Evaluation of the systemic effect of bone formation marker released by endodontic calcium silicate-based sealers in local tissues, the bloodstream, and body organs.

Calcium silicate-based sealers are bioactive materials that release ions when in contact with body fluids. Therefore, this study aims mapping/trace bone formation markers released by MTA Fillapex, BioRoot RCS, and experimental tricalcium silicate-based sealer (CEO) into subcutaneous tissues, bloodstream and body organs. Toward, polyethylene tubes filled with sealers were implanted into connective tissue of Wistar rats. On days 7, 15, 30, and 45 after implantation, blood samples were collected to measure calcium (Ca2+), phosphorus (P), and alkaline phosphatase (ALP) levels. Thereafter, the animals were killed, and the brain, liver, kidneys, and subcutaneous tissue were removed and processed to determine the concentrations of Ca2+ and P by ICP-OES. Similar Ca2+ levels were observed in subcutaneous tissue for all groups, although, at 45 days, it was identified a reduction in Ca2+ serum levels of CEO compared to those two other sealers and an increase in Ca2+ levels in the liver compared to those released by MTA Fillapex. In contrast, no trace of P was detected in any tissue; moreover, plasma P and ALP serum levels of MTA Fillapex were higher at day 30. Our findings showed that Ca2+ were identified in local tissues, bloodstream, and organs from all sealers. The up-regulation of bone marker levels promoted by sealers can modify body homeostasis and induce tissue damage. Besides, MTA Fillapex was associated with a raise of bone marker levels, suggesting a possible systemic effect. The sealer composition can affect not only the local repair process but also the systemic health.

Autologous stem cell transplantation improves cardiopulmonary exercise testing outcomes in systemic sclerosis patients.

OBJECTIVES: Autologous haematopoietic stem cell transplantation (AHSCT) is a disease-modifying treatment for patients with severe SSc. Here, we aimed at assessing cardiopulmonary function outcomes of SSc patients after AHSCT. METHODS: Twenty-seven SSc adult patients treated with AHSCT were included in this retrospective study. Most had the diffuse cutaneous subset (93%) and pulmonary involvement (85%). Before and 12 months after AHSCT, patients underwent cardiopulmonary exercise testing, transthoracic echocardiography, pulmonary function test with diffusing capacity for carbon monoxide (DLCO), 6-min walk test (6MWT) and quality of life evaluations. RESULTS: After AHSCT, the peak VO2 increased from 954 to 1029 ml/min (P = 0.02), the percentage of predicted peak VO2 increased from 48.9 to 53.5 m (P = 0.01), and the distance measured by the 6MWT increased from 445 to 502 m (P = 0.01), compared with baseline. Improvements in peak VO2 correlated positively with improvements in 6MWT distance, and negatively with a decrease in resting heart rate. At baseline, patients with DLCO >70% had higher peak VO2 values than those with DLCO <70% (P = 0.04), but after AHSCT all patients showed improved VO2 values, regardless of baseline DLCO levels. Increases in VO2 levels after AHSCT positively correlated with increases in the physical component scores of the Short Form-36 quality of life questionnaire (r = 0.70; P = 0.0003). CONCLUSION: AHSCT improves the aerobic capacity of SSc patients probably reflecting combined increments in lungs, skeletal muscle and cardiac function.

Influence of weaning management at 30, 75 and 180 days of age on non-esterified fatty acids and reproductive performance in beef cows.

This study aimed to investigate the effect of age at weaning of calves on non-esterified fatty acids (NEFA) and reproductive parameters of beef cows. Animals (n = 65) were randomly assigned to three treatments after calving: hyper-early weaning (W30) at 32 ± 0.89 days, early weaning (W75) at 77 ± 0.95 days, and conventional weaning (W180) at 183 ± 0.82 days. Body weight (BW) and body condition score (BCS) were evaluated at parturition (AP) and at 30, 45, 64, 81, 100 and 115 days postpartum (dPP). Blood samples were collected to analyze NEFA levels and progesterone (P4) at 30, 45, 64 and 81 dPP. Higher BW and BCS were observed from 64 to 115 dPP in W30 cows than W180 ones (p < 0.05). Cows subjected to W30 condition had higher levels of NEFA at 30 dPP compared to 64 and 81 dPP (p < 0.05). We also observed that cows from W180 group showed decreased levels of NEFA at 30 dPP compared to 45 (p < 0.01) and 64 dPP (p < 0.05). The highest P4 level was observed at 64 dPP in W30 cows compared to W75 and W180 (p < 0.05). We also observed higher CR of W30 (86%) compared to W180 (47%) at 45 dPP (p < 0.05). The overall pregnancy rate (PR) was higher for W30 (95.5%) than W180 (73.9%). In addition, higher BW at calving and P4 levels at 30 dPP were positively correlated with the possibility of pregnancy (p < 0.05). Improvement in BW and BCS were observed in cows subjected to hyper-early weaning management. However, levels of NEFA decreased as the postpartum period progressed. We concluded that cows who weaned calves hyper-early have greater chances of increasing cyclicity and PRs.

Photobiomodulation effect in tumoral necrosis factor-alpha(TNF-α) on the viability of random skin flap in rats.

The aim of this study was to investigate the effect of red laser (660 nm) photobiomodulation (PBM) with different energies on tumor necrosis factor-alpha(TNF-α) expression for random skin flap viability in rats. Twenty-four Wistar rats were divided into three groups: sham group (SG), PBM laser group with an energy dose of 0.29 J (0.29G), and PBM laser group with an energy dose of 7.30 J (7.30G). A cranially based dorsal skin flap measuring 10 × 4 cm was raised and a plastic barrier was placed between the flap and its bed. PBM was applied in 3 timepoints: in the immediate postoperative period, in the 1st and in the 2nd postoperative days; the animals were euthanized on the 7th postoperative day. The assessments included: TNF-α expression of 3 different flap areas (proximal, medial and distal), by immunohistochemistry; percentage of skin flap necrosis area, by the paper template method. The statistical analysis was performed through the Kruskal-Wallis and Mann-Whitney tests, the level of significance adopted was 5% (p < 0.05). TNF-α expression was significantly lower for 7.30G in the proximal area, reduced for SG in the medial point, and larger for 7.30G in the distal area. The percentage of flap necrosis area was significantly reduced for 7.30G. Higher energy doses are more efficacious than lower energy doses for modulating TNF-α expression. PBM with an energy dose of 7.30 J was effective in reducing the expression of TNF-α and increase skin flap viability.

Dysbiosis and Gut Microbiota Modulation in Systemic Sclerosis.

ABSTRACT: Gastrointestinal (GI) involvement is an early manifestation in systemic sclerosis (SSc), affecting more than 90% of patients, and severe GI disease is a marker of poor prognosis and mortality. Recent studies have hypothesized that alterations of the intestinal microbiota, known as dysbiosis, may represent 1 of the possible environmental factors influencing SSc disease status. In addition, specific microorganisms may be associated with SSc pathogenesis, progression, and GI manifestations. Therapeutic approaches aiming to modulate the intestinal microbiota have emerged, as alternatives to treat GI symptoms, and dietary interventions, probiotic administration, and fecal microbiota transplantation are potential therapies for SSc patients. However, given the complexity and variability of pathogenesis and clinical manifestations in SSc, these therapies need to be combined with additional interventions that target other disease components. Here, we summarize studies addressing intestinal dysbiosis in SSc and discuss the potential of microbiota modulators to treat SSc-related GI disorders.

Diagnostic Agreement Among General Practitioners, Residents, and Senior Rheumatologists for Rheumatic Diseases.

OBJECTIVE: The aim of this study was to evaluate the concordance of the diagnoses made by senior rheumatologists and those made by residents in rheumatology and by general practitioners (GPs). METHODS: In this cohort, 497 patients referred by GPs from August 1, 2018 to December 16, 2019 were evaluated first by a second-year resident in rheumatology. After clinical rounds, the diagnoses by senior rheumatologists were assumed as the criterion standard and defined the prevalence of the rheumatic diseases, divided into 5 groups: rheumatoid arthritis, spondyloarthritis, other connective tissue diseases and vasculitis, nonautoimmune rheumatic diseases, and nonrheumatic diseases. The follow-up ended on November 30, 2020. We calculated sensibility, specificity, positive predictive value, negative predictive value, and κ coefficient of the diagnosis by GPs and residents. RESULTS: The diagnoses were changed for 58% of the referral letters. Diseases of low complexity, such as fibromyalgia and osteoarthritis, accounted for 50% of the diagnoses. Compared with senior rheumatologists, residents in rheumatology had κ > 0.6 for all the groups, whereas GPs had κ < 0.5, with the worst performance for nonautoimmune rheumatic disease (κ = -0.18) and nonrheumatic disease (κ = 0.15). In terms of level of complexity, 46% of the letters were inappropriate. CONCLUSIONS: We found a poor level of diagnostic agreement between GPs and the rheumatology team. General practitioners had difficulties diagnosing and treating rheumatic diseases, referring patients that should be treated in the primary level of health care. One year of training in rheumatology made residents' skills comparable to those of senior rheumatologists.

Autologous haematopoietic stem cell transplantation restores the suppressive capacity of regulatory B cells in systemic sclerosis patients.

OBJECTIVES: The rationale of autologous haematopoietic stem cell transplantation (AHSCT) for autoimmune diseases is that high-dose immunosuppression eradicates autoreactive T and B cells and the infused autologous haematopoietic stem cells promote reconstitution of a naïve and self-tolerant immune system. The aim of this study was to evaluate the reconstitution of different B cell subsets, both quantitatively and functionally, in SSc patients treated with AHSCT. METHODS: Peripheral blood was harvested from 22 SSc patients before transplantation and at 30, 60, 120, 180 and 360 days post-AHSCT. Immunophenotyping of B cell subsets, B cell cytokine production, signalling pathways and suppressive capacity of regulatory B cells (Bregs) were assessed by flow cytometry. RESULTS: Naïve B cell frequencies increased from 60 to 360 days post-AHSCT compared with pre-transplantation. Conversely, memory B cell frequencies decreased during the same period. Plasma cell frequencies transiently decreased at 60 days post-AHSCT. IL-10-producing Bregs CD19+CD24hiCD38hi and CD19+CD24hiCD27+ frequencies increased at 180 days. Moreover, the phosphorylation of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase increased in B cells reconstituted post-AHSCT. Notably, CD19+CD24hiCD38hi Bregs recovered their ability to suppress production of Th1 cytokines by CD4+ T cells at 360 days post-AHSCT. Finally, IL-6 and TGF-ß1-producing B cells decreased following AHSCT. CONCLUSION: Taken together, these results suggest improvements in immunoregulatory and anti-fibrotic mechanisms after AHSCT for SSc, which may contribute to re-establishment of self-tolerance and clinical remission.

Autologous stem cell transplantation for progressive systemic sclerosis: a prospective non-interventional study from the European Society for Blood and Marrow Transplantation Autoimmune Disease Working Party.

Three randomized controlled trials in early severe systemic sclerosis demonstrated that autologous hematopoietic stem cell transplantation was superior to standard cyclophosphamide therapy. This European Society for Blood and Marrow Transplantation multi-center prospective non-interventional study was designed to further decipher efficacy and safety of this procedure for severe systemic sclerosis patients in real-life practice and to search for prognostic factors. All consecutive adult systemic sclerosis patients undergoing a first autologous hematopoietic stem cell transplantation between December 2012 and February 2016 were prospectively included in the study. Primary endpoint was progression free survival. Secondary endpoints were overall survival, non-relapse mortality, response and incidence of progression. Eighty systemic sclerosis patients were included. Median follow-up duration was 24 (6-57) months after stem cell transplantation using cyclophosphamide plus antithymocyte globulins conditioning for all, with CD34+ selection in 35 patients. At 2 years, progression free survival was 81.8%, overall survival was 90%, response was 88.7% and incidence of progression was 11.9%. The 100 days non-relapse mortality was 6.25% (n=5) with four deaths from cardiac event, including three due to cyclophosphamide toxicity. Modified Rodnan skin score and forced vital capacity improved with time (p< 0.001). By multivariate analysis, baseline skin score >24 and older age at transplant were associated with lower progression free survival (Hazard ration 3.32) and 1.77, respectively). CD34+-selection was associated with better response (Hazard ration: 0.46). This study confirms the efficacy of autologous stem cell transplantation in real-life practice for severe systemic sclerosis using non myeloablative conditioning. Careful cardio-pulmonary assessment to identify organ involvement at patient referral, reduced cyclophosphamide doses and CD34+ selection may improve outcomes. The study was registered at ClinicalTrials.gov: NCT02516124.

Automatic Quantitative Computed Tomography Evaluation of the Lungs in Patients With Systemic Sclerosis Treated With Autologous Stem Cell Transplantation.

BACKGROUND/OBJECTIVE: Interstitial lung disease stands among the leading causes of death in systemic sclerosis (SSc) patients. Autologous hematopoietic stem cell transplantation (AHSCT) has been proven superior to conventional immunosuppressive therapy in severe and progressive SSc. Here, pulmonary quantitative measurements were obtained in high-resolution computed tomography (HRCT) scans of patients with SSc before and after AHSCT. METHODS: The medical records of thirthy-three patients who underwent AHSCT between 2011 and 2017 were evaluated for clinical and tomographic features at baseline (pre-AHCST) and 18 months after the procedure. Quantitative analysis of HRCT images by a fully automated program calculated lung volumes, densities, attenuation percentiles, and vascular volume. Patients were divided into 2 groups, according to changes in forced vital capacity (FVC). The "best response" group included patients that had an increased FVC of 10% or greater, and the "stable response" group included those who had a decreased or an increased FVC of less than 10%. RESULTS: In the best response group (15 patients), there was reduction (p < 0.05) of mean lung density and density percentile values after AHSCT. In the stable response group (18 patients), there were no significant changes in lung volumes and pulmonary densities after AHSCT. Pulmonary HRCT densities showed moderate/strong correlation with function. CONCLUSIONS: Quantitative HRCT analysis identified significant reduction in pulmonary densities in patients with improved pulmonary function after AHSCT. Lung density, as evaluated by the quantitative HRCT analysis tool, has potential to become a biomarker in the evaluation of interstitial lung disease treatment in patients with SSc.

Hematopoietic Stem Cell Transplantation Improves Functional Outcomes of Systemic Sclerosis Patients.

BACKGROUND/OBJECTIVE: We sought to evaluate if autologous hematopoietic stem cell transplantation (AHSCT) influences the functional status of systemic sclerosis (SSc) patients. METHODS: From 2014 to 2018, a cohort of 27 SSc patients was assessed before, and at 6 and 12 months after AHSCT for modified Rodnan's skin score (mRSS), mouth opening, hand grip strength, range of motion (ROM), functional ability of upper limbs (DASH questionnaire and Cochin hand function scale-CHFS), 6-minute walk test (6MWT), and quality of life (SF-36 questionnaire). Linear regression models with random effects and Spearman's test were used for statistical analysis. RESULTS: At 6 and 12 months after AHSCT, respectively, we observed significant improvement of mRSS (p < 0.01 and p < 0.01), mouth opening (p = 0.02 and p < 0.01), hand function (DASH, p < 0.01 and p < 0.01; CHFS, p < 0.01 and p < 0.01; strength, p < 0.01 and p < 0.01), physical capacity (6MWT, p = 0.02 and p = 0.03) and physical (p < 0.01 and p < 0.01) and mental (ns and p = 0.02) component scores of SF-36. At 12 months after AHSCT, ROM measurements improved (p < 0.05) in five out of six evaluated joints in both hands, compared to baseline. Correlation was significant between physical capacity and quality of life (R = 0.62; p < 0.01), between DASH and quality of life (R = -0.48; p = 0.03), and between skin involvement and wrist ROM measures (dominant hand, R = -0.65, p < 0.01; non-dominant hand, R = -0.59; p < 0.01). CONCLUSIONS: AHSCT enhances the functional status of SSc patients in the first year of follow-up, significantly improving hand function, physical capacity and quality of life. These results are interpreted as positive outcomes of AHSCT for SSc.

Autologous Hematopoietic Stem Cell Therapy of the Subjects with Systemic Sclerosis: Electromyographic Results of the Masticatory Muscles.

Musculoskeletal system impairment is a major cause of functional alterations in subjects with systemic sclerosis. Autologous hematopoietic stem cell therapy (AHSCT) may have an important role in the treatment functional of systemic sclerosis patients. The aim of this pilot study was to assess whether AHSCT interferes with the electromyographic activity of the masseter and temporalis muscles of subjects with systemic sclerosis. Before transplantation, seven subjects with systemic sclerosis (mean age [± SD], 40.1 ± 9.6 years) underwent electromyographic analysis of the masseter and temporalis muscles in mandibular tasks at rest, right and left laterality, protrusion and maximum voluntary contraction. Two months after AHSCT, the subjects re-evaluated using the same methods. Data were analyzed using the repeated-measure test, with p<0.05 considered to be statistically significant. Two months after AHSCT, there was reduction in normalized electromyographic activity in the dental clenching in maximal voluntary contraction, with significant differences, for the left temporal muscle (p=0.04). AHSCT in subjects with systemic sclerosis promotes alterations in stomatognathic system function, especially those related to electromyographic activity of masticatory muscles.

Effect of Nonmyeloablative Hematopoietic Stem Cell Transplantation vs Continued Disease-Modifying Therapy on Disease Progression in Patients With Relapsing-Remitting Multiple Sclerosis: A Randomized Clinical Trial.

Importance: Hematopoietic stem cell transplantation (HSCT) represents a potentially useful approach to slow or prevent progressive disability in relapsing-remitting multiple sclerosis (MS). Objective: To compare the effect of nonmyeloablative HSCT vs disease-modifying therapy (DMT) on disease progression. Design, Setting, and Participants: Between September 20, 2005, and July 7, 2016, a total of 110 patients with relapsing-remitting MS, at least 2 relapses while receiving DMT in the prior year, and an Expanded Disability Status Scale (EDSS; score range, 0-10 [10 = worst neurologic disability]) score of 2.0 to 6.0 were randomized at 4 US, European, and South American centers. Final follow-up occurred in January 2018 and database lock in February 2018. Interventions: Patients were randomized to receive HSCT along with cyclophosphamide (200 mg/kg) and antithymocyte globulin (6 mg/kg) (n = 55) or DMT of higher efficacy or a different class than DMT taken during the previous year (n = 55). Main Outcomes and Measures: The primary end point was disease progression, defined as an EDSS score increase after at least 1 year of 1.0 point or more (minimal clinically important difference, 0.5) on 2 evaluations 6 months apart, with differences in time to progression estimated as hazard ratios. Results: Among 110 randomized patients (73 [66%] women; mean age, 36 [SD, 8.6] years), 103 remained in the trial, with 98 evaluated at 1 year and 23 evaluated yearly for 5 years (median follow-up, 2 years; mean, 2.8 years). Disease progression occurred in 3 patients in the HSCT group and 34 patients in the DMT group. Median time to progression could not be calculated in the HSCT group because of too few events; it was 24 months (interquartile range, 18-48 months) in the DMT group (hazard ratio, 0.07; 95% CI, 0.02-0.24; P < .001). During the first year, mean EDSS scores decreased (improved) from 3.38 to 2.36 in the HSCT group and increased (worsened) from 3.31 to 3.98 in the DMT group (between-group mean difference, -1.7; 95% CI, -2.03 to -1.29; P < .001). There were no deaths and no patients who received HSCT developed nonhematopoietic grade 4 toxicities (such as myocardial infarction, sepsis, or other disabling or potential life-threatening events). Conclusions and Relevance: In this preliminary study of patients with relapsing-remitting MS, nonmyeloablative HSCT, compared with DMT, resulted in prolonged time to disease progression. Further research is needed to replicate these findings and to assess long-term outcomes and safety. Trial Registration: ClinicalTrials.gov Identifier: NCT00273364.

Photobiomodulation and bacterial cellulose membrane in the treatment of third-degree burns in rats.

Burns are injuries caused mainly by thermal trauma, which can progress to unsatisfactory results healing. This study aimed to evaluate the biomaterial (bacterial cellulose membrane) and photobiomodulation, exclusively and associated, in the treatment of third degree burns in rats. Forty male Wistar rats (±280 g) were randomly divided into four groups, with 10 animals each: control group (CG); bacterial cellulose membrane group (MG); laser group (LG) and bacterial cellulose membrane and laser group (MG + L). The burn was caused with a 1 cm2 aluminum plate heated to 150 °C and pressed on the animal's back for 10 s. The treatments were started immediately after induction of injury. For to laser irradiation (660 nm, 100 mW, 25 J/cm2 and energy of 1 J) on five distinct application points were used, on alternate days, a total of five sessions. After ten days of treatment the animals were euthanized for collected samples. One-way ANOVA and Tukey's tests (P < 0.05) were used. Histological analysis revealed differences regarding the healing process phase in each experimental group. MG showed the proliferative phase. The LG demonstrated greater amount of blood vessels and immune expression of VEGF. However, when the treatments were combined, the number of vessels and the immune expression of VEGF factor was lower than LG. Thus, it was concluded that both treatments proposed (biomaterial and LLLT) are good alternatives for third degree burns when applied isolated because they stimulate the healing process by acting on the modulation of the inflammatory phase and promote stimulation of angiogenesis.

Immunological correlates of favorable long-term clinical outcome in multiple sclerosis patients after autologous hematopoietic stem cell transplantation.

High dose immunosuppression followed by autologous hematopoietic stem cell transplantation (AHSCT) induces prolonged clinical remission in multiple sclerosis (MS) patients. However, how patient immune profiles are associated with clinical outcomes has not yet been completely elucidated. In this study, 37 MS patients were assessed for neurological outcomes, thymic function and long-term immune reconstitution after AHSCT. Patients were followed for a mean (SD) of 68.5 (13.9) months post-transplantation and were retrospectively clustered into progression- and non-progression groups, based on Expanded Disease Status Scale (EDSS) outcomes at last visit. After AHSCT, both patient groups presented increased regulatory T-cell subset counts, early expansion of central- and effector-memory CD8(+)T-cells and late thymic reactivation. However, the non-progression group presented early expansion of PD-1(+)CD8(+)T-cells and of PD-1-expressing CD19(+) B-cells. Here, we suggest that along with increased numbers of regulatory T-cell subsets, PD-1 inhibitory signaling is one possible immunoregulatory mechanism by which AHSCT restores immune tolerance in MS patients.

Autologous hematopoietic stem cell transplantation in neuromyelitis optica: a registry study of the EBMT Autoimmune Diseases Working Party.

BACKGROUND: Neuromyelitis optica (NMO) is an inflammatory autoimmune disorder of the central nervous system, hallmarked by pathogenic anti-aquaporin 4 antibodies. NMO prognosis is worse compared with multiple sclerosis. OBJECTIVE: The European Group for Blood and Marrow Transplantation (EBMT) Autoimmune Diseases Working Party (ADWP) conducted a retrospective survey to analyze disease outcome following autologous stem cell transplantation (ASCT). METHODS: This retrospective multicenter study assessed the efficacy and safety of ASCT in 16 patients suffering from refractory NMO reported to the EBMT registry between 2001 and 2011. RESULTS: Fifteen patients were successfully mobilized with cyclophosphamide (Cy) and G-CSF, one with G-CSF alone. All patients received an unmanipulated autologous peripheral blood stem cell graft, after conditioning with BEAM plus anti-thymocyte globulin (ATG, n = 9 patients), thiotepa-Cy (n = 3) or Cy (200 mg/kg) plus ATG (n = 4). After a median follow-up of 47 months, three of 16 cases were progression and treatment free, while in the remaining 13 patients further treatments were administered for disability progression or relapse after ASCT. Altogether, relapse-free survival at three and five years was 31% and 10%, respectively, while progression-free survival remained 48% at three and five years. CONCLUSIONS: In these NMO patients, highly resistant to conventional treatment, ASCT allows for temporary control of the disease, despite a tendency to progress or relapse in the long term.

Association of nonmyeloablative hematopoietic stem cell transplantation with neurological disability in patients with relapsing-remitting multiple sclerosis.

IMPORTANCE: No current therapy for relapsing-remitting multiple sclerosis (MS) results in significant reversal of disability. OBJECTIVE: To determine the association of nonmyeloablative hematopoietic stem cell transplantation with neurological disability and other clinical outcomes in patients with MS. DESIGN, SETTING, AND PARTICIPANTS: Case series of patients with relapsing-remitting MS (n = 123) or secondary-progressive MS (n = 28) (mean age, 36 years; range, 18-60 years; 85 women) treated at a single US institution between 2003 and 2014 and followed up for 5 years. Final follow-up was completed in June 2014. INTERVENTIONS: Treatment with cyclophosphamide and alemtuzumab (22 patients) or cyclophosphamide and thymoglobulin (129 patients) followed by infusion of unmanipulated peripheral blood stem cells. MAIN OUTCOMES AND MEASURES: Primary end point was reversal or progression of disability measured by change in the Expanded Disability Status Scale (EDSS) score of 1.0 or greater (score range, 0-10). Secondary outcomes included changes in the Neurologic Rating Scale (NRS) score of 10 or greater (score range, 0-100), Multiple Sclerosis Functional Composite (MSFC) score, quality-of-life Short Form 36 questionnaire scores, and T2 lesion volume on brain magnetic resonance imaging scan. RESULTS: Outcome analysis was available for 145 patients with a median follow-up of 2 years and a mean of 2.5 years. Scores from the EDSS improved significantly from a pretransplant median of 4.0 to 3.0 (interquartile range [IQR], 1.5 to 4.0; n = 82) at 2 years and to 2.5 (IQR, 1.9 to 4.5; n = 36) at 4 years (P < .001 at each assessment). There was significant improvement in disability (decrease in EDSS score of ≥1.0) in 41 patients (50%; 95% CI, 39% to 61%) at 2 years and in 23 patients (64%; 95% CI, 46% to 79%) at 4 years. Four-year relapse-free survival was 80% and progression-free survival was 87%. The NRS scores improved significantly from a pretransplant median of 74 to 88.0 (IQR, 77.3 to 93.0; n = 78) at 2 years and to 87.5 (IQR, 75.0 to 93.8; n = 34) at 4 years (P < .001 at each assessment). The median MSFC scores were 0.38 (IQR, -0.01 to 0.64) at 2 years (P < .001) and 0.45 (0.04 to 0.60) at 4 years (P = .02). Total quality-of-life scores improved from a mean of 46 (95% CI, 43 to 49) pretransplant to 64 (95% CI, 61 to 68) at a median follow-up of 2 years posttransplant (n = 132) (P < .001). There was a decrease in T2 lesion volume from a pretransplant median of 8.57 cm3 (IQR, 2.78 to 22.08 cm3) to 5.74 cm3 (IQR, 1.88 to 14.45 cm3) (P < .001) at the last posttransplant assessment (mean follow-up, 27 months; n = 128). CONCLUSIONS AND RELEVANCE: Among patients with relapsing-remitting MS, nonmyeloablative hematopoietic stem cell transplantation was associated with improvement in neurological disability and other clinical outcomes. These preliminary findings from this uncontrolled study require confirmation in randomized trials.

Cardiac involvement and treatment-related mortality after non-myeloablative haemopoietic stem-cell transplantation with unselected autologous peripheral blood for patients with systemic sclerosis: a retrospective analysis.

BACKGROUND: Autologous haemopoietic stem-cell transplantation (HSCT) benefits patients with systemic sclerosis but has been associated with significant treatment-related mortality and failure to improve diffusion capacity of carbon monoxide (DLCO). We aimed to assess efficacy of HSCT and use of rigorous cardiac screening in this group. METHODS: We assessed patients with diffuse systemic sclerosis or limited systemic sclerosis and interstitial lung disease who were treated with HSCT as part of a study or on a compassionate basis at Northwestern University (Chicago, IL, USA) or the University of São Paulo (Ribeirão Preto, Brazil). Unselected peripheral blood stem cells were harvested with cyclophosphamide (2 g/m(2)) and filgrastim. The transplant regimen was a non-myeloablative regimen of cyclophosphamide (200 mg/kg) and rabbit anti-thymocyte globulin (rATG; 4·5-6·5 mg/kg). We followed patients up to 5 years for overall survival, relapse-free survival, modified Rodnan skin score, and pulmonary function tests. FINDINGS: Five (6%) of 90 patients died from treatment-related causes. Despite standard guidelines that recommend echocardiogram for screening before transplantation, four treatment-related deaths occurred because of cardiovascular complications (one constrictive pericarditis, two right heart failures without underlying infection, and one heart failure during mobilisation), and one death was secondary to sepsis without documented underlying heart disease. Kaplan-Meier analysis showed survival was 78% at 5 years (after eight relapse-related deaths) and relapse-free survival was 70% at 5 years. Compared with baseline, we noted improvements after HSCT in modified Rodnan skin scores at 1 year (58 patients; p<0·0001), 2 years (42 patients; p<0·0001), and 3 years (27 patients; p<0·0001) and forced vital capacity at 1 year (58 patients; p=0·009), 2 years (40 patients; p=0·02), and 3 years (28 patients; p=0·004), but total lung capacity and DLCO were not improved significantly after HSCT. Overall mean DLCO was significantly improved in patients with normal baseline echocardiograms (p=0·005) or electrocardiographs (p=0·05). INTERPRETATION: Autologous HSCT with a non-myeloablative regimen of cyclophosphamide and rATG with a non-selected autograft results in sustained improvement in skin thickness and forced vital capacity. DLCO is affected by baseline cardiac function. Guidelines for cardiac screening of patients with systemic sclerosis to assess treatment-related risk from pulmonary artery hypertension, primary cardiac involvement, or pericardial disease should be reconsidered and updated. FUNDING: None.