Discontinuation of antimalarial drugs in systemic lupus erythematosus

OBJECTIVE: To assess the reasons for and timing of discontinuation of antimalarial drugs, principally hydroxychloroquine (HCQ), in systemic lupus erythematosus (SLE). METHODS: A lupus database was reviewed to identify antimalarial use from inception to April 1996. Reasons for drug discontinuation were assessed by medical record review. RESULTS: Of 224 patients with SLE, 156 (70%) had received antimalarials. The 156 users received 203 courses of antimalarials, of which 197 (97%) were for HCQ. The average duration of use was 6.9 years/patient. Antimalarials were discontinued at least once in 62 patients. When only the first course of use was considered, 67, 50, and 38% of patients continued to receive antimalarials at 5, 10, and 15 years, respectively (for all courses, the rates were 82, 66, and 52%, respectively). Reasons for discontinuation were disease remission in 26 (42%), side effects in 18 (29%), noncompliance in 9 (15%), lack of efficacy in 5 (8%), and miscellaneous causes such as pregnancy/surgery in 4 (6%). When all courses were considered, 20 subjects were withdrawn for side effects, including gastrointestinal in 11; headache and dizziness, and nonretinal eye problem in 2 each; and hearing loss and rash in one each. Two developed HCQ myopathy (1.9 cases/1000 patient-years of HCQ therapy; 95% CI 0.2, 7.0). One developed HCQ retinopathy after 6 years at a dose of 6.5 mg/kg/day (0.95 cases/1000 patient-years of HCQ; 95% CI 0.0, 5.5). Among patients who had received HCQ for at least 6 years, 1.3% developed retinopathy (95% CI 0.03, 7.0%). CONCLUSION: HCQ is well tolerated in SLE. However, ophthalmologic testing remains essential, as retinopathy does occur, albeit rarely.     

Inflammatory mechanisms affecting the lipid profile in patients with systemic lupus erythematosus

OBJECTIVE: Increased low density lipoprotein (LDL) cholesterol and triglycerides, and decreased high density lipoprotein (HDL) cholesterol concentrations are associated with adverse cardiovascular risk in the general population. Patients with systemic lupus erythematosus (SLE) have an altered lipid profile characterized by increased triglycerides and decreased HDL cholesterol concentrations. We examined the relationships between lipid concentrations, cytokines, and inflammatory markers in patients with SLE. METHODS: Fasting lipid concentrations, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) were measured in 110 patients with SLE. Disease activity was quantified by the SLE Disease Activity Index (SLEDAI), and disease damage by the Systemic Lupus International Collaborating Clinics (SLICC) score. Concentrations of circulating tumor necrosis factor-alpha (TNF-alpha), interleukin 6 (IL-6), and insulin were measured and insulin sensitivity calculated. RESULTS: Lower concentrations of HDL cholesterol were independently associated with higher ESR (p < 0.001), IL-6 (p = 0.02), SLEDAI (p = 0.04), and TNF-alpha (p = 0.04) after adjustment for age, sex, race, body mass index, insulin sensitivity, and current use of corticosteroids or hydroxychloroquine. Triglyceride concentrations were associated with higher CRP concentrations (p = 0.02) and SLICC score (p = 0.04). CONCLUSION: Deleterious changes in lipid profile are independently associated with higher concentrations of markers and mediators of inflammation and disease activity and damage in patients with SLE.     

Novel therapeutic agents for systemic lupus erythematosus

The last significant breakthrough in the treatment of systemic lupus erythematosus (SLE) was the use of cyclophosphamide and methylprednisolone in the treatment of lupus nephritis. Recent advances in immunology, oncology, and endocrinology have resulted in many potential therapies for SLE. These therapies include new immunosuppressants, biologic medications, tolerizing agents, immunoablation techniques, and hormonal medications. Each of these approaches will be discussed in this review. Some therapies are currently in use in clinical rheumatology practice (mycophenolate mofetil) and others are entering phase I trials (anti-BLyS monoclonal antibody). While some of these new therapies target specific inflammatory mechanisms in SLE (anti-CD40L monoclonal antibody), others work by nonspecific inhibition of the immune system (immunoablation).     

The protective effect of antimalarial drugs on thrombovascular events in systemic lupus erythematosus

Objective

The antimalarial medication hydroxychloroquine has been proposed as a thromboprotective agent in systemic lupus erythematosus (SLE), but studies thus far have been limited by the possibility of confounding by indication. This study was conducted to assess whether exposure to antimalarial drugs is associated with a decrease in thrombovascular events (TEs) in patients with SLE.

Methods

The study was designed as a nested case–control study embedded in an inception cohort of patients with SLE, which allowed adjustments for possible confounding by calendar year, duration of disease, duration of observation, and severity of lupus. After controlling for the possible confounding variables in conditional logistic regression models, the use of antimalarial drugs was assessed for its effects on the development of TEs in lupus patients.

Results

Fifty‐four cases of TE were identified, and these were matched with 108 control subjects (lupus patients without TEs). Univariate analyses identified older age (odds ratio [OR] 1.04, 95% confidence interval [95%CI] 1.01–1.07) or being older than age 50 years (OR 3.5, 95% CI 1.4–8.6) and ever having hypertension (OR 2.5, 95% CI 1.0–5.8) as being associated with an increased risk of TEs, whereas use of antimalarial drugs (OR 0.31, 95% CI 0.13–0.71) was associated with a decreased risk of TEs. Separate analyses were done for arterial and venous TEs, which yielded similar results. In multivariate analyses, use of antimalarial drugs (OR 0.32, 95% CI 0.14–0.74) and older age (OR 1.04, 95% CI 1.01–1.07) were the only 2 variables that remained significant.

Conclusion

The results from this nested case–control study demonstrate that, after accounting for the effects of disease severity, disease duration, and calendar year, antimalarial drugs were found to be thromboprotective, being associated with a 68% reduction in the risk of all TEs, with a range of risk reduction of at least 26% up to as high as 86%.

     

Longitudinal examination of lipid profiles in pediatric systemic lupus erythematosus

OBJECTIVE: Lipid abnormalities in patients with systemic lupus erythematosus (SLE) are common and are likely to be one of the causes of premature atherosclerosis in these patients. This study was undertaken to serially examine the lipid profile in pediatric patients with SLE to determine the roles of active disease and therapy in altering lipid levels. METHODS: Serial lipid measurements were obtained in an inception cohort of 139 pediatric patients with SLE at the time of treatment with either a constant dose or differing doses of prednisone, and annually. The levels of cholesterol, triglycerides, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) were correlated with measures of disease activity and prednisone dose. RESULTS: At the time of SLE diagnosis in this pediatric cohort, the mean values for all lipids were abnormal. With each reduction in prednisone dose, there was a statistically significant decrease in cholesterol and triglyceride levels (P < 0.001) but not HDL or LDL levels. Nephrotic-range proteinuria was associated with altered cholesterol, triglyceride, and LDL levels, whereas changes in HDL were more commonly associated with active nephritis. In the absence of nephrotic-range proteinuria, increases in prednisone dose were associated with increased levels of all lipids, including HDL. CONCLUSION: Active SLE leads to a proatherogenic lipid profile. Levels of cholesterol and LDL were mainly associated with the dose of prednisone, and were abnormal only during very high disease activity. Triglyceride levels were mainly associated with proteinuria, while changes in HDL were associated with active SLE and a high dose of prednisone. Our results suggest that the lipid profile in pediatric SLE is the result of a complex interaction of disease manifestations and the effects of prednisone therapy.     

Validity of the disease repercussion profile in patients with systemic lupus erythematosus

The Disease Repercussion Profile (DRP) was developed for use with patients with rheumatoid arthritis (RA) and has been shown to be a valid and clinically useful assessment of patient-perceived handicap. This study aimed to determine whether the Disease Repercussion Profile was also suitable for use with patients with systemic lupus erythematosus (SLE). Sixty patients with a definite diagnosis of SLE from a consultant rheumatologist were recruited into the study. They completed a series of questionnaires that assessed quality of life, depression, anxiety, attitudes towards the illness and the DRP. Results showed that patients with SLE endorsed each of the six spheres of the DRP as being frequently affected by their illness. Activity was most often endorsed. Both relationships and social activity were equally frequently adversely affected, and more often affected than the remaining spheres of finance, emotions and appearance. However, as in RA, when any area of function was affected, it was rated as very important to the individual. Indicators of quality of life were reliably related to all areas of function, as was depression and attitudes towards illness. The present study indicates that the DRP does have relevance for patients with SLE. Strong correlations between quality of life indicators, depression, attitudes towards illness and DRP subscales and total score indicate that this measure is a valid tool to assess the effect of illness on individuals with SLE.     

Prolactin profile in a cohort of Chinese systemic lupus erythematosus patients

Prolactin (PRL) is an important immunoregulatory hormone secreted by the anterior pituitary gland. Hyperprolactinaemia has been implicated in the pathogenesis of systemic lupus erythematosus (SLE). However, clinical studies regarding the PRL level and lupus disease activity have yielded contradictory results. The aim of our present study was, therefore, to re-evaluate the association of PRL level and disease activity in SLE by analysing a larger patient cohort and following them up serially. Seventy-two consecutive SLE patients were recruited and the serum PRL level was measured at each visit. Our results showed that hyperprolactinaemia (> 500 mIU/l) occurred in 35% (25/72) of the patients. A total of 72% (18/25) of the hyperprolactinaemic patients had mild elevation (arbitrarily defined as 500-800 mIU/l) of the level only. No correlation could be found between the PRL level and various clinical and serological parameters of lupus disease activity. On serial follow-up of 44 patients, again no correlation between PRL and disease activity could be demonstrated. We conclude that hyperprolactinaemia occurs in some patients with SLE, but the serum level of PRL does not correlate with clinical or serological disease activity and is not a reliable marker for disease monitoring. The mechanism and pathoaetiological and clinical significance of hyperprolactinaemia in a small subset of SLE patients remain unclear and a longer follow-up is necessary.      

Predictors of lipid abnormalities in children with new-onset systemic lupus erythematosus

OBJECTIVE: Lipid abnormalities in patients with systemic lupus erythematosus (SLE) are common and likely are one of the causes of premature atherosclerosis in these patients. Our aims were to determine the frequency and pattern of dyslipoproteinemia at presentation of pediatric SLE; and to determine the association between dyslipoproteinemia and markers of disease activity and inflammatory markers at presentation of pediatric SLE. METHODS: Serum lipid measurements were obtained at diagnosis before corticosteroid treatment for an inception cohort of 54 patients. Total cholesterol, triglyceride, LDL-C, and HDL-C levels were regressed on measures of inflammation, disease activity, and disease symptoms. RESULTS: At least one lipid abnormality was present in the majority of patients (63%), an elevated triglyceride level being the most common lipid abnormality (62%). Triglycerides were best predicted by fibrinogen, nephritis, and pleuritis (model R2 = 0.6). Albumin, C4, and white blood cell count were found to predict HDL-C (model R2 = 0.6). Erythrocyte sedimentation rate, central nervous system involvement, nasal ulcers, and nephritis were found as predictors for LDL-C:HDL-C (model R2 = 0.5). No significant predictors were found for total cholesterol or LDL-C. The European Consensus Lupus Activity Measure disease activity score best predicted abnormal triglyceride and HDL-C levels (OR 1.7, 95% CI 1.2-2.3). CONCLUSION: Children with newly diagnosed SLE exhibited the distinct pattern of dyslipoprotein of increased triglycerides and depressed HDL-C that was twice as common in the presence of kidney disease. This lipid profile puts them at risk for premature atherosclerosis. Good disease control and individualized use of lipid-lowering agents based on the observed pattern of lipid abnormalities may lower the risk of premature atherosclerosis in these patients.     

Anaemia in systemic lupus erythematosus: aetiological profile and the role of erythropoietin

OBJECTIVE: To study the prevalence of different causes of anaemia in patients with systemic lupus erythematosus (SLE) and their associations with immunological and clinical parameters and to evaluate the contribution of erythropoietin (Epo) and anti-erythropoietin (anti-Epo) autoantibodies to the development of SLE anaemia. METHODS: 132 SLE patients with anaemia (defined as haemoglobin of 12 g/dl or less for women and 13.5 g/dl or less for men) from among a total of 345 consecutive SLE patients were prospectively enrolled into the study. Standard haematological and immunological tests were performed and serum Epo and anti-Epo antibodies were assayed. RESULTS: The identified causes were anaemia of chronic disease (ACD) n=49 (37.1%), iron deficiency anaemia (IDA) n = 47 (35.6%), autoimmune haemolytic anaemia (AHA) n = 19 (14.4%) and other causes n = 17 (12.9%). There was significant heterogeneity in the severity of anaemia between the four groups (p<0.01) with AHA cases being on average more severe. The proportion of patients with anticardiolipin antibodies, low complement levels and anti-dsDNA differed significantly among the four groups; these markers were particularly common in patients with AHA, and uncommon in patients with IDA. Twenty one of 100 tested patients had anti-Epo antibodies. Such antibodies were seen practically only in patients with ACD (odds ratio 3.1, p = 0.041) and in patients with high lupus activity (ECLAM) scores (odds ratio 1.27 per point, p = 0.055). Epo response was inadequate in 42.4% and 41.2% of patients with ACD and AHA, respectively. CONCLUSIONS: Anaemia in SLE usually takes the form of ACD and IDA, however autoimmune haemolysis is not uncommon. SLE patients with different causes of anaemia differ in regard to several immunological parameters. Epo response is blunted in anaemic SLE patients, particularly those with ACD and AHA.     

Newer therapeutic approaches for systemic lupus erythematosus: immunosuppressive agents

There has been unprecedented growth in new therapeutic approaches for the treatment of systemic lupus erythematosus (SLE). These approaches include re-evaluation of the doses and duration of therapy with traditional agents, including intravenous cyclophosphamide and azathioprine. Drugs that were developed for other uses are being applied to specific SLE manifestations, and have spurred larger scale trials for overall disease activity. In addition, several new agents show promise in clinical trials; many have safer toxicity profiles than do traditional therapies. Some of these agents have multiple immunomodulatory effects, whereas others interfere with a specific immunologic process in one of the pathogenetic pathways of SLE activity.     

The complex nature of the interaction between disease activity and therapy on the lipid profile in patients with pediatric systemic lupus erythematosus

OBJECTIVE: To determine the prevalence of lipid abnormalities at different times and to determine the influence of both the disease and corticosteroid therapy on lipid abnormalities in pediatric patients with systemic lupus erythematosus (SLE). METHODS: Lipid measurements were obtained in an inception cohort of 139 pediatric patients with SLE (114 females). Fasting levels of total cholesterol, triglycerides, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol in the SLE patients were compared with those in age- and sex-matched control subjects. Disease activity levels and medication dosages were obtained at the time of lipid measurements. RESULTS: At the time of diagnosis, the mean levels of total cholesterol, LDL cholesterol, and triglycerides were highest, whereas the mean levels of HDL cholesterol were lowest. The percentage of patients with abnormal triglyceride values was highest at diagnosis, decreased at year 1, and then remained relatively constant thereafter. The mean total cholesterol and LDL cholesterol levels decreased at year 1 as compared with the time of diagnosis and then remained relatively constant. The lowest mean HDL cholesterol levels were found at the time of diagnosis, and these values rose with time. Comparison of lipid levels at different prednisone dosages and disease activity levels revealed that changes in triglyceride levels were mainly associated with changes in disease activity, changes in both total cholesterol and LDL cholesterol levels were associated with changes in the prednisone dosage and not disease activity, and low levels of HDL cholesterol were associated with active SLE, whereas the prednisone dosage was associated with increased levels of HDL cholesterol. CONCLUSION: Factors intrinsic to SLE appear to alter lipid levels. Control of SLE may be the most important factor in improving abnormal lipid profiles, and paradoxically, prednisone therapy may improve abnormal lipid levels.     

T-lymphocyte signalling in systemic lupus erythematosus: a lipid raft perspective

In the last few years it has become clear that in cells of the immune system, specialized microdomains present in the plasma membrane, called lipid rafts, have been found to play a central role in regulating signalling by immune receptors. Recent studies have looked at whether lipid rafts may be connected to the abnormalities in signalling seen in T lymphocytes isolated from patients with systemic lupus erythematosus (SLE). These early findings show that in SLE T cells, the expression and protein composition of lipid rafts is different when compared with normal T cells. These results also demonstrate changes in the function and localization of critical signalling molecules such as the LCK tyrosine kinase and the CD45 tyrosine phosphatase.     

Therapeutic efficacy and safety profile of infliximab in active systemic lupus erythematosus

Since levels of the proinflammatory cytokine tumor necrosis factor alpha (TNFα) are significantly increased in systemic lupus erythematosus (SLE) and may be involved in the disease pathogenesis, we report on the safety and efficacy of infliximab, a chimeric monoclonal antibody directed against TNFα, given to a patient with difficult-to-treat active nonrenal SLE. This patient, who failed to remit with full doses of glucocorticoids, hydroxychloroquine, methotrexate, and azathioprine, went into sustained remission with the addition of infliximab infusions. Glucocorticoids could be tapered off completely.     

Pregnancy in systemic lupus erythematosus

Issues concerning contraception, fertility, and pregnancy usually arise during a typical lupus patient's disease course. Pregnancy superimposed on established lupus may alter the course of the disease, and, conversely, lupus may affect the natural history of pregnancy. Two recently described autoantibody markers, anti-SSA (Ro) and anticardiolipin, have provided new insights concerning fetal risks in these patients. Furthermore, they should lead to improved understanding of mechanisms of tissue injury and to new ideas about therapeutic interventions and/or prevention of pregnancy complications.     

系统性红斑狼疮与高同型半胱氨酸血症的临床研究

目的　观察系统性红斑狼疮 (SLE)患者血浆中同型半胱氨酸 (Hcy)水平 ,分析影响Hcy的因素和某些心血管因素的变化。 方法　测定 2 7例SLE和 31名正常对照的Hcy、维生素B12 、叶酸、C反应蛋白 (CRP)、氧化低密度脂蛋白 (oxLDL)、一氧化氮 (NO)、丙二醛 (MDA)的水平和亚甲基四氢叶酸还原酶 (MTHFR)基因 6 77位的多态性。结果　①SLE组Hcy水平明显较对照组高 ,其差异有显著性 [SLE组 (19± 7) μmol/L ,对照组 (12± 4 ) μmol/L ,P <0 0 0 1];②Hcy与维生素B12 、叶酸呈负相关 ,相关系数分别为 - 0 76 7和 - 0 6 7,P <0 0 0 0 1;③MTHFR基因 6 77位CT的突变使Hcy水平升高 [CC型 (12 8± 6 2 ) μmol/L ,CT型 (16 0± 2 1) μmol/L ,TT型 (18 9± 5 7) μmol/L ,P<0 0 0 1];TT基因型是高Hcy血症的易感基因 ,相对危险度 (RR) =31 4 9,P <0 0 5 ;TT基因型是SLE的易感基因 ,RR =6 913,P <0 0 5 ;④Hcy水平与NO、MDA、oxLDL呈正相关 ,并与CRP呈正相关。结论　①SLE患者普遍有高Hcy血症。②导致高Hcy血症的原因包括叶酸、维生素B12 的水平降低和MTHFR基因的突变 ,TT型基因是Hcy异常升高的易感基因。③TT型基因也是SLE的易感基因。④高Hcy血症可能通过损伤血管内皮 ,大量产生氧自由基 ,加速低密度