Glucocorticoid-induced diabetes mellitus in patients with systemic lupus erythematosus treated with high-dose glucocorticoid therapy

The aim of this study was to investigate the prevalence and associated factors of glucocorticoid-induced diabetes mellitus (GDM) in patients with systemic lupus erythematosus (SLE) receiving high-dose glucocorticoid therapy. Patients with SLE who had received high-dose glucocorticoid therapy (prednisolone ≥1?mg/kg/day) at Yonsei University Medical Center, Seoul, Korea, were recruited between January 1999 and June 2009. In total 127 patients with SLE were evaluated. Sixteen (12.6%) of them developed GDM after high-dose glucocorticoid therapy (95% confidence interval, 6.8-18.4%). Univariate analysis showed that old age, family history of diabetes mellitus (DM), hypertension, higher body mass index, higher mean dose of prednisolone before high-dose glucocorticoid therapy, and concurrent use of mycophenolate mofetil (MMF) were factors that would increase the likelihood of GDM. Multivariate analysis determined that age, family history of DM, mean dose of prednisolone before high-dose glucocorticoid therapy and concurrent use of MMF were independent associated factors for GDM. In summary, GDM was developed among 12.6% of patients with SLE after high-dose glucocorticoid therapy. Old age, family history of DM, higher mean dose of prednisolone before high-dose glucocorticoid therapy and concurrent use of MMF were determined to be factors responsible for increasing the risk of developing GDM.     

Osteoporosis screening in systemic lupus erythematosus: impact of disease duration and organ damage.

The aim of the present study was to assess the effects of disease severity and demonstrable organ damage as risk factors for the development of osteoporosis in systemic lupus erythematosus (SLE). Sixty-four SLE patients were included. Mean disease duration was 7.7 +/- 5.7 y. Thirty-two patients had persistent organ damage, defined as SLICC-ACR damage score > or = 1. Disease activity measured by SLAM-2 ranged from 3 to 27. Bone mineral density (BMD) measurements were performed with dual X-ray absorptiometry. In addition, biochemical markers of bone metabolism were studied. BMD was inversely correlated with disease duration, damage score and cumulative glucocorticoid intake, but no correlation was found for current glucocortioid use or with markers of bone metabolism. In a multivariate analysis, body weight, disease duration and damage index fitted best for the prediction of BMD at both lumbar spine and femoral neck. Seven out of 64 patients had osteoporosis according to WHO criteria. In conclusion, severe osteoporosis is uncommon in lupus patients. Disease activity and severity were no major risk factors for loss of BMD in this study, but persistent non-bone-related organ damage was significantly linked to the presence of osteoporosis measured as decreased BMD. Our data suggest that, in addition to patients receiving glucocorticoids, patients with an SLICC-ACR > or = 1 or a disease duration > or = 7 y might benefit from regular monitoring of BMD as secondary prevention of damage.     

Accrual of organ damage over time in patients with systemic lupus erythematosus

OBJECTIVE: To determine the pattern of accumulation of damage in an inception cohort of patients with systemic lupus erythematosus (SLE) followed yearly for at least 15 years, and to identify damage items that might be related to corticosteroid therapy. METHODS: An inception cohort was identified from among patients with SLE followed prospectively in the University of Toronto Lupus Clinic. Only patients who had at least yearly evaluations and were followed for at least 15 years were included. Using the SLICC/ACR damage index (SDI) accumulated damage was calculated at yearly intervals. Each new organ system involved was designated as either definitely, possibly, or not at all related to corticosteroid therapy. RESULTS: Of the 73 patients, 85% were women and 87.7% were Caucasian. Their mean age at diagnosis was 34.9 years. The mean (range) SLEDAI at presentation was 11.9 (0-37). Prednisone was used by 87.7% of the patients (mean maximum dose 37.7 mg/day, mean cumulative dose 36.8 g) for a mean of 117.1 months. Antimalarial drugs were used by 70% of the patients and 50% were taking immunosuppressive agents. The mean SDI for the whole cohort increased over time from 0.33 (0.89) during the first year to 1.90 (1.99) at 15 years. A significant proportion of the damage both early and late could be attributed to corticosteroid therapy, and this damage accumulated over time such that it constituted most of the damage at 15 years. CONCLUSION: While the overall accrual of damage is gradual, the specific systems demonstrate varying patterns of damage accrual.     

The rate and pattern of organ damage in late onset systemic lupus erythematosus

OBJECTIVE: To compare the extent and type of damage in patients with late onset and earlier onset systemic lupus erythematosus (SLE) using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). METHODS: A total of 86 SLE patients with disease onset after the age of 54 years were matched for center, sex, and ethnic origin with 155 SLE patients with disease onset before the age of 40 years. SDI scores were obtained at one year and 5 years after the diagnosis of SLE. Analysis was based on conditional logistic regression. RESULTS: SDI scores were higher in the late onset group than in younger patients at both one [mean 0.7 (range 0-3) vs 0.3 (range 0-3); p < 0.001] and 5 years [mean 1.6 (range 0-8) vs 0.9 (range 0-7); p < 0.001] after diagnosis. There was also a difference in the pattern of organ damage. While damage to the skin, kidneys, and central nervous system occurred with similar frequency, late onset disease was characterized by significantly more cardiovascular (OR 14.13, p < 0.001), ocular (OR 9.38, p = 0.001), and musculoskeletal (OR 2.68, p = 0.016) damage and malignancy (OR 7.04, p = 0.046). CONCLUSION: The occurrence of organ damage assessed by the SDI is greater in patients with late onset SLE than in younger patients and, by this criterion, lupus cannot be judged to be more benign in this age group. Also, the pattern of damage is different, but whether this reflects age per se or the effect of the disease in the elderly remains to be established.     

系统性红斑狼疮患者血浆骨桥蛋白水平与疾病活动性及脏器损害的相关性研究

目的 检测系统性红斑狼疮(SLE)患者血浆中骨桥蛋白(OPN)的水平,分析其与SLE活动性及脏器损害间的关系.方法 选择68例SLE患者和36名健康体检者,采用酶联免疫吸附试验(ELISA)检测其血浆中的OPN水平.记录采血时患者的系统性红斑狼疮疾病活动指数(SLEDAI)、实验室指标等.结果 SLE患者OPN血浆水平明显高于正常对照组[(4.5±2.0)ng/ml与(1.6±0.7)ng/ml,P＜0.01 ].SLE疾病活动组高于非活动组[(5.3±2.0)ng/ml与(3.4±1.3)ng/ml,P＜0.01];SLE患者伴有肾脏损害组高于无肾脏损害组[(5.8±2.1)ng/ml与(3.5±1.3)ng/ml,P＜0.01],有肺间质病变、胃肠道病变和心包炎的高于无脏器损害[(4.8±1.2)、(6.3±1.4)、(5.4±2.6)ng/ml与(3.5+1.3)ng/ml,P＜0.05],抗心磷脂抗体阳性患者OPN水平高于抗心磷脂抗体阴性患者[(5.3±2.4)ng/ml与(4.2±1.7)ng/ml,P＜0.05].OPN血浆水平与SLEDAI呈正相关(r=0.523,P＜0.01),与尿蛋白定量(24 h)呈正相关r=0.403,P=0.001),与补体C3呈负相关r=-0.398,P=0.001),与红细胞沉降率(ESR)、抗dsDNA抗体、抗Sm抗体、IgG、IgA、IgM、球蛋白及关节炎等无相关性(P＞0.05) .结论 OPN可能参与SLE的发病,临床上可作为疾病活动及脏器损伤的观察指标.     

Effects of prasterone on bone mineral density in women with systemic lupus erythematosus receiving chronic glucocorticoid therapy

OBJECTIVE: To assess the effects of treatment with prasterone (dehydroepiandrosterone) on bone mineral density (BMD) in female patients with mild to moderate systemic lupus erythematosus (SLE) receiving chronic treatment with glucocorticoids. METHODS: Fifty-five female patients with SLE who had received prednisone (or glucocorticoid equivalent) /= 6 months were treated for 1 year with either prasterone 200 mg/day (n = 24) or placebo (n = 31) in this randomized, double blind trial. Prasterone or placebo was added to each patient's one or more concomitant standard SLE medications, including glucocorticoids, nonsteroidal antiinflammatory drugs, antimalarials, methotrexate, azathioprine, and other immunosuppressives, which were to be maintained at fixed doses for the duration of the study. RESULTS: BMD was significantly improved in patients who received prasterone compared to placebo. At the lumbar spine, there was a mean (SEM) gain in BMD of 1.7 +/- 0.8% in the prasterone group compared to a mean loss in BMD of -1.1 +/- 0.5% in the placebo group (p = 0.003 between groups). For the total hip, mean gain was 2.0 +/- 0.9% in the prasterone group vs a mean loss of -0.3 +/- 0.4% in the placebo group (p = 0.013 between groups). In the prasterone treatment group, the mean gains from baseline at both lumbar spine and hip were statistically significant. CONCLUSION: Prasterone treatment prevented BMD loss and significantly increased BMD at both the lumbar spine and total hip in female patients with SLE receiving exogenous glucocorticoids.     

Predictors of organ damage in systemic lupus erythematosus: The Hopkins Lupus Cohort

Objective

The Systemic Lupus International Collaborating Clinics/American College of Rheumatology (ACR) Damage Index (SDI) is the accepted measure of permanent organ damage in systemic lupus erythematosus (SLE). We analyzed data from a large SLE cohort to identify variables associated with rates of damage accrual as measured by the SDI.

Methods

The study included 2,054 SLE patients (92% female, 56% white, and 37% African American) with a mean age at diagnosis of 33 years. The SDI score was calculated retrospectively at the time of cohort entry and prospectively during followup. The relationships between time‐invariant patient characteristics and rates of damage accrual were assessed based on the damage score at the last available followup visit. The relationships between time‐varying patient characteristics and damage accrual were assessed based on the timing of damage accrual during cohort participation.

Results

Overall, the SDI score increased at a rate of 0.13 per year. Higher rates of damage were observed for those who were older, male, or African American, had a lower income or education level, were hypertensive, were positive for lupus anticoagulant, or had proteinuria. During followup, the risk of damage was higher for those who were older, had more disease activity, had low complement levels, were positive for anti–double‐stranded DNA, satisfied more ACR criteria for SLE, or were receiving corticosteroids. Lower risk was observed among patients receiving hydroxychloroquine. After adjustment for other variables, age, hypertension, and corticosteroid use emerged as the most important predictors of damage accrual.

Conclusion

Our findings indicate that rates of damage vary in demographic subgroups, but much variation appears to be explained by hypertension and corticosteroid use. These data clearly point to the need for tight control of disease activity without reliance on corticosteroids.

     

Effect of high-dose methylprednisolone therapy on phagocyte function in systemic lupus erythematosus.

Circulating phagocytes play a major role in the defence of the host against microbial infection. In an attempt to identify the reason for the unusual susceptibility to infection of patients with systemic lupus erythematosus (SLE) various parameters of phagocytic cell function were assessed kinetically in whole blood, and the accumulation of cells in areas of inflammation was studied in vivo with the skin window technique. The effect on these parameters of conventional therapy with glucocorticoids and pulse therapy with large doses of methylprednisolone were examined. Patients on conventional doses of steroids had no abnormality of phagocyte function that might have predisposed to infection, apart from a reduced accumulation of monocytes in areas of inflammation and decreased lactoferrin secretion. Pulse therapy with methylprednisolone considerably delayed the secretion of lactoferrin and the adherence of neutrophils in most of the patients, as well as impairing bacterial killing and digestion.     

Changes in body composition after glucocorticoid therapy in patients with systemic lupus erythematosus

The aim of this study was to evaluate the changes in body composition after glucocorticoid treatment in patients with systemic lupus erythematosus (SLE). Consecutive SLE patients were recruited for serial measurements (baseline, months 2 and 6) of bone mineral density (BMD) and body composition [bone mineral content (BMC), fat and lean mass] by dual energy X-ray absorptiometry scan after high-dose oral glucocorticoid therapy. Factors correlated with changes in body composition were evaluated. 29 SLE patients were studied (age 39.7 +/- 11.5 years; 83% women with 29% postmenopausal; SLE duration 80.1 +/- 80 months). Fourteen patients (48%) were glucocorticoid-naive. The mean maximum daily dosage of prednisolone was 32.9 +/- 6.5 mg and the cumulative prednisolone dosage in 6 months was 2.7 +/- 0.7 g. At 6 months, a significant drop in BMC of the trunk (-5.0 +/- 2.2%; P = 0.04) and whole body (-1.2 +/- 0.4%; P = 0.002) compared with baseline was observed, and so was the BMD of the hip (-1.7 +/- 0.6%; P = 0.006) and whole body (-0.7 +/- 0.3%; P = 0.01). A significant increase in the fat mass of the trunk (+14.5 +/- 4.1%; P = 0.001) and limbs (+10.0 +/- 3.2%; P = 0.004), but a non-significant drop in lean mass of the trunk (-3.3 +/- 1.8%; P = 0.08) and limbs (-0.8 +/- 2.4%; P = 0.75) also occurred. The changes in whole body BMC correlated significantly with age (rho = -0.51; P = 0.02) and changes in total fat mass (rho = 0.44; P = 0.02) but not with lean mass (rho = -0.21; P = 0.27), gender, body mass index, smoking, prednisolone dosages or changes in BMD. In SLE patients, high-dose glucocorticoids lead to an early and rapid drop in bone mass, which is more serious in older patients and correlates with an increase in body fat.     

糖皮质激素受体在系统性红斑狼疮中的研究进展

系统性红斑狼疮（systemic lupus erythematosus，SLE）是自身免疫介导的，以免疫性炎症为突出表现的弥漫性结缔组织病。该病是结缔组织病中最易累及多脏器并引起严重脏器损害的常见疾病之一。糖皮质激素(glucocorticoids GC)为其首选治疗药物。GC 由肾上腺皮质束状带合成和分泌，受下丘脑-垂体-肾上腺轴的调节，具有调节碳水化合物、蛋白质、脂肪和水、盐、电解质的代谢,维持机体内环境平衡，以及抑制免疫、抗炎、抗休克、抗过敏等多项生理功能。其通过与糖皮质激素受体（glucocorticoid receptor GR）结合而发挥作用。现在研究表明糖皮质激素受体表达水平及基因多态性与SLE的发病、病情轻重及激素治疗效果相关。本文就此进行综述。     

Effects of prasterone on bone mineral density in women with active systemic lupus erythematosus receiving chronic glucocorticoid therapy

OBJECTIVE: To assess prevention of bone mineral density (BMD) loss and durability of the response during treatment with prasterone in women with systemic lupus erythematosus (SLE) receiving chronic glucocorticoids. METHODS: 155 patients with SLE received 200 mg/day prasterone or placebo for 6 months in a double-blind phase. Subsequently, 114 patients were re-randomized to receive 200 or 100 mg/day prasterone for 12 months in an open-label phase. Primary efficacy endpoints were changes in BMD at the lumbar spine (L-spine) from baseline to Month 6 and maintenance of BMD from Month 6 to 18 for patients who received prasterone during the double-blind phase. RESULTS: In the double-blind phase, there was a trend for a small gain in BMD at the L-spine for patients who received 200 mg/day prasterone for 6 months versus a loss in the placebo group (mean +/- SD, 0.003 +/- 0.035 vs -0.005 +/- 0.053 g/cm(2), respectively; p = 0.293 between groups). In the open-label phase, there was dose-dependent increase in BMD at the L-spine at Month 18 between patients who received 200 versus 100 mg/day prasterone (p = 0.021). For patients who received 200 mg/day prasterone for 18 months, the L-spine BMD gain was 1.083 +/- 0.512% (p = 0.042). There was no overall change in BMD at the total hip over 18 months with 200 mg/day prasterone treatment. The safety profile reflected the weak androgenic properties of prasterone. CONCLUSION: This study suggests prasterone 200 mg/day may offer mild protection against bone loss in women with SLE receiving glucocorticoids. (ClinicalTrials.gov Identifiers NCT00053560 and NCT00082511).     

Chronic intestinal pseudo-obstruction in systemic lupus erythematosus

Intestinal pseudo-obstruction (IPO) is an uncommon and severe complication of systemic lupus erythematosus (SLE). We report a 24-year-old female with a 2 year SLE duration who presented with abdominal pain, vomiting, constipation and abdominal distention. Plain abdominal radiograph showed multiple air-fluid levels of the small bowel. Computed tomographic scan of the abdomen revealed dilated small bowel loops without mechanical obstruction. Urinary tract involvement was also demonstrated. IPO was diagnosed and the patient responded well to immunosuppressive treatment. IPO is a recently recognized manifestation of SLE that may be the presenting manifestation of the systemic disease or occur more commonly during disease course. Early recognition of IPO is necessary to institute appropriate medical treatment and to avoid inappropriate surgical intervention.     

Anti-cytokine therapy in systemic lupus erythematosus

In the course of the disease, a wide variety of cytokines is dysregulated, many of which likely influence systemic lupus erythematosus (SLE) autoimmunity and/or lupus tissue inflammation. Proinflammatory cytokines in particular, such as TNF, IL-6, IL-18 or IFN-gamma, may play a major role in propagating the inflammatory processes responsible for tissue damage. These cytokines are overexpressed both systemically and locally, and preliminary results from open-label trials and/or animal studies suggest potential benefits of blocking either of these inflammatory mediators. Since new therapeutic agents may soon offer many ways to influence the process, controlled clinical trials following open-label safety studies are of central importance to arrive at optimized therapies for SLE patients.     

B-cell-depleting therapy in systemic lupus erythematosus

The emergence of a new class of agents (B-cell-depleting therapies) has opened a new era in the therapeutic approach to systemic lupus erythematosus, with belimumab being the first drug licensed for use in systemic lupus erythematosus in more than 50 years. Four agents deserve specific mention: rituximab, ocrelizumab, epratuzumab, and belimumab. Controlled trials have shown negative results for rituximab, promising results for epratuzumab, and positive results for belimumab. Despite these negative results, rituximab is the most-used agent in patients who do not respond or are intolerant to standard therapy and those with life-threatening presentations. B-cell-depleting agents should not be used in patients with mild disease and should be tailored according to individual patient characteristics, including ethnicity, organ involvement, and the immunological profile. Forthcoming studies of B-cell-directed strategies, particularly data from investigations of off-label rituximab use and postmarketing studies of belimumab, will provide new insights into the utility of these treatments in the routine management of patients with systemic lupus erythematosus.     

Time perspective predicts the progression of permanent organ damage in patients with systemic lupus erythematosus

Patients whose perspective is oriented to the future more than to the present may have better long-term health outcomes. We examined if time perspective predicted future organ damage in patients with systemic lupus erythematosus (SLE). We assessed the time perspectives of 87 patients with SLE using a questionnaire at a baseline visit. Permanent organ damage was assessed by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index during the same visit, and reassessed after a median of 4.6 years. Patients who were oriented more to the future were less likely to have an increase in the Damage Index than those oriented more to the present. In a multivariate analysis, each 1-point increase in the degree of orientation to the future (on a scale of 1-6) was associated with a 22% decrease in the likelihood that the Damage Index would increase over time (odds ratio 0.78; 95% confidence interval 0.64-0.94; P = 0.009). Other measures that predicted an increase in the Damage Index were lower education levels, greater health locus of control attributed to chance and greater health locus of control attributed to powerful others. In conclusion, time perspective is a significant predictor of future organ damage in SLE. Patients who have a greater orientation to the future are less likely to develop permanent organ damage.     

IgG therapy in systemic lupus erythematosus

Summary Two paediatric patients with systemic lupus erythematosus were treated with immunoglobulin G (IgG). In the first case treatment resulted in regression of the most acute symptoms and a long remission was achieved. In the second patient, who was treated during the chronic stage of the disease, there was no significant effect on the course of the SLE.Abbreviations ESR Erythrocyte sedimentation rate - T Thoracic vertebra - DNA Deoxyribonucleic acid - HLA HLA system (of histocompatibility loci) - IgG Immunoglobulin G - RES Reticuloendothelial system - SLE Systemic lupus erythematosus - CNS Central nervous system     

Anticytokine therapy in systemic lupus erythematosus

Systemic lupus erythematosus is a prototype of heterogeneous autoimmune disease. There have been few newly approved therapeutic agents in lupus treatment for many reasons. Several animal studies and human data have shown that many potential cytokines are related to the pathogenesis and disease activity of systemic lupus erythematosus. Cytokines are produced by many immune cell types and have variable functions in the immune system. Following the success of biological agents in the treatment of inflammatory arthritis, inflammatory bowel disease, and psoriasis, biological targeting to specific cytokines or receptor molecules is now promising in the treatment of systemic lupus erythematosus. In addition to B-cell deleting modalities, clinical trials targeting potential cytokines associated with disease pathogenesis are underway at various clinical stages. Among potential cytokines, targeting agents against B-cell activating factor and interferon-alpha are in the most advanced stage, and belimumab (anti-B-cell activating factor antibody) could be the first biological agent approved in the treatment of systemic lupus erythematosus. Anti-tumor necrosis factor was tried with some success, but with a potential risk of infection in a small number of patients. In this review, we discuss the rationale for anticytokine therapies and review agents currently in clinical trials, and those that could be developed in the near future for systemic lupus erythematosus. We present the results mostly from published trials and data from http://clinicaltrials.gov/ct2/     

系统性红斑狼疮的药物治疗

系统性红斑狼疮(systemic lupus erythematosus,SLE)总体上来说是一种慢性风湿病,容易复发.因此其治疗应包括两个方面:一方面是急性加重期如何治疗;另一方面是在慢性期如何予以维持治疗.近几十年来,由于糖皮质激素及免疫抑制剂的应用,SLE的死亡率及致残率已经较前明显下降.但由于SLE病因未明,因此很难根治.目前对SLE的治疗目标是:保持患者临床缓解并能进行日常活动,或应用最低剂量皮质激素或甚至停用激素情况下参加工作.     

系统性红斑狼疮的非药物治疗

系统性红斑狼疮(systemic lupus erythematosus,SLE)是一种自身免疫性疾病, 长期以来临床治疗主要依赖于糖皮质激素和免疫抑制剂等药物治疗.临床上观察到重症SLE及难治性SLE, 药物治疗往往难以控制病情, 目前难治性及重症SLE的治疗仍然非常棘手,现将其中的非药物治疗方法简介如下.