Stem Cell Transplantation (SCT) in Scleroderma

Transcription

1 Stem Cell Transplantation (SCT) in Scleroderma Yes or No? Philippe Guilpain, MD, PhD Department of Internal Medicine- Multiorganic diseases Competence center for auto-immune diseases Saint Eloi Hospital, CHRU Montpellier France & INSERM U844 COSTEM MEETING, Berlin, Oct 2013

2 Internal Medicine, Competence center for autoimmune diseases, Montpellier Inserm U844, Montpellier A. Le Quellec, S. Riviere, A. Konaté, P. Rullier, A. Schiffmann, A. Guilhem, D. Cerutti, A. Maria, R. Goulabchand, P. Guilpain Christian Jorgensen, Danièle Noël, Philippe Guilpain, Alexandre Maria, Claire Bony, Jean- Marc Brondello, Paul Chuchana, Farida Djouad Marc Mathieu, Marie Maumus, Marie Morille, Didier Philipot, Karine Toupet

3 How to argue against those evidences?

4 SCT in Scleroderma? Related questions What is Scleroderma? What are the goals of the treatment? Which patients should be treated? Should we use conventional treatments? Should we use innovative treatments? Which SCT should be used?

5 What is systemic sclerosis («scleroderma»)?

6 «Scleroderma» «Auto-immune» disease; «connective tissue disease» NOT lupus Fibrosis, microangiopathy, auto-immunity Diffuse Limited cutaneous Wells A U et al. Rheumatology 2009;48:iii40-iii44

7 Heterogeneity and complexity FIBROSIS MICROANGIOPATHY IMMUNITY

8 Heterogeneity and complexity Gut Heart FIBROSIS MICROANGIOPATHY Skin sclerosis Interstitial Pneumonia Anti-nuclear antibodies anti- scl70 anti-centromere IMMUNITY Raynaud s phenomenon Digital ulcers Telangiectasia Pulmonary Arterial Hypertension Renal crisis

9 Survival Life-threatening Involvements Renal crisis Heart involvement Pulmonary hypertension Lung fibrosis Mortality

10 Organ dysfunction and damages Chronic renal insuffiiciency Chronic Heart failure Lung fibrosis, respiratory insufficiency GI tract involvement Skin sclerosis, digital ulcers Musculoskeletal dysfunction, myopathies Mobility, autonomy Morbidity

11 Health status, disability, quality of life Mouth handicap score (MHISS), Cochin Hand Functionnal Scale (CHFS) Digital ulcers : Impact on survival Strong implication of digital ulcers, interrelation with survival

12 Systemic sclerosis The clinical involvements and their impact are very heterogenous The spectrum of the disease is really wide Survival Quality of life Organ functions It appears difficult to evaluate such a complex disease. Thus, how should we measure the effects of treatments?

13 Questions. Which patients should be treated? Which treatments should be used?

14 What are the therapeutic options in systemic sclerosis in 2013?

15 Therapeutic strategies «OLD SCHOOL» Hematopoietic SCT

16 Therapeutic strategies «OLD SCHOOL»

17 «OLD SCHOOL» strategy To suppress immune disorder To counteract each manifestation of scleroderma To adapt treatment according to patient s status IMMUNITY ORGAN DYSFUNCTION

18 «OLD SCHOOL» strategy IMMUNITY ORGAN DYSFUNCTION Immunosuppressive drugs Corticosteroids (be careful with renal crisis!) Immunosuppressive drugs (Cyclophosphamide, Azathioprine, Methotrexate) D-penicillamine Biotherapies Symptomatic treatments Ppis, prokinetics, vasodilators, Palliative treatments Lung transplantation

19 Therapeutic strategies «OLD SCHOOL» Adapt treatment to each patient Combine therapies

20 Therapeutic strategies Hematopoietic SCT

21 Hematopoietic SCT To suppress immune disorder` To reboot the immune system IMMUNITY ORGAN DYSFUNCTION ASSIST, ASTIS, SCOT trials High toxicity and treatment-related mortality Kidneys, Heart

22 Hematopoietic SCT The improvement is not so important Variability of tested endpoints Burt et al. Lancet 2011 And the disease does persist Damages persist, Fibrosis persists Relapses may occur Burt et al. Lancet 2011

23 Rebooting of the immune system? Bad in some cases Immune reconstitution? Are anti-scl-70 Abs pathogenic?

24 American Scleroderma Stem Cell versus Immune Suppression Trial (ASSIST) 10 patients HSCT vs 9 patients 6-monthly pulses of i.v. cyclophosphamide 1000 mg/m2 The study was stopped early for benefit no deaths (unusual) : sample size is small follow-up is relatively short (12-24 months) Selected patients have relatively mild disease

25 Autologous Stem cell Transplantation International Scleroderma trial (ASTIS) 79 patients : HSCT Vs 77 patients : 12-monthly pulses of i.v. cyclophosphamide 750 mg/m2 40 deaths 16 deaths in the SCT group, including 8 treatment related 24 deaths in the control group. None from treatment-related causes Only smoking status affected outcome (event-free and overall survival +++).

26 Cardiac «limits» Reduced mortality : 8/90 died from disease-related causes and 5/90 (6%) patients died from treatment-related causes 4 treatment-related deaths occurred because of cardiovascular complications (1 constrictive pericarditis, 2 right heart failures without underlying infection, and 1 heart failure during mobilisation) DLCO is affected by baseline cardiac function >>> Appropriate cardiac assessment before HSCT? not only echocardiogram but also confrontational right heart catheterisation, (with fluid challenge test) and cardiac MRI. RISK OF THESE PROCEDURES

27 NIH Public Access Author Manuscript Renal «limits» : Acute Kidney Injury (AKI) Biol Blood Marrow Transplant. Author manuscript; available in PMC 2012 May 1. Published in final edited form as: Biol Blood Marrow Transplant May ; 17(5): doi: /j.bbmt ACUTE KIDNEY INJURY IN PATIENTS WITH SYSTEMIC SCLEROSIS PARTICIPATING IN HEMATOPOIETIC CELL TRANSPLANTATION TRIALS IN THE UNITED STATES Chitra Hosing 1, Richard Nash 2, Peter McSweeney 3, Shin Mineishi 4, James Seibold 4, Linda M. Griffith 5, Howard Shulman 2, Ellen Goldmuntz 5, Maureen Mayes 6, Chirag R. Parikh 7, Leslie Crofford 8, Lynette Keyes-Elstein 9, Daniel Furst 10, Virginia Steen 11, and Keith M Sullivan 12 1 MD Anderson Cancer Center, Houston, TX 2 Fred Hutchinson Cancer Research Center, Seattle, WA 3 Three Rocky Mountain US Cancer clinical Center, Denver, trials COincluding SCOT 91 Scleroderma patients 4 University of Michigan, Ann Arbor, MI 5 National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 11 6 patients (12%) (8 autologous, 1 allogeneic, 1 pre-transplant, 1 given intravenous University of Texas, Houston, TX 7 cyclophosphamide Yale University, New Haven, CT on transplant trial) developped AKI and 8 of 11 died 8 University of Kentucky, Lexington, KY 9 Rho, Inc, Chapel Hill, NC 10 6 University renal of crisis; California, Los 3 Angeles, AKI on CA scleroderma 11 Georgetown University, Washington, DC renal disease; 2 uncertain causes 12 Duke University Medical Center, Durham, NC Abstract >>> Limiting nephrotoxins Recipients of hematopoietic cell transplantation may be at risk for developing acute kidney injury and this risk may increase in patients who undergo transplantation for severe systemic sclerosis due to cautious underlying scleroderma use renal of disease. corticosteroids Acute kidney injury after transplantation can increase transplant related mortality. To better define these risks, we analyzed 91 patients with systemic sclerosis who were enrolled in three clinical trials in the United States of autologous or allogeneic hematopoietic cell transplantation. Eleven (12%) of the 91 scleroderma patients in these studies (8 autologous, 1 allogeneic, 1 pre-transplant, 1 given intravenous cyclophosphamide on transplant trial) experienced acute kidney injury of whom eight required dialysis and/or total plasma exchange. Acute kidney injury in the 9 transplant recipients developed a median of 35 (range, 0 90) days after transplantation. Ten of 11 patients with acute kidney injury received angiotensin converting enzyme-inhibitors (ACE-I) treatment. The etiology of acute kidney injury was renal shielding during total body irradiation strict control of blood pressure and aggressive use of ACE-I

28 Selection of patients and new questions High toxicity and treatment-related mortality Appropriate selection of patients >>> HOW MANY PATIENTS WILL BE STILL ELIGIBLE? Treating less severe scleroderma patients? >>> WILL HSCT REMAIN JUSTIFIED AND ETHICALLY CORRECT?

29 2013 available treatments «OLD SCHOOL» Adapt treatment to each patient Combine therapies Hematopoietic SCT High toxicity Treatment related mortality Selection of patients Balance benefit/risk and patient information IMMUNITY ORGAN DYSFUNCTION

30 Gut Heart FIBROSIS MICROANGIOPATHY Skin sclerosis Interstitial Pneumonia Anti-nuclear antibodies anti- scl70, anti-centromere IMMUNITY Raynaud s phenomenon Digital ulcers Telangiectasia Arterial pulmonary Hypertension Renal crisis

31 2013 available treatments FIBROSIS MICROANGIOPATHY? IMMUNITY

32 HSCT Trials are justified +++ Is autologous SCT in patients with Scleroderma justified? It can be proposed in some selected patients, Especially in the context of trials

33 Are new treatments in patients with Scleroderma required? YES

34 Next Therapeutic Approaches FIBROSIS MICROANGIOPATHY IMMUNITY

35 Animal models of scleroderma Bleomycine model «Genetic» models Hypochlorite (HOCl) - induced Murine Scleroderma New Drugs New Targets Mesenchymal Stem Cell therapy Global Approach

36 Animal models of scleroderma HOCl - induced Murine Scleroderma New Drugs New Targets Mesenchymal Stem Cell therapy Global Approach

37 HOCl - induced Murine Systemic sclerosis Weeks HOCl Phenotype Skin thickening

38 HOCl - induced Murine Systemic sclerosis Several oxidants tested Best results obtained with HOCl FIBROSIS MICROANBGIOPATHY DYSIMMUNITY

39 Animal models of scleroderma HOCl - induced Murine Scleroderma New Drugs New Targets

40 New targets for pharmacological approaches

41 Animal models of scleroderma HOCl - induced Murine Scleroderma Mesenchymal Stem Cell therapy

42 Animal models of scleroderma HOCl - induced Murine Scleroderma Mesenchymal Stem Cell therapy Weeks HOCl Phenotype Skin thickening

43 Animal models of scleroderma HOCl - induced Murine Scleroderma INSERM U844 (Pr Jorgensen) Alexandre MARIA Radjiv GOULABCHAND Danièle NOEL Philippe GUILPAIN Mesenchymal Stem Cell therapy Weeks HOCl Phenotype Skin thickening

44 Fibrosis and MSC: animal models Models of fibrosis Bleomycin-induced fibrosis Acute injury and secondary fibrosis BENEFICIAL EFFECT OF MSC Moodley Y, et al Am J Pathol Jul;175(1): Zhao F, et al. Transplant Proc Jun;40(5): Moodley Y, et al Am J Pathol Jul;175(1): Kumamoto M, et al Eur Respir J Sep;34(3): Ortiz LA, et al Proc Natl Acad Sci U S A Jun 26;104(26):

45 MSC and Scleroderma : preliminary results Improvement of d-ssc following allogenic MSC (Christopeit et al. Leukemia 2008) Revascularization of leg ischemia following autologous MSC 5 cases of scleroderma treated with MSC (Giudicci et al. Ann Intern Med 2011) (Keyszer et al. Arthritis 2011) Skin & ASC (Scuderi et al Cell Transplant 2012) PHRC national France: 2011 D Farge Hôpital St Louis, AP-HP INSERM U 976

46 MSC phenotypes and properties in scleroderma «Impairment of Endothelial Cell Differentiation From Bone Marrow Derived Mesenchymal Stem Cells» (Cipriani et al Arthritis 2007) Immulogical properties (Larghero et al. ARD 2008) Altered phenotypes and hyperexpression of TGFbRII (Vanneaux et al. BMJ 2013) Senescent phenotype but prserved immunomodulation properties (Cipriani et al. Clin Exp Immunol 2013)

47 Conclusion HSCT : MSC : MAYBE (to be confirmed) to be studied A change in physicians mind is required

48 Internal Medicine, Competence center for autoimmune diseases, Montpellier Inserm U844, Montpellier A. Le Quellec, S. Riviere, A. Konaté, P. Rullier, A. Schiffmann, A. Guilhem, D. Cerutti, A. Maria, R. Goulabchand, P. Guilpain Christian Jorgensen, Danièle Noël, Philippe Guilpain, Alexandre Maria, Claire Bony, Jean- Marc Brondello, Paul Chuchana, Farida Djouad Marc Mathieu, Marie Maumus, Marie Morille, Didier Philipot, Karine Toupet