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1.  Work disability, lost productivity and associated risk factors in patients diagnosed with systemic lupus erythematosus 
Lupus Science & Medicine  2015;2(1):e000058.
Objective
To assess prevalence and correlates of work presenteeism, absenteeism and work disability (WD) in patients with systemic lupus erythematous (SLE) and matched controls.
Methods
Patients with SLE from six medical centres were recruited to complete a questionnaire consisting of several prevalidated survey instruments. The subject's rheumatologist completed medical history. Subjects recruited two non-SLE ‘best friend’ controls with matching demographics to complete a control survey. Analyses employed Student's t tests, χ2 tests and logistic regression models.
Results
344 subjects with SLE and 322 controls submitted completed questionnaires. Mean pain, fatigue, Brief Cognitive Symptoms Index (BCSI) scores and depressive symptoms were worse in patients with SLE with WD (all p<0.01). WD was associated with African–American race, older age (51–65 years) and less than 4-year college education (all p<0.01). High presenteeism was associated with low pain and fatigue levels, higher BCSI scores and negatively correlated with depressive symptoms (all p<0.05). Increased pain and fatigue were associated with elevated absenteeism (p<0.05). Subjects with physically and cognitively demanding work reported worse presenteeism compared with controls with similar jobs (77% vs 85%, p<0.05 and 75% vs 85%, p<0.001), respectively. Patients with most cognitively demanding jobs reported greater weekly absenteeism (mean, 5.9 h) compared with controls (mean, 6.9 overtime hours, p<0.05).
Conclusions
The questionnaire demonstrated increased WD in SLE. Highly physical and highly cognitive jobs are challenging to patients with SLE and had increased absenteeism compared with controls. Depressive symptoms were correlated with better presenteeism without major socio-demographic determinants. Employability may be enhanced by improving treatment of depressive symptoms in patients with SLE.
doi:10.1136/lupus-2014-000058
PMCID: PMC4305073  PMID: 25632349
Epidemiology; Systemic Lupus Erythematosus; Qualitative research
2.  Pain Severity and Neuropathic Pain symptoms in primary Sjogren’s syndrome: A comparison study of seropositive and seronegative Sjogren’s syndrome 
Arthritis care & research  2013;65(8):1291-1298.
Objectives
To compare clinical characteristics and patient-reported outcomes in seropositive versus seronegative primary Sjogren’s syndrome patients (pSS) and to investigate the effect of serological status on the prevalence of chronic pain, comorbidity and health quality.
Methods
Pain severity and neuropathic pain symptoms, comorbidity and health status were assessed in 108 pSS patients. Differences between patient groups were assessed by t-test and chi-square tests and adjusted pain-affect associations. The effect of predictor variables on pain severity was examined with multivariate regression.
Results
Pain severity was greater (p=.003) and physical function (p=.023) reduced in the seronegative patients. Prevalence of neuropathic pain, depression, anxiety and disability were similar between groups. Chronic pain, defined as daily pain for greater than 3 months, was reported by 65% of seropositive (N=65) and 75% of seronegative patients (N=40). After adjustment for age, sleep quality and psychological distress, the difference in pain severity between seropositive and seronegative patients remained significant.
Conclusion
Chronic pain is pervasive in both seropositive and seronegative pSS patients, while pain severity and functional impairment is greater in seronegative patients. Neuropathic pain is equally prevalent and is the predominant pain phenotype in patients with moderate to severe pain. Accurate assessment of pain phenotypes is needed for more effective management of chronic pain in pSS. The focus of future research should be to standardize assessment of pain and to identify the factors contributing to more severe pain in seronegative patients.
doi:10.1002/acr.21956
PMCID: PMC4137866  PMID: 23335582
3.  Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjögren’s syndrome 
Nature genetics  2013;45(11):10.1038/ng.2792.
Sjögren’s syndrome is a common autoimmune disease (~0.7% of European Americans) typically presenting as keratoconjunctivitis sicca and xerostomia. In addition to strong association within the HLA region at 6p21 (Pmeta=7.65×10−114), we establish associations with IRF5-TNPO3 (Pmeta=2.73×10−19), STAT4 (Pmeta=6.80×10−15), IL12A (Pmeta =1.17×10−10), FAM167A-BLK (Pmeta=4.97×10−10), DDX6-CXCR5 (Pmeta=1.10×10−8), and TNIP1 (Pmeta=3.30×10−8). Suggestive associations with Pmeta<5×10−5 were observed with 29 regions including TNFAIP3, PTTG1, PRDM1, DGKQ, FCGR2A, IRAK1BP1, ITSN2, and PHIP amongst others. These results highlight the importance of genes involved in both innate and adaptive immunity in Sjögren’s syndrome.
doi:10.1038/ng.2792
PMCID: PMC3867192  PMID: 24097067
4.  Comparison of the American-European Consensus Group Sjögren's syndrome classification criteria to newly proposed American College of Rheumatology criteria in a large, carefully characterized sicca cohort 
Annals of the rheumatic diseases  2013;73(1):10.1136/annrheumdis-2013-203845.
Objective
To compare the performance of the American-European Consensus Group (AECG) and the newly proposed American College of Rheumatology (ACR) classification criteria for Sjögren's syndrome in a well-characterized sicca cohort, given ongoing efforts to resolve discrepancies and weaknesses in the systems.
Methods
In a multidisciplinary clinic for the evaluation of sicca, we assessed features of salivary and lacrimal gland dysfunction and autoimmunity as defined by tests of both AECG and ACR criteria in 646 participants. Global gene expression profiles were compared in a subset of 180 participants.
Results
Application of the AECG and ACR criteria resulted in classification of 279 and 268 participants with SS, respectively. Both criteria were met by 244 participants (81%). In 26 of the 35 AECG+/ACR- participants, the minor salivary gland biopsy focal score was ≥1 (74%), while 9 had positive anti-Ro/La (26%). There were 24 AECG-/ACR+ who met ACR criteria mainly due to differences in the scoring of corneal staining. All patients with SS, regardless of classification, had similar gene expression profiles, which were distinct from the healthy controls.
Conclusion
The two sets of classification criteria yield concordant results in the majority of cases and gene expression profiling suggests that patients meeting either set of criteria are more similar to other SS participants than to healthy controls. Thus, there is no clear evidence for increased value of the new ACR criteria over the old AECG criteria from the clinical or biological perspective. It is our contention, supported by this report, that improvements in diagnostic acumen will require a more fundamental understanding of the pathogenic mechanisms than is at present available.
doi:10.1136/annrheumdis-2013-203845
PMCID: PMC3855629  PMID: 23968620
Sjögren's syndrome; Classification; Diagnosis
5.  Primary Sjogren’s Syndrome: Cognitive Symptoms, Mood and Cognitive Performance 
Acta Neurologica Scandinavica  2011;125(4):272-278.
Objective
to investigate the relationships between self-reported cognitive abilities, psychological symptoms and neuropsychological outcomes in PSS.
Methods
PSS patients and healthy controls completed a comprehensive neuropsychometric battery and questionnaires: the Centers for Epidemiological Scale-Depression, the Profile of Fatigue- mental domain (Prof-M) for cognitive symptoms, Fatigue Severity Scale and the Short-Form McGill Pain Questionnaire.
Results
Female PSS patients (N=39) were similar to controls (N=17) in estimated pre-morbid intellectual function, age and education. Depression (p=.002), cognitive symptoms (p=.001), fatigue (p=.000003) and pain (p=.024) scores were greater in the patient group. PSS patients demonstrated inferior performance relative to controls in psychomotor processing (p=.027) and verbal reasoning (p=.007). PSS patients with and without depression had similar performance on multiple tests, but depressed patients had significantly lower scores for executive function (p=.041). Cognitive symptoms correlated with verbal memory (p=.048), whereas pain correlated with executive function measures (Stroop, p=.017) and working memory (Trails B, p=.036). In the regression model, depression and verbal memory were independent predictors that accounted for 61 % of the variance in cognitive symptoms.
Conclusion
The Prof-M is a simple self-report measure which could be useful in screening PSS subjects who may benefit from detailed psychometric evaluation. Our results are consistent with the hypothesis that depression and verbal memory impairment are overlapping but independent aspects of neural involvement in PSS. While pain and depression are significant confounders of cognitive function in PSS, this study suggests that impaired verbal reasoning ability in PSS is not attributable to pain or depression.
doi:10.1111/j.1600-0404.2011.01530.x
PMCID: PMC3188671  PMID: 21651503
Cognition; Central nervous system disorders; Depression; Sjogren’s syndrome
6.  Genetics and Genomics of Sjogren's Syndrome: Research provides Clues to Pathogenesis and Novel Therapies 
Purpose
While the key inciting events that drive the progression from autoantibodies to clinical disease remain to be clarified, new light has been shed on the factors contributing to disease susceptibility and the role of genetic factors in determining Sjogren's syndrome (SS) disease phenotypes. The purpose of this review is to provide an update on the role of genetic markers in the susceptibility to and pathogenesis of Sjogren's syndrome. This paper also discusses how genomic and proteomic technology can help in the design of specific therapeutics.
Key Findings
Recent evidence suggests that inflammatory genes associated with interferon pathways, and specific regulatory genes that control the maturation and proliferation of B cells, contribute to the pathogenesis of Sjogren's syndrome. Both gene expression profiling technology and gene association studies have been used to identify these key biologic pathways. Molecularly defined subsets of pSS patients are also being revealed by these studies. Previously identified gene loci which predispose to multiple autoimmune disorders have been confirmed supporting the paradigm of “general” autoimmune disease genes. Association of SS with many additional susceptibility loci are likely to be established through ongoing genome-wide association scans (GWAS). Clues from genetic studies suggest that targeting B cells will prove to be an effective way of reducing the systemic manifestations of pSS and are supported by early clinical trials.
Summary
Genome-wide technologies are likely to identify new genes and molecular pathways in the pathogenesis of SS that will be useful not only to identify patients at risk for SS, but also to identify subsets of patients at risk for variable levels of disease severity. In the future, these studies could identify novel biomarkers that will lead to significant advances in management by providing the means to tailor therapeutic strategies to individual patients.
doi:10.1016/j.tripleo.2011.01.040
PMCID: PMC3095716  PMID: 21497524
Sjogren's; genetics; genomics; autoimmune; inflammatory; Sjögren's Syndrome; Gene Expression Profiling; Interferon; Genetics
7.  Peripheral blood gene expression profiling in Sjögren’s syndrome 
Genes and Immunity  2009;10(4):285-296.
Sjögren’s syndrome (SS) is a common chronic autoimmune disease characterized by lymphocytic infiltration of exocrine glands. Affected cases commonly present with oral and ocular dryness, thought to be the result of inflammatory cell-mediated gland dysfunction. To identify important molecular pathways involved in SS, we used high-density microarrays to define global gene expression profiles in peripheral blood. We first analyzed 21 SS cases and 23 controls and identified a prominent pattern of overexpressed genes that are inducible by interferons (IFNs). These results were confirmed by evaluation of a second independent dataset of 17 SS cases and 22 controls. Additional inflammatory and immune-related pathways with altered expression patterns in SS cases included B and T cell receptor, IGF-1, GM-CSF, PPARα/RXRα, and PI3/AKT signaling. Exploration of these data for relationships to clinical features of disease revealed that expression levels for most IFN-inducible genes were positively correlated with titers of anti-Ro/SSA (P<0.001) and anti-La/SSB (P<0.001) autoantibodies. Diagnostic and therapeutic approaches targeting IFN signaling pathway may prove most effective in the subset of SS cases who produce anti-Ro/SSA and anti-La/SSB autoantibodies. Our results strongly support innate and adaptive immune processes in the pathogenesis of SS and provide numerous candidate disease markers for further study.
doi:10.1038/gene.2009.20
PMCID: PMC3273959  PMID: 19404300
8.  Prevalence, Severity and Predictors of Fatigue in Primary Sjogren’s Syndrome 
Arthritis and rheumatism  2008;59(12):1780-1787.
OBJECTIVES
To investigate the relationship of fatigue severity to other clinical features in primary Sjogren’s syndrome (PSS) and to identify factors contributing to the physical and mental aspects of fatigue.
METHODS
We identified 94 subjects who met the American-European consensus criteria for the classification of PSS. Fatigue was assessed with a VAS, the Fatigue Severity Scale (FSS) and the Profile of Fatigue (ProF.) Associations with fatigue was compared using multivariate regression.
RESULTS
Abnormal fatigue defined as a FSS score of greater than or equal to 4 was present in 67% of the patients. Pain, helplessness and depression were the strongest predictors of both FSS and the somatic fatigue domain of the ProF (Prof-S), both with and without adjustment for physiologic and serologic characteristics. Depression was associated with higher levels of fatigue; however, the majority of patients with abnormal fatigue were not depressed. Anti-Ro/SSA positive patients were no more likely to report fatigue than seronegative patients. The regression models explained 62% of the variance in FSS and 78% of the variance in Prof-S. Mental fatigue was correlated with depression and helplessness, but the model predicted only 54% of the variance in mental fatigue (Prof-M.).
CONCLUSIONS
Psychosocial variables are determinants of fatigue, but only partly account for it. While fatigue is associated with depression, depression is not the primary cause of fatigue in PSS. Investigation of the pathophysiologic correlates of physical and mental aspects of fatigue is needed to guide the development of more effective interventions.
doi:10.1002/art.24311
PMCID: PMC3106978  PMID: 19035421
9.  Primary Sjögren's Syndrome: health experiences and predictors of health quality among patients in the United States 
Objective
To assess the health related quality of life of patients with primary Sjögren's Syndrome (PSS) in a large US sample.
Methods
Questionnaires were mailed to 547 patients with a confirmed diagnosis of PSS (PhysR-PSS) and all active members of the Sjögren's Syndrome Foundation USA (SSF-PSS), half of whom identified a friend without PSS to also complete the survey.
Results
277 PhysR-PSS patients were compared to 606 controls. The mean age was 62 years in the PhysR-PSS group and 61 years in the control group. 90% in both groups were women. Time from first symptom to diagnosis of PSS was a mean of 7 years. Sicca related morbidity, fatigue severity, depression and pain (assessed by validated questionnaires, PROFAD-SSI, FACIT-F, CES-D, BPI) were significantly greater, and all eight SF-36 domains were significantly diminished, in patients compared to controls. Somatic fatigue was the dominant predictor of physical function and of general health. Depression was the dominant predictor of emotional well being. Health care utilization was higher in patients than controls, including out of pocket dental expenses (mean: PhysR-PSS = $1473.3, controls = $503.6), dental visits (mean: PhysR-PSS = 4.0, controls = 2.3), current treatments (mean: PhysR-PSS = 6.6, controls = 2.5), and hospitalizations (53% PhysR-PSS, vs. 40% controls).
Conclusion
Diminished health quality and excess health costs are prevalent among PSS patients. Health experiences and functional impact of PSS is similar among US and European patients. Delayed diagnosis, sicca related morbidity, fatigue, pain and depression are substantial suggesting unmet health needs and the importance of earlier recognition of PSS.
doi:10.1186/1477-7525-7-46
PMCID: PMC2693523  PMID: 19473510

Results 1-9 (9)