Artritis Reumatoide

FISIOPATOLOGA

Rheumatoid arthritis (RA) is

a complex disease involving
numerous cell types,
including macrophages, T
cells, B cells, fibroblasts,
chondrocytes, and dendritic
cells.
Several genes are implicated
in susceptibility to RA and
severity of disease, including
class II major
histocompatibility complex
genes, PTPN22 ( Protena
Linfoide Tirosina Fosfatasa
LYP- codificada por el gen
PTPN22 = ejerce una
potente inhibicin en el
linfocito T activado), and
peptidylarginine transferases.

ETIOLOGY AND PATHOGENESIS

OF RHEUMATOID ARTHRITIS

Evidence of autoimmunity, including high serum levels of autoantibodies

such as rheumatoid factors and anticitrullinated peptide antibodies, can be
present for many years before the onset of clinical arthritis.

Adaptive and innate immune responses in the synovium have been

implicated in the pathogenesis of RA.

Cytokine networks involving tumor necrosis factor, interleukin-6, and many

other factors participate in disease perpetuation and can be targeted by
therapeutic agents.

Bone and cartilage destruction seem to be primarily mediated by

osteoclasts and fibroblast-like synoviocytes.

ETIOLOGY OF
RHEUMATOID ARTHRITIS
Genes play a key role in
susceptibility to RA and disease
severity.

Class II MHC genes, especially

genes containing a specific 5amino acid sequence in the
hypervariable region of HLADR4, are the most prominent
genetic association.
Newly defined genetic
associations, including
polymorphisms in PTPN22, PADI
4 (Peptidyl arginine deiminase,
type IV), and many cytokines,
suggest that the associations in
RA are complex and involve
many genes.

The primary function of HLA-DR is to present peptide antigens,

potentially foreign in origin, to the immune system for the purpose
of eliciting or suppressing T-(helper)-cell responses that eventually lead
to the production of antibodies against the same peptide antigen.
Antigen presenting cells (macrophages, B-cells and dendritic cells) are
the cells in which DR are typically found. Increased abundance of DR
'antigen' on the cell surface is often in response to stimulation, and,
therefore, DR is also a marker for immune stimulation.

POSSIBLE CAUSES OF RHEUMATOID ARTHRITIS

Many pathogens have been
associated with RA, including
viruses, retroviruses, and
Mycoplasma, although a
precise etiologic link has not
been established.
Data suggest that a specific
RA pathogen is unlikely.

The breakdown of tolerance and/or immunoregulatory mechanisms leads to autoimmune activation and recognition
in the tissues. These responses, which are 'adaptative' in their anti-self specificity, generate primary 'innate' inputs into mast
cells, such as immune complex binding to FcRs, and C3a and C5a anaphylatoxins of the complement pathway binding to
specific receptors. The molecular route for direct 'bystander' activation of mast cells by T cells remains conjectural. The mast
cell, owing to the abundance and diversity of secondary mediators in its granules, responds by activating a host of pathways,
thus amplifying the local response. Vascular permeability is increased, allowing influx of additional molecules (antibody,
complement). The adhesiveness of the vascular endothelium is increased, facilitating the homing of leukocytes (and in
particular neutrophils) provoked by chemokine and TNF- release. These leukocytes are also activated by the same
cytokines. Mast cell mediators may be also involved in remodelling connective tissue, or in biasing secondary T-cell
responses. Mast cell activation may also signal to local neuronal constituents by the release of NGF, serotonin or dopamine.
Thus, the mast cell takes in what may be a low pro-inflammatory input and amplifies it to bring about a much wider response
macrophage inflammatory protein . factor de crecimiento nervioso (NGF)

Repeated inflammatory
insults, especially through
specialized receptors that
recognize common
molecules produced by
pathogens, in a genetically
susceptible individual might
contribute to breakdown of
tolerance and subsequent
autoimmunity.

SYNOVIAL PATHOLOGY AND BIOLOGY

The synovium in RA is marked by intimal lining hyperplasia and sublining

infiltration with mononuclear cells, especially CD4+ T cells, macrophages,
and B cells.

Pannus-cartilage
junction. The invasive
front of pannus burrows
into cartilage matrix in
rheumatoid arthritis
joints. The pannus is
primarily composed of
macrophages and
mesenchymal cells.
Immunostaining with
anti-CD68 antibody
shows the distribution of
macrophages in the
invasive tissue.
(Courtesy of Dr. PaulPeter Tak.)

(A) Synovial invasion into bone in RA synovium.

(B) RASFs invading co-implanted human cartilage in the SCID mouse model of cartilage
invasion. Magnifi cation 100, insert 400.

Synovial pathology and function of synovial cells in RA are distinctive in that:

- Intimal lining FLS (fibroblast-like synovial) display unusually aggressive features.
- Macrophages in the intimal lining are highly activated.
- Lymphocytes can either diffusely infiltrate the sublining or form lymphoid aggregates
with germinal centers.
- Sublining CD4+ T cells mainly display the memory cell phenotype.
- Synovial B cells and plasma cells in RA exhibit evidence of antigen-driven maturation
and antibody production.
- DCs potentially can present antigens to T cells in synovial germinal centers.
- Mast cells produce small molecule mediators of inflammation.
- Neutrophils are rarely present in RA synovium.
Schematic diagram of disease mechanisms that likely
occur in rheumatoid arthritis. Innate immunity activates
fibroblast-like synoviocytes (FLS), dendritic cells (DC),
and macrophages (M) in the earliest phases in
individuals with underlying immune hyperreactivity as
evidenced by the production of autoantibodies. The
genetic makeup of an individual, including the presence
of certain polymorphisms in genes that regulate immune
responses, and environmental exposures are required. DC
can migrate to the central lymphoid organs to present
antigen and activate T cells, which can activate B cells.
These lymphocytes can migrate back to the synovium and
enhance adaptive immune responses in the target organ.
In addition, repeated activation of innate immunity can
lead directly to chronic inflammation and possibly antigen
presentation in the synovium. In the latter phases of
disease, many cell types activate osteoclasts (OC)
through the receptor activator of nuclear factor B
(NFB)/receptor activator of NFB ligand (RANK/RANKL)
system, although FLS and T cells likely provide the
greatest stimulus. Autonomous activation of FLS also
might contribute to this process.

Schema for the priming of citrulline-specifi

autoimmunity by dendritic cells in rheumatoid arthritis.

SYNOVIAL FLUID

RA synovial effusions
contain abundant
neutrophils and
mononuclear cells.
Immune complexes that
contain autoantibodies
such as RFs or
anticitrullinated protein
antibodies can fix
complement, leading to
the generation of
chemoattractants.

Small molecule mediators

of inflammation, such as
PGs and LTs, are present
in RA synovial fluid.

ROLE OF T CELL CYTOKINES

Multiple subsets of T cells have been implicated in the pathogenesis of RA.
Relatively low levels of T cell cytokines are present in RA synovium.
The T cell cytokines that are present, such as IFN- and IL-17, are produced by
Th1 cells or Th17 cells.
Regulatory T cell function, which suppresses activation of other T cells, might
be reduced in RA synovium.
The contribution of T cells to synovial inflammation can be through antigenindependent mechanisms, such as direct cell-cell contact with macrophages.

T-cell activation in RA. Antigen-presenting cells

(APC) present (auto)antigen(s) to naive T cells
in the context of MHC class II molecules. T
cells differentiate to Th1, Th2, or Th17 T cells,
and provide help for B cells for the production
of (auto)antibodies.

Regulation of T cells by cytokines.

The various functions of B cells. APC, antigenpresenting cell; FDC, follicular dendritic
cell. (Adapted from Drner T, Burmester GR. The role of B cells in RA: mechanisms
and therapeutic targets. Curr Opin Rheumatol 2003;15:246 252; and Lipsky PE.
Systemic lupus erythematosus: An autoimmune disease of B-cell hyperactivity. Nat
Immunol 2001;2:764766.)

Some roles for rheumatoid factor in joint pathology. (From Hochberg MC, Silman AJ,
Smolen JS, et al. Rheumatology, 4th ed. London: Mosby, 2008, fi g. 78.3, 821.)

Detailed description of complement activation pathways. Note the distinct functions

and locations within the cascade of the initiation C3 convertases as compared to the
amplifi cation loop C3 convertase, which is engaged by target-bound C3b* (center,
boxed) that can be generated by any of the three initiation mechanisms, as further
described in the text.

Two-phase model of initiation of joint inflammation and damage following the formation
of immune complexes on the cartilage surface (Phase 1) in the CAIA model and
engagement of complement, specifi cally the AP and the amplification loop. In this model,
secondary injury is initiated in the adjacent synovium through the unregulated activation
at that site of the AP (Phase 2).

ROLE OF MACROPHAGE AND FIBROBLAST CYTOKINES

Macrophage and fibroblast cytokines are abundant in RA synovium.
Cytokine networks that involve proinflammatory cytokines, such as IL-1, TNF-,
IL-6, IL-15, IL-18, GM-CSF, and many others, can help perpetuate synovial
inflammation.
Chemokines that recruit inflammatory cells into the joint generally are produced
by macrophages and fibroblasts.
Anti-inflammatory cytokines, such as IL-1Ra and IL-10, are produced in rheumatoid
synovium, albeit in amounts insufficient to offset proinflammatory cytokines.

Cytokine networks in rheumatoid

arthritis. Paracrine and autocrine
pathways can lead to activation of
fibroblast-like and macrophage-like
synoviocytes in the synovial intimal
lining. Positive (+) and negative (-)
feedback loops are present,
although in rheumatoid arthritis the
former predominate. T helper type
1 (Th1) cytokines potentially can
enhance the network, whereas Th2
cytokines are suppressive. FGF,
fibroblast growth factor; GM-CSF,
granulocyte-macrophage colonystimulating factor; IL, interleukin;
M-CSF, macrophage colonystimulating factor; TGF,
transforming growth factor; TNF,
tumor necrosis factor.

SIGNAL TRANSDUCTION
AND TRANSCRIPTION
FACTORS
Complex intracellular signaling
mechanisms regulate cytokine
production and actions in RA
synovium.
NFB, MAP kinases (mitogen activated
protein) , AP-1 (protena activadora 1,
es un factor de transcripcin) , and
several other pathways are potential
therapeutic targets in RA.
Intracellular signaling pathways initiated at the CD4 T-cell receptor complex.
The TCR and coreceptor (in this example the CD4 molecule), associated
signaling molecules, their coupling to downstream biochemical events and
culmination in nuclear gene transcription
are shown. Upon antigen:MHC ligand binding to the TCR and coreceptor, the
proximal kinases Lck and Fyn phosphorylate tyrosine residues on the ITAM
regions in the intracytoplasmic domains of CD3 and TCR, recruiting ZAP-70 to
bind to phosphorylated tyrosine residues on the TCR chains. The bound ZAP70 becomes phosphorylated, activating the kinase to phosphorylate the
adapter proteins LAT and SLP-76, which in turn leads to the activation of PLCby Tec kinases and the activation of Ras by guanine-nucleotide exchange
factors (GEFs). Activated PLC-and Ras initiate three important pathways that
culminate in the activation of transcription factors in the nucleus. Together
NFB, NFAT, and AP-1 act on the T-cell chromosomes, initiating new gene
transcription. (From Hochberg M, Silman A, Weinblatt M, et al. Rheumatology,
4th ed. London: Mosby, 2008, Fig. 12.2.)

LIFE AND DEATH IN THE RHEUMATOID SYNOVIUM

Reactive oxygen and nitrogen in RA joints

contributes to a toxic environment that can
damage cells and increase inflammation.

Deficient apoptosis, or cell death, can

contribute to the accumulation of cells in
rheumatoid synovium.

Abnormalities of key regulatory genes, such

as the p53 tumor-suppressor gene, can
enhance accumulation of cells in the joint.

Inducing apoptosis potentially can suppress

synovial inflammation and joint destruction.
Post-translational

modification of apoptotic regulators constitute an important

mechanism by which RA synovial fibroblasts are protected from apoptosis.
Specifically, increased expression of SUMO-1 results in an enhanced SUMOylation of
the nuclear PML protein, as a result of which the apoptotic modulator DAXX is bound
at increased levels in the PML nuclear bodies. Inhibition of SUMO-1 (molcula
pequea modificadora tipo ubiquitina-1) (SUMO-1) or overexpression of the nuclear
SUMOspecific protease SENP1 results in deSUMOylation of PML and the release of
DAXX, resulting in sensitization of RA fibroblasts to programmed cell death.
( SUMO 1 = apoptosis)

Candidate proinflammatory functions of mast cells

in rheumatoid synovitis. Mast cell effector functions
suggest their participation in diverse pathogenic
pathways in arthritis, including endothelial cell
activation, leukocyte recruitment and activation,
synovial fi broblast activation and hyperplasia,
angiogenesis, and cartilage and bone destruction.
Activated mast cells elaborate mediators potently
capable of enhancing vasopermeability, including
endothelial expression of adhesion molecules,
recruiting circulating leukocytes, and activating infi
ltrating leukocytes as well as resident
macrophages, thereby contributing to the early
phases of infl ammatory arthritis. In chronic
synovitis, mast cells synthesize mitogens and
cytokines that activate synovial fi broblasts, recruit
macrophages, and promote the growth of new
blood vessels, implicating them in synovial lining
hyperplasia and pannus formation. Further, mast
cells may participate in joint destruction by the
induction of matrix metalloproteinases (MMPs) from
fi broblasts, by activation of chondrocytes, and by
direct and indirect promotion of osteoclast
differentiation and activation. Because activated
synovial fi broblasts demonstrate enhanced stem
cell factor (SCF) expression, a potentially important
positive feedback loop is established in which SCF
promotes mast cell differentiation from progenitors
and survival of mature mast cells, leading to the
mastocytosis described in infl amed synovium.
Note that the importance of these candidate
pathways in vivo remains to be established. bFGF,
Basic fi broblast growth factor; IFN, Interferon; IL,
Interleukin; MCP, Monocyte chemoattractant
protein; M-CSF, Macrophage colonystimulating
factor; MIP, Macrophage infl ammatory protein;
PDGF, Platelet-derived growth factor; PMN,
Polymorphnuclear cell; Rank-L, Receptor activator
of NF-B ligand; TNF, Tumor necrosis factor. (From
Nigrovic PA, Lee DM. Mast cells in infl ammatory
arthritis. Arthritis Res Ther 2005;7:111. Graphic
design by Steve Moskowitz.)

BLOOD VESSELS IN ARTHRITIS

Angiogenesis=dynamic process in RA that provides nutrients to expanding synovium.

Angiogenic factors, such as IL-8 and vascular endothelial growth factor, can enhance
blood vessel proliferation in the synovium.
Microvascular endothelia in the synovium express adhesion molecules that guide
circulating cells into the joint under the influence of chemoattractants.

ADHESION
MOLECULE
REGULATION
Paracrine, juxtacrine, and
autocrine stimuli (left
column) and effector
molecules (right column) of
macrophage (M) activation
in RA.
Most regulatory products of
activated macrophages also
act on macrophages,
resulting in autocrine
regulatory loops with
relevance for disease
severity and chronicity.
FB, fibroblasts;
EC, endothelial cells;
NK, natural killer cells.
The (+) in the T cell
indicates the necessity of
preactivating T cells for
effective stimulation of
macrophages

Cytokine networks and cellular interactions in cartilage destruction in rheumatoid arthritis. This scheme represents the progressive destruction of
the cartilage associated with the invading synovial pannus in RA. As a result of immune cell interactions involving T and B lymphocytes,
monocyte/macrophages, and dendritic cells, a number of different cytokines are produced in the infl amed synovium due to the infl ux of infl
ammatory cells from the circulation and synovial cell hyperplasia. The upregulation of proinfl ammatory cytokines produced primarily in the
synovium, but also by chondrocytes, result in the upregulation of cartilage-degrading enzymes, of the MMP and ADAMTS (A Disintegrin And
Metalloproteinase with Thrombospondin Motifs) families, at the cartilagepannus junction. Chemokines, nitric oxide, and prostaglandins also
contribute to the infl ammation and tissue catabolism. (Adapted from Otero M, Goldring MB. Cells of the synovium in rheumatoid arthritis.
Chondrocytes. Arthritis Res Ther 2007;9:220.)

La MS en la AR contiene gran cantidad de

clulas T67. Sin embargo, ha sido difcil definir
el papel que estas desempean en el
mantenimiento y la propagacin de la
inflamacin articular. La utilizacin en el
tratamiento de la AR de una protena de
fusin CTLA-4 humano que inhibe la
coestimulacin T va CD28 ha proporcionado
una prueba indirecta pero contundente de la
importancia de los linfocitos T en la AR68. El
papel de TGF- en la diferenciacin de las
diferentes poblaciones de clulas T humanas
es mltiple. Por un lado, se ha demostrado
que la sealizacin a travs de TGF-1
protege a las clulas T reguladoras (Treg) de
la apoptosis69 y es absolutamente necesaria
para inducir la expresin de Foxp3, ya que se
ha demostrado que clulas TCD4+
deficientes en TGF-1 no pueden generar
70, 71,
71, 72,
72, 73. Las
clulas Treg in vivo e in vitro70,
clulas Treg pueden desarrollarse a partir de
precursores tmicos de clulas TCD4+ en
presencia de TGF- e IL-2, dando lugar a
clulas Treg naturales. En la periferia, las
clulas TCD4+ nave pueden convertirse en
clulas Treg inducibles a travs de la
sealizacin de STAT-5 en presencia de
TGF-, aumentando la expresin del factor
Foxp3 (Figura
(Figura 1).
1). La regulacin del promotor
de Foxp3 depende, entre otros, del factor de
transcripcin NF-AT y la sealizacin de
Smad-3 inducida por TGF-74. De hecho, el
TGF- media la expresin de Foxp3 por
unin directa al promotor de Smad. Las
clulas Treg secretan bajas cantidades de IL2 e IFN-, mientras que producen elevadas
cantidades de IL-10, IL-35 y TGF-,
esenciales para regular la supresin de las
clulas T75. Recientemente, se ha descrito
que, en ausencia de TGF-1 funcional, el
desarrollo de las clulas Treg en el cncer
podra ser producido por un mecanismo
compensatorio dependiente de la expresin
de TGF-2 y TGF-3 en el timo y la periferia76
, 77. Sin embargo, se desconoce si este
mecanismo ocurre en la AR.

Papel de TGF- en la diferenciacin de las clulas T efectoras. Efecto del

TFG- y molculas implicadas en la diferenciacin y regulacin de las
distintas poblaciones de clulas T efectoras en relacin con su funcin dentro
del sistema inmunitario. IL: interleucina; TGF-: factor de crecimiento
transformador beta; Treg: T reguladora.

TACE: metalloprotease TNF alpha converting enzyme

SAA: protena srica amiloide A

CARTILAGE AND BONE DESTRUCTION

Distinct mechanisms and cell types regulate cartilage degradation and bone
destruction in RA.
Several classes of proteases, including metalloproteinases, serine proteases,
cathepsins, and aggrecanases, are produced by intimal lining cells in RA,
especially FLS.
Synovial lining cells, especially FLS, can attach to and invade cartilage in RA.
Bone destruction is mediated by osteoclasts that are activated under the
influence of RANKL and other cytokines produced by RA synovium.

The stable activation of

synovial fibroblasts in RA is
reflected by the altered
expression of protooncogenes and tumor
suppressors, and results in
distinct changes that
comprise an increased
attachment to the
extracellular matrix of the
cartilage and alterations in
apoptosis, as well as
increased expression of
matrix-degrading enzymes
such as MMPs and
cathepsins, ultimately
leading to progressive
cartilage destruction.

Pannus-cartilage junction. The invasive front of pannus burrows into cartilage matrix
in rheumatoid arthritis joints. The pannus is primarily composed of macrophages and
mesenchymal cells. Immunostaining with anti-CD68 antibody shows the distribution
of macrophages in the invasive tissue. (Courtesy of Dr. Paul-Peter Tak.)

Tartrate-resistant acid
phosphatasepositive osteoclasts
are shown invading bone in
rheumatoid arthritis (see arrows for
examples). This process is
regulated by receptor activator of
nuclear factor B ligand (RANKL) in
the presence of other cytokines,
such as macrophage colonystimulating factor and tumor
necrosis factor-. (Courtesy of Dr.
Steven Goldring, Dr. Ellen
Gravallese, and Dr. Allison Pettit.)

Cytokines driving osteoclast differentiation in the infl amed joint. Macrophage-colony

stimulating factor (MCSF) and receptor activator of NF-B ligand (RANKL) are essential
cytokines for osteoclastogenesis, which allow differentiation of monocytes entering the
joint space to multinucleated osteoclasts. Proinfl ammatory cytokines like tumor necrosis
factor (TNF and interleukin [IL]-1, -6, and -17 support osteoclast formation through infl
uencing RANKL expression.

Joint remodeling pathways in infl ammatory disease. Catabolic joint remodeling is a

direct effect of infl ammation with induction of RANKL leading to osteoclastogenesis
and bone resorption and Dickkopf (DKK)-1 inhibiting osteoblast differentiation and
preventing bone repair. Anabolic joint remodeling is driven by a periosteal bone
response leading to formation of bony spurs (osteophytes) by increased osteoblast
activity and new bone formation. This is driven by wingless (Wnt) proteins and bone
morphogenic proteins (BMPs). At the same time, they induce osteoprotegerin (OPG),
which blocks bone resorption.

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