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