Intense Immunosuppression and Stem-Cell Transplantation for Patients With Severe Rheumatic Autoimmune Disease: A Review

Jacob M. van Laar, MD, Alan Tyndall, MD


Cancer Control. 2003;10(1) 

In This Article


In less than a decade, intense immunosuppression and autologous hematopoietic SCT has evolved from a hypothetical and experimental treatment to a potential treatment option for severe autoimmune diseases including refractory rheumatic conditions such as RA, SSc, SLE, and JIA. Although it is too early to assess the full merits of this new treatment modality, several important lessons have been learned from case reports, phase I/II studies, and data registry analyses as a result of intensive international collaboration.

First, it has been convincingly demonstrated that the treatment modality is feasible: autologous peripheral-blood stem-cell grafts can be procured containing sufficient numbers of progenitor cells to ensure rapid engraftment of all lineages. Flares have been observed with G-CSF-based mobilization, and the combination of cyclophosphamide and G-CSF was more likely to ameliorate disease activity than G-CSF alone.[56] Hematopoietic and immune reconstitution in these heavily pretreated patients was a matter of concern, especially with the use of T-cell-depleted grafts and/or in vivo T-cell depletion. In keeping with previous observations in hemato-oncologic diseases, numerical recovery of all peripheral-blood subsets has been rapid, returning to baseline levels within 6 months except for naive CD4+ T lymphocytes. Whether the prolonged lymphopenia has clinical sequelae remains to be determined. Also, levels of immunoglobulins returned to baseline quickly, although detailed functional studies have not been published yet.

Second, treatment-related morbidity and mortality have been shown to be significant in patients with SLE, SSc, and JIA, but low in those with RA.[57] Some toxicities seemed disease specific (eg, macrophage-activation syndrome in JIA, and cyclophosphamiderelated cardiotoxicity and total body irradiation-related pulmonary damage in SSc). The shared opinion in the field is that the extent and nature of organ involvement in SLE, SSc, JIA (vs the lack of it in RA) are probably important determinants. Consequently, patient selection has emerged as a critical component in this respect, with patients with advanced disease having a higher risk of complications and benefiting less than those with early-stage disease. In general, patients with a therapy-refractory, progressive, active disease who are at risk of further functional disability and early mortality are considered eligible for treatment with autologous SCT. The goal is long-term improvement of disease activity and quality of life. However, when offering SCT to patients with systemic rheumatic autoimmune diseases, these benefits should be balanced against toxicities and treatment-related mortality. Advances in identifying high-risk patients may allow for SCT at an earlier stage of the disease, before the development of severe end organ damage.

New tools based on genomics and proteomics will undoubtedly aid in outcome prediction and in the identification of patients with an adverse prognosis. More important is the willingness of physicians and patients to accept risk-taking treatment, at least for RA patients for whom alternative experimental therapies are available; a treatment-related mortality rate of more than 5% was considered unacceptable by the majority of rheumatologists and RA patients in a recent survey in the Netherlands.[58] This was in accordance with a decision analysis using Markov modeling that showed a treatment-related mortality rate of more than 3.3.% would probably not be compensated by superior efficacy of intensive immunosuppression vs continued conventional treatment.[59] These results do not necessarily apply to potentially more aggressive diseases such as SLE, SSc, or JIA patients. Long-term safety is another important issue. The use of total lymphoid irradiation to treat refractory RA in the 1980s has only recently been identified as a source of excess late mortality in these patients.[60]

Third, the observation of long-term remissions in all diseases studied underscores the potential clinical benefit of SCT. Although expectation bias on the part of patients and physicians and the use of high-dose corticosteroids during conditioning may have contributed to some of the short-term effects reported, the long-lasting effects (2 to 3 years) in a number of patients suggest that fundamental alterations in the dis-ease state were induced. It is too early to conclude which of the multiple components of any transplant protocol is critical in achieving a sustained clinical response. Conversely, failures defined as relapse or persistence of disease activity also have been reported, notably in RA and SLE, and the reasons for these are unclear. Responses and failures have been reported with all regimens used. Sensitivity to conventional drugs was regained in a number of patients with relapsed or persistent disease. From a T-cell-centered perspective, it might be inferred from the present studies that not all pathogenic T lymphocytes were eradicated or that some had been reinfused with the graft. This would imply that remissions could be achieved only by further intensification (eg, by in vivo T-cell depletion). Clearly, this could add to the toxicity, but other pathogenetic explanations for failures also can be considered, such as persistent innate immune abnormalities, intrinsic stem-cell or stromal-cell defects, or reactivation of autoaggressive lymphocytes as a result of renewed exposure to autoantigens.

From the perspective of the patient and the treating physicians, responses were clinically meaningful in a majority of patients with resultant enhanced quality of life. It remains to be seen if any superior efficacy of a more rigorous approach will compensate for increased toxicity in terms of quality-adjusted life expectancy.

The principal conclusion is that safety and efficacy should now be investigated through phase III studies comparing intensive immunosuppression with conventional treatment and employing uniform eligibility criteria, treatment regimens, and study parameters. Adequate assessment of risk/benefit requires properly designed and conducted prospective randomized, controlled trials with a long duration of follow-up. The issue is whether intense immune suppression aimed at immunoablation is superior to continuous moderate immune suppression with respect to toxicity and efficacy in the long run. Two such studies are ongoing (the Autologous Stem Cell Transplantation International Scleroderma Trial [ASTIS]) or are planned for patients with RA (ASTIRA) under the auspices of EBMT/EULAR. The ASTIS trial[61] compares intense immunosuppression and autologous SCT vs monthly pulse-therapy cyclophosphamide in patients with recent-onset diffuse SSc and major organ involvement (heart, kidney, lung) at risk of premature mortality. The ASTIRA study will compare intense immunosuppression and autologous SCT vs mobilization-dose cyclophosphamide in patients with refractory, destructive RA. Similar studies for SLE and JIA are being planned. The designs and transplant protocols for these studies differ, reflecting differences in drug sensitivity between diseases and perceived goals of the trials (eg, improving disease control in RA vs improving event-free survival in SSc).

Given the low number of eligible patients, multi-center international collaboration is essential to the success of these trials to accrue the required number of patients. Once safety and efficacy of the treatment modality have been established, future studies could focus on cost effectiveness and on the identification of the critical components of the treatment schedule. However, if intense immunosuppression proves too toxic or not sufficiently efficacious, alternative transplant strategies could be considered. More intensive (eg, myeloablative) conditioning regimens might be more efficacious, although this remains to be demonstrated in any of the autoimmune diseases described. Not unexpectedly, the more intensive conditioning protocols proved more toxic in a retrospective registry analysis.[62] Allogeneic transplantation has not yet been evaluated in systemic rheumatic autoimmune diseases due to risks of transplant-related mortality and graft-vs-host disease. Allogeneic SCT may be more effective than autologous SCT if intrinsic stem-cell abnormalities exist in these diseases and if host hematopoiesis and abnormal immune-cell populations can be eradicated via a graft-vs-autoimmunity effect. Recent advances in allografting have improved safety, thereby allowing application in nonmalignant conditions. However, whether the potential benefit of allogeneic SCT justifies the risk of graft-vs-host disease and treatment-related mortality is yet to be determined. Furthermore, a well-documented case of relapse of RA despite full donor chimerism after allografting for concomitant malignancy cautions against unrealistic optimism.[21]

Other lessons may be learned regarding pathogenesis and particularly the role of the immune system. According to the current paradigms, reinstitution of self-tolerance should be the "immunologic" goal of immunoablation, in order to cure systemic rheumatic autoimmune diseases. Also, our understanding of the processes that underlie relapses or remissions of systemic rheumatic autoimmune diseases is fragmented. These issues need to be addressed in meticulous clinical studies, with a thorough understanding of the needs and expectations of the patients involved.

The print version of this article was originally certified for CME credit. For accreditation details, contact the publisher. H. Lee Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL 33612. Telephone: (813) 632-1349. Fax: (813) 903-4950. Email:


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.