Bone Marrow Transplantation in the Treatment of Systemic Sclerosis Federico Viganego, MD*, Richard Nash, MD*, and Daniel E. Furst, MD † Address *Fred H utchinson Cancer Research Center, 1100 Fairview Avenue N orth, D1-100, Seattle, WA 98109-4417, USA. E-mail: fviganego@ fhcrc.org † Ar thritis C linical Research U nit, Virginia Mason Research C enter, 1201 9th Avenue, R1-RHE, Seattle, W A 98101, USA. E-mail: crgdrg@ vmmc.org Current Rheumatology Reports 2000, 2: 492–500 Current Science Inc. ISSN 1523-3774 Copyright © 2000 by Current Science Inc. Introduction Clinical disease Systemic sclerosis (SSc) is an uncommon disease that is characterized by the overproduction of fibrotic tissue in the skin, joints, muscles, lungs, heart, gastrointestinal (GI) tract, and kidneys, leading to progressive and often relent- less fibrosis [1]. SSc has been classified into different subsets depending on the extent of skin involvement, ranging from diffuse disease to limited disease without cutaneous fibrosis ( ie, SSc sine scleroderma) [2]. SSc may present with visceral involvement, including the GI tract, pulmonary interstitium, nerves, joints, muscles, kidneys, and myocardium. Although SSc predictably decreases survival, massive, rapid visceral involvement represents a particularly lethal variety [3]. Hypothesis for the pathogenesis of systemic sclerosis An overall hypo thesis for disease pathogenesis is pictured in Figure 1 [4]. External stimuli ( eg, benzene derivatives, L-tryptophan, silica) may lead, in genetically susceptible individuals, to the activation of the immune system. The immune system, via the release of cytokines and other inflammatory mediators, causes microvascular damage and vice versa. Both immune mediators and cytokines released from activated endothelium stimulate fibro- blasts and result in collagen synthesis. Collagen, in turn, completes the cycle to cause immunologic activation. Although evidence exists to support each step of this cycle, only the vascular and immunologic portions of this cycle are discussed here. Immunologic involvement There is evidence that validates the hypothesis that the pathogenesis of SSc involves autoimmunity [4]. First, clear signs of an activated immune system are represented by the presence of mononuclear cell infiltrates in fibrotic tissues from patients with SSc [5], particularly T cells. Seco nd, exper- iments in animal models of SSc showed evidence o f adoptive transfer of the disease by infusion of B and T lymphocytes from the tsk/+ strain into healthy mice [6]. Third, elevated levels of interleukin-2 [7], as well as a skewed T-cell reperto ire [8], were demonstrated in the peripheral blood of SSc patients. Fourth, B-cell activation is shown by the presence of several autoantibodies that often characterize different sub- groups of patients [9]. Clinically, the association with other autoimmune diseases and overlap syndromes [1], as well as the association with certain HLA antigens in some ethnic groups [10], seems to support this hypothesis. In addition, the similarity with chronic graft-versus-host disease (GVHD) (and a lack of tolerance of the donor immune system directed against the host observed in patients undergoing allogeneic bone marrow transplantation) seems to have clinical similarities with SSc [11]. Systemic sclerosis (SSc) is an uncommon, progressive, sometimes lethal fibrotic disease whose pathogenesis probably includes immunologic elements, especially early in its course. There is no proven therapy for this disease, although some promising results have been obtained with the use of immunosuppressive drugs such as cyclopho- sphamide. There exists a subgroup of patients who have rapidly progressive disease or who are not responsive to conventional treatment, and who may benefit from intensive immunosuppression with stem cell rescue (stem cell transplantation). The rationale for bone marrow transplantation (BMT), and, more recently, peripheral blood stem cell transplantation (SCT), has been validated by studies on animal models of autoimmunity. Autologous transplantation has shown encouraging anecdotal results, and it is now being evaluated in phase I/II studies in patients with predictably poor outcome. In this light, reliably identifying patients early in the course of SSc is extremely important in order to establish correct eligibility criteria. For patients unable to tolerate transplant regimens, other approaches may be feasible. In this regard, nonmyelo- ablative approaches, such as immunosuppression without rescue and mixed chimerism, are also discussed.