The treatment of systemic sclerosis (SSc) represents a great clinical challenge because of the complex disease pathogenesis including vascular, fibrotic, and immune T- and B-lymphocyte-mediated alterations. Therefore, SSc should be treated by combined or sequential therapies according to prevalent clinico-pathogenetic phenotypes. Some preliminary data suggest that rituximab (RTX) may downregulate the B-cell over expression and correlated immunological abnormalities. Here, we describe a series of 10 SSc patients (4M and 6F, mean age 46 13.5SD years, mean disease duration 6.3 2.7SD years; 5 pts had limited and 5 diffuse SSc cutaneous subset) treated with one or more cycles of RTX (4 weekly infusions of 375mg/m2). The main indications to RTX were interstitial lung fibrosis, cutaneous, and/or articular manifestations unresponsive to previous therapies; ongoing treatments remained unchanged in all cases. The effects of RTX were evaluated after 6months of the first cycle and at the end of long-term follow-up period (37 21SD months, range 18 72months). An updated review of the world literature was also done. RTX significantly improved the extent of skin sclerosis in patients with diffuse SSc at 6months evaluation (modified Rodnan skin score from 25 4.3 to 17.2 4.6; p=.022). A clinical improvement of other cutaneous manifestations, namely hypermelanosis (7/7), pruritus (6/8), and calcinosis (3/6) was observed. Moreover, arthritis revealed particularly responsive to RTX showing a clear-cut reduction of swollen and tender joints in 7/8 patients; while lung fibrosis detected in 8/10 remained stable in 6/8 and worsened in 2/8 at the end of follow-up. Pro-inflammatory cytokines, namely IL6, IL15, IL17, and IL23, evaluated in 3 patients with diffuse cutaneous SSc, showed a more or less pronounced reduction after the first RTX cycle. These observations are in keeping with the majority of previous studies including 6 single case reports and 10 SSc series (from 5 to 43 pts), which frequently reported the beneficial effects of RTX on some SSc manifestations, particularly cutaneous sclerosis, along with the improvement/stabilization of lung fibrosis. Possible discrepancies among different clinical studies can be related to the etiopathogenetic complexity of SSc and not secondarily to the patients' selection and disease duration at the time of the study. The present study and previous clinical trials suggest a possible therapeutical role of RTX in SSc, along with its good safety profile. The specific activity of RTX on B-cell-driven autoimmunity might explain its beneficial effects on some particular SSc clinical symptoms, namely the improvement of skin and articular involvement, and possibly the attenuation of lung fibrosis.

目的 介绍和阐述诺氏(Naranjo′s)评估量表在药物不良反应评价中的作用。方法 查阅近年相关研究报道，结合实例阐述诺氏评估量表在药物不良反应评价中的作用。结果 诺氏评估量表由事先设置既定分值的10个医学相关问题构成，主要用于评价和确定药物使用与药物不良反应之间的相关性。根据诺氏评估量表可明确将药物不良反应划分为“确定的(definite)”、“很可能的(probable)”、“可能的(possible)”、“可疑的(doubtful)”等4类，并附各项下具体分值及医学意义的独立问题。结论 诺氏评估量表简便实用、准确可信，是药物不良反应研究的有效工具，对评估和确定药物使用与药物不良反应之间的因果关系具有重要作用。<br/>

Arunprasath P, Gobu P, Dubashi B, Satheesh S, Balachander J.

Abstract BACKGROUND: Rituximab has rarely been associated with acute coronary syndrome (ACS). We report the case of a patient in whom rituximab, a monoclonal antibody used to treat lymphomas of B-cell origin, induced ST elevation myocardial infarction. CASE REPORT: A 46-year-old male patient diagnosed with stage II non-Hodgkin lymphoma presented to the emergency department with acute crushing, substernal chest pain that radiated to his back 1 day after a chemotherapy infusion with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone. An electrocardiogram revealed normal sinus rhythm with ST elevations in the inferior leads. The patient underwent primary percutaneous coronary intervention (PCI) of his right coronary artery and first diagonal artery with placement of drug-eluting stents. He did well postprocedure and resumed therapy with rituximab under close monitoring by the cardiology and oncology departments without any further cardiac events. CONCLUSION: In patients with ACS because of chemotherapy, complete revascularization during PCI should be considered.

The aim of this study was to describe the occurrence of acute coronary syndromes in 3 cases of rituximab infusions. We reviewed the records of 3 patients with lymphoproliferative disorders who experienced acute coronary syndromes associated with their initial infusion of rituximab. All 3 patients received rituximab according to a standardized institutional rate schedule, and all received pre-medication with acetaminophen and diphenhydramine. The median age of patients was 61 years. One patient had known atherosclerotic heart disease, and 2 patients had risk factors for coronary artery disease. All patients had varying degrees of evidenced high tumor burden, including lymphocytosis, elevated lactate dehydrogenase values, bulky tumor masses, and bone marrow involvement by lymphoma. All 3 patients experienced fairly typical chest pain syndromes and experienced elevations of cardiac enzymes consistent with myocardial ischemia. One patient died of an arrhythmia that deteriorated into asystole, and 2 patients recovered and underwent coronary angiography. Acute coronary syndromes can be associated with the infusion of rituximab. Patients with a history of previous coronary artery disease or risk factors for coronary artery disease should be observed closely for signs of myocardial ischemia, particularly during the initial infusion. The occurrence of symptoms that could be ascribed to an acute coronary syndrome should always be taken seriously during the first rituximab infusion and investigated aggressively. Patients should be aware that this is a rare, albeit serious, complication of treatment with rituximab.

A 62-year-old male was undergoing treatment of NHL with bone marrow involvement with thrombocytopenia. After 15min of starting of IV infusion of rituximab, he started having severe retrosternal chest pain, diagnosed as acute ST elevation inferior wall MI. Patient was pre-loaded with dual anti platelets. Coronary angiogram showed 100% occlusion of proximal RCA. Thrombosuction of this culprit RCA revealed underlying 90% stenosis. After that, PCI with balloon angioplasty of RCA was done. The procedure was terminated in the view of successful balloon angioplasty with good TIMI flow. He was kept on dual antiplatelet therapy for one month with regular platelet monitoring. With the growing increasing global use of rituximab for various oncological and immunological diseases, this complication of myocardial infarction should be kept in mind. Associated thrombocytopenia with high thrombus burden in this case heed primary coronary balloon angioplasty without stent placement a more suitable modality.

We present a case of an elderly with who was diagnosed with . Soon after the administration of chemotherapy, which included rituximab and , he developed with . The condition was managed successfully with primary percutaneous coronary intervention. We briefly discuss the possible pathogenic mechanisms of chemotherapy-induced ischemic syndrome and the management of chemotherapy in patients with high cardiovascular risk.

Myocardial infarction after rituximab or other monoclonal antibody therapies has been reported in rare cases, all in patients with classical cardiovascular risk factors or associated inflammatory or lymphoproliferative disorders. We report the case of a 52-year-old man, without classical cardiovascular risk factors or associated inflammatory or lymphoproliferative disorder, treated for seronegative myasthenia with rituximab infusions complicated by myocardial infarction. The exact origin of myocardial infarction after monoclonal antibody treatment is unclear. Myocardial infarction is a rare but possibly fatal complication of rituximab infusion, even occurring in relatively young patients, without classical risk factors and without associated inflammatory or lymphoproliferative disorder.

Rituximab is an anti-CD20 monoclonal antibody often used in the treatment of rheumatoid arthritis (RA). Infusion reactions sometimes develop following rituximab administration. Delayed complications are rare. Acute coronary syndromes are listed as sideeffects of rituximab therapy. We report two cases of acute myocardial infarction following rituximab therapy for RA and review the literature regarding cardiac events in patients treated with rituximab. We would like to raise awareness of this possible complication in patients treated with rituximab.

A letter to the editor related to acute myocardial infarction after first dose of rituximab infusion, published in the March 2014 issue of the journal is presented.

Abstract WHAT IS KNOWN AND OBJECTIVES: Rituximab is a chimeric monoclonal anti-CD20 antibody approved for the treatment of some lymphoid malignancies as well as for autoimmune diseases including rheumatoid arthritis (RA), idiopathic thrombocytopenic purpura (ITP) and vasculitis. Generally, rituximab is well tolerated; nevertheless, some patients develop adverse effects including infusion reactions. Albeit rare, these reactions may in some cases be life-threatening conditions. Rituximab cardiovascular side effects include more common effects such as hypertension, oedema and rare cases of arrhythmias and myocardial infarction. CASE SUMMARY: In this article, we report a case of a 58-year-old man with a history of overlap syndrome including RA and limited scleroderma who was treated with rituximab and developed a dramatic ST-elevation myocardial infarction (STEMI) during the drug administration. WHAT IS NEW AND CONCLUSION: This report underlines previous published reports emphasizing the awareness of such an association. This communication also warrants the importance of screening for ischaemic heart disease in selected cases of patients treated with rituximab. 2017 John Wiley & Sons Ltd.

It is not clear if the downward trend in cardiovascular disease (CVD) observed for ages up to 85 years can be extended to the oldest old, those 85 years and above. This nationwide cohort study presents age specific trends of CVD as well as for myocardial infarction (MI) and stroke separately for the period 1994 to 2010 for individuals 85 to 99 years old in Sweden. Data were extracted from national registries. All analyses were based on one-year age- and sex- specific figures. The risk for CVD increased with every age above 85 years although the rate of increase leveled off with age. Over time, the risk for CVD and MI decreased for all ages, and for stroke for ages up to 89 years. However, the risk of MI increased until around 2001 in all age groups and both sexes but decreased after that. The overall mortality improved for all outcomes over the period 1994 to 2010, so did the survival within 28 days from an event. The average annual decline in mortality over all ages, 85 and above was 3% for MI, 2% for stroke and for 2% CVD. Corresponding figures for ages 60 84 was 4% for each of MI, stroke and CVD. The results were similar for men and women. Improvements in CVD risks observed among ages up to 85 years appear to have extended also to ages above 85 years, even if the rate of improvement plateaued with age. The improvements in survival for all ages up to 99 years give no support to the hypothesis that more fragile individuals reach higher ages. Additional research is needed to find out if improvement in survival can be seen also for the second and third event of CVD, stroke and MI.

Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that are regulated by inflammatory signals to mediate changes in extracellular matrix. Members of the MMP family share sequence homology, act on interstitial protein substrates, acutely participate in inflammatory processes and chronically mediate tissue remodelling. MMPs are important in vascular remodelling, not only in the overall vasculature architecture but also, more importantly, in the advancing atherosclerotic plaque. MMP activation modifies the architecture of the plaque and may directly participate in the process of plaque rupture. MMPs also participate in cardiac remodelling following myocardial infarction and development of dilated cardiomyopathy. Soluble MMPs are now potential biomarkers in delineating cardiovascular risk for plaque rupture and coronary risk. They also constitute innovative direct or indirect targets to modify cardiovascular tissue remodelling in atherosclerosis and heart failure.

Abstract OBJECTIVES: Polymorphonuclear neutrophils (PMN) in atherosclerotic plaques have been identified only recently, and their contribution to plaque development is not yet fully understood. In this study, production of elastase, interleukin (IL)-8 and vascular endothelial growth factor (VEGF) by PMN was investigated in subjects with carotid stenosis undergoing carotid endarterectomy (CEA). METHODS: The study enrolled 50 patients (Pts) and 10 healthy subjects (HS). Circulating PMN (cPMN) isolated from venous blood (in both Pts and HS) and from plaques (pPMN, in Pts) were cultured, alone or with 0.1 M fMLP. Elastase, IL-8 and VEGF mRNA were analyzed by real-time PCR. In CEA specimens, PMN were localized by immunohistochemistry. RESULTS: In both Pts cPMN and pPMN, IL-8 mRNA was higher at rest but lower after fMLP (P<0.01 vs HS), and VEGF mRNA was higher both at rest and after fMLP (P<0.01 vs HS), while elastase mRNA was not significantly different. On the contrary, protein production was always higher in cPMN of HS with respect to values measured in cells of Pts. In CEA specimens, CD66b+ cells localized to areas with massive plaque formation close to neovessels. Pts with soft and mix plaques, as defined by computed tomography, did not differ in cPMN or pPMN IL-8, VEGF or elastase mRNA, or in intraplaque CD66b+ cell density. However, Pts with soft plaques had higher white blood cell count due to increased PMN. CONCLUSIONS: In Pts with carotid plaques, both circulating and intraplaque PMN produce IL-8, VEGF and elastase, which are crucial for plaque development and progression. These findings suggest mechanistic explanations to the reported correlation between PMN count and cardiovascular mortality in carotid ATH.

最近,中华医学会心血管病学分会动脉粥样硬化和冠心病学组组织专家对我国2010年《急性ST段抬高型心 肌梗死(STEMI)诊断和治疗指南》作了修订(以下简称《新指南》),并在2015年第5期《中华心血管病杂志》上发表.现对《新指南》作一解析,希望 能为临床医生提供指导.