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Some patients with systemic lupus erythematosus (SLE) are refractory to traditional therapies, dependent on chronic corticosteroids, have organ damage, and are at high risk of mortality. In this group of patients, we report outcome at a median of five years after autologous hematopoietic stem cell transplant (HSCT) using two different non-myeloablative regimens. Four patients received a conditioning regimen of cyclophosphamide (200 mg/kg) and alemtuzumab (60 mg), while 26 patients underwent conditioning with cyclophosphamide (200 mg/kg), rATG (Thymoglobulin) (5.5 mg/kg), and rituximab 1000 mg. Unselected peripheral blood stem cells were infused on day 0. There were no treatment related deaths. Of the four patients treated with cyclophosphamide and alemtuzumab, none entered remission. For the 26 patients treated with cyclophosphamide, rATG, and rituximab, disease remission defined as no immune suppressive drugs except hydroxychloroquine and/or 10 mg or less of prednisone a day was 92% at 6 months, 92% at one year, 81% at 2 years, 71% at 3 years, and 62% at 4 and 5 years post-HSCT. Autologous HSCT outcome is dependent on the conditioning regimen but prior organ damage may cause lingering symptoms.

Low-dose tolerance therapy with nucleosomal histone peptide epitopes blocks lupus disease in mouse models, but effect in humans is unknown. Herein, we found that CD4(+)CD25(high)FoxP3(+) or CD4(+)CD45RA(+)FoxP3(low) T-cells, and CD8(+)CD25(+)FoxP3(+) T-cells were all induced durably in PBMCs from inactive lupus patients and healthy subjects by the histone peptide/s themselves, but in active lupus, dexamethasone or hydroxychloroquine unmasked Treg-induction by the peptides. The peptide-induced Treg depended on TGFβ/ALK-5/pSmad 2/3 signaling, and they expressed TGF-β precursor LAP. Lupus patients' sera did not inhibit Treg induction. The peptide epitope-induced T cells markedly suppressed type I IFN related gene expression in lupus PBMC. Finally, the peptide epitopes suppressed pathogenic autoantibody production by PBMC from active lupus patients to baseline levels by additional mechanisms besides Treg induction, and as potently as anti-IL6 antibody. Thus, low-dose histone peptide epitopes block pathogenic autoimmune response in human lupus by multiple mechanisms to restore a stable immunoregulatory state., (© 2013.)

Autologous haematopoietic stem cell transplantation (AHSCT) has been proposed as a treatment modality which may arrest the autoimmune disease process and lead to sustained treatment-free remissions. Since the first consensus statement in 1997, approximately 200 autologous bone marrow or haematopoietic stem cell transplantations (HSCTs) have been reported worldwide for systemic lupus erythematosus (SLE). The current state of AHSCT in SLE was reviewed at a recent meeting of the autoimmune working party of the European Group for Blood and Marrow Transplantation. There was general agreement among experts in this field that in patients with severe SLE refractory to conventional immunosuppressive treatments, AHSCT can achieve sustained clinical remissions (ranging from 50% to 70% disease-free survival at 5 years) associated with qualitative immunological changes not seen with other forms of treatment. However, this clinical benefit is associated with an increase in short-term mortality in most studies. Improving patient selection, long-term follow-up of patients after AHSCT, optimisation of induction and maintenance treatment together with detailed analysis of the immune system are identified as key areas for future research. Optimally, AHSCT should be compared with conventional treatment in randomised controlled trials. Development of stronger transplant registries, defining a core set of clinical data and standardising biological sample collections would make future collaborations and comparison of studies more feasible.

Compared with conventional drug therapy, autologous hemopoietic stem cell transplantation (HSCT) can induce very-long-term remission in refractory lupus patients. Herein, we show that in posttransplant patients, both CD4(+)CD25(high)FoxP3(+) and an unusual CD8(+)FoxP3(+) Treg subset return to levels seen in normal subjects; accompanied by almost complete inhibition of pathogenic T cell response to critical peptide autoepitopes from histones in nucleosomes, the major lupus autoantigen from apoptotic cells. In addition to a stably sustained elevation of FoxP3, posttransplant CD8 T cells also maintained markedly higher expression levels of latency-associated peptide (LAP), CD103, PD-1, PD-L1, and CTLA-4, as compared with pretransplant CD8 T cells that were identically treated by a one-time activation and rest in short-term culture. The posttransplant CD8 regulatory T cells (Treg) have autoantigen-specific and nonspecific suppressive activity, which is contact independent and predominantly TGF-beta dependent. By contrast, the pretransplant CD8 T cells have helper activity, which is cell contact dependent. Although CD4(+)CD25(high) Treg cells return during clinical remission of conventional drug-treated lupus, the posttransplant patient's CD8 Treg cells are considerably more potent, and they are absent in drug-treated patients in whom CD4 T cell autoreactivity to nucleosomal epitopes persists even during clinical remission. Therefore, unlike conventional drug therapy, hemopoietic stem cell transplantation generates a newly differentiated population of LAP(high)CD103(high) CD8(TGF-beta) Treg cells, which repairs the Treg deficiency in human lupus to maintain patients in true immunological remission.

Systemic lupus erythematosus (SLE) is considered the paradigm of autoimmune diseases (AD), and the murine models are known to be curable by means of allogeneic hematopoietic stem cell transplantation (HSCT). However autologous transplantations were predominantly utilized in the clinic, starting from 1996, and by now well over 150 very severe patients have been transplanted worldwide. Transplant-related mortality (TRM) in 153 cases was 7%, with a wide center effect (from 0-2% to 13%). The disease arresting effect was dramatic even in patients on dialysis, although ASCT should not be considered a last resource, salvage therapy, but a disease- modifying intervention to be utilized in the early stages of patently aggressive disease. The autoimmune biological parameters are consistently modified, although some degree of ANA-positivity generally persists. Similar encouraging results have been obtained in the primary antiphospholipid syndrome (APS) and in bullous disorders of the skin.

Background: Calciphylaxis and calcinosis can both cause severe morbidity and mortality in patients with systemic lupus erythematosus (SLE). Haematopoietic stem cell transplantation (HSCT) has been successfully used to treat patients with refractory SLE. It was hypothesized that in calciphylaxis and calcinosis, ongoing inflammatory activity contributes to the calcium deposition in the media of small arteries, as well as perivascular and periarticular tissues. We report three patients whose soft-tissue calcification syndromes dramatically resolved after undergoing HSCT., Methods: Three patients referred for refractory SLE underwent HSCT at a tertiary care medical center. SLE serologies and clinical features before and after HSCT were recorded., Results: Despite receiving >6 months of intravenous cyclophosphamide (CYC), three SLE patients showed signs of persistent lupus activity, including severe soft-tissue calcification. The first patient was on haemodialysis and developed severe calciphylaxis with large ulcers and tissue necrosis. The second patient had calcinosis, with palpable crystals extruding from ulcers. The third patient had calcinosis characterized by subcutaneous nodules and plaques. Because prior conventional therapies had failed, the three were treated with high-dose CYC, anti-thymocyte globulin and HSCT. They have been followed post-HSCT for 26-38 months, with excellent clinical responses, including sustained resolution of skin abnormalities., Conclusions: The successful treatment of advanced calcium deposition by aggressive immune ablation underscores the contribution of SLE-mediated inflammation to soft-tissue calcification syndromes.

Patients with cardiac dysfunction may be at increased risk of cardiac toxicity when undergoing hematopoietic stem cell transplantation (HSCT), which may preclude them from receiving this therapy. Cardiac dysfunction is, however, common in systemic lupus erythematosus (SLE) patients. While autologous HSCT (auto-HSCT) has been performed increasingly for SLE, its impact on cardiac function has not previously been evaluated. We, therefore, performed a retrospective analysis of SLE patients who had undergone auto-HSCT in our center to determine the prevalence of significant cardiac involvement, and the impact of transplantation on this. The records of 55 patients were reviewed, of which 13 were found to have abnormal cardiac findings on pre-transplant two-dimensional echocardiography or multi-gated acquisition scan: impaired left ventricular ejection fraction (LVEF) (n = 6), pulmonary hypertension (n = 5), mitral valve dysfunction (n = 3) and large pericardial effusion (n = 1). At a median follow-up of 24 months (8-105 months), there were no transplant-related or cardiac deaths. With transplant-induced disease remission, all patients with impaired LVEF remained stable or improved; while three with symptomatic mitral valve disease similarly improved. Elevated pulmonary pressures paralleled activity of underlying lupus. These data suggest that auto-HSCT is feasible in selected patients with lupus-related cardiac dysfunction, and with control of disease activity, may improve.

Context: Manifestations of systemic lupus erythematosus (SLE) may in most patients be ameliorated with medications that suppress the immune system. Nevertheless, there remains a subset of SLE patients for whom current strategies are insufficient to control disease., Objective: To assess the safety of intense immunosuppression and autologous hematopoietic stem cell support in patients with severe and treatment-refractory SLE., Design, Setting, and Participants: A single-arm trial of 50 patients with SLE refractory to standard immunosuppressive therapies and either organ- or life-threatening visceral involvement. Patients were enrolled from April 1997 through January 2005 in an autologous nonmyeloablative hematopoietic stem cell transplantation (HSCT) study at a single US medical center., Interventions: Peripheral blood stem cells were mobilized with cyclophosphamide (2.0 g/m2) and granulocyte colony-stimulating factor (5 microg/kg per day), enriched ex vivo by CD34+ immunoselection, cryopreserved, and reinfused after treatment with cyclophosphamide (200 mg/kg) and equine antithymocyte globulin (90 mg/kg)., Main Outcome Measures: The primary end point was survival, both overall and disease-free. Secondary end points included SLE Disease Activity Index (SLEDAI), serology (antinuclear antibody [ANA] and anti-double-stranded (ds) DNA), complement C3 and C4, and changes in renal and pulmonary organ function assessed before treatment and at 6 months, 12 months, and then yearly for 5 years., Results: Fifty patients were enrolled and underwent stem cell mobilization. Two patients died after mobilization, one from disseminated mucormycosis and another from active lupus after postponing the transplantation for 4 months. Forty-eight patients underwent nonmyeloablative HSCT. Treatment-related mortality was 2% (1/50). By intention to treat, treatment-related mortality was 4% (2/50). With a mean follow-up of 29 months (range, 6 months to 7.5 years) for patients undergoing HSCT, overall 5-year survival was 84%, and probability of disease-free survival at 5 years following HSCT was 50%. Secondary analysis demonstrated stabilization of renal function and significant improvement in SLEDAI score, ANA, anti-ds DNA, complement, and carbon monoxide diffusion lung capacity adjusted for hemoglobin., Conclusions: In treatment-refractory SLE, autologous nonmyeloablative HSCT results in amelioration of disease activity, improvement in serologic markers, and either stabilization or reversal of organ dysfunction. These data are nonrandomized and thus preliminary, providing the foundation and justification for a definitive randomized trial. Clinical Trial Registration ClinicalTrials.gov Identifier: NCT00271934.

Systemic lupus erythematosus (SLE) is the most common disease associated with antiphospholipid syndrome (APS). We, therefore, evaluated 46 patients with refractory SLE treated by autologous hematopoietic stem cell transplantation (HSCT) for a history of APS prior to transplantation. The prevalence of SLE-related APS in our patient population was 61% (28 of 46 patients with refractory SLE). Nineteen of 28 patients with APS had lupus anticoagulant (LA) or high titers of anticardiolipin antibodies (ACLAs), either immunoglobulin (Ig)G or IgM, when evaluated at study entry. Six of 8 evaluable LA+ patients became and remained LA-; 5 of 7 initially ACLA IgG+ patients and 9 of 11 ACLA IgM+ patients demonstrated normalization of ACLA titers when followed after HSCT. Eighteen of 22 patients refractory to chronic anticoagulation discontinued anticoagulation therapy a median of 4 months after transplantation; 78% of them remained free of thrombotic events and in complete SLE remission for up to 78 months (median, 15 months) after HSCT. There was no treatment-related mortality. Autologous HSCT may be performed safely in patients with APS and appears to be effective therapy for eliminating ALPAs and preventing thrombotic complications in patients with SLE.

Aim: To report the prevalence and reversibility of pulmonary function test (PFT) abnormalities among systemic lupus erythematosus (SLE) patients, refractory to therapy, undergoing hematopoietic stem cell transplantation (HSCT)., Methods: Thirty-four SLE patients received 200 mg/kg cyclophosphamide and 90 mg/kg equine antithymocyte globulin followed by HSCT. PFTs were performed prior to, at 6 months, and yearly following HSCT., Results: The prevalence of significant PFT abnormalities was high (97%). Low FEV(1) and FVC occurred in 26 of 34 patients (76%). A significant abnormality in diffusion capacity of the lung for carbon monoxide (Dlco) occurred in 26 of 32 individuals able to complete Dlco testing (81%). Dlco 18 months after HSCT. Five of 28 patients had a normal entry FVC; for each, the FVC remains normal. Of the 23 patients with an abnormal baseline FVC, 18 have improved, 15 completely and 3 partially. Eight of these 18 patients also have improved Dlco. The two patients with a diagnosis of SLS and one patient with SLE-related pulmonary hypertension improved in both parameters. Only 5 of 23 patients with an abnormal FVC did not improve. Each of these five patients retained active lupus in spite of HSCT., Conclusion: The prevalence of lung impairment among SLE patients requiring long-term immune suppression is high. Following HSCT, pulmonary impairments can improve, which is sustained if disease control is sustained.

At Northwestern University, a phase I/II trial of hematopoietic stem cell transplant (HSCT) for systemic lupus erythematosus (SLE) has shown promising results. A phase III HSCT trial is being developed to confirm efficacy of HSCT vs continuing the currently accepted standard of care, intravenous pulse cyclophosphamide.

Hematopoietic stem cell transplantation was first reported for patients with systemic lupus erythematosus in 1997. The procedure has since been performed worldwide including in Europe, in Brazil, and in China. A National Institutes of Health-funded phase III clinical trial of hematopoietic stem cell transplantation for refractory systemic lupus erythematosus is anticipated to begin in 2003. Encouraging responses are raising new hope about the role of adult hematopoietic stem cells in systemic lupus erythematosus.

Objective: To determine the safety and long-term efficacy of immune ablation and autologous hematopoietic stem cell transplantation (HSCT) in severe systemic lupus erythematosus (SLE)., Methods: Fifteen patients with persistently active SLE after intravenous (IV) cyclophosphamide (CYC) therapy underwent HSCT. Stem cells were mobilized with CYC (2.0 gm/m(2)) and granulocyte colony-stimulating factor (5 microg/kg/day). Lymphocytes were depleted from the graft by selection of CD34-positive cells. The conditioning regimen used was CYC (200 mg/kg), antithymocyte globulin (90 mg/kg), and methylprednisolone (3 mg/kg). Outcome was evaluated by the SLE Disease Activity Index (SLEDAI), serum complement levels, serologic features, function of diseased organs, and immunosuppressive medication requirements., Results: Fifteen patients with persistent, severe SLE, 7 of whom were critically ill, were treated. No deaths occurred following treatment. The median followup after HSCT has been 36 months (range 12-66 months). All patients demonstrated a gradual, but marked, improvement. The SLEDAI score has declined to 1 year after HSCT, 10 have discontinued immunosuppressive medications, and the prednisone dosage has been tapered to 15 mg/day in 1. Only 2 patients have demonstrated clinical evidence of recurrence of active lupus. One of these patients currently requires no immunosuppressive medication and has a normal performance status. The other patient is currently receiving IV CYC., Conclusion: In patients experiencing the persistence of organ-threatening lupus following standard, aggressive therapy, HSCT may be performed safely, with marked improvement and sustained withdrawal of all immunosuppressive medication for most patients. A phase III randomized trial is warranted to determine the relative efficacy and durability of remission of HSCT compared with standard therapies.

Background: Patients with systemic lupus erythematosus (SLE) who experience persistent multiorgan dysfunction, despite standard doses of intravenous cyclophosphamide, represent a subset of patients at high risk of early death. We investigated the safety and efficacy of immune suppression and autologous haemopoietic stem-cell infusion to treat such patients., Methods: From 1996, we selected patients with persistent SLE despite use of cyclophosphamide. Patients underwent dose-intense immune suppression and autologous haemopoietic stem-cell (CD34) infusion. Peripheral blood lymphocytes were analysed by flow cytometry, ELISA, and T-cell-receptor spectratyping before and after transplantation. We mobilised autologous haemopoietic stem cells with 2.0 g/m2 cyclophosphamide and 10 microg/kg granulocyte colony stimulating factor daily, enriched with CD34-positive selection, and reinfused after immunosuppression with 200 mg/kg cyclophosphamide, 1 g methylprednisolone, and 90 mg/kg equine antithymocyte globulin., Results: Nine patients underwent stem-cell mobilisation but two were excluded before transplantation because of infection. The remaining seven received high-dose chemotherapy and stem-cell infusion. Median time to an absolute neutrophil count higher than 0.5x10(9)/L and nontransfused platelet count higher than 20x10(9)/L was 9 days (range 8-11) and 11 days (10-13), respectively. At a median follow-up of 25 months (12-40), all patients were free from signs of active lupus. Renal, cardiac, pulmonary, and serological markers, and T cell phenotype and repertoire had normalised., Interpretation: Patients remained free from active lupus and improved continuously after transplantation, with no immunosuppressive medication or small residual doses of prednisone. T-cell repertoire diversity and responsiveness was restored. Durability of remission remains to be established.

The treatment of severe autoimmune diseases has been recently revitalized by the introduction of intense immune suppression with immune ablative intent followed by three different procedures. These are allogeneic hematopoietic stem cell transplantation (HSCT), autologous HSCT (using either marrow or peripheral blood), and intense immune suppression without stem cell support. Current trials suggest that high dose immune suppressive therapy with or without autologous hematopoietic stem cell support can induce remission of previously refractory disease. Follow-up is too brief to determine if intense immune suppression, and more specifically autologous HSCT, will ultimately cure SLE. It is conceivable that an allogeneic source of stem cells from a normal donor (e.g. HLA matched sibling) will be required to achieve a cure. It is also possible that autologous HSCT, even if not curative, may prolong the life of patients with otherwise high-risk features. In carefully selected patients, the potential benefits of this procedure may outweigh the risks.

Objective: For patients with systemic lupus erythematosus (SLE) who are at risk of disease-related mortality, we have initiated a protocol of intensive immunosuppression and haematopoietic stem cell support. The first patient enrolled in this study was in the midst of a lupus flare manifest by nephritis and rapidly declining renal function, uncontrolled hypertension, immune-mediated cytopenias, and serositis characterized by a large pericardial effusion and abdominal pain. Antinuclear antibody (ANA), anti-double-stranded (ds) DNA and complement were abnormal. This patient is now more than 1 yr post-stem cell transplant and is taking no immunosuppressive medication. Her serologies are normal, effusions have resolved, blood pressure is normal and renal function is markedly improved. The clinical and serological course of this patient is summarized here., Methods: Autologous haematopoietic stem cells (HSC) were mobilized with cyclophosphamide (2.0 g/m2) and granulocyte colony-stimulating factor (G-CSF) (10 microg/kg/day). Stem cells were enriched ex vivo using CD34-positive immunoselection and reinfused after immunosuppression with cyclophosphamide (200 mg/kg) and antithymocyte globulin (ATG) (90 mg/kg)., Results: White blood cell engraftment with an absolute neutrophil count (ANC) of >500/microl (0.5 x 10(9)/l) and platelet engraftment with a non-transfused platelet count of >20000/microl (20 x 10(9)/l) occurred on day 10 and 14, respectively. Therapy was complicated by a cell lysis-like effect with hyperphosphataemia, hyperuricaemia, normal anion gap metabolic acidosis and transient exacerbation of renal insufficiency., Conclusion: This is the first autologous T-cell-depleted haematopoietic stem cell transplantation performed to treat lupus in an active flare. This patient has, for the first time since discase onset (13 yr ago), entered a complete clinical and serological remission which persists at >1 yr of follow-up. The durability of this remission is unknown.