1
Rheumatoid Arthritis
M Handel
1st Feb 2012
Definition of the Problem
Rheumatoid Arthritis is a multi-system autoimmune disease of unknown
cause characterized by inflammatory changes in the joints
3
Features of Rheumatoid Arthritis
• Prevalence of approximately 1% in adult population
• Age of onset usually between 30 – 50 years
• Two- to three-fold more common in women
• Chronic, progressive and disabling
• Higher mortality rates
– Shortens life span by 3 to 18 years
Koopman WJ, et al. Arthritis & Allied Conditions. 13th ed. 1997.
FUSIFORM SWELLING
MCP & PIP SWELLING
Hammer Toe Deformities
MTP Erosive Disease
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Potential Pathogenic Pathway in RA
Initiating
Event
Inflammation
Clinical
Symptoms
X-ray
Changes
QoL
Change
Synovitis
Pain and
Stiffness
Swelling
Joint Space
Narrowing (JSN)
Pain
Pannus
Joint
Erosions (JE)
Structural
Damage
Adapted from: Kirwan JR. Rheum Dis Clin North Am. 2001;27:389.
Immune-Mediated Inflammatory
Process of RA
APC
MHC
CD4
CD4+
TCR T cell
IL-1
IL-2
TNF- IFN-
IL-6 TNF-
IL-8
IL-4
IL-10 iNOS
TGF-
Perpetuation/
Regulation
Inflammation/
Joint Destruction
Ag
Initiation
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B cells
Immunoglobulins
Synoviocytes
Adhesion molecule
activation
Metalloproteinases
Lymphocytes, PMNs,
macrophages
APC = antigen-presenting cell; MHC = major histocompatibility complex; TCR = T-cell receptor;
TGF = transforming growth factor; iNOS = inducible nitric oxide synthase; PMNs =
polymorphonuclear cells
Moreland LW, et al. Arthritis Rheum. 1997;40:397-409.
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The Pathogenesis of Rheumatoid Arthritis
Feldmann M, et al. Ann Rev of Immunol. 1996;14:397-440.
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RA Synovium
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RA Synovium
Rosenberg A. In: Cotran RS et al, eds. Robbins Pathologic Basis of
Disease. 6th ed. Philadelphia, PA: WB Saunders; 1999:1215.
Inflamed synovium invading and
destroying cartilage and bone
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Clinical Course of RA
Joint involvement in RA
64 %
• Main presenting symptoms:
– Swelling of the joint and/or
joint margins
– Joint tenderness
– Systemic malaise
– Loss of energy
– Severe morning stiffness
38 %
17 %
78 %
91%
65 %
50 %
43 %
Guerne PA and Weisman MH. Am J Med 1992;16:451-460; Lee DM and Weinblatt E. The Lancet 2001; 358 : 903-911
“Kelley's Textbook of Rheumatology”, 2008; “Eular Compendium on Rheumatic Diseases”, Ed. Bijlsma JWJ, 2009
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Clinical Course of RA
•
Clinical course of RA is highly variable
– From mild arthritis
– To rapidly progressive multisystem inflammation
 With profound morbidity & mortality
•
Rate of disease progression
1. Variable presentation
 periods of increasing disease activity (early
years)
 relentless linear progression
 aggressive and malignant without remission
2. But always progress with irreversible destruction
at all phase of disease
Lee DM and Weinblatt E. The Lancet 2001; 358 : 903-911
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Puffy, hands, early arthritis
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Nodular, erosive rheumatoid arthritis
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Joint Destruction and disability in RA
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Progression of RA joint damage
Inflammation
Disability
Radiographs
Severity (Arbitrary Units)
Intended for internal use only. Subject to local regulatory review prior to external use
Relationship Between Inflammation,
Radiographic Progression and Disability
0
5
10
15
20
25
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Duration of Disease (years)
“In early RA irreversible damage is seen in 60% of patients within
the first 2 years of diagnosis.”
Kirwan J. Rheum 1999;26:720. Saleem et al. Clin Exp Rheum 2006;24:S33. Illustration source unknown.
EXTRA-ARTICULAR MANIFESTATIONS
Neurologic –
Ocular – Episcleritis
Neuritis, Stroke
Lungs – Pulmonary
Heart – Pericarditis
Nodules, Effusions
Vascular – Vasculitis
Skin -Nodules
Rheumatoid Nodule
Episcleritis
Scleromalacia Perforans
Periungual Infarcts and Digital Gangrene
Associated with Severe Rheumatoid Vasculitis.
Atlanto axial subluxation
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Rheumatoid Arthritis
Classification
1987 ACR Classification Criteria for RA
At least 4 of the following criteria must be met:
• AM stiffness lasting > 1 hour*
• Swelling of  3 joints*
• Swelling of hand joints*
• Symmetric joint involvement*
• Radiographic changes
(erosion or bony decalcification)
• Presence of rheumatoid nodules
• Rheumatoid factor in serum
*Must be present for at least 6 weeks.
Arnett FC et al. Arthritis Rheum. 1988:31:315-324.
2010 ACR Classification Criteria for RA
Synovitis plus score of ≥6/10 needed for the classification of definite RA
Joint involvement
Serology#
Acute-phase reactants#
Duration of symptoms
One large joint
0
2-10 large joints
1
1-3 small joints*
2
4-10 small joints*
3
>10 joints (at least one small joint)
5
RF- and ACPA-
0
Low RF+ or low ACPA+
2
High RF+ or high ACPA+
3
Normal CRP and normal ESR
0
Abnormal CRP or abnormal ESR
1
<6 weeks
0
≥6 weeks
1
*With or without involvement of large joints. # at least one test result needed for classification . ACPA: Anti-citrullinated
protein/peptide antibodies; CRP: C-reactive protein; ESR: Erythrocyte sedimentation rate
Aletaha et al. Ann Rheum Dis 2010;69:1580-1588
Tree Algorithm to Classify Definite RA
or to Exclude its Current Presence
APR: acute-phase response; Serology+: low-positive for RF or ACPA; serology++: high-positive for RF or ACPA;
serology+/++: serology either + or ++
Aletaha et al. Ann Rheum Dis
2010;69:1580-1588
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Rheumatoid Arthritis
Disease assessment tools
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Measuring Treatment Outcomes:
Common Clinical Trial Endpoints
Requirements
Trial
Duration
Validated
Measure
Other
Improvement in
Signs/Symptoms
6 mo
Prevention of
Structural Damage
1 y
Prevention of
Disability
2-5 y
• ACR 20 (or other
composite
endpoint)
• Pain, tenderness,
swelling
• Larsen
• HAQ
• Sharp scores
• SF-36
• Global
assessments
• Maintenance of
erosion-free
state
• ACR core set
• Prevention of
new erosions
“Patients
should not
worsen on
these measures
over the
duration of the
trial”
• Response over
time preferred
FDA, Center for Drug Evaluation and Research. Guidance for Industry.
http://www.fda.gov/cder/guidance/1203fnl.htm. February 1999.
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Definition of ACR 20, 50, or 70
• Measures response to treatment in a clinical trial:
– Is the patient an ACR 20 responder or not
• A 20%, 50%, or 70% reduction in
– the number of swollen joints
and
– the number of tender joints
and
– the same degree of improvement in
at least 3 of 5 other variables:
•
•
•
•
•
pain
degree of disability according to the HAQ
patient’s global assessment
physician’s global assessment
erythrocyte sedimentation (ESR)/ C-reactive protein (CRP)
level
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Disease Activity Score (DAS) and
Definition of Response
• Continuous variable:
– Patient’s disease activity is described on a scale of 1 to 10 using a
composite index
• Composite Index incorporating:
– ESR
– Number of Swollen joints (SJC) (1-28)
– Number of Tender joints (TJC) (1-28)
– Assessment of patient’s general health (VAS 1-100)
DAS 28 at Endpoint
3.2
(low activity)
3.2 and 5.1
(moderate activity)
5.1
(high activity)
Improvement in DAS or DAS28 from Baseline
1.2
0.6
0.6
(clinically
(within error)
and 1.2
significant)
Good
Moderate
None
den Broeder, A. et al., Rheumatology. 2002; 41:638-42.
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Health Assessment Questionnaire (HAQ)
Widely accepted, validated, rheumatology-specific instrument
to assess physical function in RA
 20 questions covering eight types of activities
 Dressing and grooming, arising, eating, walking, hygiene,
reaching, gripping, activities of daily living
 A mean decrease of at least 0.22 in HAQ score is considered a
minimum clinically important difference (MCID)
HAQ Disability Index (HAQ-DI)
 Scores the worst items within each of the eight scales
 Based on use of aids and devices
Buchbinder R, et al. Arthritis Rheum. 1995;38:1568–1580; Sullivan FM, et al. Ann Rheum Dis.
1987;46:598–600;
Kosinski M, et al. Arthritis Rheum. 2000;43:1478–1487.
Modified van der Heijde-Sharp Scoring
Method (vdHSS)
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Schema of Radiographic Joint Evaluation
= Joint narrowing

Erosions
20 joints evaluated
20 joints evaluated
6 joints evaluated
6 joints evaluated
Range: 0 – 528
Van der Heijde D, et al. Ann Rheum Dis. 2005;64(Suppl II):ii61-ii64.
EROSIONS
0
NARROWING
VdHSS: Joint Erosions Scored 0 – 5 and
Joint Space Narrowing Scored 0 – 4
0
1
2
1
3
2
4
3
5
4
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Estimated continuation (%)
Continuation of DMARDs
Methotrexate (253)*
Parenteral gold (269)
HCQ (228)
Oral gold (84)
D-Pen (193)
Azathioprine (56)
100
80
MTX vs
60
all other drugs
40
(P < 0.001)
20
Oral gold vs
all other drugs
(P < 0.001)
0
0
12
24
36
48
60
Months
*Numbers represent courses of therapy
Pincus T et al, J Rheumatol 19:1885–1894, 1992