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Pentraxin-3 (PTX3) is a component of humoral innate immunity with essential functions both in promotion and resolution of inflammation. We aimed to study the PTX3 in the plasma and in the muscle of patients with idiopathic inflammatory myopathies (IIM) and whether PTX3 may correlate with disease activity. Plasma PTX3 levels were assessed in 20 patients with IIMs, 10 dermatomyositis (DM), and 10 polymyositis (PM), compared to 10 patients with rheumatoid arthritis (RA) and 10 healthy donors (HDs) aged, sex, and body mass index matched. Disease activity in IIMs was assessed by Myositis Disease Activity Assessment Visual Analog Scale (MYOACT), while disease activity score on 28 joints (DAS28) was used for RA patients. Muscle histopathology and immunohistochemical (IHC) analyses were also performed. Mean plasma PTX3 levels were significantly higher in IIM patients than HDs (518 ± 260 pg/ml vs. 275 ± 114 pg/ml, P = 0.009). Linear regression analysis adjusted for age, sex, and disease duration showed a direct correlation between PTX3 and CPK levels (β: 0.590), MYOACT (β: 0.759), and physician global assessment of disease activity (β: 0.832) in IIMs. No association between PTX3 levels and DAS28 was found in RA. Global PTX3 pixel fraction was higher in IIM than HDs muscle, but a lower PTX3 expression was found in perifascicular areas of DM and in myofibers with sarcolemmal staining for membrane attack complement. PTX3 plasma levels were increased in IIMs and correlated with disease activity suggesting a possible role as biomarker of disease activity. PTX3 showed a different distribution in DM or PM muscle. Pentraxin-3 (PTX3), an inflammatory protein produced by different cell types in loco, correlates with global disease activity in idiopathic inflammatory myopathies (IIMs). In muscle histology, we observed a higher expression of PTX3 within the sarcoplasm of type 2 fast-twitch myofibers, mainly in IIMs muscles. [ABSTRACT FROM AUTHOR]