Treatment decision-making in diffuse cutaneous systemic sclerosis: a patient's perspective.

OBJECTIVES: To examine the treatment decision-making process of patients with dcSSc in the context of haematopoietic stem cell transplantation (HSCT). METHODS: A qualitative semi-structured interview study was done in patients before or after HSCT, or patients who chose another treatment than HSCT. Thematic analysis was used. Shared decision-making (SDM) was assessed with the 9-item Shared Decision Making Questionnaire (SDM-Q-9). RESULTS: Twenty-five patients [16 male/nine female, median age 47 (range 27-68) years] were interviewed: five pre-HSCT, 16 post-HSCT and four following other treatment. Whereas the SDM-Q-9 showed the decision-making process was perceived as shared [median score 81/100 (range 49-100)], we learned from the interviews that the decision was predominantly made by the rheumatologist, and patients were often steered towards a treatment option. Strong guidance of the rheumatologist was appreciated because of a lack of accessible, reliable and SSc-specific information, due to the approach of the decision-making process of the rheumatologist, the large consequence of the decision and the trust in their doctor. Expectations of outcomes and risks also differed between patients. Furthermore, more than half of patients felt they had no choice but to go for HSCT, due to rapid deterioration of health and the perception of HSCT as 'the holy grail'. CONCLUSION: This is the first study that provides insight into the decision-making process in dcSSc. This process is negatively impacted by a lack of disease-specific education about treatment options. Additionally, we recommend exploring patients' preferences and understanding of the illness to optimally guide decision-making and to provide tailor-made information.

Exhaustion of the bone marrow progenitor cell reserve is associated with major events in severe limb ischemia.

Lower numbers of progenitor cells (PCs) in peripheral blood (PB) have been associated with cardiovascular events in high-risk populations. Therapies aiming to increase the numbers of PCs in circulation have been developed, but clinical trials did not result in better outcomes. It is currently unknown what causes the reduction in PB PC numbers: whether it is primary depletion of the progenitor cell reserve, or a reduced mobilization of PCs from the bone marrow (BM). In this study, we examine if PB and BM PC numbers predict Amputation-Free Survival (AFS) in patients with Severe Limb Ischemia (SLI). We obtained PB and BM from 160 patients enrolled in a clinical trial investigating BM cell therapy for SLI. Samples were incubated with antibodies against CD34, KDR, CD133, CD184, CD14, CD105, CD140b, and CD31; PC populations were enumerated by flow cytometry. Higher PB CD34+ and CD133+ PC numbers were related to AFS (Both Hazard Ratio [HRevent] = 0.56, p = 0.003 and p = 0.0007, respectively). AFS was not associated with the other cell populations in PB. BM PC numbers correlated with PB PC numbers and showed similar HRs for AFS. A further subdivision based on relative BM and PB PC numbers showed that BM PC numbers, rather than mobilization, associated with AFS. Both PB and BM PC numbers are associated with AFS independently from traditional risk factor and show very similar risk profiles. Our data suggest that depletion of the progenitor cell reserve, rather than decreased PC mobilization, underlies the association between PB PC numbers and cardiovascular risk.

Paracrine Proangiogenic Function of Human Bone Marrow-Derived Mesenchymal Stem Cells Is Not Affected by Chronic Kidney Disease.

BACKGROUND: Cell-based therapies are being developed to meet the need for curative therapy in chronic kidney disease (CKD). Bone marrow- (BM-) derived mesenchymal stromal cells (MSCs) enhance tissue repair and induce neoangiogenesis through paracrine action of secreted proteins and extracellular vesicles (EVs). Administration of allogeneic BM MSCs is less desirable in a patient population likely to require a kidney transplant, but potency of autologous MSCs should be confirmed, given previous indications that CKD-induced dysfunction is present. While the immunomodulatory capacity of CKD BM MSCs has been established, it is unknown whether CKD affects wound healing and angiogenic potential of MSC-derived CM and EVs. METHODS: MSCs were cultured from BM obtained from kidney transplant recipients (N = 15) or kidney donors (N = 17). Passage 3 BM MSCs and BM MSC-conditioned medium (CM) were used for experiments. EVs were isolated from CM by differential ultracentrifugation. BM MSC differentiation capacity, proliferation, and senescence-associated ß-galactosidase activity was assessed. In vitro promigratory and proangiogenic capacity of BM MSC-derived CM and EVs was assessed using an in vitro scratch wound assay and Matrigel angiogenesis assay. RESULTS: Healthy and CKD BM MSCs exhibited similar differentiation capacity, proliferation, and senescence-associated ß-galactosidase activity. Scratch wound migration was not significantly different between healthy and CKD MSCs (P = 0.18). Healthy and CKD BM MSC-derived CM induced similar tubule formation (P = 0.21). There was also no difference in paracrine regenerative function of EVs (scratch wound: P = 0.6; tubulogenesis: P = 0.46). CONCLUSIONS: Our results indicate that MSCs have an intrinsic capacity to produce proangiogenic paracrine factors, including EVs, which is not affected by donor health status regarding CKD. This suggests that autologous MSC-based therapy is a viable option in CKD.

A randomised placebo-controlled double-blind trial to assess the safety of intramuscular administration of allogeneic mesenchymal stromal cells for digital ulcers in systemic sclerosis: the MANUS Trial protocol.

INTRODUCTION: Systemic sclerosis (SSc) is an autoimmune disease characterised by inflammation, fibrosis and vasculopathy. Digital ulcers (DUs) are a frequent manifestation of vasculopathy in patients with SSc. Despite recent advances in pharmacological treatments, DU still have major health and economic implications. As there is currently no proven therapeutic strategy to promote DU healing, new treatments are urgently needed. Mesenchymal stem or stromal cells (MSCs) may provide a novel therapy for DU in SSc, because of their immunomodulatory and vasculoregenerative properties. Allogeneic MSC therapy involves functionally competent MSCs from healthy donors and may be used as 'off-the-shelf' available treatment. This study will evaluate whether allogeneic MSC therapy is a safe and potentially efficacious treatment for DU of SSc. METHODS AND ANALYSIS: The MANUS (Mesenchymal stromal cells for Angiogenesis and Neovascularization in digital Ulcers of Systemic Sclerosis) Trial is a double-blind randomised placebo-controlled trial. 20 patients with SSc with refractory DU will be randomised to receive eight intramuscular injections with either placebo or 50*106 MSCs. The primary outcome is the toxicity of the treatment at 12 weeks after administration. Secondary outcomes include (serious) adverse events, number and time to healing of DU, pain, reported hand function, quality of life and SSc disease activity. We will also evaluate changes in nailfold capillaroscopy pattern, as well as biochemical parameters and biomarkers in peripheral blood and skin biopsies. Follow-up visits will be scheduled at 48 hours and 2, 4, 8, 12, 24 and 52 weeks post-treatment. If the results confirm safety, feasibility and potential efficacy, a large multicentre randomised controlled trial with longer follow-up will be initiated focusing on efficacy. ETHICS AND DISSEMINATION: The study has been approved by the Dutch Central Committee on Research Concerning Human Subjects (protocol no: NL51705.000.15). The results will be disseminated through patient associations and conventional scientific channels. TRIAL REGISTRATION NUMBER: NCT03211793; Pre-results.

Hematopoietic stem-cell transplantation in systemic sclerosis: an update.

PURPOSE OF REVIEW: To provide an overview of recently published work on autologous hematopoietic stem-cell transplantation (HSCT) in patients with systemic sclerosis (SSc). RECENT FINDINGS: Superiority of HSCT vs. intravenous cyclophosphamide pulses was demonstrated in the randomized controlled American Scleroderma: Cyclophosphamide or Transplantation (SCOT) Trial (n = 75), supporting the results from earlier studies. In the SCOT Trial, total body irradiation was used instead of the nonmyeloablative regimens used in other trials, and considered well tolerated during a follow-up time of 4.5 years. Three small uncontrolled prospective cohorts (n = 4, 14 and 18) and one retrospective analyses (n = 18), using various nonmyeloablative regimens, also showed improvement in skin involvement and lung volumes post-HSCT. Transplant-related toxicity and mortality remain an essential issue in HSCT. High treatment-related mortality was reported in one prospective cohort (n = 18), using alemtuzumab as a conditioning agent. Furthermore, cardiac complications, either treatment or disease related, require special attention. In translational studies, trends are reported in number of regulatory T cells and diversity of T-cell receptor repertoire at baseline and post-HSCT correlating with treatment response. SUMMARY: There is increasing evidence that patients with rapidly progressive SSc may benefit from HSCT. However, optimal patient selection, pretransplantation workup and posttransplant management, still have to be established.

Resetting the T Cell Compartment in Autoimmune Diseases With Autologous Hematopoietic Stem Cell Transplantation: An Update.

Autologous hematopoietic stem cell transplantation (aHSCT) for autoimmune diseases has been applied for two decades as a treatment for refractory patients with progressive disease. The rationale behind aHSCT is that high-dose immunosuppression eliminates autoreactive T and B cells, thereby resetting the immune system. Post-aHSCT the cytotoxic CD8+ T cells normalize via clonal expansion due to homeostatic proliferation within a few months. CD4+ T cells recover primarily via thymopoiesis resulting in complete renewal of the T cell receptor (TCR) repertoire which requires years or never normalize completely. The increase in naïve T cells inducing immune tolerance, renewal of especially the regulatory TCR repertoire, and a less pro-inflammatory functional profile of the CD4+ T cells seem essential for successful immune reconstitution inducing long-term remission. There is currently a knowledge gap regarding the immune response in tissue sites post-aHSCT, as well as disease-specific factors that may determine remission or relapse. Future studies on lymphocyte dynamics and function may pave the way for optimized conditioning regimens with a more individualized approach.

Rationale and design of the SAIL trial for intramuscular injection of allogeneic mesenchymal stromal cells in no-option critical limb ischemia.

BACKGROUND: Critical limb ischemia (CLI) represents the most severe form of peripheral artery disease and has an immense impact on quality of life, morbidity, and mortality. A considerable proportion of CLI patients are ineligible for revascularization, leaving amputation as the only option. Mesenchymal stromal cells (MSCs), because of their vasculoregenerative and immunomodulatory characteristics, have emerged as a potential new treatment. METHODS: The primary objective of this trial is to investigate whether intramuscular administration of allogeneic bone marrow (BM)-derived MSCs is safe and potentially effective. The SAIL (allogeneic mesenchymal Stromal cells for Angiogenesis and neovascularization in no-option Ischemic Limbs) trial is a double-blind, placebo-controlled randomized clinical trial to investigate the effect of allogeneic BM-MSCs in patients with CLI who are not eligible for conventional revascularization. A total of 66 patients will be included and randomized (1:1) to undergo 30 intramuscular injections with either BM-MSCs (5 × 106 MSCs per injection) or placebo in the ischemic lower extremity. Primary outcome, that is, therapy success, a composite outcome consisting of mortality, limb status, clinical status, and changes in pain score, will be assessed at 6 months. All study-related procedures will take place in the University Medical Center Utrecht in The Netherlands. CONCLUSIONS: If our results indicate that intramuscular allogeneic BM-MSC therapy for CLI is safe and potentially effective, this will have important consequences for treatment of patients with CLI. A large multicenter clinical trial with longer follow-up focusing on hard end points should then be initiated to confirm these findings.

Autologous hematopoietic stem cell transplantation in systemic sclerosis: A reset to tolerance?

Autologous hematopoietic stem cell transplantation (ASCT) is an effective therapy for refractory autoimmune disease, in particular diffuse cutaneous systemic sclerosis (dcSSc). ASCT is the only treatment that can induce long term remission in dcSSc. However, the mechanism of action of ASCT has not yet been fully elucidated. The current hypothesis is that ASCT induces a long term 'reset' of the immune system, but there is no clear definition yet of such an immunological 'reset to tolerance', nor has it been established how to distinguish a 'reset' from long term immunosuppression. Here, we review the literature on immunological changes after ASCT in dcSSc patients to gain more insight whether changes in immunological parameters can help elucidate the mechanism of action of ASCT. We identified 12 studies. While some immunological parameters could be correlated to clinical response, heterogeneity in the studies, short follow-up time and the small sample sizes preclude firm conclusions. Importantly, most patients displayed a sustained clinical response despite the presence of auto-antibodies or higher-than-normal concentrations of cytokines and proteins associated with disease activity. This suggests that the mechanism of ASCT may not be solely immunological. Future research should focus on larger cohorts of patients and also take functional evaluation of immune cells into account in order to determine whether ASCT induces long term immunosuppression or resets the immune system to tolerance. Answering this question is key to further optimizing ASCT for dcSSc patients.

Cellular Therapies in Systemic Sclerosis: Recent Progress.

Systemic sclerosis (SSc) is a rare autoimmune connective tissue disease with a high mortality and morbidity. While progress has been made in terms of identifying high-risk patients and implementing new treatment strategies, therapeutic options remain limited. In the past few decades, various cellular therapies have emerged, which have been studied in SSc and other conditions. Here, we provide a comprehensive review of currently available cellular therapies and critically assess their merit as disease-modifying treatment for SSc. Currently, hematopoietic stem cell transplantation is the only cellular therapy that has demonstrated clinical effects on the immune system, neoangiogenesis, and fibrosis. Robust mechanistic studies as well as clinical trials are essential to move the field forward.