IMMUNOLOGY DISORDER AND

ACTUAL MANAGEMENT OF ARTRITIS

REUMATOID

ZAINALARIFINADNAN
Rheumatologydivisioninternalmedicinedepartment
Sebelasmaretuniversitymedicalfacultydr.Moewardihospital
Surakarta

DEFINISI RHEUMATOID ARTHRITIS

A chronic autoimmune disease characterized by the inflammation of the synovial joints

Has a symmetrical bilateral effect on joints

Results in joint deformity and immobilization
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by joint swelling, joint
tenderness, and destruction of synovial joints, leading to severe disability and premature mortality
(EULAR 2010)

(The Arthritis Society, 2012; Gulanick & Myers, 2011; Firth, 2011)

Systemic symptoms and signs :

Fatigue
Weakness
Depression
General malaise
Low-grade fever of undetermined origin
Unexplained weight loss

Anderson RJ. In: Klippel JH, et al, eds. Primer on the Rheumatic Diseases. 12th ed. Atlanta, GA:
Arthritis Foundation; 2001:218225.

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SYSTEMIC ORGAN INVOLVEMENT OBSERVED IN RA

Ocular manifestations
Keratoconjunctivitis sicca, episcleritis, scleritis
Pulmonary manifestations
Inflammation of the cricoarytenoid joint, interstitial fibrosis,
pulmonary nodules, pleuritis, pleural effusions
Vasculitis
Subcutaneous nodules, leukocytoclastic vasculitis, dermal
lesions, ischemic ulcers
Neurologic complications
Peripheral neuropathy, entrapment syndromes, cervical
myelopathy, mononeuritis multiplex, Feltys syndrome
Hematologic manifestations
Anemia, thrombocytosis
Anderson RJ. In: Klippel JH, et al, eds. Primer on the Rheumatic Diseases. 12th ed. Atlanta, GA: Arthritis
Foundation; 2001:218225.

I.4

EPIDEMIOLOGY OF RA
Prevalence ranges from 0.5% to 1%, affecting nearly
2.5 million Americans and 165 million people
worldwide
Prevalence may be as high as 7% and as low as 0% in
different ethnic groups
Up to 7% in certain American Indian tribes
Virtually 0% in Asia and southern Africa
Age of onset is typically between 25 and 50 years
Female-to-male ratio is approximately 3:1
Annual incidence ranges from 14.3 cases per
100,000 in men to 35.9 cases per 100,000 in
women
Silman AJ, Pearson JE. Arthritis Res. 2002;4(suppl 3):S265S272; CDC National Center for Chronic Disease
Prevention and Health Promotion. Available at: http://cdc.gov/nccdphp/aag/aag_arthritis.htm;
Gabriel SE. Rheum Dis Clin North Am. 2001;27:269281; Lawrence R, et al. Arthritis Rheum. 1998;41:778799. I.7

RA: MORBIDITY
Increased morbidity for patients with RA
Twice as likely to develop a myocardial infarction (MI)
70% more likely to suffer a stroke
70% more likely to develop an infection
Increased risk of lymphoma
Up to 26-fold higher risk, depending on severity of
disease and exposure to immunosuppressive drugs,
including methotrexate
Increased morbidity for women with RA
2- to 3-fold increase in the risk of developing an MI
48% higher risk of suffering a stroke
Brown SL, et al. Arthritis Rheum. 2002;46:31513158; Bjornadal L, et al. J Rheumatol. 2002;29:906912;
Wolfe F, et al. J Rheumatol. 2003;30:3640; Doran MF, et al. Arthritis Rheum. 2002;46:22872293;
Asten P, et al. J Rheumatol. 1999;26:17051714; Jones M, et al. Br J Rheumatol. 1996;35:738745;
Baecklund E, et al. BMJ. 1998;317:180181; Isomaki HA, et al. J Chronic Dis. 1978;31:691696;
Solomon DH, et al. Circulation. 2003;107:13031307.

I.11

RA: MORTALITY RATES

RA results in higher mortality rates

27% higher than in the general population
(41% higher for women)
Life expectancy in patients with RA is reduced
by as much as 18 years compared to age- and
sex-matched controls without RA

Brown SL, et al. Arthritis Rheum. 2002;46:31513158; Bjornadal L, et al. J Rheumatol. 2002;29:906912;
Wolfe F, et al. J Rheumatol. 2003;30:3640; Gabriel SE, et al. Arthritis Rheum. 2003;48:5458; Doran MF, et al.
Arthritis Rheum. 2002;46:22872293; Asten P, et al. J Rheumatol. 1999;26:17051714; Jones M, et al. Br J
Rheumatol. 1996;35:738745; Baecklund E, et al. BMJ. 1998;317:180181; Isomaki HA, et al. J Chronic Dis.
1978;31:691696; Gridley G, et al. J Natl Cancer Inst. 1993;85:307311; Thomas E, et al. Int J Cancer.
2000;88:497502; Wolfe F, et al. Arthritis Rheum. 1994;37:481494.
I.10

RA: Impact on Quality of Life

RA has a negative impact on quality of life
Pain associated with functional disability
81% of patients suffer fatigue, 42% with severe fatigue
Up to 40% of patients suffer depression that impacts
personal and family life
Loss of productivity in patients with RA is well known
Average of 30 lost days of work per year
Average earnings loss is 50%

Allaire SH, et al. PharmacoEconomics. 1994;6:513522; Wolfe F, et al. J Rheumatol. 1996;23:14071417;

Verhoeven AC, et al. Br J Rheumatol. 1998;37:612619; Lard LR, et al. Am J Med. 2001;111:446451;
Goldbach-Mansky R, Lipsky PE. Annu Rev Med. 2003;54:197216.

I.12

RA: IMPACT ON QUALITY OF LIFE

SF-36 MEASURES
Mean Score
Variable
Physical Functioning
Social Functioning
Role Limitations
Physical
Emotional
Mental Health
Energy/vitality
Bodily Pain
General health
PCS
MCS

General Population

RA Population

73
80

40*
65*

69
79
72
44
38
67
45
50

30*
60*
69*
42*
37*
58*
32*
50

*P < 0.0001; P = NS.

PCS and MCS = physical and mental component summary, respectively.
SF-36 is based on a scale of 0 (worst possible health state) to 100 (best possible health state).
Kosinski M, et al. Med Care. 1999;37(suppl):MS23MS39.

I.13

FEATURES RELATED TO POOR OUTCOMES IN RA

Extra-articular signs and symptoms (eg, cutaneous ulcers,
vasculitic rash, neuropathy, scleritis, subcutaneous nodules)
Female gender
Shared epitopes
Poor functional status
Involvement of multiple joints
Early radiographic evidence of erosive changes
Advanced age at onset of disease
High RF titer
Sustained elevation of acute-phase reactants (eg, ESR)
Low socioeconomic status/educational level

Anaya JM, et al. Ann Rheum Dis. 1994;53:782783; Pincus T, Callahan LF. Ballieres Clin Rheumatol.
1992;6:161191; Furst DE. Rheum Dis Clin North Am. 1994;20:309319.

I.14

SPECTRUM OF AR
Onset
Mild
Symptoms

Pain
Stiffness

Fatigue
Extra-articular
Malaise
manifestations
Fever

Intermediate

Severe

Polysynovitis
Systemic
Functional limitation manifestations
Secondary FM
Depression

Nodules
Interstitial lung disease
Sjgrens

Soft tissue Joint space

Disease
swelling
narrowing
progression
Osteopenia Erosions

Ankylosis
Deformity

Impaired
Morbidity & function
mortality Pain

Surgery
Hospitalization
Death

Disability
Comorbidities
RA complications

I.15

DISTRIBUTION OF AR

Clinical Spectrum of RA

Images courtesy of J. Cush, 2002.

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RA Progression
Inflammation
Disability
Severity (arbitrary units)

Radiographs

10

15

20

25

30

Duration of Disease (years)

Adapted from Kirwan JR. J Rheumatol. 2001;28:881886.

I.6

THE CHALLENGES OF RA
Reliable diagnosis of early RA
RA is a heterogeneous disease that differs substantially from patient to patient
in presentation and progression

Detection of early inflammatory arthritis

Detection of the earliest events that
predictably lead to destructive synovitis

Silman AJ, Pearson JE. Arthritis Res. 2002;4(suppl 3):S265S272; El-Gabalawy HD, Lipsky PE.
Arthritis Res. 2002;4(suppl 3):S297S301.

I.19

THE ETIOLOGY OF RA IS PRESENTLY UNKNOWN

Infectious agent(s)?
Genetic susceptibility?
HLA-DR4 and -DR1 Class II MHC leukocyte antigen
types
Especially Dw4, Dw14, and Dw15
Enhanced T cell responses to inflammatory stimuli
Autoimmune mechanisms
Intrinsic abnormalities in synovial responses
Environmental factors?
Do environmental or genetic effects account for ethnic
differences in the prevalence of RA?
Silman AJ, Pearson JE. Arthritis Res. 2002;4(suppl 3):S265S272; El-Gabalawy HD, Lipsky PE. Arthritis
Res. 2002;4(suppl 3):S297S301.

I.18

Cytokine Functions Relevant to RA

Regulation of the inflammatory response
Proinflammatory: TNF, IL-1, IL-6, IL-7, chemokines
Anti-inflammatory: IL-10, TGF, IL-4, IL-1Ra, sTNFR I/II, IL-1R II

Modulation of the immune response

Modify Th1/Th2 bias
Th1: IL-12, IL-18, IFN
Th2: IL-4, IL-13, IL-10, chemokines
Mediate activation/apoptosis: IL-2, IL-15, IFN, IL-3, IL-5, IL-7

Tissue Remodeling
Bone and cartilage destruction: IL-1, TNF, OPG/RANKL
Angiogenesis/growth factors: TNF, VEGF, TGF
Kavanaugh A. Arthritis Rheum. 2002;47:8792.

Disease Progression
Normal Joint
Early RA

Bone

Neutrophils

Capsule

Hyperplastic
synovial
membrane

Synovial
membrane

Cartilage

Synoviocytes

Capillary formation
Hypertrophic
synoviocyte

T Cells

B Cells

Established RA
Neutrophils
Plasma cell
Synovial villi
Extensive
angiogenesis
Eroded bone

Adapted with permission from Choy EH, Panayi GS. N Engl J Med. 2001;344:907916.

Pannus

Cytokine Signaling Pathways Involved in RA

RF
IL-4
IL-6
IL-10

Plasma
cell

IL-4
IL-10

Synovium

Macrophage

Th0
IFN
IL-12

B cell

Th2

Interferon

CD4 + T cell
CD11
CD69
OPGL
CD69 CD11

Osteoclast

Fibroblast

Chondrocyte

Production of metalloproteinases and

other effector molecules
Migration of polymorphonuclear cells
Erosion of bone and cartilage

Choy EH, Panayi GS. N Engl J Med. 2001;344:907916.

TNF
IL-1
IL-6

T Cells, Macrophages, and

Cytokines in Autoimmune Diseases
IL-18

IL-12

IL-2
TNF

LT
IFN

TNF
IFN

IL-12

IL-18
IL-1

IL-1

IFN

TNF

Shibatomi K, et al. Arthritis Rheum. 2001;44:884892; Brennan FM, Feldman M. Curr Opin Immunol.
1992;4:754759; Pruimboom WM, et al. Prostaglandins Leukot Essent Fatty Acids. 1994;50:183192.

I N F LAM M AT I O N

I N F LAM M AT I O N

IMMUNE DEFECT
ANTIGEN

Effects of IL-1 and TNF on Bone Remodeling

T cell
Osteoclast
precursor

IL-1 TNF

TNF

M-CSF
RANKL

RANK

OPG

Bone-lining cells

IL-1
Bone

Osteoclas
t

Adapted from Gravallese EM, Goldring SR. Arthritis Rheum. 2000;43:2143

2151.

Restoration of Equilibrium in Rheumatoid Synovitis

Anti-inflammatory
-

TIMPs

Proinflammatory
TGF
MMPs

IL-1, TNF
GM-CSF, IFN
IL-6, IL-8
IL-15, IL-16
IL-17, IL-18

Autoimmune diseases
Adapted from Arend WP. Arthritis Rheum. 2001;45:101106.

IL-1Ra
sIL-1RII
IL-1 Ra
MAb to IL-6R
MAb to TNF
sTNFR, IL-4, IL-10
IL-11, IL-13, IL-18 BP

Inhibition of Cytokines
Normal interaction

Neutralization of cytokines

Inflammatory
cytokine

Monoclonal
antibody

Cytokine
receptor

Soluble
receptor

Inflammatory
signal

No signal

Receptor blockade

Activation of
anti-inflammatory pathways

Monoclonal
antibody
Receptor
antagonist
No signal

Adapted with permission from Choy EH, Panayi GS. N Engl J Med. 2001;344:907916.

Anti-inflammatory
cytokine
Suppression of
inflammatory
cytokines

RA: CURRENT PHARMACOLOGIC OPTIONS

Agents that are effective in controlling the signs
and symptoms of RA, but have no effect on
disease progression
NSAIDs reduce inflammation and pain
COX-2 inhibitors are similar to NSAIDs, but with improved
GI safety and tolerability
DMARDs impact the signs, symptoms, and disease
progression of RA, as well as improve the
quality of life and functionality of the patient
Corticosteroids have anti-inflammatory and
immunoregulatory activity, but nominal diseasemodifying capability
Irvine S, et al. Ann Rheum Dis. 1999;58:510513; Madhok R, Capell HA. Lancet 1999;353:257258;
ACR Subcommittee on RA Guidelines. Arthritis Rheum. 2002;46:328346; Goldbach-Mansky R, Lipsky PE.
Annu Rev Med. 2003;54:197216.

I.20

1.
2.
3.
4.
5.
6.
7.

RA CLASSIFICATION CRITERIA 1987

AMERICAN COLLEGE OF
RHEUMATOLOGY
Morning
stiffness in and around the joints lasting at least
1 hour
At least 3 joint areas simultaneously have had soft tissue
swelling or fluid (PIP, MCP, wrist, elbow, knee, ankle, and
MTP)
At least 1 area swollen (as defined above) in a wrist,
MCP, or PIP joint
Symmetrical involvement of the same joint areas (as
defined in 2)
Subcutaneous nodules over bony prominences, extensor
surfaces, or in juxta-articular regions
Postive serum Rheumatoid Factor
Radiographic changes typical of rheumatoid arthritis on
hand and wrist radiographs (must include erosions or
unequivocal bony decalcification)

Felson DT et al. Arthritis Rheum.

Rheum. 1995;38:727735.

Need 4 of 7 for Diagnosis

.

Felson DT et al. Arthritis Rheum.

Rheum. 1998;41:1564
1998;41:15641570

MEDICATIONS

There are four types of medications used to treat

RA:
Non-steroidal anti-inflammatory drugs (NSAIDs)
Disease-modifying anti-rheumatic drugs(DMARDS).
Corticosteroids
Biologic Response Modifiers (Bioligics)

(Arthritis Foundation, 2012; Gulanick & Myers 2011)

METHOTREXATE (MTX)
MTX is the most frequently used DMRAD for RA
Recommended dosage is 7.5 mg once weekly 15-20
mg weekly
Level function test must be checked every 3-6 month
and also Hb, WBC and thrombocyt.
Few of patient gets mild lung fibrosis

Treatment: The Earlier the Better

Delayed Treatment*
(median treatment lag time = 123 days; n = 109)
Early Treatment*
(median treatment lag time = 15 days; n = 97)

Change in Median
Sharp Score

14
12
10
8
6
4
2
0
0

12

18

24

Time (months)
*Patients were treated with chloroquine or azathioprine.
Lard LR, et al. Am J Med. 2001;111:446451.

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ANTI MALARIA ~ HYDROCHLOROQUINE

Hydrochloroquine 200 mg daily is usually
recommended dose
Eye test in every 6 month must be checked
for early side effects like maculopathy,
retinopathy
Few of patient experiences heart palpitation
in the beginning of therapy

SALASOPYRINE & AZATHIOPYRINE

Salasopyrine
By oral and starting with 500 mg 2 gram daily
(sometimes till 3 gram)
Side effects is similar to group sulfadiazine and
sulfa derivate
Azathiopyrine/Imuran
This groups are not more used since the
introducing the biologic agents (Endoxan,
Sandimun)

GOLD THERAPY
For Injection can be injected starting with 10 mg
20 mg 50 mg until the remission will achieve
reduce till 50 mg monthly
Oral Gold Auronofin can be used with dose 3 mg
twice daily
Check urine for early reversible proteinurie and bone
marrow depression are recommended although the
side effects are very rare and reversible

BIOLOGIC DMARDS
Characteristic

Anakinra

Etanercept

Infliximab

Adalimumab

Class

IL-1Ra

sTNFR

TNF MAb

TNF MAb

Construct

Recombinant

Recombinant
fusion protein

Chimeric MAb

Recombinant
human MAb

Half-life

46 hours

4 days

810 days

1020 days

Binding target

Type I IL-1Ra

TNF/LT

TNF

TNF

Administration

100 mg
SC
Daily

25 mg
SC
Twice weekly

310 mg/kg
IV with MTX
Every 48 wk

40 mg
SC
Every other
week*

*May be administered weekly as monotherapy (ie, 40 mg SC without concomitant MTX)

IL = interleukin; IV = intravenous; LT = lymphotoxin; MAb = monoclonal antibody;
SC = subcutaneous; sTNFR = soluble TNF receptor human IgG complex
Enbrel (etanercept) package insert, 2002; Remicade (infliximab) package insert, 2002; Humira
(adalimumab) package insert, 2002; Kineret (anakinra) package insert, 2002.

Safety Considerations With Biologic DMARDs

Serious infections
Opportunistic infections (TB)
Malignancies
Demyelination
Hematologic abnormalities
Administration reactions
Congestive heart failure
Autoantibodies and lupus

REMISSION CRITERIA

TERIMA
KASIH