Rheumatoid arthritis :

the importance of early

diagnosis and treatment

Handono Kalim
Div of Reumato-immunology,
Internal Medicine Department,
Brawijaya University, Malang
RA : a chronic and progressive joints
damage
 Progressive joint damage in RA
Early phase Intermediate phase Late phase
 Early arthritis rheumatoid

Periarticular osteoporosis

Joint swelling

Extensive erosive
destruction

Loss of joint space

RA two years after the onset

of the disease
 Most RA Patients Develop Bone
Erosions During First 2 Years of Disease

100
Cumulative Percentage of

90
Patients with Erosions

80
70
60
50
Hands
40
Feet
30
Hands or Feet
20
Hands and Feet
10
0
Baseline 1 2 3 4 5
Years of Follow-Up

Patients with RA < 1 year underwent annual radiologic assessment of hands and feet.
Hulsmans HM et al. Arthritis Rheum. 2000;43:1927-1940.
 75 Grip strength
Sedimentation rate
50
Percentage Ritchie articular rate
improvement*
Walking time
25 Morning stiffness
Pain VAS
Haemoglobin
0

-25
Radiological score
Percentage
deterioration* -50

-75

Contrast between improvement in measures of

disease activity and deterioration in joint damage
 Radiological damage is a major determinant of disability
over time

Inflammation
(arbitrary units)

Disability
Severity

Radiographs

0 5 10 15 20 25 30

Duration of disease (years)

Kirwan JR. J Rheumatol. 1999;26:720-725.

RA: a systemic disease
 RA: a joint and systemic disease
Articular
Polyarticular, often
symmetrical
Extra-articular
Joint swelling and tenderness
Rheumatoid nodules
Limitation of motion
Vasculitis
Malalignment of joints
Pulmonary fibrosis
Pain, often at rest
Ocular disease
Marked morning stiffness
(sicca, episcleritis)
Systemic Carditis, pericarditis
Fever, weight loss, fatigue,
anemia, increased CRP
Morning stiffness almost
universal
 Vasculitis
Sub cutaneus nodule

Raynaud Phenomena
Xerophthalmia (Dry Eyes)

Xerostomia
(Dry Mouth)

Osteoporosis
Pulmonary Fibrosis
Pleural effusion
 Increased risk of Functional Decline Begins
cardiovascular disease Early in RA

CV death OA

Moderate Severe Very severe

CHF loss of loss of loss of
RA function* function function*
*
CVA

MI

1.0 1.5 2.0

Odd ratio
Wolfe J Rheumatol 2003, Haara
Ann Rheum Dis 2003
0 2 5 10
Years from Symptom Onset
* 50% rates of loss of function based on HAQ
scores
Wolfe F, Cathey MA. J Rheumatol. 1991;18:1298-1306.
The need of early diagnosis
and treatment
New paradigm in the treatment of RA :
the need of early diagnosis

ACR 1987 CLASSIFICATION CRITERIA FOR RA

Requires four out of the seven criteria:

1. Morning stiffness*
2. Arthritis of three or more joints*
3. Arthritis of hand joints*
4. Symmetric arthritis*
5. Rheumatoid nodules
6. Serum rheumatoid factor
7. Radiographic changes
*Must have been present for at least six weeks
 ACR/EULAR 2010 Rheumatoid Arthritis criteria
A Joint involvement 1 large joint 0

2-10 large joints 1

1-3 small joints 2
4-10 small joints 3
> 10 joints ( min. 1 small joint ) 5
B Serology RF or ACPA negative 0
RF or ACPA low positive 2
RF or ACPA high positive 3
C Acute phase reactant Normal CRP or ESR 0
Abnormal CRP or ESR 1
D Duration of illness < 6 weeks 0
> 6 weeks 1
New paradigm in the treatment of RA
: the need of aggressive approach

Biologic

The third-line drug

(DMARDs)
The second-line drug
(Corticosteroid)

The first-line drug

(NSAID)

Akira Hashimoto: Mansei Kansetu Ryuumachi, Hoken Dohjinsha Inc., pp. 70

 ACR treatment guidelines: Diagnosis and
initial therapy
Establish diagnosis of rheumatoid arthritis early
Document baseline disease activity and damage
Estimate prognosis
Primary care physician

INITIATE THERAPY
Patient education
Start DMARD(s) within 3 months
Rheumatologist

Consider NSAIDs
Consider local or low-dose systemic steroids
Physical therapy/occupational therapy

Periodically assess disease activity

Inadequate response
Adequate response (ongoing active disease after
with decreased disease activity 3 months of maximal therapy)

ALTERNATIVE TREATMENT REGIMEN

ACR Subcommittee on Rheumatoid Arthritis Guidelines. Arthritis Rheum 2002; 46:328346.
Indicators of Poor Prognosis in RA
- Reduced functional status
- Early radiographic changes
- Multiple involved joints
- Older age at onset
- High titers of rheumatoid factor
- Prolonged elevation of ESR
- Lower educational level
- Genetics (shared epitope)
 Commonly Used Conventional DMARD

DMARD Typical dosage Common Side Effects

regiments
Methotrexate 7.5-15 mg / 25 mg weekly, Nausea, mouth ulcers,
orally or s.c. neutropenia, thrombocytopenia,
(MTX)
hepatoxicity, lung fibrosis
teratogenicity

Hydroxychloroqui 200-400 mg daily, orally Nausea, corneal deposits,

retinopathy, skin rashes
ne
Sulphasalazine 500 mg daily orally, Nausea, rash, neutropenia,
increasing weekly up to 2-3 thrombocytopenia,
g daily hepatotoxicity, light sensititivity

Leflunomide 100 mg daily for 3 days Diarrhoea, alopecia,rash,

(optional), then 10-20 mg hypertension, hepatotoxicity,
daily neutropenia, thrombocytopenia,
teratogenicity

Cyclosporine A 2.5 mg/kg/day orally for 6 Renal impairment, hypertension,

weeks, then 4 mg/kg/day abnormal liver biochemistry,
nausea
 ACR treatment guidelines: Recommended
strategy following failure of initial therapy

Change/add
DMARDS
MTX Suboptimal
naive MTX response

MTX Other Combination Combination Other Biologics

monotherapy therapy therapy monotherapy

Monoterapi
Monotherapy Combination
therapy

Multiple DMARD failure

Symptomatic and/or
structural joint
damage

Surgery

ACR Subcommittee on Rheumatoid Arthritis Guidelines. Arthritis Rheum 2002; 46:328346.

Monotherapy with Tocilizumab
( ACTEMRA )
Effects of IL-6 on the biologic functions of various cells

Monocyte/ Mesenchyimal cells,

Endothel
macrophag fibroblast/
synoviocytes

T cells
activation
IL-6 Hepatocytes

Neutrophile Acute-phase proteins,

e.g. hepcidin, CRP

Megakariocytes
maturation B cells
Osteoclast activation,
bone resorption

Thrombocytosis Auto-antibodies (RF) Hyper--globulinaemia

Choy E. Rheum Dis Clin N Am 2004;30:405415.
Rose-John S, et al. Expert Opin Ther Targets 2007;11:613624.
 Tocilizumab mechanism of action
Tocilizumab block signalling pathway and gen
activation by the binding to IL-6r.1
A B
,
IL-6

ACTEMRA
ACTEMRA

mIL-6R sIL-6R

Tocilizumab bind to IL-6 cell surface (A) and soluble

receptors (B) , block activation of IL-6r.1
Tocilizumab monotherapy significantly inhibits radiographic
progression at Week 52 compared with DMARDs (SAMURAI)
Inclusion criteria: DMARD-IR, active RA 6 mo but <5 yrs, MTX 8 wks, 6 tender joints,
6 swollen joints, ESR of 30 mm/h and/or CRP of 2 mg/dl
DMARDs (n=143) Tocilizumab 8 mg/kg (n=157)
p<0.01
7
Mean change from baseline

6.1
6

5
p<0.001 p<0.05
4
3.2
2.9
3
2.3
2 1.5
0.9
1

0
Total Sharp score Erosion score Joint space
(primary endpoint) narrowing score
Nishimoto N, et al. Ann Rheum Dis 2007; 66:11621167.
 Tocilizumab inhibits 81% joints destruction better than
MTX in 2 years evaluation (LITHE study)

Placebo + MTX (n=393) ACTEMRA 8 mg/kg + MTX (n=398)

2.5 p<0.001
Mean change from baseline

2.0 1.96
p<0.001
81%
1.5 inhibition
1.24
p<0.001
1.0
0.72

0.5 0.37
0.22 0.15
n= 294 353 294 353 294 353
0.0
Total Sharp Erosion Joint space
Genant score score narrowing score
Numbers within the bars are the total numbers of patients
who reached the time point and had valid assessments.
Linear extrapolation post-rescue and post-withdrawal
data excluded. Fleischmann R, et al. EULAR 1619 June, 2010; Poster FRI0205.
ACTRAY STUDY:Tocilizumab+MTX is EQUIVALENT to Tocilizumab
monotherapy for achieving clinical endpoints at Week 24
DAS28 remission
p=0.028

70
61.7
60
51.4
50
Patients (%)

40

30

20

10

0
Analysis population:
TCZ + MTX TCZ + PBO
ITT n=142/276 n=171/277
Dougados M, et al. Ann Rheum Dis 2011;70(Suppl3):73
 Consistently high remission rate in various patients
type
MTX-nave/free DMARD-IR Anti-TNF-IR
ACTEMRA 8 mg/kg ACTEMRA 8 mg/kg ACTEMRA 8 mg/kg
monotherapy (n=286) + DMARD (n=1,406) + MTX (n=170)
MTX monotherapy (n=284) Placebo + DMARD (n=1,010) Placebo + MTX (n=158)

Odds ratio: 5.8

40 p<0.0001 p=0.0001
(95% CI 3.310.4)
34
31 30
30
Patients (%)

20
12
10
3 2
0
AMBITION1 POOLED: RADIATE3
LITHE + OPTION + TOWARD2
CI = confidence interval.
* Using erythrocyte sedimentation rate. 1Jones G, et al. Ann Rheum Dis 2010; 69:8896.
MTX-nave or MTX-free for 6 months 2F. Hoffmann-La Roche. Data on file. Pooled analysis (LITHE, OPTION, TOWARD).

prior to randomisation. 3Emery P, et al. Ann Rheum Dis 2008; 67:15161523.

 ADACTA
(TCZ monotherapy VS ADALIMUMAB monotherapy)

Response rate at week 24

ADA (N = 162) TCZ (N = 163)
100%
90%
OR : 2.0 ( 1.2-3.0 )
80%
70% 65.0%* OR : 2.4 ( 1.5-3.9 )
Patients, %

60% OR : 2.3 ( 1.2-3.8 )

49.4% 47.2%
50%
40% 32.5%*
30% 27.8%
17.9%
20%
10%
0%
ACR 20 ACR 50 ACR70

*P < 0.005 (vs ADA). P < 0.0005 (vs ADA).

Significance was determined using a logistic regression analysis (covariates included treatment, region, and duration of RA).
LOCF was used for missing TJC, SJC. If CRP was missing ESR was substituted.
Source: etefrsp01_ne_1, eteplog01_acr20_v8_ne_1, eteplog01_acr50_v8_ne_1, eteplog01_acr70_v8_ne_1 28
 Treatment response to Tocilizumab compared
with other biologic agents. 2 X of ACR 70
response compared with TNF- Inhibitor
80%
rituximab
abatacept
65% TNF- inhibitors
63%
Tocilizumab
60% placebo

44% 2x greater
40% 39%
32%
29%

20%
16%
12%
4%
0%
ACR20 ACR50 ACR70
Bergman G et al. Semin Arthr Rheum 2010: in press.
 Summary

RA is a systemic disease with joint damage in RA occurs early

and progresses at rapid rate
RA treatment is often too late
Early diagnosis and early aggressive treatment makes different
out come
Early treatment with biologic agents gives significantly better
outcome
ACTEMRA has a rapid, potent and comprehensive effect on RA
 Rheumatoid arthritis

(Source : Rheumatology Clinic Dr.Saiful Anwar Hospital slide collection)

 Peran IL-6 dan sitokin yang lain pada
pathogenesis AR.
Efek biologik IL-6 TNF IL-1
Kadar dalam darah dan cairan sinovial ++++ + +
Aktivasi endotel lokal ++ ++
Aktivasi sel PMN ++ + +
Sekresi protease, MMP + ++ +++
Aktivasi sel sel tulang ++ + +
Fungsi/ Kehidupan sel B +++ _ +
Diferensiasi Th17 ++ _ ++
Produksi Protein Fase Akut (APR) +++ + +
Anemi ++ + +
CNS ( kelelahan ) +++ ++ ++
Dayer J-M, Choy E. Rheumatology 2010;49:15-24
 Summary
IL-6R inhibition: The promise

By inhibiting IL-6R signalling, ACTEMRA has a rapid, potent and

comprehensive effect on RA, with:
High efficacy and consistent rates of remission15
Monotherapy that is uniquely superior to MTX
monotherapy4
Unique combination of a rapid clinical response and
increasing efficacy over time6,7
Profound inhibition of progression of joint damage5
Unique systemic effects15
Predictable and manageable safety profile7

1Smolen J, et al. Lancet 2008; 371:987997. 2Genovese M, et al. Arthritis Rheum 2008; 58:29682980.
3Emery P, et al. Ann Rheum Dis 2008; 67:15161523. 4Jones G, et al. Ann Rheum Dis 2010; 69:8896.
5Fleischmann R, et al. EULAR 1619 June, 2010; Poster FRI0205. 6Smolen J, et al. ACR 2429 October, 2008; Abstract 989.
7RoACTEMRA (tocilizumab) Summary of Product Characteristics. Roche Registration Limited. June 2010.