RA, the binding of TNF to these cells
must be blocked. The left figure shows normal
interaction of a cytokine with its cell surface
receptor, leading to signaling in the cell. On the
right, 2 methods to prevent this signaling are shown.
Cytokine can be bound by a soluble receptor or by a
monoclonal antibody, thereby preventing its binding
to the cell surface receptor.
TNF-
TNFR

Proinflammatory
signal

Anti-TNF-
MAB
Soluble
Receptor
No signal

sReceptor

Cytokine

Target cell

Receptor antagonist

Inflammatory
signal

BLOCKED

MAB
Ac monoclonal
Anti-Cytokine
anti-receptor

MAB
Ac monoclonal
Anti-Receptor
anti-receptor
Cytokine Receptor

Soluble TNF- Receptor

ETANERCEPT

p75 TNF
receptor
uman
S S
SS
CH2

Regiunea
constanta
a lantului
greu

S S

Regiunea
balamalei
Regiunea de legare a
complementului
341

CH3
S S

This protein is a fusion protein

that consists of the
extracellular ligand-binding
domain of p75 combined with a
segment of human
immunoglobulin. Because
these recombinant proteins
contain the important region
for binding TNF, when
administered, they bind to TNF
and carry it away from the
normal TNF receptors (p55 or
p75) on the surface of the
target cells.

446

Fc


FN
T

ETANERCEPT

FTN

TNF-

TNF

TNF

Soluble TNF-
TN

TN
F

F-

Membrane TNF-

TNF

TNF- Receptor
Target Cell

ETANERCEPT

Anti TNF MAB

IV Complet umanizat
III Umanizat
II Chimeric
I Murine

Uman
(fara proteina de soarece)
10% proteina de soarece
25% proteina de soarece

100% proteina de soarece

Afelimomab

Infliximab

CDP870

Adalimumab
(D2E7)

SS

S
SS
SS

CH2

ADALIMUMAB

CH3

TN
F
-

TNF

S
SS
SS

SS

CH2

CH3

TN
F

VL

CH
1

CL

TNF

VH

SS

SS
S SS

CH3

TNF- membranar

CH2

SS
SS

TNF

TNF- solubil

SS

SS

S
SS
SS

CH2

Receptor TNF-

CH3

INFLIXIMAB

Target Cell

Infliximab

gr
e

La
nt

10
7

tu
so
r

INFLIXIMAB

Fab

SS

SS

7
11

S S
S S
CH2

Fc
CH3

Infliximab is a chimeric
anti-TNF human IgG1k
engrafted to the murine Fv
region of a high-affinity
neutralizing murine antiHuTNF- antibody.
V
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
referred to as being
antigenic or
Human
immunogenic.
Mouse

La
n

COO

446

INFLIXIMAB
sTNF-

mTNF-

10
7

Fab

SS

SS

7
11

S S
S S

235

CH2

This recombinant human

IgG1 monoclonal
antibody holds the
potential advantages of
being less immunogenic
and having a longer halflife and thus requires less
frequent subcutaneous
dosing intervals

La
nt
us
La
or
nt
gr
eu

ADALIMUMAB

341
CH3

Secventa umana
*van de Putte, et al. Ann Rheum Dis, 2004;63:508-16

COO

446

Regiunea de
legare a
complementului
Fc

CD
8

0/8

6 C
D4

MHC II

Plasmocit

M
MH
HC
C III
I

CD
CT 28
LA
4

CD
4

CD
4

CD40

TNF-

IL-1

Cartilaj

LB
CD20

Osteoclast
Osteoblaste

Condrocite

IL-2
CD40L

Fibroblasti

MMP

TC
R/C
D3

0L

LTh

PANUS

Y FR

MH
M
HC
CI
III

APC

OS

BONE

CD20
CD20
VH

VL

CH
1

CL

CL

SS

CH
1

S
SS
S SS

SS
S
S

S SS
S

VL
VH

CL
S

CH
1

SS

SS
S S
S

LB
CD20
CD20
C

C H2

C H3

SS
L

RITUXIMAB

CH2

CH3

SS
SS

II
C

APC

Ag

APC

M
MH
HC
C II
II

MH

MHC II

CD40

CD80/86
CD40L

CD4

CD28

CD80/86

TCR/CD3

CTLA4

LT
T cell activation

CD28

ABATACEPT

T cell inhibition

CTLA-4

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
IL6

sIL-6R

mIL-6R

gp130

gp130

Semnal transmembranar Semnal de transductie

NON-PHARMACOLOGICAL
TREATMENT
Surgery
Synovectomy
Surgery

for carpal tunnel syndrome,

tendonous breaking

Total

joint prothesys

Its the greatest time to

be a rheumatologist!!!
Prof. Edward Keystone
EULAR, Viena iunie 2005

Thank you!