Konstantinos Tselios

Dyslipidemia in systemic lupus erythematosus: just another comorbidity?

OBJECTIVE Among traditional atherosclerotic risk factors, dyslipidemia is believed to decisively affect the long-term prognosis of lupus patients, not only with regard to cardiovascular events but also by influencing other manifestations, such as lupus nephritis. The aim of this study was to review the epidemiology, pathogenesis, evidence for its impact on atherosclerosis manifestations and management of dyslipidemia in lupus patients. METHODS English-restricted MEDLINE database search (Medical Subject Headings: lupus or systemic lupus erythematosus and dyslipidemia or hyperlipidemia). RESULTS The prevalence of dyslipidemia in systemic lupus erythematosus (SLE) ranges from 36% at diagnosis to 60% or even higher after 3 years, depending on definition. Multiple pathogenetic mechanisms are implicated, including antibodies against lipoprotein lipase and cytokines affecting the balance between pro- and anti-atherogenic lipoproteins. Dyslipidemia has a clear impact on clinical cardiovascular disease and surrogate markers for subclinical atherosclerosis. Moreover, it negatively affects end-organ damage (kidneys and brain). Treatment with statins yielded contradictory results as per minimizing cardiovascular risk. CONCLUSIONS Dyslipidemia is a significant comorbidity of lupus patients with multiple negative effects in the long term. Its treatment represents a modifiable risk factor; prompt and adequate treatment can minimize unnecessary burden in lupus patients, thus reducing hospitalizations and their overall morbidity and mortality.

Mycophenolate Mofetil in Nonrenal Manifestations of Systemic Lupus Erythematosus: An Observational Cohort Study.

Objective. Mycophenolate mofetil (MMF), along with corticosteroids, is considered as the standard of care in lupus nephritis (LN); however, little is known regarding its efficacy in extrarenal manifestations of systemic lupus erythematosus (SLE). We aimed to determine its effectiveness in nonrenal SLE. Methods. One hundred seventy-seven patients with SLE were enrolled; 105 for whom MMF was introduced for active LN (mean age 35.6 ± 10.7 yrs, mean disease duration 8.9 ± 7.8 yrs) and 72 for extrarenal manifestations (mean age 38.6 ± 11.7 yrs, mean disease duration 11.7 ± 9.2 yrs). The main indication for MMF initiation was based on the respective SLE Disease Activity Index element that was present at that time. Patients were subdivided according to the major nonrenal manifestation. Improvement was defined as the absence of the initial clinical or laboratory manifestation after 6 and 12 months. Results. Cumulatively, the initial clinical manifestation or hematological abnormality was resolved in 42/72 nonrenal patients (58.3%) after 6 months and in 45/72 (62.5%) after 12 months. Corticosteroid dose was reduced in 44/72 patients (61.1%, p < 0.001, mean dose 18.4 ± 12.6 mg/day at baseline to 12.1 ± 9.0 mg/day after 12 mos, p < 0.05). In renal patients, 40 (38.1%) had complete resolution of the extrarenal manifestation after 6 months, while 53 (50.5%) achieved complete response after 12 months. Prednisone dose was reduced in 73/105 patients (69.5%) after 12 months (mean dose 29.2 ± 16.6 mg/day at baseline to 15.3 ± 9.7 mg/day, p < 0.001). Conclusion. MMF seems to be an efficacious alternative in refractory to standard of care nonrenal manifestations of SLE in the long term, allowing for disease activity control and significant reduction in corticosteroid dose.

Do current arterial hypertension treatment guidelines apply to systemic lupus erythematosus patients? A critical appraisal

OBJECTIVE Arterial hypertension (HTN) is reported to burden up to 74% of systemic lupus erythematosus (SLE) patients and contributes significantly to accelerated atherosclerosis and increased cardiovascular (CV) risk. Current HTN treatment guidelines have not incorporated lupus patients in their recommendations; whether these guidelines can be fully implemented in SLE is doubtful. METHODS A critical appraisal of the existing HTN guidelines in regard to SLE is presented in this review, based upon clinical and experimental data. Particular issues addressed are the time of antihypertensive therapy initiation, the optimal blood pressure level, the antihypertensive agent of first-choice and the need for reduction of the total cardiovascular risk in SLE. RESULTS Antihypertensive therapy should be recommended at levels of 140/90 mmHg (systolic and diastolic BP, respectively) in newly diagnosed lupus patients without overt target organ involvement. In the case of lupus nephritis (LN) or diabetes mellitus (DM), therapy should be implemented at lower levels, such as 130/80 mmHg. Hypertensive lupus patients should be considered at high or very high CV risk and, consequently, the optimal BP level should be less than 130/80 mmHg. Angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) seem to be a safe and efficacious first-choice antihypertensive treatment in lupus patients. Total CV risk should be considered and co-morbidities (dyslipidemia, antiphospholipid syndrome, etc.) should be managed promptly. CONCLUSIONS Current HTN therapeutic guidelines, lacking data from large-scale clinical trials, may not adequately apply to SLE patients. The assessment of the aforementioned recommendations in randomized clinical trials is expected to confirm their value in reducing CV risk in SLE.

Does renin‐angiotensin system blockade protect lupus nephritis patients from atherosclerotic cardiovascular events? A case‐control study

Angiotensin‐converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are used as an adjuvant treatment in lupus nephritis (LN) patients with proteinuria. The primary aim of this study was to discover whether ACE inhibitors/ARBs have an atheroprotective effect similar to other, at‐risk, populations.

Systemic lupus erythematosus and pulmonary arterial hypertension: links, risks, and management strategies

Systemic lupus erythematosus (SLE) is characterized by the second highest prevalence of pulmonary arterial hypertension (PAH), after systemic sclerosis, among the connective tissue diseases. SLE-associated PAH is hemodynamically defined by increased mean pulmonary artery pressure at rest (≥25 mmHg) with normal pulmonary capillary wedge pressure (≤15 mmHg) and increased pulmonary vascular resistance. Estimated prevalence ranges from 0.5% to 17.5% depending on the diagnostic method used and the threshold of right ventricular systolic pressure in studies using transthoracic echocardiogram. Its pathogenesis is multifactorial with vasoconstriction, due to imbalance of vasoactive mediators, leading to hypoxia and impaired vascular remodeling, collagen deposition, and thrombosis of the pulmonary circulation. Multiple predictive factors have been recognized, such as Raynaud’s phenomenon, pleuritis, pericarditis, anti-ribonuclear protein, and antiphospholipid antibodies. Secure diagnosis is based on right heart catheterization, although transthoracic echocardiogram has been shown to be reliable for patient screening and follow-up. Data on treatment mostly come from uncontrolled observational studies and consist of immunosuppressive drugs, mainly corticosteroids and cyclophosphamide, as well as PAH-targeted approaches with endothelin receptor antagonists (bosentan), phosphodiesterase type 5 inhibitors (sildenafil), and vasodilators (epoprostenol). Prognosis is significantly affected, with 1- and 5-year survival estimated at 88% and 68%, respectively.

Antimalarial-induced cardiomyopathy: a systematic review of the literature:

Background Antimalarials (AMs) are widely used in the treatment of connective tissue diseases. Their main side effect is retinal damage, while heart disease has been described in isolated cases. The aim of this study is to systematically review the existing literature on AM-induced cardiomyopathy (AMIC). Methods The PubMed database was searched for heart biopsy-confirmed AMIC cases. Information on demographics, clinical presentation, concomitant AM-related toxicity, cardiological investigations, treatment and outcome were collected. Descriptive statistics were used. Results Forty-seven cases (42 females) were identified with a mean age at diagnosis 56.4 ± 12.6 and mean AM treatment duration 12.7 ± 8.2 years. Systemic lupus erythematosus (n = 19) and rheumatoid arthritis (n = 18) were the most common primary diseases. Clinical presentation was that of congestive heart failure in 77%, while eight patients presented with syncope (17%). Complete atrioventricular block was reported in 17 patients; 24 received a permanent pacemaker (51%). Impaired systolic function was detected in 52.8%, bi-ventricular hypertrophy in 51.4% and restrictive filling pattern of the left ventricle in 18 patients. Cardiac magnetic resonance showed late gadolinium enhancement in seven cases, with a non-vascular pattern in the interventricular septum. Cardiomyocyte vacuolation was reported in all cases; intravacuolar lamellar and curvilinear bodies were observed in 46 (98%) and 42 (89.4%) respectively. Mortality rate was 45% (18/40). Conclusion AMIC is a rare, probably under-recognized, complication of prolonged AM treatment. It presents as a hypertrophic, restrictive cardiomyopathy with or without conduction abnormalities. Early recognition and drug withdrawal are critical with a survival rate of almost 55%.

Evolution of Risk Factors for Atherosclerotic Cardiovascular Events in Systemic Lupus Erythematosus: A Longterm Prospective Study

Objective. We previously reported the effect of certain factors on cardiovascular disease (CVD) in 250 women with systemic lupus erythematosus (SLE) followed for 8 years. The aim of this study was to delineate their evolution after 15 years of followup. Methods. There were 210 women with SLE and 138 age-matched healthy women available for analysis after 15 years. Cardiovascular events (CVE) included angina pectoris, myocardial infarction (fatal and nonfatal), transient ischemic attack, and stroke (fatal and nonfatal). Analysis was performed with SAS 9.3 software; p < 0.05 was considered significant. Results. CVE occurred in 41/210 patients (19.5%) and 9/138 controls (6.5%), most of them in the second part (2008–2015) of the study (24/210, 11.4% vs 17/241, 7.1% in SLE group). Coronary artery disease was more common in patients (32/210, 15.2% vs 5/138, 3.6%, p = 0.0041). There was no significant difference for cerebrovascular disease (10/210, 4.8% vs 3/138, 2.2%, p = 0.213). SLE was the most prominent CVE predictor in the first 8 years (HR 2.8, 95% CI 1.3–6.3). Hypertension and diabetes were more frequent in patients who developed CVE during the second half of the study. Thirty-one deaths occurred in patients with SLE (10 because of CVD) and 6 in controls (none because of CVD). Conclusion. The relative importance of atherosclerotic risk factors is significantly differentiated over time in SLE. Disease-related factors seem to dominate CV risk during the early stages while traditional factors, partially related to corticosteroid treatment, play a significant role later in the disease course.

Canadian Rheumatology Association Recommendations for the Assessment and Monitoring of Systemic Lupus Erythematosus

Objective. To develop recommendations for the assessment of people with systemic lupus erythematosus (SLE) in Canada. Methods. Recommendations were developed using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach. The Canadian SLE Working Group (panel of Canadian rheumatologists and a patient representative from Canadian Arthritis Patient Alliance) was created. Questions for recommendation development were identified based on the results of a previous survey of SLE practice patterns of members of the Canadian Rheumatology Association. Systematic literature reviews of randomized trials and observational studies were conducted. Evidence to Decision tables were prepared and presented to the panel at 2 face-to-face meetings and online. Results. There are 15 recommendations for assessing and monitoring SLE, with varying applicability to adult and pediatric patients. Three recommendations focus on diagnosis, disease activity, and damage assessment, suggesting the use of a validated disease activity score per visit and annual damage score. Strong recommendations were made for cardiovascular risk assessment and measuring anti-Ro and anti-La antibodies in the peripartum period and conditional recommendations for osteoporosis and osteonecrosis. Two conditional recommendations were made for peripartum assessments, 1 for cervical cancer screening and 2 for hepatitis B and C screening. A strong recommendation was made for annual influenza vaccination. Conclusion. These are considered the first guidelines using the GRADE method for the monitoring of SLE. Existing evidence is largely of low to moderate quality, resulting in more conditional than strong recommendations. Additional rigorous studies and special attention to pediatric SLE populations and patient preferences are needed.

Monophasic Disease Course in Systemic Lupus Erythematosus

Objective. Disease course in systemic lupus erythematosus (SLE) is primarily relapsing-remitting. Long quiescent and chronically active patterns are less frequent. We recently described an atypical “monophasic” course in a small number of patients. The aim of the present study was to assess the prevalence and characteristics of such patients in a defined SLE cohort. Methods. The inception patients of the University of Toronto Lupus Clinic (enrolled within 18 mos of diagnosis) were investigated. No time interval > 18 months was allowed between consecutive visits. A monophasic course was defined as Systemic Lupus Erythematosus Disease Activity Index 2000 = 0 (serology excluded), achieved within 5 years since enrollment and maintained for ≥ 10 years. Descriptive statistics were used. Results. Of 267 inception patients, 27 (10.1%) achieved prolonged clinical remission (≥ 10 yrs) and 20 (7.5%) sustained remission for the entire followup (18 yrs on average). Twelve patients were receiving no maintenance treatment 10 years after achieving remission. Clinical manifestations at diagnosis (apart from skin and musculoskeletal involvement) included 25% in each of central nervous system involvement and lupus nephritis (LN). Half the patients were serologically active. Ten years after achieving remission, two-thirds of the patients had discontinued glucocorticosteroids; the remaining were treated with 5 mg/day on average. Seven patients relapsed after 10 years, 4 with arthritis, 2 LN, and 1 catastrophic antiphospholipid syndrome. Conclusion. A monophasic disease course was observed in 7.5% in this inception cohort. Patients sustained remission for 18 years on average, eventually without medications. Further study of such patients may provide unique pathophysiologic insights for SLE.

Abnormal Cardiac Biomarkers in Patients with Systemic Lupus Erythematosus and No Prior Heart Disease: A Consequence of Antimalarials?

Objective. Cardiac involvement in systemic lupus erythematosus (SLE) is often undiagnosed in its early phases. Specific heart biomarkers may identify patients at risk. We sought to investigate the prevalence and associated factors for such biomarkers in SLE. Methods. Brain natriuretic peptide (BNP) and cardiac troponin I (cTnI) were measured simultaneously in 151 consecutive patients with no history of heart disease or pulmonary arterial hypertension (PAH). None had electrocardiographic abnormalities suggestive of acute coronary syndrome. Cross-sectional comparisons and logistic regression analyses were performed. Patients with abnormal biomarkers were investigated to delineate the specific cause. Results. Sixteen patients (16/151, 10.6%) had elevated BNP, and 9 of them also had abnormal cTnI. Compared to subjects with normal biomarkers, they were older, had longer disease and antimalarial (AM) use duration, and more frequently persistent creatine phosphokinase (CPK) elevation. Multivariable regression analysis showed prolonged AM treatment (> 5.6 yrs) and persistent CPK elevation to be important predictors for elevated cardiac biomarkers. Six patients were diagnosed with definite (based on endomyocardial biopsy, n = 2) or possible (based on cardiac magnetic resonance after exclusion of other causes) AM-induced cardiomyopathy (AMIC); all had both BNP and cTnI elevated. Alternative causes were identified in 5, while no definitive diagnosis could be made in the remaining patients. Conclusion. About 10% of patients with SLE had elevated myocardial biomarkers, in the absence of prior cardiac disease or PAH. One-third of them were diagnosed with AMIC. Prolonged AM therapy and persistent CPK elevation conferred an increased risk for abnormal BNP and cTnI, which might predict AMIC.