Autologous non-myeloablative hematopoietic stem cell transplantation in patients with systemic sclerosis

Autologous hematopoietic stem cell transplantation (HSCT) utilizing a myeloablative regimen containing total body irradiation has been performed in patients with systemic sclerosis (SSc), but with substantial toxicity. We, therefore, conducted a phase I non-myeloablative autologous HSCT study in 10 patients with SSc and poor prognostic features. PBSC were mobilized with CY and G-CSF. The PBSC graft was cryopreserved without manipulation and re-infused after the patient was treated with a non-myeloablative conditioning regimen of 200 mg/kg CY and 7.5 mg/kg rabbit antithymocyte globulin. There was a statistically significant improvement of modified Rodnan skin score whereas cardiac (ejection fraction, pulmonary arterial pressure), pulmonary function (DLCO) and renal function (creatinine) remained stable without significant change. One patient with advanced disease died 2 years after the transplant from progressive disease. After median follow-up of 25.5 months, the overall and progression-free survival rates are 90 and 70% respectively. Autologous HSCT utilizing a non-myeloablative conditioning regimen appears to result in improved skin flexibility similar to a myeloablative TBI containing regimen, but without the toxicity and risks associated with TBI.     

Update on Stem Cell Transplantation for Systemic Sclerosis: Recent Trial Results

Systemic sclerosis (SSc) is a heterogeneous condition characterized by the deposition of excess collagen in skin and internal organs due to vasculopathy, immune activation, low grade inflammation, and fibrosis. Progressive diffuse cutaneous SSc with organ involvement has a poor prognosis. The employment of autologous hematopoietic stem cell transplantation (HSCT) as a means to escalate immunosuppressive therapy has resulted in rapid and sustained improvement of skin thickening and functional ability, stabilization of major organ function with some improvement of vital capacity in pilot studies, registry analyses, and the phase II ASSIST trial. Results from the phase III ASTIS trial corroborate these findings and show long-term survival benefit of HSCT. The ASTIS and SCOT trials will determine whether the benefits of HSCT outweigh the risks of serious adverse events including treatment-related mortality of around 6–10 % and potential long-term complications. Better patient selection and safer transplant regimens may improve the outcome of HSCT for SSc.     

Phase I/II trial of autologous stem cell transplantation in systemic sclerosis: procedure related mortality and impact on skin disease

BACKGROUND: Systemic sclerosis (SSc, scleroderma) in either its diffuse or limited skin forms has a high mortality when vital organs are affected. No treatment has been shown to influence the outcome or significantly affect the skin score, though many forms of immunosuppression have been tried. Recent developments in haemopoietic stem cell transplantation (HSCT) have allowed the application of profound immunosuppression followed by HSCT, or rescue, to autoimmune diseases such as SSc. METHODS: Results for 41 patients included in continuing multicentre open phase I/II studies using HSCT in the treatment of poor prognosis SSc are reported. Thirty seven patients had a predominantly diffuse skin form of the disease and four the limited form, with some clinical overlap. Median age was 41 years with a 5:1 female to male ratio. The skin score was >50% of maximum in 20/33 (61%) patients, with some lung disease attributable to SSc in 28/37 (76%), the forced vital capacity being <70% of the predicted value in 18/36 (50%). Pulmonary hypertension was described in 7/37 (19%) patients and renal disease in 5/37 (14%). The Scl-70 antibody was positive in 18/32 (56%) and the anticentromere antibody in 10% of evaluable patients. Peripheral blood stem cell mobilisation was performed with cyclophosphamide or granulocyte colony stimulating factor, alone or in combination. Thirty eight patients had ex vivo CD34 stem cell selection, with additional T cell depletion in seven. Seven conditioning regimens were used, but six of these used haemoimmunoablative doses of cyclophosphamide +/- anti-thymocyte globulin +/- total body irradiation. The median duration of follow up was 12 months (3-55). RESULTS: An improvement in skin score of >25% after transplantation occurred in 20/29 (69%) evaluable patients, and deterioration in 2/29 (7%). Lung function did not change significantly after transplantation. One of five renal cases deteriorated but with no new occurrences of renal disease after HSCT, and the pulmonary hypertension did not progress in the evaluable cases. Disease progression was seen in 7/37 (19%) patients after HSCT with a median period of 67 (range 49-255) days. Eleven (27%) patients had died at census and seven (17%) deaths were considered to be related to the procedure (direct organ toxicity in four, haemorrhage in two, and infection/neutropenic fever in one). The cumulative probability of survival at one year was 73% (95% CI 58 to 88) by Kaplan-Meier analysis. CONCLUSION: Despite a higher procedure related mortality rate from HSCT in SSc compared with patients with breast cancer and non-Hodgkin's lymphoma, the marked impact on skin score, a surrogate marker of mortality, the trend towards stabilisation of lung involvement, and lack of other treatment alternatives justify further carefully designed studies. If future trials incorporate inclusion and exclusion criteria based on this preliminary experience, the predicted procedure related mortality should be around 10%.     

Stem cell therapies for systemic sclerosis

The presence of autoimmune diseases, including Systemic Sclerosis (SSc), suggest failure of the normal immune regulatory processes leading to activation and expansion of autoreactive effector immune cells. Recently, stem cell transplantation emerged as a novel rescue therapy for a variety of refractory autoimmune diseases. The therapeutic strategy involves the ablation of the aberrant self‐reactive immune cells by chemotherapy and the regeneration of a new self‐tolerant immune system formed by the transplanted stem cells. In the last few years, thousands of patients worldwide have received haematopoietic stem cell transplantation (HSCT), mostly autologous, as treatment for severe irreversible autoimmune diseases, with promising results. Here we review the results of published small series of SSc patients treated with allogeneic and autologous HSCT, as well as three randomized trials, exploring the safety and efficacy of autologous HSCT in SSc. Although the results are encouraging, nonetheless, the correct application of stem cell transplantation remains an area of active investigation. Results of larger randomized, double blind clinical trials, will certainly improve our knowledge of the appropriate clinical use of stem cell therapy in SSc patients.     

Long-term follow-up after nonmyeloablative allogeneic hematopoietic stem cell transplantation for systemic sclerosis

Systemic sclerosis (SSc) characteristically consists of fibrotic changes in various organs, and immunological abnormality is the main cause of the disease. Although high-dose immunosuppressive therapies with autologous or allogeneic hematopoietic stem cell support can reverse the disease course, they have a high treatment-related mortality. We report the successful use of nonmyeloablative allogeneic hematopoietic stem cell transplantation (HSCT) for SSc. A 40-year-old woman with diffuse scleroderma and interstitial pneumonia underwent allogeneic peripheral blood stem cell transplantation from an HLA-identical sibling after conditioning with low-dose total-body irradiation and fludarabine. Prophylaxis for graft-versus-host disease (GVHD) consisted of cyclosporine and mycophenolate mofetil. No infection or acute GVHD developed. One year after transplantation, the patient developed membranous glomerulopathy caused by chronic GVHD that was successfully treated with prednisolone. The patient's skin score decreased dramatically, and her pulmonary function is stable 4 years after transplantation. Nonmyeloablative allogeneic HSCT may be more effective than conventional therapies for SSc.     

Haemopoietic stem cell transplantation--an evolving treatment for severe autoimmune and inflammatory diseases in rheumatology, neurology and gastroenterology

The concept of haemopoietic stem cell transplantation (HSCT) to treat severe autoimmune diseases has been around for several decades. Advances in the safety of HSCT have made it a clinical reality since 1995. Databases have registered around a thousand patients treated specifically for a wide range of diseases, predominantly multiple sclerosis (MS), systemic sclerosis (SSc), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Phase I/II prospective and retrospective studies have supported the potential of autologous HSCT as a treatment option in severely affected patients, with profound and prolonged clinical responses in some diseases, although procedures are generally not curative. Allogeneic HSCT appears to offer curative potential, but the potential of high toxicity has limited its use in this context. The exact role of HSCT remains to be defined, particularly in the context of other advances in the treatment of autoimmune disease. Along with other groups, the European Group for Blood and Marrow Transplantation (EBMT) are overseeing several phase III trials in autologous transplantation. Given the risks of the HSCT, eligibility is restricted to patients who have severe, treatment resistant disease, in whom the prognosis is otherwise poor. This review aims to summarise the current published data in this evolving treatment for relatively rare patients with resistant or rapidly progressive disease where treatment options are otherwise limited. This cross-fertilization of knowledge between many specialties may provide increasing therapeutic opportunities in otherwise untreatable diseases. Moreover, destroying and rebuilding immune systems may provide insights into autoimmune diseases.     

Autologous haematopoietic stem cell transplantation for Japanese patients with systemic sclerosis: Long-term follow-up on a phase II trial and treatment-related fatal cardiomyopathy

Objectives: The objective of this study is to elucidate the efficacy and safety of autologous haematopoietic stem cell transplantation (HSCT) for Japanese patients with systemic sclerosis (SSc).

Methods: A phase II clinical trial included SSc patients diagnosed within the last three years having at least one of the following clinical features: diffuse skin sclerosis with modified Rodman total thickness skin score (mRSS)?≥?15, refractory digital ulcer or interstitial lung disease (ILD). HSCT were performed after conditioning using cyclophosphamide.

Results: Fourteen patients were enrolled and underwent HSCT. Median follow-up period was 137 months. Overall survival or event-free survival rate was 93% or 40% at 10 years, respectively. Eight patients (57%) achieved more than a 50% decrease in mRSS from baseline within six months after HSCT. Six patients (43%) required additional immunosuppressive treatments due to progression of diffuse skin sclerosis and/or ILD during follow-up period. Adverse events related to HSCT occurred in six patients (43%). Severe cardiomyopathy occurred in two patients, and one of them had a fatal course.

Conclusion: HSCT is a feasible treatment bringing favourable results to more than half of our patients with SSc. Careful selection of the patients is essential for whom benefited from HSCT, considering the risk-benefit balance of the treatment.     

Skin involvement in scleroderma--where histological and clinical scores meet

OBJECTIVES: A clinico-pathological study in diffuse systemic sclerosis (SSc) patients was performed to analyse whether the skin histological organization and the pro-fibrotic signals elicited by TGF-beta in fibroblasts vary according to the modified Rodnan skin score (mRSS). METHODS: Twenty-seven SSc patients underwent 45 skin biopsies with simultaneous measure of mRSS before or after treatment by immunosuppressive drugs, with or without autologous peripheral haematopoietic stem cell transplantation (HSCT). RESULTS: Double-blind optic microscopy analysis of the biopsies standard extracellular matrix stains allowed to define three histological subgroups: 6 with grade 1 weak fibrosis, 30 with grade 2 moderate fibrosis and 9 with grade 3 severe fibrosis. A significant (P < 0.0001) was identified between the grades of fibrosis and the mRSS. In skin fibroblast cultures, Smad3 phosphorylation levels, as well as mRNA steady-state levels of two transforming growth factor (TGF)-beta/Smad3 targets, COL1A2 and PAI-1, increased in parallel with the mRSS. When compared with pre-transplant values the degree of fibrosis observed after HSCT in the papillary and in the reticular dermis decreased in parallel with the fall in mRSS (n = 5 consecutive patients with repeated biopsies). CONCLUSIONS: The histological extent of skin fibrosis correlates closely with the mRSS. Both parameters appeared to regress after HSCT. The extent of TGF-beta signalling activation in SSc skin fibroblasts appears to parallel the severity of disease.     

Up regulated expression of tumour necrosis factor {alpha} converting enzyme in peripheral monocytes of patients with early systemic sclerosis

BACKGROUND: Systemic sclerosis (SSc) is accompanied by abnormalities in humoral and cellular immune systems. OBJECTIVE: To determine the genes specifically expressed in the immune system in SSc by analysis of the gene expression profile of peripheral blood mononuclear cells (PBMC) from patients with SSc, including those treated with haematopoietic stem cell transplantation (HSCT). Additionally, to investigate the clinical significance of the up regulation of tumour necrosis factor alpha (TNFalpha) converting enzyme (TACE). METHODS: PBMC from patients with SSc (n = 23) and other autoimmune diseases (systemic lupus erythematosus (SLE, n = 16), rheumatoid arthritis (RA, n = 29)), and from disease-free controls (n = 36) were examined. Complementary DNA arrays were used to evaluate gene expression of PBMC, in combination with real time quantitative polymerase chain reactions. TACE protein expression in PBMC was examined by fluorescence activated cell sorter (FACS). RESULTS: In patients with SSc 118 genes were down regulated after HSCT. Subsequent comparative analysis of SSc without HSCT and healthy controls indicated SSc-specific up regulation for three genes: monocyte chemoattractant protein-3 (p = 0.0015), macrophage inflammatory protein 3alpha (p = 0.0339), and TACE (p = 0.0251). In the FACS analysis, TACE protein was mainly expressed on CD14(+) monocytes both in patients with SSc and controls. TACE expression on CD14(+) cells was significantly increased in patients with early SSc (p = 0.0096), but not in those with chronic SSc, SLE, or RA. TACE protein levels in SSc monocytes correlated with the intracellular CD68 levels (p = 0.0016). CONCLUSIONS: Up regulation of TACE expression was a unique profile in early SSc, and may affect the function of TNFalpha and other immunoregulatory molecules.     

High-dose immunoablative therapy with hematopoietic stem cell support in the treatment of severe autoimmune disease: current status and future direction

In the past 5 years approximately 500 patients worldwide suffering from severe autoimmune disease (AD) have received an autologous hematopoietic stem cell transplantation (HSCT) as treatment following high-dose chemotherapy. The EBMT and EULAR data base contains 370 registrations, the most frequently transplanted ADs being multiple sclerosis (MS), systemic sclerosis (SSc), rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), systemic lupus erythematosus (SLE) and idiopathic thrombocytopenic purpura (ITP). Around 70% responded initially well, with durable remission/stabilization seen more frequently in MS and SSc than in RA and SLE, the latter having around 2/3 relapses, the majority of which respond to simple agents. Overall 8% transplant-related mortality was seen with large inter AD differences (12.5% in SSc and only one patient in RA) probably reflecting the degree of vital organ involvement at the time of transplant. This phase I/II data has led to a running phase III randomized trial in SSc called the Autologous Stem cell Transplantation International Scleroderma (ASTIS) trial, and it will soon begin in MS (ASTIMS) and RA (ASTIRA). The concept of immunological "re-setting" has evolved, and needs to be confirmed by longer follow-up and the multicentre, international phase III randomized studies.     

Autologous stem cell transplantation in the treatment of systemic sclerosis: report from the EBMT/EULAR Registry

OBJECTIVE: To analyse the durability of the responses after haematopoietic stem cell transplantation (HSCT) for severe systemic sclerosis (SSc) and determine whether the high transplant related mortality (TRM) improved with experience. This EBMT/EULAR report describes the longer outcome of patients originally described in addition to newly recruited cases. METHODS: Only patients with SSc, treated by HSCT in European phase I-II studies from 1996 up to 2002, with more than 6 months of follow up were included. Transplant regimens were according to the international consensus statements. Repeated evaluations analysed complete, partial, or non-response and the probability of disease progression and survival after HSCT (Kaplan-Meier). RESULTS: Given as median (range). Among 57 patients aged 40 (9.1-68.7) years the skin scores improved at 6 (n = 37 patients), 12 (n = 30), 24 (n = 19), and 36 (n = 10) months after HSCT (p<0.005). After 22.9 (4.5-81.1) months, partial (n = 32) or complete response (n = 14) was seen in 92% and non-response in 8% (n = 4) of 50 observed cases. 35% of the patients with initial partial (n = 13/32) or complete response (n = 3/14) relapsed within 10 (2.2-48.7) months after HSCT. The TRM was 8.7% (n = 5/57). Deaths related to progression accounted for 14% (n = 8/57) of the 23% (n = 13/57) total mortality rate. At 5 years, progression probability was 48% (95% CI 28 to 68) and the projected survival was 72% (95% CI 59 to 75). CONCLUSION: This EBMT/EULAR report showed that response in two thirds of the patients after HSCT was durable with an acceptable TRM. Based on these results prospective, randomised trials are proceeding.     

Autologous hematopoietic stem cell transplantation for autoimmune diseases

Ten years have passed since the first published consensus statement on the use of hematopoietic stem cell transplantation (HSCT) in the treatment of severe autoimmune disease (AD) appeared. During that time, around 700 patients suffering from severe AD have undergone HSCT in the frame of phase I/II clinical trials from over 20 countries including the US. The majority have received an autologous HSCT using one of a limited number of regimens, consistent with the original consensus statement. Long-term drug-free remissions, remission then relapse, no response and treatment-related mortality (TRM) were seen in all the subgroups of AD. An overall TRM of 7% was observed, with marked variation between ADs, i.e. 11% in systemic lupus erythematosus (SLE) and only 1 patient in rheumatoid arthritis (RA). Phase III prospective, comparative randomized trials are running or being planned in multiple sclerosis (MS), systemic sclerosis (SSc), SLE and RA. Basic science programs are also being undertaken to study the immunological mechanisms underlying the clinical events observed.     

Autologous bone marrow transplantation in the treatment of refractory systemic sclerosis: early results from a French multicentre phase I-II study

Haematopoietic stem cell transplantation (HSCT) has been proposed for refractory autoimmune diseases, including systemic sclerosis (SSc). A sequential Bayesian phase I-II clinical trial was conducted in SSc patients to assess the feasibility, the tolerance and the efficacy of autologous HSCT. Peripheral blood stem cells (PBSC) were collected using cyclophosphamide (4 g/m2) and recombinant human granulocyte colony-stimulating factor (5 micro g/kg/d) and reinfused after positive CD34+ selection. Conditioning used cyclophosphamide (200 mg/kg) or melphalan (140 mg/m2) according to cardiac function. The main end-point was the failure of the procedure, defined by failure of either PBSC mobilization, CD34+ selection or intensification procedure, or by procedure-related death. Among the 12 enrolled patients, three failures occurred: one PBSC mobilization, one CD34+ selection and one CD34+ intensification. Probability of graft failure was estimated at 0.286 (95% confidence interval: 0.095-0.54). Autologous PBSC (n = 10) or bone marrow (n = 1) transplantation was actually performed in 11 patients with one procedure-related death. Median time to neutrophil (> 0.5 x 10(9)/l) and platelet (> 25 x 10(9)/l) haematopoietic reconstitution was 12 and 10 d respectively. After 18 months (range 1-26), eight out of 11 patients have shown major or partial response. Non-myeloablative conditioning, followed by a T cell-depleted autologous PBSC or bone marrow transplantation, appears feasible with low toxicity in severe SSc with short-term clinical benefits.     

High serum levels of YKL-40 in patients with systemic sclerosis are associated with pulmonary involvement

OBJECTIVES: YKL-40, a growth factor of connective tissue cells, is elevated in sera from patients with diseases characterized by inflammation, tissue remodelling, or fibrosis. The aim of the study was to determine serum YKL-40 levels in patients with systemic sclerosis (SSc) and to explore any possible clinical and prognostic associations. METHODS: YKL-40 was measured in sera from 88 patients with SSc (26 with diffuse and 62 with limited skin involvement) and in sera from 88 matched healthy controls. Immunohistochemical staining for YKL-40 antigen was performed in a biopsy from a patient with pulmonary SSc. RESULTS: Serum YKL-40 levels of the SSc patients were significantly higher than those of the controls (p<0.00001). Patients with pulmonary fibrosis by chest X-ray, obstructive ventilatory pattern, reduced diffusing capacity (DLco), and digital joint deformity due to skin retraction had significantly higher serum YKL-40 compared with patients without these findings. Patients with elevated serum YKL-40 had shorter survival times than patients with normal serum YKL-40 (p = 0.0005), although this was not independent of age and pulmonary function. YKL-40 protein expression was found in inflammatory cells in fibrosing pulmonary tissue from a patient with SSc. CONCLUSIONS: Serum YKL-40 is elevated in patients with SSc with pulmonary involvement.     

Liver cirrhosis due to autoimmune hepatitis combined with systemic sclerosis

Systemic sclerosis (SSc) is a chronic systemic disease that affects the skin, lungs, heart, gastrointestinal tract, kidneys, and musculoskeletal system. Although up to 90% of patients with scleroderma have been estimated to have gastrointestinal involvement, liver disease has been reported only rarely. A 51-year-old woman was hospitalized due to esophageal variceal bleeding. Her serum was positive for anti-nuclear antibody and anti-centromere antibody. Sclerodactyly was noted on both hands, and she had recently developed Raynaud's syndrome. Punch biopsy of the hand showed hyperkeratosis, regular acanthosis, and increased basal pigmentation in the epidermis, and thick pale collagenous bundles in the dermis. Liver biopsy showed chronic active hepatitis with bridging fibrosis. Consequently, she was diagnosed with liver cirrhosis due to autoimmune hepatitis (AIH) combined with SSc. AIH had subsided after administration of prednisolone at 40 mg per day. She received 5-10 mg/day of prednisolone as an outpatient, and her condition has remained stable. Patients with either AIH or SSc should be monitored for further development of concurrent autoimmune diseases. The early diagnosis of AIH combined with SSc will be helpful in achieving optimal management.     

Foot involvement in systemic sclerosis: a longitudinal study of 100 patients

OBJECTIVE: To investigate the clinical and radiologic features of foot involvement in systemic sclerosis (SSc). PATIENTS: One hundred patients (91 women, 9 men; mean age, 51.9 +/- 11 years) with SSc (mean disease duration, 17.4 +/- 10.5 years) were retrospectively studied. Seventy-four subjects had limited scleroderma and 26 diffuse scleroderma. METHODS: Radiologic changes of foot involvement were assessed at presentation (time of diagnosis) and follow-up ranging from 1 to 28 years (median range, 7 years) and were compared with changes detected in the hands of each patient at the same presentation and follow-up. Correlations with skin and internal organ involvement were assessed. RESULTS: Ninety patients had foot involvement clinically. Forty-three had it at initial evaluation; 47 developed it during follow-up. Median time to clinical event occurrence was 10 years (95% CI, 6.7-13.3) with 44% censored case probability at this time. The onset of clinically evident foot involvement was later in limited SSc than in diffuse SSc. In comparison with hands with SSc, feet with SSc had lower rates of necrotizing Raynaud's phenomenon and tendon friction rubs and decreased skin thickening scores, whereas arthralgias occurred significantly more often. At presentation, 37 patients had radiologic abnormalities of their feet compared with 69 of their hands (P <.001); the hands had a significantly higher prevalence of acroosteolysis (P <.001). At the end of the follow-up, 35 of 50 SSc patients had radiographic foot involvement compared with 50 of 51 with hand involvement (P <.001). A significantly higher prevalence of acroosteolysis (P <.001), calcinosis (P <.05), and erosions (P <.05) of the hands were detected at that time. CONCLUSION: This study shows that compared with hand involvement in SSc, foot involvement in SSc has a later onset and is relatively less frequent but can be disabling.     

Nonmyeloablative stem cell transplant in a patient with advanced systemic sclerosis and systemic lupus erythematosus

Systemic sclerosis (SSc) is an uncommon connective tissue disease characterized by excessive collagen deposition within the skin and internal organs. Most patients with diffuse severe SSc are treated with immunosuppressive agents, but patients with advanced disease have very high 5-year mortality rates despite adequate therapy. We describe a patient with both diffuse cutaneous SSc and systemic lupus erythematosus who showed mixed chimerism 29 months after undergoing nonmyeloablative stem cell transplant. She experienced remission of both diseases.     

Effects of oral cyclophosphamide and prednisolone therapy on the endothelial functions and clinical findings in patients with early diffuse systemic sclerosis

OBJECTIVE: The endothelial damage of microvascular structures in systemic sclerosis (SSc; scleroderma) is associated with increased levels of endothelial adhesion molecules and endothelium-associated cytokines, including E-selectin and thrombomodulin. Although there is still no ideal specific pharmacologic therapy for SSc, cyclophosphamide has resulted in clinical improvement in patients with SSc-related active alveolitis. This study was designed to assess the expression of E-selectin and thrombomodulin in patients with early diffuse SSc, and to investigate the effects of oral cyclophosphamide combined with prednisolone therapy on the levels of these endothelium-associated cytokines and on the patients' clinical outcomes. METHODS: Thirteen patients with early diffuse SSc were treated with oral cyclophosphamide (2-2.5 mg/kg/day) and methylprednisolone (30 mg/every other day) for 1 year. The outcomes were determined as clinical (skin score) and laboratory parameters (including the erythrocyte sedimentation rate, complete blood cell count, levels of C-reactive protein, antinuclear antibody, anti-double-stranded DNA, rate of creatinine clearance, and findings on pulmonary function tests, esophageal manometry, and echocardiography). The concentrations of E-selectin and thrombomodulin were measured in the pretreatment and posttreatment serum samples from the SSc patients and from 12 healthy adults as controls. RESULTS: In the patients with early diffuse SSc, pretreatment and posttreatment mean levels of E-selectin were 51 ng/ml (range 34.2-135.5) and 33.4 ng/ml (range 23-62.5), respectively (P = 0.01), and those of thrombomodulin were 82 ng/ml (range 35.8-120.5) and 74.6 ng/ml (range 23.3-91.3), respectively (P = 0.016). Clinical and laboratory parameters (the skin score and measures of pulmonary function [forced vital capacity and diffusing capacity for carbon monoxide]) were also improved (P < 0.05 for each) at the end of the followup period. CONCLUSION: Combination therapy with cylophosphamide plus prednisolone is effective in the treatment of early diffuse SSc. Circulating levels of E-selectin and thrombomodulin not only demonstrate the extent of endothelial injury and/or activation, but also could be a useful marker to monitor the disease activity in SSc.     

Risk factor analysis for thrombotic microangiopathy after reduced-intensity or myeloablative allogeneic hematopoietic stem cell transplantation

Thrombotic microangiopathy (TMA) impairs long-term survival after allogeneic hematopoietic stem cell transplantation (HSCT). As the allogeneic HSCT procedure has developed, addressing risk factors for TMA has become more complicated. The aim of this study was to investigate the impact of transplant-associated factors on TMA incidence in patients who have undergone HSCT in various settings. One hundred twenty-three consecutive allogeneic HSCT patients with hematologic diseases receiving myeloablative and reduced-intensity conditioning were evaluated retrospectively. Of 123 patients, 22 (17.9%) developed TMA after HSCT. Multivariate analysis showed the significance of GVHD grade II-IV, and the use of FK506 and the use of high-dose busulfan (Bu) (16 mg/kg) persisted. The hazard ratios of the use of FK506, the use of high-dose Bu (16 mg/kg), and GVHD grade II-IV for TMA were 8.7 (95% CI 2.0-37), 5.7 (95% CI 1.5-21), and 3.4 (95% CI 1.3-9.1), respectively. In the present study, reduced-intensity conditioning did not have an advantage over myeloablative conditioning in decreasing the incidence of TMA after HSCT. Our results also showed that high-dose Bu (16 mg/kg) for the conditioning and FK506 for the prophylaxis of GVHD might contribute more significantly to TMA onset after HSCT than other agents.