Por: Dr. Marco Matucci Cerinic (ITA) XIII Congreso Colombiano de Reumatologia 2011 Barranquilla

1. ColombianCongressofRheumatology, Barranquilla 2011 Systemic Sclerosis,myths, truths & challenges Marco MatucciCerinic Dept Biomedicine, DivRheumatology UnivFlorence, Italy

3. Truth-SScis a dreadfuldisease…

4. Challenge- SSc can bediagnosedveryearly…

6. Myth-SScisasfibroticdisease… SScis more thanthat, Itis a vasculardisease… !!??

7. Barbara G. May 2005 Paolieri Lidia T. January 2005 G.P, March 2004

8. disease evolution lung, heart, GI, kidney intermediate skin thickness early late DIFFUSE SSc Dermal inflammation Early dSSc Established disease pulmonary hypert., malabsorption intermediate late early LIMITED SSc 2 5 10 20 disease duration (years) Medsger T & Steen V, SystemicSclerosis, 1995, p 51,Williams & Wilkins

9. What’s going on under the skin… into the vessels ? Endothelial damage and apoptosis Progressive arteriolar alteration with intima hypertrophy and progressive stranglement of the vessel lumen Skin, Lung, Kidney, Heart

10. Fleischmajeret al, J amAcadDermatol 1980

11. Tha TAT VIIa IL-2 F 1+2 TF IIa IL-1 DS Fb t-PA Lp vW VCAM TNF CF PAI G vW F ICAM PA E-sel GF uPAr of Endothelial Cells Apoptosis Collagen Smooth Muscle Cells Fibroblasts MatucciCerinicet al SeminarsArthritisRheum 2003

12. Vasculopathy of SSc complications…“the challenge for the future” Intimal proliferation Adventitial fibrosis Lumen narrowing & obliteration Fingers Lung Kidney Heart PAH Ulcers/gangrene SRC Infarct

13. Hypoxia,Thrombosis ROS Continuous Vasospasm ENDOTHELIAL DAMAGE RAYNAUD’s Phenomenon TELEANGECTASIAS ULCERS

14. normal early active late

16. Iloprost January 2006

18. Iloprost weekly infusions

20. Patient is painful again, the 5° right finger is again problematic

22. Digitalarterywith a thrombusformation due toendothelialcelldysfunction: increasedplateletactivity and increasedthrombogenicity in SSc HE x 15, CourtesyofPetrosEfthimiou, MD, NY

23. 11.3.03 23.12.02 28.4.03

24. Truth…SScis a dreadfuldisease… William Osler (1849-1919) “Sclerodermais a shrinkingskinof steel” In its more aggravatedformsof diffuse sclerodermaisoneof the mostterribleofallhumanills. LikeTithonustowitherslowly and likehimtobebeaten down and marred, wasteduntiloneisliterally a mummy, encased in anevershrinking, slowlycontractingskinof steel, is a fate notpictured in anytragedy, ancient or modern. J Cutan & Genitourinar Dis 1898, 16, 49

25. Self-portrait Embrace General Chef du Barbare

26. 1940 Captive

27. Death and Fire, 1940

29. Independent riskfactorsforincreasedmortality(Cox-proportional hazard model) FVC<80% Proteinuria HR= 3.34 HR= 1.64 Pulmonary hypertension Dyspnoea (PAPsys >40 mmHg) HR= 2.02 HR= 1.61 Huegleet al ARD 2010

30. Survival Curves of Scleroderma Patients With Pulmonary Hypertension, Lung Involvement, or No Major Organ Involvement 100 90 80 None 70 60 Survival, % 50 Lung Involvement (without PHTN) 40 30 PHTN 20 10 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Years From Diagnosis of PHT Koh et al. BrJ Rheumatol. 1996;35:989-993.

32. New-onset accelerated phase hypertension

33. Headaches

34. Visual disturbances

35. Encephalopathy with seizures

36. Flash pulmonary oedema

37. Fevers / malaise

38. Pericardial effusion

39. +/- MAHA

40. Hypereninaemia

41. ARF + occlusive renal vascular lesions may occur without hypertension at presentation (Helfrich 1989)Schistocytes - MAHA Courtesy of Dr C Denton, RFH, UK

42. Scleroderma renal crisis - biopsy features thrombotic vascular occlusion hypertensive vascular damage glomerularischaemia fibrosis Courtesy of Dr C Denton, RFH, UK

43. Challenge SSc can bediagnosedveryearly

44. VeryEarlySystemicSclerosis Raynaud’s phenomenon Pre-SSc Puffy Fingers UCTD MCTD Anti-nuclear antibodies Capillaroscopy MatucciCerinicet al , AnnRheumDis2009

45. Raynaud Fenomenus,Quo Vadis… ?

47. send patient to to other specialist HRCT , PFT & Esophageal manometry If positive… If negative… Choice of treament Follow up Avouacet al ARD 2010

48. Disease evolution lung, heart, GI, kidney intermediate skin thickness early late DIFFUSE SSc pulmonary hypert., malabsorption intermediate late LIMITED SSc early 2 5 10 20 disease duration (years) Medsger T & Steen V, SystemicSclerosis, 1995, p 51,Williams & Wilkins

49. May we treat a very early SSc? A Windowofopportunity

50. disease evolution lung, heart, GI, kidney intermediate skin thickness early late DIFFUSE SSc Dermal inflammation Early dSSc Established disease pulmonary hypert., malabsorption intermediate late early LIMITED SSc 2 5 10 20 disease duration (years) Medsger T & Steen V, SystemicSclerosis, 1995, p 51,Williams & Wilkins

51. Facts… When observing a Raynaud’s ph an accurate diagnostic procedure should be used to differentiate between a primary or a secondary form Follow up of these patients is mandatory Raynaud’s ph is the first sign of a very early Systemic Sclerosis “red flags” must always induce the suspect of a very early SSc !

52. The facts The Mythoffibrosisistoo late !! WestillhaveTruths & Challenges…

53. What are the followingcases ? An earlySSc or somethingveryearly ?Where do we position thesepatients in the diseaseevolution ?

57. Cardiac MRI Patient dies 10 months after the diagnosis

58. DE 15.4.04Finger edema & RaynaudNVC- Active patternAnticentromereposLES Dysfunction

60. Topo I

61. NVC late

62. FVC & DLCO normal

64. DE 2010RPANA/ACA posNVC activeLES dysfunctionFVC & DLCO normal

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

66. Do we really have to treat these patients… ? WE DO NOT KNOW AS EVIDENCE BASE DATA ARE NOT AVAILABLE… & predictors of evolution are missing but STILL REMAINS MANDATORY to block the disease evolution and organ damage An early aggressive therapymightbechosenwhen:: Topo I antibodies/RNA pol III rapidlyprogressingskininvolvement Tendonfrictionrubs

67. The window of opportunity…!!! Paul Klee The window

68. Educationisofparamountimportance !!

69. www.eustar.org www.W-S-F.org Scleroderma Foundation

70. VEDOSS Very Early Diagnosis Of SSc  Partnership between EULAR, EUSTAR and FESCA toestablisha programme to: Create clinics devoted to the early diagnosis of SSc Educate primary care professionals throughout Europe In the earliest symptoms of SSc (Raynaud’s, ANA  capillaroscopy / anti-nuclear antibody tests) To send any patient presenting with Red Flags to special SSc clinics Launch datetocoincidewithEuropean Scleroderma Awareness Day: 29th June 2010

71. DeptRheumatology AVC Dept Biomedicine & DivRheumatology AOUC Dept Medicine & DENOtheCentre UniversityofFlorence Dr. ML Conforti Dr A Righi Dr G Baccano Dr. S MaddaliBongi Dr. A Del Rosso Dr. D Melchiorre Dr. M Maresca Dr. F Bandinelli Dr. S BellandoRandone 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 DigitalUlcersUnit Dr. G Fiori Signora F Braschi RegionalReferenceCentreforSystemicSclerosis Dottssa P Cerboni LaboratoryUnit Dr M Manetti Dr C Ceccarelli Dr E Romano Young Adults Clinic Prof F Falcini