Il fenomeno di Raynaud e la
diagnosi precoce delle malattie del
connettivo
Marco Matucci Cerinic
Raynaud Fenomenus,
Quo Vadis… ?
Table II: Raynaud’s phenomenon classification:
Primary Raynaud’s phenomenon (fig 1): young women below 30 years, attacks are symmetric and
limited in time, no tissue lesions (digital pitting scars, teleangectasia) and no complications (digital
ulcers, necrosis/gangrene) on the extremities, capillaroscopy normal, antinuclear antibodies negative,
history and clinical examination negative, erythrocyte sedimentation rate normal
Secondary Raynaud’s phenomenon: age over 30 years, attacks are asymmetric, extremely painful and
prolonged in time, associated with digital lesions and some time with complications, auto-antibodies
positive, capillaroscopic changes, clinical features characteristic of a connective tissue disease or another
disease (fig …).
The following are the possible causes of secondary RP:
Autoimmune/Connective tissue diseases: Systemic sclerosis , Systemic lupus erythematosus,
Dermatomyositis, polymyositis, Siogren’s syndrome, Primary biliary cirrhosis
Joint diseases: Rheumatoid arthritis
Arterial diseases: Thromboangiitis obliterans (Buerger’s disease), Takayasu aortitis, Giant cell arteritis
Brachiocephalic atherosclerosis, Migraine or vascular headaches, Prinzmetal angina
Mechanical : Vibration (Hand arm vibration syndrome), Crutch pressure, Thoracic outlet syndrome,
scalenus anticus syndrome, cervical rib, carpal tunnel syndrome.
Temperature: Frost bite
Endocrine disorders: Carcinoid syndrome, Pheochromocytoma, Hypothyroidism
Neoplasias: ovarian carcinoma, angiocentric lymphoma
Rheological and coagulation disorders: cryoglobulins, cryofibrinogenaemia, cold agglutinins,
paraproteinaemia, plasmacytoma, polycythaemia, micro thromboembolism, Protein C, Protein S &
Antithrombin III deficiency, Factor V Leiden
Infections: Parvovirus B19 , Helicobacter pylori , Hepatitis C and B, mycoplasma (agglutinins)
Chemicals : Polyvinyl chloride, toluene, xylene, acetone
Drugs: Bleomycin, Vinblastine, b blockers, Ergots, Methysergide, Interferon a & b, Tegafur, amphetamines,
cyclosporine A, cocaine.
Matucci Cerinic M in press 2013
Raynaud’s ph
Classification
Phase/colour
simmetricity
pain
limb
Primary/secondary
Bi-triphasic/ white,blue,red
Primary-bilateral & symmetrical
Secondary-mono/bilateral
asymmetric
++
Hands, feet, nose, ears, tongue
T° extremities
Cold
Precipitated by
Cold
Erythromelalgia
Livedo Reticularis
Primary/secondary
familial, (autosomal
dominant )/sporadic
juvenile/adult
Primary/secondary
Mono/ dark blue
Mono/erythematous
macular, violaceous, netlike
rings
Bilateral
Bilateral
++++
-----
Acral Cyanosis
Mono/bilateral
uncommon
Hands, feet
Cold
Cold & lowering of the
limb
Feet, (may extend to hand,
ears and nose)
Upper and lower limbs
Hot
Cold
Hot
Cold
Phase/duration
Paroxistic/lasts from minutes to
hours
hyperhydrosis
Modification of the position of
the limb
Complications
+
No change
Ulcers, gangrene,amputation
Chronic/ seasonal
(amelioration in summer)
+++
Normalizes when limb is
elevated
None
Intermittent/ may last from
minutes to days
Significant reduction
No change
None
Primary:chronic
Secondaryacute/intermittent/chronic
---No change
None in primary
in secondary necrosis and gangrene
Ascertain that what the patient is complaining for is Raynaud’s phenomenon with adequate questions
Obtain a detailed patient’s history and drugs (chemotherapy et al) and working exposures (chemical, vibration) as
well as quality of attacks of RP (symmetricity, frequency)
Perform a basic clinical assessment in search for any sign or symptom
that may indicate an underlying disease
Heart (arrhytmias, fibrillation,murmurs) & lung (shortness of breath,
crackles and velcro) ,; vascular ( ); Muscles (weakness, atrophy) & joints
(synovitis, deformities); Liver, thryroid & lymphonodal palpation
After minimal lab work up ( esr, crp,ANA,
platelets, clotting) move to more lab
investigations. if signs and symptoms
indicate any specific abnorrmality
Inspections of the
extremities:
TSH, tpoAtb,tgAtb
HCV +,
Crioglobuline +
Thyroiditis
Hypothiroidism
Crioglobulinemia
Hepatologist
Sclerodactily, proximal
scleroderma, puffy fingers,
teleangectasias, vasculitis
Endocrinologist
ANA +
Topo I/ ACA +
Hyperviscosity s.
Topo I/ ACA -
Hematologist
smoke
Echodoppler
IgG k/l, hiperg
Bence Jones
protiduria
Myeloma
Plasmacytoma
digital ulcers,
DPS, necrosis
Digital
paresthesias
NC +
VEDOSS
Angiography
Angio MRI
EMG
Neck xray
Wrist US
Carpal
tunnel s.
Burger s.
Follow up
Skin fibrosis
Organ involv.
SSc
Atherosclerosis
Outlet syndrome
Figure 3
Raynaud’s phenomenon in SSc
•
•
•
•
12% of patients with RP develop SSc1
Commonly the first clinical sign of SSc2
Occurs in ~96% of SSc patients3
Precedes the first non-RP
clinical feature of SSc by
several years3
– 4.8 years in lcSSc
– 1.9 years in dcSSc
1. Koenig M, et al. Arthritis Rheum 2008; 58:3902-12.
2. Korn JH. Cleve Clin J Med 2003; 70:954-68.
3. Walker UA, et al. Ann Rheum Dis 2007; 66:754-63.
.
Raynaud’ ph e “puffy fingers”
The disease evolution
lung, heart, GI, kidney
intermediate
skin
thickness
late
early
DIFFUSE SSc
pulmonary hypert
intermediate
late
5
10
disease duration (years)
20
early
2
Medsger T & Steen V, Systemic Sclerosis, 1995, p 51,Williams & Wilkins
., malabsorption
LIMITED SSc
Changes in causes of SSc-related
deaths over time
50
Scleroderma renal crisis
PAH
Interstitial lung disease
Frequency (%)
40
30
20
10
0
1972-1976
1977-1981
1982-1986
1987-1991
1992-1996
1997-2001
Time period
Slide courtesy of Virginia Steen.
Window of
Opportunity
Very Early SSc
Puffy fingers
ANA
NVC
ACA/ATA
Raynaud ph
Early SSc
Established SSc
fibrotic & atrophic
Skin Fibrosis & Atrophy
Esophageal/Anal
Heart, Lung, Kidney
Digital Ulcers
Matucci Cerinic et al ARD 2012
Vasospasm vs Obstructive Vascculopathy
13
Lidia T. January 2005
The disease evolution
lung, heart, GI, kidney
intermediate
skin
thickness
late
early
DIFFUSE SSc
pulmonary hypert
intermediate
late
5
10
disease duration (years)
20
early
2
Medsger T & Steen V, Systemic Sclerosis, 1995, p 51,Williams & Wilkins
., malabsorption
LIMITED SSc
Mean time to diagnosis
(years)
Diagnosis of SSc is typically delayed
5
4
3
2
1
0
1970-79
1980-89
1990-99
> 2000
Decade
No significant change in time to diagnosis of SSc in past 3 decades
 Improvements are needed
Johnson SR, et al. J Rheumatol 2006; 33:1123-7.
It is not easy to recognise an early SSc patient
because…
ANA
RP
PUFFY FINGERS
SLE, Sjogren’s Sindrome, MCTD, UCTD, SSc,
Antiphospholipid syndrome and others
autoimmune diseases
Very Early Systemic Sclerosis
Raynaud’s phenomenon
Pre-SSc
Puffy
Fingers
UCTD
MCTD
Anti-nuclear antibodies
Matucci Cerinic et al , Ann Rheum Dis 2009
Capillaroscopy
Autoantibodies and microvascular damage are independent
predictive factors for the progression of Raynaud's phenomenon to
systemic sclerosis: a twenty-year prospective study of 586 patients,
with validation of proposed criteria for early systemic sclerosis.
Of the 586 patients who were followed
up for 3,197 person-years, 74 (12.6%)
developed definite SSc.
In RP evolving to definite SSc,
microvascular damage is dynamic and
sequential,
while
SSc
specific
autoantibodies are associated with the
course and type of capillary abnormalities.
Abnormal findings on NCM at baseline
together with an SSc-specific autoantibody
indicate a very high probability of
developing definite SSc, whereas their
absence rules out this outcome.
At followup, 79.5% of patients with 1 of
these autoantibodies and abnormal
findings on NCM at baseline had
developed definite SSc.
Koenig M, et al Arthritis Rheum. 2008 ;58:3902-12
Sclerosi Sistemica
Il quadro clinico molto precoce e
precoce
VEDOSS: Criteria to trigger early
referral
VEDOSS red flags
 Raynaud’s phenomenon
 Puffy fingers
 Positive antinuclear antibodies
Avouac J, et al. Ann Rheum Dis 2010
normal
active
early
late
From Raynaud‘s to SSc:
Early damage
Loss of red blood cells
from the damaged wall
Enlarged and damaged
vessel wall
Slide courtesy of Maurizio Cutolo.
Serological subsets in SSc
Diffuse
Limited
50-60% have 3 common Ab
Anti-centromere, anti-SCL70,
Anti-RNA pol III
Anti- Scl-70 = pulmonary
fibrosis
Anti-Centromere = PAH
Anti-RNA pol III = renal crisis
Anti-PM-Scl = SSc-myositis
overlap
Anti-U3RNP and Anti-Th=
nucleolar pattern on ANA
Anti-U3RNP
Anti-U1RNP
Overlap
Clements PJ and Furst DE. Systemic Sclerosis.
Lippincott, Williams & Wilkins, Baltimore, 2004.
VEDOSS- Very Early Diagnosis Of SSc
Presence of red flags raises
suspicion of very early SSc
1. Capillaroscopy
2. Serology (TOPO-I, ACA)
If either one is positive, diagnosis of very
early SSc & further investigations
?
1st level:
Suspicion
2nd level:
Diagnosis of
very early
SSc
3nd level:
Diagnosis
of early SSc
Avouac J, et al. Ann Rheum Dis 2010;
Signs of pre-clinical organ
involvement in early SSc
Patients with early SSc* demonstrated signs of preclinical SSc-related internal organ involvement:
Pre-clinical internal
organ involvement
Definition
Occurrence
(n/N)
Early SSc cardiac
involvement
Inverted mitral E : A ratio
1/19
Early lung involvement
Diffusing lung capacity for CO < 80%
of predictive value
7/19
Early oesophageal
involvement
Basal low oesophageal sphincter
pressure < 15 mmHg
4/18
*As defined by Koenig M, et al. Arthritis Rheum 2008; 58:3902-12.
n = no. of patients with organ involvement; N = no. of patients investigated.
Valentini G, et al. Rheumatology (Oxford) 2010
VEDOSS- Very Early Diagnosis Of SSc
Presence of red flags raises
suspicion of very early SSc
1. Capillaroscopy
2. Serology (TOPO-I, ACA)
If either one is positive, diagnosis of very
early SSc & further investigations
1. Oesophageal manometry
2. Chest HRCT & PFTs
3. echocardiography
If either one is positive, diagnosis of early
SSc & further investigations
1st level:
Suspicion
2nd level:
Diagnosis of
very early
SSc
3nd level:
Diagnosis
of early SSc
Avouac J, et al. Ann Rheum Dis 2010;
VEDOSS patients
25/110 pz reported
history and/or showed
the presence of DU
9/25 DU
previous
2/25 DU
active +
previous
14/25 DU
active
previo
us
previo
us+actDU
ive
active
Bruni et al (submitted)
Data from a VEDOSS Clinic
Digital Ulcers a «sentinel sign» of organ involvement
in vedoss patients…!!!
Digital Ulcers
DU
110 VEDOSS patients
• 4 pts with DPS (3.6%)
• 16 pts active DU (14.5%) of whom 14 also had a
previous history of DU
• 9 pts a history of DU (8.2%)
2 groups:
• With lung/GI involv.- 25 pts with DU or history DU
105 pts(95.4%)!!!
( 22.7 %)
• Without organ involv.- No DU or history DU ( 0%)
Organ
Involvement
Bruni et al 2013 ARD in press
Reversible and irreversible patterns
Normal
Myocardial fibrosis Myocardial oedema
irreversible
reversible
MRI provides information on
heart and lung disease
activity in the early phase of
SSc.
Pingitore et al Matucci Cerinic
Rheumatology 2013
myocardial oedema, 2 pts
abnormal
Myocardial oedema
normal
After 30 days
of steroid therapy
normal
After 2 months
FIG. 1 T2-weighted fast spin-echo images with fat suppression of the basal,
middle and distal myocardial segments
before (a) and after (b) corticosteroid therapy.
Pingitore and Matucci Cerinic Rheumatology 2013
DE 15.4.04
RP
ANA/ACA pos
NVC active
Elvira D. 15.4.04
1.
2.
3.
4.
Finger edema & Raynaud
NVC- Active pattern
Anticentromere pos
LES Dysfunction
Limited cutaneous SSc
2009
RP
ANA/Topo I pos
NVC active
RP
ANA/ACA pos
NVC early
Simona C. December 2004
Claudia P. 2005
RP
ANA/Topo I pos
NVC active
RP
ANA/ACA pos
NVC early
Diffuse SSc- Six months
Simona C. December 2004
Limited SSc- five years
Claudia P. 2005
Matucci Cerinic M. Kahaleh B, Wigley F: «Scleroderma is a vascular disease», A&R 2013
Asymptomatic SSc
Very Early
Early
Established Advanced
Silent phase
years to decades
???
Lung
GG
reticulation
Skin Puffy fingers Sclerodactily (fibrosis)
Vascular
PAH
Raynaud
Autoantibodies
Ulcers
ANS Esophageal/anal
Intestine
Honey combing
Retraction (Atrophy)
Fatti…
1.
2.
3.
4.
5.
6.
7.
Diagnosi è difficile e speso ritardata
F Raynaud’s ph è il primo segno della fase precoce della
malattia
“red flags” devono sempre indurre sospetto di una
malattia molto precoce !
Di fronte ad un F Raynaud deve essere condotta una
attenta DD per differenziare una forma primaria da una
secondaria
L’indagine sulla condizione degli organi interni è
fondamentale per comprendere se la malattia è evoluta
verso una forma precoce
Il follow up dei pazienti è necessario per comprendere
l’evoluzione della malattia
The window of opportunity…!!!
Paul Klee
La finestra
Very early versus early disease:
the evolving definition of the many faces of Systemic Sclerosis
M Matucci Cerinic , S Bellando Randone, G Lepri, C Bruni, S Guiducci
ARD 2013
Paul Klee
«The window»
Very Early SSc
Puffy fingers
ANA
NVC
ACA/ATA
Raynaud ph
Early SSc
Established SSc
fibrotic & atrophic
Skin Fibrosis & Atrophy
Esophageal/Anal
Heart, Lung, Kidney
Digital Ulcers
Early Phase
Oedema
Strike the iron when it is hot !!
Fibrosis
Many Faces of SSc !!!!
Advanced
phase
Atrophy
VEDOSS
Very Early Diagnosis Of SSc
• EUSTAR initiative to identify criteria for VEDOSS
• Experts in field of SSc from 171 EUSTAR centres asked to
participate in a Delphi exercise
• Experts proposed and rated preliminary criteria for VEDOSS
based on clinical relevance and their importance in leading to
an early referral
• Validation of criteria ongoing in prospective EUSTAR
observational cohort

 www.eustar.org
Dept Rheumatology AVC
Dept Biomedicine & Div Rheumatology AOUC
Dept Medicine & DENOthe Centre
University of Florence
Dr F Galluccio
Dr. ML Conforti
Dr S Cappelli
Dr A Righi
Dr V Denaro
Dr G Baccano
Dr T Barskova
Dr. S Maddali Bongi
Dr R De Luca
Clinical Trial Unit
Dr L Giovannini
Dr. A Del Rosso
Dr. F Nacci
Dr A Calabrò
Dr. D Melchiorre
Dr. F Bartoli
Dr E Bellucci
Dr. M Maresca
Digital Ulcers Unit
Dr M Orlandi
Dr F Peruzzi
Dr. F Bandinelli
Dr. G Fiori
Dr C Bruni
Dr. S Bellando Randone
Signora F Braschi
Dr. S Guiducci
Regional Reference Centre for
Dr. G Salvadorini
Systemic Sclerosis
Dr. F Porta
Dr. J Blagojevic
Dottssa P Cerboni
Dr. G Carnesecchi
Laboratory Unit
Young Adults Clinic
Dr M Manetti
Prof F Falcini
Dr C Ceccarelli
Dr E Romano