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POLSKIE ARCHIWUM MEDYCYNY WEWNTRZNEJ 2012; 122 (Suppl 1)18

Iui Systemic sclerosis (SSc) is a chronic disease characterized by widespread brosis o

the skin and internal organs, a smallvessel vas

culopathy, and evidence o immune dysregulation

with the production o autoantibodies. Te in

cidence o SSc is estimated between 4 and 20

new cases per 1,000,000 per year and the preva

lence between 30 and 450 cases per 1,000,000.1,2

In the United States, it ranges across studies rom

3 to 21/106 population.3 It is a clinically heteroge

neous disease ranging rom a milder orm with

less extensive involvement o the internal organs

to a more rapid widespread internal organ in

volvement resulting in disability and death with

in several years.4

All classications distinguish between limited

cutaneous SSc, in which the skin lesions do not

extend beyond the elbows and knees and involve

the ace, and diuse cutaneous SSc, which aects

also the thighs, arms, and torso. Te current di

vision o SSc into subsets is useul in the clinic

but cannot help dene or understand very early SSc.

In act, the preliminary criteria developed since

1980 by the American College o Rheumatology

(ACR) are illsuited to early disease and limit

ed subsets with no skin lesions beyond the n

gers, no nger ulcers, and no interstitial lung dis

ease (ILD).5

In order to overcome the limitations o the ACR

criteria, LeRoy et al.6 ormulated criteria or

the limited orms o SSc which basically dene

a group o preSSc. According to the LeRoy cri

teria, patients with limited SSc must have Ray

nauds phenomenon (RP) plus sclerodermatype

nailold capillary changes and/or autoantibod

ies.7 However, they did not mention which oth

er symptom/sign/laboratory/instrumental nd

ing should be considered as an exclusion criterion

or the diagnosis o limited SSc. Te current vali

dated or proposed criteria are not appropriate to

make a very early diagnosis o SSc, and this im

plies that the diagnosis o SSc and, consequently,

appropriate therapy is delayed until the appear

ance o skin involvement and/or clinically detect

able internal organ involvement810 when micro

vascular remodeling, tissue brosis, or atrophyare already irreversible.11 Tis limits the possi

bility o an early treatment and the prevention

o disease evolution and tissue damage, leading

Correspondence to:

Prof. Marco MatucciCerinic, MD,

PhD, Department of Rheumatology,

University of Florence,

V.le Pieraccini 18, Florence, Italy,

phone/fax: +39557949271,

email: [email protected]

Received: April 16, 2012.

Conflict of interest: none declared.Pol Arch Med Wewn. 2012;

122 (Suppl 1): 1823

Copyright by Medycyna Praktyczna,

Krakw 2012

AbstrAct

Systemic sclerosis (SSc) is an incurable chronic autoimmune disease associated with high morbidity and

mortality. The current validated or proposed criteria are not appropriate to make a very early diagnosis

of SSc. This implies that the diagnosis of SSc and, consequently, an appropriate therapy are delayed

until the appearance of skin involvement and/or clinically detectable internal organ involvement when

microvascular remodeling, tissue fibrosis, or atrophy are already irreversible.

In a recent Delphi exercise, 4 signs/symptoms have been identified as necessary for the very early di-

agnosis of SSc: Raynauds phenomenon (RP), puffy swollen digits turning into sclerodactily, antinuclear

antibodies and specific SSc antibodies (anticentromere and antitopoisomeraseI antibodies), and abnormal

capillaroscopy with scleroderma pattern.

Patients with very early SSc are the target of the recently launched the VEDOSS program, which has been

designed to diagnose SSc very early and to examine whether this may change the disease prognosis.

Although patients with RP, autoantibodies, and SSc capillaroscopic pattern could be easily followed up,

there is still no agreement on the predictors that may allow us to identify patients who will develop

an established disease.

Key words

early diagnosis,

Raynauds

phenomenon,

systemic sclerosis

reVIew ArtIcLe

Very early diagnosis o systemic sclerosisSilvia BellandoRandone1, Serena Guiducci2, Marco MatucciCerinic3

1 Department of Rheumatology, Azienda OspedalieroUniversitaria Careggi, University of Florence, Florence, Italy

2 Department of Biomedicine and Division of Rheumatology, Azienda OspedalieroUniversitaria Careggi, University of Florence, Florence, Italy

3 Department of Medicine and DENOthe Centre, University of Florence, Florence, Italy


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reVIew ArtIcLe Very early diagnosis of systemic sclerosis 19

decisions are compromised by a lack o agreement

and validation o the criteria to dene early dis

ease and predictors o disease evolution.

Diagnostic and therapeutic standards vary

widely across the global clinical community, and

no consensus has been reached on the optimum

approach to screening and diagnosis.19 Patients

with very early SSc are the target o the recently

launched Very Early Diagnosis o Systemic Sclero

sis (VEDOSS) program, which has been designed

to diagnose SSc very early and to examine whether this may change the disease prognosis. Te hy

pothesis is that the ollowup will allow us to de

ne prognostic clinical or genetic markers dur

ing the patients care.14

In recent studies, ater an extended screen

ing program during a mean (standard deviation)

ollowup period o 11.2 (3.9) years, the preva

lence o transition rom primary to secondary

RP, identied by diagnosis o an associated dis

ease, was 14.9% o the cases.20 Although patients

with RP, autoantibodies, and SSc capillaroscopic

pattern could be easily ollowed up, we still lack

an agreement on the predictors that may allow

us to identiy patients that will develop an estab

lished disease.21

Patients must be ollowed up regularly even

though the ideal requency o such visits has

not yet been established. Valentini et al.22 clear

ly showed that the subclinical involvement in SSc

is early, while the clinical signs o organ involve

ment may appear later. Furthermore, organ in

volvement is usually progressive and complica

tions requent, both in the limited and diuse

subsets o SSc.

why is very early diagnosis mandatory? In SSc, severe organbased complications are requently ob

served including scleroderma renal crisis (SRC),

sudden death, ILD and pulmonary arterial hy

pertension (PAH), digital ulceration [DU]. Tese

complications produce a high casespecic mor

tality rate observed among patients with SSc.21,23

For these reason, all eorts are now aimed at pre

venting the delay in diagnosis.

sloma nal ii Despite the use o angiotensinconverting enzyme inhibitors to pre

vent SRC, it occurs in 6% o SSc patients and in

10% to 15% o those with diuse SSc. In SRC, 40%

o the patients may require dialysis, and mor

tality at 5 years is rom 30% to 40%. Patients at

the greatest risk o developing SRC are those with

diuse cutaneous or rapidly progressive orms o

SSc, a recent onset o SSc without evidence o RP,

a recent treatment with highdose corticosteroids,

and the presence o tendon riction rubs.

Te course o SRC is characterized by an abrupt

onset o hypertension, acute renal ailure, head

aches, ever, malaise, hypertensive retinopathy,

encephalopathy, and pulmonary edema. Laboratory tests may demonstrate hypercreatinemia,

microangiopathic hemolytic anemia, thrombo

cytopenia, and hyperreninemia.

to loss o unction and decrease in the quality o

lie. Moreover, because o the changes in patients

appearance due to skin sclerosis, muscle atrophy,

and joint contracture, it has also a substantial im

pact on the patients emotional and psychological

wellbeing.12,13 For these reasons, SSc is consid

ered as one o the greatest challenges in the man

agement o rheumatic diseases.

According to the populationbased studies, mild

SSc may be a more requent disease than has pre

viously been suspected; thereore, the identication o very early SSc with an early diagnosis is

o crucial importance.11

V al iagi mi li: am

aliy? SSc is easy to diagnose when the dis

ease has already evolved to obliterative vasculop

athy, with skin brosis and signicant endorgan

damage. Te clinical presentation may depend ei

ther on the extent o brotic changes and/or im

paired blood supply caused by vascular changes.

By the time o the onset o an organrelated symp

tom, the brotic/vascular involvement may have

started several months or even years beore.11

Very early stages o SSc are clinically character

ized by the onset o RP, sclerodactily, and oten

by the presence o SScspecic autoantibodies.7

Te denition o early SSc as a state character

ized by RP, puy ngers, diseasespecic autoan

tibodies, and pathognomonic microvascular alter

ation detected by capillaroscopy (requiring at least

2, or better, all 3 items to be present) has been pro

posed.14 Still today, SSc diagnosis is delayed several

years ollowing the onset o RP and several years a

ter the onset o the rst nonRP symptom. In a re

cent Delphi exercise, 4 signs/symptoms have beenidentied as necessary or the very early diagnosis

o SSc: RP, puy swollen digits turning into scle

rodactily, specic SSc antibodies (anticentromere

and antitopoisomeraseI antibodies), and abnor

mal capillaroscopy with scleroderma pattern.15 RP

and puy swollen digits turning into sclerodactily

were considered in the nal analysis o the whole

assembly o the European League Against Rheu

matism Scleroderma rials and Research members

as red fags or the general practitioner leading

to the suspect o a very early SSc and thus, to re

er the patient to a specialist or the nal diagno

sis o very early SSc. Specic autoantibodies (an

ticentromere and antitopoisomeraseI antibodies)

and nailold capillaroscopy were considered as pre

erred diagnostic tools to nally dene a patient

suspected o very early SSc.

However, these early disease eatures are

not specic or SSc, because other entities may

also display a combination o these characteris

tics. At this point, doctors may ace 2 challeng

es: 1) to conrm that a patient with these ea

tures is already aected by SSc or at least a con

dition within the scleroderma spectrum, includ

ing prescleroderma,16

undierentiated connective tissue disease,17 or mixed connective tissue

disease18; 2) to decide how to treat this patient

aggressively or wait and stand by. In reality, these


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POLSKIE ARCHIWUM MEDYCYNY WEWNTRZNEJ 2012; 122 (Suppl 1)20

the investigation o early therapeutic interven

tion or PAH in a randomized trial.35

digial ul In some patients, particularly inthose with limited SSc, ulcers are the most dis

abling complication, causing pain (especially when

inected), limited unction, digital resorption, and

osteomyelitis.36

Various studies have revealed that among pa

tients with SSc, rom 15% to 25% have active

DU37

and 35% have active DU or have had DU inthe past.38 Tese numbers vary in dierent stud

ies, possibly due to dierent geographical areas or

dierent study methods and designs.39,40

Te early detection o patients with high risk

o developing DU could allow to introduce a pre

ventive treatment and thus reduce morbidity

and social costs.

Nailold videocapillaroscopy (NVC) is an imag

ing technique or a microcirculation study, and

it represents one o the most reliable tools or

the classication and diagnosis o SSc and relat

ed conditions.41,42

Sebastiani et al.43 have developed a capilla

roscopic skin ulcer risk index that can predict

the onset o new digital ulcers by using NVC in

patients with SSc.Alivermini et al.36 reported that

the best independent DU predictors in SSc pa

tients are interleukin6 levels higher than 2 pg/ml,

lupus anticoagulant positivity, and the presence o

avascular areas on the NVC analysis. Teir results

could be useul or physicians in daily practice to

identiy which SSc patients have higher risk o de

veloping skin ulcers during the course o the dis

ease. Tis diuse SSc subset, with lung and car

diopulmonary involvement, thrombophilia, andavascular areas on NVC, represents the major risk

actor or the development o DU.36

caia involvmn Te presence o cardiac involvement in SSc is underestimated due to the oc

cult nature o the signs and symptoms. More

over, symptoms o cardiac maniestations are o

ten attributed to noncardiac causes such as pul

monary, musculoskeletal, or esophageal involve

ment. More recent studies suggest that clinical

evidence o myocardial disease may be seen in

20% to 25% o SSc patients.44

Clinical actors, such as age and systemic ex

tent o disease, appear to correlate with cardiac

rhythm disturbances observed by ambulatory

electrocardiography, although there are confict

ing data regarding the association between pre

dictive actors o lung disease and the incidence

o ventricular tachyarrhythmias. Interestingly,

sex, duration o disease, extent o skin involve

ment, and the presence o serum anticentrom

ere antibody do not appear to predict ventricu

lar arrhythmias.45

Symptoms such as palpitations or syncope are

predictive o electrocardiographic abnormalitiesin SSc patients.46 Ambulatory electrocardiogra

phy is also useul or the risk stratication o SSc

patients. Kostis et al.45 reported that ventricular

Renal crisis is also linked to a positive antinu

clear antibodies speckled pattern, antibodies to

RNA polymerase I and II, and an absence o an

ticentromere antibodies.24

Early diagnosis and treatment may thus be cru

cial in improving outcomes. In act, SSc patients

renal unction has to be regularly controlled by

laboratory test, creatinine clearance, and renal

echo Doppler to exclude the presence o an in

creased renal resistance index or a reduction o

renal blood fow.

Interstitial lung disease and pulmonary arterial hyper-

nion Pulmonary disease due to ILD or PAHis now the major cause o death,2527 with up to

30% o deaths directly associated with pulmo

nary brosis.27

PAH is dened as the mean pulmonary arterial

pressure o 25 mmHg at rest with normal pulmo

nary capillary wedge pressure (


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