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1.

Objective

Although juvenile‐onset proliferative lupus nephritis (PLN ) leads to significant morbidity and mortality, there is no clinical trials–based evidence to support the treatment effectiveness of any therapy for juvenile‐onset PLN . Marginal structural models enable us to estimate treatment effectiveness using observational data while accounting for confounding by indication.

Methods

We used prospectively collected data to examine the effect of mycophenolate mofetil (MMF ), compared to the use of other therapies, on the long‐term outcome of a juvenile‐onset PLN cohort (age at PLN onset <18 years). The major outcome variable was the estimated glomerular filtration rate (GFR ) using the revised Schwartz formula. Confounding by indication was corrected for marginal structural model.

Results

A total of 172 subjects with juvenile‐onset PLN , with a mean followup duration of approximately 4 years, were included. Overall, MMF was superior to other therapies, with a relative effect estimate for MMF of 1.06, i.e., 6% better estimated GFR on average (95% confidence interval 0.7, 11.3), corrected for potential confounding by indication. We found that beginning in year 4 there was a significant improvement in estimated GFR in the patients who were treated with MMF versus other therapies. This improvement was maintained until the end of the study.

Conclusion

MMF was more beneficial than other therapies in improving/maintaining long‐term renal function in patients with juvenile‐onset PLN up to a maximum followup of 7 years. This finding is consistent with evidence from adult PLN clinical trials.
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2.
3.

Objective

No previous study has studied the longitudinal disease course of childhood‐onset systemic lupus erythematosus (cSLE). Our objectives are to assess distinguishable differences in disease activity trajectories in cSLE patients, determine baseline factors predictive of disease trajectory membership, and assess if the different disease activity trajectories are associated with different damage trajectories.

Methods

This is a retrospective, longitudinal inception cohort of cSLE patients. Patients were followed from diagnosis as children, until they were adults. SLE disease activity was modeled as a latent characteristic, jointly using the Systemic Lupus Erythematosus Disease Activity Index 2000 and prednisone in a Bayesian growth mixture model. Baseline factors were tested for membership prediction of the latent classes of disease trajectories. Differences in damage trajectories by disease activity classes were tested using a mixed model.

Results

A total of 473 patients (82% females), with median age at diagnosis of 14.1 years, were studied. We studied 11,992 visits (2,666 patient‐years). We identified 5 classes of disease activity trajectories. Baseline major organ involvement, number of American College of Rheumatology criteria, and age at diagnosis predicted memberships into different classes. A higher proportion of Asians was in class 2 compared to class 5. Class 1 was associated with the most accrual of damage, while class 5 was associated with no significant damage accrual, even after 10 years.

Conclusion

There are 5 distinct latent classes of disease trajectory in patients with cSLE. Membership within disease trajectories is predicted by baseline clinical and demographic factors. Membership in different disease activity trajectory classes is associated with different damage trajectories.
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4.

Objective

Systemic lupus erythematosus (SLE) is a multisystem inflammatory disease characterized by the production of various autoantibodies. The aim of this study was to investigate the presence of anti–ficolin‐2 antibodies in SLE patients and to evaluate the association between the levels of these autoantibodies, clinical manifestations, and disease activity.

Methods

This is a comparative study using a cohort of 165 SLE patients and 48 healthy subjects. SLE patients were further divided into 2 groups (low disease activity [SLE Disease Activity Index (SLEDAI) score ≤4, n = 88] and high disease activity [SLEDAI score >4, n = 77]). Clinical manifestations were defined according to the physician in charge. Active lupus nephritis (LN) was documented by kidney biopsy. Detection of anti–ficolin‐2 antibodies was performed by enzyme‐linked immunosorbent assay.

Results

Levels of anti–ficolin‐2 autoantibodies were significantly higher in SLE patients as compared to healthy subjects and associated with SLEDAI score. They were found to be positive in 61 of 165 SLE patients (37%). The presence of anti–ficolin‐2 antibodies was significantly related only to renal involvement, with a very high prevalence (86%) of anti–ficolin‐2 antibodies in SLE patients with active LN. Patients with active proliferative LN had significantly more positive anti–ficolin‐2 antibodies than those with nonproliferative LN. The combination of anti–ficolin‐2, anti–ficolin‐3, and anti‐C1q demonstrated a very high specificity (98%) for the diagnosis of active LN.

Conclusion

Our results support the usefulness of anti–ficolin‐2 as a complementary serologic biomarker for the diagnosis of active lupus with renal manifestations.
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5.

Objective

Systemic lupus erythematosus (SLE) and asthma share inheritable IgE‐related pathophysiology, but the association between maternal SLE and asthma in the offspring has not been explored. Our aim was to investigate the association between maternal SLE during pregnancy and childhood asthma and examine the role of preterm birth as a mediator of the association using Swedish register data.

Methods

Information on 12,000 singleton live births (2001–2013) was collected from the Medical Birth Register. Childhood asthma was defined as at least 1 International Classification of Diseases–coded visit in the National Patient Register. Prevalent maternal SLE at delivery was identified from the Medical Birth Register and the National Patient Register. Risk ratios for asthma were estimated while controlling for confounders. Mediation analysis was used to estimate what percentage of the total effect can be explained by preterm birth (defined as either <34 or <37 weeks of gestation).

Results

We compared 775 children born to mothers with SLE with 11,225 born to mothers without SLE. Ninety seven children of mothers with SLE (13%) were diagnosed with asthma, compared to 1,211 in the unexposed group (11%). The risk ratio for childhood asthma was 1.46 (95% confidence interval 1.16–1.84). In mediation analysis, 20–29% of the total effect of SLE was explained by preterm birth.

Conclusion

Prevalent maternal SLE during pregnancy is associated with an increased risk of asthma in the offspring. While preterm birth can explain a fair proportion of this association, additional unidentified mechanisms also likely play a role.
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6.
7.

Objective

The American College of Rheumatology and the European League Against Rheumatism embarked on a project to reevaluate classification criteria for systemic lupus erythematosus (SLE). The first phase of the classification project involved generation of a broad set of items potentially useful for classification of SLE and their selection for use in a subsequent forced‐choice decision analysis.

Methods

A large international group of expert lupus clinicians was invited to participate in a 2‐step process to generate, rate, and select items based on their importance in diagnosing early and established SLE, via a web‐based survey.

Results

A total of 135 and 147 experts were invited to participate in the item‐generation and item‐reduction process, respectively. Of 145 items generated, item reduction resulted in 40 candidate items moving forward to the next phase. Key features for classifying both early and established SLE included characteristic autoantibodies, specific renal features, and skin manifestations. A small majority (51%) stated that 1 organ system would be sufficient for classifying SLE, but that additional typical laboratory features (antinuclear antibody, anti–double‐stranded DNA) would be required. Notably, 85% of the expert group would positively classify SLE if renal pathology alone showed lupus nephritis.

Conclusion

The Delphi exercise resulted in a set of 40 candidate criteria for the classification of SLE for subsequent assessment. This study comprised the largest panel ever involved in the development of SLE classification criteria, providing a broadly representative view of the current approach to classification of SLE.
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8.

Objective

Systemic lupus erythematosus (SLE) is a complex autoimmune disease that can affect multiple organ systems, with specialists from many disciplines often involved, which may lead to inconsistent care. We aimed to describe the attitudes and perspectives of specialists from different medical disciplines on the management of people with SLE.

Methods

Face‐to‐face semistructured interviews were conducted with rheumatologists (n = 16), nephrologists (n = 16), and immunologists (n = 11) providing care to adults with SLE from 19 centers across Australia in 2015. All interviews were transcribed and analyzed thematically.

Results

Five themes were identified: uncertainties in judgments (hampered by unknown and unclear etiology, inapplicable evidence, comprehending information dispersion), reflexive responses (anchoring to specialty training, anticipating outcomes, avoiding disaster, empathy for the vulnerable), overarching duty to patients (achieving patient priorities, maximizing adherence, controlling the disease, providing legitimate information, having adequate and relevant expertise), safeguarding professional opportunities (diversifying clinical skills, protecting colleagues’ interests), and optimizing access to treatment (capitalizing on multidisciplinary care, acquiring breakthrough therapies).

Conclusion

Specialists strive to deliver evidence‐informed patient‐centered care, but recognize that they are anchored by their training. To overcome uncertainties in clinical management due to lack of high‐quality evidence and specialty silo structures, specialists translated evidence from other disease settings and collaborated with other specialists in routine care. Developing robust evidence, tools to support evidence‐informed decisions, and multidisciplinary shared‐care pathways may improve the management of people with this complex disease.
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9.

Objective

Little is known about how people with psoriatic arthritis (PsA) cope with and manage their condition, but data show that psychological problems are underrecognized and undertreated. The Common Sense Self‐Regulatory Model (CS‐SRM) suggests illness beliefs, mediated by coping, may influence health outcomes. The study aimed to investigate the roles of disease severity, illness beliefs, and coping strategies in predicting depression, anxiety, and quality of life (QoL) in people with PsA. Additionally, we aimed to assess the role of depression and anxiety in predicting QoL.

Methods

We conducted a cross‐sectional observational study, where adults with PsA (n = 179) completed validated measures of predictor (illness beliefs, coping strategies, disease severity) and outcome variables (depression, anxiety, QoL) using an online survey distributed via social media.

Results

The participants were a community sample of 179 adults with PsA, ages 20 to 72 years (77.1% female). After controlling for disease severity, hierarchical multiple regression models indicated that more negative beliefs about consequences and behavioral disengagement as a coping method predicted levels of depression, and self‐blame predicted anxiety. Beliefs about consequences and the presence of depression predicted quality of life scores after controlling for disease severity.

Conclusion

This study offers support for the use of the CS‐SRM in explaining variation on psychological outcomes in individuals with PsA. The illness beliefs and coping strategies identified as predictors in this article are potential targets for interventions addressing PsA‐related distress and QoL.
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10.

Objective

Limited evidence suggests a potentially increased risk of allergic conditions in offspring born to women with systemic lupus erythematosus (SLE). In a large population‐based study, we aimed to determine if children born to mothers with SLE have an increased risk of allergic conditions compared to children born to mothers without SLE.

Methods

Using the Offspring of SLE Mothers Registry, we identified children born live to mothers with SLE and their matched controls, and ascertained the number of allergic conditions (asthma, allergic rhinitis, eczema, urticaria, angioedema, and anaphylaxis) based on ≥1 hospitalization or ≥1 or 2 physician(s) visit(s) with a relevant diagnostic code. We adjusted for maternal age, education, race/ethnicity, obstetrics complications, calendar year of birth, sex of the child, and maternal medication.

Results

There were 509 women with SLE who had 719 children, while 5,824 matched controls had 8,493 children. The mean ± SD followup period was 9.1 ± 5.8 years. Compared to controls, more children born to mothers with SLE had evidence of allergic conditions (43.9% [95% confidence interval (95% CI) 40.4–47.6] versus 38.1% [95% CI 37.0–39.1]). In multivariate analysis (n = 9,212), children born to mothers with SLE had an increased risk of allergic conditions versus control children (odds ratio 1.35 [95% CI 1.13–1.61]).

Conclusion

Compared to children from the general population, children born to women with SLE may have an increased risk of allergic conditions. Genetics, shared environmental exposures, as well as in utero exposure to maternal autoantibodies and cytokines may mediate this increased risk.
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11.

Objective

In juvenile dermatomyositis (DM), microvascular abnormalities, measured by nailfold capillaroscopy (NFC), are common early in the disease course. We aimed to compare the presence of NFC abnormalities in patients with medium‐ to long‐term juvenile DM with that of controls, and to explore associations between NFC abnormalities and disease activity and other disease characteristics.

Methods

Fifty‐eight juvenile DM patients with a median disease duration of 16.8 (range 2–38) years were clinically examined and compared with matched controls. By NFC, we assessed nailfold capillary density (NCD), giant capillaries, scleroderma, and neovascular pattern (defined as scleroderma active or late pattern). NFC was analyzed with researchers blinded to patient/control identity and disease characteristics. We measured disease activity and damage by validated tools, and patients were categorized as having active or inactive disease according to the Paediatric Rheumatology International Trials Organisation criteria.

Results

Compared to controls, patients had decreased NCD (mean ± SD 6.4 ± 2.1/mm versus 7.6 ± 0.8/mm; P = 0.001) and showed more abnormality in all other NFC parameters; 36% of patients versus 4% of controls had NCD <6/mm (P < 0.001). Giant capillaries, scleroderma, and neovascular pattern were found in 9%, 84%, and 41% of patients, respectively. Patients with active disease (n = 30) presented more frequently with neovascular pattern than patients with inactive disease (n = 28) (P = 0.041). Decreased NCD and neovascular pattern were associated with higher levels of disease activity and impaired muscle function.

Conclusion

After medium‐ to long‐term followup, juvenile DM patients had decreased NCD and, often, neovascular pattern; both were associated with higher levels of disease activity and impaired muscle function. This suggests that NFC can be a biomarker for disease activity in longstanding juvenile DM too.
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12.

Objective

Approximately 30–45% of patients with familial Mediterranean fever (FMF) have been reported to have attacks despite colchicine treatment. Currently, data on the treatment of colchicine‐unresponsive or colchicine‐intolerant FMF patients are limited; the most promising alternatives seem to be anti–interleukin‐1 (anti–IL‐1) agents. Here we report our experience with the off‐label use of anti–IL‐1 agents in a large group of FMF patients.

Methods

In all, 21 centers from different geographical regions of Turkey were included in the current study. The medical records of all FMF patients who had used anti–IL‐1 treatment for at least 6 months were reviewed.

Results

In total, 172 FMF patients (83 [48%] female, mean age 36.2 years [range 18–68]) were included in the analysis; mean age at symptom onset was 12.6 years (range 1–48), and the mean colchicine dose was 1.7 mg/day (range 0.5–4.0). Of these patients, 151 were treated with anakinra and 21 with canakinumab. Anti–IL‐1 treatment was used because of colchicine‐resistant disease in 84% and amyloidosis in 12% of subjects. During the mean 19.6 months of treatment (range 6–98), the yearly attack frequency was significantly reduced (from 16.8 to 2.4; P < 0.001), and 42.1% of colchicine‐resistant FMF patients were attack free. Serum levels of C‐reactive protein, erythrocyte sedimentation rate, and 24‐hour urinary protein excretion (5,458.7 mg/24 hours before and 3,557.3 mg/24 hours after) were significantly reduced.

Conclusion

Anti–IL‐1 treatment is an effective alternative for controlling attacks and decreasing proteinuria in colchicine‐resistant FMF patients.
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13.

Objective

To review the published literature on the performance of indirect immunofluorescence (IIF)–HEp‐2 antinuclear antibody (ANA) testing for classification of systemic lupus erythematosus (SLE).

Methods

A systematic literature search was conducted in the Medline, Embase, and Cochrane databases for articles published between January 1990 and October 2015. The research question was structured according to Population, Intervention, Comparator, Outcome (PICO) format rules, and Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) recommendations were followed where appropriate. Meta‐regression analysis for diagnostic tests was performed, using the ANA titer as independent variable, while sensitivity and specificity were dependent variables.

Results

Of 4,483 publications screened, 62 matched the eligibility criteria, and another 2 articles were identified through reference analysis. The included studies comprised 13,080 SLE patients in total, of whom 12,542 (95.9%) were reported to be IIF‐ANA positive at various titers. For ANA at titers of 1:40, 1:80, 1:160, and 1:320, meta‐regression gave sensitivity values of 98.4% (95% confidence interval [95% CI] 97.6–99.0%), 97.8% (95% CI 96.8–98.5%), 95.8% (95% CI 94.1–97.1%), and 86.0% (95% CI 77.0–91.9%), respectively. The corresponding specificities were 66.9% (95% CI 57.8–74.9%), 74.7% (95% CI 66.7–81.3%), 86.2% (95% CI 80.4–90.5%), and 96.6% (95% CI 93.9–98.1%), respectively.

Conclusion

The results of this systematic literature review and meta‐regression confirm that IIF‐ANAs have high sensitivity for SLE. ANAs at a titer of 1:80 have sufficiently high sensitivity to be considered as an entry criterion for SLE classification criteria, i.e., formally test other classification criteria for SLE only if ANAs of at least 1:80 have been found.
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14.

Objective

Systemic sclerosis (SSc) is an autoimmune disease that can cause disfiguring changes in appearance. This study examined the structural validity, internal consistency reliability, convergent validity, and measurement equivalence of the Social Appearance Anxiety Scale (SAAS) across SSc disease subtypes.

Methods

Patients enrolled in the Scleroderma Patient‐centered Intervention Network Cohort completed the SAAS and measures of appearance‐related concerns and psychological distress. Confirmatory factor analysis (CFA) was used to examine the structural validity of the SAAS. Multiple‐group CFA was used to determine whether SAAS scores can be compared across patients with limited and diffuse disease subtypes. Cronbach's alpha was used to examine internal consistency reliability. Correlations of SAAS scores with measures of body image dissatisfaction, fear of negative evaluation, social anxiety, and depression were used to examine convergent validity. SAAS scores were hypothesized to be positively associated with all convergent validity measures, with correlations significant and moderate to large in size.

Results

A total of 938 patients with SSc were included. CFA supported a 1‐factor structure (Comparative Fit Index 0.92, Standardized Root Mean Residual 0.04, and Root Mean Square Error of Approximation 0.08), and multiple‐group CFA indicated that the scalar invariance model best fit the data. Internal consistency reliability was good in the total sample (α = 0.96) and in disease subgroups. Overall, evidence of convergent validity was found with measures of body image dissatisfaction, fear of negative evaluation, social anxiety, and depression.

Conclusion

The SAAS can be reliably and validly used to assess fear of appearance evaluation in patients with SSc, and SAAS scores can be meaningfully compared across disease subtypes.
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15.

Objective

To validate whether the 2016 American College of Rheumatology/European League Against Rheumatism classification criteria of macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (JIA) is practical in the real world.

Methods

A combination of expert consensus and analysis of real patient data was conducted by a panel of 15 pediatric rheumatologists. A total of 65 profiles comprised 18 patients with systemic JIA–associated MAS and 47 patients with active systemic JIA without evidence of MAS. From these profiles, 10 patient data points for full‐blown MAS, 11 patient data points for MAS onset, and 47 patient data points for acute systemic JIA without MAS were evaluated.

Results

Evaluation of the classification criteria to discriminate full‐blown MAS from acute systemic JIA without MAS showed a sensitivity of 1.000 and specificity of 1.000 at the time of full‐blown MAS. Sensitivity was 0.636 and specificity was 1.000 at the time of MAS onset. The number of measurement items that fulfilled the criteria increased in full‐blown MAS compared to that at MAS onset. At MAS onset, the positive rates of patients who met the criteria for platelet counts and triglycerides were low, whereas those for aspartate aminotransferase were relatively high. At full‐blown MAS, the number of patients who met the criteria for each measurement item increased.

Conclusion

The classification criteria for MAS complicating systemic JIA had a very high diagnostic performance. However, the diagnostic sensitivity for MAS onset was relatively low. For the early diagnosis of MAS in systemic JIA, the dynamics of laboratory values during the course of MAS should be further investigated.
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16.

Objective

To describe physical functioning, pain, and health‐related quality of life (HRQoL) in adults with juvenile idiopathic arthritis (JIA), investigate changes over time, and identify predictors of poorer HRQoL after 30 years of disease.

Methods

Patients (n = 176) clinically examined after 15 years were reassessed using the Health Assessment Questionnaire disability index (HAQ DI), the visual analog scale pain subscale (VAS pain), and the Medical Outcomes Study Short Form 36 (SF‐36) after 23 years and 30 years. Patients with signs of active disease after a minimum of 15 years were clinically examined again at 30 years. Patients were compared to matched controls.

Results

At the 30‐year followup, 82 patients (47%) had HAQ DI scores >0, and the median VAS pain score in patients was 0.6 (range 0–10). Patients had lower SF‐36 physical component summary (PCS) scores compared with controls (P < 0.001), and this was evident for patients both with and without clinical remission (P ≤ 0.01). No group differences were found in SF‐36 mental component summary scores. Patients also scored worse than controls on all SF‐36 subscales (P ≤ 0.01) except mental health. PCS scores worsened significantly between the 15‐ and 30‐year followup time points (P = 0.001). Worse HAQ DI, VAS pain, and patient's global assessment of well‐being scores, and receiving disability/social living allowance at 30 years, were correlated with lower PCS scores. Worse HAQ DI, patient's global assessment of well‐being, and VAS fatigue scores at 15‐year followup predicted lower PCS scores at 30‐year followup.

Conclusion

JIA had a detrimental effect on physical HRQoL as measured by the PCS of the SF‐36. The strongest correlates were physical disability, pain, fatigue, well‐being, and receiving disability/social living allowance.
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17.
18.

Objective

Accumulation of apoptotic cells may lead to the development of systemic lupus erythematosus (SLE) through a breakdown in immune tolerance. Altered neutrophil apoptosis may contribute to nuclear autoantigen exposure, ultimately leading to autoantibody generation. This study aimed to determine whether neutrophil apoptosis is altered in patients with juvenile‐onset SLE as compared with controls.

Methods

Apoptosis was measured in neutrophils from patients with juvenile‐onset SLE (n = 12), adult‐onset SLE (n = 6), and pediatric patients with inflammatory (n = 12) and noninflammatory (n = 12) conditions. Annexin V staining and flow cytometry were used to determine neutrophil apoptosis. Proapoptotic and antiapoptotic proteins were measured in sera and in neutrophil cell lysates.

Results

Neutrophil apoptosis was significantly increased in patients with juvenile‐onset SLE as compared with the noninflammatory controls at time 0. Incubation of neutrophils with sera from patients with juvenile‐onset SLE further increased neutrophil apoptosis as compared with incubation with sera from pediatric controls. Concentrations of TRAIL and FasL were significantly increased in sera from patients with juvenile‐onset SLE, whereas interleukin‐6, tumor necrosis factor α, and granulocyte–macrophage colony‐stimulating factor (GM‐CSF) were significantly decreased. Addition of GM‐CSF to sera from patients with juvenile‐onset SLE significantly decreased neutrophil apoptosis as compared with juvenile‐onset SLE sera alone. The expression of proapoptotic proteins (caspase 3, Fas, and FADD) was elevated in juvenile‐onset SLE neutrophils, whereas the expression of antiapoptotic proteins (cellular inhibitor of apoptosis 1 and 2 and X‐linked inhibitor of apoptosis) was decreased. Neutrophil apoptosis correlated with biomarkers of disease activity (erythrocyte sedimentation rate and double‐stranded DNA concentration) and the British Isles Lupus Assessment Group disease activity score.

Conclusion

Our data demonstrate an imbalance in proapoptotic and antiapoptotic factors in both neutrophils and sera from patients with juvenile‐onset SLE. This imbalance results in increased neutrophil apoptosis in these patients. Correlations with markers of disease activity indicate that altered neutrophil apoptosis in juvenile‐onset SLE patients may play a pathogenic role in this condition.
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19.

Objective

Identifying incident rheumatoid arthritis (RA) is desirable in order to create inception cohorts. We evaluated an approach to identify incident RA in health plan claims data.

Methods

Both Medicare and commercial claims data were linked to Corrona, a US RA registry. We evaluated the accuracy of year of RA onset in the registry (gold standard) versus different claims algorithms, varying International Classification of Diseases, Ninth Revision codes for RA/arthritis, duration of health plan enrollment preceding diagnosis (minimum of 1 versus 2 years), and use of RA medications. Results were reported as positive predictive values (PPVs) of the claims‐based algorithm for incident RA.

Results

Depending on the algorithm tested and whether patients were enrolled in Medicare or the commercial health plan, the PPVs for incident RA ranged from 68–81%. A 2‐year clean period free of all RA‐related diagnoses and medications was somewhat more optimal although, by comparison, a 1‐year clean period yielded similar PPVs and retained approximately 90% more RA patients for analysis.

Conclusion

Claims‐based algorithms can accurately identify incident RA.
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20.
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