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

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 disease Dermal inflammation Established disease

5. Immunosuppression disrupts inflammation-driven fibrogenesis (or does it?) Early diffuse disease Dermal inflammation Established disease

6. Early targeted intervention prevents fibrosis Early diffuse disease Dermal inflammation Established disease

7. Cardiac fibrosis Pericarditis Intima fibrosis Lung 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 Organ involvement: No Yes Ioannidis et al, Am J Med 2005

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

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 • CHF • symptomatic pericarditis • arrhythmia requiring treatment Steen & Medsger, Arthritis Rheum 2000

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. Echocardiography and pulmonary function as screening tests for pulmonary arterial hypertension in systemic sclerosis. The positive predictive accuracy of currently usednon-invasive tests are adequate for the diagnosis of advancedPAH provided sufficiently high thresholds (TG > 45 mmHg orDLCO < 55% predicted) are used.. 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? Treat her symptoms Put her on immunosuppression 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. McLaughlin et al. Rheumatology 2009

26. Hunzelmann & Brinckmann, Ann Rheum Dis 2010

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

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

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. Skin Score during follow-up 50 40 30 mRSS 20 10 0 Baseline Year1 Year2 Year3 Changes skin score in observational study in dcSSc-UK Scleroderma Study Group- ATG then MMF Other (MTX etc) Cyclo then MMF MMF No active therapy Herrick et al, J Rheum2010) Slide kindly provided by C Denton

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

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? Review the patient, exclude other causes Try MMF Try azathioprine Something new, eg biological

42. Biologic therapy for systemic sclerosis: a systematic review. 23 studies: 3xinfliximab, 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. Stem cell transplantation: a treatment option for for systemic sclerosis? Huegle & van Laar, ArthrRes Ther 2008

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

48. HSCT reverses fibrosis and vasculopathy Induction of neoangiogenesis Reduction in dermal fibrosis Nash et al, Blood 2007 Aschwanden et al, Ann Rheum Dis 2008

49. Benefit cure Stem cell transplantation remission Conventional immunosuppression Risks