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
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.
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
Varga and Abraham, JCI 2007 Myofibroblast is key effector cell in fibrosis
http://tyrosinekinaseinhibitor.com/ Preclinical data support use of Tyrosine Kinase Inhibitors (TKI) in fibrotic conditions.
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.
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
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)
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
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, 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.
Effects of rituximab in systemic sclerosis Bosello et al, Arthritis Res Ther 2009
Smoking status is a determinant of overall survival
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
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.
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’)
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.