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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 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 Raynaud’s ph Acral CyanosisErythromelalgia Livedo Reticularis ClassificationPrimary/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 & symmetrical Secondary-mono/bilateral asymmetric Mono/bilateral Bilateral pain ++ uncommon limbHands, feet, nose, ears, tongue Hands, feet Feet, (may extend to hand, ears and nose) Upper and lower limbs T° extremities 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:chronic Secondary- acute/intermittent/chronic hyperhydrosis Significant reduction ---- Modification of the position of the limb No change Normalizes when limb is elevated No change Complications Ulcers, gangrene,amputation None None in primary in secondary necrosis and gangrene

5 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 + VEDOSS Topo I/ ACA - Follow up Digital paresthesias EMG Wrist US Carpal tunnel s. Outlet syndrome Echodoppler Burger s. smoke Crioglobulinemia IgG  /, hiper  Bence Jones protiduria Myeloma Plasmacytoma Hyperviscosity s. Skin fibrosis Organ involv. SSc Thyroiditis Hypothiroidism 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 Angiography Angio 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

6 Raynaud’s phenomenon in SSc 12% of patients with RP develop SSc 1 Commonly the first clinical sign of SSc 2 Occurs in ~96% of SSc patients 3 Precedes the first non-RP clinical feature of SSc by several years 3 – 4.8 years in lcSSc – 1.9 years in dcSSc 1.Koenig M, et al. Arthritis Rheum 2008; 58: Korn JH. Cleve Clin J Med 2003; 70: Walker UA, et al. Ann Rheum Dis 2007; 66 :

7 Raynaud’ ph e “puffy fingers”

8 The disease evolution skin thickness disease duration (years) early intermediatelate 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

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

12 Very Early SSc Early SSc ANA NVC ACA/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 13 Vasospasm vs Obstructive Vascculopathy

14 Lidia T. January 2005

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16 The disease evolution skin thickness disease duration (years) early intermediatelate 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

17 Diagnosis of SSc is typically delayed Johnson SR, et al. J Rheumatol 2006; 33: No significant change in time to diagnosis of SSc in past 3 decades  Improvements are needed Decade Mean time to diagnosis (years)

18 It is not easy to recognise an early SSc patient because… ANARPPUFFY FINGERS SLE, Sjogren’s Sindrome, MCTD, UCTD, SSc, Antiphospholipid syndrome and others autoimmune diseases

19 Puffy Fingers Very Early Systemic Sclerosis Pre-SSc UCTD MCTD Capillaroscopy Anti-nuclear antibodies Raynaud’s phenomenon 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. 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 ;58:

21 Sclerosi Sistemica Il quadro clinico molto precoce e precoce

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23 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

24 normalearly active late

25 Enlarged and damaged vessel wall Loss of red blood cells from the damaged wall Slide courtesy of Maurizio Cutolo. From Raynaud‘s to SSc: Early damage

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 DiffuseLimited Overlap 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 Clements PJ and Furst DE. Systemic Sclerosis. Lippincott, Williams & Wilkins, Baltimore, % have 3 common Ab Anti-centromere, anti-SCL70, Anti-RNA pol III

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

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 ratio1/19 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 1.Capillaroscopy 2.Serology (TOPO-I, ACA) 1.Oesophageal manometry 2.Chest HRCT & PFTs 3.echocardiography If either one is positive, diagnosis of very early SSc & further investigations 1 st level: Suspicion 2 nd level: Diagnosis of very early SSc VEDOSS- Very Early Diagnosis Of SSc Presence of red flags raises suspicion of very early SSc Avouac J, et al. Ann Rheum Dis 2010;. 3 nd level: Diagnosis of early SSc If either one is positive, diagnosis of early SSc & further investigations

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)

31 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%) Organ Involvement 105 pts(95.4%)!!! 110 VEDOSS patients

32 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

33 myocardial oedema, 2 pts Myocardial oedemaAfter 30 days of steroid therapy After 2 months abnormalnormal

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 RP ANA/ACA pos NVC active

36 Elvira D Finger edema & Raynaud 2.NVC- Active pattern 3. Anticentromere pos 4.LES Dysfunction Limited cutaneous SSc 2009

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

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

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

40 1.Diagnosi è difficile e speso ritardata 2. 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 secondaria 6.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…

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

42 Very Early SSc Early SSc ANA NVC ACA/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

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

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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 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 Regional Reference Centre for Systemic Sclerosis Clinical Trial Unit Dr. F Nacci Dr. F Bartoli Dr F Peruzzi Dr C Bruni Digital Ulcers Unit Dr. G Fiori Signora F Braschi Dottssa P Cerboni Young Adults Clinic Prof F Falcini Laboratory Unit Dr M Manetti Dr C Ceccarelli Dr E Romano

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