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1.
Curr Opin Rheumatol ; 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31389814

RESUMO

PURPOSE OF REVIEW: The management of lupus nephritis remains unsatisfactory due to insufficiently effective treatment regimens and the dearth of reliable predictors of disease onset or progression to guide individualized therapeutic decisions. This review summarizes new findings related to lupus nephritis over the last 18 months and discusses clinical needs that should be considered to advance trials of mechanism-based therapeutic strategies. RECENT FINDINGS: Collaborative teams are addressing how to improve disease definitions and are developing predictive models for disease onset, disease response and risk of flare in individual patients. More attention is being paid to clinical trial design. Advanced technologic approaches are allowing the analysis of small amounts of human tissue and urine in unprecedented detail so as to discover new pathogenic mechanisms and identify disease biomarkers. Novel therapies continue to be tested in disease models and include new strategies to protect renal tissue from cell damage and fibrosis. SUMMARY: The collaborative efforts of patients, clinical and translational researchers, the pharmaceutical industry and funding sources are needed to advance therapies for lupus nephritis. Specialized clinical centers can then deliver optimal and more personalized patient care that will improve patient outcomes.

2.
Arthritis Rheumatol ; 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31390162

RESUMO

OBJECTIVES: In a multi-ethnic/racial, prospective SLE inception cohort, to determine the frequency, clinical characteristics, associations and outcomes in different types of peripheral nervous system (PNS) disease. METHODS: Patients were evaluated annually for 19 neuropsychiatric (NP) events including seven types of PNS disease. SLE disease activity, organ damage, autoantibodies, patient and physician assessment of outcome were measured. Time to event and linear regressions were used as appropriate. RESULTS: Of 1,827 SLE patients, 88.8% were female, 48.8% Caucasian. The mean±SD age was 35.1±13.3 years, disease duration at enrollment 5.6±4.2 months and follow-up 7.6±4.6 years. There were 161 PNS events in 139/1,827 (7.6%) patients. The predominant events were peripheral neuropathy [66/161 (41.0%)], mononeuropathy [44/161 (27.3%)] and cranial neuropathy [39/161 (24.2%)] and the majority were attributed to SLE. Multivariate Cox regressions suggested longer time to resolution in patients with prior history of neuropathy, older age at SLE diagnosis, higher SLEDAI-2K scores, and for peripheral neuropathy versus other neuropathies. Neuropathy was associated with significantly lower SF-36 physical and mental component summary scores versus patients without NP events. By physician assessment, the majority of neuropathies resolved or improved over time and this was associated with improvements in SF-36 summary scores for peripheral neuropathy and mononeuropathy. CONCLUSION: PNS disease is an important component of total NPSLE and has a significant negative impact on health related quality of life. The outcome is favourable for most patients, but we noted several factors associated with longer time to resolution. This article is protected by copyright. All rights reserved.

3.
JCI Insight ; 4(9)2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-31045579

RESUMO

IgG antinuclear antibodies (ANAs) are a dominant feature of several autoimmune diseases. We previously showed that systemic lupus erythematosus (SLE) is characterized by increased ANA+ IgG plasmablasts/plasma cells (PCs) through aberrant IgG PC differentiation rather than an antigen-specific tolerance defect. Here, we aimed to understand the differentiation pathways resulting in ANA+ IgG PCs in SLE patients. We demonstrate distinct profiles of ANA+ antigen-experienced B cells in SLE patients, characterized by either a high frequency of PCs or a high frequency of IgG+ memory B cells. This classification of SLE patients was unrelated to disease activity and remained stable over time in almost all patients, suggesting minimal influence of disease activity. A similar classification applies to antigen-specific B cell subsets in mice following primary immunization with T-independent and T-dependent antigens as well as in lupus-prone mouse models (MRL/lpr and NZB/W). We further show that, in both lupus-prone mice and SLE patients, the classification correlates with the serum autoantibody profile. In this study, we identified B cell phenotypes that we propose reflect an extrafollicular pathway for PC differentiation or a germinal center pathway, respectively. The classification we propose can be used to stratify patients for longitudinal studies and clinical trials.

4.
J Rheumatol ; 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30988130

RESUMO

OBJECTIVE: To construct a Frailty Index (FI) as a measure of vulnerability to adverse outcomes among patients with systemic lupus erythematosus (SLE), using data from the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort. METHODS: The SLICC inception cohort consists of recently diagnosed patients with SLE followed annually with clinical and laboratory assessments. For this analysis, the baseline visit was defined as the first study visit at which sufficient information was available for construction of an FI. Following a standard procedure, variables from the SLICC database were evaluated as potential health deficits. Selected health deficits were then used to generate a SLICC-FI. The prevalence of frailty in the baseline dataset was evaluated using established cutpoints for FI values. RESULTS: The 1683 patients with SLE (92.1% of the overall cohort) eligible for inclusion in the baseline dataset were mostly female (89%) with mean (SD) age 35.7 (13.4) years and mean (SD) disease duration 18.8 (15.7) months at baseline. Of 222 variables, 48 met criteria for inclusion in the SLICC-FI. Mean (SD) SLICC-FI was 0.17 (0.08) with a range from 0 to 0.51. At baseline, 27.1% (95% CI 25.0-29.2) of patients were classified as frail, based on SLICC-FI values > 0.21. CONCLUSION: The SLICC inception cohort permits feasible construction of an FI for use in patients with SLE. Even in a relatively young cohort of patients with SLE, frailty was common. The SLICC-FI may be a useful tool for identifying patients with SLE who are most vulnerable to adverse outcomes, but validation of this index is required prior to its use.

5.
Rheumatology (Oxford) ; 58(7): 1259-1267, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30753683

RESUMO

OBJECTIVES: To assess the prevalence of combined hormonal contraceptives (CHCs) in reproductive-age women with SLE with and without possible contraindications and to determine factors associated with their use in the presence of possible contraindications. METHODS: This observational cohort study included premenopausal women ages 18-45 years enrolled in the SLICC Registry ⩽15 months after SLE onset, with annual assessments spanning 2000-2017. World Health Organization Category 3 or 4 contraindications to CHCs (e.g. hypertension, aPL) were assessed at each study visit. High disease activity (SLEDAI score >12 or use of >0.5 mg/kg/day of prednisone) was considered a relative contraindication. RESULTS: A total of 927 SLE women contributed 6315 visits, of which 3811 (60%) occurred in the presence of one or more possible contraindication to CHCs. Women used CHCs during 512 (8%) visits, of which 281 (55%) took place in the setting of one or more possible contraindication. The most frequently observed contraindications were aPL (52%), hypertension (34%) and migraine with aura (22%). Women with one or more contraindication were slightly less likely to be taking CHCs [7% of visits (95% CI 7, 8)] than women with no contraindications [9% (95% CI 8, 10)]. CONCLUSION: CHC use was low compared with general population estimates (>35%) and more than half of CHC users had at least one possible contraindication. Many yet unmeasured factors, including patient preferences, may have contributed to these observations. Further work should also aim to clarify outcomes associated with this exposure.

6.
Arthritis Rheumatol ; 71(8): 1297-1307, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30771242

RESUMO

OBJECTIVE: To evaluate the properties of a frailty index (FI), constructed using data from the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort, as a novel health measure in systemic lupus erythematosus (SLE). METHODS: For this secondary analysis, the baseline visit was defined as the first study visit at which both organ damage (SLICC/American College of Rheumatology Damage Index [SDI]) and health-related quality of life (Short-Form 36 [SF-36] scores) were assessed. The SLICC-FI was constructed using baseline data. The SLICC-FI comprises 48 health deficits, including items related to organ damage, disease activity, comorbidities, and functional status. Content, construct, and criterion validity of the SLICC-FI were assessed. Multivariable Cox regression was used to estimate the association between baseline SLICC-FI values and mortality risk, adjusting for demographic and clinical factors. RESULTS: In the baseline data set of 1,683 patients with SLE, 89% were female, the mean ± SD age was 35.7 ± 13.4 years, and the mean ± SD disease duration was 18.8 ± 15.7 months. At baseline, the mean ± SD SLICC-FI score was 0.17 ± 0.08 (range 0-0.51). Baseline SLICC-FI values exhibited the expected measurement properties and were weakly correlated with baseline SDI scores (r = 0.26, P < 0.0001). Higher baseline SLICC-FI values (per 0.05 increment) were associated with increased mortality risk (hazard ratio 1.59, 95% confidence interval 1.35-1.87), after adjusting for age, sex, steroid use, ethnicity/region, and baseline SDI scores. CONCLUSION: The SLICC-FI demonstrates internal validity as a health measure in SLE and might be used to predict future mortality risk. The SLICC-FI is potentially valuable for quantifying vulnerability among patients with SLE, and adds to existing prognostic scores.

7.
J Rheumatol ; 46(5): 492-500, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30647177

RESUMO

OBJECTIVE: In cross-sectional studies, elevated osteopontin (OPN) levels have been proposed to reflect, and/or precede, progressive organ damage and disease severity in systemic lupus erythematosus (SLE). We aimed, in a cohort of patients with recent-onset SLE, to determine whether raised serum OPN levels precede damage and/or are associated with disease activity or certain disease phenotypes. METHODS: We included 344 patients from the Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort who had 5 years of followup data available. All patients fulfilled the 1997 American College of Rheumatology (ACR) criteria. Baseline sera from patients and from age- and sex-matched population-based controls were analyzed for OPN using ELISA. Disease activity and damage were assessed at each annual followup visit using the SLE Disease Activity Index 2000 (SLEDAI-2K) and the SLICC/ACR damage index (SDI), respectively. RESULTS: Compared to controls, baseline OPN was raised 4-fold in SLE cases (p < 0.0001). After relevant adjustments in a binary logistic regression model, OPN levels failed to significantly predict global damage accrual defined as SDI ≥ 1 at 5 years. However, baseline OPN correlated with SLEDAI-2K at enrollment into the cohort (r = 0.27, p < 0.0001), and patients with high disease activity (SLEDAI-2K ≥ 5) had raised serum OPN (p < 0.0001). In addition, higher OPN levels were found in patients with persistent disease activity (p = 0.0006), in cases with renal involvement (p < 0.0001) and impaired estimated glomerular filtration rate (p = 0.01). CONCLUSION: The performance of OPN to predict development of organ damage was not impressive. However, OPN associated significantly with lupus nephritis and with raised disease activity at enrollment, as well as over time.

8.
JCI Insight ; 4(1)2019 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-30626758

RESUMO

To address challenges in the diagnosis of cognitive dysfunction (CD) related to systemic lupus erythematosus-associated (SLE-associated) autoimmune mechanisms rather than confounding factors, we employed an integrated approach, using resting-state functional (FDG-PET) and structural (diffusion tensor imaging [DTI]) neuroimaging techniques and cognitive testing, in adult SLE patients with quiescent disease and no history of neuropsychiatric illness. We identified resting hypermetabolism in the sensorimotor cortex, occipital lobe, and temporal lobe of SLE subjects, in addition to validation of previously published resting hypermetabolism in the hippocampus, orbitofrontal cortex, and putamen/GP/thalamus. Regional hypermetabolism demonstrated abnormal interregional metabolic correlations, associated with impaired cognitive performance, and was stable over 15 months. DTI analyses demonstrated 4 clusters of decreased microstructural integrity in white matter tracts adjacent to hypermetabolic regions and significantly diminished connecting tracts in SLE subjects. Decreased microstructural integrity in the parahippocampal gyrus correlated with impaired spatial memory and increased serum titers of DNRAb, a neurotoxic autoantibody associated with neuropsychiatric lupus. These findings of regional hypermetabolism, associated with decreased microstructural integrity and poor cognitive performance and not associated with disease duration, disease activity, medications, or comorbid disease, suggest that this is a reproducible, stable marker for SLE-associated CD that may be may be used for early disease detection and to discriminate between groups, evaluate response to treatment strategies, or assess disease progression.

10.
Artigo em Inglês | MEDLINE | ID: mdl-30439406

RESUMO

BACKGROUND: IgG anti-nuclear antibodies (ANA) are a feature of several autoimmune diseases. These antibodies arise through defects in central or peripheral tolerance checkpoints. The specific checkpoints breached in autoimmune disease are not fully understood. OBJECTIVES: To study whether autoreactive plasma cells in lupus models and SLE patients arise as a consequence of defective antigen-specific selection or a global enhancement of IgG PC differentiation. METHODS AND RESULTS: We optimized and validated a novel technique to detect naturally occurring ANA+ B cells and PC. We observed a major checkpoint for generation of ANA+ IgG+ PC in both non-autoimmune mice and healthy human subjects. Interestingly, we observed increased numbers of ANA+ IgG+ PC despite normal tolerance checkpoints in immature and naïve B cells in lupus-prone MRL/lpr and NZB/W mice as well as patients with systemic lupus erythematosus (SLE). This increase was due to increased numbers of total IgG+ PC rather than lack of selection against ANA+ PC. CONCLUSION: Using a method that permits quick and accurate quantification of autoreactive B cells and PC in vivo within a native B cell repertoire in mice and humans, we demonstrate the importance of a checkpoint that restricts the generation of IgG plasma cells and protects against IgG ANA. Our observations suggest a fundamentally revised understanding of SLE: that it is a disease of aberrant B cell differentiation rather than a defect in antigen-specific B cell tolerance. CLINICAL IMPLICATION: Therapies for SLE might need to be targeted at IgG plasma cell differentiation rather than antigen-specific tolerance.

11.
Arthritis Rheumatol ; 2018 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-30375754

RESUMO

OBJECTIVES: To determine, in a multi-ethnic/racial, prospective SLE inception cohort, the frequency, attribution, clinical and autoantibody associations with lupus psychosis and the short and long-term outcome as assessed by physicians and patients. METHODS: Patients were evaluated annually for 19 neuropsychiatric (NP) events including psychosis. SLE disease activity 2000, SLICC/ACR damage index and SF-36 scores were collected. Time to event and linear regressions were used as appropriate. RESULTS: Of 1,826 SLE patients, 88.8% were female, 48.8% Caucasian. The mean±SD age was 35.1±13.3 years, disease duration 5.6±4.2 months and follow-up 7.4±4.5 years. There were 31 psychotic events in 28/1,826 (1.53%) patients and most [(26/28; 93%)] had a single event. In the majority of patients [20/25; (80%)] and events [28/31; (90%)] psychosis was attributed to SLE, usually within 3 years of SLE diagnosis. Positive associations [hazard ratio and 95% confidence interval [HR (95%CI)] with lupus psychosis were prior SLE NP events [3.59, (1.16, 11.14), male sex [3.0, (1.20, 7.50)], younger age at SLE diagnosis [(per 10 years younger), 1.45 (1.01, 2.07)] and African ancestry [4.59 (1.79, 11.76)]. By physician assessment most psychotic events resolved by the second annual visit following onset, in parallel with an improvement in patient reported SF-36 summary and subscale scores. CONCLUSION: Psychosis is an infrequent manifestation of NPSLE. Generally, it occurs early after SLE onset and has a significant negative impact on health status. As determined by patient and physician report, the short and long term outlook is good for most patients, though careful follow-up is required. This article is protected by copyright. All rights reserved.

12.
Arthritis Rheumatol ; 2018 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-30225865

RESUMO

OBJECTIVE: Endpoints currently used in lupus nephritis (LN) clinical trials lack uniformity and questionably reflect long-term kidney survival. The objective of this investigation was to identify short-term endpoints that predict long-term kidney outcomes for use in clinical trials. METHODS: A database of 944 LN patients was assembled from 3 clinical trials and 12 longitudinal cohorts. Variables from the first 12 months of treatment after diagnosis of active LN (prediction period) were assessed as potential predictors of long-term outcomes in a 36 month follow-up period. The long-term outcomes examined were new or progressive chronic kidney disease (CKD), severe kidney injury (SKI), and the need for permanent renal replacement therapy (RRT). Hazard Index Tools (HITs) to predict risk for each outcome were derived using multivariable analysis with Cox proportional hazards regression. RESULTS: Among 550 eligible subjects 54 CKD, 55 SKI and 22 RRT events occurred. Variables in the final CKD HIT were prediction period CKD status, 12-month proteinuria and12-month serum creatinine (SCr). The SKI HIT included prediction period CKD status, ISN Class, 12-month proteinuria, 12-month SCr, race and an interaction between ISN Class and 12-month proteinuria. The RRT HIT included age at diagnosis, 12-month proteinuria and 12-month SCr. Each HIT validated well internally (c-indices 0.84-0.92) and in an independent LN cohort (c-indices 0.83-0.92). CONCLUSION: HITs, derived from short-term kidney responses to treatment correlate with long-term kidney outcomes, and now must be validated as surrogate endpoints for LN clinical trials. This article is protected by copyright. All rights reserved.

13.
JCI Insight ; 3(17)2018 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-30185675

RESUMO

Belimumab has therapeutic benefit in active systemic lupus erythematosus (SLE), especially in patients with high-titer anti-dsDNA antibodies. We asked whether the profound B cell loss in belimumab-treated SLE patients is accompanied by shifts in the immunoglobulin repertoire. We enrolled 15 patients who had been continuously treated with belimumab for more than 7 years, 17 matched controls, and 5 patients who were studied before and after drug initiation. VH genes of sort-purified mature B cells and plasmablasts were subjected to next-generation sequencing. We found that B cell-activating factor (BAFF) regulates the transitional B cell checkpoint, with conservation of transitional 1 (T1) cells and approximately 90% loss of T3 and naive B cells after chronic belimumab treatment. Class-switched memory B cells, B1 B cells, and plasmablasts were also substantially depleted. Next-generation sequencing revealed no redistribution of VH, DH, or JH family usage and no effect of belimumab on representation of the autoreactive VH4-34 gene or CDR3 composition in unmutated IgM sequences, suggesting a minimal effect on selection of the naive B cell repertoire. Interestingly, a significantly greater loss of VH4-34 was observed among mutated IgM and plasmablast sequences in chronic belimumab-treated subjects than in controls, suggesting that belimumab promotes negative selection of activated autoreactive B cells.

14.
Mol Med ; 24(1): 24, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30134810

RESUMO

BACKGROUND: Systemic lupus erythematosus (SLE) is an autoimmune disease with genetic, hormonal, and environmental influences. In Western Europe and North America, individuals of West African descent have a 3-4 fold greater incidence of SLE than Caucasians. Paradoxically, West Africans in sub-Saharan Africa appear to have a low incidence of SLE, and some studies suggest a milder disease with less nephritis. In this study, we analyzed sera from African American female SLE patients and four other cohorts, one with SLE and others with varying degrees of risk for SLE in order to identify serologic factors that might correlate with risk of or protection against SLE. METHODS: Our cohorts included West African women with previous malaria infection assumed to be protected from development of SLE, clinically unaffected sisters of SLE patients with high risk of developing SLE, healthy African American women with intermediate risk, healthy Caucasian women with low risk of developing SLE, and women with a diagnosis of SLE. We developed a lupus risk index (LRI) based on titers of IgM and IgG anti-double stranded DNA antibodies and levels of C1q. RESULTS: The risk index was highest in SLE patients; second highest in unaffected sisters of SLE patients; third highest in healthy African-American women and lowest in healthy Caucasian women and malaria-exposed West African women. CONCLUSION: This risk index may be useful in early interventions to prevent SLE. In addition, it suggests new therapeutic approaches for the treatment of SLE.

15.
Rheumatology (Oxford) ; 57(4): 677-687, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29361147

RESUMO

Objectives: To describe glucocorticoid (GC) use in the SLICC inception cohort and to explore factors associated with GC use. In particular we aimed to assess temporal trends in GC use and to what extent physician-related factors may influence use. Methods: Patients were recruited within 15 months of diagnosis of SLE from 33 centres between 1999 and 2011 and continue to be reviewed annually. Descriptive statistics were used to detail oral and parenteral GC use. Cross sectional and longitudinal analyses were performed to explore factors associated with GC use at enrolment and over time. Results: We studied 1700 patients with a mean (s.d.) follow-up duration of 7.26 (3.82) years. Over the entire study period, 1365 (81.3%) patients received oral GCs and 447 (26.3%) received parenteral GCs at some point. GC use was strongly associated with treatment centre, age, race/ethnicity, sex, disease duration and disease activity. There was no change in the proportion of patients on GCs or the average doses of GC used over time according to year of diagnosis. Conclusion: GCs remain a cornerstone in SLE management and there have been no significant changes in their use over the past 10-15 years. While patient and disease factors contribute to the variation in GC use, between-centre differences suggest that physician-related factors also contribute. Evidence-based treatment algorithms are needed to inform a more standardized approach to GC use in SLE.


Assuntos
Prescrições de Medicamentos/estatística & dados numéricos , Grupos Étnicos , Glucocorticoides/administração & dosagem , Nível de Saúde , Cooperação Internacional , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Adulto , Algoritmos , Ásia/epidemiologia , Estudos Transversais , Progressão da Doença , Relação Dose-Resposta a Droga , Europa (Continente)/epidemiologia , Feminino , Seguimentos , Humanos , Lúpus Eritematoso Sistêmico/etnologia , Masculino , Morbidade/tendências , América do Norte/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Fatores de Tempo , Adulto Jovem
16.
Arthritis Care Res (Hoboken) ; 70(10): 1478-1487, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29316357

RESUMO

OBJECTIVE: To determine the frequency, characteristics, and outcomes of cerebrovascular events (CerVEs), as well as clinical and autoantibody associations in a multiethnic/racial inception cohort of patients with systemic lupus erythematosus (SLE). METHODS: A total of 1,826 patients were assessed annually for 19 neuropsychiatric (NP) events, including 5 types of CerVEs: 1) stroke, 2) transient ischemia, 3) chronic multifocal ischemia, 4) subarachnoid/intracranial hemorrhage, and 5) sinus thrombosis. Global disease activity (Systemic Lupus Erythematosus Disease [SLE] Activity Index 2000), damage scores (SLE International Collaborating Clinics/American College of Rheumatology Damage Index), and Short Form 36 (SF-36) scores were collected. Time to event, linear and logistic regressions, and multistate models were used as appropriate. RESULTS: CerVEs were the fourth most frequent NP event: 82 of 1,826 patients had 109 events; of these events, 103 were attributed to SLE, and 44 were identified at the time of enrollment. The predominant events were stroke (60 of 109 patients) and transient ischemia (28 of 109 patients). CerVEs were associated with other NP events attributed to SLE, non-SLE-attributed NP events, African ancestry (at US SLICC sites), and increased organ damage scores. Lupus anticoagulant increased the risk of first stroke and sinus thrombosis and transient ischemic attack. Physician assessment indicated resolution or improvement in the majority of patients, but patients reported sustained reduction in SF-36 summary and subscale scores following a CerVE. CONCLUSION: CerVEs, the fourth most frequent NP event in SLE, are usually attributable to lupus. In contrast to good physician-reported outcomes, patients reported a sustained reduction in health-related quality of life following a CerVE.

17.
Arthritis Care Res (Hoboken) ; 70(9): 1294-1302, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29193883

RESUMO

OBJECTIVE: Little is known about the long-term costs of lupus nephritis (LN). The costs were compared between patients with and without LN using multistate modeling. METHODS: Patients from 32 centers in 11 countries were enrolled in the Systemic Lupus International Collaborating Clinics inception cohort within 15 months of diagnosis and provided annual data on renal function, hospitalizations, medications, dialysis, and selected procedures. LN was diagnosed by renal biopsy or the American College of Rheumatology classification criteria. Renal function was assessed annually using the estimated glomerular filtration rate (GFR) or estimated proteinuria. A multistate model was used to predict 10-year cumulative costs by multiplying annual costs associated with each renal state by the expected state duration. RESULTS: A total of 1,545 patients participated; 89.3% were women, the mean ± age at diagnosis was 35.2 ± 13.4 years, 49% were white, and the mean followup duration was 6.3 ± 3.3 years. LN developed in 39.4% of these patients by the end of followup. Ten-year cumulative costs were greater in those with LN and an estimated glomerular filtration rate (GFR) <30 ml/minute ($310,579 2015 Canadian dollars versus $19,987 if no LN and estimated GFR >60 ml/minute) or with LN and estimated proteinuria >3 gm/day ($84,040 versus $20,499 if no LN and estimated proteinuria <0.25 gm/day). CONCLUSION: Patients with estimated GFR <30 ml/minute incurred 10-year costs 15-fold higher than those with normal estimated GFR. By estimating the expected duration in each renal state and incorporating associated annual costs, disease severity at presentation can be used to anticipate future health care costs. This is critical knowledge for cost-effectiveness evaluations of novel therapies.

18.
Arthritis Rheumatol ; 70(2): 277-286, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29073350

RESUMO

OBJECTIVE: IgG anti-DWEYS antibodies cross-reactive with DNA and the N-methyl-d-aspartate receptor subunits GluN2A and GluN2B are known to be associated with neuropsychiatric systemic lupus erythematosus (NPSLE). IgG anti-DWEYS have not been investigated in demyelinating NPSLE or in another demyelinating disorder, neuromyelitis optica spectrum disorder (NMOSD), which is a disease also found mainly in young women and associated with aquaporin 4 (AQP-4) or myelin oligodendrocyte glycoprotein (MOG) antibodies. This study was undertaken to investigate the frequency of all of these brain-reactive antibodies in patients with NPSLE, those with demyelinating NPSLE, and those with NMOSD. METHODS: Serum samples from patients with NPSLE (n = 108), patients with SLE without neuropsychiatric manifestations (n = 38), patients with NMOSD (n = 33), and healthy controls (n = 106) were assessed for the frequency of IgG anti-brain antibodies as well as IgG antibodies to AQP-4, MOG, GluN2A/GluN2B, and double-stranded DNA (dsDNA). RESULTS: Sera were positive for IgG anti-AQP-4 antibodies in 27 (82%) of 33 patients with NMOSD and 3 (27%) of 11 patients with demyelinating NPSLE, whereas all sera from patients with non-demyelinating NPSLE, patients with SLE, and healthy controls were negative for IgG anti-AQP-4. IgG anti-MOG were detected at high titers in 3 (50%) of 6 patients with NMOSD who were negative for IgG anti-AQP-4, and at low titers in 2 (18%) of 11 patients with demyelinating NPSLE and 1 (1%) of 97 patients with non-demyelinating NPSLE. IgG antibodies to dsDNA were present in 11 (33%) of 33 patients with NMOSD. Only 4 (12%) of 33 patients with NMOSD were positive for IgG anti-DWEYS, compared to 11 (29%) of 38 patients with SLE and 59 (55%) of 108 patients with NPSLE. IgG anti-DWEYS antibodies were present in 56 (58%) of 97 patients with non-demyelinating NPSLE and 3 (27%) of 11 patients with demyelinating NPSLE. Serum IgG brain-reactive antibodies were present at a similar frequency in patients with non-demyelinating NPSLE (72 [75%] of 96), those with demyelinating NPSLE (9 [82%] of 11), and those with SLE (32 [84%] of 38), but were less frequent in patients with NMOSD (20 [61%] of 33). CONCLUSION: Patients with demyelinating NPSLE should be tested for IgG antibodies to AQP-4, MOG, and DWEYS. IgG anti-AQP-4 can be considered diagnostic for NMOSD, whereas none of these antibodies appear to be diagnostic for demyelinating NPSLE. Moreover, IgG anti-dsDNA are present in patients with NMOSD but are not cross-reactive with IgG anti-DWEYS, indicating that the antigenic stimulus and mechanisms of tissue damage are potentially different between demyelinating NPSLE and NMOSD.

19.
Sci Rep ; 7(1): 270, 2017 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-28325905

RESUMO

C1q collagen-like region (CLR) engaging and activating the LAIR-1 inhibitory immunoreceptor represents a non-complement mechanism for maintaining immune quiescence. Given the binding promiscuity of C1q's globular region (gC1q), we hypothesized that C1q concurrently associates with distinct inhibitory immunoreceptors to produce C1q-mediated modulatory networking. Like LAIR-1, CD33 inhibitory immunoreceptors are highly expressed on monocytes. Binding CD33 restricts cell activation/differentiation; however, natural ligands for CD33 remain elusive. CD33 has IgC2-like domains potentially recognized by gC1q. Thus, we asked whether C1q binds to CD33 and if C1q mediates CD33/LAIR-1 crosslinking. Our findings demonstrate that C1q and gC1q interact with CD33 to activate its inhibitory motifs, while CLR does not. Whole C1q is required to crosslink CD33 and LAIR-1 and concurrently activate CD33/LAIR-1 inhibitory motifs. While C1q binds CD33C2 domains, decreased C1q-CD33 interactions resulting from sialic acid masking of CD33C2 domains suggests a process for regulating C1q-CD33 activity. Consistent with defective self-tolerance, CD33/LAIR-1 expression is reduced in systemic lupus erythematosus (SLE) myelomonocytes. The anti-inflammatory cytokine M-CSF, but not DC growth factors, sustains CD33/LAIR-1 expression on both healthy and SLE cells suggesting further biological control of C1q-CD33/LAIR-1 processes.


Assuntos
Complemento C1q/metabolismo , Receptores Imunológicos/metabolismo , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo , Células Cultivadas , Expressão Gênica , Humanos , Ligação Proteica
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