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Transcript of 1 Rheumatoid Arthritis M Handel 1 st Feb 2012. Rheumatoid Arthritis is a multi-system autoimmune...
1
Rheumatoid Arthritis
M Handel
1st Feb 2012
Rheumatoid Arthritis is a multi-system autoimmune disease of unknown cause characterized by inflammatory changes in the joints
Rheumatoid Arthritis is a multi-system autoimmune disease of unknown cause characterized by inflammatory changes in the joints
Definition of the ProblemDefinition of the Problem
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
7
Potential Pathogenic Pathway in RA
Initiating Event
Synovitis Pannus
Clinical Symptoms
X-rayChanges
Joint Space Narrowing (JSN)
Pain and Stiffness
Swelling
Joint Erosions (JE)
Adapted from: Kirwan JR. Rheum Dis Clin North Am. 2001;27:389.
QoL Change
Pain Structural Damage
Inflammation
8Immune-Mediated Inflammatory Process of RA
Initiation
Perpetuation/Regulation
Inflammation/Joint Destruction
IL-1TNF-IL-6IL-8
IL-10TGF-
IL-2IFN-TNF-IL-4
iNOS
B cellsSynoviocytes
Adhesion moleculeactivation
Immunoglobulins MetalloproteinasesLymphocytes, PMNs,
macrophages
TCR
CD4+
T cell
CD4APC
MHC
Ag
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.
9
Feldmann M, et al. Ann Rev of Immunol. 1996;14:397-440.
The Pathogenesis of Rheumatoid Arthritis
10
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.
12Inflamed synovium invading and destroying cartilage and bone
Clinical Course of RAClinical Course of RA
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
91%
78 %
64 %
65 %
50 %
43 %
38 %
17 %
Joint involvement in RA • Main presenting symptoms:– Swelling of the joint and/or
joint margins– Joint tenderness– Systemic malaise– Loss of energy– Severe morning stiffness
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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
15
Puffy, hands, early arthritis
16
Nodular, erosive rheumatoid arthritis
17
Joint Destruction and disability in RA
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Progression of RA joint damage
Inte
nd
ed
fo
r in
tern
al
us
e o
nly
. S
ub
jec
t to
lo
ca
l re
gu
lato
ry r
ev
iew
pri
or
to e
xte
rna
l u
se Relationship Between Inflammation,
Radiographic Progression and Disability S
ever
ity
(Arb
itra
ry U
nit
s)
0
Duration of Disease (years)
5 10 15 20 25 30
InflammationDisabilityRadiographs
“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 MANIFESTATIONSEXTRA-ARTICULAR MANIFESTATIONS
Skin -NodulesSkin -Nodules
Heart – PericarditisHeart – PericarditisLungs – Pulmonary Nodules, EffusionsLungs – Pulmonary Nodules, Effusions
Neurologic – Neuritis, Stroke
Neurologic – Neuritis, Stroke
Vascular – VasculitisVascular – Vasculitis
Ocular – EpiscleritisOcular – Episcleritis
Rheumatoid NoduleRheumatoid Nodule
EpiscleritisEpiscleritis
Scleromalacia PerforansScleromalacia Perforans
Periungual Infarcts and Digital Gangrene Associated with Severe Rheumatoid Vasculitis.
Periungual Infarcts and Digital Gangrene Associated with Severe Rheumatoid Vasculitis.
Atlanto axial subluxationAtlanto axial subluxation
25
Rheumatoid Arthritis
Classification
Arnett FC et al. Arthritis Rheum. 1988:31:315-324.
*Must be present for at least 6 weeks.
1987 ACR Classification Criteria for RAAt 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
Aletaha et al. Ann Rheum Dis 2010;69:1580-1588
2010 ACR Classification Criteria for RA
Joint involvement 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
Serology# RF- and ACPA- 0
Low RF+ or low ACPA+ 2
High RF+ or high ACPA+ 3
Acute-phase reactants# Normal CRP and normal ESR 0
Abnormal CRP or abnormal ESR 1
Duration of symptoms <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
Synovitis plus score of ≥6/10 needed for the classification of definite RA
Tree Algorithm to Classify Definite RA or to Exclude its Current Presence
Aletaha et al. Ann Rheum Dis 2010;69:1580-1588APR: acute-phase response; Serology+: low-positive for RF or ACPA; serology++: high-positive for RF or ACPA;serology+/++: serology either + or ++
29
Rheumatoid Arthritis
Disease assessment tools
30
Measuring Treatment Outcomes: Common Clinical Trial Endpoints
Requirements
Improvement in Signs/Symptoms
Prevention of Structural Damage
Prevention of Disability
Trial Duration
6 mo 1 y 2-5 y
Validated Measure
• ACR 20 (or other composite endpoint)
• Larsen
• Sharp scores
• HAQ
• SF-36
Other • Pain, tenderness, swelling
• Global assessments
• ACR core set
• Response over time preferred
• Prevention of new erosions
• Maintenance of erosion-free state
“Patients should not worsen on
these measures over the
duration of the trial”
FDA, Center for Drug Evaluation and Research. Guidance for Industry.http://www.fda.gov/cder/guidance/1203fnl.htm. February 1999.
31
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 jointsand– 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
32
Disease Activity Score (DAS) and Definition of Response
Improvement in DAS or DAS28 from Baseline
DAS 28 at Endpoint1.2
(clinically significant)
0.6 and 1.2
0.6(within error)
3.2(low activity) Good
None
3.2 and 5.1(moderate activity) Moderate
5.1(high activity)
den Broeder, A. et al., Rheumatology. 2002; 41:638-42.
• 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)
33
Health Assessment Questionnaire (HAQ)
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.
Widely accepted, validated, rheumatology-specific instrumentto 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
34
= Joint narrowing
Schema of Radiographic Joint Evaluation
20 joints evaluated
6 joints evaluated
Modified van der Heijde-Sharp Scoring Method (vdHSS)
Range: 0 – 528
Erosions
6 joints evaluated
20 joints evaluated
Van der Heijde D, et al. Ann Rheum Dis. 2005;64(Suppl II):ii61-ii64.
35VdHSS: Joint Erosions Scored 0 – 5 and Joint Space Narrowing Scored 0 – 4
1 54320
1 4320
ER
OS
ION
SN
AR
RO
WIN
G
36
Continuation of DMARDs
Pincus T et al, J Rheumatol 19:1885–1894, 1992
100
80
60
40
20
0
0 12 24 36 48 60
Parenteral gold (269)
Oral gold (84)
Azathioprine (56)
Methotrexate (253)*
HCQ (228)
D-Pen (193)
Est
imat
ed c
on
tin
uat
ion
(%
)
Months
(P < 0.001)
(P < 0.001)
MTX vs
all other drugs
Oral gold vsall other drugs
*Numbers represent courses of therapy