52 research outputs found
Developments in the scientific understanding of lupus
Systemic lupus erythematosus is a systemic autoimmune disease characterized by the production of antinuclear antibodies (ANAs). Recent research into human and murine lupus suggests that disease susceptibility results from genetic polymorphisms regulating immune responses as well as impairing the clearance of apoptotic cells. Because the products of dead cells, including nucleic acids, have immunologic activity, this situation can promote antigen-driven ANA responses. Furthermore, immune complexes of ANAs can drive the production of proinflammatory cytokines, inducing the 'interferon signature', and intensifying disease. Together, these findings point to new genetic and immunologic markers of disease as well as targets for new therapies
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The potential role of Colchicine in preventing coronary vascular disease in childhood‐onset lupus: a new view on an old drug
Background
Patients with systemic lupus erythematous have a significantly increased risk of cardiovascular disease, which is not fully explained by traditional cardiovascular disease risk factors. Despite increasing life expectancy in patients with systemic lupus erythematous, mortality due to cardiovascular disease, the major cause of death in these patients, has not changed. Children with lupus suffer from more aggressive disease compared to their adult counterparts, and there is a growing concern for their increased risk of cardiovascular disease as they age.
Body:
There is an unmet need for therapies to address the increased risk of cardiovascular disease in childhood-onset lupus. Colchicine has many anti-inflammatory and cardiovascular protective properties, including inhibition of IL-1β and IL-18 activity, key proinflammatory cytokines that are predictive of future adverse cardiovascular events. In the Colchicine Cardiovascular Outcomes Trial (COLCOT), colchicine was recently found to have significant benefit with minimal risk in adults with previous myocardial infarction for prevention of secondary vascular disease. While adult studies are promising, no studies have been conducted in pediatric patients to investigate colchicine’s potential for cardiovascular protection in children and adolescents with lupus.
Conclusions
Studies investigating colchicine’s potential role for cardiovascular protection are needed in pediatric patients with systemic lupus erythematous
The complement system and human autoimmune diseases
Genetic deficiencies of early components of the classical complement activation pathway (especially C1q, r, s, and C4) are the strongest monogenic causal factors for the prototypic autoimmune disease systemic lupus erythematosus (SLE), but their prevalence is extremely rare. In contrast, isotype genetic deficiency of C4A and acquired deficiency of C1q by autoantibodies are frequent among patients with SLE. Here we review the genetic basis of complement deficiencies in autoimmune disease, discuss the complex genetic diversity seen in complement C4 and its association with autoimmune disease, provide guidance as to when clinicians should suspect and test for complement deficiencies, and outline the current understanding of the mechanisms relating complement deficiencies to autoimmunity. We focus primarily on SLE, as the role of complement in SLE is well-established, but will also discuss other informative diseases such as inflammatory arthritis and myositis
The role of cell death in the pathogenesis of autoimmune disease: HMGB1 and microparticles as intercellular mediators of inflammation
Cell death is critical to normal homeostasis, although this process, when increased aberrantly, can lead to the production of pro-inflammatory mediators promoting autoimmunity. Two novel intercellular mediators of inflammation generated during cell death are high mobility group box 1 (HMGB1) protein and microparticles (MPs). HMGB1 is a nuclear protein that functions in transcription when inside the nucleus but takes on pro-inflammatory properties when released during cell death. Microparticles are small, membrane-bound structures that extrude from cells when they die and contain cell surface proteins and nuclear material from their parent cells. MPs circulate widely throughout the vasculature and mediate long-distance communication between cells. Both MPs and HMGB1 have been implicated in the pathogenesis of a broad spectrum of inflammatory diseases, including the prototypic autoimmune conditions systemic lupus erythematosus and rheumatoid arthritis. Given their range of activity and association with active disease, both structures may prove to be targets for effective therapy in these and other disorders
Development of a Novel Renal Activity Index of Lupus Nephritis in Children and Young Adults
OBJECTIVE:
Noninvasive estimation of the degree of inflammation seen on kidney biopsy with lupus nephritis (LN) remains difficult. The objective of this study was to develop a Renal Activity Index for Lupus (RAIL) that, based solely on laboratory measures, accurately reflects histologic LN activity.
METHODS:
We assayed traditional LN laboratory tests and 16 urine biomarkers (UBMs) in children (n = 47) at the time of kidney biopsy. Histologic LN activity was measured by the National Institutes of Health activity index (NIH-AI) and the tubulointerstitial activity index (TIAI). High LN-activity status (versus moderate/low) was defined as NIH-AI scores >10 (versus ≤10) or TIAI scores >5 (versus ≤5). RAIL algorithms that predicted LN-activity status for both NIH-AI and TIAI were derived by stepwise multivariate logistic regression, considering traditional biomarkers and UBMs as candidate components. The accuracy of the RAIL for discriminating by LN-activity status was determined.
RESULTS:
The differential excretion of 6 UBMs (neutrophil gelatinase-associated lipocalin, monocyte chemotactic protein 1, ceruloplasmin, adiponectin, hemopexin, and kidney injury molecule 1) standardized by urine creatinine was considered in the RAIL. These UBMs predicted LN-activity (NIH-AI) status with >92% accuracy and LN-activity (TIAI) status with >80% accuracy. RAIL accuracy was minimally influenced by concomitant LN damage. Accuracies between 71% and 85% were achieved without standardization of the UBMs. The strength of these UBMs to reflect LN-activity status was confirmed by principal component and linear discriminant analyses.
CONCLUSION:
The RAIL is a robust and highly accurate noninvasive measure of LN activity. The measurement properties of the RAIL, which reflect the degree of inflammatory changes as seen on kidney biopsy, will require independent validation
American College of Rheumatology Provisional Criteria for Global Flares in Childhood-Onset Systemic Lupus Erythematosus
Objective: To validate the preliminary criteria of global flare for childhood-onset SLE (cSLE). Methods: Pediatricians experienced in cSLE care (n = 268) rated unique patient profiles; results of standard cSLE laboratory testing and information about the cSLE flare descriptors were presented as follows: global assessment of patient well-being, physician global assessment of disease activity (MD-global), Disease Activity Index score, protein/creatinine ratio (PCR), and erythrocyte sedimentation rate (ESR). Using rater interpretation of the course of cSLE (baseline versus followup as the gold standard), performance (sensitivity, specificity, area under the receiver operating characteristic curve [AUC]) of the preliminary flare criteria was tested. An international consensus conference was held to rank the preliminary flare criteria as per the American College of Rheumatology recommendations and delineate threshold scores for minor, moderate, and major flares. Results: The accuracy of the 2 highest-ranked candidate criteria that consider absolute changes ( 06) of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) or British Isles Lupus Assessment Group (BILAG) (numeric scoring: A = 12, B = 8, C = 1, and D/E = 0), MD-global, PCR, and ESR were confirmed (both AUC >0.93). For the SLEDAI-based criteria (0.5
7 06SLEDAI + 0.45
7 06PCR + 0.5
7 06MD-global + 0.02
7 06ESR) flare scores 656.4/3.0/0.6 constituted major/moderate/minor flares, respectively. For the BILAG-based algorithm (0.4
7 06BILAG + 0.65
7 06PCR + 0.5
7 06MD-global + 0.02
7 06ESR) flare scores 657.4/3.7/2.2 delineated major/moderator/minor flares, respectively. These threshold values (SLEDAI, BILAG) were all >82% sensitive and specific for capturing flare severity. Conclusion: Provisional criteria for global flares in cSLE are available to identify patients who experienced a flare. These criteria also allow for discrimination of the severity of cSLE exacerbations
Measuring Disease Damage and Its Severity in Childhood-Onset Systemic Lupus Erythematosus
Objective: To describe the frequency and types of disease damage occurring with childhood-onset systemic lupus erythematosus (SLE) as measured by the 41-item Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI), and to assess the SDI's ability to reflect damage severity. Methods: Information for the SDI was prospectively collected from 1,048 childhood-onset SLE patients. For a subset of 559 patients, physician-rated damage severity measured by visual analog scale (MD VAS damage) was also available. Frequency of SDI items and the association between SDI summary scores and MD VAS damage were estimated. Finally, an international consensus conference, using nominal group technique, considered the SDI's capture of childhood-onset SLE\u2013associated damage and its severity. Results: After a mean disease duration of 3.8 years, 44.2% of patients (463 of 1,048) already had an SDI summary score >0 (maximum 14). The most common SDI items scored were proteinuria, scarring alopecia, and cognitive impairment. Although there was a moderately strong association between SDI summary scores and MD VAS damage (Spearman's r = 0.49, P < 0.0001) in patients with damage (SDI summary score >0), mixed-effects analysis showed that only 4 SDI items, each occurring in <2% of patients overall, were significantly associated with MD VAS damage. There was consensus among childhood-onset SLE experts that the SDI in its current form is inadequate for estimating the severity of childhood-onset SLE\u2013associated damage. Conclusion: Disease damage as measured by the SDI is common in childhood-onset SLE, even with relatively short disease durations. Given the shortcomings of the SDI, there is a need to develop new tools to estimate the impact of childhood-onset SLE\u2013associated damage
American College of Rheumatology Provisional Criteria for Clinically Relevant Improvement in Children and Adolescents With Childhood-Onset Systemic Lupus Erythematosus
10.1002/acr.23834ARTHRITIS CARE & RESEARCH715579-59
Secondary analysis of APPLE study suggests atorvastatin may reduce atherosclerosis progression in pubertal lupus patients with higher C reactive protein
Technical Adequacy and Acceptability of Curriculum-Based Measurement and the Measures of Academic Progress
Curriculum-based measurement in reading (CBM-R) and the Measures of Academic Progress (MAP) are assessment tools widely employed for universal screening in schools. Although a large body of research supports the validity of CBM-R, limited empirical evidence exists supporting the technical adequacy of MAP or the acceptability of either measure for universal screening. Purposes of the current study were to replicate and extend prior research by (a) examining the extent to which CBM-R performance measures more than word reading skills, (b) evaluating the concurrent validity of MAP with CBM-R, (c) determining the potential benefit of administering MAP with CBM-R for universal screening, and (d) examining teachers’ acceptability of MAP and CBM-R. Participants included 802 students in Grades 1 to 5 who were administered three CBM-R probes and the MAP during universal screening and 86 elementary teachers who completed a universal screening assessments survey. Results provide evidence of the concurrent validity of MAP with CBM-R and suggest both measures are acceptable to teachers. Implications for research and practice are discussed
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