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

Abstract and Introduction

Background: Intense immunosuppression plus stem-cell transplantation (SCT) has emerged as a new treatment modality for patients with refractory, severe rheumatic autoimmune disease. Its rationale is based on eliminating autoaggressive lymphocytes by lympho-or myeloablative conditioning followed by stem-cell rescue. Preclinical studies in animal models of autoimmune disease and observations in patients with rheumatoid arthritis (RA) who were cured after allogeneic bone marrow transplantation for concomitant hematologic malignancy have provided support for the concept.
Methods: The authors reviewed the results of recent phase I/II studies and data from the EBMT/EULAR Registry on more than 400 patients with autoimmune diseases including RA, systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and juvenile idiopathic arthritis (JIA).
Results: Toxicity resulting from stem-cell grafting depended on underlying disease and the intensity of the conditioning regimen. Treatment-related mortality was low in RA (1.4%) but relatively high (>10%) in patients with JIA, SLE, and SSc, possibly related to visceral involvement in these patients. With the application of uniform and strict criteria, safety has improved. Long-term remissions up to 4 years have been observed in SSc and JIA, while relatively more relapses have occurred in patients with SLE and RA. Sensitivity to anti-rheumatic drugs was restored in RA and SLE patients, however, resulting in improved disease control.
Conclusions: Intense immunosuppression and SCT may be an effective therapy for selected patients with severe rheumatic autoimmune disease. Its merits need to be proven via multicenter phase III studies by comparing efficacy and safety with conventional therapy.

Systemic rheumatic autoimmune diseases include rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), systemic lupus erythematosus (SLE), and systemic sclerosis (SSc). Although the etiology of each of these diseases remains unclear, significant progress has been made in identifying genetic and environmental components of the pathogenesis of these diseases that determine severity and outcome. Genetic components encompass functional polymorphisms of genes active in apoptosis, antigen recognition, adhesion, and cytokine production that may play a role in the immune dysregulation characteristic of these disorders.[1] Most of the immune abnormalities pertain to B and T lymphocytes and myeloid cells, all derived from hematopoietic stem cells, and stromal cells. In addition to genetic factors, environmental or stochastic factors must also play an important role, as illustrated by the observations that transfer of stem cells from a patient with RA and one with SLE did not result in disease in the recipient and that concordance rates of HLA-identical siblings in RA and SLE are relatively low (10% to 30%).[2,3,4] Environmental factors include external triggers such as smoking and infection, as well as internal triggers such as changes in the levels of estrogens during and after pregnancy, which may explain the female preponderance of these disorders.[1]

Major clinical hallmarks of these diseases are chronic inflammation of musculoskeletal structures (eg, joints, skin, and bone) and the endothelium, which underlies the protean manifestations of vasculopathy. The complexity of these diseases is mirrored by the striking heterogeneity of clinicopathologic features even within each disease category. While most patients have relapsing, remitting, or smoldering disease, others experience progressive disease that results in tissue destruction, severe disability, or even death. Although these diseases cannot be categorized as malignant, considering them as benign conditions underestimates their potential impact on morbidity, quality of life, and survival.[5] Severity of the disease is determined not only by musculoskeletal symptoms, but also by systemic and extra-articular or visceral manifestations. Outcomes in SLE, RA, and JIA improved substantially after the introduction of effective conventional treatments, such as tumor necrosis factor (TNF) blocking medication for RA and JIA. However, disease control remains unsatis-factory in a significant number of patients, and these diseases are incurable in the majority of patients despite the new therapies. In patients with SSc, out-come has improved for the subset of patients developing renal crisis but not for those with diffuse SSc and lung involvement. For these patients, the 5-year mortality rate ranges from 30% to 70%.[6]

Because of the sensitivity of these diseases to immunosuppressive and cytostatic agents, the dismal outlook for a subset of patients, and the recognition that immune mechanisms play a notable role in the pathogenesis of the disease, intense immunosuppression with autologous stem-cell transplantation (SCT) has been developed as an approach to control these conditions. The conditioning regimen may delete the pathogenetically relevant autoreactive lymphocyte populations or "reset" the dysbalanced immune system.[7] This may allow regeneration of a nonautoaggressive immune repertoire in the absence of the environmental triggers that originally perturbed the immune system of a genetically predisposed host. The subsequent transfusion of hematopoietic stem cells avoids prolonged cytopenias and associated infectious or bleeding complications and allows timely hematopoietic reconstitution.


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