scholarly journals Combining FORGE Score and Histopathological Diagnostic Criteria of Atypical Meningioma Enables Risk Stratification of Tumor Progression

Diagnostics ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 2011
Author(s):  
Johannes Wach ◽  
Tim Lampmann ◽  
Ági Güresir ◽  
Hartmut Vatter ◽  
Albert J. Becker ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Diagnostic Criteria ◽  
Predictive Value ◽  
Cox Regression ◽  
Roc Curves ◽  
Atypical Meningioma ◽  
Brain Invasion ◽  
Cox Regression Analysis ◽  
Increased Risk ◽  
Atypical Meningiomas

More than 50% of atypical meningiomas regrow within 5 years after surgery. FORGE score is a newly created tool to estimate the MIB-1 index in cranial meningiomas. In this investigation, we aimed to assess the predictive value of the FORGE score in combination with major diagnostic criteria of atypical meningioma (brain invasion, mitotic count ≥ 4) regarding recurrence in atypical meningiomas. We included patients operated on primary atypical meningiomas in our center from 2011 to 2019. The study included 71 patients (58% women, median age 63 years). ROC curves revealed a superiority of FORGE score combined with histopathological diagnostic criteria of atypical meningioma (AT-FORGE) in the prediction of tumor progression compared to FORGE score only (AUC: 0.72; 95% CI: 0.54–0.91, cut-off: ≥5/<5, sensitivity: 75%, specificity: 78%). Patients with an AT-FORGE score ≥ 5 had a shorter time to tumor progression (32.8 vs. 71.4 months, p < 0.001) in the univariable analysis. Multivariable cox regression analysis revealed significant predictive value of Simpson grade > II, presence of multiple meningiomas and AT-FORGE score ≥ 5 for tumor progression. The combination of histopathological diagnostic criteria for atypical meningioma with FORGE score might facilitate an effective identification of patients with an atypical meningioma who have an increased risk of tumor progression.

Radiation Therapy for Residual or Recurrent Atypical Meningioma

Neurosurgery ◽  
2015 ◽  
Vol 79 (1) ◽  
pp. 23-32 ◽  
Author(s):  
Sam Q. Sun ◽  
Chunyu Cai ◽  
Rory K.J. Murphy ◽  
Todd DeWees ◽  
Ralph G. Dacey ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Tumor Progression ◽  
Cox Regression ◽  
Atypical Meningioma ◽  
Locoregional Control ◽  
External Beam Radiation ◽  
Subtotal Resection ◽  
Adjuvant Radiation ◽  
Beam Radiation ◽  
Brain Invasion

Abstract BACKGROUND Optimal use of stereotactic radiosurgery (SRS) vs external beam radiation therapy (EBRT) for treatment of residual/recurrent atypical meningioma is unclear. OBJECTIVE: To analyze features associated with progression after radiation therapy. METHODS: Fifty radiation-naive patients who received SRS or EBRT for residual and/or recurrent atypical meningioma were examined for predictors of progression using Cox regression and Kaplan-Meier analyses. RESULTS: Thirty-two patients (64%) received adjuvant radiation after subtotal resection, 12 patients (24%) received salvage radiation after progression following subtotal resection, and 6 patients (12%) received salvage radiation after recurrence following gross total resection. Twenty-one patients (42%) received SRS (median 18 Gy), and 7 (33%) had tumor progression. Twenty-nine patients (58%) received EBRT (median 54 Gy), and 13 (45%) had tumor progression. Whereas tumor volume (P = .53), SRS vs EBRT (P = .45), and adjuvant vs salvage (P = .34) were not associated with progression after radiation therapy, spontaneous necrosis (hazard ratio [HR] = 82.3, P &lt; .001), embolization necrosis (HR = 15.6, P = .03), and brain invasion (HR = 3.8, P = .008) predicted progression in univariate and multivariate analyses. Tumors treated with SRS/EBRT had 2- and 5-year actuarial locoregional control rates of 91%/88% and 71%/69%, respectively. Tumors with spontaneous necrosis, embolization necrosis, and no necrosis had 2- and 5-year locoregional control rates of 76%, 92%, and 100% and 36%, 73%, and 100%, respectively (P &lt; .001). CONCLUSION: This study suggests that necrosis may be a negative predictor of radiation response regardless of radiation timing or modality.

scholarly journals High concentrations of plasma trimethylamine-n-oxide is associated with long-term cardiovascular mortality in patients with acute coronary syndrome

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
C Eyileten ◽  
J Jarosz-Popek ◽  
D Jakubik ◽  
M Wolska ◽  
A Fitas ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Acute Coronary Syndrome ◽  
Predictive Value ◽  
Cox Regression ◽  
Independent Predictor ◽  
Cox Regression Analysis ◽  
Coronary Syndrome ◽  
Increased Risk ◽  
All Cause Mortality

Abstract Background Acute coronary syndrome (ACS) remains a leading cause of mortality worldwide [1]. Patients who experienced ACS are at high risk of future cardiovascular events and death [2–4]. Identification of reliable predictive tools could potentially improve the risk stratification [5]. Numerous studies revealed that intestinal microbial organisms (microbiota) and its metabolites, as TMAO (trimethylamine-N-oxide) may play a pathogenic role in a cardiovascular disease (CVD) and ACS [6]. Elevated concentration of circulating TMAO has been associated with increased risk of CVD and major adverse cardiac events (MACE), including myocardial infarction (MI), stroke, major bleeding and all-cause mortality [7]. Purpose To investigate the association of liver metabolite TMAO with cardiovascular disease (CV)-related and all-cause mortality in patients with acute coronary syndrome (ACS) who underwent percutaneous coronary intervention. Methods Our prospective observational study enrolled 292 patients with ACS. Plasma concentrations of TMAO were measured during the hospitalization for ACS. Observation period lasted 7 years in the median. Adjusted Cox-regression analysis was used for prediction of mortality. Results ROC curve analysis revealed that increasing concentrations of TMAO levels assessed at the time point of ACS significantly predicted the risk of CV mortality (c-index=0.78, p&lt;0.001). The cut-off value of &gt;4 μmol/L, labeled as high TMAO level (23% of study population), provided the greatest sum of sensitivity (85%) and specificity (80%) for the prediction of CV mortality and was associated with a positive predictive value of 16% and a negative predictive value of 99%. A multivariate Cox regression model revealed that high TMAO level was a strong and independent predictor of CV death (HR=11.62, 95% CI: 2.26–59.67; p=0.003). High TMAO levels as compared with low TMAO levels were associated with the highest risk of CV death in a subpopulation of patients with diabetes mellitus (27.3% vs 2.6%; p=0.004). Although increasing TMAO levels were also significantly associated with all-cause mortality, their estimates for diagnostic accuracy were low. Conclusions High TMAO level is a strong and independent predictor of long-term CV mortality among patients presenting with ACS. TMAO concentration of 4 μmol/L may be a cut-off value for prognosis of ACS patients. FUNDunding Acknowledgement Type of funding sources: None. Figure 1. Kaplan-Meier curves Table 1

scholarly journals Predictive Value of Small Dense Low-density Lipoprotein Cholesterol and Remnant-like Particle Cholesterol for Cardiovascular Events in Chinese Elder Diabetes Mellitus Patients

2020 ◽  
Author(s):  
Li Xu ◽  
Feifei Lu ◽  
Jingfen Lu ◽  
Yan Xu ◽  
Nuoer Chen ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Predictive Value ◽  
Cardiovascular Events ◽  
Cox Regression ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Cox Regression Analysis ◽  
Type 2 Dm ◽  
Increased Risk

Abstract BackgroundAs a subcomponent of lipoprotein cholesterol (LDL-C), small dense LDL-C (sdLDL-C) have been suggested to be a better predictor of cardiovascular diseases(CVD). This research was to evaluate the predictive of the sdLDL-C in cardiovascular events (CVs) in Chinese elder type 2 diabetes mellitus(DM) patients.MethodsSerum sdLDL-C measured by homogeneous method was compared in 386 consecutive type 2 DM patients between December 2014 and December 2016. Finally, 92 type 2 DM patients had CVs during the 48-month follow-up period. Receiver operating characteristic (ROC) curves were used for assess the predictive value of baseline parameters to major CVs.ResultsNinety-two CVs occurred during the study period.The ROC curve manifested that sdLDL-C in the study population had a matchable discriminatory power (AUC for sdLDL-C was 0.7366, P = 0.003). In addition, kaplan-Meier event-free survival curves displayed a obvious increase of CVs risk for sdLDL-C ≧ 26 mg/dL (log-rank = 9.10,P = 0.003). This phenomenon had analogousresultsin patients who received statins at baseline (log rank = 7.336༌P = 0.007).The study discovered that the increase in HbA1c, glucose, LDL-C, sdLDL-C, non-HDL-C and ApoB and the decrease in ApoA1 were obviously interrelated with heightened CVs risk through Cox regression analysis. Multivariate analysis demonstrated that the increase of sdLDL-C and HbA1c was obviously correlated with CVs. The results of the study indicated that sdLDL-C (per 10 mg/dL) was a increased risk for CVs in the multivariate model (HR 1.281, 95% CI 1.225–16.032; P < 0.01).ConclusionThe consequences demonstrated that sdLDL-C was more effective than RLP-C in predicting the future CVs of Chinese elder type 2 DM patients

Sex differences in transaortic flow rate and association with all-cause mortality in patients with severe aortic stenosis

2021 ◽  
Author(s):  
Sahrai Saeed ◽  
Anastasia Vamvakidou ◽  
Spyridon Zidros ◽  
George Papasozomenos ◽  
Vegard Lysne ◽  
...  
Keyword(s):  
Sex Differences ◽  
Aortic Stenosis ◽  
Flow Rate ◽  
Cox Regression ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Cox Regression Analysis ◽  
Increased Risk ◽  
All Cause Mortality

Abstract Aims It is not known whether transaortic flow rate (FR) in aortic stenosis (AS) differs between men and women, and whether the commonly used cut-off of 200 mL/s is prognostic in females. We aimed to explore sex differences in the determinants of FR, and determine the best sex-specific cut-offs for prediction of all-cause mortality. Methods and results Between 2010 and 2017, a total of 1564 symptomatic patients (mean age 76 ± 13 years, 51% men) with severe AS were prospectively included. Mean follow-up was 35 ± 22 months. The prevalence of cardiovascular disease was significantly higher in men than women (63% vs. 42%, P &lt; 0.001). Men had higher left ventricular mass and lower left ventricular ejection fraction compared to women (both P &lt; 0.001). Men were more likely to undergo an aortic valve intervention (AVI) (54% vs. 45%, P = 0.001), while the death rates were similar (42.0% in men and 40.6% in women, P = 0.580). A total of 779 (49.8%) patients underwent an AVI in which 145 (18.6%) died. In a multivariate Cox regression analysis, each 10 mL/s decrease in FR was associated with a 7% increase in hazard ratio (HR) for all-cause mortality (HR 1.07; 95% CI 1.03–1.11, P &lt; 0.001). The best cut-off value of FR for prediction of all-cause mortality was 179 mL/s in women and 209 mL/s in men. Conclusion Transaortic FR was lower in women than men. In the group undergoing AVI, lower FR was associated with increased risk of all-cause mortality, and the optimal cut-off for prediction of all-cause mortality was lower in women than men.

scholarly journals Fast-Track Programs in Total Hip and Knee Replacement at Swedish Hospitals—Influence on 2-Year Risk of Revision and Mortality

2021 ◽  
Vol 10 (8) ◽  
pp. 1680
Author(s):  
Urban Berg ◽  
Annette W-Dahl ◽  
Anna Nilsdotter ◽  
Emma Nauclér ◽  
Martin Sundberg ◽  
...  
Keyword(s):  
Fast Track ◽  
Cox Regression ◽  
Cox Regression Analysis ◽  
Total Hip ◽  
Total Knee Replacements ◽  
Risk Of Death ◽  
Kaplan Meier ◽  
Increased Risk ◽  
Hip And Knee Arthroplasty ◽  
Total Knee

Purpose: We aimed to study the influence of fast-track care programs in total hip and total knee replacements (THR and TKR) at Swedish hospitals on the risk of revision and mortality within 2 years after the operation. Methods: Data were collected from the Swedish Hip and Knee Arthroplasty Registers (SHAR and SKAR), including 67,913 THR and 59,268 TKR operations from 2011 to 2015 on patients with osteoarthritis. Operations from 2011 to 2015 Revision and mortality in the fast-track group were compared with non-fast-track using Kaplan–Meier survival analysis and Cox regression analysis with adjustments. Results: The hazard ratio (HR) for revision within 2 years after THR with fast-track was 1.19 (CI: 1.03–1.39), indicating increased risk, whereas no increased risk was found in TKR (HR 0.91; CI: 0.79–1.06). The risk of death within 2 years was estimated with a HR of 0.85 (CI: 0.74–0.97) for TKR and 0.96 (CI: 0.85–1.09) for THR in fast-track hospitals compared to non-fast-track. Conclusions: Fast-track programs at Swedish hospitals were associated with an increased risk of revision in THR but not in TKR, while we found the mortality to be lower (TKR) or similar (THR) as compared to non-fast track.

scholarly journals High rate of second ACL injury following ACL reconstruction in male professional footballers: an updated longitudinal analysis from 118 players in the UEFA Elite Club Injury Study

2021 ◽  
pp. bjsports-2020-103555
Author(s):  
Francesco Della Villa ◽  
Martin Hägglund ◽  
Stefano Della Villa ◽  
Jan Ekstrand ◽  
Markus Waldén
Keyword(s):  
Acl Reconstruction ◽  
Cox Regression ◽  
Injury Rate ◽  
Acl Injury ◽  
High Rate ◽  
Football Players ◽  
Professional Football ◽  
Cox Regression Analysis ◽  
Career Length ◽  
Increased Risk

BackgroundStudies on subsequent anterior cruciate ligament (ACL) ruptures and career length in male professional football players after ACL reconstruction (ACLR) are scarce.AimTo investigate the second ACL injury rate, potential predictors of second ACL injury and the career length after ACLR.Study designProspective cohort study.SettingMen’s professional football.Methods118 players with index ACL injury were tracked longitudinally for subsequent ACL injury and career length over 16.9 years. Multivariable Cox regression analysis with HR was carried out to study potential predictors for subsequent ACL injury.ResultsMedian follow-up was 4.3 (IQR 4.6) years after ACLR. The second ACL injury rate after return to training (RTT) was 17.8% (n=21), with 9.3% (n=11) to the ipsilateral and 8.5% (n=10) to the contralateral knee. Significant predictors for second ACL injury were a non-contact index ACL injury (HR 7.16, 95% CI 1.63 to 31.22) and an isolated index ACL injury (HR 2.73, 95% CI 1.06 to 7.07). In total, 11 of 26 players (42%) with a non-contact isolated index ACL injury suffered a second ACL injury. RTT time was not an independent predictor of second ACL injury, even though there was a tendency for a risk reduction with longer time to RTT. Median career length after ACLR was 4.1 (IQR 4.0) years and 60% of players were still playing at preinjury level 5 years after ACLR.ConclusionsAlmost one out of five top-level professional male football players sustained a second ACL injury following ACLR and return to football, with a considerably increased risk for players with a non-contact or isolated index injury.

Predictors of tumor progression among children with gangliogliomas

2009 ◽  
Vol 3 (6) ◽  
pp. 461-466 ◽  
Author(s):  
Mostafa El Khashab ◽  
Lynn Gargan ◽  
Linda Margraf ◽  
Korgun Koral ◽  
Farideh Nejat ◽  
...  
Keyword(s):  
Risk Factors ◽  
Tumor Progression ◽  
Cox Regression ◽  
Tumor Resection ◽  
Progression Free Survival ◽  
Initial Presentation ◽  
Subtotal Resection ◽  
Low Grade ◽  
Cox Regression Analysis ◽  
Presenting Symptoms

Object Few reports describe the outcome and prognostic factors for children with gangliogliomas. The objective of this report was to describe the progression-free survival (PFS) for children with low-grade gangliogliomas and identify risk factors for tumor progression. Methods A retrospective study was performed in children with low-grade gangliogliomas who were evaluated and treated in the neuro-oncology department between 1986 and 2006 to determine risk factors for subsequent tumor progression. Results A total of 38 children with newly diagnosed gangliogliomas were included in this report. Thirty-four children were treated with surgery alone, 3 with subtotal resection and radiation therapy, and 1 with subtotal resection and chemotherapy. The follow-up ranged from 4 months to 15.8 years (mean 5.7 ± 4.2 years [± SD]). Seven children have experienced tumor progression, and 1 child died after his tumor subsequently underwent malignant transformation. The 5-year PFS was calculated to be 81.2% using Kaplan-Meier survival analysis. Initial presentation with seizures (p = 0.004), tumor location in the cerebral hemisphere (p = 0.020), and complete tumor resection (p = 0.035) were associated with prolonged PFS. Further analysis of the above significant variables by a Cox regression model identified initial presentation with seizures as being associated with prolonged PFS (p = 0.028). Conclusions The PFS and overall survival of children with gangliogliomas are good. Tumors located in the cerebral hemispheres, the achievement of total resection, and seizures at presentation were associated with prolonged PFS. Cox regression analysis identified presenting symptoms including seizures as significant predictive factors of PFS. Prospective studies with larger numbers of children are needed to define the significant factors of tumor progression.

Diagnostic and prognostic significance of miR-451a in patients with atherosclerosis

Vascular ◽  
2021 ◽  
pp. 170853812110585
Author(s):  
Baizhi Wang ◽  
Xingliang Duan ◽  
Qing Xu ◽  
Yani Li
Keyword(s):  
Operating Characteristic ◽  
Cox Regression ◽  
Prognostic Biomarker ◽  
Prognostic Significance ◽  
High Sensitivity ◽  
Roc Curves ◽  
Cox Regression Analysis ◽  
Chi Squared ◽  
Cardiovascular Endpoint ◽  
Inflammatory Vascular Disease

Objectives Atherosclerosis (AS) is a chronic inflammatory vascular disease. This study aimed to detect the expression level of miR-451a and investigate the diagnostic and prognostic values of miR-451a for AS patients. Methods The relative expression of miR-451a was assessed by qRT-PCR. Comparison of groups was analyzed with the t-test and chi-squared test. Pearson analysis was used to validate the correlation of miR-451 with CRP and CIMT. The receiver operating characteristic (ROC) curves, K-M analysis, and Cox regression analysis were conducted to explore the roles of miR-451a in diagnosing AS patients and predicting outcomes of AS patients. Results The expression of miR-451a was significantly decreased in the serum of AS patients. The results of Pearson analysis showed the expression of miR-451a was negatively correlated with CRP and CIMT. The data of ROC proposed miR-451a could differentiate AS patients from healthy individuals with high sensitivity and specificity. K-M analysis and Cox regression showed miR-451a might be an independent biomarker of suffering cardiovascular endpoint diseases in AS patients. The expression of miR-451a was obviously inhibited in AS patients with cardiovascular endpoint events. Conclusion Deregulation of miR-451a might be associated with the development of AS. MiR-451a might be used as a promising diagnostic and prognostic biomarker for clinical treatment of AS patients.

684 Cardiac troponins and adverse outcomes in European patients with atrial fibrillation: a report from the ESC-EHRA EORP atrial fibrillation general long-term registry

2021 ◽  
Vol 23 (Supplement_G) ◽  
Author(s):  
Marrco Vitolo ◽  
Vincenzo Livio Malavasi ◽  
Marco Proietti ◽  
Igor Diemberger ◽  
Laurent Fauchier ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Regression Analysis ◽  
Cox Regression ◽  
Adverse Outcomes ◽  
Cox Regression Analysis ◽  
Coronary Syndrome ◽  
Increased Risk ◽  
History Of ◽  
Cardiac Troponins

Abstract Aims Cardiac troponins (cTn) have been reported to be predictors for adverse outcomes in atrial fibrillation (AF), patients, but their actual use is still unclear. To assess the factors associated with cTn testing in routine clinical practice and to evaluate the association of elevated levels of cTn with adverse outcomes in a large contemporary cohort of European AF patients. Methods and results Patients enrolled in the ESC-EHRA EORP-AF General Long-Term Registry were stratified into three groups according to cTn levels as (i) cTn not tested, (ii) cTn in range (≤99th percentile), and (iii) cTn elevated (&gt;99th percentile). The composite outcome of any thromboembolism/any acute coronary syndrome (ACS)/cardiovascular (CV) death, defined as major adverse cardiovascular events (MACE) and all-cause death were the main endpoints. 10 445 (94.1%) AF patients were included in this analysis [median age 71 years, interquartile range (IQR): 63–77; males 59.7%]. cTn were tested in 2834 (27.1%). Overall, cTn was elevated in 904 (8.7%) and in-range in 1930 (18.5%) patients. Patients in whom cTn was tested tended to be younger (P &lt; 0.001) and more frequently presenting with first detected AF and atypical AF-related symptoms (i.e. chest pain, dyspnoea, or syncope) (P &lt; 0.001). On multivariable logistic regression analysis, female sex, in-hospital enrollment, first-detected AF, CV risk factors, history of coronary artery disease (CAD), and atypical AF symptoms were independently associated with cTn testing. After a median follow-up of 730 days (IQR: 692–749), 957 (9.7%) composite endpoints occurred while all-cause death was 9.5%. Kaplan–Meier analysis showed a higher cumulative risk for both outcomes in patients with elevated cTn levels (Figure) (Log Rank tests, P &lt; 0.001). On adjusted Cox regression analysis, elevated levels of cTn were independently associated with a higher risk for MACE [hazard ratio (HR): 1.74, 95% confidence interval (CI): 1.40–2.16] and all-cause death (HR 1.45, 95% CI: 1.21–1.74). Elevated levels of cTn were independently associated with a higher occurrence of MACE, all-cause death, any ACS, CV death and hospital readmission even after the exclusion of patients with history of CAD, diagnosis of ACS at discharge, those who underwent coronary revascularization during the admission and/or who were treated with oral anticoagulants plus antiplatelet therapy. Conclusions Elevated cTn levels were independently associated with an increased risk of all-cause mortality and adverse CV events, even after exclusion of CAD patients. Clinical factors that might enhance the need to rule out CAD were associated with cTn testing.

scholarly journals Varicella zoster virus infections increase the risk of disease flares in patients with SLE: a matched cohort study

2019 ◽  
Vol 6 (1) ◽  
pp. e000339 ◽  
Author(s):  
Fangfang Sun ◽  
Yi Chen ◽  
Wanlong Wu ◽  
Li Guo ◽  
Wenwen Xu ◽  
...  
Keyword(s):  
Propensity Score ◽  
Varicella Zoster Virus ◽  
Cox Regression ◽  
Control Period ◽  
Cox Regression Analysis ◽  
Varicella Zoster ◽  
Propensity Score Weighting ◽  
Kaplan Meier ◽  
Increased Risk ◽  
Risk Of Disease

ObjectiveTo explore whether varicella zoster virus (VZV) infection could increase the risk of disease flares in patients with SLE.MethodsPatients who had VZV reactivations between January 2013 and April 2018 were included from the SLE database (n=1901) of Shanghai Ren Ji Hospital, South Campus. Matched patients with SLE were selected as background controls with a 3:1 ratio. Patients with SLE with symptomatic bacterial infections of the lower urinary tract (UTI) were identified as infection controls. Baseline period and index period were defined as 3 months before and after infection event, respectively. Control period was the following 3 months after the index period. Flare was defined by SELENA SLEDAI Flare Index. Kaplan-Meier analysis, Cox regression model and propensity score weighting were applied.ResultsPatients with VZV infections (n=47), UTI controls (n=28) and matched SLE background controls (n=141) were included. 16 flares (34%) in the VZV group within the index period were observed, as opposed to only 7.1% in UTI controls and 9.9% in background controls. Kaplan-Meier curve revealed that patients with a VZV infection had a much lower flare-free survival within the index period compared with the controls (p=0.0003). Furthermore, after adjusting for relevant confounders including baseline disease activity and intensity of immunosuppressive therapy, Cox regression analysis and propensity score weighting confirmed that VZV infection within 3 months was an independent risk factor for SLE flares (HR 3.70 and HR 4.16, respectively).ConclusionsIn patients with SLE, recent VZV infection within 3 months was associated with increased risk of disease flares.

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