RHEUMATOID ARTHRITIS

Dr.FAIZAL DRISSA HASIBUAN, SpPD

Bagian Penyakit Dalam
FK UNIV.YARSI JAKARTA
2013

Artritis Reumatoid :
Tersebar luas, semua kelompok, ras, etnik di dunia
Penyakit inflamasi sistemik autoimun
Inflamasi yg kronik pd sendi
Suatu poli artritis progresif
Sendi dan organ tubuh lain
Gejala penyakit kronis yang hilang timbul
kerusakan sendi deformitas
disabilitas
Etiologi pasti ????

Autoimmune Diseases

Autoimmune diseases occur

when the immune system
mistake self tissue for nonself and mounths an
inappropriate attack
Most autoimmune disorders
affect women more
frequently
RA-3: 1
Autoimmune disorders may
result from multiple
interactions of genes and
environmental factors

Autoimmune diseases can affect

different systems within the body
Nervous system Blood
Multiple sclerosis Autoimmune
haemolytic
anaemia
Skin
Psoriasis

Endocrine system
Type 1 diabetes

Multiple organs
Systemic lupus
Erythematosus

Bones and joints

Arthritis

Penyakit autoimun :

Sistem imun teraktivasi

Menyerang jaringan yg sehat

Inflamasi dan kerusakan jaringan / organ

Proses autoimun melibatkan :

Sel

limfosit T & sel B

Messenger molecules
Antibodi (RF)
Anti cyclyc citrullinated C-peptic antibody (anti-CCP-ab)
Berbagai sitokin
- Interleukin-1 (IL-1)
- Tumor necrosis factor (TNF- )
- Kemokin dan Reseptornya
Signalling and co stimulatory molecules
Sel mast

Sinoviosit
Ectopic lymphoid neogenesis
Angiogenesis
HLA-class II
Non-MHC risk genes
Arthritogenic antigen
Macrofag
Sel dendrit
Blys (B-lymphocytes stimulator)
APRIL (a proliferating inducing legand)
Merokok
Gender

Banyak sekali faktor yg terlibat

Ada interaksi diantara faktor-faktor tsb

- breakdown of self tolerance

- inflamasi yg merusak jaringan

Epidemiology
Common

disease: affects ~1% of the population

Predominantly
Onset

affects women

of disease is usually between 40 and 50

years of age, but can start at any age

Occurs

in all races and ethnic groups, but is rare in

less developed and more rural parts of the world

Aetiology/pathogenesis
Rheumatoid

arthritis (RA) is a chronic, inflammatory,

systemic, autoimmune disease

Mainly

a polyarticular disease

Chronic

inflammation in the synovial membrane of

affected joints

The

specific cause of RA is unknown, but the immune

response is well characterised

PATOGENESIS ETIOLOGIK
Perubahan berupa :
Kerusakan mikrovaskuler, oedem jaringan sinovial, proliferasi
lining sel pada sinovial.
Terdapat sel leukosit polimorfonuklear pada permukaan
sinovial.
Terjadi obliterasi pada pembuluh darah kecil akibat adanya
inflamasi dan trombi yang terorganisir.
Cairan sinovial mengandung banyak sel mononuklear leukosit

PATOLOGI SELULER
Tampak adanya :
Oedema sinovial
Hiperplasia dan hipertropi sel lining sinovial yang dapat
menebal oleh karena peningkatan sel A (reticuloendothelial
like) dan sel tipe B
Lisosom merusak
Obstruksi kapiler
infiltrasi sel neutrofil pada dinding arteri
Daerah trombosis
Perdarahan perivaskuler

Etiopathogenese RA

Kombinasi berbagai faktor genetik

Respon imun atau inflamasi akibat infeksi

Autoimunitas terhadap berbagai komponen sendi,

seperti sinovium dan rawan sendi, akibat auto antibodi
patogen atau sel T yg mengalami auto reaksi

Kelainan pengaturan produksi berbagai sitokin yg

berfungsi sebagai sitokin proinflamasi atau dlm
kerusakan sendi

Transformasi komponen seluler sinovium menjadi

autonom, membentuk sel-sel yg dpt menginvasi jaringan

Sitokin Proinflamasi :
TNF- , IL-1 , GM-CSF, M-CSF dan IL-8
Sitokin anti inflamasi :
IL-10, IL-11, TGF-
Antagonis reseptor IL-1, reseptor TNF terlarut

PATOGENESA

Rantai peristiwa imunologis

Antigen dalam membran sinovial diproses APC (sinoviosit

A, sel dendritik, makrofag) HLA DR

Ag dikenali, diproses, diikat oleh CD4 +

kompleks trimolekular. Dengan bantuan IL-1
menyebabkan aktivasi CD4+

Ag kompleks trimolekular mengekspresikan IL-2 pada

permukaan CD4+

 CD4+

yang teraktivasi juga mensekresi gamma

interferon, TNF-, IL-3, IL-4, granulocyte colony
stimulating factor (GM-CSF)

merangsang makrofag =>fagositosis

aktivasi sel B =>produksi Ab
Ab yang dihasilkan membentuk kompleks imun
aktivasi sistem komplemen

 Fagositosis

kompleks imun disertai pembentukan

dan pembebasan radikal bebas, leukotrin , PG,
protease neutral erosi rawan sendi dan tulang

Radikal

bebas depolimerasi hialuronat

viskositas cairan sendi .

Radikal

bebas juga merusak kolagen dan

proteoglikan rawan sendi

Masuknya

sel radang ke membran sinovial

pannus (jar. Granulasi yang terdiri dari fibroblas,
mikrovaskular dan berbagai jenis sel radang)

PROSES PENGRUSAKAN
- Kerusakan rawan
- Kerusakan tendon

- Kerusakan ligament
- Kerusakan tulang

Penipisan proteoglikan : - Tidak normal

- Tidak mengkilat
- Tidak kenyal
- Kurang kuat
Proliferasi membran sinovial
Pannus : jaringan granulasi vaskuler terdiri dari
fibroblas yang berproliferasi
pembuluh darah kecil
sel inflamasi
menimbulkan kerusakan

Primer penyakit synovial,

Sekunder perobahan pada sinovial, fluid,
cartilage, paraarticuler, tendon dan komponen
vascular.

Pathogenesis

APC = antigen presenting cell

Maini. Rheumatology

Potential Roles of B Cells in the

Immunopathogenesis of RA

Secretion of proinflammatory
cytokines

Antigen presentation

T-cell activation

B cell

B cell

B cell

Dendritic
cell
IL-6

TNF-

Autoantibody production
and self-perpetuation

IL-10

Plasma
cell

T cell

RF
TNF-

Macrophage

RF

RF

RF

RF

Fix complement

IL-1
IL-6

TNF-

IL-10

Inflammatory
damage
(Drner & Burmester, 2003; Edwards et al, 1999; Gause & Berek,
2001; Shaw et al, 2003; Takemura et al, 2001; Zhang & Bridges,
1986)

Cartilage loss

Inflamed
synovia

Compromised integrity of
the joint structure leading to disability

Clinical pattern
Progressive

onset (from
weeks to months)
Pain and stiffness
(synovitis)
Swollen joints
Symmetric articular pattern
Flu-like symptoms
Morning stiffness
Fatigue
Lipsky (1998); Wolfe
(1996)

Clinical pattern (contd)

At

onset, RA usually affects hands, wrists

and feet
Often a chronic cyclical course
During flare-ups, new joints are affected
and existing lesions are worsened
Joints become deformed, leading to
additional disability

TANGAN
Bentuk jari spindle- shape fusiform ok pembengkakan PIP
Swan neck deformitis ( hiperextensi PIP flexi DIP )
Boutonniere deformitas ( Flexi PIP extensi DIP)
Ibu jari :
- hiperextensi sendi interphalang dan flexsi MCP
daya jepit jempol menghilang

Lateral deviation of the MCP joints

Slide 9

- Simetris
Penting untuk RA
Bedakan dengan arthritis yang lain
DIP tak kena
morning stiffness dapat dipakai sebagai ukuran beratnya
penyakit

PERGELANGAN TANGAN
(Sangat sering terkena A.R.)
* Boggy synovium
* Pembengkakan ulnar
* Dorsoflexi pergelangan tangan terganggu
* Sindrome Carpal-tunnel ( N.Medianus tertekan)

SIKU

BAHU

* fleksi kontraktur

* Sendi glenohumeralis

* Pembengkakan

* Acromioclavicularis

* Destruksi para-olekranon

* Thoracoscapularis

* Dislokasi sendi

PANGGUL

LUTUT

(jarang terkena A.R)

(sering terkena A.R)

* Hypertrofi sinovium

* Langkah abnormal

* Efusi sendi

* Gerak sendi terbatas

* Atrofi otot quadricep

* Rasa tak enak pd lipatan

* Terbentuk kista Baker

paha

(bila pecah keluhan mirip

thromboplebitis)
* Instabilitas sendi

KAKI DAN PERGELANGAN KAKI

Gerakan fleksi dan ekstensi terbatas
Sakit pada daerah tumit atau bursa dibawah
tendon Achiles dan telapak kaki bila berjalan
Hallux valgus (deviasi lateral ibu jari

CERVICAL
* Nyeri dan kaku leher
* Erosi progressif
* Sub luxatio Atlanto axial.
= compressi Med. Spinalis gejala neurologis
= perputaran dan penekanan arteri vertebralis
(dpt menimbulkan sinkope sewaktu menundukan kepala)
* Nyeri lokal
* Spasme otot gerak memutar terbatas
* Sakit kepala daerah occiput

Extra-articular pattern
In

some cases, RA has an extra-articular pattern

(involvement of other organ systems)

Usually

occurs in rheumatoid factor (RF)-positive

patients with more severe articular disease

More

common in men

 Vaskulitis
Kelainan Paru (Pleuritis, Pneumonitis)
Perikarditis
Nodul Reumatik : - bursa olekranon
- eksternal lengan atas
- tendo Achilles
- telinga
Neuropati
Lesi kornea dan konjunctiva
Skleritis

 Pembesaran kelenjar getah bening

Pembesaran limfa
Hiperpigmentasi
Ulkus di kulit
Limf adenopati
Anemia
Thrombositopenia

LABORATORIUM
* BSR meninggi
* Anemia ringan
* Rheuma factor :
Rose waaler lebih spesific / latex lebih sensitif.
* Faktor APF amat spesifik
* Darah rutin, urine rutin, faal ginjal, faal hepar
* Cairan sinovial berupa exudat

Diagnosis
Clinical

pattern

Biology
Imagery

Biology

Elevation of common non-specific serum markers of

inflammation contributes to the assessment of disease
activity level
Erythrocyte

sedimentation rate (ESR)

C-reactive protein (CRP)

Rheumatoid factors (RF)

Usually

appear in the first year of the disease

~80% of RA patients are RF+ (IgM the main isotype)
Associated with more rapidly evolving the more erosive
disease and a higher incidence of extra-articular
manifestations
RF can be detected in healthy patients during infections (4%
in Caucasians)
RF also associated with other chronic diseases (1)

Imagery conventional X-ray

Performed

at disease onset and on a regular basis

Usually hands and feet; other joints monitored
according to the disease pattern
Bone erosions and joint space narrowing patterns
noted
Approximately 30% of patients already have bony
erosion at disease onset (>60% at 2 years)

Common X-ray features

Cartilage

damage (joint
space narrowing)

Bone

erosion

Ultrasounds and MRI

Synovitis

detection is mainly assessed

clinically
In

difficult cases, ultrasound may be useful

to detect synovitis and tenosynovitis

MRI

is not used in routine practice

Diagnostic criteria
The

diagnosis of RA relies on criteria

defined by the American College of
Rheumatology (ACR) classification

As

the disease generally has a

progressive course, a formal diagnosis is
usually delayed by some months from the
appearance of the first symptoms

Diagnostic criteria (ACR)

Presence of at least 4 of the following criteria:

Morning stiffness 1 hour

Arthritis of 3 of the following joints: right or left proximal
interphalangeal (PIP), metacarpophalangeal (MCP), wrist,
elbow, knee, ankle and metatarsophalangeal (MTP) joints
Arthritis of wrist, MCP or PIP joint
Symmetric involvement of joints
Rheumatoid nodules over bony prominences, or extensor
surfaces, or in juxta-articular regions
Positive serum RF
Radiographical changes, including erosions or bony
decalcification localised in or adjacent to the involved joints

Artritis Reumatoid ( ACR, 1987 ) :

1. Kaku pagi minimal 1 jam untuk jangka
waktu minimal 6 minggu
2. Bengkak 3 sendi atau lebih untuk
jangka waktu minimal 6 minggu
3. Bengkak sendi pergelangan tangan,
metacapofalangeal atau proksimal
interfalang selama 6 minggu atau lebih
4. Bengkak sendi yang simetrik

5. Perubahan radilogik tangan yang tipikal

untuk artritis reumatoid yang harus
meliputi erosi dan dekalsifikasi tulang
unequivocal.
6. Nodul reumatoid
7. Faktor reumatoid positif (dengan metode
dimana orang normal positif kurang dari 5 %)
Diagnosa artritis reumatoid ditegakkan bila
ditemukan 4 kriteria atau lebih.

DIAGNOSA BANDING
Rheumatic Fever :

- respons dengan salisylate

- carditis, chorea, skin rash
- ASTO meninggi

SLE :

- Butterfly rash
- Renal disease
- L.E positif

Osteoarthrosis ::

- tanda inflamasi minimal

- Pain sore

Gouty Arthritis:

- acute onsetc
- rystal urate
- tophi

Pyogenic Arthritis : demam, micr. organism didapat

Therapeutic goals
Primary

goals in the treatment of RA

Prevention

or control of structural damage to

joints
Prevention or reversal of disability
Pain relief
To improve quality of life
The

ultimate goal is to achieve disease

remission

Current treatment strategy in RA

The goal is to achieve low disease activity
or remission
Early and intensive treatment intervention
Control efficacy by monitoring disease activity
Rapid switching with lack of improvement

Treatment strategy approaches

Dramatically

changed over the last decade

Moved towards an early pharmacological
treatment intervention
To induce remission
To slow (prevent) radiological
progression and prevent disability

Treatment strategy approaches

Since the 1990s
Emphasis

on limiting joint destruction

Earlier use of intensive treatment
Methotrexate and sulfasalazine are considered
first-choice DMARDs
Use of combination therapy including triple
therapy in difficult disease (methotrexate,
sulfasalazine, fractal signature analysis)

ACR GUIDELINES IN RA TREATMENT

ESTABLISH
RA DIAGNOSIS

Evaluate
Disease activity/extent of synovitis
Structural damage
Functional/psychosocial status

Initiate Treatment
Patient education
Physical and occupational therapy, etc.
NSAIDs
Possible local or oral steroids ( 10 mg. Prednisone)

Assess Disease Activity

ACR GUIDELINES IN RA TREATMENT

Assess Disease Activity

Spontaneous Remission (uncommon)

Persistent Active Disease

Monitor Disease Activity

Start DMARD
Consult Rheumatologist
Persistent Active Disease

Reactivation of Disease
Remission or Satisfactory Control

Monitor Disease Activity

Reactivation of Disease

Revise Treatment Plan

Consult Rheumatologist Remission or Satisfactory Control
Change NSAIDs
Monitor Disease Activity
Change/add DMARDs
Periodically
Local or oral steroids
Rehabilitation

ACR GUIDELINES IN RA TREATMENT

Revise Treatment Plan
Consult Rheumatologist
Change NSAIDs
Change/add DMARDs
Local or oral steroids
Rehabilitation
Mechanical Joint Symptoms

Surgical Intervention
Mechanical Joint Symptoms

Monitor Disease Activity

Periodically
Reactivation of Disease

Persistent
Active
Disease

Refractory Rheumatoid Arthritis

Consult Rheumatologist
Most effective NSAID
Most effective DMARD
Possible local or oral steroids Remission or Satisfactory Control
Rehabilitation

EULAR Definition of Improvement in RA

EULAR response criteria are based on DAS28

DAS is divided into 3 categories:

Low disease activity (2.4)

Moderate disease activity (>2.4 and 3.7)
High disease activity (>3.7)

Improvement in the DAS is compared with a patients baseline DAS

Good response is defined as a >1.2 improvement in the DAS compared with
baseline and a DAS attained during follow-up of 2.4

(Improvement in DAS from baseline)

2.4
>2.4 and 3.7

>1.2
Good response

1.2 and >0.6

0.6

Moderate response

>3.7
(DAS attained
during follow-up)
(van Gestel 1996)

No response

4. Anti inflamasi non steroid (NSAID)

- ibuprofen (600-1200 mg/hari)
- naproxen (375-750 mg/hari)
- piroxicam (10-40 mg/hari)
- profenid (100-600 mg/hari)
- ketoprofen (100-200 mg/hari)
NSAID
Menghambat enzim cyclo-oxigenase menekan sintesis
prostaglandin.
Memungkinkan stabilisasi membrane lysosomal
Menghambat pembebasan aktifitas mediator inflamasi
Menghambat migrasi sel ketempat peradangan
Menghambat proliferasi seluler

Tabel 1. Beberapa jenis analgetik dan NSAID yang umum digunakan

dalam terapi penyakit reumatik

Nama Generik
Parasetamol
Mefenamic acid
Tramadol
Metamizole
Methampyron
Morphin sulfate
Meloxicam
Nimesulide
Etodolac
Fenbufen

Golongan

Preparat
Panadol 500 mg
Ponstant 250, 500 mg
Novalges 50 mg
Novalgin 500 mg
Neoralgin 500 mg
MST continus 10,15,30,60,100 mg
Meloxin tabs 7,5 mg, 15 mg
Nicox tabs 100 mg
lonene 100, 300 mg
Cybufeb 300 mg

Nama Generik

Golongan

Preparat

Piroxicam

Oxicam

Feldene caps 10,20 mg

Tenoxicam

Oxicam

Na.Diclofenac
Indomethasin
Diflunisal
Tiaprofenic acid
Ibuprofen
Ketoprofen
Naproxen
Pirprofen
Carprofen

Acetic Acid
Acetic Acid

Tilcotil tabs 20 mg
Voltaren tabs 25,50,SR75 mg
Indocid caps 25 mg

Carbonic Acid

Diflonid tabs 250,500 mg

Propionic Acid

Surgam tabs 200 mg

Propionic Acid

Motrin tabs 200,400 mg

Propionic Acid
Propionic Acid

Profenid E50, E100, 200 mg & supp

Naxen tabs 250,500 mg

Propionic Acid

Rengasil tabs 200 mg

Propionic Acid

Imadil tabs 150 mg

Celecoxib

Cox 2 inhibitor

Celebrex 150, 300 mg

OBAT-OBAT REMITIF
DMADRS
Bekerja lambat menunggu kadar di darah cukup
Khasiat baru mulai 3-12 bulan
Side effect dan toksisitas tinggi
Diharapkan dapat menghentikan progresifitas/
menjadi remisi.

= destruksi sendi pada masa dini (90% RA erosi 2 thn pertama.

= Hasil pengobatan yang buruk mungkin karena terlambat
memulai DMARD

 Diagnosa pasti : DMARD segera diberi

Tersangka RA, respons NSAID minimal mulai DMARD
Setelah pakai 3-6 bulan tak memuaskan
Ganti DMARD lain
Kombinasi dengan yang lain

Klasifikasi obat-obat anti rematik (Edmon et al) :

1. Symptom-modifying anti-rheumatic drugs (SMARDs)
Ini akan memperbaiki simptom dan gejala klinis
NSAIDs
Kortikosteroid
Obat-obat kerja lambat : antimalaria, SASP, garam emas,
DP, obat sitotoksik
2. Disease controlling anti rheumatic therapy
Obat ini merubah perjalanan penyakit RA, dengan cara:
Memperbaiki dan mempertahankan fungsi sehubungan
dengan berkurangnya peradangan sinovial
Mencegah dan mengurangi progresifitas kerusakan struktur
sendi

 DMARD

yang lazim digunakan dalam

pengobatan AR

1. Klorokuin atau hidroksiklorokuinm

2. Sulfasalazine
3. D-penisilamin
4. Garam emas
5. MTX
6. Siklosporin -A
7. Leflunomide
Gene therapy
Biological agent

CHLOROQUIN PHOSPHAT : 250 - 500 MG / HARI

HYDROXYCHLOROQUIN : 200 - 400 MG / HARI

Terapi AR sejak tahun 1950-an

Di Indonesia paling banyak

Mengandung 4-aminoquinoline. Klorokuin

=>kelompok ethyl, hidroksiklorokuin =>
hydroxyethyl