结节病易误诊,据王洪武等~([1])收集国内18篇关于此病误诊的文献,误诊率高达63.2%,当然有误诊就会有误治,如孙永昌等~([2])报道26例结节病在影像学检查诊断的第一印象中拟诊结核5例,其中就有2例完成规范的抗结核治疗,为此应引起临床对本病诊治的重视。

Sarcoidosis

Importance High-dose immunosuppressive therapy and autologous hematopoietic stem cell transplantation (HSCT) have shown efficacy in systemic sclerosis in phase 1 and small phase 2 trials. Objective To compare efficacy and safety of HSCT vs 12 successive monthly intravenous pulses of cyclophosphamide. Design, Setting, and Participants The Autologous Stem Cell Transplantation International Scleroderma (ASTIS) trial, a phase 3, multicenter, randomized (1:1), open-label, parallel-group, clinical trial conducted in 10 countries at 29 centers with access to a European Group for Blood and Marrow Transplantation–registered transplant facility. From March 2001 to October 2009, 156 patients with early diffuse cutaneous systemic sclerosis were recruited and followed up until October 31, 2013. Interventions HSCT vs intravenous pulse cyclophosphamide. Main Outcomes and Measures The primary end point was event-free survival, defined as time from randomization until the occurrence of death or persistent major organ failure. Results A total of 156 patients were randomly assigned to receive HSCT (n = 79) or cyclophosphamide (n = 77). During a median follow-up of 5.8 years, 53 events occurred: 22 in the HSCT group (19 deaths and 3 irreversible organ failures) and 31 in the control group (23 deaths and 8 irreversible organ failures). During the first year, there were more events in the HSCT group (13 events [16.5%], including 8 treatment-related deaths) than in the control group (8 events [10.4%], with no treatment-related deaths). At 2 years, 14 events (17.7%) had occurred cumulatively in the HSCT group vs 14 events (18.2%) in the control group; at 4 years, 15 events (19%) had occurred cumulatively in the HSCT group vs 20 events (26%) in the control group. Time-varying hazard ratios (modeled with treatment × time interaction) for event-free survival were 0.35 (95% CI, 0.16-0.74) at 2 years and 0.34 (95% CI, 0.16-0.74) at 4 years. Conclusions and Relevance Among patients with early diffuse cutaneous systemic sclerosis, HSCT was associated with increased treatment-related mortality in the first year after treatment. However, HCST conferred a significant long-term event-free survival benefit. Trial Registration isrctn.org Identifier:ISRCTN54371254

https://jamanetwork.com/journals/jama/articlepdf/1883019/joi140072.pdf

Autologous Hematopoietic Stem Cell Transplantation vs Intravenous Pulse Cyclophosphamide in Diffuse Cutaneous Systemic Sclerosis: A Randomized Clinical Trial

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(11)60982-3.pdf

Autologous non-myeloablative haemopoietic stem-cell transplantation compared with pulse cyclophosphamide once per month for systemic sclerosis (ASSIST): an open-label, randomised phase 2 trial

Context Stem cell therapy is rapidly developing and has generated excitement and promise as well as confusion and at times contradictory results in the lay and scientific literature. Many types of stem cells show great promise, but clinical application has lagged due to ethical concerns or difficulties in harvesting or safely and efficiently expanding sufficient quantities. In contrast, clinical indications for blood-derived (from peripheral or umbilical cord blood) and bone marrow–derived stem cells, which can be easily and safely harvested, are rapidly increasing. Objective To summarize new, nonmalignant, nonhematologic clinical indications for use of blood- and bone marrow–derived stem cells. Evidence Acquisition Search of multiple electronic databases (MEDLINE, EMBASE, Science Citation Index), US Food and Drug Administration [FDA] Drug Site,
and National Institutes of Health Web site to identify studies published from January 1997 to December 2007 on use of hematopoietic stem cells (HSCs) in autoimmune, cardiac, or vascular diseases. The search was augmented by hand searching of reference lists in clinical trials,
review articles, proceedings booklets, FDA reports, and contact with study authors and device and pharmaceutical companies. Evidence Synthesis Of 926 reports identified, 323 were examined for feasibility and toxicity, including those with small numbers of patients, interim or substudy reports, and reports on multiple diseases, treatment of relapse, toxicity, mechanism of action, or stem cell mobilization.
Another 69 were evaluated for outcomes. For autoimmune diseases, 26
reports representing 854 patients reported treatment-related mortality of less than 1% (2/220 patients) for nonmyeloablative, less than 2%
(3/197) for dose-reduced myeloablative, and 13% (13/100) for intense myeloablative regimens, ie, those including total body irradiation or high-dose busulfan. While all trials performed during the inflammatory stage of autoimmune disease suggested that transplantation of HSCs may have a potent disease-remitting effect, remission duration remains unclear, and no randomized trials have been published. For reports involving cardiovascular diseases, including 17 reports involving 1002 patients with acute myocardial infarction, 16 involving 493 patients with chronic coronary artery disease, and 3 meta-analyses, the evidence suggests that stem cell transplantation performed in patients with coronary artery disease may contribute to modest improvement in cardiac function. Conclusions Stem cells harvested from blood or marrow, whether administered as purified HSCs or mesenchymal stem cells or as an unmanipulated or unpurified product can, under appropriate conditions in select patients, provide disease-ameliorating effects in some autoimmune diseases and cardiovascular disorders. Clinical trials are needed to determine the most appropriate cell type, dose, method, timing of delivery, and adverse effects of adult HSCs for these and other nonmalignant disorders.

/pdf/clinical-applications-of-blood-derived-and-marrow-derived-1l5yx0imc3.pdf

Clinical Applications of Blood-Derived and Marrow-Derived Stem Cells for Nonmalignant Diseases

Background Autologous hematopoietic stem cell transplantation has been used since 1996 for the treatment of severe autoimmune diseases refractory to approved therapies. We evaluated the long-term outcomes of these transplants and aimed to identify potential prognostic factors.Design and Methods In this observational study we analyzed all first autologous hematopoietic stem cell transplants for autoimmune diseases reported to the European Group for Blood and Marrow Transplantation (EBMT) registry between 1996–2007. The primary end-points for analysis were overall survival, progression-free survival and transplant-related mortality at 100 days.Results Nine hundred patients with autoimmune diseases (64% female; median age, 35 years) who underwent a first autologous hematopoietic stem cell transplant were included. The main diseases were multiple sclerosis (n=345), systemic sclerosis (n=175), systemic lupus erythematosus (n=85), rheumatoid arthritis (n=89), juvenile arthritis (n=65), and hematologic immune cytopenia (n=37). Among all patients, the 5-year survival was 85% and the progression-free survival 43%, although the rates varied widely according to the type of autoimmune disease. By multivariate analysis, the 100-day transplant-related mortality was associated with the transplant centers’ experience (P=0.003) and type of autoimmune disease (P=0.03). No significant influence of transplant technique was identified. Age less than 35 years (P=0.004), transplantation after 2000 (P=0.0015) and diagnosis (P=0.0007) were associated with progression-free survival.Conclusions This largest cohort studied worldwide shows that autologous hematopoietic stem cell transplantation can induce sustained remissions for more than 5 years in patients with severe autoimmune diseases refractory to conventional therapy. The type of autoimmune disease, rather than transplant technique, was the most relevant determinant of outcome. Results improved with time and were associated with the transplant centers’ experience. These data support ongoing and planned phase III trials to evaluate the place of autologous hematopoietic stem cell transplantation in the treatment strategy for severe autoimmune diseases.

Autologous hematopoietic stem cell transplantation for autoimmune diseases: an observational study on 12 years’ experience from the European Group for Blood and Marrow Transplantation Working Party on Autoimmune Diseases

Objective: Systemic sclerosis (SSc) is a generalised autoimmune disease, causing morbidity and a reduced life expectancy, especially in patients with rapidly progressive diffuse cutaneous SSc. As no proven treatment exists, autologous haematopoietic stem cell transplantation (HSCT) is employed as a new therapeutic strategy in patients with a poor prognosis. This study reports the effects on survival, skin and major organ function of HSCT in patients with severe diffuse cutaneous SSc. Patients and methods: A total of 26 patients were evaluated. Peripheral blood stem cells were collected using cyclophosphamide (4 g/m2) and rHu G-CSF (5 to 10 μg/kg/day) and were reinfused after positive CD34+ selection. For conditioning, cyclophosphamide 200 mg/kg was used. Results: After a median follow-up of 5.3 (1–7.5) years, 81% (n = 21/26) of the patients demonstrated a clinically beneficial response. The Kaplan–Meier estimated survival at 5 years was 96.2% (95% CI 89–100%) and at 7 years 84.8% (95% CI 70.2–100%) and event-free survival, defined as survival without mortality, relapse or progression of SSc, resulting in major organ dysfunction was 64.3% (95% CI 47.9–86%) at 5 years and 57.1% (95% CI 39.3–83%) at 7 years. Conclusion: This study confirms that autologous HSCT in selected patients with severe diffuse cutaneous SSc results in sustained improvement of skin thickening and stabilisation of organ function up to 7 years after transplantation.

https://ard.bmj.com/content/annrheumdis/67/1/98.full.pdf

Long-term follow-up results after autologous haematopoietic stem cell transplantation for severe systemic sclerosis

severe systemic sclerosis haematopoietic stem cell transplantation for Long-term follow-up results after autologous

Background Autologous bone marrow transplant is a new treatment for autoimmune diseases (AD). Objectives To determine the feasibility, tolerance and efficacy of autologous HSC transplantation with CD34+ selection in severe scleroderma (Sc) and myositis (M). Methods We designed a national, non randomised, open, phase I-II trial.1Mobilisation of HSC used cyclophosphamide (CYCLO) (4 g/m2)+ G-CSF (5 microg/kg day) or G-CSF alone (10 microg/kg day) if left ventricular ejection fraction (LVEF) was Results 12 Sc + 3 M, age 36 yrs, were included in 2 years, meanwhile 10 candidates died from their disease. HSC mobilisation was successful in 14 patients, but in 2 cases did not yield enough HSC to allow CD34+ selection. After 2 (1–4) aphereses, the total number of CD34+ collected for each patient was 10.9 × 106/kg (3.9?34.3). Purity was 99.2% (92–99.8). CD34+ cells yield was 60.7% (46.4–80). Intensive immunosuppression was performed in 13 patients with low toxicity. Number of reinfused cells was 5.8 × 106 CD34+/kg (3.3–10.2). Duration of aplasia was 2.9 weeks (2.5–3) with low toxicity. No mortality was associated with the procedure. Early clinical evolution (18 mths) showed improved functional status (PS, SHAQ) and fall in skin score in 8/12 Sc and no clinical benefit in M. Conclusion Autologous HSC transplantation is feasible in Sc and M, with a lower risk compared to spontaneous evolution of AD and early clinical benefit in Sc. These results call for phase III studies to compare cyclophosphamide alone versus autologous transplantation in Sc and for more myositis in phase I–II studies. Reference Farge D, Gluckman E, Tyndall A. Treatment of severe autoimmune diseases by immunoablative chemotherapy and autologous bone marrow transplantation. EJIM 1999;10:88–96

https://ard.bmj.com/content/annrheumdis/60/Suppl_1/A118.2.full.pdf

P Roblot

Papers

Long-term follow-up results after autologous haematopoietic stem cell transplantation for severe systemic sclerosis

severe systemic sclerosis haematopoietic stem cell transplantation for Long-term follow-up results after autologous

OP0038 Autologous hematopoietic stem cells (hsc) transplantation in scleroderma and myositis