Serum levels of the soluble urokinase plasminogen activator receptor (suPAR) correlates with disease activity in early rheumatoid arthritis and reflects joint damage over time

Abstract

Soluble urokinase plasminogen activator receptor (suPAR) is intensively studied as a biomarker of inflammation and disease outcome in various diseases. In rheumatoid arthritis (RA), suPAR have shown an association with inflammation and swollen joints, but data on suPAR in relation to early disease course and disease progression are lacking. This study investigates the potential of suPAR to predict or reflect disease outcome in early RA. Serum suPAR was measured by enzyme-linked immunosorbent assay at disease onset and after 3 and 36 months in 252 patients from a Swedish prospective observational early RA cohort. Levels and changes of suPAR were analyzed in relation to the 28-joint disease activity score (DAS28) and joint damage according to the Larsen score at inclusion and during follow-up. 100 healthy blood donors served as controls. Circulating levels of suPAR were higher in RA patients at all time points as compared to healthy controls. Baseline suPAR was significantly associated with baseline disease activity whereas suPAR levels at 36 months were associated with joint damage at 36 months. No predictive value of suPAR levels or changes in suPAR levels over time were found. In conclusion, suPAR levels associate with disease activity in early untreated RA and reflects joint damage at later stages. Increased suPAR in established RA could indicate patients in need of frequent monitoring of joint status, irrespective of disease activity. In the view of suPAR as a rapidly emerging biomarker, it is important to be aware of its ability to reflect both inflammation and subsequent damage. (Translational Research 2021; 232:142À149) Abbreviations: ACPA = antiÀcitrullinated protein antibodies; ACR87 = American College of Rheumatology 1987; CCP = citrullinated cyclic peptide; CRP = C-reactive protein; CV = coefficient of variation; DAS28 = 28-joint disease activity score; ELISA = enzyme-linked immunosorbent assay; ESR = erythrocyte sedimentation rate; RF = rheumatoid factor; RA = rheumatoid arthritis; suPAR = soluble urokinase plasminogen activator receptor; uPA = urokinase plasminogen activator

Soluble Urokinase Plasminogen Activator Receptor (suPAR) as a Biomarker of Systemic Chronic Inflammation

“…Likewise, increased suPAR levels are also associated with a wide range of diseases and disorders-non-communicable and infectious diseases alike, Figure 4 and Appendix II. So far suPAR has been shown elevated in cardiovascular disease, including stroke, ischemic heart disease, venous thromboembolism, and incident atrial fibrillation (96, 107, 108); type 1 diabetes and diabetic complications (109,110); incident and manifest type 2 diabetes (76,111,112); different types of cancer (see Figure 4 and Appendix II) (15,(113)(114)(115)(116)(117)(118)(119)(120)(121)(122)(123)(124)(125)(126)(127)(128)(129)(130); rheumatic disease, including rheumatoid arthritis (78,79,131) and systemic lupus erythematosus (22); asthma and chronic obstructive pulmonary disease (132); acute and chronic pancreatitis (115,133); chronic liver disease, including non-alcoholic fatty liver disease and cirrhosis (68,134,135); incident acute kidney injury (136,137) and chronic kidney disease (CKD) (138,139); and dementia (77). As previously mentioned, suPAR is also elevated in infectious diseases caused by v...…”

“…Likewise, increased suPAR levels are also associated with a wide range of diseases and disorders—non-communicable and infectious diseases alike, Figure 4 and Appendix II . So far suPAR has been shown elevated in cardiovascular disease, including stroke, ischemic heart disease, venous thromboembolism, and incident atrial fibrillation ( 96 , 107 , 108 ); type 1 diabetes and diabetic complications ( 109 , 110 ); incident and manifest type 2 diabetes ( 76 , 111 , 112 ); different types of cancer (see Figure 4 and Appendix II ) ( 15 , 113 – 130 ); rheumatic disease, including rheumatoid arthritis ( 78 , 79 , 131 ) and systemic lupus erythematosus ( 22 ); asthma and chronic obstructive pulmonary disease ( 132 ); acute and chronic pancreatitis ( 115 , 133 ); chronic liver disease, including non-alcoholic fatty liver disease and cirrhosis ( 68 , 134 , 135 ); incident acute kidney injury ( 136 , 137 ) and chronic kidney disease (CKD) ( 138 , 139 ); and dementia ( 77 ). As previously mentioned, suPAR is also elevated in infectious diseases caused by viruses, bacteria, and parasites, e.g., coronavirus disease 2019 (COVID-19) ( 37 , 140 ), hepatitis B and C ( 135 , 141 ), human immunodeficiency virus (HIV) ( 142 ), bacteremia ( 143 , 144 ), meningitis ( 17 , 145 ), urinary tract infection ( 88 ), pneumonia ( 71 , 146 ), sepsis ( 23 , 147 ), tuberculosis ( 148 ), malaria ( 149 , 150 ), hantavirus ( 151 ), and Crimean-Congo hemorrhagic fever ( 87 ).…”

Soluble Urokinase Plasminogen Activator Receptor (suPAR) Independently Predicts Severity and Length of Hospitalisation in Patients With COVID-19

“…Apart from urokinase plasminogen activator (uPA, also known as urokinase), uPAR interacts and cooperates with many ligands and receptors, primarily integrins, to facilitate intracellular signalling, cell migration, cell adhesion and tissue remodelling (20). Soluble uPAR (suPAR) results from proteolytic cleavage of uPAR (21), and has gained increased interest as circulating levels are found to reflect severity and prognosticate outcome of several malignant (22)(23)(24)(25)(26), autoimmune (27)(28)(29)(30) and infectious diseases (31)(32)(33)(34)(35)(36)(37). Additionally, suPAR is used in triaging of patients in acute care settings to early predict clinical deterioration due to suspected bacterial infections (38)(39)(40)(41)(42).…”

Targeting the Urokinase-Type Plasminogen Activator Receptor (uPAR) in Human Diseases With a View to Non-invasive Imaging and Therapeutic Intervention

“…Studies on biopsies from arthritic lesions in RA patients by in situ zymography revealed pronounced elevations in uPA activity in the hyperproliferative synovial lining ( Busso et al, 1997 ). Accordingly, these lesions express markedly elevated levels of both uPA and uPAR by infiltrating neutrophils, macrophages, and fibroblast-like cells in the inflamed RA synovium ( Almholt et al, 2018 ) and increased plasma levels of soluble uPAR correlate to disease activity ( Slot et al, 1999 ; Enocsson et al, 2021 ).…”