Objective
To describe the features and treatment of macrophage activation syndrome (MAS) in a single‐center cohort of patients with childhood‐onset systemic lupus erythematosus (SLE), and to compare ...childhood‐onset SLE manifestations and outcomes between those with and those without MAS.
Methods
We included all patients with childhood‐onset SLE followed up at The Hospital for Sick Children from 2002 to 2012, and identified those also diagnosed as having MAS. Demographic, clinical, and laboratory features of MAS and SLE, medication use, hospital and pediatric intensive care unit (PICU) admissions, as well as damage indices and mortality data were extracted from the Lupus database. Student's t‐tests and Fisher's exact tests were used to compare continuous and categorical variables, respectively. We calculated incidence rate ratios of hospital and PICU admissions comparing patients with and those without MAS, using Poisson models. Kaplan‐Meier survival analysis was used to examine the time to disease damage accrual.
Results
Of the 403 patients with childhood‐onset SLE, 38 (9%) had MAS. The majority (68%) had concomitant MAS and SLE diagnoses. Fever was the most common MAS clinical feature. The frequency of renal and central nervous system disease, hospital admissions, the average daily dose of steroids, and time to disease damage were similar between those with and those without MAS. We observed a higher mortality rate among those with MAS (5%) than those without MAS (0.2%) (P = 0.02).
Conclusion
MAS was most likely to develop concomitantly with childhood‐onset SLE diagnosis. The majority of the MAS patients were successfully treated with corticosteroids with no MAS relapses. Although the numbers were small, there was a higher risk of death associated with MAS compared to SLE without MAS.
Diabetes is the leading cause of ESRD. Despite evidence for a substantial heritability of diabetic kidney disease, efforts to identify genetic susceptibility variants have had limited success. We ...extended previous efforts in three dimensions, examining a more comprehensive set of genetic variants in larger numbers of subjects with type 1 diabetes characterized for a wider range of cross-sectional diabetic kidney disease phenotypes. In 2843 subjects, we estimated that the heritability of diabetic kidney disease was 35% (P=6.4×10
). Genome-wide association analysis and replication in 12,540 individuals identified no single variants reaching stringent levels of significance and, despite excellent power, provided little independent confirmation of previously published associated variants. Whole-exome sequencing in 997 subjects failed to identify any large-effect coding alleles of lower frequency influencing the risk of diabetic kidney disease. However, sets of alleles increasing body mass index (P=2.2×10
) and the risk of type 2 diabetes (P=6.1×10
) associated with the risk of diabetic kidney disease. We also found genome-wide genetic correlation between diabetic kidney disease and failure at smoking cessation (P=1.1×10
). Pathway analysis implicated ascorbate and aldarate metabolism (P=9.0×10
), and pentose and glucuronate interconversions (P=3.0×10
) in pathogenesis of diabetic kidney disease. These data provide further evidence for the role of genetic factors influencing diabetic kidney disease in those with type 1 diabetes and highlight some key pathways that may be responsible. Altogether these results reveal important biology behind the major cause of kidney disease.
To examine the relationship between being overweight or obese and developing rheumatoid arthritis (RA) in two large prospective cohorts, the Nurses' Health Study (NHS) and Nurses' Health Study II ...(NHSII).
We followed 109 896 women enrolled in NHS and 108 727 in NHSII who provided lifestyle, environmental exposure and anthropometric information through biennial questionnaires. We assessed the association between time-varying and cumulative Body Mass Index (BMI) in WHO categories of normal, overweight and obese (18.5-<25, 25.0-<30, ≥30.0 kg/m(2)) and incident RA meeting the 1987 American College of Rheumatology (ACR) criteria. We estimated HRs for overall RA and serologic subtypes with Cox regression models adjusted for potential confounders. We repeated analyses restricted to RA diagnosed at age 55 years or younger.
During 2 765 195 person-years of follow-up (1976-2008) in NHS and 1 934 518 person-years (1989-2009) in NHSII, we validated 1181 incident cases of RA (826 in NHS, 355 in NHSII). There was a trend toward increased risk of all RA among overweight and obese women (HR (95% CI) 1.37 (0.95 to 1.98) and 1.37 (0.91, 2.09), p for trend=0.068). Among RA cases diagnosed at age 55 years or younger, this association appeared stronger (HR 1.45 (1.03 to 2.03) for overweight and 1.65 (1.34 to 2.05) for obese women (p trend <0.001)). Ten cumulative years of being obese, conferred a 37% increased risk of RA at younger ages (HR 1.37 (1.11 to 1.69)).
Risks of seropositive and seronegative RA were elevated among overweight and obese women, particularly among women diagnosed with RA at earlier ages.
Objectives To determine the frequency and characteristics of clinical signs, symptoms, laboratory findings, and medication use in children with pediatric systemic lupus erythematosus (pSLE) at ...presentation and during the course of the disease, and to examine correlations among disease manifestations, disease activity, and damage over time. Study design The study involved an analysis of medical records and the SLE database of an inception cohort of 256 patients with pSLE (female:male ratio, 4.7:1). Results The most common clinical manifestations were arthritis (67%), malar rash (66%), nephritis (55%), and central nervous system (CNS) disease (27%). At diagnosis, patients with both renal and CNS disease had the highest SLE Disease Activity Index (SLEDAI) scores ( P < .0001), but these scores were similar to those of the total group at 1 year ( P = .11). Patients who developed renal and CNS disease more than 1 year after diagnosis had higher SLEDAI scores at disease onset. Some 34% of patients had Systemic Lupus International Collaborative Clinics Damage Index (SLICC-DI) scores >1 at a mean follow-up of 3.5 years. A greater proportion of patients with renal and CNS disease had SLICC-DI scores of >1, and these patients had higher mean scores compared with patients without major organ involvement (70% vs 11% P < .0001 and 1.4 vs 0.1 P < .0001, respectively). Conclusions Most of the patients in our cohort exhibited major organ involvement. These patients had the highest SLEDAI scores at diagnosis, which normalized at 1 year but preceded development of renal and CNS disease. The average SLICC-DI score was lower than that previously reported in patients with pSLE.
Objective
Anti‐Ro antibody–positive mothers are frequently referred for serial echocardiography due to the fetal risk of developing heart block and endocardial fibroelastosis. Little is known why ...only some and not all offspring develop these cardiac manifestations of neonatal lupus (CNL). This prospective study examined associations between anti‐Ro antibody titers and fetal CNL.
Methods
Antibody‐positive mothers referred since 2018 for fetal echocardiography at risk of CNL (group 1; n = 240) or with CNL (group 2; n = 18) were included. Maternal antibody titers were measured with a chemiluminescent immunoassay (CIA). Additional testing on diluted serum samples was used to quantify anti–Ro 60 antibody titers above the analytical measuring range (AMR) of the standard CIA (≥1,375 chemiluminescent units CU).
Results
Among 27 total mothers with a fetal diagnosis of CNL, all displayed anti–Ro 60 antibody titers that exceeded the AMR of the CIA at least 10‐fold. Of 122 mothers in group 1 who underwent additional anti–Ro 60 antibody testing, event rates of CNL (n = 9) were 0% (0 of 45) among mothers with anti–Ro 60 antibody titers from 1,375–10,000 CU, 5% (3 of 56) among mothers with titers from 10,000–50,000 CU, but 29% (6 of 21) among mothers with titers >50,000 CU (odds ratio 13.1, P = 0.0008). Of mothers in group 2 with a primary diagnosis of CNL, 0% (0 of 18 mothers) had anti–Ro 60 antibody titers <10,000 CU, 44% (8 of 18 mothers) had titers from 10,000–50,000 CU, and 56% (10 of 18 mothers) had titers >50,000 CU.
Conclusion
CNL is associated with substantially higher anti‐Ro antibody titers than are obtained using a standard CIA. Enhancing the assay measuring range allows an improved specificity of identifying pregnancies at risk of CNL.
Objective
To examine the epidemiology of serious infections, a significant cause of morbidity and mortality in systemic lupus erythematosus (SLE), in a nationwide cohort of SLE and lupus nephritis ...(LN) patients.
Methods
Using the Medicaid Analytic eXtract database for the years 2000–2006, we identified patients ages 18–64 years who had SLE and the subset who had LN. We ascertained cases of serious hospitalized infections using validated algorithms, and we determined 30‐day mortality rates. Poisson regression was used to calculate infection incidence rates and multivariable Cox proportional hazards models were used to calculate hazard ratios (HRs) for the first infection, adjusted for sociodemographic variables, medication use, and an SLE‐specific risk adjustment index.
Results
We identified 33,565 patients with SLE, 7,113 of whom had LN. There were 9,078 serious infections in 5,078 SLE patients and 3,494 infections in 1,825 LN patients. The infection incidence rate per 100 person‐years was 10.8 in the SLE cohort and 23.9 in the LN subcohort. In adjusted models for the SLE cohort, we observed increased risks of infection in men as compared to women (HR 1.33 95% confidence interval (95% CI) 1.20–1.47), in blacks as compared to whites (HR 1.14 95% CI 1.06–1.21), and in users of glucocorticoids (HR 1.51 95% CI 1.43–1.61) and immunosuppressive drugs (HR 1.11 95% CI 1.03–1.20) as compared to never users. Hydroxychloroquine users had a reduced risk of infection as compared to never users (HR 0.73 95% CI 0.68–0.77). The 30‐day mortality rate per 1,000 person‐years among those hospitalized with infections was 21.4 in the SLE cohort and 38.6 in the LN subcohort.
Conclusion
In this diverse, nationwide cohort of SLE patients, we observed a substantial burden of serious infections with many subsequent deaths, particularly among those with LN.
Elevated levels of interferons (IFNs) are a characteristic feature of systemic autoimmune rheumatic diseases (SARDs) and may be useful in predicting impending symptomatic progression in anti-nuclear ...antibody-positive (ANA
) individuals lacking a SARD diagnosis. Typically, these are measured by their effect on gene expression in the blood, which has limited their utility in clinical settings. Here, we assessed whether the measurement of serum IFN-α or selected IFN-induced cytokines accurately mirrors IFN-induced gene expression in ANA
individuals and investigated their utility as biomarkers of clinical progression.
A total of 280 subjects were studied, including 50 ANA
healthy controls, 160 ANA
individuals without a SARD diagnosis (96 asymptomatic, 64 with undifferentiated connective tissue disease), and 70 SARD patients. IFN-induced gene expression was measured by nanoString and cytokine levels by ELISA or Simoa. ANA
individuals lacking a SARD diagnosis who had the new onset of SARD criteria over the subsequent 2 years were defined as progressors.
Measurement of IFN-α levels by high-sensitivity ELISA or Simoa correlated much better with IFN-induced gene expression than measurement of CXCL-10 or Galectin-9 levels. Despite this, high CXCL-10 and Galectin-9 levels were better predictors of subsequent progression in ANA
individuals than measures of IFN-α or IFN-induced gene expression with the optimal combination of predictive cytokines (CXCL-10 and IFN-α as measured by ELISA), resulting in a specificity and positive predictive value of 100%.
Easily performed ELISA assays for CXCL-10 and IFN-α can be used to predict ANA
individuals at high risk of imminent symptomatic progression.
Systemic lupus erythematosus (SLE) is a systemic, autoimmune, multisystem disease with a heterogeneous clinical phenotype. Genome-wide association studies have identified multiple susceptibility ...loci, but these explain a fraction of the estimated heritability. This is partly because within the broad spectrum of SLE are monogenic diseases that tend to cluster in patients with young age of onset, and in families. This article highlights insights into the pathogenesis of SLE provided by these monogenic diseases. It examines genetic causes of complement deficiency, abnormal interferon production, and abnormalities of tolerance, resulting in monogenic SLE with overlapping clinical features, autoantibodies, and shared inflammatory pathways.
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