Medicine and Health Sciences Commons^™

Jak-Stat Signaling And Beyond In The Pathogenesis Of Spondyloarthritis And Their Clinical Significance, Siba P Raychaudhuri, Ruchi J Shah, Sneha Banerjee, Smriti K Raychaudhuri

Student and Faculty Publications

Purpose of Review

Janus kinase–signal transducers and activators of transcription cell signaling proteins (JAK-STATs) play a key regulatory role in functioning of several inflammatory cytokines. JAK-STAT signaling proteins are the key regulators of the cytokine/cytokine receptor system involved in the pathogenesis of various autoimmune disease including spondyloarthritis (SpA). This article mainly highlights the JAK-STAT signaling system, its association with the relevant cytokine/cytokine-receptor system, and its regulatory role in pathogenesis of SpA. Also, we have briefly addressed the principle for the use JAKi in SpA and the current status of use of JAK inhibitors (JAKi) in SpA.

Recent Findings

Recent developments …

Correlational Analysis Of Sarcopenia And Multimorbidity Among Older Inpatients, Wenjing Xia, Kang Luo, Ziwei Gu, Jianping Hu, Xintong Liu, Qian Xiao

Student and Faculty Publications

BACKGROUND: Sarcopenia and multimorbidity are common in older adults, and most of the available clinical studies have focused on the relationship between specialist disorders and sarcopenia, whereas fewer studies have been conducted on the relationship between sarcopenia and multimorbidity. We therefore wished to explore the relationship between the two.

METHODS: The study subjects were older patients (aged ≥ 65 years) who were hospitalized at the Department of Geriatrics of the First Affiliated Hospital of Chongqing Medical University between March 2016 and September 2021. Their medical records were collected. Based on the diagnostic criteria of the Asian Sarcopenia Working Group in …

Mir-574-5p Activates Human Tlr8 To Promote Autoimmune Signaling And Lupus, Tao Wang, Dan Song, Xuejuan Li, Yu Luo, Dianqiang Yang, Xiaoyan Liu, Xiaodan Kong, Yida Xing, Shulin Bi, Yan Zhang, Tao Hu, Yunyun Zhang, Shuang Dai, Zhiqiang Shao, Dahan Chen, Jinpao Hou, Esteban Ballestar, Jianchun Cai, Feng Zheng, James Y Yang

Student and Faculty Publications

Endosomal single-stranded RNA-sensing Toll-like receptor-7/8 (TLR7/8) plays a pivotal role in inflammation and immune responses and autoimmune diseases. However, the mechanisms underlying the initiation of the TLR7/8-mediated autoimmune signaling remain to be fully elucidated. Here, we demonstrate that miR-574-5p is aberrantly upregulated in tissues of lupus prone mice and in the plasma of lupus patients, with its expression levels correlating with the disease activity. miR-574-5p binds to and activates human hTLR8 or its murine ortholog mTlr7 to elicit a series of MyD88-dependent immune and inflammatory responses. These responses include the overproduction of cytokines and interferons, the activation of STAT1 signaling …

Effect Of Aspirin Versus Low-Molecular-Weight Heparin Thromboprophylaxis On Medication Satisfaction And Out-Of-Pocket Costs: A Secondary Analysis Of A Randomized Clinical Trial, Nathan N O'Hara, Katherine P Frey, Deborah M Stein, Joseph F Levy, Gerard P Slobogean, Renan Castillo, Reza Firoozabadi, Madhav A Karunakar, Joshua L Gary, William T Obremskey, Rachel B Seymour, Joseph Cuschieri, C Daniel Mullins, Robert V O'Toole, Metrc

Student and Faculty Publications

BACKGROUND: Current guidelines recommend low-molecular-weight heparin for thromboprophylaxis after orthopaedic trauma. However, recent evidence suggests that aspirin is similar in efficacy and safety. To understand patients' experiences with these medications, we compared patients' satisfaction and out-of-pocket costs after thromboprophylaxis with aspirin versus low-molecular-weight heparin.

METHODS: This study was a secondary analysis of the PREVENTion of CLots in Orthopaedic Trauma (PREVENT CLOT) trial, conducted at 21 trauma centers in the U.S. and Canada. We included adult patients with an operatively treated extremity fracture or a pelvic or acetabular fracture. Patients were randomly assigned to receive 30 mg of low-molecular-weight heparin (enoxaparin) …

Reliability And Validity Of The Promis-29 Health Profile In Ankylosing Spondylitis Patients: A Cross-Sectional Study, Mark C Hwang, Cynthia Bell, Yvette Farran, Alexis Ogdie, Charles Green, John Reveille

Student and Faculty Publications

The Patient-Reported Outcomes Measurement Information System 29-Item Health Profile (PROMIS-29) is a generic measure of health-related quality of life that is not well-studied in Ankylosing Spondylitis (AS) patients. Our objective was to investigate the reliability and validity of the PROMIS-29 in AS. About 169 consecutive AS patients were enrolled from 2017 to 2022 with 167/169 patients fully completing the PROMIS-29 in this cross-sectional study. Test-retest reliability and internal consistency was assessed using intraclass correlation coefficients (ICC) and Cronbach alpha, respectively. We studied structural validity with confirmatory factor analysis (CFA) of our hypothesized and general population models. We evaluated model fit …

Potential Value Of A Rapid Syndromic Multiplex Pcr For The Diagnosis Of Native And Prosthetic Joint Infections: A Real-World Evidence Study., Stéphanie Pascual, Brooklyn Noble, Nusreen Ahmad-Saeed, Catherine Aldridge, Simone Ambretti, Sharon Amit, Rachel Annett, Shaan Ashk O'Shea, Anna Maria Barbui, Gavin Barlow, Lucinda Barrett, Mario Berth, Alessandro Bondi, Nicola Boran, Sara E Boyd, Catarina Chaves, Martin Clauss, Peter Davies, Ileana T Dianzo-Delgado, Jaime Esteban, Stefan Fuchs, Lennart Friis-Hansen, Daniel Goldenberger, Andrej Golle, Juha O Groonroos, Ines Hoffmann, Tomer Hoffmann, Harriet Hughes, Marina Ivanova, Peter Jezek, Gwennan Jones, Zeynep Ceren Karahan, Cornelia Lass-Flörl, Frédéric Laurent, Laura Leach, Matilde Lee Horsbøll Pedersen, Caroline Loiez, Maureen Lynch, Robert J Maloney, Martin Marsh, Olivia Milburn, Shanine Mitchell, Luke S P Moore, Lynn Moffat, Marianna Murdjeva, Michael E Murphy, Deepa Nayar, Giacomo Nigrisoli, Fionnuala O'Sullivan, Büşra Öz, Teresa Peach, Christina Petridou, Mojgan Prinz, Mitja Rak, Niamh Reidy, Gian Maria Rossolini, Anne-Laure Roux, Patricia Ruiz-Garbajosa, Kordo Saeed, Llanos Salar-Vidal, Carlos Salas Venero, Mathyruban Selvaratnam, Eric Senneville, Peter Starzengruber, Ben Talbot, Vanessa Taylor, Rihard Trebše, Deborah Wearmouth, Birgit Willinger, Marjan Wouthuyzen-Bakker, Brianne Couturier, Florence Allantaz

Student and Faculty Publications

Introduction: The BIOFIRE Joint Infection (JI) Panel is a diagnostic tool that uses multiplex-PCR testing to detect microorganisms in synovial fluid specimens from patients suspected of having septic arthritis (SA) on native joints or prosthetic joint infections (PJIs). Methods: A study was conducted across 34 clinical sites in 19 European and Middle Eastern countries from March 2021 to June 2022 to assess the effectiveness of the BIOFIRE JI Panel. Results: A total of 1527 samples were collected from patients suspected of SA or PJI, with an overall agreement of 88.4 % and 85 % respectively between the …

Early Resveratrol Treatment Mitigates Joint Degeneration And Dampens Pain In A Mouse Model Of Pseudoachondroplasia (Psach), Jacqueline T Hecht, Alka C Veerisetty, Debabrata Patra, Mohammad G Hossain, Frankie Chiu, Claire Mobed, Francis H Gannon, Karen L Posey

Student and Faculty Publications

Pseudoachondroplasia (PSACH), a severe dwarfing condition associated with early-onset joint degeneration and lifelong joint pain, is caused by mutations in cartilage oligomeric matrix protein (COMP). The mechanisms underlying the mutant-COMP pathology have been defined using the MT-COMP mouse model of PSACH that has the common D469del mutation. Mutant-COMP protein does not fold properly, and it is retained in the rough endoplasmic reticulum (rER) of chondrocytes rather than being exported to the extracellular matrix (ECM), driving ER stress that stimulates oxidative stress and inflammation, driving a self-perpetuating cycle. CHOP (ER stress signaling protein) and TNFα inflammation drive high levels of mTORC1 …

Conquer Scleroderma: Association Of Gastrointestinal Tract Symptoms In Early Disease With Resource Utilization, Sarah Luebker, Tracy M Frech, Shervin Assassi, Brian Skaug, Jessica K Gordon, Kimberly Lakin, Elana J Bernstein, Yiming Luo, Virginia D Steen, Ami A Shah, Laura K Hummers, Carrie Richardson, Duncan F Moore, Dinesh Khanna, Flavia V Castelino, Lorinda Chung, Puneet Kapoor, Faye N Hant, Victoria K Shanmugam, John M Vanburen, Jessica Alvey, Monica Harding, Ankoor Shah, Ashima Makol, Dorota Lebiedz-Odrobina, Julie K Thomas, Elizabeth R Volkmann, Jerry A Molitor, Nora Sandorfi

Student and Faculty Publications

OBJECTIVES: SSc is associated with increased health-care resource utilization and economic burden. The Collaborative National Quality and Efficacy Registry (CONQUER) is a US-based collaborative that collects longitudinal follow-up data on SSc patients withparticipants.

METHODS: CONQUER participants who had completed a baseline and 12-month Gastrointestinal Tract Questionnaire (GIT 2.0) and a Resource Utilization Questionnaire (RUQ) were included in this analysis. Patients were categorized by total GIT 2.0 severity: none-to-mild (0-0.49); moderate (0.50-1.00), and severe-to-very severe (1.01-3.00). Clinical features and medication exposures were examined in each of these categories. The 12-month RUQ responses were summarized by GIT 2.0 score categories at 12 …

Lowering Of Circulating Sclerostin May Increase Risk Of Atherosclerosis And Its Risk Factors: Evidence From A Genome-Wide Association Meta-Analysis Followed By Mendelian Randomization, Jie Zheng, Eleanor Wheeler, Maik Pietzner, Till F M Andlauer, Michelle S Yau, April E Hartley, Ben Michael Brumpton, Humaira Rasheed, John P Kemp, Monika Frysz, Jamie Robinson, Sjur Reppe, Vid Prijatelj, Kaare M Gautvik, Louise Falk, Winfried Maerz, Ingrid Gergei, Patricia A Peyser, Maryam Kavousi, Paul S De Vries, Clint L Miller, Maxime Bos, Sander W Van Der Laan, Rajeev Malhotra, Markus Herrmann, Hubert Scharnagl, Marcus Kleber, George Dedoussis, Eleftheria Zeggini, Maria Nethander, Claes Ohlsson, Mattias Lorentzon, Nick Wareham, Claudia Langenberg, Michael V Holmes, George Davey Smith, Jonathan H Tobias

Student and Faculty Publications

OBJECTIVE: In this study, we aimed to establish the causal effects of lowering sclerostin, target of the antiosteoporosis drug romosozumab, on atherosclerosis and its risk factors.

METHODS: A genome-wide association study meta-analysis was performed of circulating sclerostin levels in 33,961 European individuals. Mendelian randomization (MR) was used to predict the causal effects of sclerostin lowering on 15 atherosclerosis-related diseases and risk factors.

RESULTS: We found that 18 conditionally independent variants were associated with circulating sclerostin. Of these, 1 cis signal in SOST and 3 trans signals in B4GALNT3, RIN3, and SERPINA1 regions showed directionally opposite signals for sclerostin levels and …

Reduced Digestion Of Circulating Genomic Dna In Systemic Sclerosis Patients With The Dnase1l3 R206c Variant, Brian Skaug, Xinjian Guo, Yuanteng Jeff Li, Julio Charles, Kay T Pham, Jacob Couturier, Dorothy E Lewis, Claudia Bracaglia, Ivan Caiello, Maureen D Mayes, Shervin Assassi

Student and Faculty Publications

OBJECTIVES: Polymorphism in a coding region of deoxyribonuclease I-like III (DNASE1L3), causing amino acid substitution of Arg-206 to Cys (R206C), is a robustly replicated heritable risk factor for SSc and other autoimmune diseases. DNASE1L3 is secreted into the circulation, where it can digest genomic DNA (gDNA) in apoptosis-derived membrane vesicles (AdMVs). We sought to determine the impact of DNASE1L3 R206C on digestion of circulating gDNA in SSc patients and healthy controls (HCs).

METHODS: The ability of DNASE1L3 to digest AdMV-associated gDNA was tested in vitro. The effect of R206C substitution on extracellular secretion of DNASE1L3 was determined using a transfected …

A Novel Comorbidity Score For Older Adults With Non-Hodgkin Lymphoma: The 3-Factor Risk Estimate Scale, Max J Gordon, Zhigang Duan, Hui Zhao, Loretta Nastoupil, Alessandra Ferrajoli, Alexey V Danilov, Sharon H Giordano

Student and Faculty Publications

For patients with non-Hodgkin lymphoma (NHL), formal comorbidity assessment is recommended but is rarely conducted in routine practice. A simple, validated measure of comorbidities that standardizes their assessment could improve adherence to guidelines. We previously constructed the 3-factor risk estimate scale (TRES) among patients with chronic lymphocytic leukemia (CLL). Here, we investigated TRES in multiple NHL subtypes. In the surveillance, epidemiology, and end results-Medicare database, patients with NHL diagnosed from 2008 to 2017 were included. Upper gastrointestinal, endocrine, and vascular comorbidities were identified using ICD-9/ICD-10 codes to assign TRES scores. Patient characteristic distributions were compared using χ2 or t test. …

Quantitative Proteomic Screening Uncovers Candidate Diagnostic And Monitoring Serum Biomarkers Of Ankylosing Spondylitis, Mark Hwang, Shervin Assassi, Jim Zheng, Jessica Castillo, Reyna Chavez, Kamala Vanarsa, Chandra Mohan, John Reveille

Student and Faculty Publications

BACKGROUND: We sought to discover serum biomarkers of ankylosing spondylitis (AS) for diagnosis and monitoring disease activity.

METHODS: We studied biologic-treatment-naïve AS and healthy control (HC) patients' sera. Eighty samples matched by age, gender, and race (1:1:1 ratio) for AS patients with active disease, inactive disease, and HC were analyzed with SOMAscan™, an aptamer-based discovery platform. T-tests tests were performed for high/low-disease activity AS patients versus HCs (diagnosis) and high versus low disease activity (Monitoring) in a 2:1 and 1:1 ratio, respectively, to identify differentially expressed proteins (DEPs). We used the Cytoscape Molecular Complex Detection (MCODE) plugin to find clusters …

Blood Neutrophil Count And Neutrophil-To-Lymphocyte Ratio For Prediction Of Disease Progression And Mortality In Two Independent Systemic Sclerosis Cohorts, Nancy Wareing, Vishnu Mohan, Rana Taherian, Elizabeth R Volkmann, Marka A Lyons, Holly Wilhalme, Michael D Roth, Rosa M Estrada-Y-Martin, Brian Skaug, Maureen D Mayes, Donald P Tashkin, Shervin Assassi

Faculty and Staff Publications

OBJECTIVE: To assess the predictive significance of blood neutrophil count and the ratio between neutrophil and lymphocyte count (neutrophil-to-lymphocyte ratio [NLR]) for disease severity and mortality in systemic sclerosis (SSc).

METHODS: Neutrophil and lymphocyte counts were prospectively measured in the Genetics versus Environment in Scleroderma Outcome Study (GENISOS) and the Scleroderma Lung Study II (SLS II). Forced vital capacity percent predicted (FVC%) and modified Rodnan skin thickness score (MRSS) were used as surrogate measures for disease severity. Longitudinal analyses were performed using generalized linear mixed models. Cox proportional hazards models evaluated the predictive significance of these cell counts for mortality. …

Blood Neutrophil Count And Neutrophil-To-Lymphocyte Ratio For Prediction Of Disease Progression And Mortality In Two Independent Systemic Sclerosis Cohorts, Nancy Wareing, Vishnu Mohan, Rana Taherian, Elizabeth R Volkmann, Marka A Lyons, Holly Wilhalme, Michael D Roth, Rosa M Estrada-Y-Martin, Brian Skaug, Maureen D Mayes, Donald P Tashkin, Shervin Assassi

Faculty and Staff Publications

OBJECTIVE: To assess the predictive significance of blood neutrophil count and the ratio between neutrophil and lymphocyte count (neutrophil-to-lymphocyte ratio [NLR]) for disease severity and mortality in systemic sclerosis (SSc).

METHODS: Neutrophil and lymphocyte counts were prospectively measured in the Genetics versus Environment in Scleroderma Outcome Study (GENISOS) and the Scleroderma Lung Study II (SLS II). Forced vital capacity percent predicted (FVC%) and modified Rodnan skin thickness score (MRSS) were used as surrogate measures for disease severity. Longitudinal analyses were performed using generalized linear mixed models. Cox proportional hazards models evaluated the predictive significance of these cell counts for mortality. …

Risks Of Mortality And Severe Coronavirus Disease 19 (Covid-19) Outcomes In Patients With Or Without Systemic Lupus Erythematosus, Sebastian Bruera, Xiudong Lei, Hui Zhao, Jinoos Yazdany, Mariana Chavez-Macgregor, Sharon H Giordano, Maria E Suarez-Almazor

Student and Faculty Publications

OBJECTIVES: We compared the outcomes of patients with or without systemic lupus erythematosus (SLE) who were diagnosed with coronavirus disease 19 (COVID-19) and evaluated factors within patients with SLE associated with severe outcomes.

METHODS: This retrospective cohort study used the deidentified Optum COVID-19 electronic health record dataset to identify patients with COVID-19 from 1/1/2020 to 31/12/2020. Cases with SLE were matched with general controls at a ratio of 1:10 by age, sex, race and ethnicity and COVID-19 diagnosis date. Outcomes included 30-day mortality, mechanical ventilation, hospitalisation and intensive care unit admission. We evaluated the relationship between COVID-19-related outcomes and SLE …

The Ra-Be-Real Multinational, Prospective, Observational Study In Patients With Rheumatoid Arthritis Receiving Baricitinib, Targeted Synthetic, Or Biologic Disease-Modifying Therapies: A 6-Month Interim Analysis, Rieke Alten, Gerd R Burmester, Marco Matucci-Cerinic, Jean-Hugues Salmon, Pedro Lopez-Romero, Walid Fakhouri, Inmaculada De La Torre, Liliana Zaremba-Pechmann, Thorsten Holzkämper, Bruno Fautrel

Student and Faculty Publications

INTRODUCTION: RA-BE-REAL has the overall aim of defining a profile of patients with rheumatoid arthritis (RA) starting baricitinib or any other targeted synthetic (ts) or any biologic (b) disease-modifying antirheumatic drug (DMARD) for the first time, and the primary objective of estimating time until discontinuation from any cause (excluding sustained response) of the initial treatment.

METHODS: RA-BE-REAL is an ongoing, prospective, observational, 36-month study in patients with RA initiating treatment with baricitinib (cohort A) or any other tsDMARD or any bDMARD (cohort B) for the first time. The primary objective is to assess the time until treatment discontinuation from any …

Challenges And Promise Of Targeting Mirrna In Rheumatic Diseases: A Computational Approach To Identify Mirna Association With Cell Types, Cytokines, And Disease Mechanisms, Farheen S Shaikh, Ruby J Siegel, Aayush Srivastava, David A Fox, Salahuddin Ahmed

Student and Faculty Publications

MicroRNAs (miRNAs) are small non-coding RNAs that alter the expression of target genes at the post-transcriptional level, influencing diverse outcomes in metabolism, cell differentiation, proliferation, cell survival, and cell death. Dysregulated miRNA expression is implicated in various rheumatic conditions, including ankylosing spondylitis (AS), gout, juvenile idiopathic arthritis (JIA), osteoarthritis (OA), psoriatic arthritis, rheumatoid arthritis (RA), Sjogren's syndrome, systemic lupus erythematosus (SLE) and systemic sclerosis. For this review, we used an open-source programming language- PowerShell, to scan the massive number of existing primary research publications on PubMed on miRNAs in these nine diseases to identify and count unique co-occurrences of individual …

High-Frequency Ultrasound In Patients With Seronegative Rheumatoid Arthritis, Junkui Wang, Miao Wang, Qinghua Qi, Zhibin Wu, Jianguo Wen

Student and Faculty Publications

This study aimed to investigate the value of high-frequency ultrasound (HFUS) in differentiation of the seronegative rheumatoid arthritis (SNRA) and osteoarthritis (OA) and in the diagnosis of SNRA. 83 patients diagnosed with SNRA (SNRA group) and 40 diagnosed with OA (OA group) who received HFUS were retrospectively analyzed. The grayscale (GS) scores, power Doppler (PD) scores, and bone erosion (BE)scores were recorded, and added up to calculate the total scores of US variables. The correlations of the total scores of US variables with the 28-joint disease activity score (DAS28), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were analyzed. The …

False Positive Anti-Topoisomerase I (Scl-70) Antibody Results In Clinical Practice: A Case Series From A Scleroderma Referral Center, Brian H Lam, Shervin Assassi, Julio Charles, Rana Taherian, Marka A Lyons, Bochra Jandali, Maureen D Mayes, Brian Skaug

Faculty and Staff Publications

PURPOSE: To determine if some patients who tested positive for anti-Scl-70 antibody in clinical practice, but did not have classifiable systemic sclerosis, were negative for anti-Scl-70 antibody by the more specific immunodiffusion method of testing.

METHODS: Patients evaluated by a rheumatologist at a Scleroderma referral center who had tested positive for anti-Scl-70 antibody prior to referral, but did not have classifiable SSc based on clinical criteria, were invited to undergo testing for anti-Scl-70 antibody by immunodiffusion. Patient demographics and clinical features were recorded at the time of their evaluation, and diagnostic testing results were reviewed using the medical records.

RESULTS: …

Biological Treatment Usage In Patients With Hiv And Rheumatic Disease, 2003-2021: Long-Term Safety And Follow-Up, Benjamin Sornrung Naovarat, Gloria Salazar, Mariko Ishimori, Francis M Williams, John D Reveille

Faculty and Staff Publications

OBJECTIVE: This study examined the safety and efficacy of biological agents, especially tumour necrosis factor (TNF) inhibitors, for HIV-positive rheumatology patients refractory to standard therapy.

METHODS: This study is a retrospective case series including patients derived from a community HIV clinic as well as from two academic centres. Initial visit data collected included: sociodemographic characteristics, CD4 counts, HIV viral load and medication use. Patients with persistent disease activity despite standard conservative therapy were begun on biological agents.The main outcomes were patient and physician global assessment of treatment response and medication side effects in patients with rheumatological disorders treated with biological …

Perifollicular Hypopigmentation In Systemic Sclerosis: Associations With Clinical Features And Internal Organ Involvement, Melody P Chung, Christopher A Mecoli, Jamie Perin, Carrie Richardson, Zsuzsanna H Mcmahan

Faculty and Staff Publications

OBJECTIVE: To determine whether perifollicular hypopigmentation in systemic sclerosis (SSc) is associated with demographics, distinct clinical features, and autoantibody profiles.

METHODS: Patients with SSc were prospectively enrolled, with a standardized data form used to collect anatomic distribution of perifollicular hypopigmentation. Associations between hypopigmentation and features of SSc were assessed.

RESULTS: Of 179 adult patients with SSc, 36 (20%) patients had perifollicular hypopigmentation. Of these 36 patients, 94% (n = 34) were female and 33% (n = 12) had limited cutaneous SSc. In univariable logistic regression, Black race (odds ratio [OR] 15.63, 95% CI 6.6-37.20,

CONCLUSION: Perifollicular hypopigmentation is observed in …

The Need For Space To Plan The Future For Spondyloarthritis, Mark Hwang, Michael H Weisman

Faculty and Staff Publications

No abstract provided.