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

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Presentation on theme: "Il fenomeno di Raynaud e la diagnosi precoce delle malattie del connettivo Marco Matucci Cerinic."— Presentation transcript:

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

2 Raynaud Fenomenus, Quo Vadis… ?

3 Matucci Cerinic M in press 2013
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

4 Acral Cyanosis Erythromelalgia Livedo Reticularis Raynaud’s ph
Raynaud’s ph Acral Cyanosis Erythromelalgia Livedo Reticularis Classification Primary/secondary familial, (autosomal dominant )/sporadic juvenile/adult Phase/colour Bi-triphasic/ white,blue,red Mono/ dark blue Mono/erythematous macular, violaceous, netlike rings simmetricity Primary-bilateral & symmetrical Secondary-mono/bilateral asymmetric Mono/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 Hot Precipitated by Cold & lowering of the limb Phase/duration Paroxistic/lasts from minutes to hours Chronic/ seasonal (amelioration in summer) Intermittent/ may last from minutes to days Primary:chronic Secondary- acute/intermittent/chronic hyperhydrosis + +++ Significant reduction ---- Modification of the position of the limb No change Normalizes when limb is elevated Complications Ulcers, gangrene,amputation None None in primary in secondary necrosis and gangrene

5 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) After minimal lab work up ( esr, crp,ANA, platelets, clotting) move to more lab investigations. if signs and symptoms indicate any specific abnorrmality 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 Inspections of the extremities: Sclerodactily, proximal scleroderma, puffy fingers, teleangectasias, vasculitis digital ulcers, DPS, necrosis smoke HCV +, Crioglobuline + TSH, tpoAtb,tgAtb Thyroiditis Hypothiroidism Crioglobulinemia Echodoppler Digital paresthesias Hepatologist Endocrinologist ANA + NC + IgG k/l, hiperg Bence Jones protiduria Topo I/ ACA + Angiography Angio MRI EMG VEDOSS Neck x-ray Wrist US Hyperviscosity s. Topo I/ ACA - Burger s. Carpal tunnel s. Myeloma Plasmacytoma Skin fibrosis Organ involv. Follow up Atherosclerosis Outlet syndrome SSc Hematologist Figure 3

6 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 Koenig M, et al. Arthritis Rheum 2008; 58: Korn JH. Cleve Clin J Med 2003; 70: 3. Walker UA, et al. Ann Rheum Dis 2007; 66: .

7 Raynaud’ ph e “puffy fingers”

8 The disease evolution skin thickness early DIFFUSE SSc LIMITED SSc
lung, heart, GI, kidney skin thickness intermediate early late DIFFUSE SSc pulmonary hypert., malabsorption intermediate late LIMITED SSc early disease duration (years) Medsger T & Steen V, Systemic Sclerosis, 1995, p 51,Williams & Wilkins

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11 Changes in causes of SSc-related deaths over time
50 Scleroderma renal crisis PAH 40 Interstitial lung disease 30 Frequency (%) 20 10 Time period Slide courtesy of Virginia Steen.

12 Skin Fibrosis & Atrophy
Window of Opportunity Established SSc fibrotic & atrophic Very Early SSc Early SSc Puffy fingers Skin Fibrosis & Atrophy ANA NVC ACA/ATA Esophageal/Anal Heart, Lung, Kidney Raynaud ph Digital Ulcers Matucci Cerinic et al ARD 2012

13 Vasospasm vs Obstructive Vascculopathy

14 Lidia T. January 2005

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16 The disease evolution skin thickness early DIFFUSE SSc LIMITED SSc
lung, heart, GI, kidney skin thickness intermediate early late DIFFUSE SSc pulmonary hypert., malabsorption intermediate late LIMITED SSc early disease duration (years) Medsger T & Steen V, Systemic Sclerosis, 1995, p 51,Williams & Wilkins

17 Diagnosis of SSc is typically delayed
Mean time to diagnosis (years) 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:

18 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

19 Very Early Systemic Sclerosis
Raynaud’s phenomenon Pre-SSc Puffy Fingers UCTD MCTD Anti-nuclear antibodies Capillaroscopy Matucci Cerinic et al , Ann Rheum Dis 2009

20 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 ;58:

21 Il quadro clinico molto precoce e precoce
Sclerosi Sistemica Il quadro clinico molto precoce e precoce

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23 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

24 normal early active late

25 From Raynaud‘s to SSc: Early damage
Loss of red blood cells from the damaged wall Enlarged and damaged vessel wall Figure 5: Pattern observable in patients with dermatomyositis (DM) (magnification 200x) Slide courtesy of Maurizio Cutolo.

26 Serological subsets in SSc
Anti-topoisomerase I (Scl-70) Anti-centromere Anti-RNA polymerase I-III Anti-Th Anti-U3RNP Anti-U1RNP Anti- PM-Scl Diffuse Limited Overlap 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 Commercially available, false positive anti-SCL-70 Ab by ELISA, repeat with immunodiffusion Clements PJ and Furst DE. Systemic Sclerosis. Lippincott, Williams & Wilkins, Baltimore, 2004.

27 VEDOSS- Very Early Diagnosis Of SSc
Presence of red flags raises suspicion of very early SSc 1st level: Suspicion Capillaroscopy Serology (TOPO-I, ACA) 2nd level: Diagnosis of very early SSc If either one is positive, diagnosis of very early SSc & further investigations ? 3nd level: Diagnosis of early SSc Avouac J, et al. Ann Rheum Dis 2010; .

28 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 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: n = no. of patients with organ involvement; N = no. of patients investigated. Valentini G, et al. Rheumatology (Oxford) 2010

29 VEDOSS- Very Early Diagnosis Of SSc
Presence of red flags raises suspicion of very early SSc 1st level: Suspicion Capillaroscopy Serology (TOPO-I, ACA) 2nd level: Diagnosis of very early SSc If either one is positive, diagnosis of very early SSc & further investigations Oesophageal manometry Chest HRCT & PFTs echocardiography 3nd level: Diagnosis of early SSc If either one is positive, diagnosis of early SSc & further investigations Avouac J, et al. Ann Rheum Dis 2010; .

30 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 . Bruni et al (submitted) 30 30

31 Data from a VEDOSS Clinic Digital Ulcers a «sentinel sign» of organ involvement in vedoss patients…!!! Digital Ulcers 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%) DU 2 groups: With lung/GI involv.- 25 pts with DU or history DU ( %) Without organ involv.- No DU or history DU ( 0%) Organ Involvement 105 pts(95.4%)!!! Bruni et al ARD in press

32 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

33 myocardial oedema, 2 pts Myocardial oedema After 30 days
abnormal normal normal Myocardial oedema After 30 days of steroid therapy After 2 months

34 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

35 DE 15.4.04 RP ANA/ACA pos NVC active

36 Elvira D Finger edema & Raynaud NVC- Active pattern Anticentromere pos LES Dysfunction Limited cutaneous SSc 2009

37 RP ANA/Topo I pos NVC active Simona C. December 2004 RP ANA/ACA pos NVC early Claudia P. 2005

38 RP ANA/Topo I pos NVC active Diffuse SSc- Six months Simona C. December 2004 RP ANA/ACA pos NVC early Limited SSc- five years Claudia P. 2005

39 Silent phase years to decades
Matucci Cerinic M. Kahaleh B, Wigley F: «Scleroderma is a vascular disease», A&R 2013 Very Early Early Established Advanced Asymptomatic SSc Silent phase years to decades ? ? ? Lung GG reticulation Honey combing Skin Puffy fingers Sclerodactily (fibrosis) Retraction (Atrophy) PAH Vascular Raynaud Ulcers Autoantibodies Esophageal/anal Intestine ANS

40 Fatti… 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

41 The window of opportunity…!!!
Paul Klee La finestra

42 Early SSc Very Early SSc Paul Klee «The window»
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» Established SSc fibrotic & atrophic Very Early SSc Early SSc Puffy fingers Skin Fibrosis & Atrophy ANA NVC ACA/ATA Esophageal/Anal Heart, Lung, Kidney Raynaud ph Digital Ulcers

43 Strike the iron when it is hot !!
Early Phase Oedema Strike the iron when it is hot !! Fibrosis Many Faces of SSc !!!! Advanced phase Atrophy

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45 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

46 Clinical Trial Unit Digital Ulcers Unit Young Adults Clinic
Dept Rheumatology AVC Dept Biomedicine & Div Rheumatology AOUC Dept Medicine & DENOthe Centre University of Florence Dr. ML Conforti Dr A Righi Dr G Baccano Dr. S Maddali Bongi Dr. A Del Rosso Dr. D Melchiorre Dr. M Maresca Dr. F Bandinelli Dr. S Bellando Randone Dr. S Guiducci Dr. G Salvadorini Dr. F Porta Dr. J Blagojevic Dr. G Carnesecchi Dr F Galluccio Dr S Cappelli Dr V Denaro Dr T Barskova Dr R De Luca Dr L Giovannini Dr A Calabrò Dr E Bellucci Dr M Orlandi Clinical Trial Unit Dr. F Nacci Dr. F Bartoli Dr F Peruzzi Dr C Bruni Digital Ulcers Unit Dr. G Fiori Signora F Braschi Regional Reference Centre for Systemic Sclerosis Dottssa P Cerboni Laboratory Unit Dr M Manetti Dr C Ceccarelli Dr E Romano Young Adults Clinic Prof F Falcini

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