Systemic Sclerosis Jacob M van Laar Professor of Clinical Rheumatology Newcastle University, UK Systemic sclerosis is a rare, heterogeneous, slow-motion disease, with (allegedly) a small window of opportunity to fundamentally change the course of the disease. Early diffuse disease Dermal inflammation Established disease Immunosuppression disrupts inflammation-driven fibrogenesis (or does it?) Early diffuse disease Dermal inflammation Established disease Early targeted intervention prevents fibrosis Early diffuse disease Dermal inflammation Established disease Cardiac fibrosis Lung fibrosis Pericarditis Intima fibrosis Hunzelmann & Brinckmann, Ann Rheum Dis 2010 30-yr young woman with progressive systemic sclerosis since 2 years Raynauds and digital ulcers, contractures, heartburn, swallowing problems bibasilar interstitial abnormalities What is the most concerning manifestation? A. Raynauds? B. Contractures? C. Skin score? D. GI-problems? E. Lungs? F. All of the above? Survival of pooled groups of scleroderma patients Organ involvement: No Yes Ioannidis et al, Am J Med 2005 Rate of loss of percent vital capacity in 76 SSc patients with severe fibrosis. Steen VD, J Clin Rheumatol 2005. Survival of patients with systemic sclerosis and pulmonary arterial hypertension, with or without fibrosis. Mukerjee et al. Ann Rheum Dis 2003;62:1088-93. Severe organ involvement in systemic sclerosis, results from the Pittsburgh study • CHF • symptomatic pericarditis • arrhythmia requiring treatment Steen & Medsger, Arthritis Rheum 2000 The Pittsburgh study Steen & Medsger, Arthritis Rheum 2000 The Pittsburgh study Steen & Medsger, Arthritis Rheum 2000 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? 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 Echocardiography and pulmonary function as screening tests for pulmonary arterial hypertension in systemic sclerosis. 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.. Mukerjee et al. Rheumatol 2004;43:461-6. 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. What’s next? A. Treat her symptoms B. Put her on immunosuppression C. Refer her to a colleague with expertise in SSc Hunzelmann & Brinckmann, Ann Rheum Dis 2010 Progress in understanding of pathogenesis of PAH has led to breakthrough in its treatment. McLaughlin et al. Rheumatology 2009 Endothelin-1 blockade delays clinical worsening of PAH; Combination-therapy with iloprost is feasible and effective. McLaughlin et al. Rheumatology 2009 Hunzelmann & Brinckmann, Ann Rheum Dis 2010 Myofibroblast is key effector cell in fibrosis Varga and Abraham, JCI 2007 Preclinical data support use of Tyrosine Kinase Inhibitors (TKI) in fibrotic conditions. http://tyrosinekinaseinhibitor.com/ 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 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. Spiera et al. Ann Rheum Dis 2011. Hunzelmann & Brinckmann, Ann Rheum Dis 2010 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 Nihtynova et al. Rheumatology 2007 Changes skin score in observational study in dcSSc -UK Scleroderma Study GroupSkin Score during follow-up 50 40 mRSS ATG then MMF 30 Other (MTX etc) Cyclo then MMF MMF 20 No active therapy 10 0 Baseline Year1 Year2 Year3 Herrick et al, J Rheum 2010) Slide kindly provided by C Denton 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 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? 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 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, HAQDI, 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. Effects of rituximab in systemic sclerosis Bosello et al, Arthritis Res Ther 2009 Study Design (n=86) TCZ trial, c/2012 Stem cell transplantation: a treatment option for for systemic sclerosis? Huegle & van Laar, Arthr Res Ther 2008 Changes in skin score, HAQ, lung/kidney/heart function in 27 transplanted patients in USA Skin score HAQ Lung function Lung function Kidney function Heart function Nash et al, Blood 2007 HSCT reverses fibrosis and vasculopathy Reduction in dermal fibrosis Nash et al, Blood 2007 Induction of neoangiogenesis Aschwanden et al, Ann Rheum Dis 2008 Benefit cure Stem cell transplantation remission Conventional immunosuppression Risks ASTIS trial Autologous Stem Cell Transplantation International Scleroderma trial ISRCTN54371254 Mobilisation CYC 2x2 g/m2, G-CSF 10 µg/kg Leukapheresis + CD34-selection Conditioning CYC 200 mg/kg, rbATG 7.5 mg/kg Reinfusion CD34+ PBSC S R E 12x monthly i.v. pulse CYC 750 mg/m2 ASTIS trial Jan 2012 JvL 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/1st 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) Primary endpoint = event-free survival EFS SCT Control EFS = survival minus persistent major organ failure (heart, lung, kidney) sample size 150 patients based on 10-yr accrual, 11-yr followup; alpha = 0.05, power = 0.67, HR 0.5; intention-to-treat. ASTIS trial Jan 2012 JvL Overall survival overall survival (%) 100 80 Time-dependent hazard, P=0.011 60 FU (yr): HR (95%CI), P-value ¼ : 2.45 (.76 - 7.89), 0.13 ½ : 1.42 (.58 - 3.51), 0.44 1 : 0.39 (.18 - .82), 0.014 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 40 20 Control 0 Transplant 0 1 2 3 4 6 7 8 9 10 Number at risk Control 77 Transplant 79 5 Years 69 68 65 67 55 64 40 55 31 39 21 26 15 19 10 12 7 11 3 7 Smoking status is a determinant of overall survival Smoking status / (no) Smoking status / (yes) 100 Projected overall survival (%) 100 80 60 40 20 Control 0 0 Number at risk Control Transplant 43 41 1 39 33 2 37 32 3 34 31 4 25 24 80 60 40 20 Transplant 5 Years 6 21 20 14 13 7 10 11 8 7 7 Control 0 9 5 7 10 2 5 Number at risk Control Transplant Transplant 0 1 2 3 4 5 Years 6 7 8 9 10 34 38 30 35 28 35 21 33 15 31 10 19 7 13 5 8 3 5 2 4 1 2 Changes in secondary outcome parameters* 100 P<0.001 0.04 0.006 0.84 0.017 0.96 80 Worsening Improvement 60 40 HSCT CYC 20 0 mRSS HAQ VC DCLO Creat cl LVEF -20 * Measured as % change AUC in first 2 years. 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. Take home messages (‘learning objectives’) • 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. 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 How to identify poor prognosis patients? Principal investigator: Sponsors: Study chairpersons: Study administration: Statistician: Co-investigators: IDMC: Financial support: EBMT/EULAR Scleroderma Study Group EBMT, EULAR, AP-HP JM van Laar, CI (Newcastle), D Farge (Paris), A Tyndall (Basel) 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) JK Sont (Leiden) 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). J Apperley (London), D Furst (Los Angeles), F Wolheim (Lund) EBMT, EULAR, AP-HP, NIHR, Amgen Europe, Genzyme (Sangstat), Miltenyi Biotec.