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Ann Rheum Dis. Aug 2004; 63(8): 974–981.
PMCID: PMC1755096

Autologous stem cell transplantation in the treatment of systemic sclerosis: report from the EBMT/EULAR Registry

Abstract

Objective: To analyse the durability of the responses after haematopoietic stem cell transplantation (HSCT) for severe systemic sclerosis (SSc) and determine whether the high transplant related mortality (TRM) improved with experience. This EBMT/EULAR report describes the longer outcome of patients originally described in addition to newly recruited cases.

Methods: Only patients with SSc, treated by HSCT in European phase I–II studies from 1996 up to 2002, with more than 6 months of follow up were included. Transplant regimens were according to the international consensus statements. Repeated evaluations analysed complete, partial, or non-response and the probability of disease progression and survival after HSCT (Kaplan-Meier).

Results: Given as median (range). Among 57 patients aged 40 (9.1–68.7) years the skin scores improved at 6 (n = 37 patients), 12 (n = 30), 24 (n = 19), and 36 (n = 10) months after HSCT (p<0.005). After 22.9 (4.5–81.1) months, partial (n = 32) or complete response (n = 14) was seen in 92% and non-response in 8% (n = 4) of 50 observed cases. 35% of the patients with initial partial (n = 13/32) or complete response (n = 3/14) relapsed within 10 (2.2–48.7) months after HSCT. The TRM was 8.7% (n = 5/57). Deaths related to progression accounted for 14% (n = 8/57) of the 23% (n = 13/57) total mortality rate. At 5 years, progression probability was 48% (95% CI 28 to 68) and the projected survival was 72% (95% CI 59 to 75).

Conclusion: This EBMT/EULAR report showed that response in two thirds of the patients after HSCT was durable with an acceptable TRM. Based on these results prospective, randomised trials are proceeding.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • LeRoy EC, Black C, Fleischmajer R, Jablonska S, Krieg T, Medsger TA, Jr, Rowell N, Wollheim F. Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol. 1988 Feb;15(2):202–205. [PubMed]
  • Wilson TJ, Van de Water J, Mohr FC, Boyd RL, Ansari A, Wick G, Gershwin ME. Avian scleroderma: evidence for qualitative and quantitative T cell defects. J Autoimmun. 1992 Jun;5(3):261–276. [PubMed]
  • van Bekkum DW. New opportunities for the treatment of severe autoimmune diseases: bone marrow transplantation. Clin Immunol Immunopathol. 1998 Oct;89(1):1–10. [PubMed]
  • Wells AU, Lorimer S, Majumdar S, Harrison NK, Corrin B, Black CM, Jeffery PK, du Bois RM. Fibrosing alveolitis in systemic sclerosis: increase in memory T-cells in lung interstitium. Eur Respir J. 1995 Feb;8(2):266–271. [PubMed]
  • Yurovsky VV, Wigley FM, Wise RA, White B. Skewing of the CD8+ T-cell repertoire in the lungs of patients with systemic sclerosis. Hum Immunol. 1996 Jun-Jul;48(1-2):84–97. [PubMed]
  • Denton CP, Xu S, Welsh KI, Pearson JD, Black CM. Scleroderma fibroblast phenotype is modulated by endothelial cell co-culture. J Rheumatol. 1996 Apr;23(4):633–638. [PubMed]
  • Sakkas Lazaros I, Xu Bin, Artlett Carol M, Lu Song, Jimenez Sergio A, Platsoucas Chris D. Oligoclonal T cell expansion in the skin of patients with systemic sclerosis. J Immunol. 2002 Apr 1;168(7):3649–3659. [PubMed]
  • Giordano M, Valentini G, Migliaresi S, Picillo U, Vatti M. Different antibody patterns and different prognoses in patients with scleroderma with various extent of skin sclerosis. J Rheumatol. 1986 Oct;13(5):911–916. [PubMed]
  • Negi VS, Tripathy NK, Misra R, Nityanand S. Antiendothelial cell antibodies in scleroderma correlate with severe digital ischemia and pulmonary arterial hypertension. J Rheumatol. 1998 Mar;25(3):462–466. [PubMed]
  • Altman RD, Medsger TA, Jr, Bloch DA, Michel BA. Predictors of survival in systemic sclerosis (scleroderma). Arthritis Rheum. 1991 Apr;34(4):403–413. [PubMed]
  • Bulpitt KJ, Clements PJ, Lachenbruch PA, Paulus HE, Peter JB, Agopian MS, Singer JZ, Steen VD, Clegg DO, Ziminski CM, et al. Early undifferentiated connective tissue disease: III. Outcome and prognostic indicators in early scleroderma (systemic sclerosis). Ann Intern Med. 1993 Apr 15;118(8):602–609. [PubMed]
  • Bryan C, Knight C, Black CM, Silman AJ. Prediction of five-year survival following presentation with scleroderma: development of a simple model using three disease factors at first visit. Arthritis Rheum. 1999 Dec;42(12):2660–2665. [PubMed]
  • Ferri Clodoveo, Valentini Gabriele, Cozzi Franco, Sebastiani Marco, Michelassi Claudio, La Montagna Giovanni, Bullo Arianna, Cazzato Massimiliano, Tirri Enrico, Storino Franca, et al. Systemic sclerosis: demographic, clinical, and serologic features and survival in 1,012 Italian patients. Medicine (Baltimore) 2002 Mar;81(2):139–153. [PubMed]
  • Scussel-Lonzetti Lilian, Joyal France, Raynauld Jean-Pierre, Roussin André, Rich Eric, Goulet Jean-Richard, Raymond Yves, Senécal Jean-Luc. Predicting mortality in systemic sclerosis: analysis of a cohort of 309 French Canadian patients with emphasis on features at diagnosis as predictive factors for survival. Medicine (Baltimore) 2002 Mar;81(2):154–167. [PubMed]
  • Steen VD, Medsger TA., Jr Severe organ involvement in systemic sclerosis with diffuse scleroderma. Arthritis Rheum. 2000 Nov;43(11):2437–2444. [PubMed]
  • Silver RM, Warrick JH, Kinsella MB, Staudt LS, Baumann MH, Strange C. Cyclophosphamide and low-dose prednisone therapy in patients with systemic sclerosis (scleroderma) with interstitial lung disease. J Rheumatol. 1993 May;20(5):838–844. [PubMed]
  • Akesson A, Scheja A, Lundin A, Wollheim FA. Improved pulmonary function in systemic sclerosis after treatment with cyclophosphamide. Arthritis Rheum. 1994 May;37(5):729–735. [PubMed]
  • Várai G, Earle L, Jimenez SA, Steiner RM, Varga J. A pilot study of intermittent intravenous cyclophosphamide for the treatment of systemic sclerosis associated lung disease. J Rheumatol. 1998 Jul;25(7):1325–1329. [PubMed]
  • Davas EM, Peppas C, Maragou M, Alvanou E, Hondros D, Dantis PC. Intravenous cyclophosphamide pulse therapy for the treatment of lung disease associated with scleroderma. Clin Rheumatol. 1999;18(6):455–461. [PubMed]
  • Griffiths Bridget, Miles Sarah, Moss Hilary, Robertson Rod, Veale Douglas, Emery Paul. Systemic sclerosis and interstitial lung disease: a pilot study using pulse intravenous methylprednisolone and cyclophosphamide to assess the effect on high resolution computed tomography scan and lung function. J Rheumatol. 2002 Nov;29(11):2371–2378. [PubMed]
  • Schnabel A, Reuter M, Gross WL. Intravenous pulse cyclophosphamide in the treatment of interstitial lung disease due to collagen vascular diseases. Arthritis Rheum. 1998 Jul;41(7):1215–1220. [PubMed]
  • White B, Moore WC, Wigley FM, Xiao HQ, Wise RA. Cyclophosphamide is associated with pulmonary function and survival benefit in patients with scleroderma and alveolitis. Ann Intern Med. 2000 Jun 20;132(12):947–954. [PubMed]
  • Marmont AM. Immune ablation followed by allogeneic or autologous bone marrow transplantation: a new treatment for severe autoimmune diseases? Stem Cells. 1994 Jan;12(1):125–135. [PubMed]
  • Giesecke J. HTLV screening of Swedish blood donors. Lancet. 1995 Apr 15;345(8955):978–978. [PubMed]
  • van de Putte LB, Tyndall A, van den Hoogen FH, Smolen JS. Hematopoietic stem cell transplants for autoimmune disease: role of EULAR. European League Against Rheumatism. J Rheumatol Suppl. 1997 May;48:98–99. [PubMed]
  • Tyndall A, Gratwohl A. Haemopoietic stem and progenitor cells in the treatment of severe autoimmune diseases. Ann Rheum Dis. 1996 Mar;55(3):149–151. [PMC free article] [PubMed]
  • Tyndall A, Gratwohl A. Blood and marrow stem cell transplants in auto-immune disease: a consensus report written on behalf of the European League against Rheumatism (EULAR) and the European Group for Blood and Marrow Transplantation (EBMT) Bone Marrow Transplant. 1997 Apr;19(7):643–645. [PubMed]
  • Ikehara S, Good RA, Nakamura T, Sekita K, Inoue S, Oo MM, Muso E, Ogawa K, Hamashima Y. Rationale for bone marrow transplantation in the treatment of autoimmune diseases. Proc Natl Acad Sci U S A. 1985 Apr;82(8):2483–2487. [PMC free article] [PubMed]
  • Marmont AM. New horizons in the treatment of autoimmune diseases: immunoablation and stem cell transplantation. Annu Rev Med. 2000;51:115–134. [PubMed]
  • Good RA, Ikehara S. Preclinical investigations that subserve efforts to employ bone marrow transplantation for rheumatoid or autoimmune diseases. J Rheumatol Suppl. 1997 May;48:5–12. [PubMed]
  • Marmont AM. Immunoablation followed or not by hematopoietic stem cells as an intense therapy for severe autoimmune diseases. New perspectives, new problems. Haematologica. 2001 Apr;86(4):337–345. [PubMed]
  • Storb R. Hematopoietic stem cell transplantation in nonmalignant diseases. J Rheumatol Suppl. 1997 May;48:30–35. [PubMed]
  • Jantunen E, Myllykangas-Luosujärvi R. Stem cell transplantation for treatment of severe autoimmune diseases: current status and future perspectives. Bone Marrow Transplant. 2000 Feb;25(4):351–356. [PubMed]
  • Binks M, Passweg JR, Furst D, McSweeney P, Sullivan K, Besenthal C, Finke J, Peter HH, van Laar J, Breedveld FC, et al. Phase I/II trial of autologous stem cell transplantation in systemic sclerosis: procedure related mortality and impact on skin disease. Ann Rheum Dis. 2001 Jun;60(6):577–584. [PMC free article] [PubMed]
  • McSweeney Peter A, Nash Richard A, Sullivan Keith M, Storek Jan, Crofford Leslie J, Dansey Roger, Mayes Maureen D, McDonagh Kevin T, Nelson J Lee, Gooley Theodore A, et al. High-dose immunosuppressive therapy for severe systemic sclerosis: initial outcomes. Blood. 2002 Sep 1;100(5):1602–1610. [PMC free article] [PubMed]
  • Farge Dominique, Marolleau Jean Pierre, Zohar Sarah, Marjanovic Zora, Cabane Jean, Mounier Nicolas, Hachulla Eric, Philippe Pierre, Sibilia Jean, Rabian Claire, et al. Autologous bone marrow transplantation in the treatment of refractory systemic sclerosis: early results from a French multicentre phase I-II study. Br J Haematol. 2002 Dec;119(3):726–739. [PubMed]
  • Tyndall A, Fassas A, Passweg J, Ruiz de Elvira C, Attal M, Brooks P, Black C, Durez P, Finke J, Forman S, et al. Autologous haematopoietic stem cell transplants for autoimmune disease--feasibility and transplant-related mortality. Autoimmune Disease and Lymphoma Working Parties of the European Group for Blood and Marrow Transplantation, the European League Against Rheumatism and the International Stem Cell Project for Autoimmune Disease. Bone Marrow Transplant. 1999 Oct;24(7):729–734. [PubMed]
  • Clements P, Lachenbruch P, Siebold J, White B, Weiner S, Martin R, Weinstein A, Weisman M, Mayes M, Collier D, et al. Inter and intraobserver variability of total skin thickness score (modified Rodnan TSS) in systemic sclerosis. J Rheumatol. 1995 Jul;22(7):1281–1285. [PubMed]
  • Kahaleh MB, Sultany GL, Smith EA, Huffstutter JE, Loadholt CB, LeRoy EC. A modified scleroderma skin scoring method. Clin Exp Rheumatol. 1986 Oct-Dec;4(4):367–369. [PubMed]
  • Clements PJ, Hurwitz EL, Wong WK, Seibold JR, Mayes M, White B, Wigley F, Weisman M, Barr W, Moreland L, et al. Skin thickness score as a predictor and correlate of outcome in systemic sclerosis: high-dose versus low-dose penicillamine trial. Arthritis Rheum. 2000 Nov;43(11):2445–2454. [PubMed]
  • Tyndall A, Gratwohl A. Immune ablation and stem-cell therapy in autoimmune disease. Clinical experience. Arthritis Res. 2000;2(4):276–280. [PMC free article] [PubMed]
  • Binks M, Passweg JR, Furst D, McSweeney P, Sullivan K, Besenthal C, Finke J, Peter HH, van Laar J, Breedveld FC, et al. Phase I/II trial of autologous stem cell transplantation in systemic sclerosis: procedure related mortality and impact on skin disease. Ann Rheum Dis. 2001 Jun;60(6):577–584. [PMC free article] [PubMed]
  • Waters TM, Bennett CL, Pajeau TS, Sobocinski KA, Klein JP, Rowlings PA, Horowitz MM. Economic analyses of bone marrow and blood stem cell transplantation for leukemias and lymphoma: what do we know? Bone Marrow Transplant. 1998 Apr;21(7):641–650. [PubMed]
  • Laffel GL, Barnett AI, Finkelstein S, Kaye MP. The relation between experience and outcome in heart transplantation. N Engl J Med. 1992 Oct 22;327(17):1220–1225. [PubMed]
  • Denton CP, Cailes JB, Phillips GD, Wells AU, Black CM, Bois RM. Comparison of Doppler echocardiography and right heart catheterization to assess pulmonary hypertension in systemic sclerosis. Br J Rheumatol. 1997 Feb;36(2):239–243. [PubMed]
  • Naik MM, Diamond GA, Pai T, Soffer A, Siegel RJ. Correspondence of left ventricular ejection fraction determinations from two-dimensional echocardiography, radionuclide angiography and contrast cineangiography. J Am Coll Cardiol. 1995 Mar 15;25(4):937–942. [PubMed]
  • Snowden JA, Biggs JC, Milliken ST, Fuller A, Staniforth D, Passuello F, Renwick J, Brooks PM. A randomised, blinded, placebo-controlled, dose escalation study of the tolerability and efficacy of filgrastim for haemopoietic stem cell mobilisation in patients with severe active rheumatoid arthritis. Bone Marrow Transplant. 1998 Dec;22(11):1035–1041. [PubMed]
  • Openshaw H, Stuve O, Antel JP, Nash R, Lund BT, Weiner LP, Kashyap A, McSweeney P, Forman S. Multiple sclerosis flares associated with recombinant granulocyte colony-stimulating factor. Neurology. 2000 Jun 13;54(11):2147–2150. [PubMed]
  • Fassas A, Anagnostopoulos A, Kazis A, Kapinas K, Sakellari I, Kimiskidis V, Tsompanakou A. Peripheral blood stem cell transplantation in the treatment of progressive multiple sclerosis: first results of a pilot study. Bone Marrow Transplant. 1997 Oct;20(8):631–638. [PubMed]
  • Burt RK, Traynor AE, Pope R, Schroeder J, Cohen B, Karlin KH, Lobeck L, Goolsby C, Rowlings P, Davis FA, et al. Treatment of autoimmune disease by intense immunosuppressive conditioning and autologous hematopoietic stem cell transplantation. Blood. 1998 Nov 15;92(10):3505–3514. [PubMed]
  • Burt RK, Fassas A, Snowden J, van Laar JM, Kozak T, Wulffraat NM, Nash RA, Dunbar CE, Arnold R, Prentice G, et al. Collection of hematopoietic stem cells from patients with autoimmune diseases. Bone Marrow Transplant. 2001 Jul;28(1):1–12. [PubMed]
  • Burt Richard K, Slavin Shimon, Burns William H, Marmont Alberto M. Induction of tolerance in autoimmune diseases by hematopoietic stem cell transplantation: getting closer to a cure? Blood. 2002 Feb 1;99(3):768–784. [PubMed]
  • Traynor AE, Schroeder J, Rosa RM, Cheng D, Stefka J, Mujais S, Baker S, Burt RK. Treatment of severe systemic lupus erythematosus with high-dose chemotherapy and haemopoietic stem-cell transplantation: a phase I study. Lancet. 2000 Aug 26;356(9231):701–707. [PubMed]
  • Verburg RJ, Kruize AA, van den Hoogen FH, Fibbe WE, Petersen EJ, Preijers F, Sont JK, Barge RM, Bijlsma JW, van de Putte LB, et al. High-dose chemotherapy and autologous hematopoietic stem cell transplantation in patients with rheumatoid arthritis: results of an open study to assess feasibility, safety, and efficacy. Arthritis Rheum. 2001 Apr;44(4):754–760. [PubMed]
  • Clements PJ, Lachenbruch PA, Seibold JR, Zee B, Steen VD, Brennan P, Silman AJ, Allegar N, Varga J, Massa M, et al. Skin thickness score in systemic sclerosis: an assessment of interobserver variability in 3 independent studies. J Rheumatol. 1993 Nov;20(11):1892–1896. [PubMed]
  • Nagy Z, Czirják L. Predictors of survival in 171 patients with systemic sclerosis (scleroderma). Clin Rheumatol. 1997 Sep;16(5):454–460. [PubMed]
  • Simeon CP, Armadans L, Fonollosa V, Vilardell M, Candell J, Tolosa C, Mearin F, Rodrigo MJ, Solans R, Lima J, et al. Survival prognostic factors and markers of morbidity in Spanish patients with systemic sclerosis. Ann Rheum Dis. 1997 Dec;56(12):723–728. [PMC free article] [PubMed]
  • Euler HH, Marmont AM, Bacigalupo A, Fastenrath S, Dreger P, Hoffknecht M, Zander AR, Schalke B, Hahn U, Haas R, et al. Early recurrence or persistence of autoimmune diseases after unmanipulated autologous stem cell transplantation. Blood. 1996 Nov 1;88(9):3621–3625. [PubMed]
  • Stratton RJ, Wilson H, Black CM. Pilot study of anti-thymocyte globulin plus mycophenolate mofetil in recent-onset diffuse scleroderma. Rheumatology (Oxford) 2001 Jan;40(1):84–88. [PubMed]

Figures and Tables

Figure 4
 Cumulative probability of survival was 72+13% at 5 years according to Kaplan-Meier plot calculation.
Figure 1
 Evaluation of skin score in patients with severe systemic sclerosis before inclusion (n = 47) and then at 6 (n = 37), 12 (n = 30), 24 (n = 19), and 36 (n = 10) months after HSCT. The proportional change from baseline measurement was calculated ...
Figure 2
 Evaluation of vital capacity (VC) in patients with severe systemic sclerosis before inclusion (n = 47) and then at 6 (n = 26), 12 (n = 27), 24 (n = 18), and 36 (n = 10) months after HSCT. There was no significant deterioration for each patient ...
Figure 3
 Evaluation of TLCO in patients with severe SSc before inclusion (n = 47) and then at 6 (n = 25), 12 (n = 26), 24 (n = 18), and 36 (n = 10) months after HSCT. The proportional change from baseline measurement was calculated for each patient at ...
Figure 5
 Cumulative probability of disease progression in 57 patients with severe SSc, as reported by local investigators, was estimated at 48+20% at 5 years according to the Kaplan-Meier method calculation. Disease progression was defined by an increase ...

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