Molecular Pathway of

RHEUMATOID
ARTHRITIS

Hetty Rieskaliana
1306343050

OUTLINE
Physiology of normal synovium
2. Molecular pathophysiology of
rheumatoid arthritis
3. Molecular pharmacology of
rheumatoid arthritis medications
1.

Molecular Pathway of
RHEUMATOID ARTHRITIS

Physiology of normal
synovium

Rheumatoid arthritis (RA)

The American College of Rheumatology (ACR)

and the European League Against Rheumatism
(EULAR):

RA is a chronic inflammatory
disease characterized by joint
swelling, joint tenderness, and
destruction of synovial joints,
leading to severe disability and
premature mortality [1]

RA is considered an autoimmune disease

RA affects 0.5-1% of the world population
There are 2.5 times as many women as
men with the disease

Li YR, Kauffman JM (2014) Molecular Medicine of Rheumatoid Arthritis: From Molecular Pathphysiology to Novel Therapeutics and EvidenceBased Practice. Ann Orthop Rheumatol 2(2): 1014.

Normal joint (a) and a joint

affected by RA(b)

Choy, Ernest 2012. Understanding the dynamics pathways involved in the pathogenesis of rheumatoid arthritis.

Normal synovium

The synovium is the

soft tissue that lines
diarthrodial joints
Consists of 2 distinct
layers:
Intima layer
(lining)
Subintima layer
(sublining)

Normal synovium
Lining/intimal

layer containing 2 distinct

cells:
Macrophage-like type A synoviocytes
Fibroblast-like type B synoviocytes
In RA, lining layer becomes hyperplastic and forms an
aggrevive front term pannus

Sublining/

subintima layer consists of

scattered blood vessels, fat cells, and
fibroblasts residing in a matrix of fibrils
and proteoglycans

Normal synovium
Synovial

Macrophages
Synovial Fibroblasts
hyaluronan production
Other

Sub-intimal Cell Populations

CD3+ T cells, (including CD4+ and CD8+

cells), with some having a memory T cell
phenotype, B cells and plasma cells

Synovial Macrophages
Macrophages

are antigen presenting

cells (APCs) and act as one of the first
responders in the immune response
process.
Once activated, a macrophage releases
cytokines and chemokines.
Cytokines affect the way other cells act.
Chemokines attract other leukocytes the
area to battle the invaders in a process
called chemotaxis.

Immune System

Immune
System

Innate
(non
specific)
Adaptive
(specific)

Humoral
mediated
Cell
mediated

Innate immune system

The innate immunity relies on receptors that

detect common pathogenic features (ex:
bacterial cell wall polysaccharides)
When it encounters a bacterium,
a macrophage first engulfs it in a
pouch (vesicle) called a
phagosome.
This vesicle is then taken inside
the macrophage, where it fuses
with another vesicle termed a
lysosome.
Lysosomes contain powerful
chemicals and enzymes which
can destroy bacteria.

Adaptive immune system

The

receptors are designed to

respond to only one feature, called
an antigen.
Saat ada invader yang teridentifikasi,
hanya limfosit yang reseptornya
cocok dengan invader saja yang
teraktivasi. Antibodi dilepaskan oleh
limfosit B dan mengandung reseptor
yang sama dengan antigen.

Lymphocyte
There

are two major types of

lymphocytes:
T lymphocytes
B lymphocytes

T lymphocytes (T cells) are so called

because they mature in the thymus.
B lymphocytes (B cells) are lymphocytes
that develop in the bone marrow. Their
primary job upon activation is to
produce antibodies.

Lymphocytes
Upon activation, B
cells
proliferate and then
become plasma
cells, secreting
antibodies

T cells destroy
infected cells

T Lymphocytes
The T cells later develop into CD4 and CD8 T
cells
CD8 has marked cytotoxic (cell-killer) T cells,
and CD4 has marked whelper T cells, which
further differentiate into two subclasses, TH1
and TH2 cells
T cells do not produce an immune response by
binding to an antigen. The antigen must be
displayed by major histocompatibility
complex (MHC).
CD4 binds to MHC II, while CD8 binds to MHC I.

When CD4 T cells bind to MHC II on B

cells, they stimulate the B cell to
produce antibodies.
When they bind with MHC II on
macrophages, they activate the
macrophages to destroy the cells in their
phagosomes.
lymphocytes that bind with MHC too
strongly could possibly cause
autoimmune disease.

Molecular Pathway of
RHEUMATOID ARTHRITIS

Molecular pathophysiology of
rheumatoid arthritis

Molecular pathway of
inflammatory
The

clinical manifestations of
rheumatoid arthritis are initiated by
lymphocytes that localize to synovial
tissue where, when activated, they
cause pain and swelling.
These lymphocytes produce protein
mediators (cytokines) that initiate
inammation, attract other immune cells
to the site, activate resident cells, and
cause excess synovial uid production.

Molecular pathway of
inflammatory
Lymphocyte cells
migration:

Tethering: aliran leukosit

melambat dan menepi ke
dinding pembuluh darah
Rolling: lekosit akan
bergerak berputar-putar
menepi dan tertambat pada
sel-sel endotelial pada
dinding pembuluh darah
Sel lekosit melekat pada sel
endotelial, kemudian
bermigrasi menuju jaringan
dengan bantuan chemokine

Molecular pathway of
inflammatory

LFA =lymphocyte function antigen; ICAM = intercellular adhesion molecule;IFN = interferon; IL =

interleukin;
MHC = major histocompatibility complex;
NO = nitricoxide;TNF = tumor necrosis factor

Molecular pathway of
inflammatory

Limfosit CD4+ dan makrofag teraktivasi,

menghasilkan: IL-2, TNF dan IL-1.
IL-2: memicu proliferasi limfosit, sehingga
memperbanyak sitokin yang dihasilkan,
menyebabkan inamasi
Selanjutnya, limfosit T akan mengaktifkan
limfosit B menghasilkan autoantibodi,
diantaranya rheumatoid factor (Ig M-RF) dan
anti-cyclic citrullinated protein (anti-CCP)
Diagnosis artritis rematoid awal:
Ig M-RF > 40
Anti-CCP >50

Molecular pathway of
destruction of the cartilage
Destruksi

kartilago akan
menyebabkan disfungsi sendi yang
akan mempengaruhi kualitas hidup
pasien rheumatoid arthtritis
Kartilago: sejenis jaringan ikat
khusus yang terdiri atas satu tipe
sel, yaitu chondrocyte, yang
memproduksi extracelullar matrix
(ECM)
Normal: keseimbangan sintesis ECM

Molecular pathway of
destruction of the cartilage
Rheumatoid

arthtritis: degradasi
ECM > sintesis ECM, sehingga terjadi
dekstruksi kartilago.
Enzim yang berperan dalam
degradasi ECM: matrix
metalloproteinase (MMP)
MMP bersifat inducible, dipicu oleh
antara lain: sitokin IL-1 dan TNF-

Molecular pathway of
destruction of the cartilage
Klasifikasi
1.
2.
3.
4.
5.

MMP
Collagenase (MMP-1, MMP-8, dan
MMP-13)
Gelatinase (MMP-2 dan MMP-9)
Stromelysin (MMP-3 dan MMP-10)
Metalloelastase (MMP-12, MMP-19)
Enamelysin ((MMP-20 dan MMP-23)

 MMP

diinaktivasi oleh suatu inhibitor,

yaitu
Tissue Inhibitors of Metallo
Proteinases (TIMPs) regulator pada
sirkulasi sistemik
-2 macroglobulin (-2M) lokal di
jaringan
Target pengembangan obat
inhibitor selektif terhadap MMP-1,
seperti cipemastat (uji klinik belum

Molecular Pathway of
RHEUMATOID ARTHRITIS

Molecular pharmacology of
rheumatoid arthritis medications

Rheumatoid arthtritis
therapy
Symptomatic

therapy using nonsteroid anti infamatory drugs

(NSAID)

Disease-modifying

drugs (DMARD)

antirheumatic

non-steroid anti infamatory

drugs (NSAID)
First

line drugs in mild/early case

Afford symptomatic relief in pain,
swelling, morning stiffness
Do not arrest disease process
Mechanism of action:
competitive active site inhibitors of
enzym (cyclooxigenase)

AINS
Non-selective cox
inhibitors
Naproxen,
piroxicam,
diclofenac
Selective cox-2
inhibitors
Celecoxib,
etoricoxib

Disease-modifying
antirheumatic drugs (DMARD)
Current

recomendation is to add
DMARDs as soon as the diagnosis is
confirmed
Slow acting, take 6 weeks 6
months to show the effects
Alter disease progression

Disease-modifying
antirheumatic drugs (DMARD)

Methotrexate
Considered

first choice to treat RA

Mechanism of action: it probably relates to
inhibition of aminoimidazolecarboxamide
ribonucleotide (AICAR) transformylase
MTX may act in RA through reducing cell
proliferation, increasing the rate of
apoptosis of T cells, increasing
endogenous adenosine concentrations and
altering cytokine production and humoral
responses

Methotrexate

Methotrexate
Adenosine

is a purine nucleoside
that binds four specific adenosine
receptors, A1, A2a, A2b and A3
Ligation of the A1-receptor leads to
immuno stimulation of neutrophils,
where as ligation of the A2a-receptor
leads to immuno supression

Biology DMARDs
Anti

TNF
Antagonis IL-1
Antagonis IL-6
Anti CD-20
Cytotoxic T-lymphocyte-associated
Antigen 4 (CTLA4)

1. Anti-TNF
Anti-TNF:

a.
b.
c.
d.
e.

Iniximab
Etanercept
Adalimumab
Golimumab
Certolizumab pegol

2. Antagonis reseptor IL1

Contoh: anakinra

Anakinra block IL-1R

(Interleukin-1
receptor)

3. Antagonis reseptor IL6

Obat

yang dikembangkan dengan

target IL-6 adalah toclizumab.
Toclizumab bekerja dengan mengikat
secara spesifik reseptor IL-6

3. Anti CD-20
Contoh:

Rituximab

CD-20 is a phosphoprotein
expressed in B cells

5. CTLA4
APC: CD80 and CD
86
T lymphocyte:
CD28 (activate)
and cytotoxic Tlymphosyteassociated antigen
4 (inhibit)

Terima Kasih !