Response to placebo in non-renal, non-neuropsychiatric systemic lupus erythematosus: a systematic review and pooled analysis.

OBJECTIVES: Most randomized controlled trials (RCTs) in SLE have failed to reach their respective end points, with the rates of response to placebo (plus standard-of-care treatment) being unexpectedly high. The aim of this systematic review was to quantify the response to placebo in non-renal, non-neuropsychiatric lupus. METHODS: The PubMed database was searched (from 2000 to December 2019) for phase II/III RCTs assessing the efficacy and safety of biologics in non-renal, non-neuropsychiatric SLE. Data on the efficacy and safety of the placebo-treated patients were collected in a pre-established data retrieval form. Descriptive statistics were used. RESULTS: A total of 24 RCTs (n = 11128 in total) were included. Placebo-treated patients (n = 3899) were mostly females (93.5%), Caucasians (60.2%), of mean age 39.7 years, and having a mean disease duration of 7.4 years. Their mean initial SLEDAI 2000 was 10.4, whereas 60.5% had positive anti-dsDNA antibodies, 41.9% low C3 and 35.6% low C4 at randomization. Standard-of-care treatment included glucocorticosteroids in 85.9%, antimalarials in 72.8% and immunosuppressives in 48.5%. The response to placebo was 36.2% for the primary end point (as defined in each study), 39.8% for the SLE Responder Index-4 (SRI-4), 29.2% for SRI-5, 28.4% for SRI-6 and 30.9% for BILAG-based Combined Lupus Assessment response. Regarding safety, there were serious adverse events in 16.3% of patients, serious infections in 5.5% and malignancies in 0.3%, and death occurred in 0.56% of patients. CONCLUSION: More than one-third of the placebo-treated patients achieved their respective primary end points in RCTs with biologics in non-renal, non-neuropsychiatric SLE. The response rate was higher for certain end points, such as the SRI-4, while it decreased with more stringent end points.

Factors Associated With Rapid Progression to Endstage Kidney Disease in Lupus Nephritis.

OBJECTIVE: Lupus nephritis (LN) may lead to endstage kidney disease (ESKD) in 22% of patients over a period of 15 years, with the risk being particularly higher in diffuse proliferative forms. The rate of kidney function decline varies. However, a catastrophic course leading to ESKD within a few years from onset is uncommon. The aim of the present study was to assess the factors associated with rapid progression to ESKD in patients with LN. METHODS: Patients from the Toronto Lupus Clinic with biopsy-proven LN at presentation and estimated glomerular filtration rate (eGFR) 60 mL/min/1.73 m2, who developed ESKD within 3 years were retrieved. Pathology reports were reviewed with particular emphasis on distinct histopathologic features. Demographic, clinical, laboratory, and therapeutic variables were also analyzed. RESULTS: Ten patients (1.8% of the total LN population) developed ESKD within 3 years of diagnosis. Their mean age was 34.2 ± 7.3 years, mean time to ESKD 19.2 ± 12.4 months, initial eGFR 90.2 ± 24.9 mL/min/1.73 m2, proteinuria 2.7 ± 1.04 g/24 h. The median rate of kidney function decline was > 43 mL/min/1.73 m2/year. One patient had LN class III, 5 had LN class IV, 2 had membranous LN (class V), and another 2 had mixed IV/V. Moreover, 2 patients had extensive thrombotic microangiopathy, 1 collapsing glomerulonephritis, and 1 concomitant antiglomerular basement membrane (anti-GBM) nephropathy. Four patients showed no unusual kidney pathology; all of them had severe noncompliance (discontinued all medications to follow alternative treatment). CONCLUSION: Catastrophic progression to ESKD is uncommon in LN. The major associated factors are poor compliance and distinct histopathologic features such as thrombotic microangiopathy, collapsing glomerulopathy, and concomitant anti-GBM nephropathy.

All-cause, cause-specific and age-specific standardised mortality ratios of patients with systemic lupus erythematosus in Ontario, Canada over 43 years (1971-2013).

BACKGROUND: Survival in systemic lupus erythematosus (SLE) has improved substantially in the last 50 years. The aim of the present study was to assess the evolution of the all-cause, cause-specific and age-specific standardised mortality ratios (SMRs) of patients with lupus in Ontario, Canada. PATIENTS AND METHODS: Between 1971 and 2013, 1732 patients were followed in the Toronto Lupus Clinic. Causes of death were retrieved from death certificates, autopsy reports, hospital records or the records of the family physicians. They were categorised as atherosclerotic, infectious, malignancy, active lupus and others. For the calculation of the SMR (indirect standardisation method), data from the general population of Ontario, Canada were used (Statistics Canada). RESULTS: Two hundred and forty-nine patients (205 women) died (infections 24.5%, atherosclerosis 15.7%, active lupus 13.3%, malignancy 9.6%); mean age was 53.2±16.6 years and mean disease duration 15.2±11.7 years. The all-cause SMR was substantially decreased from the 1970s (13.5, 95% CI 8.6 to 18.5) to recent years (2.2, 95% CI 1.4 to 3.1). Similar trends were observed for atherosclerosis, infections and malignancies over time. The all-cause age-specific SMR was particularly high in younger (19-39 years old) patients (SMR=12.4, 95% CI 9.7 to 15.1) as compared with individuals older than 40 years (SMR=3.1, 95% CI 2.6 to 3.6). The cause-specific SMR was also higher in younger patients, particularly for infections and malignancies. CONCLUSIONS: The all-cause and cause-specific SMR significantly decreased over time, likely reflecting the advances in the management of SLE and certain comorbidities. The all-cause and cause-specific SMR was particularly high for younger patients (<40 years old).

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.

Antimalarial-induced Cardiomyopathy in Systemic Lupus Erythematosus: As Rare as Considered?

OBJECTIVE: Antimalarials (AM) are recommended for all systemic lupus erythematosus (SLE) patients without specific contraindications. Their main adverse effect is retinal damage; however, heart disease has been described in isolated cases. The aim of our study is to describe 8 patients with AM-induced cardiomyopathy (AMIC) in a defined SLE cohort. METHODS: Patients attending the Toronto Lupus Clinic and diagnosed with definite (based on endomyocardial biopsy; EMB) and possible AMIC were included [based on cardiac magnetic resonance imaging (cMRI) and other investigations]. RESULTS: Eight female patients (median age 62.5 yrs, disease duration 35 yrs, AM use duration 22 yrs) were diagnosed with AMIC in the past 2 years. Diagnosis was based on EMB in 3 (extensive cardiomyocyte vacuolation, intracytoplasmic myelinoid, and curvilinear bodies). In 4 patients, cMRI was highly suggestive of AMIC (ventricular hypertrophy and/or atrial enlargement and late gadolinium enhancement in a nonvascular pattern). Another patient was diagnosed with complete atrioventricular block, left ventricular and septal hypertrophy, along with concomitant ocular toxicity. All patients had abnormal cardiac troponin I (cTnI) and brain natriuretic peptide (BNP), whereas 7/8 also had chronically elevated creatine phosphokinase. During followup, 1 patient died from refractory heart failure. In the remaining patients, hypertrophy regression and a steady decrease of heart biomarkers were observed after AM cessation. CONCLUSION: Once considered extremely rare, AMIC seems to be underrecognized, probably because of the false attribution of heart failure or hypertrophy to other causes. Certain biomarkers (cTnI, BNP) and imaging findings may lead to early diagnosis and enhance survival.

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.

Optimal Monitoring For Coronary Heart Disease Risk in Patients with Systemic Lupus Erythematosus: A Systematic Review.

OBJECTIVE: Premature coronary heart disease (CHD) significantly affects morbidity and mortality in systemic lupus erythematosus (SLE). Several studies have detected factors influencing the atherosclerotic process, as well as methods to quantify the atherosclerotic burden in subclinical stages. The aim of this systematic review was to identify the minimum investigations to optimally monitor CHD risk in SLE. METHODS: English-restricted literature review was performed using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines through Ovid Medline, Embase, and Cochrane Central databases, from inception until May 2014 (Medline until October 2014). Specific search terms included, among others, "SLE," "atherosclerosis," "CHD," "myocardial ischemia," "acute coronary syndrome," "myocardial infarction," and "angina pectoris." We identified 101 eligible articles, 23 with cardiovascular events (CVE) as endpoints and 78 with measures of subclinical atherosclerosis. The Newcastle-Ottawa scale was used for quality assessment. RESULTS: Certain traditional and disease-specific factors were identified as independent predictors for CHD. Among the former were age (particularly postmenopausal state), male sex, arterial hypertension, dyslipidemia, and smoking. Disease activity and duration, cumulative damage, antiphospholipid antibodies, high sensitivity C-reactive protein, and renal disease were the most consistent disease-related factors. Corticosteroids were linked to increased CHD risk whereas antimalarials were protective. Concerning imaging techniques, carotid ultrasonography (intima-media thickness and plaque) was shown to independently predict CVE. CONCLUSION: Premature CHD in SLE is multifactorial; modifiable variables should be monitored at frequent intervals to ensure prompt management. Disease-specific factors also affect the atherogenic process and should be evaluated regularly. Carotid ultrasonography may hold promise in predicting CVE in selected high-risk patients.

Systemic sclerosis and silicone breast implant: a case report and review of the literature.

Environmentally induced systemic sclerosis is a well-recognized condition, which is correlated with exposure to various chemical compounds or drugs. However, development of scleroderma-like disease after exposure to silicone has always been a controversial issue and, over time, it has triggered spirited debate whether there is a certain association or not. Herein, we report the case of a 35-year-old female who developed Raynaud's phenomenon and, finally, systemic sclerosis shortly after silicone breast implantation surgery.