Lupus

The understanding of systemic lupus erythematosus (SLE) and lupus nephritis (LN) pathogenesis remains incomplete. This review assessed LN development in SLE, within-LN progression and progression to end-stage renal disease (ESRD).

A keyword-based literature search was conducted, and 26 publications were included.

Overall, 7–31% of patients had LN at SLE diagnosis; 31–48% developed LN after SLE diagnosis, most within 5 years. Class IV was the most commonly found LN class and had the worst prognosis. Histological transformation occurred in 40–76% of patients, more frequently from non-proliferative rather than proliferative lesions. Cumulative 5- and 10-year ESRD incidences in patients with SLE were 3% and 4%, respectively, and 3–11% and 6–19%, respectively, in patients with SLE and LN.

Elevated serum creatinine was identified as a predictor of worsening disease state, and progression within LN classes and from SLE/LN to ESRD. This review highlights the substantial risk for developing LN and progressing to ESRD amongst patients with SLE.

Cutaneous lupus erythematosus is a chronic autoimmune disease that can leave important sequelae.

To determine the factors that predict the activity and damage of the skin disease, and the impact of tobacco on the efficacy of antimalarials using the Cutaneous Lupus Erythematosus Disease Area and Severity Index.

A consecutive case series was performed on 260 patients with cutaneous lupus erythematosus (α = 0.05; precision ± 6.5%). We carried out a descriptive analysis of the variables included, with a multivariate analysis to measure the association of variables with the Cutaneous Lupus Erythematosus Disease Area and Severity Index activity and damage (p value < 0.05).

The Cutaneous Lupus Erythematosus Disease Area and Severity Index activity was greater in smokers than non-smokers (4.0 ±5.3 vs 1.2 ±3.4, p = 0.006). No significant differences were observed in the Cutaneous Lupus Erythematosus Disease Area and Severity Index activity when the efficacy of antimalarials was analyzed between smokers and non-smokers. Cutaneous Lupus Erythematosus Disease Area and Severity Index damage was higher in smokers than in non-smokers (2.0 ± 3.6 vs 1.2 ± 2.6, p = 0.029). Cutaneous Lupus Erythematosus Disease Area and Severity Index activity was associated with: (a) being an active smoker (odds ratio 3.04, 95% confidence interval 1.68–5.51, p < 0.001; regression coefficient 2.05, 95% confidence interval 0.69–3.42, p = 0.003); (b) the chronic cutaneous lupus erythematosus subtype (odds ratio 1.98, 95% confidence interval 1.02–3.84, p = 0.044); and (c) C-reactive protein increase (≥0.5 mg/dL) (regression coefficient 2.56, 95% confidence interval 0.40–4.71, p = 0.020). Cutaneous Lupus Erythematosus Disease Area and Severity Index damage was associated with: (a) the activity (regression coefficient 0.11, 95% confidence interval 0.01–0.20, p = 0.024); (b) the chronic cutaneous lupus erythematosus subtype (regression coefficient 2.46, 95% confidence interval 1.37–3.56, p < 0.001); (c) the use of topical treatment (regression coefficient 1.31, 95% confidence interval 0.01–2.61, p = 0.049); and (d) systemic treatment (regression coefficient 1.44, 95% confidence interval 0.35–2.53, p < 0.010).

Smoking is related to an increase risk and a greater activity of cutaneous lupus erythematosus. The chronic cutaneous lupus erythematosus subtype and an increased C-reactive protein level were also associated with a higher disease activity. The sequelae were related to the activity, the chronic cutaneous lupus erythematosus subtype, and the use of topical and systemic treatment. The impact of tobacco on the efficacy of antimalarials may be caused by an increase in the severity of the disease more than by resistance in smokers.

To evaluate the role of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-neutrophil ratio (PNR), platelet-to-monocyte ratio (PMR), and neutrophil-to-monocyte ratio (NMR) as predictors for lupus nephritis (LN) patients without infection or as biomarkers for distinguishing between infection or flare with LN patients.

LN patients were divided into three groups: LN without infection, LN with infection, and LN with flare. A total of 57 healthy subjects were enrolled as controls. The differentiation was analyzed between LN without infection and control group, and LN with infection and LN with flare. Correlations among variables were assessed in the LN group without infection. Receiver operating characteristic curves were constructed in two comparable groups.

NLR, PLR, and MLR were increased significantly in the LN group without infection as compared with those in healthy controls. NLR (area under the curve (AUC): 0.75) and MLR (AUC: 0.79) were useful for distinguishing between LN patients without infection and healthy subjects. In differentiating LN patients without infection from the controls, optimal cutoffs of NLR and MLR were 3.43 (sensitivity: 45.6%, specificity: 96.5%, and overall accuracy: 68.8%) and 0.24 (sensitivity: 75.0%, specificity: 73.7%, and overall accuracy: 73.6%), respectively. In addition, NLR (r = 0.322, p = 0.011) and PLR (r = 0.283, p = 0.026) were positively correlated with CRP. Importantly, NLR and NMR were increased while PNR was decreased in the LN group with infection in comparison with those in the LN group with flare. NLR (AUC: 0.80), NMR (AUC: 0.78), and PNR (AUC: 0.74) were useful in differentiating LN patients with infection and flare, and their optimal cutoffs were 4.02 (sensitivity: 82.6%, specificity: 69.6%, and overall accuracy: 75.5%), 12.19 (sensitivity: 80.4%, specificity: 73.9%, and overall accuracy: 77.5%), and 28.26 (sensitivity: 65.2%, specificity: 76.8%, and overall accuracy: 71.6%), respectively.

We demonstrated, for the first time, that MLR or NMR had the best accuracy in differentiating LN patients without infection from healthy subjects, or differentiating infection from flare in LN patients, respectively. Our results implied that NLR, MLR, PNR, and NMR may be useful biomarkers in predicting LN.

Bone marrow mesenchymal stem cells are multipotent adult stem cells that can differentiate into osteoblasts, adipocytes, and chondrocytes. Our recently published data demonstrate that systemic lupus erythematous bone marrow mesenchymal stem cells produce increased quantities of interferon β based on a positive feedback loop involving the innate signaling molecule mitochondrial antiviral signaling protein. Moreover, this pathway contributes to human systemic lupus erythematous bone marrow mesenchymal stem cell senescence-like features. Here we investigate the differentiation defects of systemic lupus erythematous bone marrow mesenchymal stem cells and the potential for therapeutic interventions.

The six systemic lupus erythematous patients recruited in this study satisfy the American College of Rheumatology 1997 classification criteria for systemic lupus erythematous. Systemic Lupus Erythematous Disease Activity Index-2K was used to determine disease activity. Systemic lupus erythematous bone marrow mesenchymal stem cells were isolated with Ficoll centrifugation and phenotyped using flow cytometry. In vitro studies included real-time polymerase chain reaction and western blotting.

We compared six age-paired bone marrow aspirates from healthy controls and systemic lupus erythematous patients. Systemic lupus erythematous bone marrow mesenchymal stem cells display significantly reduced alkaline phosphatase staining, as well as reduced expression of osteogenic markers alkaline phosphatase, Runt-related transcription factor 2, and bone sialoprotein. When healthy bone marrow mesenchymal stem cells were treated with interferon β for 6 hours, expression of these same osteogenic markers was markedly reduced. Conversely the application of interferon β neutralizing antibody enhanced the expression of osteoblastogenesis markers. When the underlying mechanisms for interferon β inhibition of osteoblastogenesis were investigated, we found that IFNβ pre-treatment activates the inhibitory Smad6 and Smad7 expression through JAK1/STAT1, leading to reduced Smad1 phosphorylation and nuclear translocation.

Our present work suggests that interferon β affects osteogenesis. By revealing the essential role of interferon β on systemic lupus erythematous bone marrow mesenchymal stem cell differentiation, our study sheds light on systemic lupus erythematous pathogenesis and provides a new potential therapeutic target for the bone complications found in systemic lupus erythematous.

The objective of this paper is to assess the prevalence of the main clinical manifestations and laboratory features at disease onset and during the ensuing 10 years of a large cohort of patients with antiphospholipid syndrome (APS) from a single center.

The study included all consecutive APS patients followed longitudinally in our center from 2003 to 2013. Descriptive statistics for demographics, clinical and laboratory features and mortality were performed.

A total of 160 patients were included. Most of them, 128 (78.8%), were women and the mean (SD) age at diagnosis was 39.1 (14.0) years. The majority of them, 104 (65.0%), had primary APS, 36 (22.5%) had APS associated with systemic lupus erythematous, and 20 (12.5%) had APS associated with other autoimmune disease. During the study period, thrombotic events occurred in 27 (16.9%) patients, the most common being strokes, nonbacterial thrombotic endocarditis and deep venous thrombosis. Regarding obstetric morbidity, 18 women (14.3%) became pregnant and 90% of pregnancies succeeded in having live births. The most common obstetric complication was early pregnancy loss (15% of pregnancies). Prematurity (11.1% of live births) and intrauterine growth restriction (5.6% of live births) were the most frequent fetal morbidities. Ten (6.3%) patients died and the most frequent causes of death were severe thrombosis, hemorrhage, and cancer. Three (0.9%) cases of catastrophic APS occurred. The survival probability at 10 years was 93.8%.

Patients with APS develop significant morbidity and mortality despite current treatment. It is imperative to identify prognostic factors and therapeutic measures to prevent these complications.

To compare the performance of cytology, colposcopy and human papillomavirus in detecting cervical intraepithelial lesions in women with systemic lupus erythematosus.

Papanicolaou smears (normal, low-grade squamous intraepithelial lesion, high grade squamous intraepithelial lesion), colposcopy findings, human papillomavirus and co-testing (Papanicolaou smear + human papillomavirus) were compared with cervical biopsy findings in women with systemic lupus erythematosus. Sensitivity, specificity, false-positive and false-negative rates, positive and negative predictive values and likelihood ratios of cytologic smears, colposcopy findings, human papillomavirus and co-testing were determined.

Cytology and colposcopy were performed in 170 systemic lupus erythematosus women (mean age and disease duration of 43.7±12.1 years and 9.7±5.3 years, respectively) and biopsies were performed in 55 patients (38.2% normal, 60.0% low-grade squamous intraepithelial lesion and 1.8% high grade squamous intraepithelial lesion). The sensitivity, specificity, positive predictive value and negative predictive value of cytology were 14.7% (95% confidence interval 5.5–31.8%), 95.2% (95% confidence interval 74.1–99.7%), 83.3% (95% confidence interval 36.4–99.1%) and 40.8% (95% confidence interval 27.3–55.7%), respectively. The sensitivity, specificity and positive predictive value of colposcopy findings were 100.0% (95% confidence interval 87.3–100.0%), 0.0% (95% confidence interval 0.0–19.2%) and 61.8% (95% confidence interval 47.7–74.2%), respectively. The sensitivity and specificity of co-testing were 8.0% (95% confidence interval 1.3–27.5%) and 100.0% (95% confidence interval 71.6–100.0%). The positive predictive value and negative predictive values were 100.0% (95% confidence interval 19.7–100.0%) and 36.1% (95% confidence interval 33.5–38.8%), respectively.

In systemic lupus erythematosus patients, colposcopy impressions were more sensitive than cytology and co-testing. However, cytology and co-testing were the most specific tests. The results should be interpreted with caution due to the small sample size.

Mycophenolic acid (MPA) is an effective oral immunosuppressive drug used to treat lupus nephritis (LN), which exhibits large pharmacokinetic variability. This study aimed to characterize MPA pharmacokinetic behaviour in Mexican LN patients and to develop a population pharmacokinetic model which identified factors that influence MPA pharmacokinetic variability.

Blood samples from LN patients treated with mycophenolate mofetil (MMF) were collected pre dose and up to six hours post dose. MPA concentrations were determined by a validated ultra-performance liquid chromatography tandem mass spectrometry technique. Patients were genotyped for polymorphisms in enzymes (UGT1A8, 1A9 and 2B7) and transporters (ABCC2 and SLCO1B3). The anthropometric, clinical, genetic and co-medication characteristics of each patient were considered as potential covariates to explain the variability.

A total of 294 MPA concentrations from 40 LN patients were included in the development of the model. The data were analysed using NONMEM software and were best described by a two-compartment linear model. MPA CL, Vc, Vp, Ka and Q were 15.4 L/h, 22.86 L, 768 L, 1.28 h⁻¹ and 20.3 L/h, respectively. Creatinine clearance and prednisone co-administration proved to have influence on clearance, while body weight influenced Vc. The model was internally validated, proving to be stable. MMF dosing guidelines were obtained through stochastic simulations performed with the final model.

This is the first MPA population pharmacokinetic model to have found that co-administration of prednisone results in a considerable increase on clearance. Therefore, this and the other covariates should be taken into account when prescribing MMF in order to optimize the immunosuppressant therapy in patients with LN.

We aimed to perform a systematic review and meta-analysis of studies assessing the homeostasis model assessment for insulin resistance (HOMA-IR) values, serum adiponectin, leptin and resistin levels in patients with systemic lupus erythematosus (SLE).

Online databases were searched on 31 March 2019 in order to identify studies comparing HOMA-IR, serum adiponectin, leptin and resistin levels between patients with SLE and controls. A random-effects model was adopted.

Fifty-six studies involving a total of 4460 patients with SLE were included. Patients with SLE had significantly higher HOMA-IR values (standardized mean difference (SMD)=0.425; 95% confidence interval (CI) 0.156–0.693; I²=93.8%) than the control group. The serum levels of adiponectin (SMD=0.547; 95% CI 0.219–0.874; I²=90.1%), leptin (SMD=0.843; 95% CI 0.454–1.231; I²=94.4%) and resistin (SMD=0.856; 95% CI 0.199–1.513; I²=96.6%) were all higher among patients with SLE than controls. A meta-regression analysis revealed that the serum resistin level was positively correlated with disease activity (coefficient 0.123; 95% CI 0.051–0.195; p<0.001).

Patients with SLE have higher HOMA-IR values and serum levels of adiponectin, leptin and resistin than individuals without SLE. The serum level of resistin correlates with SLE disease activity.

Sexual dysfunction in systemic lupus erythematous (SLE) patients is an important issue to be tackled. We aimed to study the prevalence of sexual dysfunction in SLE women and detect its association with depression, functional disability and quality of life.

This study included 94 SLE females. Ninety-eight control females agreed to participate. Patients and controls answered a written form of the Arabic version of the Female Sexual Function Index (FSFI), Beck Depression Inventory (BDI), Health Assessment Questionnaire–Disability Index (HAQ-DI) and Short Form 36 (SF-36). Disease activity and damage were assessed using the SLE Disease Activity Index and the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index.

The frequency of sexual dysfunction was similar in the patients and control groups (77.7% versus 82.7%) while the BDI, HAQ-DI and SF-36 scores were significantly worse in SLE patients. SLE patients with and without sexual dysfunction differed in neither disease characteristics nor disease activity and damage indices. The FSFI showed a strong positive correlation with SF-36, and strong inverse correlations with BDI and HAQ-DI in the patients group while it had a weaker positive correlation with SF-36 and no correlations with the other two indices in the control group.

No significant difference was found in the prevalence of sexual dysfunction between SLE patients and controls. Sexual dysfunction in SLE patients is mostly related to depression, poor functional status, increased pain, poor health perception and bad quality of life. Neither disease activity nor damage contributes significantly to sexual dysfunction in lupus females.

Type-I interferons contribute to pathogenesis in systemic lupus erythematosus, including nephritis. Interferons consist of a family of 16 proteins yet are often characterized in patients without knowledge of the specific interferon subtypes involved. Different interferons may function in the kidneys, and other organs, relative to what is often measured in patient blood. Moreover, antibodies to interferons may potentially modulate systemic or organ-specific interferon activity. The aim of this study was to characterize global interferon activity levels and identify autoantibodies to the 12 interferon α subtypes in patient serum and urine.

Interferon activity levels in serum and urine were measured using an interferon bioassay. Anti-interferon and anti-cytokine autoantibodies were measured by ELISA. Serum and urine samples were also characterized for their ability to neutralize the biological activity of exogenously added interferons.

Serum interferon activity was increased in 62% of systemic lupus erythematosus patient samples, relative to healthy donor controls, whereas binding interferon α autoantibodies to at least one interferon α subtype were found in 68% of the samples evaluated. High Systemic Lupus Erythematosus Disease Activity Index scores were significantly (p = 0.001) associated with patient samples containing interferon α autoantibodies to three or more interferon α subtypes in their serum. Interferon α autoantibodies that potently block interferon activity were rare (∼5% of samples), but collectively bound to all 12 interferon α subtypes. Urine interferon activity and interferon α autoantibody profiles did not correlate with their serum counterparts, suggesting immune responses in systemic lupus erythematosus kidneys can be distinct from those measured in serum. Analysis of autoantibodies to 15 additional cytokines in serum identified higher frequencies of granulocyte-macrophage colony-stimulating factor and interleukin 17A autoantibodies, suggesting these signaling pathways may potentially contribute, with interferons, to systemic lupus erythematosus pathogenesis.

The measurement of autoantibodies to multiple interferon subtypes in serum and urine may provide an alternative method for following interferon-mediated systemic lupus erythematosus disease activity. The results suggest autoantibodies might be used for patient monitoring and/or identifying additional cytokine signaling pathways that are functioning in different systemic lupus erythematosus patients.

Paediatric systemic lupus erythematosus is a rare autoimmune disease with a wide spectrum of clinical presentation in different populations. We present a cohort of paediatric systemic lupus erythematosus in Malaysia where the disease features and outcomes are still largely unknown.

A retrospective review of all paediatric systemic lupus erythematosus patients with at least 6 months follow-up at Selayang Hospital from 2004 to 2016. Epidemiological, clinical and outcome data were collected and analysed.

A total of 141 paediatric systemic lupus erythematosus patients, 87.9% females, were followed up for a median 6.3 years (interquartile range 3.6–9.0). The median age at diagnosis was 10.8 years (interquartile range 9.0–12.0 years), positive family history of systemic lupus erythematosus was present in 12.1% and the majority (61.7%) were of Malay ethnicity. Common presentations included fever (87.2%), vasculitic rash (72.3%) and lethargy (69.5%). At diagnosis, leukopenia (51.1%), thrombocytopenia (41.8%) and cutaneous lupus (56%) predominate with significant renal involvement (39.7%). Renal (45.4%), liver (26%) and the central nervous system (17%) were important major organs involved during the course of the disease. At diagnosis, almost all (99.3%) patients had high disease activity (mean Systemic Lupus Erythematosus Disease Activity Index score 20.1 ± 9.6). The majority (62.4%) achieved remission or low disease activity after 6 months, maintained over the next 10 years. Damage occurred early (39.1% at 1 year) and increased with time. Ocular damage was the most common side effect (29%) and was predominantly corticosteroid related (93%). Growth retardation was significant (38.2%) with no gonadal failure or secondary malignancies. End-stage renal disease occurred in 3.1% patients whereas 53.1% had sustained renal remission. Overall mortality was 1.4%.

Despite high disease activity at diagnosis, the majority had good sustained response to treatment with low overall mortality. However, there was progressive accrual of organ damage, highlighting the need for further research and refinements into therapies for paediatric systemic lupus erythematosus.

Treatment of Libman–Sacks (LS) endocarditis in patients with systemic lupus erythematosus (SLE) is challenging due to the lack of data. This study aimed to identify the clinical characteristics of SLE patients and LS endocarditis, and to investigate the treatment and prognosis of LS endocarditis.

Of all the patients with SLE who underwent echocardiography between 2010 and 2019, 11 and 29 patients with and without LS endocarditis, respectively, were included. We compared the inflammatory and thrombotic profiles between patients with and without LS endocarditis, and investigated the treatment and long-term outcome of LS endocarditis.

No significant differences were observed in disease activity, clinical characteristics and inflammatory marker levels between patients with and without LS endocarditis. Patients with LS endocarditis had a significantly higher prevalence of antiphospholipid antibody (aPL) but a lower prevalence of SLE-specific antibody. Triple positivity of aPL was found in 72.7% and 13.8% of patients with and without LS endocarditis, respectively. Of 11 patients with LS endocarditis, six patients received anticoagulation therapy, and five patients received augmented immunosuppressive therapies. One patient who did not receive anticoagulation therapy developed cerebral infarction. Nine (82%) patients with LS endocarditis were classified as having antiphospholipid syndrome (APS). Despite the residual vegetation and valve dysfunction, surgical intervention was not required during the follow-up period of 56.8 months.

A significant correlation was observed between APS and LS endocarditis. Anticoagulation therapy should be considered to prevent thromboembolic complications in SLE patients with LS endocarditis.

Systemic lupus erythematosus (SLE) is a clinically heterogeneous autoimmune disease, and in some conditions, admission to the intensive care unit (ICUs) is required. This study describes the clinical and prognostic factors in SLE patients admitted to the ICU.

We conducted a retrospective study that reviewed all clinical records of patients with SLE admitted to the ICU between 2011 and 2018.

We evaluated 188 patients, with 279 ICU admissions. Most patients were female (n = 159; 84.57%) with a median age of 35 years (interquartile range (IQR) = 25–48 years). Infection was the leading cause of admission in 77 (27.60%) cases, followed by lupus flare. The average length of hospitalization was 5 days (IQR 3–11 days), and the SLE Disease Activity Index 2000, Acute Physiology, Age and Chronic Health Evaluation (APACHE II), and Sequential Organ Failure Assessment (SOFA) scores were 9 (IQR 2–17), 14 (IQR 10–17), and 3 (IQR 2–5), respectively. Non-survivors presented with higher APACHE II and SOFA scores. Infection was the leading cause of mortality (n = 38; 20.21%), and predictors of mortality included invasive mechanical ventilation, vasoactive medication requirement, higher SOFA scores, and antiphospholipid syndrome comorbidity.

We found that infection was the leading cause of ICU admissions and mortality in patients with SLE. Factors identified here as predictors of mortality should be accurately identified at admission for the prompt treatment of SLE patients.

This study aimed to compare the clinical features, damage accrual, and survival of patients with familial and sporadic systemic lupus erythematosus (SLE).

A multi-ethnic, multinational Latin American SLE cohort was studied. Familial lupus was defined as patients with a first-degree SLE relative; these relatives were interviewed in person or by telephone. Clinical variables, disease activity, damage, and mortality were compared. Odds ratios (OR) and 95% confidence intervals (CI) were estimated. Hazard ratios (HR) were calculated using Cox proportional hazard adjusted for potential confounders for time to damage and mortality.

A total of 66 (5.6%) patients had familial lupus, and 1110 (94.4%) had sporadic lupus. Both groups were predominantly female, of comparable age, and of similar ethnic distribution. Discoid lupus (OR = 1.97; 95% CI 1.08–3.60) and neurologic disorder (OR = 1.65; 95% CI 1.00–2.73) were significantly associated with familial SLE; pericarditis was negatively associated (OR = 0.35; 95% CI 0.14–0.87). The SLE Disease Activity Index and Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) were similar in both groups, although the neuropsychiatric (45.4% vs. 33.5%; p = 0.04) and musculoskeletal (6.1% vs. 1.9%; p = 0.02) domains of the SDI were more frequent in familial lupus. They were not retained in the Cox models (by domains). Familial lupus was not significantly associated with damage accrual (HR = 0.69; 95% CI 0.30–1.55) or mortality (HR = 1.23; 95% CI 0.26–4.81).

Familial SLE is not characterized by a more severe form of disease than sporadic lupus. We also observed that familial SLE has a higher frequency of discoid lupus and neurologic manifestations and a lower frequency of pericarditis.