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Por: Dr. Marco Matucci Cerinic (ITA)XIII Congreso Colombiano de Reumatologia 2011 Barranquilla
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Systemic Sclerosis, myths, truths & challenges
Marco Matucci Cerinic Dept Biomedicine, Div Rheumatology
Univ Florence, Italy
Colombian Congress of Rheumatology, Barranquilla 2011
SSc- myths, truths & challenges
• Myth- SSc is as fibrotic disease…• Truth- SSc is a dreadful disease…• Challenge- SSc can be diagnosed very early…• Conclusions
“…wasted until one is literally a mummy,…” William Osler 1898
Myth- SSc is as fibrotic disease…
Myth- SSc is as fibrotic disease…
SSc is more than that, It is a vascular disease… !!??
Barbara G. May 2005
Lidia T. January 2005Paolieri
G.P, March 2004
Early dSSc Established disease
Dermal inflammation
disease evolution
skinthickness
2 5 10 20 disease duration (years)
early
intermediate late
LIMITED SSc
pulmonary hypert., malabsorption
early
intermediate
late
lung, heart, GI, kidney
Medsger T & Steen V, Systemic Sclerosis, 1995, p 51,Williams & Wilkins
DIFFUSE SSc
What’s going on under the skin… into the vessels ?
• Endothelial damage and apoptosis•
Skin, Lung, Kidney, Heart
Progressive arteriolar alteration with intima
hypertrophy and progressive stranglement of the vessel
lumen
Fleischmajer et al, J am Acad Dermatol 1980
ThaTAT
F 1+2
IIa
Fb
CF
t-PA
F
LpPAI
vW
vW
VCAM
ICAM
E-sel
DS
PA
SmoothMuscle Cells
Collagenof Endothelial Cells
TFVIIa
GF
G
IL-2
IL-1
TNF
Fibroblasts
Apoptosis
Matucci Cerinic et al Seminars Arthritis Rheum 2003
uPAr
Vasculopathy of SSc complications…“the challenge for the future”
• Intimal proliferation• Adventitial fibrosis• Lumen narrowing &
obliteration
LungFingers KidneyHeart
PAHUlcers/gangrene SRCInfarct
Hypoxia,Thrombosis ROSContinuous Vasospasm
ENDOTHELIAL DAMAGE
RAYNAUD’s Phenomenon
TELEANGECTASIAS
ULCERS
normal early
active late
January 2006
• Calcium Channel blockers• Iloprost
August 2006
• Nifedipine• Iloprost weekly infusions• Patient coming seldom for medication
Patient is painful again, the 5° right finger is again problematic
Digital artery with a thrombus formation due
to endothelial cell dysfunction: increased
platelet activity and increased
thrombogenicity in SSc HE x 15, Courtesy of Petros
Efthimiou, MD, NY
23.12.0211.3.03
28.4.03
Truth…SSc is a dreadful disease…
J Cutan & Genitourinar Dis 1898, 16, 49
“Scleroderma is a shrinking skin of steel” In its more aggravated forms of diffuse scleroderma
is one of the most terrible of all human ills. Like Tithonus to wither slowly and like him to be beaten
down and marred, wasted until one is literally a mummy, encased in an evershrinking, slowly
contracting skin of steel, is a fate not pictured in any tragedy, ancient or modern.
William Osler (1849-1919)
1. Self-portrait
2. Embrace
3. General Chef du Barbare
1. 1940
2. Captive
Death and Fire, 1940
Independent risk factors for increased mortality
(Cox-proportional hazard model)
HR= 3.34
HR= 1.64
HR=2.02
HR= 1.61
Proteinuria FVC<80%
Pulmonary hypertension
(PAPsys >40 mmHg)
Dyspnoea
Huegle et al ARD 2010
Koh et al. Br J Rheumatol. 1996;35:989-993.
0
10
20
30
40
50
60
70
80
90
100
0 1 2 3 4 5 6 7 8 9 10 11 12 13
Years From Diagnosis of PHT
PHTN
Lung Involvement (without PHTN)
None
Survival Curves of Scleroderma Patients With Pulmonary Hypertension, Lung Involvement, or No Major Organ Involvement
Survival, %
Scleroderma renal crisisClinical picture
Rapidly progressive renal impairment New-onset accelerated phase hypertension
Headaches Visual disturbances Encephalopathy with seizures Flash pulmonary oedema Fevers / malaise Pericardial effusion
+/- MAHA Hypereninaemia ARF + occlusive renal vascular lesions may occur
without hypertension at presentation (Helfrich 1989)
Grade IV retinopathy
Schistocytes - MAHACourtesy of Dr C Denton, RFH, UK
Scleroderma renal crisis - biopsy features
hypertensive vascular damage
glomerular ischaemia
thrombotic vascular
occlusion
fibrosis
Courtesy of Dr C Denton, RFH, UK
Challenge
SSc can be diagnosed very early
Puffy Fingers
Very Early Systemic Sclerosis
Pre-SSc
UCTD MCTD
CapillaroscopyAnti-nuclear antibodies
Raynaud’s phenomenon
Matucci Cerinic et al , Ann Rheum Dis 2009
Raynaud Fenomenus,Quo Vadis… ?
Patients suspect for very early SSc, characterised by
Raynaud’s phenomenon,puffy fingers/sclerodactilyantinuclear antibodies
Evaluation of patients Capillaroscopy & SSc-specific antibodies
1st level
2nd level
HRCT , PFT & Esophageal manometry
If negative…
• differential diagnosis• send patient to to other specialist
If positive…
Choice of treament
If negative…
Follow up
If either one is positive, diagnosis of very early SSc & further
investigations
Suspicion
diagnosis
Red Flags
Avouac et al ARD 2010
Disease evolution
skinthickness
2 5 10 20 disease duration (years)
early
intermediate late LIMITED SSc
pulmonary hypert., malabsorption
early
intermediate
late
lung, heart, GI, kidney
Medsger T & Steen V, Systemic Sclerosis, 1995, p 51,Williams & Wilkins
DIFFUSE SSc
May we treat a very early SSc?
A Window of
opportunity
Early dSSc Established disease
Dermal inflammation
disease evolution
skinthickness
2 5 10 20 disease duration (years)
early
intermediate late
LIMITED SSc
pulmonary hypert., malabsorption
early
intermediate
late
lung, heart, GI, kidney
Medsger T & Steen V, Systemic Sclerosis, 1995, p 51,Williams & Wilkins
DIFFUSE SSc
• When observing a Raynaud’s ph an accurate diagnostic procedure should be used to differentiate between a primary or a secondary form
• Follow up of these patients is mandatory • Raynaud’s ph is the first sign of a very early
Systemic Sclerosis• “red flags” must always induce the suspect of
a very early SSc !
Facts…
The facts The Myth of fibrosis is
too late !!We still have Truths &
Challenges…
What are the following cases ?
An early SSc or something very early ?
Where do we position these patients in the disease evolution ?
DE 15.4.04 Finger edema & Raynaud
NVC- Active pattern Anticentromere pos
LES Dysfunction
• RP & puffy fingers• Topo I• NVC late• FVC & DLCO normal• chest HRCT normal
Simona C. December 2004
RPANA/Topo I posNVC active
Claudia P. 2005
RPANA/ACA posNVC early
Are these already SSc ?Early or very early ?
DE 2010RPANA/ACA posNVC activeLES dysfunctionFVC & DLCO normal
Simona C. December 2004
RPANA/Topo I posNVC active
Claudia P. 2005
RPANA/ACA posNVC early
Diffuse SSc- Six months
Limited SSc-Three years
Do we really have to treat these patients… ?
WE DO NOT KNOW AS EVIDENCE BASE DATA ARE NOT AVAILABLE…
& predictors of evolution are missing but STILL REMAINS MANDATORY to block the disease evolution and organ damage
1. Topo I antibodies/RNA pol III2. rapidly progressing skin involvement 3. Tendon friction rubs
An early aggressive therapy might be chosen when::
The window of opportunity…!!!
Paul KleeThe window
Education is of paramount
importance !!
www.eustar.org
www.W-S-F.org
Scleroderma Foundation
VEDOSS Very Early Diagnosis Of SSc
Partnership between EULAR, EUSTAR and FESCA to establish a programme to:
• Create clinics devoted to the early diagnosis of SSc• Educate primary care professionals throughout Europe – In the earliest symptoms of SSc
• (Raynaud’s, ANA capillaroscopy / anti-nuclear antibody tests)
– To send any patient presenting with Red Flags to special SSc clinics
• Launch date to coincide with European Scleroderma Awareness Day: 29th June 2010
Dept Rheumatology AVCDept Biomedicine & Div Rheumatology AOUC
Dept Medicine & DENOthe Centre University of Florence
Dr. ML ConfortiDr A RighiDr G BaccanoDr. S Maddali BongiDr. A Del RossoDr. D MelchiorreDr. M MarescaDr. F BandinelliDr. S Bellando RandoneDr. S GuiducciDr. G SalvadoriniDr. F PortaDr. J BlagojevicDr. G Carnesecchi
Dr F GalluccioDr S CappelliDr V DenaroDr T BarskovaDr R De LucaDr L GiovanniniDr A CalabròDr E BellucciDr M Orlandi
Regional Reference Centre for Systemic
Sclerosis
Clinical Trial Unit
Dr. F NacciDr. F Bartoli
Dr F Peruzzi Dr C Bruni
Digital Ulcers Unit
Dr. G Fiori Signora F Braschi
Dottssa P Cerboni
Young Adults ClinicProf F Falcini
Laboratory UnitDr M ManettiDr C CeccarelliDr E Romano
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