WASHINGTON, DC—Several randomized, controlled trials of stem cell transplantation for autoimmune disease are underway, but a recent report and editorial in Arthritis & Rheumatism1,2 along with a number of presentations at the American College of Rheumatology (ACR) 2006 meeting suggest that researchers remain deeply divided over myeloablative vs nonmyeloablative approaches, as well as over whether stem cells are even needed.3-8

"Even if autologous HSCT turns out not to be curative, temporarily arresting the ongoing autoimmune and inflammatory processes ('resetting the clock') may enable prevention of the reemergence of autoimmunity by targeted therapies, such as the use of costimulatory blockade." —Gabor G. Illei, MD, PhD.
In addition to the promising phase I data on nonmyeloablative peripheral blood stem cell (PBSC) transplantation in patients with systemic sclerosis reported by Barr et al,3 the following studies have revealed important findings:

● Ina Koetter, MD, and colleagues from University Hospital, in Tuebingen, Germany, reported a phase I-II pilot study of autologous PBSC in 15 patients with treatment-resistant autoimmune diseases (including nine with systemic sclerosis), which showed partial remissions in eight/nine patients with systemic sclerosis (SSc), and complete remissions in two of four patients with vasculitis, along with an elevated risk of post-transplant viral infections.4
● Madelon C. Vonk, MD, and colleagues from Radboud University Nijmegen Medical Centre, in The Netherlands, reported 5-year follow-up data showing rapid, sustained clinical improvement in 26 patients with diffuse cutaneous SSc treated with autologous HSCT.5 The preparative regimen was cyclophosphamide plus G-CSF.
● In other 5-year follow-up data, Richard A. Nash, MD, and colleagues at the Fred Hutchinson Cancer Research Center in Seattle, Washington, reported responses sustained for a median of 4 years and marked improvement in skin and overall function in high-risk SSc patients treated with CD34-selected, high-dose immunosuppressive therapy.6
● Hiroshi Tsukamoto, MD, and colleagues from Kyushu University, Fukuoka, Japan, examined immune reconstitution after high-dose cyclophosphamide immune suppressive therapy and auto-PBSC transplantation for systemic sclerosis. They report that the long-term efficacy of this approach appears to be due to suppression of CD4+ T cells and correction of cytokine imbalances.7

Richard K. Burt, MD, recently reviewed the development from myeloablative to nonmyeloablative (lymphoablative) transplant regimens in autoimmune diseases.2 Dr. Burt discussed three important ongoing randomized controlled trials of autologous HSCT for SSc: the Autologous Stemcell Transplantation International Scleroderma (ASTIS) trial, the American Scleroderma Stem Cell versus Immune Suppression Trial (ASSIST), and the Scleroderma: Cyclophosphamide or Transplantation (SCOT) trial.

The ASTIS and ASSIST trials use nonmyeloablative conditioning regimens; the SCOT trial uses a myeloablative regimen. One major design difference involves the use of total body irradiation (TBI), which is used only in the SCOT trial. "While autologous HSCT appears to induce remissions and improve quality of life in the majority of patients, it remains unclear whether either myeloablative or lymphoablative autologous HSCT can cure autoimmune disorders, and randomized controlled trials are needed to confirm the benefit and cost-effectiveness of this therapy," Dr. Burt concludes.

Stem cell transplant may not always be necessary, however. Christopher V. Tehlirian, MD, and colleagues from Johns Hopkins School of Medicine in Baltimore, Maryland, reported rapid reductions in disease activity in three of four SSc patients treated with high-dose cyclophosphamide alone.8

In an editorial in Arthritis & Rheumatism, Gabor G. Illei, MD, head of the Sjogren's Syndrome Clinic, Gene Therapy and Therapeutics Branch, National Institute of Dental and Craniofacial Research, in Bethesda, Maryland, wrote, "Even if autologous HSCT turns out not to be curative, temporarily arresting the ongoing autoimmune and inflammatory processes ('resetting the clock') may enable prevention of the reemergence of autoimmunity by targeted therapies, such as the use of costimulatory blockade."1

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References

1. Illei GG. Hematopoietic stem cell transplantation in autoimmune diseases: Is the glass half full or half empty? (editorial). Arthritis Rheum. 2006;54:3730–3734.
2. Burt RK, Marmont A, Oyama Y, et al. Randomized controlled trials of autologous hematopoietic stem cell transplantation for autoimmune diseases. The evolution from myeloablative to lymphoablative transplant regimens. Arthritis Rheum. 2006;54:3750–3760.
3. [CIAOMed Link] #1036. ACR Conference News: Non-Myeloablative Stem Cell Transplants Safe, Effective in Scleroderma. Tuesday, November 14, 2006.
4. Koetter I, Henes J, Wacker A, et al. Autologous peripheral blood stem cell transplantation (auto-pbsct) for treatment-resistant autoimmune diseases. Results of a phase I-II pilot study with 15 patients. Presented at: American College of Rheumatology Meeting; November 11–15, 2006; Washington, DC. Abstract 1299.
5. Vonk MC, Marjanovic Z, van den Hoogen FHJ, et al. Long-term follow-up results after autologous hematopoietic stem cell transplantation for severe systemic sclerosis. Presented at: American College of Rheumatology Meeting; November 11–15, 2006; Washington, DC. Abstract 692.
6. Nash RA, McSweeney PA, Crofford LJ, et al. 5-Year follow-up of high-dose immunosuppressive therapy (HDIT) for systemic sclerosis (SSc). Presented at: American College of Rheumatology Meeting; November 11–15, 2006; Washington, DC. Abstract 691.
7. Tsukamoto H, Nagafuji K, Horiuchi T, et al. High-dose immune suppressive therapy and autologous peripheral blood stem cell transplantation for systemic sclerosis: analysis of immune reconstitution. Presented at: American College of Rheumatology Meeting; November 11–15, 2006; Washington, DC. Abstract 690.
8. Tehlirian CV, Hummers LK, Forbes E, et al. High dose cyclophosphamide without stem cell transplantation in systemic sclerosis. Presented at: American College of Rheumatology Meeting; November 11–15, 2006; Washington, DC. Abstract 689.