3Matucci 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 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 arthritisArterial 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 biteEndocrine 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
4Acral Cyanosis Erythromelalgia Livedo Reticularis Raynaud’s ph Raynaud’s phAcral CyanosisErythromelalgiaLivedo ReticularisClassificationPrimary/secondaryfamilial, (autosomaldominant )/sporadicjuvenile/adultPhase/colourBi-triphasic/ white,blue,redMono/ dark blueMono/erythematousmacular, violaceous, netlike ringssimmetricityPrimary-bilateral & symmetricalSecondary-mono/bilateral asymmetricMono/bilateralBilateralpain++uncommon++++-----limbHands, feet, nose, ears, tongueHands, feetFeet, (may extend to hand, ears and nose)Upper and lower limbsT° extremitiesColdHotPrecipitated byCold & lowering of the limbPhase/durationParoxistic/lasts from minutes to hoursChronic/ seasonal (amelioration in summer)Intermittent/ may last from minutes to daysPrimary:chronicSecondary- acute/intermittent/chronichyperhydrosis++++Significant reduction----Modification of the position of the limbNo changeNormalizes when limb is elevatedComplicationsUlcers, gangrene,amputationNoneNone in primaryin secondary necrosis and gangrene
5Ascertain 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 abnorrmalityPerform a basic clinical assessment in search for any sign or symptom that may indicate an underlying diseaseHeart (arrhytmias, fibrillation,murmurs) & lung (shortness of breath, crackles and velcro) ,; vascular ( ); Muscles (weakness, atrophy) & joints (synovitis, deformities); Liver, thryroid & lymphonodal palpationInspections of the extremities:Sclerodactily, proximal scleroderma, puffy fingers, teleangectasias, vasculitisdigital ulcers,DPS, necrosissmokeHCV +,Crioglobuline +TSH, tpoAtb,tgAtbThyroiditisHypothiroidismCrioglobulinemiaEchodopplerDigitalparesthesiasHepatologistEndocrinologistANA +NC +IgG k/l, hipergBence JonesprotiduriaTopo I/ ACA +AngiographyAngio MRIEMGVEDOSSNeck x-rayWrist USHyperviscosity s.Topo I/ ACA -Burger s.Carpaltunnel s.MyelomaPlasmacytomaSkin fibrosisOrgan involv.Follow upAtherosclerosisOutlet syndromeSScHematologistFigure 3
6Raynaud’s phenomenon in SSc 12% of patients with RP develop SSc1Commonly the first clinical sign of SSc2Occurs in ~96% of SSc patients3Precedes the first non-RP clinical feature of SSc by several years34.8 years in lcSSc1.9 years in dcSScKoenig 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:.
17Diagnosis of SSc is typically delayed Mean time to diagnosis (years)DecadeNo significant change in time to diagnosis of SSc in past 3 decades Improvements are neededJohnson SR, et al. J Rheumatol 2006; 33:
18It is not easy to recognise an early SSc patient because… ANARPPUFFY FINGERSSLE, Sjogren’s Sindrome, MCTD, UCTD, SSc, Antiphospholipid syndrome and others autoimmune diseases
19Very Early Systemic Sclerosis Raynaud’s phenomenonPre-SScPuffy FingersUCTDMCTDAnti-nuclear antibodiesCapillaroscopyMatucci Cerinic et al , Ann Rheum Dis 2009
20Autoantibodies 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:
21Il quadro clinico molto precoce e precoce Sclerosi SistemicaIl quadro clinico molto precoce e precoce
25From Raynaud‘s to SSc: Early damage Loss of red blood cellsfrom the damaged wallEnlarged and damagedvessel wallFigure 5: Pattern observable in patients with dermatomyositis (DM) (magnification 200x)Slide courtesy of Maurizio Cutolo.
26Serological subsets in SSc Anti-topoisomerase I(Scl-70)Anti-centromereAnti-RNApolymerase I-IIIAnti-ThAnti-U3RNPAnti-U1RNPAnti-PM-SclDiffuseLimitedOverlap50-60% have 3 common AbAnti-centromere, anti-SCL70,Anti-RNA pol IIIAnti- Scl-70 = pulmonary fibrosisAnti-Centromere = PAHAnti-RNA pol III = renal crisisAnti-PM-Scl = SSc-myositis overlapAnti-U3RNP and Anti-Th= nucleolar pattern on ANACommercially available, false positive anti-SCL-70 Ab by ELISA, repeat with immunodiffusionClements PJ and Furst DE. Systemic Sclerosis. Lippincott, Williams & Wilkins, Baltimore, 2004.
27VEDOSS- Very Early Diagnosis Of SSc Presence of red flags raises suspicion of very early SSc1st level: SuspicionCapillaroscopySerology (TOPO-I, ACA)2nd level:Diagnosis of very early SScIf either one is positive, diagnosis of very early SSc & further investigations?3nd level:Diagnosis of early SScAvouac J, et al. Ann Rheum Dis 2010; .
28Signs 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 involvementDefinitionOccurrence (n/N)Early SSc cardiac involvementInverted mitral E : A ratio1/19Early lung involvementDiffusing lung capacity for CO < 80% of predictive value7/19Early oesophageal involvementBasal low oesophageal sphincter pressure < 15 mmHg4/18*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
29VEDOSS- Very Early Diagnosis Of SSc Presence of red flags raises suspicion of very early SSc1st level: SuspicionCapillaroscopySerology (TOPO-I, ACA)2nd level:Diagnosis of very early SScIf either one is positive, diagnosis of very early SSc & further investigationsOesophageal manometryChest HRCT & PFTsechocardiography3nd level:Diagnosis of early SScIf either one is positive, diagnosis of early SSc & further investigationsAvouac J, et al. Ann Rheum Dis 2010; .
30VEDOSS patients25/110 pz reported history and/or showed the presence of DU9/25 DU previous 2/25 DU active + previous 14/25 DU active.Bruni et al (submitted)3030
31Data from a VEDOSS Clinic Digital Ulcers a «sentinel sign» of organ involvement in vedoss patients…!!!Digital Ulcers110 VEDOSS patients4 pts with DPS (3.6%)16 pts active DU (14.5%) of whom 14 also had a previous history of DU9 pts a history of DU (8.2%)DU2 groups:With lung/GI involv.- 25 pts with DU or history DU ( %)Without organ involv.- No DU or history DU ( 0%)OrganInvolvement105 pts(95.4%)!!!Bruni et al ARD in press
32Reversible and irreversible patterns NormalMyocardial fibrosisMyocardial oedemairreversiblereversibleMRI provides information on heart and lung diseaseactivity in the early phase of SSc.Pingitore et al Matucci CerinicRheumatology 2013
33myocardial oedema, 2 pts Myocardial oedema After 30 days abnormalnormalnormalMyocardial oedemaAfter 30 daysof steroid therapyAfter 2 months
34FIG. 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
37RPANA/Topo I posNVC activeSimona C. December 2004RPANA/ACA posNVC earlyClaudia P. 2005
38RPANA/Topo I posNVC activeDiffuse SSc- Six monthsSimona C. December 2004RPANA/ACA posNVC earlyLimited SSc- five yearsClaudia P. 2005
39Silent phase years to decades Matucci Cerinic M. Kahaleh B, Wigley F: «Scleroderma is a vascular disease», A&R 2013Very EarlyEarlyEstablishedAdvancedAsymptomatic SScSilent phase years to decades? ? ?LungGGreticulationHoney combingSkinPuffy fingersSclerodactily (fibrosis)Retraction (Atrophy)PAHVascularRaynaudUlcersAutoantibodiesEsophageal/analIntestineANS
40Fatti… 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 secondariaL’indagine sulla condizione degli organi interni è fondamentale per comprendere se la malattia è evoluta verso una forma precoceIl follow up dei pazienti è necessario per comprendere l’evoluzione della malattia
41The window of opportunity…!!! Paul KleeLa finestra
42Early SSc Very Early SSc Paul Klee «The window» Very early versus early disease:the evolving definition of the many faces of Systemic SclerosisM Matucci Cerinic , S Bellando Randone, G Lepri, C Bruni, S GuiducciARD 2013Paul Klee«The window»Established SSc fibrotic & atrophicVery Early SScEarly SScPuffy fingersSkin Fibrosis & AtrophyANANVCACA/ATAEsophageal/AnalHeart, Lung, KidneyRaynaud phDigital Ulcers
43Strike the iron when it is hot !! Early PhaseOedemaStrike the iron when it is hot !!FibrosisMany Faces of SSc !!!!AdvancedphaseAtrophy
45VEDOSS Very Early Diagnosis Of SSc EUSTAR initiative to identify criteria for VEDOSSExperts in field of SSc from 171 EUSTAR centres asked to participate in a Delphi exerciseExperts proposed and rated preliminary criteria for VEDOSS based on clinical relevance and their importance in leading to an early referralValidation of criteria ongoing in prospective EUSTAR observational cohort
46Clinical Trial Unit Digital Ulcers Unit Young Adults Clinic Dept Rheumatology AVCDept Biomedicine & Div Rheumatology AOUCDept Medicine & DENOthe CentreUniversity of FlorenceDr. 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 CarnesecchiDr F GalluccioDr S CappelliDr V DenaroDr T BarskovaDr R De LucaDr L GiovanniniDr A CalabròDr E BellucciDr M OrlandiClinical Trial UnitDr. F NacciDr. F BartoliDr F PeruzziDr C BruniDigital Ulcers UnitDr. G FioriSignora F BraschiRegional Reference Centre for Systemic SclerosisDottssa P CerboniLaboratory UnitDr M ManettiDr C CeccarelliDr E RomanoYoung Adults ClinicProf F Falcini