A review of the current use of rituximab in autoimmune diseases

Rituximab is a human/murine chimeric monoclonal antibody primarily used for treating non-Hodgkin's B-cell lymphoma. Recently it has also been used in the treatment of several autoimmune diseases. A literature review was conducted to determine the efficacy of rituximab in the treatment of some of these autoimmune diseases. Multiple mechanisms proposed for the rituximab mediated B cell depletion are also discussed. The efficacy of rituximab is well-established and it is FDA approved for treatment of Rheumatoid arthritis. In this review, data on the use of rituximab is presented from 92 studies involving 1197 patients with the following diseases: systemic lupus erythematosus, idiopathic thrombocytopenic purpura, anti-neutrophil cytoplasmic antibody associated vasculitis, Grave's disease, autoimmune hemolytic anemia, pemphigus vulgaris, hemophilia A, cold agglutinin disease, Sjogren's syndrome, graft vs. host disease, thrombotic thrombocytopenic purpura, cryoglobulinemia, IgM mediated neuropathy, multiple sclerosis, neuromyelitis optica, idiopathic membranous nephropathy, dermatomyositis, and opsoclonus myoclonus. The efficacy varies among different autoimmune diseases. The cumulative data would suggest that in the vast majority of studies in this review, RTX has a beneficial role in their treatment. While rituximab is very effective in the depletion of B cells, current research suggests it may also influence other cells of the immune system by re-establishing immune homeostasis and tolerance. The safety profile of RTX reveals that most reactions are infusion related. In patients with autoimmune diseases the incidence of serious and severe side effects is low. Systemic infection still remains a major concern and may result in death.     

Excess cardiovascular risk in inflammatory rheumatic diseases: pathophysiology and targeted therapy

The article reviews the evidence and extent of the excess cardiovascular risk in patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and ankylosing spondylitis. RA entails nearly twice as high a standardized mortality ratio and is considered an equivalent of type 2 diabetes with regard to cardiovascular risk. The associated excess cardiovascular risk can only partly be explained by traditional risk factors, and the underlying inflammation is crucially involved in the pathogenesis. Data obtained from patients with early RA suggest that serum triglycerides, a proxy of disease activity as markers of systemic inflammation, impaired function of apolipoprotein A-I and HDL particles, and mediating hypertension are determinants of the excess cardiovascular risk. These changes seem to be preceded by a lowering of total cholesterol and are followed in the course of the disease by immune processes typically illustrated by positivity of rheumatoid factor. Evidence is available to postulate the notion that reduced plasma lipoprotein- associated phospholipaseA2 mass or activity, mediated by diminished hydrolysis of VLDL triglycerides and of Lp(a) phospholipids, may induce reduction or altered composition of HDL particles and apoA-I dysfunction which, along with elevated plasma triglycerides, initiate and contribute to chronic inflammation. Lifestyle modification, traditional non-steroidal anti-inflammatory drugs and cyclo-oxygenase-2 inhibitors, low-dose corticosteroids, statins, tumor-necrosis-α inhibitors and, particularly, the immunosuppressive methotrexate, all have potential beneficial effects in eliciting a reduction in disease activity and cardiovascular risk. Adherence to the recent EULAR recommendations is a key in the prevention and management of cardiovascular risk among patients with rheumatic diseases.     

B cells move to centre stage: novel opportunities for autoimmune disease treatment

The B-cell arm of the immune system has long been appreciated for its crucial role in pathogen resistance, but in the study of many autoimmune diseases, T cells have dominated the limelight for decades. However, the development of the B-cell-depleting antibody rituximab as a lymphoma therapy has provided a tool to probe the contribution made by B cells in several immune disorders. Recently, the success of B-cell depletion with rituximab in the treatment of rheumatoid arthritis has stimulated investigation of its effects in several other immune disorders, and considerable interest in the potential of drugs that can modulate B-cell function for the treatment of such diseases in general. This article discusses the role of B cells in a range of autoimmune disorders, including rheumatoid arthritis and systemic lupus erythematosus, and analyses approaches to therapeutic B-cell manipulation.     

Novel mechanistic and clinical implications concerning the safety of statin discontinuation

The beneficial effects of statins have been discussed widely, and their preventative role has been confirmed in cardiovascular disorders, primary and secondary prevention settings, and in asymptomatic subjects with a high cardiovascular risk. Despite these benefits, discontinuation of statins is frequent in cardiac patients and might be associated with adverse outcomes in several conditions involving acute coronary syndromes or acute stroke. In this review, we focus on the mechanistic background of statins that might contribute to such negative changes and that extend beyond cholesterol-lowering effects, including the so-called pleiotropic statin activity. In particular, findings regarding the detrimental impact of statin withdrawal on endothelial function, inflammation, platelet activity or AT1 signaling are discussed, along with the possible clinical implications for statin safety.     

他汀类药物的安全性风险评价

他汀类药物是最广泛的可用药物治疗降低胆固醇水平,并控制其发展的处方药。所有的他汀类药物,如阿托伐他汀、氟伐他汀、洛伐他汀、匹伐他汀、普伐他汀、瑞舒伐他汀和辛伐他汀可用于心血管疾病事件的预防。众所周知,在治疗过程中一些服用他汀类药物的患者出现不良反应,如肝损害、癌症的风险和骨骼肌损害。因此,认识他汀类药物的安全性风险是很重要的。根据发表的他汀类药物的临床研究文献数据,分析和认识这类药物的安全性、不良反应及毒性的风险,并简要介绍了由美国心脏协会和美国心脏病学院基于4年评述而制定的2013年他汀类降胆固醇药物新使用指南。     

Rituximab pharmacokinetics in patients with rheumatoid arthritis: B-cell levels do not correlate with clinical response

This study characterized the relationship between clinical response, serum rituximab concentrations, and peripheral B-cell levels in patients with rheumatoid arthritis treated with rituximab. Data were analyzed from a double-blind, phase IIa trial in which 161 patients with active rheumatoid arthritis despite continuing methotrexate were randomized to methotrexate alone (10-25 mg/wk), rituximab alone (single course: 1000 mg administered intravenously on days 1 and 15), rituximab plus cyclophosphamide (750 mg administered intravenously on days 3 and 17), or rituximab plus methotrexate. Serum samples for pharmacokinetic analysis were collected through 24 weeks, and peripheral circulating CD19+ B-cell levels were measured through 48 weeks. All treatments were generally well tolerated, with no clinically relevant excess of adverse events leading to withdrawal among patients who received rituximab compared with those who received methotrexate alone. The proportions of patients who achieved an American College of Rheumatology score of 50 at week 24 were 13% (methotrexate alone), 33% (rituximab alone), 41% (rituximab plus cyclophosphamide), and 43% (rituximab plus methotrexate). Peripheral B-cell depletion occurred by day 15 in all patients treated with rituximab. There was no relationship between B-cell depletion and clinical response. Recovery of peripheral B cells was variable and showed no relationship with return of disease activity in patients who responded to rituximab. The mean terminal half-life of rituximab was 19 to 22 days; pharmacokinetic parameters were similar whether rituximab was administered alone or with methotrexate or cyclophosphamide. Because the level of peripherally circulating B cells does not appear to correlate with a maintained clinical response in patients with rheumatoid arthritis, the timing of rituximab retreatment should be based on clinical symptoms rather than peripheral B-cell levels.     

Role of HMG-CoA reductase inhibitors in neurological disorders : progress to date

Inhibitors of HMG-CoA reductase (statins) are cholesterol-lowering agents that dramatically reduce morbidity and mortality in patients with established cardiovascular disease. In addition, they exhibit pleiotropic effects that operate independently of lipid modification. Statin administration results in greater nitric oxide bioavailability, improved endothelial function, enhanced cerebral blood flow, immune modulation with anti-inflammatory action, decreased platelet aggregation and antioxidant activity. Some or all of these effects may improve outcome or ameliorate symptoms in neurological disorders. This article examines the potential role of statins in treating stroke, Alzheimer's disease, multiple sclerosis and Parkinson's disease. Studies are ongoing in this controversial area, but there are no firm conclusions. The appropriateness of initiating statin therapy for neurological disorders is not established at this time. The exception is stroke, in which recurrence is significantly reduced by statin therapy.     

Effects of synthetic and biological disease modifying antirheumatic drugs on lipid and lipoprotein parameters in patients with rheumatoid arthritis

BackgroundDyslipidemia in rheumatoid arthritis (RA) patients is frequently observed, and treatment with anti-rheumatic drugs has an impact on lipid profiles. Pathophysiologically, inflammation leads to decreased blood lipids and lipoproteins; RA treatment reduces inflammation and therefore may increase lipids and lipoproteins. Whether the lipid changes with RA treatment confer an increased risk of cardiovascular disease or just reflect their potentially atheroprotective anti-inflammatory effect is currently unclear due to limited and conflicting data.ObjectiveThe aim of this review is to summarize the current knowledge on the effects of synthetic and biological disease modifying antirheumatic drugs for the treatment of RA on lipid and lipoprotein parameters.ResultsRecent studies on methotrexate emphasize its anti-atherogenic effect. Golimumab combined with methotrexate revealed a trend towards an anti-atherogenic potential. The known pro-atherogenic lipid-spectrum alterations caused by tofacitinib can be effectively treated with atorvastatin. Tocilizumab signals a favorable impact on the extent of lipid modifications when combined with methotrexate. Abatacept indicated a trend towards an anti-atherogenic lipid profile demonstrated by favorable effects on HDL-C and on the TC/HDL-C ratio. Rituximab has beneficial effects on HDL-C and ApoA1, as well as on the ApoB/ApoA1 ratio.Clinical implicationsAnti-rheumatic drugs have various effects on lipid parameters, which in part appear pro-atherogenic. However, because many of these lipid changes may well reflect their potentially atheroprotective anti-inflammatory action the cardiovascular impact of these changes remains unclear. Whatsoever, cardiovascular safety trials for antirheumatic drugs would be valuable.     

The antiplatelet and antithrombotic actions of statins

Several studies over the last years have demonstrated that statins exhibit actions beyond that of lipid-lowering (pleiotropic effects) ranging from improving endothelial function, modulating the inflammatory response, maintaining plaque stability and preventing thrombus formation. Since the interplay among platelets, cells and other components of atherosclerotic lesions as well as the coagulation system play an important role in the progression of atherosclerosis and in the development of acute coronary syndromes, these non-lipid properties of statins may help to explain the early and significant reduction of cardiovascular events reported in several clinical trials of statin therapy. This review focuses on the experimental and clinical results regarding the antiplatelet/antithrombotic effects of statins.     

Treatment of rheumatoid arthritis.

PURPOSE: Current and investigational treatments of rheumatoid arthritis (RA) are described. SUMMARY: The current therapies used to treat RA include nonsteroidal antiinflammatory drugs (NSAIDs), used for the management of pain and inflammation; disease-modifying antirheumatic drugs (DMARDs), used as first-line therapy for all newly diagnosed cases of RA; and biological-response modifiers, targeted agents that selectively inhibit specific molecules of the immune system. Glucocorticoids and other antirheumatic drugs are also used to treat RA. DMARDs include methotrexate, hydroxychloroquine, sulfasalazine, and leflunomide. NSAIDs and glucocorticoids are effective in controlling the pain, inflammation, and stiffness related to RA. Unlike NSAIDs, they slow clinical and radiographic progression of RA. The biological-response modifiers include infliximab, etanercept, and adalimumab (inhibitors of tumor necrosis factor [TNF]-alpha); anakinra, a recombinant inhibitor of interleukin-1; abatacept, the first costimulation blocker; and rituximab, a chimeric anti-CD20 monoclonal antibody. Investigational therapies for RA include anti-interleukin-6-receptor monoclonal antibodies, new TNF-alpha inhibitors (including one for oral administration), and antibodies against proteins critical for B-cell function and survival. Data accumulated in the past decade favor early aggressive therapy for patients suspected of having RA, including early referral to a rheumatologist, new diagnostic techniques, and aggressive therapy with DMARDs, glucocorticoids, and biological agents. The benefits of this approach have been demonstrated in clinical trials. CONCLUSION: Pharmacologic treatments of RA include NSAIDs, glucocorticoids, DMARDs, and biological agents. With an improved understanding of the pathophysiology of RA and the evidence from various clinical trials with the agents, early aggressive therapy with a combination of drugs or biological agents may be warranted for the effective treatment of RA.     

Role and significance of statins in the treatment of hypertensive patients

ABSTRACT

Background: Statins are the first-line drug therapy in the treatment of hypercholesterolemia. The beneficial clinical impact of statins on the cardiovascular system results not only from their lipid-lowering action but also from other effects. Recently, it has been suggested that statins can reduce blood pressure, especially in hypertensive patients.

Aim: The role of the hypotensive action of statins and other mechanisms which reduce cardiovascular risk in hypertensive patients are discussed in this review.

Methods: Electronic databases searched were [MEDLINE (1966 – February 2009), EMBASE and SCOPUS (1965 – February 2009), DARE (1966 -- February 2009)]. Additionally, abstracts from national and international cardiovascular meetings were studied to identify unpublished studies. The main data search terms were: blood pressure, hypertension, hypercholesterolemia and statins.

Findings: At present, it is difficult to unequivocally assess the impact of statins on blood pressure. However, according to most authors, the impact of statins on the decrease in BP is slight, but significant, especially among patients with hypertension.     

To cardiovascular disease and beyond: new therapeutic perspectives of statins in autoimmune diseases and cancer

Statins have been successfully used in patients with hypercholesterolemia and cardiovascular diseases, but there is increasing evidence that they exert effects by much exceeding the lowering of cholesterol levels. Statins have antiatherosclerotic, antiinflammatory, antioxidant, immunomodulatory and antithrombotic effects. These "pleiotropic" effects stem from their inhibition of prenylation of the small GTP-binding proteins Ras and Rho, and to the disruption, or depletion, of cholesterol rich membrane micro-domains (membrane rafts). Through these pathways statins modulate immune responses by altering cytokine levels and by affecting the function of cells involved in both innate and adaptive responses. Anti-inflammatory and immunosuppressory properties of statins provide the rationale for their potential application in conditions in which the inflammation and immune response represent key pathogenic mechanisms, such as antiphospholipid syndrome, rheumatoid arthritis and systemic lupus erythematosus. Reduction of atherosclerosis progression in autoimmunity is also a very important effect. Statins pathways of action in systemic autoimmune diseases, and their potential therapeutic use are discussed in this review. The inhibition of mevalonate pathway by statins impairs modification of Ras and Rho GTPases, which play key roles in signaling pathways related to tumor formation, metastasis and cell death. There is experimental and clinical evidence that statins may improve the therapeutic outcome of anticancer drugs. Thus, this review will also discuss recent insights into the molecular mechanisms underlying the anticancer effects of statins and their assessment as promising candidates for inclusion into current therapeutic regimens for the treatment of malignant diseases.     

Crucial role of interferon-gamma and stimulated macrophages in cardiovascular disease

Inflammation and immune activation are crucially involved in the pathogenesis of atherosclerosis and cardiovascular disease. Accordingly, markers of inflammation such as fibrinogen, ferritin, C-reactive protein or neopterin are found in patients with vascular diseases, correlating strongly with the extent of disease and predicting disease progression. Neopterin formation by human monocyte-derived macrophages and dendritic cells is induced by the pro-inflammatory cytokine interferon-gamma, which is released by activated T-lymphocytes. Human macrophages are centrally involved in plaque formation, and interferon-gamma and macrophages are also of importance in the development of oxidative stress for antimicrobial and antitumoural defence within the cell-mediated immune response. Interferon-gamma also stimulates the enzyme indoleamine-2,3-dioxygenase, which degrades tryptophan to kynurenine. Again, macrophages are the most important cell type executing this enzyme reaction, but also other cells like dendritic cells, endothelial cells or fibroblasts can contribute to the depletion of tryptophan. Likewise, enhanced tryptophan degradation was reported in patients with coronary heart disease and was found to correlate with enhanced neopterin formation. In chronic diseases such as in cardiovascular disease, biochemical reactions induced by interferon-gamma may have detrimental consequences for host cells. In concert with other pro-inflammatory cytokines, interferon-gamma is the most important trigger for the formation and release of reactive oxygen species (ROS). Chronic ROS-production leads to the depletion of antioxidants like vitamin C and E and glutathione, with a consequence that oxidative stress develop. Oxidative stress plays a major role in the atherogenesis and progression of cardiovascular disease, and it may also account for the irreversible oxidation of other oxidation-sensitive substances like B-vitamins (e.g. folic acid and B12). They are essential cofactors in homocysteine-methionine metabolism. Associations between moderate hyperhomocysteinaemia and cellular immune activation are found in several diseases including coronary heart disease, and data indicate that hyperhomocysteinaemia may develop as a consequence of immune activation. Homocysteine accumulation in the blood is established as an independent risk factor for cardiovascular disease. Homocysteine itself has the capacity to further enhance oxidative stress. Interferon-gamma appears to be a central player in atherogenesis and in the development and progression of cardiovascular disease. Anti-inflammatory and immunosuppressive treatment (e.g. with non-steroidal anti-inflammatory drugs or statins) may among other consequences, also contribute to a slow-down of the adverse effects of interferon-gamma.     

Investigating cardiovascular risk reduction--the Rosuvastatin GALAXY Programme

The GALAXY Programme is a comprehensive global research initiative that will address several important unanswered questions in statin research and investigate the impact of rosuvastatin on cardiovascular risk reduction and patient outcomes. Studies already completed demonstrate that rosuvastatin provides greater reductions in low-density lipoprotein cholesterol (LDL-C) than other statins, enabling more patients to achieve LDL-C treatment goals. Additionally, rosuvastatin provides beneficial effects on other components of the atherogenic lipid profile. Ongoing studies will evaluate whether these effects translate into beneficial effects on atherosclerosis and significant reductions in cardiovascular events. Important information will also be provided on the role of statins in less well studied groups, including patients with heart failure, end stage renal disease, and individuals without elevated LDL-C but at heightened vascular risk as a result of increased systemic inflammation. Ultimately, the GALAXY Programme will provide clinical data that will enable physicians to make more effective statin treatment decisions, which will lead to improved patient care and cardiovascular outcomes.     

Treatment of early rheumatoid arthritis: Methotrexate and beyond

For the last several decades, the standard of care for the initial management of rheumatoid arthritis (RA) has been methotrexate. Methotrexate is effective as monotherapy and in combination with conventional, biologic, and targeted-synthetic therapies. Methotrexate is generally well-tolerated, but has important, albeit uncommon, potential side-effects including a risk of liver toxicity and cytopenias. Some studies suggest that more active monitoring in patients with fatty liver disease may be appropriate. With reassuring safety data, more rapid dose escalation and use of subcutaneous therapy may provide even greater success. Some off-target benefits such as a reduction in cardiovascular disease risk have also been demonstrated, though these studies may suffer from confounding. Recent published guidelines continue to endorse methotrexate as first-line therapy. Methotrexate is a low-cost, safe, and effective therapy for RA that should not be overlooked nor too quickly abandoned.     

Emerging anti-inflammatory drugs for atherosclerosis

Introduction: Cardiovascular disease is the most common cause of morbidity and mortality worldwide. Inflammation is responsible for initiation and progression of atherosclerosis, and leads to plaque vulnerability. Evidence-based therapies reduce the risk of initial and recurrent cardiovascular events but many patients experience recurrent events due to the failure of conventional therapies to adequately address inflammation.

Areas covered: Statins were originally developed for their LDL cholesterol-lowering effects, but are now thought to improve cardiovascular morbidity and mortality through anti-inflammatory effects as well. Drugs that inhibit the various inflammatory pathways responsible for atherosclerosis are the subject of current research. These include antioxidants, phospholipase A₂ inhibitors, leukotriene pathway inhibitors, CCL2-CCR2 pathway inhibitors, non-specific anti-inflammatory drugs (i.e., methotrexate), IL-1 inhibitors and p-selectin inhibitors.

Expert opinion: Currently, only three anti-inflammatory drugs (methotrexate, darapladib and canakinumab) are being investigated in Phase III clinical trials of atherosclerosis. The development of cardiovascular drugs requires long, expensive Phase III trials to demonstrate incremental improvement in cardiovascular events. Imaging end points and soluble biomarkers accelerate Phase II development, but further validation is needed before these can be used as surrogate end points in the large trials leading to drug approval. Improved access to currently available therapies like statins would decrease the burden of cardiovascular disease worldwide.     

Impact of traditional therapies and biologics on cardiovascular diseases in rheumatoid arthritis

In chronic inflammatory diseases such as rheumatoid arthritis (RA), systemic inflammation appears as an independent risk factor, contributing to increased cardiovascular mortality. This high cardiovascular mortality reveals the existence of accelerated atherosclerosis, the pathogenesis of which may be associated with traditional risk factors such as smoking, hypertension, dyslipidemia, deterioration of insulin sensitivity, and less traditional risk factors such as hyperhomocysteinemia, inflammatory conditions and endothelial dysfunction. Control of systemic inflammation theoretically provides a means of preventing this higher cardiovascular mortality among RA patients. In this review we address the question of the impact of anti-rheumatic drugs currently used in RA, such as non-steroidal anti-inflammatory drugs (e.g. non-selective or cyclooxygenase-2 selective inhibitors), steroidal anti-inflammatory drugs (glucocorticoids), traditional disease-modifying anti-rheumatic drugs (e.g. methotrexate) or biologics (e.g. anti-tumour necrosis factor alpha anti-tumour necrosis factor alpha) on cardiovascular diseases in RA patients. We also discuss the specific mechanisms involved in the differential cardiovascular effects of these therapeutic agents.