Background: Antimalarial drugs (AM), chloroquine (CQ) and hydroxychloroquine (HCQ), are frequently withdrawn in lupus patients with either severe or remitting disease. However, additional effects beyond immunomodulation have been recently described. Our aim was to analyse all the published evidence of the beneficial and adverse effects of AM therapy in SLE. Methods: Systematic review of the English literature between 1982-2007 using MEDLINE and EMBASE. Randomised controlled trials (RCTs) and observational studies were selected. Case reports were excluded except for toxicity reports. The GRADE system was used to analyse the quality of the evidence. Results: 95 articles were included in the systematic review. We have found high evidence that AM prevent lupus flares and increase long-term survival of SLE patients; moderate evidence of protection against irreversible organ damage, thrombosis and bone mass loss .Toxicity related to AM is infrequent, mild and usually reversible, with HCQ having a safer profile. In pregnant women, we have found high evidence that AM, particularly HCQ, decrease lupus activity without harming the baby. On the other hand, evidence supporting an effect on severe lupus activity, lipid levels and subclinical atherosclerosis was weak. Individual papers suggest effects in preventing the evolution from SLE-like to full-blown SLE, influencing vitamin D levels and protecting lupus patients against cancer. Conclusion: Given the broad spectrum of beneficial effects and the safety profile, HCQ should be given to most patients with SLE during the whole course of the disease, irrespective of its severity, and be continued during pregnancy.

https://ard.bmj.com/content/annrheumdis/early/2009/08/28/ard.2008.101766.full.pdf

Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review

Understanding the Epidemiology and Progression of Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disease that can affect many organs, including the skin, joints, the central nervous system and the kidneys. Women of childbearing age and certain racial groups are typically predisposed to developing the condition. Rare, inherited, single-gene complement deficiencies are strongly associated with SLE, but the disease is inherited in a polygenic manner in most patients. Genetic interactions with environmental factors, particularly UV light exposure, Epstein-Barr virus infection and hormonal factors, might initiate the disease, resulting in immune dysregulation at the level of cytokines, T cells, B cells and macrophages. Diagnosis is primarily clinical and remains challenging because of the heterogeneity of SLE. Classification criteria have aided clinical trials, but, despite this, only one drug (that is, belimumab) has been approved for use in SLE in the past 60 years. The 10-year mortality has improved and toxic adverse effects of older medications such as cyclophosphamide and glucocorticoids have been partially offset by newer drugs such as mycophenolate mofetil and glucocorticoid-sparing regimes. However, further improvements have been hampered by the adverse effects of renal and neuropsychiatric involvement and late diagnosis. Adding to this burden is the increased risk of premature cardiovascular disease in SLE together with the risk of infection made worse by immunosuppressive therapy. Challenges remain with treatment-resistant disease and symptoms such as fatigue. Newer therapies may bring hope of better outcomes, and the refinement to stem cell and genetic techniques might offer a cure in the future.

Systemic lupus erythematosus.

Neutrophil-specific genes are abundant in PBMC microarrays from lupus patients because of the presence of low-density granulocytes (LDGs) in mononuclear cell fractions. The functionality and pathogenicity of these LDGs have not been characterized. We developed a technique to purify LDGs from lupus PBMCs and assessed their phenotype, function, and potential role in disease pathogenesis. LDGs, their autologous lupus neutrophils, and healthy control neutrophils were compared with regard to their microbicidal and phagocytic capacities, generation of reactive oxygen species, activation status, inflammatory cytokine profile, and type I IFN expression and signatures. The capacity of LDGs to kill endothelial cells and their antiangiogenic potential were also assessed. LDGs display an activated phenotype, secrete increased levels of type I IFNs, TNF-alpha, and IFN-gamma, but show impaired phagocytic potential. LDGs induce significant endothelial cell cytotoxicity and synthesize sufficient levels of type I IFNs to disrupt the capacity of endothelial progenitor cells to differentiate into mature endothelial cells. LDG depletion restores the functional capacity of endothelial progenitor cells. We conclude that lupus LDGs are proinflammatory and display pathogenic features, including the capacity to synthesize type I IFNs. They may play an important dual role in premature cardiovascular disease development in systemic lupus erythematosus by simultaneously mediating enhanced vascular damage and inhibiting vascular repair.

A Distinct Subset of Proinflammatory Neutrophils Isolated from Patients with Systemic Lupus Erythematosus Induces Vascular Damage and Synthesizes Type I IFNs

Adolescents with a chronic condition: challenges living, challenges treating.

Objective

To determine the baseline (time 0) risk factors associated with the subsequent occurrence of vascular events in a multiethnic US cohort (LUMINA [LUpus in MInorities: NAture versus nurture]) of patients with systemic lupus erythematosus (SLE).



Methods

Five hundred forty-six LUMINA patients were assessed at time 0 for traditional and nontraditional (disease-related) risk factors for vascular events. These were defined as 1) cardiovascular (myocardial infarction and/or definite or classic angina and/or the undergoing of a vascular procedure for myocardial infarction [coronary artery bypass graft]), 2) cerebrovascular (stroke), and 3) peripheral vascular (arterial claudication and/or gangrene or significant tissue loss and/or arterial thrombosis in peripheral arteries). The observation time (followup time in the cohort) was the interval between time 0 and the last visit. The unit of analysis was the patient and not each vascular event. Variables at time 0 and vascular events were examined by univariable and multivariable (logistic and Cox proportional hazards regression) analyses. Age, sex, ethnicity, followup time, and all known risk factors for the occurrence of vascular events were included in the model.



Results

Thirty-four patients (6.2%) developed one or more vascular event after time 0. The overall median duration of followup in the cohort was 73.8 months (range 10.8–111.3 months). Vascular events (13 cardiovascular, 18 cerebrovascular, 5 peripheral vascular) occurred in 7 Hispanics from Texas (6.5%), 1 Hispanic from Puerto Rico (1.2%), 15 African Americans (7.5%), and 11 Caucasians (7.1%). The mean total number of traditional risk factors was significantly higher in patients who developed vascular events than in those who did not (7.1 versus 5.6). Independent predictors of vascular events were older age, current smoking status, longer followup time, elevated serum levels of C-reactive protein (CRP), and the presence of any antiphospholipid antibody. The same variables were identified when time-dependent analyses were performed, although azathioprine use was also found to be a contributing factor.



Conclusion

Smoking, previously not reported in SLE, emerged as a predictor of vascular events and should be strongly discouraged. Antiphospholipid antibodies and CRP support the role of inflammation and autoimmunity in the development of accelerated atherosclerosis in SLE. Ethnicity was not associated with vascular events in our patients.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/art.20622

Systemic lupus erythematosus in a multiethnic US cohort (LUMINA). XXIII. Baseline predictors of vascular events.

Despite a recent decline, atherosclerosis remains the most common cause of death in the Western world. The disease course of atherosclerosis is characterized by its chronicity, with progression in its initial stages being particularly insidious. Chronic inflammation is the pathological hallmark of atherosclerosis,1–4 and inflammatory processes are instrumental at all stages of this disease. Even before the development of detectable intimal lesions, the expression pattern of the endothelium has been shown to be inflammatory in nature, conforming to the response-to-injury hypothesis first postulated by the late Russell Ross.5 Thus, in lesion-prone sites of the arterial tree, the endothelial expression of adhesion molecules is upregulated, reflecting endothelial dysfunction secondary to unfavorable blood rheology6 and/or hypercholesterolemia.7–9

Atherosclerosis is known today to be associated with the burden of infection as well.10 The presence of infectious/inflammatory pathogeneses raises the autoimmune aspect of the condition.11–14

Anti–oxidized LDL (oxLDL) antibodies are exceptional among the autoantibodies prevalent in atherosclerosis: on the one hand, a correlation was found between the existence and titers of anti-oxLDL antibodies and the extent of atherosclerosis and cardiovascular disease (CVD) (Table 1). On the other hand, experimental data indicate that anti-oxLDL antibodies may be protective. 

View this table:

TABLE 1. Correlation Between Titers of Anti-oxLDL Abs and Atherosclerosis and CVD 



oxLDL frequently presents in the sera of patients with autoimmune conditions, acute coronary syndrome, or stable coronary artery disease (CAD).15–18 OxLDL has been associated with both subclinical atherosclerosis and inflammatory variables.19 A large amount of oxLDL accumulates in atherosclerotic plaques,20–22 and the serum concentrations of circulating oxLDL may correlate with the severity of CAD23 and acute coronary syndrome.24 OxLDL seems to be an immunogenic molecule that stimulates the induction of anti-oxLDL antibodies. Thus, it is not surprising that an association was found between the presence …

Oxidized Low-Density Lipoprotein Antibodies Pathogenic or Protective? -

Are Anti–Oxidized Low-Density Lipoprotein Antibodies Pathogenic or Protective?

Objective

Systemic lupus erythematosus and rheumatoid arthritis represent independent risk factors for atherosclerosis (ATS), although this may be confounded by continuous pharmacologic treatment. Primary Sjogren's syndrome (SS) shares several features of these diseases and may therefore represent an interesting model for verifying the presence of accelerated ATS in the absence of pharmacologic interference. The present study therefore used this model to describe the presence of accelerated ATS in a group of young women.



Methods

Thirty-seven untreated white women with primary SS were evaluated clinically and serologically. Carotid and femoral artery intima-media thickness (IMT) was evaluated in the patients and in 35 age-matched healthy women who served as controls.



Results

The patients had a higher IMT than did the controls at both the carotid (mean ± SD 0.82 ± 0.24 mm versus 0.63 ± 0.20 mm; P ≤ 0.001) and the femoral (0.81 ± 0.26 mm versus 0.67 ± 0.23 mm; P ≤ 0.019) levels, and had a higher prevalence of carotid intima-media thickening (49% versus 11% of controls; P ≤ 0.001). The patient subset with high carotid IMT showed an increased prevalence of leukopenia and circulating anti-SSA antibodies; interestingly, the number of leukocytes was inversely correlated with the level of arterial IMT in patients with SS. Multivariate analysis demonstrated that anti-SSA antibodies were independent predictors of carotid artery thickening, while leukopenia was a predictor of both carotid and femoral artery thickening.



Conclusion

Subclinical ATS was evident in about one-half of the patients with SS. Its association with some features typical of connective tissue diseases, such as the presence of anti-SSA and leukopenia, suggests that the immune dysregulation characterizing this autoimmune disorder may play a key role in inducing early ATS.

Precocious intima-media thickening in patients with primary Sjögren's syndrome

Objective : The aim of this study was to examine whether intravenous immunoglobulin (IVIg) preparations contain anti-oxLDL and anti-anti-oxLDL antibodies. Background : Oxidized low-density lipoprotein (oxLDL) is one of the major players in atherogenesis. IVIg can reduce atherosclerosis in experimental animal models. Methods : Six commercial IVIg preparations were tested for the presence of anti-oxLDL antibodies by EIA. Inhibition studies were performed with the different IVIg preparations and IgGs purified from a pool of sera from patients with high anti-oxLDL antibody levels. Absorption assays were carried out to evaluate the presence of anti-idiotypes against anti-oxLDL antibodies in IVIg preparations. Results : IVIg preparations tested had various degrees of reactivity towards oxLDL. Absorption experiments suggested that the reactivity was specific because it could be effectively absorbed by oxLDL and not by an irrelevant antigen PPD. The reactivity was smaller than that observed with the IgG from the ...

Ruihua Wu

Papers

Systemic lupus erythematosus in a multiethnic US cohort (LUMINA). XXIII. Baseline predictors of vascular events.

Oxidized Low-Density Lipoprotein Antibodies Pathogenic or Protective? -

Are Anti–Oxidized Low-Density Lipoprotein Antibodies Pathogenic or Protective?

Precocious intima-media thickening in patients with primary Sjögren's syndrome

Anti-idiotypes to oxidized LDL antibodies in intravenous immunoglobulin preparations--possible immunomodulation of atherosclerosis.