Document 6498665

Types of criteria in the rheumatic disease
Type
Purpose
1 Classification criteria
Subclassification
criteria
To distinguish those with a specific
disease from those without it
To separate those with particular disease
or subset of disease within a disease
cluster
2 Prognostic criteria
To separate subjects with a good or
potentially favorable outcome from those
with a poor outcome
3 Disease status criteria
Activity indices
Damage indices
To assess present disease activity or
accumulated damage from the disease
and/or treatment
4 Outcome criteria
To measure the overall impact of a disease
Fries et al. Arthritis and Rheumatism 1994, 32: 531-537)
ACTIVITY INDEXES ASSESS THE CURRENT LEVEL OF
INFLAMMATORY, IMMUNOLOGIC, OR CLINICAL
MANIFESTATIONS OF DISEASE. DAMAGE INDEXES
QUANTITATE THE IRREVERSIBLE DESTRUCTION OF TISSUE
AS A RESULT OF THE DISEASE.
ACTIVITY
POTENTIALLY REVERSIBLE
PART OF THE DISEASE
PROCESS
DAMAGE
IRREVERSIBOL PART OF THE
DISEASE PROCESS BY EITHER
DEISEASE OR TREATMENT
SYSTEMIC SCLEROSIS
MORPHOLOGICAL FEATURES
¾ Vasculopathy: obliterative at microvessels;
proliferative at small
arteries
¾ Interstitial
fibrosis:
by accumulation of
matrix constituents
PATHOLOGIC PROCESSES EXPRESSING ACTIVITY
OR DAMAGE IN SYSTEMIC SCLEROSIS
ACTIVITY
Reversible vasoconstriction
DAMAGE
Fixed vascular defect
Fibrin deposition
Avascular areas
Ongoing fibrosis
Atrophy
Alveolitis
Interstitial fibrosis
Arthritis
Flexion deformities
Serosal effusions
Serosal fibrosis
ASPECTS PREVENTING AN EASY
DEFINITION OF DISEASE ACTIVITY IN SSc
9 Absence of distinct phases of flare and
quiescence
9 Occurrence of patients with a slowly indolent
course
9 Interstitial fibrosis more apparent than
inflammation
Previously proposed definitions
of disease activity
Disease evolution in the preceding
period
¾ Extent of the disease
¾ Alterations in laboratory parameters
indicating either immuneactivation or
collagen production
¾
CORRELATIONS BETWEEN CLINICAL ASPECTS AND
LABORATORY MEASURES OF DISEASE ACTIVITY
P
Circulating activity marker
Clinical correlate
IL-10
Total skin thickness score
0.025
sIL-2r and IL_8
Raynaud’s phenomenon
0.007
sIL-2r
Renal crisis
<0.001
ICAM-1
“Ground glass”* on HRCT
OSM
Swollen joint count
IL-6, IL-10,VEGF, sIL-2r
Cardiomegaly
0.01
0.007
<0.001
D.Veale et al. Arthritis Rheum 2001
PITFALLS IN USING CELLULAR ACTIVATION
MARKERS AS SURROGATE OF DISEASE
ACTIVITY IN SYSTEMIC SCLEROSIS
¾ Lack of correlation with disease activity in
different organ/systems
¾ Normalization of the parameter in clinical trials
despite the inefficacy of the tested drug
e.g. sIL2-r
under chlorambucil
Proc III-NP under alfa-interferon
Correlation of serum anti-DNA
Topoisomerase I antibody with
disease severity and activity in
systemic sclerosis with diffuse
cutaneous involvement
Hu et al. Arthritis Rheum 2003
ASSESSMENT OF RAYNAUD’S
ACTIVITY
¾ Raynaud condition score
¾ Patient and Physician VAS
¾ Digital ulcer/infarct measure
¾ HAQ
¾ AIMS2
P.A.Merkel et al. Arthritis Rheum 2002
PRELIMINARY DISEASE ACTIVITY
INDICES FOR SSC
Criteria
whole series
TSS > 20
1.0
Scleredema
0.5
∆-skin
2.0
Digital necrosis
0.5
∆-Vasc
0.5
Arthritis
0.5
∆-JM
dSSc
lSSc
0.5
3.0
2.5
2.0
1.0
1.0
1.0
Reduced DLCO
0.5
∆-HL
2.0
ESR > 30 mm/hr
1.5
2.5
Hypocomplementemia
1.0
1.0
Total maximum disease activity index
10.0
4.0
10.0
1.5
10.0
VALIDATION PROCESS
G.Valentini et al. Ann Rheum Dis 2001
The 3 indexes were validated by Jackknife technique
Whole series
r = 0.837 ± 0.0002
dSSc
r = 0.768 ± 0.0006
lSSc
r = 0.778 ± 0.0004
External validation: correlations between the rankings
given by 4 investigators and the calculated index
Whole
n=30
Diffuse
n=17
Limited
n=13
HN
rho
p
0.686
<0.001
0.821
<0.001
0.367
>0.05
PGV
rho
p
0.623
<0.001
0.357
>0.05
0.417
>0.05
CMB
rho
p
0.530
<0.001
0.778
<0.001
0.379
>0.05
LC
rho
p
0.712
<0.001
0.840
<0.001
0.851
<0.001
G.Valentini et al. Ann Rheum Dis 2003
EScSG whole series index
G.Valentini et al. Ann Rheum Dis 2003
Item
Score
mRTSS>14
1.0
Scleredema
0.5
Delta-Skin
2.0
Digital necrosis
0.5
Delta-Vasc
0.5
Arthritis
0.5
DCLO<80%
0.5
Delta-HL
2.0
ERS>30mm/1 st h
1.5
Hypocomplementemia
1.0
Total maximum disease activity index
10.0
™ Face validity
™ Construct validity
™ Content validity
™ Criterion validity
The EscSG whole series activity index has an
inherent face validity (i.e. it makes sense); it has
been both internally and externally assessed for
the construct validity; it has a nearly complete
content
validity
(except
for
kidney
involvement); its discriminant and criterion
validities must be assessed.
Actually, an activity index should be able to
predict future damage and prognosis.
FEATURE STEPS IN THE DEFINITION OF A
FULLY VALIDETED TOOL TO ASSESS DISEASE
ACTIVITY IN SYSTEMIC SCLEROSIS
9 Analysis of the discriminant validity of the ESSG
activity index
9 Analysis of the its predictivity of damage
9 Analysis of the relationships among anti-Scl 70
titre, activation markers and ESSG activity index
9 Definition of the laboratory parameter(s) which
improve(s) the performance of the ESSG index
9 Definition of the best tool (probably a composite
index) to assess global disease activity
Aspects preventing a clearcut definition
of damage in Systemic Sclerosis
™ Fibrosis can express both activity and
damage
™ Damage and activity coexist particularly in
patients with dcSSc
SEVERITY
PROGNOSTIC PARAMETER
PREDICTIVE OF DISEASE
EVOLUTION i.e. QUALITY OF LIFE
AND/OR SURVIVAL
Disease severity
reflects either
activity or damage
or
both
Skin thickness
DISEASE COURSE
in
dc and lc SSc
joint contractures, GI,
lung, heart, kidney
Diffuse cutaneous
intermediate
Limited cutaneous
early
5
pulmonary hypertension,
malabsorption
late
intermediate
early
0
late
10
15
20
Disease duration (years)
T.A. Medsger jr.
NEGATIVE PROGNOSTIC FACTORS
¾
¾
¾
¾
¾
Male sex
Race
Late age at onset
Clinically evident internal
organ involvement
Short R-S interval
Ferri et al.: Medicine 2002: 81: 139
Ferri et al.: Medicine 2002: 81: 139
Ferri et al.: Medicine 2002: 81: 139
Ferri et al.: Medicine 2002: 81: 139
Proteinuria
¾ Elevated ESR
¾ Low DLCO
¾
High accuracy in predicting survival!
Bryan et al. Arthritis Rheum 1999
REVISED PRELIMINARY SSc SEVERITY SCALE
Organ system
0 (normal)
A
1 (mild)
4(endstage)
1. General
Wt loss <5%
Hb 12.3+ Gm/dl
Wt loss 5.0-9.9%
Hb 11.0-12.2 Gm/dl
Wt loss 20+ %
Hb <8.3 Gm/dl
2 .Peripheral
vascular
RP not requiring
vasodilators
RP requiring
vasodilators
Digital gangrene
3. Skin
TSS 0
TSS 1-14
TSS 40+
4. Joint/
tendon
FTP 0-0.09 cm
FTP 1.0-1.9 cm
TP 5.0+ cm
5. Muscle
Normal proximal
muscle strength
Proximal weakness
mild
Ambulation
aids required
T.A. Medsger et al. Clin Exp Rheumatol 2003
REVISED PRELIMINARY SSc SEVERITY SCALE
Organ
system
0 (normal)
B
1 (mild)
4 (endstage)
6. GI tract
Normal
esophagram
Distal esophageal
hyperistalsis
Hyperalimentation
required
7. Lung
FVC-DLCO >80 %
No fibrosis
sPAP <35 mmHg
FVC-DLCO 70-79%
Fibrosis
sPAP 35-49 mmHg
Oxygen required
8. Heart
EKG normal
LVEF >50 %
Conduction defect
LVEF 45-49%
CHF
9. Kidney
No Hx SRC
Creatinine
<1.3 mg/dl
Hx SRC
Creatinine
<1.6 mg/dl
Hx SRC
Dialysis required
T.A. Medsger et al. Clin Exp Rheumatol 2003
The main limitation of this criteria set is the
fact that the different types of organ
involvement in SSc are not weighted.
Therefore, a total severity score that would be
comparable between patients with different
patterns of organ involvement cannot be
calculated
FUTURE STEPS IN THE DEFINITION OF
DAMAGE AND SEVERITY IN SYSTEMIC
SCLEROSIS
¾ Searching for a measure indicative of
damage in each organ involved and
validating it
¾ Defining a composite damage index
and validating it
¾ Developing and validating a global
severity index
EPIDEMIOLOGICAL AND CLINICAL FEATURES OF
THE SSc SERIES INVESTIGATED
A
Sex
Age
Disease duration
ACR criteria
Subset
Autoantibody profile
Altered inflammation indices
Activity
F/M
Median (range)
Median (range)
N
lSSc/dSSc
ANA positive
ACA positive
Anti-Scl-70 positive
(anti-RNA pol I-III positive)
N
Active*/Inactive
*ESSG activity index ≥3
G.Valentini et al. Clin Exp Rheumatol 2003
EPIDEMIOLOGICAL AND CLINICAL FEATURES OF
THE SSc SERIES INVESTIGATED
B
Organ
Involvement
General
Yes/No
Peripheral vascular Yes/No
Skin
Yes/No
Joint/tendon
Yes/No
Muscle
Yes/No
GI tract
Yes/No
Lung
Yes/No
Heart
Yes/No
Kidney
Yes/No
Severity
Median (range)
Median (range)
Median (range)
Median (range)
Median (range)
Median (range)
Median (range)
Median (range)
Median (range)
G.Valentini et al. Clin Exp Rheumatol 2003