il fenomeno di raynaud e la diagnosi precoce delle malattie del connettivo marco matucci cerinic
TRANSCRIPT
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