Il fenomeno di Raynaud e la diagnosi precoce delle malattie del connettivo Marco Matucci Cerinic.

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 normalSecondary 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 cirrhosisJoint diseases: Rheumatoid arthritis Arterial diseases: Thromboangiitis obliterans (Buerger’s disease), Takayasu aortitis, Giant cell arteritis Brachiocephalic atherosclerosis, Migraine or vascular headaches, Prinzmetal anginaMechanical : 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, HypothyroidismNeoplasias: ovarian carcinoma, angiocentric lymphomaRheological and coagulation disorders: cryoglobulins, cryofibrinogenaemia, cold agglutinins, paraproteinaemia, plasmacytoma, polycythaemia, micro thromboembolism, Protein C, Protein S & Antithrombin III deficiency, Factor V LeidenInfections: Parvovirus B19 , Helicobacter pylori , Hepatitis C and B, mycoplasma (agglutinins)Chemicals : Polyvinyl chloride, toluene, xylene, acetoneDrugs: Bleomycin, Vinblastine, b blockers, Ergots, Methysergide, Interferon a & b, Tegafur, amphetamines, cyclosporine A, cocaine. Matucci Cerinic M in press 2013

Raynaud’s ph Acral Cyanosis Erythromelalgia Livedo Reticularis Classification Primary/secondary Primary/secondary familial, (autosomal

dominant )/sporadic juvenile/adult

Primary/secondary

Phase/colour Bi-triphasic/ white,blue,red Mono/ dark blue Mono/erythematous macular, violaceous, netlike rings

simmetricity Primary-bilateral & symmetricalSecondary-mono/bilateral asymmetric

Mono/bilateral Bilateral Bilateral

pain ++ uncommon ++++ ----- limb Hands, feet, nose, ears, tongue Hands, feet Feet, (may extend to hand, ears

and nose)Upper and lower limbs

T° extremities Cold Cold Hot Cold Precipitated by Cold Cold & lowering of the limb Hot Cold

Phase/duration

Paroxistic/lasts from minutes to hours

Chronic/ seasonal (amelioration in summer)

Intermittent/ may last from minutes to days

Primary:chronicSecondary- acute/intermittent/chronic

hyperhydrosis + +++ Significant reduction ----

Modification of the position of the limb

No change Normalizes when limb is elevated

No change No change

Complications Ulcers, gangrene,amputation None None None in primary in secondary necrosis and gangrene

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

HCV +, Crioglobuline +

ANA +Hepatologist

After minimal lab work up ( esr, crp,ANA,

platelets, clotting) move to more lab investigations. if signs and symptoms

indicate any specific abnorrmality

NC +Topo I/ ACA +

VEDOSSTopo I/ ACA -

Follow up

Digital paresthesias

EMG

Wrist US

Carpal tunnel s.

Outlet syndrome

Echodoppler

Burger s.

smoke

Crioglobulinemia

IgG k/l, hipergBence Jones protiduria

MyelomaPlasmacytoma

Hyperviscosity s.

Skin fibrosisOrgan involv.

SSc

ThyroiditisHypothiroidism

TSH, tpoAtb,tgAtb

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)

Inspections of the extremities:

Sclerodactily, proximal scleroderma, puffy fingers, teleangectasias, vasculitis

Figure 3

AngiographyAngio MRI

Hematologist

Endocrinologist

digital ulcers, DPS, necrosis

Atherosclerosis

Neck x-ray

Ascertain that what the patient is complaining for is Raynaud’s phenomenon with adequate questions

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

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

Changes in causes of SSc-related deaths over time

Time periodSlide courtesy of Virginia Steen.

Fre

que

ncy

(%)

0

10

20

30

40

50

1972-1976 1977-1981 1982-1986 1987-1991 1992-1996 1997-2001

Scleroderma renal crisisPAHInterstitial lung disease

Very Early SSc Early SSc

ANANVCACA/ATA

Established SSc fibrotic & atrophic

Skin Fibrosis & Atrophy

Heart, Lung, Kidney

Digital Ulcers

Esophageal/Anal

Window of Opportunity

Puffy fingers

Raynaud ph

Matucci Cerinic et al ARD 2012

13

Vasospasm vs Obstructive Vascculopathy

Lidia T. January 2005

The 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

Diagnosis of SSc is typically delayed

Johnson SR, et al. J Rheumatol 2006; 33:1123-7.

No significant change in time to diagnosis of SSc in past 3 decades Improvements are needed

1970-79 1980-89 1990-99 > 20000

0.51

1.52

2.53

3.54

4.55

Decade

Mea

n tim

e to

dia

gnos

is

(yea

rs)

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

Puffy Fingers

Very Early Systemic Sclerosis

Pre-SSc

UCTD MCTD

CapillaroscopyAnti-nuclear antibodies

Raynaud’s phenomenon

Matucci Cerinic et al , Ann Rheum Dis 2009

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.

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.

Of the 586 patients who were followed up for 3,197 person-years, 74 (12.6%) developed definite SSc.

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

Raynaud’s phenomenon

Puffy fingers

Positive antinuclear antibodies

VEDOSS red flags

Avouac J, et al. Ann Rheum Dis 2010

normal early

active late

Enlarged and damagedvessel wall

Loss of red blood cellsfrom the damaged wall

Slide courtesy of Maurizio Cutolo.

From Raynaud‘s to SSc: Early damage

Serological subsets in SSc

Anti-topoiso

merase I

(Scl-70)

Anti-centromereAnti-RNA

polymerase I-III

Anti-ThAnti-U3RNP

Anti-U1RNP

Anti-PM-Scl

Diffuse Limited

Overlap

Anti- Scl-70 = pulmonary fibrosisAnti-Centromere = PAHAnti-RNA pol III = renal crisisAnti-PM-Scl = SSc-myositis overlapAnti-U3RNP and Anti-Th= nucleolar pattern on ANA Clements PJ and Furst DE. Systemic Sclerosis.

Lippincott, Williams & Wilkins, Baltimore, 2004.

50-60% have 3 common AbAnti-centromere, anti-SCL70,

Anti-RNA pol III

1. Capillaroscopy2. 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

VEDOSS- Very Early Diagnosis Of SScPresence of red flags

raises suspicion of very early SSc

Avouac J, et al. Ann Rheum Dis 2010; .

3nd level:

Diagnosis of early SSc

?

Signs of pre-clinical organ involvement in early SSc

Patients with early SSc* demonstrated signs of pre-clinical SSc-related internal organ involvement:

Pre-clinical internal organ involvement Definition Occurren

ce (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

1. Capillaroscopy2. Serology (TOPO-I,

ACA)

1.Oesophageal manometry

2.Chest HRCT & PFTs3.echocardiography

If either one is positive, diagnosis of very early SSc & further investigations

1st level: Suspicion

2nd level:Diagnosis of

very early SSc

VEDOSS- Very Early Diagnosis Of SScPresence of red flags

raises suspicion of very early SSc

Avouac J, et al. Ann Rheum Dis 2010; .

3nd level:

Diagnosis of early SSc

If either one is positive, diagnosis of early SSc & further investigations

VEDOSS patients

85

25

No DU DU

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

DU

previousprevious+activeactive

Bruni et al (submitted)

Data from a VEDOSS Clinic Digital Ulcers a «sentinel sign» of organ involvement

in vedoss patients…!!!

Digital Ulcers• 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%)

DU

Bruni et al 2013 ARD in press

2 groups:• With lung/GI involv.- 25 pts with DU or history DU

( 22.7 %)• Without organ involv.- No DU or history DU ( 0%)

OrganInvolvement

105 pts(95.4%)!!!

110 VEDOSS patients

Reversible and irreversible patterns

Myocardial oedemaNormal Myocardial fibrosis

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

Myocardial oedema After 30 days of steroid therapy

After 2 months

abnormal normal normal

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 15.4.04RP

ANA/ACA posNVC active

Elvira D. 15.4.04

1. Finger edema & Raynaud2. NVC- Active pattern3. Anticentromere pos4. LES Dysfunction

Limited cutaneous SSc 2009

Simona C. December 2004

RPANA/Topo I posNVC active

Claudia P. 2005

RPANA/ACA posNVC early

Simona C. December 2004

RPANA/Topo I posNVC active

Claudia P. 2005

RPANA/ACA posNVC early

Diffuse SSc- Six months

Limited SSc- five years

Silent phase years to decades

Autoantibodies

ANS

Asymptomatic SSc Very Early Early Advanced

Raynaud

GG

Puffy fingers Sclerodactily (fibrosis)

Established

Esophageal/anal Intestine

Skin Retraction (Atrophy)

Lung reticulation Honey combing

Ulcers

PAHVascular

? ? ?

Matucci Cerinic M. Kahaleh B, Wigley F: «Scleroderma is a vascular disease», A&R 2013

1. Diagnosi è difficile e speso ritardata2. 3. F Raynaud’s ph è il primo segno della fase precoce della

malattia 4. “red flags” devono sempre indurre sospetto di una malattia

molto precoce !5. Di fronte ad un F Raynaud deve essere condotta una attenta

DD per differenziare una forma primaria da una secondaria6. L’indagine sulla condizione degli organi interni è

fondamentale per comprendere se la malattia è evoluta verso una forma precoce

7. Il follow up dei pazienti è necessario per comprendere l’evoluzione della malattia

Fatti…

The window of opportunity…!!!

Paul Klee La finestra

Very Early SSc Early SSc

ANANVCACA/ATA

Established SSc fibrotic & atrophic

Skin Fibrosis & Atrophy

Heart, Lung, Kidney

Digital Ulcers

Esophageal/Anal

Puffy fingers

Raynaud ph

M Matucci Cerinic , S Bellando Randone, G Lepri, C Bruni, S Guiducci ARD 2013

Paul Klee «The window»

Very early versus early disease: the evolving definition of the many faces of Systemic Sclerosis

Early Phase

Strike the iron when it is hot !!

Advanced phase Atrophy

Fibrosis

Oedema

Many Faces of SSc !!!!

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 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