系统性红斑狼疮患者的用药选择及其与肾脏损害相关性的回顾性分析

目的 了解系统性红斑狼疮(SLE)患者用药的基本情况,探讨规范化应用免疫抑制剂治疗的重要性,为改善SLE患者预后提供临床依据.方法 采用流行病学现况调查的研究方法,随机调查252例SLE患者,记录患者自发病以来的用药情况,并分析用药以及就诊情况等因素与肾脏损害之间的关系.结果 在252例SLE患者中药物治疗以糖皮质激素(99.2%)、免疫抑制剂(75.8%)、羟氯喹(61.5%)为主.免疫抑制剂以环磷酰胺为常用药(75.9%).应用免疫抑制剂6个月以上的患者仅有128例(50.8%).因惧怕不良反应而擅自停药仍为患者停用免疫抑制剂、羟氯喹的主要原因.通过单因素及多因素Logistic回归分析表明,规范应用激素、免疫抑制剂、羟氯喹治疗可以显著降低狼疮肾脏损害的发生率;并且应用免疫抑制剂治疗时间超过3个月,其肾损害以及肾功能不全的发生率明显降低(χ2=3.996,P＜0.05;χ2=13.196,P＜0.01),尤其是达到6个月以上的患者,这种差异更加明显(χ2=4.505,P＜0.05;χ2=8.453,P＜0.01).结论 SLE患者治疗主要是应用糖皮质激素联合免疫抑制剂、羟氯喹.尽早及规范应用糖皮质激素联合免疫抑制剂或羟氯喹治疗,可以显著降低狼疮肾脏损害的发生率.     

B-cell depletion in the treatment of lupus nephritis

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that is clinically heterogeneous and affects multiple organs. Lupus nephritis is the most frequent severe manifestation of SLE. Conventional immunosuppressive therapy has increased the life expectancy of patients diagnosed with lupus nephritis, but only 70-80% of patients respond to this treatment and its adverse effects are considerable. B cells are central to the pathogenesis of SLE and are, therefore, an attractive therapeutic target. B-cell depletion has been used successfully to treat other autoimmune diseases, such as rheumatoid arthritis and antineutrophil cytoplasmic antibody-associated vasculitis, and many case reports and small nonrandomized trials of B-cell-depleting agents in patients with lupus nephritis have reported positive results. By contrast, two large placebo-controlled trials designed to investigate the efficacy of the B-cell-depleting agents rituximab and ocrelizumab as a treatment for lupus nephritis, failed to meet their primary efficacy end points (LUNAR and BELONG, respectively). This Review discusses the current evidence on the use of B-cell depletion in the treatment of lupus nephritis, which is derived from case studies and clinical trials including a total of over 800 patients.     

Antimalarial drugs, systemic lupus erythematosus and pregnancy

Antimalarial drugs containing the 4-amino quinoline radical are used to help control disease activity in discoid lupus erythematosus and systemic lupus erythematosus (SLE). Many patients with these complaints are young women, some of whom will become pregnant. The use of these substituted 4-amino quinoline compounds in pregnancy is controversial. We studied the full obstetric histories of 8 women with SLE who had taken either chloroquine phosphate or hydroxychloroquine sulphate (Plaquenil) throughout the entire length of at least 1 pregnancy. These 8 women had 14 pregnancies while receiving antimalarial drugs. Fetal wastage was high in these patients, regardless of antimalarial therapy, and was almost 100% in patients who were clinically active. Six normal full term spontaneous deliveries resulted from these pregnancies with clinically healthy normal babies born despite exposure to antimalarial therapy throughout the pregnancies.     

Current state of evidence on 'off-label' therapeutic options for systemic lupus erythematosus, including biological immunosuppressive agents, in Germany, Austria and Switzerland--a consensus report

Systemic lupus erythematosus (SLE) can be a severe and potentially life-threatening disease that often represents a therapeutic challenge because of its heterogeneous organ manifestations. Only glucocorticoids, chloroquine and hydroxychloroquine, azathioprine, cyclophosphamide and very recently belimumab have been approved for SLE therapy in Germany, Austria and Switzerland. Dependence on glucocorticoids and resistance to the approved therapeutic agents, as well as substantial toxicity, are frequent. Therefore, treatment considerations will include 'off-label' use of medication approved for other indications. In this consensus approach, an effort has been undertaken to delineate the limits of the current evidence on therapeutic options for SLE organ disease, and to agree on common practice. This has been based on the best available evidence obtained by a rigorous literature review and the authors' own experience with available drugs derived under very similar health care conditions. Preparation of this consensus document included an initial meeting to agree upon the core agenda, a systematic literature review with subsequent formulation of a consensus and determination of the evidence level followed by collecting the level of agreement from the panel members. In addition to overarching principles, the panel have focused on the treatment of major SLE organ manifestations (lupus nephritis, arthritis, lung disease, neuropsychiatric and haematological manifestations, antiphospholipid syndrome and serositis). This consensus report is intended to support clinicians involved in the care of patients with difficult courses of SLE not responding to standard therapies by providing up-to-date information on the best available evidence.     

Antimalariamittel

In contrast to many other medications, chloroquine and hydroxychloroquine are approved treatment options for systemic lupus erythematosus (SLE). Antimalarials reduce the frequency of disease flares and contribute to the maintenance of remission. Apart from its direct effects on SLE activity, antimalarials seem to protect against thrombotic events and have a beneficial effect on glucose and lipid profiles, which might help reduce the high cardiovascular risk of SLE. Hydroxychloroquine is the only treatment shown to be effective in reducing the risk of damage accrual in SLE patients. Finally, antimalarials are inexpensive, especially compared with more recent treatments, and are well tolerated in SLE. Despite all these benefits, still only about 40%–50% of SLE patients are treated with (hydroxy)chloroquine. Particularly in early disease phases, antimalarials should be considered for every lupus patient, assuming there are no contraindications.     

Safety of treatment with chloroquine and hydroxychloroquine: A ten-year systematic review and meta-analysis

ObjectiveTo estimate the incidence rate ratio (IRR) of adverse events (AE) in chloroquine or hydroxychloroquine users.MethodsWe systematically reviewed randomized controlled trials (RCTs), using MEDLINE (2010-2020) and EMBASE (2010-2020) databases, reporting AE in chloroquine or hydroxychloroquine users during treatment for lupus, rheumatoid arthritis, malaria and COVID-19. The protocol for this systematic review is registered at the PROSPERO database (CRD42020197938). The quality of the included studies was assessed using the Cochrane risk-of-Bias tool and relevant data were extracted though a customized data collection form, independently, by two authors. The IRR of AE was estimated using a random-effect model meta-analysis and heterogeneity was evaluated by T² and I². Subgroup analysis was performed, and publication bias was assessed by funnel-plot.ResultsForty-six RCTs met our eligibility criteria and were included in our analysis (23132 patients). There was not a single death attributed to chloroquine or hydroxychloroquine use in the included RCTs. The IRR of general AE during antimalarial use was 1.15 [CI 95% 1.01-1.31]. COVID-19 patients treated with either antimalarial presented an 83% and 165% higher risk of developing general and gastrointestinal AE, respectively, in comparison with controls. The use of antimalarial increased the risk of developing dermatological AE by 92% in malarial studies and reduced by 65% in lupus studies. We did not find a significatively higher risk of cardiovascular nor ophthalmological AE in antimalarial users.ConclusionsOur data reinforces that chloroquine and hydroxychloroquine have a good safety profile though caution is advised when using higher than usual doses in hospitalized COVID-19 patients.     

Treatment of Mild,Moderate, and Severe Lupus Erythematosus: Focus on New Therapies

Despite large-scale efforts devoted to the conduct of clinical trials in systemic lupus erythematosus (SLE), no new therapy has been approved for treatment of this disease in more than 50 years. Increased understanding of the immunologic mechanisms underlying SLE has led to the development of a variety of biologic agents that target specific aspects of the adaptive and innate arms of the immune system, including B cells, T cells, dendritic cells, and various cytokines. One of these agents, belimumab, was the subject of two positive phase 3 trials in nonrenal lupus that have given us hope that a new therapy for SLE may be finally within our grasp. In addition to these newer therapies, recent studies of standard-of-care medications such as mycophenolate mofetil and hydroxychloroquine have better defined the efficacy and safety of these agents for the treatment of lupus nephritis and nonrenal lupus. This article provides a discussion of several novel biologic agents at different stages of development for the treatment of SLE, as well as an analysis of newer data on agents that have been used in the treatment of SLE for many years.     

Alternative therapies: what role do they have in the management of lupus?

Systemic lupus erythematosus (SLE) is an autoimmune disease with higher morbidity and mortality among ethnic Chinese patients than Whites. Corticosteroid and other immunosuppressive drugs, including cyclophosphamide, azathioprine, and hydroxychloroquine are traditional therapies for this disease. Since the year 2000, mycophenolate mofetil and rituximab have been widely used in refractory SLE or severe lupus nephritis. Because the high disease activity remains, even after active therapy, and serious side effects from Western medicines may develop, more than 40% of SLE patients in Western countries are pursuing complementary and alternative therapies (CATs). CAT remedies are multiplex, and include herbal medicines, diets and vitamins, acupuncture, chiropractice, folk medicine, massage, spiritual healing, etc. Many herbal formulas have been used but in general their efficacy in treating lupus is doubted because of the lack of strong evidence. Tripterygium (T2) has demonstrated good efficacy in rheumatoid arthritis (RA) and SLE, but widespread use is limited due to the side effects. Through randomized clinical trials, we hope in the future that some Chinese medicines may be found helpful as CATs for SLE.     

Complete atrioventricular block following long term treatment with chloroquine

Antimalarial agents are routinely used in the management of connective tissues diseases and various skin disorders. Ophthalmologic, neurological and digestive side effects of antimalarial agents are well known. However, cardiac toxicity is uncommon. We report a 49-year-old patient, treated with chloroquine for 21 years for a systemic lupus erythematosus and a discoid lupus, who presented a complete atrioventricular block that required implantation of a cardiac pacemaker in emergency. This patient did not have significant cardiovascular past medical history. Investigations excluded known causes of atrioventricular block and chloroquine toxicity was diagnosed. This case report illustrates the cardiotoxicity of synthetic antimalarial agents. A regular cardiovascular monitoring (especially with electrocardiogram) could be useful in patients receiving long-term treatment with antimalarial agents.     

Inflammatory bowel disease and lupus: A systematic review of the literature

Coexistence of systemic lupus erythematosus (SLE) should be considered in patients with inflammatory bowel disease (IBD) and complex extraintestinal manifestations and the diagnosis of IBD could be established either before or after the diagnosis of SLE. Differential diagnosis of concomitant SLE and IBD is difficult and should always exclude infectious conditions, lupus-like reactions, visceral vasculitis and drug-induced lupus.The underlying mechanism by which 5-ASA/sulphasalazine induces SLE or lupus-like syndromes is not clear and high awareness for possible predictive factors is demanded for early prevention.In most cases the symptoms from drug-induced lupus have been reversible after the discontinuation of the drug and response to steroids is favorable. Treatment of patients co-diagnosed with SLE and IBD may include corticosteroids, immunosupressants and hydroxychloroquine.In severe lupus and IBD patients cyclophosphamide pulse may be of benefit while infliximab may be beneficiary in patients with lupus nephritis. However, the role TNFalpha plays in humans with SLE and IBD is controversial and data on the likely effects of blocking TNFalpha on anti-DNA autoantibody production is always of interest.     

Treatment of systemic lupus erythematosus.

Reports on a variety of therapies for systemic lupus erythematosus have been published over the past year. Most of these are single case reports or open studies. As reported last year in this journal, the potential uses of intravenous gamma globulin and plasmapheresis continue to be explored. The use of cyclophosphamide for nonrenal manifestations follows studies last year of its use for lupus nephritis. No major double-blind studies of therapy for lupus nephritis were published; however, the course of lupus patients receiving dialysis or grafts was the subject of three interesting studies. An interesting study on the ability of hydroxychloroquine to prevent disease exacerbations was also published. In summary, the reports of therapy over the past year represent variations on themes. The use of new agents will most likely be based on improvements in our understanding of the pathogenesis of systemic lupus erythematosus.     

Retinal toxicity caused by hydroxychloroquine in patients with systemic lupus erythematosus: A case report

Rationale:Hydroxychloroquine has excellent anti-inflammatory and immunomodulatory effects as one of the antimalarial drugs. In particular, hydroxychloroquine was once widely used as a treatment for the new coronavirus pneumonia epidemic in 2020. Retinopathy caused by hydroxychloroquine is normally irreversible, but little attention has been paid to it.Patient concerns:A 38-year-old young Chinese woman was taking oral hydroxychloroquine 400 mg daily to control lupus disease activity for six years after the diagnosis of systemic lupus erythematosus (SLE). She did not have any history of eye disease and was admitted to the hospital with a sudden blurring of both eyes.Diagnoses:The diagnosis of retinal macular degeneration caused by hydroxychloroquine was made after excluding other interfering diseases based on the patient''s long-term use of hydroxychloroquine and the results of the eye examination.Interventions:The patient was discontinued from hydroxychloroquine. To control the recurrence of SLE, she was given intravenous methylprednisolone, oral tacrolimus and mycophenolate. Meanwhile, she was asked to take extra care of her eyes and to come to the hospital every three months to have her vision checked.Outcomes:The patient''s blurred vision improved one week later. Three months later, her vision examination showed no further decline (0.4 in the right eye and 0.6 in the left eye). Meanwhile, the SLE disease activity index (SLEDAI) decreased from six points to five points currently.Lessons:Retinopathy caused by hydroxychloroquine is irreversible and there is no particularly effective treatment. Discontinuation of hydroxychloroquine, better daily eye protection, and regular vision checks are the keys to preventing retinopathy. Although hydroxychloroquine causing retinal toxicity was mentioned several years ago, the rate and severity of retinal toxicity require further research. How to get more patients to take care of their eyes requires continuous and increased education by doctors.     

Management des systemischen Lupus erythematodes

In the last few decades a number of small, often largely unrecognized steps have fundamentally changed the management of systemic lupus erythematosus (SLE). The current goal is to stop all disease activity without long-term use of more than 5 mg prednisolone per day. Remission, i.e. absence of activity in the SLE activity score of choice, is the defined target in the treat to target approach. The essential basic measures include life-long hydroxychloroquine as well as protection from sunlight (UV) and vitamin D substitution. Patients suffering from SLE need more vaccinations than the healthy population and control of risk factors for atherosclerosis is critical for long-term survival. Methotrexate is on par with azathioprine. If disease activity cannot be controlled in this way, belimumab is an approved therapeutic option. Cyclophosphamide is still used but only in life-threatening situations, such as lupus nephritis or central nervous system (CNS) vasculitis and in drastically reduced doses. Alternatively, off-label mycophenolate mofetil (MMF) can be used particularly for lupus nephritis and off-label rituximab in refractory disease courses. Numerous novel approaches are being tested in controlled trials and it is hoped that new drugs will be available for SLE patients within a few years.     

Previous antimalarial therapy in patients diagnosed with lupus nephritis: influence on outcomes and survival

The aim of this study was to analyze the effect of exposure to antimalarial drugs at diagnosis of lupus nephritis on the outcome of the disease, especially renal failure, comorbid processes, and survival. We analyzed a cohort of 206 consecutive patients with biopsy-proven lupus nephritis. Renal biopsies were categorized according to the classification proposed by the ISN/RPS in 2003. Exposure to antimalarial drugs (chloroquine and hydroxychloroquine) was defined as the use of these drugs before the diagnosis of lupus nephritis independent of dose and duration. Fifty-six (27%) patients had received antimalarials before the diagnosis of lupus nephritis. During the follow-up, these patients had a lower frequency of creatinine values >4 mg/dL (2% vs 11%, P = 0.029) and end-stage renal failure (2% vs 11%, P = 0.044) in comparison with those never treated with antimalarials. Patients exposed to antimalarials also had a lower frequency of hypertension (32% vs 50%, P = 0.027), infections (11% vs 29%, P = 0.006), and thrombotic events (5% vs 17%, P = 0.039). Twenty patients (10%) died during the study period. Patients exposed to antimalarials had a lower mortality rate at the end of the follow-up (2% vs 13% for those not exposed to antimalarials, P = 0.029). Multivariate analysis identified thrombosis and infections as statistically significant independent variables. Kaplan-Meier plots showed a lower rate of end-stage renal failure (log rank = 0.04) in patients exposed to antimalarials. In conclusion, exposure to antimalarials before the diagnosis of lupus nephritis was negatively associated with the development of renal failure, hypertension, thrombosis and infection, and with a better survival rate at the end of the follow-up. This, together with other published data, suggests that antimalarials should be considered a mandatory therapeutic option in all patients diagnosed with systemic lupus erythematosus.     

Antimalarial therapy: a panacea for mild lupus?

Antimalarial therapy has a long and successful track record in the management of patients with mild SLE. Medium to long term use of hydroxychloroquine, alone or in combination with mepacrine, ameliorates lupus and may reduce the relapse rate. Recent guidelines for monitoring hydroxychloroquine have reduced the need for frequent visual checks. Antimalarials have other beneficial effects on lipid and glucose metabolism as well as having weak anticoagulant activity. They should be considered for most patients with mild lupus.     

Adherence to ophthalmologic monitoring for antimalarial toxicity in a lupus cohort

OBJECTIVE: Antimalarial agents (hydroxychloroquine and chloroquine) are important in the treatment of various rheumatic diseases, including systemic lupus erythematosus (SLE). Although these agents may lead to ocular complications, little is known about adherence to policies for ophthalmologic monitoring. We investigated adherence to the 1996 American College of Rheumatology (ACR) guidelines (recommending yearly ophthalmologic assessments) at our clinic, and determined the factors associated with nonadherence. METHODS: Chart review of the Montreal General Hospital lupus clinic cohort. RESULTS: Of 195 subjects with at least one full year of antimalarial exposure during 1996-2001, 5 refused participation and data on ophthalmology monitoring was incomplete for 42. Of the remaining 148 patients, 47 (32%) had missed at least one annual ophthalmology assessment (were nonadherent) during the interval; almost half of these had missed 相似文献   

Continuation of long term treatment with hydroxychloroquine in systemic lupus erythematosus and rheumatoid arthritis.

BACKGROUND: Hydroxychloroquine is used for the treatment of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Long term studies have shown a high rate of termination of hydroxychloroquine treatment in patients with RA. Although it has been shown that discontinuation of treatment with hydroxychloroquine is associated with exacerbation of SLE, long term maintenance rates of treatment with hydroxychloroquine in patients with SLE have not been investigated. METHODS: Hydroxychloroquine use in patients with RA and SLE in a group of patients in a single community rheumatology practice was studied. Information was drawn from a computer drug use database containing details of the beginning and end of treatment. Data were analysed using life table methods. RESULTS: Four hundred and three treatment episodes (366 patients with RA, 37 patients with SLE) were observed over eight years. In patients with RA, the cumulative probability of discontinuing treatment was 37% at 12 months and 54% at 24 months. In contrast, hydroxychloroquine treatment of patients with SLE continued over significantly longer periods of time (p < 0.001); the discontinuation probabilities at 12 and 24 months were 8 and 24% respectively. Treatment terminations were predominantly for inefficacy; terminations for toxicity were limited to the first 19 months of treatment. No ocular toxicity was observed. CONCLUSIONS: Treatment of patients with RA in a community rheumatology practice with hydroxychloroquine has a low probability of long term continuation, mostly because of inadequate control of disease manifestations rather than toxicity. In patients with SLE, treatment with hydroxychloroquine has a significantly higher probability of long term continuation.     

Biological treatments for systemic lupus erythematosus

There have been many recent advances in therapeutic approaches to systemic lupus erythematosus (SLE). The roles of cyclophosphamide, hydroxychloroquine, methotrexate and hormonal treatments in the management of SLE have been investigated in recent randomised controlled trials (1). However, although these pharmacological agents have a role to play in some patients with lupus, broad based effects have led to problems with side effects and adverse reactions. For this reason, more specific therapies are urgently required. Such strategies currently under evaluation include altering the cytokine balance, reducing T cell activation and inducing tolerance, blocking T cell costimulatory molecules, reducing auto-antibody production from B cells, targetting specific genes and stem cell transplantation. These are known as "biological" treatments as their aim is to alter patho-physiological processes occurring in the diseased state. This review will focus on the biological therapies currently under investigation-with particular attention on the cytokine-directed therapies.     

Hydroxychloroquine cardiotoxicity in systemic lupus erythematosus: a report of 2 cases and review of the literature

BACKGROUND: Hydroxychloroquine (HCQ) is extensively used in the long-term treatment of systemic lupus erythematosus (SLE). Although considered by clinicians to be relatively safe, serious side effects have been documented in the literature. Retinotoxicity has received the most attention, whereas neuromyotoxicity and cardiotoxicity have been described in isolated case reports. We present 2 cases of potential cardiotoxicity occurring in patients with SLE while receiving long-term HCQ therapy. OBJECTIVE: To review the incidence, presentation, and mechanism of serious antimalarial toxicity, and to discuss the impact of HCQ on cardiac health in SLE. METHODS: The authors reviewed the English-language literature from 1948 to December 2002 using Medline databases. RESULTS: In addition to our patients, there are 2 published cases of biopsy-proven HCQ cardiotoxicity in the English-language literature. Both occurred in patients with SLE. The literature indicates that antimalarial cardiotoxicity may be of particular importance in patients with SLE given their already increased cardiac risk due to primary heart disease and accelerated atherosclerosis. Endomyocardial biopsy reveals a constellation of findings including vacuolar myopathy, myeloid bodies, and curvilinear bodies. CONCLUSIONS: As HCQ use among SLE patients increases, clinicians should be alert to the possibility of antimalarial cardiotoxicity. The potential severity and reversibility of this complication underscore the importance of timely diagnosis. The cases presented here, one with biopsy and one without, illustrate the utility of endomyocardial biopsy in HCQ-treated SLE patients with cardiac complaints to ensure accurate diagnosis and appropriate management.     

Lupus Nephritis: Review of the Literature

Physicians in practice should be knowledgeable regarding several aspects of autoimmune disorders, especially systemic lupus erythematosus (SLE) and lupus nephritis. These disorders can present to the clinician’s clinic and private office regardless of their speciality. This review will discuss various aspects of SLE, its mechanisms of disease, role of accelerated atherosclerosis, proinflammatory cytokines, and therapeutic approaches. The role of vascular endothelial growth factor in which and plasma levels have been associated with disease activity, classification of severity, and diagnosis of lupus nephritis is addressed. Current treatment options, prognosis, and future therapeutic approaches and common side effects are also discussed.