Publications by authors named "Leslie J Crofford"

166 Publications

A comprehensive framework for navigating patient care in systemic sclerosis: A global response to the need for improving the practice of diagnostic and preventive strategies in SSc.

Best Pract Res Clin Rheumatol 2021 09 15;35(3):101707. Epub 2021 Sep 15.

Federation of European Scleroderma Associations, Copenhagen, Denmark; Federation of European Scleroderma Associations, Budapest, Hungary; Federation of European Scleroderma Associations, London, UK.

Systemic sclerosis (SSc), the most lethal of rheumatologic conditions, is the cause of death in >50% of SSc cases, led by pulmonary fibrosis followed by pulmonary hypertension and then scleroderma renal crisis (SRC). Multiple other preventable and treatable SSc-related vascular, cardiac, gastrointestinal, nutritional and musculoskeletal complications can lead to disability and death. Vascular injury with subsequent inflammation transforming to irreversible fibrosis and permanent damage characterizes SSc. Organ involvement is often present early in the disease course of SSc, but requires careful history-taking and vigilance in screening to detect. Inflammation is potentially reversible provided that treatment intensity quells inflammation and other immune mechanisms. In any SSc phenotype, opportunities for early treatment are prone to be under-utilized, especially in slowly progressive phenotypes that, in contrast to severe progressive ILD, indolently accrue irreversible organ damage resulting in later-stage life-limiting complications such as pulmonary hypertension, cardiac involvement, and malnutrition. A single SSc patient visit often requires much more physician and staff time, organization, vigilance, and direct management for multiple organ systems compared to other rheumatic or pulmonary diseases. Efficiency and efficacy of comprehensive SSc care enlists trending of symptoms and bio-data. Financial sustainability of SSc care benefits from understanding insurance reimbursement and health system allocation policies for complex patients. Sharing care between recognised SSc centers and local cardiology/pulmonary/rheumatology/gastroenterology colleagues may prevent complications and poor outcomes, while providing support to local specialists. As scleroderma specialists, we offer a practical framework with tools to facilitate an optimal, comprehensive and sustainable approach to SSc care. Improved health outcomes in SSc relies upon recogntion, management and, to the extent possible, prevention of SSc and treatment-related complications.
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http://dx.doi.org/10.1016/j.berh.2021.101707DOI Listing
September 2021

Amelioration of post-traumatic osteoarthritis via nanoparticle depots delivering small interfering RNA to damaged cartilage.

Nat Biomed Eng 2021 09 19;5(9):1069-1083. Epub 2021 Aug 19.

Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA.

The progression of osteoarthritis is associated with inflammation triggered by the enzymatic degradation of extracellular matrix in injured cartilage. Here we show that a locally injected depot of nanoparticles functionalized with an antibody targeting type II collagen and carrying small interfering RNA targeting the matrix metalloproteinase 13 gene (Mmp13), which breaks down type II collagen, substantially reduced the expression of MMP13 and protected cartilage integrity and overall joint structure in acute and severe mouse models of post-traumatic osteoarthritis. MMP13 inhibition suppressed clusters of genes associated with tissue restructuring, angiogenesis, innate immune responses and proteolysis. We also show that intra-articular injections of the nanoparticles led to greater reductions in disease progression than either a single injection or weekly injections of the steroid methylprednisolone. Sustained drug retention by targeting collagen in the damaged extracellular matrix of osteoarthritic cartilage may also be an effective strategy for the treatment of osteoarthritis with other disease-modifying drugs.
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http://dx.doi.org/10.1038/s41551-021-00780-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8497446PMC
September 2021

Human and Machine Intelligence Together Drive Drug Repurposing in Rare Diseases.

Front Genet 2021 28;12:707836. Epub 2021 Jul 28.

Vanderbilt Institute for Clinical and Translational Research, Vanderbilt University Medical Center, Nashville, TN, United States.

Repurposing is an increasingly attractive method within the field of drug development for its efficiency at identifying new therapeutic opportunities among approved drugs at greatly reduced cost and time of more traditional methods. Repurposing has generated significant interest in the realm of rare disease treatment as an innovative strategy for finding ways to manage these complex conditions. The selection of which agents should be tested in which conditions is currently informed by both human and machine discovery, yet the appropriate balance between these approaches, including the role of artificial intelligence (AI), remains a significant topic of discussion in drug discovery for rare diseases and other conditions. Our drug repurposing team at Vanderbilt University Medical Center synergizes machine learning techniques like phenome-wide association study-a powerful regression method for generating hypotheses about new indications for an approved drug-with the knowledge and creativity of scientific, legal, and clinical domain experts. While our computational approaches generate drug repurposing hits with a high probability of success in a clinical trial, human knowledge remains essential for the hypothesis creation, interpretation, "go-no go" decisions with which machines continue to struggle. Here, we reflect on our experience synergizing AI and human knowledge toward realizable patient outcomes, providing case studies from our portfolio that inform how we balance human knowledge and machine intelligence for drug repurposing in rare disease.
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http://dx.doi.org/10.3389/fgene.2021.707836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8355705PMC
July 2021

CD19 + CD21 cells are increased in systemic sclerosis-associated interstitial lung disease.

Clin Exp Med 2021 Aug 10. Epub 2021 Aug 10.

Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.

Interstitial lung disease (ILD) represents a significant cause of morbidity and mortality in systemic sclerosis (SSc). The purpose of this study was to examine recirculating lymphocytes from SSc patients for potential biomarkers of interstitial lung disease (ILD). Peripheral blood mononuclear cells (PBMCs) were isolated from patients with SSc and healthy controls enrolled in the Vanderbilt University Myositis and Scleroderma Treatment Initiative Center cohort between 9/2017-6/2019. Clinical phenotyping was performed by chart abstraction. Immunophenotyping was performed using both mass cytometry and fluorescence cytometry combined with t-distributed stochastic neighbor embedding analysis and traditional biaxial gating. This study included 34 patients with SSc-ILD, 14 patients without SSc-ILD, and 25 healthy controls. CD21 cells are significantly increased in SSc-ILD but not in SSc without ILD (15.4 ± 13.3% vs. 5.8 ± 0.9%, p = 0.002) or healthy controls (5.0 ± 0.5%, p < 0.0001). While CD21 B cells can be identified from a single biaxial gate, tSNE analysis reveals that the biaxial gate is comprised of multiple distinct subsets, all of which are increased in SSc-ILD. CD21 cells in both healthy controls and SSc-ILD are predominantly tBET positive and do not have intracellular CD21. Immunohistochemistry staining demonstrated that CD21 B cells diffusely infiltrate the lung parenchyma of an SSc-ILD patient. Additional work is needed to validate this biomarker in larger cohorts and longitudinal studies and to understand the role of these cells in SSc-ILD.
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http://dx.doi.org/10.1007/s10238-021-00745-5DOI Listing
August 2021

High-Throughput Detection of Autoantigen-Specific B Cells Among Distinct Functional Subsets in Autoimmune Donors.

Front Immunol 2021 24;12:685718. Epub 2021 May 24.

Department of Medicine, Division of Rheumatology and Immunology, Vanderbilt University Medical Center, Nashville, TN, United States.

Antigen-specific B cells (ASBCs) can drive autoimmune disease by presenting autoantigen to cognate T cells to drive their activation, proliferation, and effector cell differentiation and/or by differentiating into autoantibody-secreting cells. Autoantibodies are frequently used to predict risk and diagnose several autoimmune diseases. ASBCs can drive type 1 diabetes even when immune tolerance mechanisms block their differentiation into antibody-secreting cells. Furthermore, anti-histidyl tRNA synthetase syndrome patients have expanded IgM Jo-1-binding B cells, which clinically diagnostic IgG Jo-1 autoantibodies may not fully reflect. Given the potential disconnect between the pathologic function of ASBCs and autoantibody secretion, direct study of ASBCs is a necessary step towards developing better therapies for autoimmune diseases, which often have no available cure. We therefore developed a high-throughput screening pipeline to 1) phenotypically identify specific B cell subsets, 2) expand them , 3) drive them to secrete BCRs as antibody, and 4) identify wells enriched for ASBCs through ELISA detection of antibody. We tested the capacity of several B cell subset(s) to differentiate into antibody-secreting cells following this robust stimulation. IgM and/or IgD, CD27 memory, memory, switched memory, and B B cells secreted B cell receptor (BCR) as antibody following stimulation, whereas few plasmablasts responded. Bimodal responses were observed across autoimmune donors for IgM CD21 and IgM CD21 B cells, consistent with documented heterogeneity within the CD21 subset. Using this approach, we detected insulin-binding B cell bias towards CD27 memory and CD27 memory subsets in pre-symptomatic type 1 diabetes donors. We took advantage of routine detection of Jo-1-binding B cells in Jo-1+ anti-histidyl tRNA synthetase syndrome patients to show that Jo-1-binding B cells and total B cells expanded 20-30-fold using this culture system. Overall, these studies highlight technology that is amenable to small numbers of cryopreserved peripheral blood mononuclear cells that enables interrogation of phenotypic and repertoire attributes of ASBCs derived from autoimmune patients.
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http://dx.doi.org/10.3389/fimmu.2021.685718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8256427PMC
October 2021

Pain, Goal Engagement, and Eudaemonic Well-Being: Moderation by Autonomous Motivation.

J Gerontol B Psychol Sci Soc Sci 2021 Jun 15. Epub 2021 Jun 15.

Department of Internal Medicine, Vanderbilt University School of Medicine.

Objectives: Pain may decrease well-being in older adults by limiting social and leisure activities. However, some activities can exacerbate pain. We hypothesized that autonomously motivated goal engagement could ameliorate negative effects of pain on goal engagement and amplify positive effects of goal engagement on eudaemonic well-being (EWB).

Method: Midlife and older women (N=200) were oversampled for chronic pain. Daily diaries (n=10,697) including goal lists and ratings, pain, and EWB were completed for 7 days every 3 months for 2 years.

Results: Pain was not a correlate of goal engagement. More engagement was associated with higher EWB when motivation was autonomous. However, more goal engagement correlated with lower EWB the next day and, when not autonomously motivated, higher pain.

Discussion: Goal engagement can benefit people with or without physical pain, but the motivation behind goal engagement is equally if not more important. Goals motivated by autonomous sources increase EWB and may protect against maladaptive patterns of activity associated with pain.
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http://dx.doi.org/10.1093/geronb/gbab105DOI Listing
June 2021

Anti-tRNA synthetase syndrome interstitial lung disease: A single center experience.

Respir Med 2021 May 4:106432. Epub 2021 May 4.

Vanderbilt University Medical Center, Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Nashville, TN, 37232, USA.

Background: Recognition of Anti-tRNA synthetase (ARS) related interstitial lung disease (ILD) is key to ensuring patients have prompt access to immunosuppressive therapies. The purpose of this retrospective cohort study was to identify factors that may delay recognition of ARS-ILD.

Methods: Patients seen at Vanderbilt University Medical Center between 9/17/2017-10/31/2018 were included in this observational cohort. Clinical and laboratory features were obtained via chart abstraction. Kruskal-Wallis ANOVA, Mann-Whitney U, and Fisher's exact t tests were utilized to determine statistical significance.

Results: Patients with ARS were found to have ILD in 51.9% of cases, which was comparable to the frequency of ILD in systemic sclerosis (59.5%). The severity of FVC reduction in ARS (53.2%) was comparable to diffuse cutaneous systemic sclerosis (56.8%, p = 0.48) and greater than dermatomyositis (66.9%, p = 0.005) or limited cutaneous systemic sclerosis (71.8%, p = 0.005). Frank honeycombing was seen with ARS antibodies but not other myositis autoantibodies. ARS patients were more likely to first present to a pulmonary provider in a tertiary care setting (53.6%), likely due to fewer extrapulmonary manifestations. Only 33% of ARS-ILD were anti-nuclear antibody, rheumatoid factor, or anti-cyclic citrullinated peptide positive. Patients with ARS-ILD had a two-fold longer median time to diagnosis compared to other myositis-ILD patients (11.0 months, IQR 8.5-43 months vs. 5.0 months, IQR 3.0-9.0 months, p = 0.003).

Conclusions: ARS patients without prominent extra-pulmonary manifestations are at high risk for not being recognized as having a connective tissue disease related ILD and miscategorized as usual interstitial pneumonia/idiopathic pulmonary fibrosis without comprehensive serologies.
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http://dx.doi.org/10.1016/j.rmed.2021.106432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8566329PMC
May 2021

Arthritis Care & Research: A Look Back and a View Forward.

Arthritis Care Res (Hoboken) 2021 06;73(6):765-766

Vanderbilt University Medical Center, Nashville, Tennessee.

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http://dx.doi.org/10.1002/acr.24641DOI Listing
June 2021

Eudaemonic Well-Being in Midlife Women: Change in and Correspondence Between Concurrent and Retrospective Reports.

Collabra Psychol 2021 25;7(1). Epub 2021 Mar 25.

Division of Rheumatology and Immunology, Vanderbilt University Medical School.

Concurrent and retrospective reports correspond for personality, affect, and coping. The present study described how autonomy, competence, and relatedness components of eudaemonic well-being (EWB) change over days and months and tested correspondences of daily and retrospective reports between and within people. Midlife and older (50-75 years) women (N = 200) completed online diaries daily for 1 week for 9 bursts over 2 years and answered questionnaires at the end of each burst (burst n = 1,529). Multilevel models partialed levels of variance and tested correspondence. Women varied in their daily experiences of EWB but did not vary substantially between bursts. Burst-level diary means and questionnaire responses corresponded between people, but changes within people were less strongly related. The daily, but not monthly, time scale of change is important for capturing within-person changes in EWB. Finding EWB change over months to years may depend on measurement designed to capture medium-term change.
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http://dx.doi.org/10.1525/collabra.21433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8104436PMC
March 2021

Electronic Delivery of Pain Education for Chronic Overlapping Pain Conditions: A Prospective Cohort Study.

Pain Med 2021 10;22(10):2252-2262

Department of Anesthesiology, University of Michigan, Ann Arbor, Michigan, USA.

Objective: To examine the impact of educational materials for chronic overlapping pain conditions (COPCs), the feasibility of delivering materials online, and to explore its impact on self-reported self-management applications at 3-month follow-up.

Design: Prospective cohort study.

Setting: Online.

Subjects: Individuals from a university-wide active research repository with ≥1 coded diagnostic COPC by ICD-9/10 in the medical record.

Methods: We determined the number of COPCs per participant as indicated by diagnostic codes in the medical record. Consenting participants completed self-report questionnaires and read educational materials. We assessed content awareness and knowledge pre- and post-exposure to education. Comprehension was assessed via embedded questions in reading materials in real time. Participants then completed assessments regarding concept retention, self-management engagement, and pain-related symptoms at 3-months.

Results: N = 216 individuals enrolled, with 181 (84%) completing both timepoints. Results indicated that participants understood materials. Knowledge and understanding of COPCs increased significantly after education and was retained at 3-months. Patient characteristics suggested the number of diagnosed COPCs was inversely related to age. Symptoms or self-management application did not change significantly over the 3-month period.

Conclusions: The educational materials facilitated teaching of key pain concepts in self-management programs, which translated easily into an electronic format. Education alone may not elicit self-management engagement or symptom reduction in this population; however, conclusions are limited by the study's uncontrolled design. Education is likely an important and meaningful first step in comprehensive COPC self-management.
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http://dx.doi.org/10.1093/pm/pnab018DOI Listing
October 2021

Recent Advances in Clinical Translation of Intra-Articular Osteoarthritis Drug Delivery Systems.

Adv Ther (Weinh) 2021 Jan 28;4(1). Epub 2020 Sep 28.

Department of Biomedical Engineering, Vanderbilt University, 5824 Stevenson Center, Nashville, TN 37232, United States.

Osteoarthritis (OA) is a degenerative disease of the joints and a leading cause of physical disability in adults. Intra-articular (IA) therapy is a popular treatment strategy for localized, single-joint OA; however, small-molecule drugs such as corticosteroids do not provide prolonged relief. One possible reason for their lack of efficacy is high clearance rates from the joint through constant lymphatic drainage of the synovial tissues and synovial fluid and also by their exchange via the synovial vasculature. Advanced drug delivery strategies for extended release of therapeutic agents in the joint space is a promising approach to improve outcomes for OA patients. Broadly, the basic principle behind this strategy is to encapsulate therapeutic agents in a polymeric drug delivery system (DDS) for diffusion- and/or degradation-controlled release, whereby degradation can occur by hydrolysis or tied to relevant microenvironmental cues such as pH, reactive oxygen species (ROS), and protease activity. In this review, we highlight the development of clinically tested IA therapies for OA and highlight recent systems which have been investigated preclinically. DDS strategies including hydrogels, liposomes, polymeric microparticles (MPs) and nanoparticles (NPs), drug conjugates, and combination systems are introduced and evaluated for clinical translational potential.
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http://dx.doi.org/10.1002/adtp.202000088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941755PMC
January 2021

Jo-1 autoantigen-specific B cells are skewed towards distinct functional B cell subsets in anti-synthetase syndrome patients.

Arthritis Res Ther 2021 01 19;23(1):33. Epub 2021 Jan 19.

Department of Medicine, Division of Rheumatology and Immunology, Vanderbilt University Medical Center, Medical Center North T3113, 1161 21st Avenue South, Nashville, TN, 37232, USA.

Background: Anti-Jo-1 autoantibodies which recognize histidyl-tRNA synthetase identify patients with the rare rheumatologic disease, anti-histidyl-tRNA synthetase syndrome (Jo-1 ARS), a phenotypically distinct subset of idiopathic inflammatory myopathies (IIM). Jo-1-binding B cells (JBCs) are implicated in disease pathogenesis, yet they have not been studied directly. We therefore aimed to characterize JBCs to better understand how they expand and function in Jo-1 ARS.

Methods: We enrolled 10 IIM patients diagnosed with Jo-1 ARS, 4 patients with non-Jo-1 IIM, and 8 age- and sex-matched healthy controls. We phenotypically characterized peripheral blood mononuclear cells (PBMCs) ex vivo using flow cytometry to define the B cell subsets in which JBCs reside. We further tested their ability to differentiate into antibody-secreting cells following stimulation in vitro.

Results: The majority of JBCs were IgM (not class-switched). Compared to non-JBCs in the same donors, JBCs contained a higher percentage of autoimmune-prone CD21 cells and were increased in the CD21 IgM IgD CD27 memory subset relative to healthy donor B cells. Whereas non-JBCs were present in the anergic B B cell subset, JBCs were nearly absent from this compartment. JBCs were detected among plasmablasts in some donors, but a reduced frequency of JBCs differentiated into CD3824 plasmablasts compared to non-JBCs present in the same wells following in vitro stimulation.

Conclusions: JBCs are enriched for autoimmune-prone CD21 B cells, some of which exhibit a memory phenotype in the peripheral repertoire of Jo-1 ARS patients. JBCs undergo limited class switch and show reduced capacity to differentiate into antibody-secreting cells. This suggests complex B cell biology exists beyond class-switched cells that differentiate to secrete anti-Jo-1 autoantibody (i.e., what is captured through serum autoantibody studies). New Jo-1 ARS therapies should thus ideally target non-class-switched JBCs in addition to those that have undergone IgG class-switching to most effectively block cross-talk with autoreactive T cells.
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http://dx.doi.org/10.1186/s13075-020-02412-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814460PMC
January 2021

Qualitative Analysis of Treatment Needs in Interstitial Cystitis/Bladder Pain Syndrome: Implications for Intervention.

Can J Pain 2020 1;4(1):181-198. Epub 2020 Sep 1.

Department of Medicine, Vanderbilt University School of Medicine.

Background: Interstitial cystitis/bladder pain syndrome (IC/BPS) is a debilitating condition carrying substantial psychosocial burden. Psychological treatment for IC/BPS is little studied, and there are barriers to its use in clinical management. Whether psychological treatments benefit patients with IC/BPS is unclear and we do not know if such treatments would meet patient needs.

Aims: Incorporating patient-reported needs and acknowledging diversity in pain experiences can inform patient-centered interventions for IC/BPS. This project characterized the experience of living with IC/BPS and patient perceptions of needs in its treatment, with the goal of informing patient-centered treatment for IC/BPS.

Methods: Using both quantitative and qualitative methods, 27 females with IC/BPS participated in a focus group and completed validated self-report assessments evaluating urinary symptoms, pain, and emotional functioning. Focus groups were audio recorded and transcribed, then coded and analyzed using an iterative inductive/deductive approach. Linear regression models evaluated the relationship between psychological functioning and symptom severity.

Results: We conducted six focus groups between 8/2017-12/2017. Five major themes emerged from qualitative analysis: managing physical symptoms, emotional symptoms, impact on daily life and socio-contextual factors, responding to illness, and addressing needs in treatment. The physiological and emotional consequences of IC/BPS were reported, highlighting their impact on interpersonal relationships and challenges obtaining appropriate treatment for IC/BPS. Quantitative analysis showed depression levels were significantly associated with worsened IC/BPS symptomology, after controlling for known confounding factors.

Conclusion: Individuals with IC/BPS could benefit from tailored psychological interventions focusing on pain management, emotion regulation, communications skills, along with sexual dysfunction and intimacy fears.
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http://dx.doi.org/10.1080/24740527.2020.1785854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7751614PMC
September 2020

Reduction in movement-evoked pain and fatigue during initial 30-minute transcutaneous electrical nerve stimulation treatment predicts transcutaneous electrical nerve stimulation responders in women with fibromyalgia.

Pain 2021 05;162(5):1545-1555

Department of Physical Therapy and Rehabilitation Science, University of Iowa, Iowa City, IA, United States.

Abstract: We previously showed that 1 month of transcutaneous electrical nerve stimulation (TENS) reduces movement-evoked pain and fatigue in women with fibromyalgia (FM). Using data from this study (Fibromyalgia Activity Study with TENS [FAST]), we performed a responder analysis to identify predictors of clinical improvement in pain and fatigue with TENS, validated these models using receiver operator characteristic, and determined number needed to treat and number needed to harm. Participants were randomly assigned to active-TENS (2-125 Hz; highest-tolerable intensity), placebo-TENS, or no-TENS for 1 month. At the end of the randomized phase, placebo-TENS and no-TENS groups received active-TENS for 1 month. The predictor model was developed using data from the randomized phase for the active-TENS group (n = 103) and validated using data from placebo-TENS and no-TENS groups after active-TENS for 1 month (n = 155). Participant characteristics, initial response to TENS for pain and fatigue, sleep, psychological factors, and function were screened for association with changes in pain or fatigue using a logistic regression model. Predictors of clinical improvement in pain were initial response to pain and widespread pain index (area under the curve was 0.80; 95% confidence interval: 0.73-0.87). Predictors of clinical improvement in fatigue were marital status, sleep impairment, and initial response to TENS (area under the curve was 0.67; 95% confidence interval: 0.58-0.75). Number needed to treat for pain and fatigue ranged between 3.3 and 5.3. Number needed to harm ranged from 20 to 100 for minor TENS-related adverse events. The response to an initial 30-minute TENS treatment predicts who responds to longer-term TENS use in women with FM, making this a clinically useful procedure. Number needed to treat and number needed to harm suggest that TENS is effective and safe for managing pain and fatigue in FM.
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http://dx.doi.org/10.1097/j.pain.0000000000002144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049882PMC
May 2021

Large-Scale Characterization of Systemic Sclerosis Serum Protein Profile: Comparison to Peripheral Blood Cell Transcriptome and Correlations With Skin/Lung Fibrosis.

Arthritis Rheumatol 2021 04 28;73(4):660-670. Epub 2021 Feb 28.

The University of Texas Health Science Center at Houston and McGovern Medical School, Houston.

Objective: To provide a large-scale assessment of serum protein dysregulation in diffuse cutaneous systemic sclerosis (dcSSc) and to investigate serum protein correlates of SSc fibrotic features.

Methods: We investigated serum protein profiles of 66 participants with dcSSc at baseline who were enrolled in the Scleroderma: Cyclophosphamide or Transplant Trial and 66 age- and sex-matched healthy control subjects. A panel of 230 proteins, including several cytokines and chemokines, was investigated. Whole blood gene expression profiling in concomitantly collected samples was performed.

Results: Among the participants with dcSSc, the mean disease duration was 2.3 years. All had interstitial lung disease (ILD), and none were being treated with immunosuppressive agents at baseline. Ninety proteins were differentially expressed in participants with dcSSc compared to healthy control subjects. Similar to previous global skin transcript results, hepatic fibrosis, granulocyte and agranulocyte adhesion, and diapedesis were the top overrepresented pathways. Eighteen proteins correlated with the modified Rodnan skin thickness score (MRSS). Soluble epidermal growth factor receptor was significantly down-regulated in dcSSc and showed the strongest negative correlation with the MRSS, being predictive of the score's course over time, whereas α -antichymotrypsin was significantly up-regulated in dcSSc and showed the strongest positive correlation with the MRSS. Furthermore, higher levels of cancer antigen 15-3 correlated with more severe ILD, based on findings of reduced forced vital capacity and higher scores of disease activity on high-resolution computed tomography. Only 14 genes showed significant differential expression in the same direction in serum protein and whole blood RNA gene expression analyses.

Conclusion: Diffuse cutaneous SSc has a distinct serum protein profile with prominent dysregulation of proteins related to fibrosis and immune cell adhesion/diapedesis. The differential expression for most serum proteins in SSc is likely to originate outside the peripheral blood cells.
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http://dx.doi.org/10.1002/art.41570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005427PMC
April 2021

Machine learning predicts stem cell transplant response in severe scleroderma.

Ann Rheum Dis 2020 12 15;79(12):1608-1615. Epub 2020 Sep 15.

Molecular and Systems Biology, Dartmouth College Geisel School of Medicine, Hanover, New Hampshire, USA

Objective: The Scleroderma: Cyclophosphamide or Transplantation (SCOT) trial demonstrated clinical benefit of haematopoietic stem cell transplant (HSCT) compared with cyclophosphamide (CYC). We mapped PBC (peripheral blood cell) samples from the SCOT clinical trial to scleroderma intrinsic subsets and tested the hypothesis that they predict long-term response to HSCT.

Methods: We analysed gene expression from PBCs of SCOT participants to identify differential treatment response. PBC gene expression data were generated from 63 SCOT participants at baseline and follow-up timepoints. Participants who completed treatment protocol were stratified by intrinsic gene expression subsets at baseline, evaluated for event-free survival (EFS) and analysed for differentially expressed genes (DEGs).

Results: Participants from the fibroproliferative subset on HSCT experienced significant improvement in EFS compared with fibroproliferative participants on CYC (p=0.0091). In contrast, EFS did not significantly differ between CYC and HSCT arms for the participants from the normal-like subset (p=0.77) or the inflammatory subset (p=0.1). At each timepoint, we observed considerably more DEGs in HSCT arm compared with CYC arm with HSCT arm showing significant changes in immune response pathways.

Conclusions: Participants from the fibroproliferative subset showed the most significant long-term benefit from HSCT compared with CYC. This study suggests that intrinsic subset stratification of patients may be used to identify patients with SSc who receive significant benefit from HSCT.
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http://dx.doi.org/10.1136/annrheumdis-2020-217033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8582621PMC
December 2020

Mean Levels and Variability in Psychological Well-Being and Associations With Sleep in Midlife and Older Women.

Ann Behav Med 2021 05;55(5):436-445

Department of Psychology, The University of Kentucky, Lexington, KY, USA.

Background: Disturbed sleep is prevalent in older adulthood and particularly among women. Greater psychological well-being (PWB) is associated with better sleep, but intraindividual variability in PWB has not been examined.

Purpose: The current study examined whether mean levels and variability in PWB were associated with sleep disturbances in midlife and older women.

Methods: Participants (N = 189) completed up to seven daily diaries and an end of the week assessment every 3 months for nine waves. Participants answered questions about their nightly sleep disturbances and reported their PWB using Ryff's six dimensions of PWB.

Results: Regression models indicated that greater variability in one aspect of PWB, positive relations with others, was related to greater sleep disturbance even after adjusting for mean levels of well-being. Greater variability in environmental mastery, purpose in life, and self-acceptance were also associated with sleep disturbance, but these associations were no longer significant after adjusting for mean levels of well-being.

Conclusions: Results suggest that fluctuations in positive relations with others are related to sleep in adult women above and beyond mean levels of well-being. Results highlight the importance of considering variability in addition to mean levels of PWB.
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http://dx.doi.org/10.1093/abm/kaaa069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8427537PMC
May 2021

Characterization of Cortisol Dysregulation in Fibromyalgia and Chronic Fatigue Syndromes: A State-Space Approach.

IEEE Trans Biomed Eng 2020 11 5;67(11):3163-3172. Epub 2020 Mar 5.

Objective: Fibromyalgia syndrome (FMS) and chronic fatigue syndrome (CFS) are complicated medical disorders, with little known etiologies. The purpose of this research is to characterize FMS and CFS by studying the variations in cortisol secretion patterns, timings, amplitudes, the number of underlying pulses, as well as infusion and clearance rates of cortisol.

Methods: Using a physiological state-space model with plausible constraints, we estimate the hormonal secretory events and the physiological system parameters (i.e., infusion and clearance rates).

Results: Our results show that the clearance rate of cortisol is lower in FMS patients as compared to their matched healthy individuals based on a simplified cortisol secretion model. Moreover, the number, magnitude, and energy of hormonal secretory events are lower in FMS patients. During early morning hours, the magnitude and energy of the hormonal secretory events are higher in CFS patients.

Conclusion: Due to lower cortisol clearance rate, there is a higher accumulation of cortisol in FMS patients as compared to their matched healthy subjects. As the FMS patient accumulates higher cortisol residues, internal inhibitory feedback regulates the hormonal secretory events. Therefore, the FMS patients show a lower number, magnitude, and energy of hormonal secretory events. Though CFS patients have the same number of secretory events, they secrete lower quantities during early morning hours. When we compare the results for CFS patients against FMS patients, we observe different cortisol alteration patterns.

Significance: Characterizing CFS and FMS based on the cortisol alteration will help us to develop novel methods for treating these disorders.
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http://dx.doi.org/10.1109/TBME.2020.2978801DOI Listing
November 2020

A System Theoretic Investigation of Cortisol Dysregulation in Fibromyalgia Patients with Chronic Fatigue.

Annu Int Conf IEEE Eng Med Biol Soc 2019 Jul;2019:6896-6901

Fibromyalgia Syndrome (FMS) and Chronic Fatigue Syndrome (CFS) are complex medical conditions with similar symptoms such as anxiety, fatigue, depression, headaches, muscle aches and joint pain. The etiology of both these syndromes is unknown. The objective of this study is to characterize FMS, both in the presence and in the absence of CFS, by analyzing variations in cortisol secretion patterns, timings, amplitudes, and the number of the underlying pulses as well as infusion and clearance rates. The comparison is performed against matched healthy control subjects. We estimate the hormonal secretory events by deconvolving cortisol data using a two-step coordinate descent approach. The first step implements a sparse recovery approach to infer the amplitudes and the timings of the cortisol secretion events from limited cortisol hormone data. The main advantage of this method is estimating the cortisol secretory events using a system theoretic approach. The second step is to estimate the physiological system parameters (i.e. infusion and clearance rates). This approach has been verified on healthy individuals previously. Our results show that the clearance rate of cortisol by the liver is relatively lower in patients as compared to the matched healthy individuals. This suggests that there is a relatively higher accumulation of serum cortisol in patients when compared to matched healthy subjects.
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http://dx.doi.org/10.1109/EMBC.2019.8857427DOI Listing
July 2019

Rule-based and machine learning algorithms identify patients with systemic sclerosis accurately in the electronic health record.

Arthritis Res Ther 2019 12 30;21(1):305. Epub 2019 Dec 30.

Department of Medicine, Vanderbilt University Medical Center, 1161 21st Avenue South T3113 MCN, Nashville, TN, 37232, USA.

Background: Systemic sclerosis (SSc) is a rare disease with studies limited by small sample sizes. Electronic health records (EHRs) represent a powerful tool to study patients with rare diseases such as SSc, but validated methods are needed. We developed and validated EHR-based algorithms that incorporate billing codes and clinical data to identify SSc patients in the EHR.

Methods: We used a de-identified EHR with over 3 million subjects and identified 1899 potential SSc subjects with at least 1 count of the SSc ICD-9 (710.1) or ICD-10-CM (M34*) codes. We randomly selected 200 as a training set for chart review. A subject was a case if diagnosed with SSc by a rheumatologist, dermatologist, or pulmonologist. We selected the following algorithm components based on clinical knowledge and available data: SSc ICD-9 and ICD-10-CM codes, positive antinuclear antibody (ANA) (titer ≥ 1:80), and a keyword of Raynaud's phenomenon (RP). We performed both rule-based and machine learning techniques for algorithm development. Positive predictive values (PPVs), sensitivities, and F-scores (which account for PPVs and sensitivities) were calculated for the algorithms.

Results: PPVs were low for algorithms using only 1 count of the SSc ICD-9 code. As code counts increased, the PPVs increased. PPVs were higher for algorithms using ICD-10-CM codes versus the ICD-9 code. Adding a positive ANA and RP keyword increased the PPVs of algorithms only using ICD billing codes. Algorithms using ≥ 3 or ≥ 4 counts of the SSc ICD-9 or ICD-10-CM codes and ANA positivity had the highest PPV at 100% but a low sensitivity at 50%. The algorithm with the highest F-score of 91% was ≥ 4 counts of the ICD-9 or ICD-10-CM codes with an internally validated PPV of 90%. A machine learning method using random forests yielded an algorithm with a PPV of 84%, sensitivity of 92%, and F-score of 88%. The most important feature was RP keyword.

Conclusions: Algorithms using only ICD-9 codes did not perform well to identify SSc patients. The highest performing algorithms incorporated clinical data with billing codes. EHR-based algorithms can identify SSc patients across a healthcare system, enabling researchers to examine important outcomes.
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http://dx.doi.org/10.1186/s13075-019-2092-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937803PMC
December 2019

Transcutaneous Electrical Nerve Stimulation Reduces Movement-Evoked Pain and Fatigue: A Randomized, Controlled Trial.

Arthritis Rheumatol 2020 05 18;72(5):824-836. Epub 2020 Mar 18.

University of Iowa, Iowa City.

Objective: Fibromyalgia (FM) is characterized by pain and fatigue, particularly during physical activity. Transcutaneous electrical nerve stimulation (TENS) activates endogenous pain inhibitory mechanisms. This study was undertaken to investigate if using TENS during activity would improve movement-evoked pain and other patient-reported outcomes in women with FM.

Methods: Participants were randomly assigned to receive active TENS (n = 103), placebo TENS (n = 99), or no TENS (n = 99) and instructed to use it at home during activity 2 hours each day for 4 weeks. TENS was applied to the lumbar and cervicothoracic regions using a modulated frequency (2-125 Hz) at the highest tolerable intensity. Participants rated movement-evoked pain (primary outcome measure) and fatigue on an 11-point scale before and during application of TENS. The primary outcome measure and secondary patient-reported outcomes were assessed at baseline (time of randomization) and at 4 weeks.

Results: After 4 weeks, a greater reduction in movement-evoked pain was reported in the active TENS group versus the placebo TENS group (group mean difference -1.0 [95% confidence interval -1.8, -0.2]; P = 0.008) and versus the no TENS group (group mean difference -1.8 [95% confidence interval -2.6, -1.0]; P < 0.0001). A reduction in movement-evoked fatigue was also reported in the active TENS group versus the placebo TENS group (group mean difference -1.4 [95% confidence interval -2.4, -0.4]; P = 0.001) and versus the no TENS group (group mean difference -1.9 [95% confidence interval -2.9, -0.9]; P = <0.0001). A greater percentage of the patients in the active TENS group reported improvement on the global impression of change compared to the placebo TENS group (70% versus 31%; P < 0.0001) and the no TENS group (9%; P < 0.0001). There were no TENS-related serious adverse events, and <5% of participants experienced minor adverse events from TENS.

Conclusion: Among women who had FM and were on a stable medication regimen, 4 weeks of active TENS use compared to placebo TENS or no TENS resulted in a significant improvement in movement-evoked pain and other clinical outcomes. Further research is needed to examine effectiveness in a real-world setting to establish the clinical importance of these findings.
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http://dx.doi.org/10.1002/art.41170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188591PMC
May 2020

Optimism and Pain Interference in Aging Women.

Ann Behav Med 2020 02;54(3):202-212

Department of Psychology, University of Kentucky, Lexington, KY, USA.

Background: Pain interferes with people's daily lives and often limits the extent to which they can pursue goals and engage in activities that promote well-being. However, people vary in how much interference they experience at a given level of pain.

Purpose: The present study tested how optimism affects and is affected by pain interference and goal-directed activity among older women.

Methods: Every 3 months for 2 years, community-dwelling middle- and older-age women (N = 199) completed online daily diaries at home for a 7 day period, in which they reported their daily pain, pain interference, and goal-directed activity. Optimism was measured at the start and end of the study. Multilevel models tested the between- and within-person relationships among pain, optimism, and pain interference or goal-directed activity. Linear regression predicted change in optimism over 2 years from pain interference and goal-directed activity.

Results: Pain best predicted pain interference and optimism best predicted goal-directed activity. There were subtle interactions between optimism and pain-predicting interference and goal-directed activity. Accumulated goal-directed activity and pain interference across the study predicted longitudinal changes in optimism, with higher activity and lower pain interference predicting increased optimism over 2 years.

Conclusions: Optimism may play a protective role in disruptions caused by pain on a day-to-day basis, leading to increased goal-directed activity and possibly decreased pain interference. In turn, less interference and more goal-directed activity feed forward into increased optimism, resulting in a virtuous cycle that enhances optimism and well-being among older women.
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http://dx.doi.org/10.1093/abm/kaz040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7309584PMC
February 2020

Prostaglandin regulation of T cell biology.

Pharmacol Res 2019 11 22;149:104456. Epub 2019 Sep 22.

Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.

Prostaglandins (PG) are pleiotropic bioactive lipids involved in the control of many physiological processes, including key roles in regulating inflammation. This links PG to the modulation of the quality and magnitude of immune responses. T cells, as a core part of the immune system, respond readily to inflammatory cues from their environment, and express a diverse array of PG receptors that contribute to their function and phenotype. Here we put in context our knowledge about how PG affect T cell biology, and review advances that bring light into how specific T cell functions that have been newly discovered are modulated through PG. We will also comment on drugs that target PG metabolism and sensing, their effect on T cell function during disease, and we will finally discuss how we can design new approaches that modulate PG in order to maximize desired therapeutic T cell effects.
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http://dx.doi.org/10.1016/j.phrs.2019.104456DOI Listing
November 2019

Reply.

Arthritis Rheumatol 2019 12 21;71(12):2133-2134. Epub 2019 Oct 21.

Vanderbilt University Medical Center, Department of Veterans Affairs Medical Center and Vanderbilt University, Nashville, TN.

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http://dx.doi.org/10.1002/art.41077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8509633PMC
December 2019

Myeloablation followed by autologous stem cell transplantation normalises systemic sclerosis molecular signatures.

Ann Rheum Dis 2019 10 7;78(10):1371-1378. Epub 2019 Aug 7.

Hematologic Malignancy and Cellular Therapy, Duke University, Durham, North Carolina, USA.

Objective: In the randomised scleroderma: Cyclophosphamide Or Transplantation (SCOT trial) (NCT00114530), myeloablation, followed by haematopoietic stem cell transplantation (HSCT), led to improved clinical outcomes compared with monthly cyclophosphamide (CYC) treatment in systemic sclerosis (SSc). Herein, the study aimed to determine global molecular changes at the whole blood transcript and serum protein levels ensuing from HSCT in comparison to intravenous monthly CYC in 62 participants enrolled in the SCOT study.

Methods: Global transcript studies were performed at pretreatment baseline, 8 months and 26 months postrandomisation using Illumina HT-12 arrays. Levels of 102 proteins were measured in the concomitantly collected serum samples.

Results: At the baseline visit, interferon (IFN) and neutrophil transcript modules were upregulated and the cytotoxic/NK module was downregulated in SSc compared with unaffected controls. A paired comparison of the 26 months to the baseline samples revealed a significant decrease of the IFN and neutrophil modules and an increase in the cytotoxic/NK module in the HSCT arm while there was no significant change in the CYC control arm. Also, a composite score of correlating serum proteins with IFN and neutrophil transcript modules, as well as a multilevel analysis showed significant changes in SSc molecular signatures after HSCT while similar changes were not observed in the CYC arm. Lastly, a decline in the IFN and neutrophil modules was associated with an improvement in pulmonary forced vital capacity and an increase in the cytotoxic/NK module correlated with improvement in skin score.

Conclusion: HSCT contrary to conventional treatment leads to a significant 'correction' in disease-related molecular signatures.
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http://dx.doi.org/10.1136/annrheumdis-2019-215770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7167108PMC
October 2019

Response to Wolfe. Letter to the Editor, "Fibromyalgia Criteria".

J Pain 2019 06 26;20(6):741-742. Epub 2019 Feb 26.

Epidemiology Group and Aberdeen Centre for Arthritis and Musculoskeletal Health, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, United Kingdom.

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http://dx.doi.org/10.1016/j.jpain.2019.02.003DOI Listing
June 2019

Posttraumatic Stress Symptoms Mediate the Effects of Trauma Exposure on Clinical Indicators of Central Sensitization in Patients With Chronic Pain.

Clin J Pain 2019 05;35(5):385-393

Department of Psychology, The Ohio State University, Columbus, OH.

Objective: Evidence supports high rates of co-occurrence of posttraumatic stress disorder (PTSD) and chronic pain disorders involving central sensitization (CS). The nature of this relationship, however, remains relatively unexplored. In this study, we aimed to (1) assess how both trauma exposure and current PTSD symptoms are related to clinical manifestations of CS, and (2) test whether PTSD symptoms explain the relationship between trauma exposure and CS. Because experiential avoidance has been shown to impact the relationship between trauma and health outcomes, we (3) explored experiential avoidance as a possible mediator or moderator of the trauma-CS relationship.

Methods: A sample of 202 adult patients (79% female) with chronic pain completed validated self-report measures of trauma exposure, current PTSD symptoms, experiential avoidance, and 3 manifestations of CS: widespread pain, greater pain severity, and polysomatic symptom reporting. We used path analysis and multivariate regression to assess our study aims.

Results: Both trauma exposure and PTSD symptoms were significantly associated with all 3 clinical indicators of CS. PTSD symptoms partially explained the relationship between trauma exposure and widespread pain, pain intensity, and polysomatic symptoms. Experiential avoidance did not mediate or moderate the trauma-CS relationship.

Conclusions: Our findings suggest that trauma exposure is linked to elevated clinical markers of CS but a critical factor in this relationship is the mediating effect of current PTSD symptoms.
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http://dx.doi.org/10.1097/AJP.0000000000000689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6450707PMC
May 2019

Nonsteroidal Anti-inflammatory Drugs Alter the Microbiota and Exacerbate Colitis while Dysregulating the Inflammatory Response.

mBio 2019 01 8;10(1). Epub 2019 Jan 8.

Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA

infection (CDI) is a major public health threat worldwide. The use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with enhanced susceptibility to and severity of CDI; however, the mechanisms driving this phenomenon have not been elucidated. NSAIDs alter prostaglandin (PG) metabolism by inhibiting cyclooxygenase (COX) enzymes. Here, we found that treatment with the NSAID indomethacin prior to infection altered the microbiota and dramatically increased mortality and the intestinal pathology associated with CDI in mice. We demonstrated that in -infected animals, indomethacin treatment led to PG deregulation, an altered proinflammatory transcriptional and protein profile, and perturbed epithelial cell junctions. These effects were paralleled by increased recruitment of intestinal neutrophils and CD4 cells and also by a perturbation of the gut microbiota. Together, these data implicate NSAIDs in the disruption of protective COX-mediated PG production during CDI, resulting in altered epithelial integrity and associated immune responses. infection (CDI) is a spore-forming anaerobic bacterium and leading cause of antibiotic-associated colitis. Epidemiological data suggest that use of nonsteroidal anti-inflammatory drugs (NSAIDs) increases the risk for CDI in humans, a potentially important observation given the widespread use of NSAIDs. Prior studies in rodent models of CDI found that NSAID exposure following infection increases the severity of CDI, but mechanisms to explain this are lacking. Here we present new data from a mouse model of antibiotic-associated CDI suggesting that brief NSAID exposure prior to CDI increases the severity of the infectious colitis. These data shed new light on potential mechanisms linking NSAID use to worsened CDI, including drug-induced disturbances to the gut microbiome and colonic epithelial integrity. Studies were limited to a single NSAID (indomethacin), so future studies are needed to assess the generalizability of our findings and to establish a direct link to the human condition.
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http://dx.doi.org/10.1128/mBio.02282-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6325247PMC
January 2019

mPGES-1-Mediated Production of PGE and EP4 Receptor Sensing Regulate T Cell Colonic Inflammation.

Front Immunol 2018 14;9:2954. Epub 2018 Dec 14.

Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, United States.

PGE is a lipid mediator of the initiation and resolution phases of inflammation, as well as a regulator of immune system responses to inflammatory events. PGE is produced and sensed by T cells, and autocrine or paracrine PGE can affect T cell phenotype and function. In this study, we use a T cell-dependent model of colitis to evaluate the role of PGE on pathological outcome and T-cell phenotypes. CD4 T effector cells either deficient in mPGES-1 or the PGE receptor EP4 are less colitogenic. Absence of T cell autocrine mPGES1-dependent PGE reduces colitogenicity in association with an increase in CD4RORγt cells in the lamina propria. In contrast, recipient mice deficient in mPGES-1 exhibit more severe colitis that corresponds with a reduced capacity to generate FoxP3 T cells, especially in mesenteric lymph nodes. Thus, our research defines how mPGES-1-driven production of PGE by different cell types in distinct intestinal locations impacts T cell function during colitis. We conclude that PGE has profound effects on T cell phenotype that are dependent on the microenvironment.
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http://dx.doi.org/10.3389/fimmu.2018.02954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6302013PMC
October 2019

AAPT Diagnostic Criteria for Fibromyalgia.

J Pain 2019 06 16;20(6):611-628. Epub 2018 Nov 16.

Epidemiology Group and Aberdeen Centre for Arthritis and Musculoskeletal Health, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Scotland, United Kingdom.

Fibromyalgia (FM) is a common chronic pain disorder that presents diagnostic challenges for clinicians. Several classification, diagnostic and screening criteria have been developed over the years, but there continues to be a need to develop criteria that reflect the current understanding of FM and are practical for use by clinicians and researchers. The Analgesic, Anesthetic, and Addiction Clinical Trial Translations Innovations Opportunities and Networks (ACTTION) public-private partnership with the U.S. Food and Drug Administration (FDA) and the American Pain Society (APS) initiated the ACTTION-APS Pain Taxonomy (AAPT) to develop a diagnostic system that would be clinically useful and consistent across chronic pain disorders. The AAPT established an international FM working group consisting of clinicians and researchers with expertise in FM to generate core diagnostic criteria for FM and apply the multidimensional diagnostic framework adopted by AAPT to FM. The process for developing the AAPT criteria and dimensions included literature reviews and synthesis, consensus discussions, and analyses of data from large population-based studies conducted in the United Kingdom. The FM working group established a revised diagnosis of FM and identified risk factors, course, prognosis, and pathophysiology of FM. Future studies will assess the criteria for feasibility, reliability, and validity. Revisions of the dimensions will also be required as research advances our understanding of FM. PERSPECTIVE: The ACTTION-APS FM taxonomy provides an evidence-based diagnostic system for FM. The taxonomy includes diagnostic criteria, common features, comorbidities, consequences, and putative mechanisms. This approach might improve the recognition of FM in clinical practice.
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http://dx.doi.org/10.1016/j.jpain.2018.10.008DOI Listing
June 2019
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