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