BIODATA

Nama : dr. Nyoman Suci Widyastiti, M.Kes, SpPK

Riwayat pendidikan :
-Dokter Umum FK UNDIP, 1996
- Magister Biomedik konsentrasi Imunologi, Program Pasca
Sarjana UNDIP, 2000
- Spesialis Patologi Klinik FK UNDIP, 2005
- S3 Kedokteran Unair, 2008 sekarang
Riwayat pekerjaan :
- Staf Pengajar Bagian Patologi Klinik FK UNDIP 1996sekarang
- Staf pengajar Pasca Sarjana / S2 Biomedik UNDIP 2001
sekarang
- Sekretaris Program Studi PPDS Patologi Klinik UNDIP 2009sekarang

RHEUMATOID ARTHRITIS
FROM BASIC TO CLINIC

Nyoman Suci W
Bagian Patologi Klinik
FK UNDIP/RS dr Kariadi

One of the most common systemic

autoimmune diseases, affecting
approximately 0.51.0% of the world
population.

The American Rheumatism Association

criteria for the classification of RA :
* morning stiffness,
* arthritis of three or more joint areas,
* arthritis of hand joints,
* symmetric arthritis,
* rheumatoid nodules,
* serum rheumatoid factor (RF)
* radiographic changes
A patient should have four of the seven criteria to be diagnosed
with RA and the first four criteria should be present for at least six
weeks.

Autoimmune processes are predicted to occur up to years prior to the clinical onset of disease and represent a pre-articular or lymphoid phase of disease.
Transition to the articular phase, which corresponds to the clinical manifestation of the disease, is initiated by ill-defined processes, such as biomechanical
and neurological events. Thereafter inflammation-driven pathogenesis occurs, which leads to joint destruction and increases co-morbidity, including
cardiovascular disease and osteoporosis. Autoimmune processes may defer to inflammatory pathways as the disease progresses. CCP, cyclic citrullinated
peptide; CTLA4, cytotoxic T-lymphocyte antigen 4; GP39, cartilage glycoprotein 39; PADI4, peptidyl arginine deiminase, type IV; PTPN22, protein tyrosine
phosphatase, non-receptor type 22.

SISTEM GEN HLA

Environmental factors
* Exposure to bacteria Mycoplasma
organisms, Epstein-Barr virus, rubella
virus, and Streptococcus,
* A particular diet a lack of Vitamin C
* Smoking
a major environmental risk
factor

Systemic Acute Inflammatory Response

Prostaglandins

Fever

Hypothalamus

F
N
,T
1
IL

6
LI
,

ACTH (via
pituitary)

Adrenal
cortex
Corticosteroids

IL-1, TNF , IL-6, LIF, OSM

Local acute
inflammatory
response
IL
-6,
T

C-reactive protein (CRP)

Serum amyloid A (SAA)

Liver
NF

Leukocytosis
Bone
marrow

Acute phase proteins :

Fibrinogen
Mannose-binding protein
Complement component

Gambaran utama :
Auto imunitas
Inflamasi kronis
Kerusakan sendi

Patogenesis RA
Terkait MHC kelas II
TH-1 cell mediated

Figure 5-2

Synovial T cells may be activated by T-cell receptor (TCR) and co-stimulation pathways and by cytokine- or Toll-like receptor (TLR)-driven stimuli. In particular,
the synovial milieu contains interleukin-12 (IL-12), IL-23, IL-6 and transforming growth factor- (TGF ), and as such promotes the differentiation of T helper 1
(TH1) and TH17 cells. Regulatory T cells, although present, may not exhibit optimal regulatory activity. In rodent models, regulatory T cells are present in high
numbers in the joints, whereas in human disease the relative contribution of these subsets remains unknown. Activated T cells mediate effector function in
rheumatoid arthritis through the release of cytokines, to promote downstream leukocyte and mesenchymal-cell activation, through the provision of help to B cells
and, in the case of CD8+ effector T cells, cytotoxic activity. They also activate macrophages, fibroblasts and endothelial cells through direct cell contact. CD40L,
CD40 ligand; GM-CSF, granulocyte/macrophage colony-stimulating factor; RANKL, receptor activator of nuclear factor- B (RANK) ligand; IFN , interferon- ; TNF,
tumour-necrosis factor.

The component cells of the inflamed rheumatoid synovial membrane are depicted in innate and adaptive predominant compartments of the inflammatory
response. Pivotal cytokine pathways are depicted in which activation of dendritic cells (DCs), T cells, B cells and macrophages underpins the dysregulated
expression of cytokines that in turn drive activation of effector cells, including neutrophils, mast cells, endothelial cells and synovial fibroblasts. The clinical
manifestations of such effects are highlighted. Only key cytokines are shown in each domain for relative simplicity; the main text contains more detailed
description of the precise role of additional cytokines in these processes. Bidirectional arrows represent a relationship between cells that is influenced by the
cytokines listed. The pathways that lead to tissue destruction via osteoclast and chondrocyte activation are detailed in Figs 4,5. APRIL, a proliferation-inducing
ligand; BAFF, B-cell activating factor; bFGF, basic fibroblast growth factor; CCL21, CC-chemokine ligand 21; CXCL13, CXC-chemokine ligand 13; FcgR, Fc
receptor for IgG; IFN, interferon; IL, interleukin; LT , lymphotoxin- ; M-CSF, macrophage colony-stimulating factor; PAR2, protease-activated receptor 2; RANKL,
receptor activator of nuclear factor- B (RANK) ligand; TGF , transforming growth factor- ; TH, T helper; TLR, Toll-like receptor; TNF, tumour-necrosis factor;
VEGF, vascular endothelial growth factor.

Kerusakan sendi pada RA

Osteoklas pada sisi antara jaringan

sinovial dan tulang sendi menginduksi
resorbsi tulang invasi sel membran
sinovial pannus

AKTIVITAS RESORBSI TULANG PADA RA

The essential cytokine mediators are RANKL (receptor activator of nuclear factor- B (RANK) ligand) and M-CSF (macrophage colony-stimulating factor), which
are expressed by synovial fibroblasts and T helper 1 (TH1) cells. Osteoclast differentiation is achieved by the actions of tumour-necrosis factor (TNF) and
interleukin-1 (IL-1), as well as of IL-17, produced by TH17 cells, and IL-7, produced by synovial fibroblasts. By contrast, IL-4 and IL-10, which are produced by

MEKANISME DISINTEGRASI TULANG RAWAN PADA RA

Cartilage degradation is a multistep process based on the release of matrix-degrading enzymes such as aggrecanases (ADAMTS) and matrix
metalloproteinases (MMPs). Cytokines such as interleukin-1 (IL-1) and IL-17 induce a switch in the synthesis pattern of chondrocytes from matrix molecules to
matrix-degrading enzymes. In addition, synovial fibroblasts start producing matrix-degrading enzymes and invade cartilage when activated by cytokines such as
tumour-necrosis factor (TNF) and IL-1. Chondrocyte death is another feature of cartilage damage, it leads to the formation of empty lacunae and deprives
cartilage from the ability to replenish matrix.

BIOMARKER

Defined as a structural or physical measure,

or a cellular, molecular, or genetic change or
feature by which alterations in a biologic
process can be identified and monitored.
may thereby have diagnostic or prognostic
utility
measuring the intended analyte and/or
process with sufficient specificity

BIOMARKER in RA

Biomarker of autoantibody
Biomarker of bone turnover
Biomarker of cartilage turnover

BIOMARKER of AUTOANTIBODI
Rheumatoid Factor (RF)
Anti-CCP Antibodies
* includes a group of autoantibodies with

shared reactivity for proteins containing

arginine residues that have been modified to
citrulline

* includes : antiperinuclear factor (APF),

antikeratin antibody (AKA), and antifilaggrin
antibody (AFA)

Possible links between rheumatoid arthritis (RA) specific anti-cyclic

citrullinated peptide (anti-CCP) antibodies and RA-associated genetic factors.
(a) PADI4 single nucleotide polymorphisms (SNPs) may lead to elevated PAD4 expression and
to increased citrullination of proteins (b) RA-associated HLA-DR4 molecules (DR4) can bind and
present citrullinated peptides much more efficiently than noncitrullinated peptides (c) IL-10
promoter SNPs are associated with increased anti-CCP antibody production and severity of the
disease (d) Various cytokine polymorphisms are associated with RA and may lead to stronger
effects of immune complex activated cells.

KONVERSI ENZIMATIK ARGININ SITRULIN

Anti-CCP Antibodies
Has a remarkably high specificity for
RA, of the order 98%, which is superior
to that of RF
Predictive of progression to erosive RA
and a more severe disease course
Determined early in the course of RA
are good predictors of radiographic joint
damage
Combined with RF provides the most
accurate prediction of erosive disease

European League Against Rheumatism

(EULAR) Recommendations :
In every patient presenting with early arthritis
to the rheumatologist, the following factors
predicting persistent and erosive disease
should be measured by:
Number of tender and swollen joints
ESR or CRP
Levels of rheumatoid factor and anti-CCP
antibodies
Radiographic erosions

BIOMARKER of BONE TURNOVER

Markers of bone formation
Serum osteocalcin, serum bone-specific alkaline
phosphatase, and serum levels of N- and Cpropeptides of type I procollagen (PINP and
PICP)

Markers of bone resorption (degradation)

Urinary pyridinoline (PYD) and deoxypyridinoline
(DPD), urinary and serum levels of the N- and Ctelopeptides of type I collagen (NTX and CTX),
and serum levels of tartrate-resistant acid
phosphatase 5b (TRACP-5b)

BIOMARKER of CARTILAGE TURNOVER

Markers of Cartilage Degradation

Urine CartiLaps (CTX-II), cartilage oligomeric
matrix protein (COMP), human cartilage
glycoprotein 39 (HC gp-39; YKL-40)

Markers of Cartilage Synthesis

N- and C-propeptides of type II procollagen
and the chondroitin sulphate (CS) 846
epitope of aggrecan

PRA ANALITIK
Variasi biologis
Asupan makanan
Status renal dan hepatik pasien

VARIASI BIOLOGIS
Terutama berpengaruh pada
pengukuran petanda degradasi
tulang
Variasi hingga 50 70 % dari kadar
rerata
Perhatikan waktu pengambilan
spesimen !

PENGARUH ASUPAN MAKANAN

Terutama pada petanda resorbsi
tulang (CTX-1, NTX)
Pengambilan spesimen pada pasien
puasa
Pengaruh pada petanda cartilage
turnover (?) Exercise COMP

STATUS RENAL & HEPATIK PASIEN

Tergantung organ ekskretor

biomarker
CTX-1, NTX, PINP, Osteoklasin
diekskresi oleh ginjal
TRACP, BSAP diekskresi hepar