1. Systemic Sclerosis Jacob M van Laar Professor of Clinical Rheumatology Newcastle University, UK

3. Systemic sclerosis is a rare, heterogeneous, slow-motion disease, with (allegedly) a small window of opportunity to fundamentally change the course of the disease.

4. Early diffuse diseaseEstablished diseaseDermal inflammation

5. Early diffuse diseaseEstablished diseaseDermal inflammation Immunosuppression disrupts inflammation-driven fibrogenesis (or does it?)

6. Early diffuse diseaseEstablished diseaseDermal inflammation Early targeted intervention prevents fibrosis

7. Cardiac fibrosisPericarditis Lung fibrosis Intima fibrosis

8. Hunzelmann & Brinckmann, Ann Rheum Dis 2010

9. 30-yr young woman with progressive systemic sclerosis since 2 years Raynauds and digital ulcers, contractures, heartburn, swallowing problems bibasilar interstitial abnormalities

10. What is the most concerning manifestation? A. Raynauds? B. Contractures? C. Skin score? D. GI-problems? E. Lungs? F. All of the above?

11. Survival of pooled groups of scleroderma patients Ioannidis et al, Am J Med 2005 Organ involvement: No Yes

12. Steen VD, J Clin Rheumatol 2005. Rate of loss of percent vital capacity in 76 SSc patients with severe fibrosis.

13. Survival of patients with systemic sclerosis and pulmonary arterial hypertension, with or without fibrosis. Mukerjee et al. Ann Rheum Dis 2003;62:1088-93.

14. Severe organ involvement in systemic sclerosis, results from the Pittsburgh study Steen & Medsger, Arthritis Rheum 2000 CHF symptomatic pericarditis arrhythmia requiring treatment

15. The Pittsburgh study Steen & Medsger, Arthritis Rheum 2000

16. The Pittsburgh study Steen & Medsger, Arthritis Rheum 2000

18. Work-up of systemic sclerosis patient with or without cardiopulmonary symptoms 6MWT Echocardiography (LVEF, PAH, valves) MRI? Plasma BNP, troponin ECG, Holter Exercise test Myocardial biopsy?

19. Exercise performance, measured by maximum oxygen uptake (max < 80% of predicted), was impaired in 43/46 patients. Cuomo et al. Scand J Rheumatol. 2010 May 17. Epub

20. The positive predictive accuracy of currently used non-invasive tests are adequate for the diagnosis of advanced PAH provided sufficiently high thresholds (TG > 45 mmHg or DLCO < 55% predicted) are used.. Echocardiography and pulmonary function as screening tests for pulmonary arterial hypertension in systemic sclerosis. Mukerjee et al. Rheumatol 2004;43:461-6.

21. 30-yr young woman with progressive systemic sclerosis since 2 years You decide to examine her incl skin score and request further investigations: lab, PFT, echo, ECG, NFC. No barium or manometry.

22. What’s next? A.Treat her symptoms B.Put her on immunosuppression C.Refer her to a colleague with expertise in SSc

23. Hunzelmann & Brinckmann, Ann Rheum Dis 2010

24. Progress in understanding of pathogenesis of PAH has led to breakthrough in its treatment. McLaughlin et al. Rheumatology 2009

25. Endothelin-1 blockade delays clinical worsening of PAH; Combination-therapy with iloprost is feasible and effective.

26. Hunzelmann & Brinckmann, Ann Rheum Dis 2010

27. Varga and Abraham, JCI 2007 Myofibroblast is key effector cell in fibrosis

28. http://tyrosinekinaseinhibitor.com/ Preclinical data support use of Tyrosine Kinase Inhibitors (TKI) in fibrotic conditions.

29. 12/20 completed study, 7 discontinued because of AEs, 1 lost to followup. Common AEs (>20%) included fatigue, facial/lower extremity edema, nausea and vomiting, diarrhea, generalized rash, and new-onset proteinuria. Treatment with imatinib showed a trend toward improvement in the FVC % predicted (1.74%; P not significant) and the MRSS (3.9 units; P<0.001). Khanna et al, Arthritis Rheum 2011

30. Enrollment discontinued after 10 patients (9 imatinib, 1 placebo) due to poor tolerability and high rates of AEs. No difference in mean MRSS (imatinib 31>29 at months), CRP, ESR, physician’s global assessment, patient’s global assessment, response to the Health Transition query, or HAQ scores between those who did and those who did not complete 6 months of therapy. Side effects: edema, fluid retention, fatigue, nausea, cramps/myalgias, diarrhea, alopecia, and anemia. Most side effects occurred within the first week of treatment, and even when imatinib was reintroduced at a lower dosage (200 mg daily), it was poorly tolerated. Two patients were hospitalized because of side effects of the medication. In general, biomarker levels in plasma and skin did not change. Conclusion: imatinib was poorly tolerated. Pope et al, Arthritis Rheum 2011.

31. Spiera et al. Ann Rheum Dis 2011.

33. Hunzelmann & Brinckmann, Ann Rheum Dis 2010

34. EULAR recommendations for the treatment of systemic sclerosis Glucocorticoids: low dose are commonly used for inflammatory arthritis, RCT lacking Immunosuppressives: Methotrexate: 2RCTs have shown benefit on skin in early dcSSc Cyclophosphamide: 2 RCTs have shown benefit on skin and lung MMF, azathioprine: uncontrolled studies support use. Ciclosporin A: not recommended Kowal-Bielecka et al, Ann Rheum Dis 2009

37. Nihtynova et al. Rheumatology 2007

38. Changes skin score in observational study in dcSSc -UK Scleroderma Study Group- 0 10 20 30 40 50 mRSS BaselineYear1Year2Year3 Skin Score during follow-up Herrick et al, J Rheum 2010) Slide kindly provided by C Denton Cyclo then MMF ATG then MMF MMF No active therapy Other (MTX etc)

39. Mycophenolate mofetil has antifibrotic effects in vitro Roos et al, J Phramacol Exp Therap 2007 MMF inhibits type I collagen gene expressionMMF increases MMP-1 gene expression MMF inhibits fibroblast motility

40. 30-yr young woman with progressive systemic sclerosis since 2 years You treated her symptoms (max PPI), advised her to get fit, and after extensive consultation (risk of infertility vs refractory disease) with i.v. pulse cyclophosphamide: stabilisation for 6 m, then 10% drop in VC. What do you do?

41. What to do with cyclophosphamide-refractory SSc? A.Review the patient, exclude other causes B.Try MMF C.Try azathioprine D.Something new, eg biological

42. Biologic therapy for systemic sclerosis: a systematic review. 23 studies: 3x infliximab, 3x etanercept, 3x antithymocyte globulin, 3x imatinib, 6x rituximab, 1x IFN-γ, IFN-α, relaxin, delipidated, deglycolipidated Mycobacterium vaccae, human TGF-ß1 antibody, and oral type I collagen. Studies of etanercept and infliximab suggest improvements in arthritis and HAQ-DI. None of the other biologic agents demonstrated reproducible, statistically significant improvements in joint count, HAQ- DI, or skin score. CONCLUSION: TNFi may improve inflammatory arthritis and disability in SSc. The effect on skin score is uncertain. Adequately powered trials are needed to evaluate efficacy, and longitudinal studies are needed to evaluate longterm safety of these agents in SSc. Phumethum, Jamal, Johnson. J Rheumatol 2011;38:289-96.

43. Effects of rituximab in systemic sclerosis Bosello et al, Arthritis Res Ther 2009

44. Study Design (n=86) TCZ trial, c/2012

45. Huegle & van Laar, Arthr Res Ther 2008 Stem cell transplantation: a treatment option for for systemic sclerosis?

47. Skin score Lung function Kidney function HAQ Lung function Heart function Changes in skin score, HAQ, lung/kidney/heart function in 27 transplanted patients in USA Nash et al, Blood 2007

48. Reduction in dermal fibrosis Aschwanden et al, Ann Rheum Dis 2008 Induction of neoangiogenesis HSCT reverses fibrosis and vasculopathy

49. Benefit Risks cure remission Conventional immunosuppression Stem cell transplantation

53. Mobilisation CYC 2x2 g/m 2, G-CSF 10 µg/kg Leukapheresis + CD34-selection Conditioning CYC 200 mg/kg, rbATG 7.5 mg/kg Reinfusion CD34 + PBSC 12x monthly i.v. pulse CYC 750 mg/m 2 RSE ASTIS trial Autologous Stem Cell Transplantation International Scleroderma trial ISRCTN54371254 ASTIS trial Jan 2012 JvL

54. Inclusion criteria age 16-65 yrs diffuse scleroderma with: I. disease duration  4 yrs + skin score  15 (0-51) + involvement heart/lung/kidney II. disease duration  2 yrs + skin score  20 + ESR>25mm/1 st hr and/or Hb<11 gr/dL Exclusion criteria PHT > 50 mmHg, DLCO < 40%. creat.cl. < 40 ml/min. LVEF < 45%; uncontrolled arhythmia; cardiac tamponade, infection, etc. previous extensive treatment with cyclophosphamide (>5 gr iv, >3 months oral)

55. sample size 150 patients based on 10-yr accrual, 11-yr follow- up; alpha = 0.05, power = 0.67, HR 0.5; intention-to-treat. SCT Control EFS Primary endpoint = event-free survival EFS = survival minus persistent major organ failure (heart, lung, kidney ) ASTIS trial Jan 2012 JvL

56. Time-dependent hazard, P=0.011 FU (yr): HR (95%CI), P-value 0 20 40 60 80 100 overall survival (%) 796867645539261912117Transplant 77696555403121151073Control Number at risk 012345678910 Years ControlTransplant Overall survival ¼ : 2.45 (.76 - 7.89), 0.13 ½ : 1.42 (.58 - 3.51), 0.44 2 : 0.22 (.08 -.58), 0.002 4 : 0.22 (.08 -.58), 0.002 6 : 0.22 (.08 -.58), 0.002 8 : 0.22 (.08 -.58), 0.002 1 : 0.39 (.18 -.82), 0.014

57. Smoking status is a determinant of overall survival

58. Changes in secondary outcome parameters* * Measured as % change AUC in first 2 years. Worsening Improvement P<0.001 0.04 0.006 0.84 0.017 0.96

59. 30-yr young woman with progressive systemic sclerosis since 2 years You treated her symptoms (max PPI), advised her to get fit, and after extensive consultation (risk of infertility vs refractory disease) with HSCT, which stopped disease progression. She has been stable since 1997.

60. Systemic sclerosis is a complex connective tissue disease, requiring expert management. Medication is reasonably effective for organ manifestations. HSCT induces long-term remission in early, severe dcSSc. Take home messages (‘learning objectives’)

61. Organ-based treatment options for systemic sclerosis Vasculopathy: Calcium-channel blockers, ET-1RA, sildenafil SRC: ACEi, ATRA Lung: cyclophosphamide, MMF, rituximab Skin: MMF, MTX, cyclophosphamide, HSCT Heart: ICD, nifedipine Gut: somatostatin, PPI Joints: NSAID, low dose prednisone

62. How to identify poor prognosis patients?

63. Principal investigator: EBMT/EULAR Scleroderma Study Group Sponsors: EBMT, EULAR, AP-HP Study chairpersons: JM van Laar, CI (Newcastle), D Farge (Paris), A Tyndall (Basel) Study administration: S Hales, K Naraghi (Middlesbrough), A Versluys-van Duinhoven, I de Jonge (Leiden), M Bettar, S Parlier (Paris), I Gerber, C Bocelli-Tyndall (Basel), L Clark, R Uddin, K Champion, Z Doran (EBMT Clinical Trials Office, London) Statistician: JK Sont (Leiden) Co-investigators:Z Marjanovic, J Larghero, G Socie (Paris), A Schuerwegh, E Marijt, WE Fibbe (Leiden), M Vonk, FHJ van den Hoogen, AVMB Schattenberg (Nijmegen), I Miniati, R Saccardi, M Matucci-Cerinic (Florence), A Voskuyl, A van de Loosdrecht, P Huygens (Amsterdam), I Koetter, M Schmalzing (Tübingen), S Weiner, A Kreuter (Bochum-Herne-Trier), T Martin, J Sibilia (Strasbourg), I Gerber, T Daikeler, P Hasler, P Villiger, A Gratwohl (Aarau-Basel-Bern), K Warnatz, HH Peter, J Finke (Freiburg), K Machold (Vienna), S Dass, M Buch, P Emery (Leeds), F Sarrot-Reynauld (Grenoble), JM Durand (Marseille), HP Tony, S Kleinert (Wurzburg), J Constans (Bordeaux), D Adoue (Toulouse), D Launay (Lille), I Quere (Montpellier), C Deligny, S Arfi (W Indies), E Rich (Montreal), A Fassas (Thessaloniki), A Lo Monaco (Ferrara), N Del Papa (Milan), R Westhovens (Leuven), B Griffiths, M Collin (Newcastle-Middlesbrough). IDMC: J Apperley (London), D Furst (Los Angeles), F Wolheim (Lund) Financial support:EBMT, EULAR, AP-HP, NIHR, Amgen Europe, Genzyme (Sangstat), Miltenyi Biotec.