{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T12:56:57Z","timestamp":1770987417211,"version":"3.50.1"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,11,18]],"date-time":"2021-11-18T00:00:00Z","timestamp":1637193600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Secondary hemophagocytic lymphohistiocytosis (sHLH) is a rare but fatal complication in idiopathic inflammatory myopathy (IIM) patients. The clinical value of radiological manifestations and serum cytokines remain unknown in this systemic crisis. This study aims to investigate the clinical value of PET\/CT scan and cytokine profiles in predicting and understanding sHLH in IIM patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Adult IIM patients who were admitted to the four divisions of the First Affiliated Hospital, Zhejiang University School of Medicine (FAHZJU) from January 1, 2017 to December 31, 2020 were reviewed. PET\/CT scan, cytokine profiles, and other factors of patients who met the inclusion and exclusion criteria were collected and analyzed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Sixty-nine out of 352 IIM patients were finally enrolled into the study. Ten patients developed sHLH and 70.0% of them died within 6 months. After false discovery rate (FDR) correction and multivariate logistic regression analysis, increased serum interferon (IFN)-\u03b3 level (<jats:italic>p<\/jats:italic> = 0.017), higher spleen mean standard uptake value (SUVmean, <jats:italic>p<\/jats:italic> = 0.035), and positivity of anti-MDA5 antibody (<jats:italic>p<\/jats:italic> = 0.049) were found to be significantly correlated with development of sHLH in IIM patients. The combination of serum IFN-\u03b3, spleen SUVmean, and anti-MDA5 antibody found a balanced and satisfying predictor with a cutoff value of 0.047 and AUC of 0.946. A moderate correlation was identified between ferritin and spleen SUVmean (<jats:italic>p<\/jats:italic> = 0.001, <jats:italic>r<\/jats:italic> = 0.380) as well as serum IFN-\u03b3(<jats:italic>p<\/jats:italic> = 0.001, <jats:italic>r<\/jats:italic> = 0.398). Before FDR correction, higher bilateral lung SUVmean (<jats:italic>p<\/jats:italic> = 0.034) and higher colon\/rectum SUVmean (<jats:italic>p<\/jats:italic> = 0.013) were also observed in IIM patients who developed sHLH. By narrowing down to IIM patients with sHLH, anti-MDA5-antibody-positive DM patients tended to suffer from unfavorable outcome (<jats:italic>p<\/jats:italic> = 0.004) in Kaplan\u2013Meier survival analysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Increased serum level of IFN-\u03b3, elevated splenic FDG uptake, and positivity of anti-MDA5 antibody were significantly correlated with development of sHLH in IIM patients. Lung and lower digestive tract might also be affected due to systemic immune activation in IIM patients with sHLH. In addition, splenic FDG uptake, in combination with serum IFN-\u03b3and anti-MDA5 antibody, was found valuable in predicting development of sHLH in IIM patients. Among IIM patients with sHLH, anti-MDA5-antibody-positive DM patients showed higher tendency for unfavorable outcome.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2021.745211","type":"journal-article","created":{"date-parts":[[2021,11,18]],"date-time":"2021-11-18T07:12:50Z","timestamp":1637219570000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["Clinical Value of 18F-FDG PET\/CT Scan and Cytokine Profiles in Secondary Hemophagocytic Lymphohistiocytosis in Idiopathic Inflammatory Myopathy Patients: A Pilot Study"],"prefix":"10.3389","volume":"12","author":[{"given":"Junyu","family":"Liang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heng","family":"Cao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bowen","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yinuo","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ye","family":"He","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bei","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yiduo","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bingjue","family":"Ye","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jin","family":"Lin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,11,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2019000761","article-title":"Mechanisms of Action of Ruxolitinib in Murine Models of Hemophagocytic Lymphohistiocytosis","volume":"134","author":"Albeituni","year":"2019","journal-title":"Blood"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2020008206","article-title":"Contribution of Clonal Hematopoiesis to Adult-Onset Hemophagocytic Lymphohistiocytosis","volume":"136","author":"Miller","year":"2020","journal-title":"Blood"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2020008738","article-title":"RhoG Deficiency Abrogates Cytotoxicity of Human Lymphocytes and Causes Hemophagocytic Lymphohistiocytosis","volume":"137","author":"Kalinichenko","year":"2021","journal-title":"Blood"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/S2352-3026(19)30156-5","article-title":"Ruxolitinib in Adult Patients With Secondary Haemophagocytic Lymphohistiocytosis: An Open-Label, Single-Centre, Pilot Trial","volume":"6","author":"Ahmed","year":"2019","journal-title":"Lancet Haematol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.semarthrit.2015.07.004","article-title":"Infection is the Major Trigger of Hemophagocytic Syndrome in Adult Patients Treated With Biological Therapies","volume":"45","author":"Brito-Zeron","year":"2016","journal-title":"Semin Arthritis Rheum"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/S2665-9913(20)30096-5","article-title":"Silencing the Cytokine Storm: The Use of Intravenous Anakinra in Haemophagocytic Lymphohistiocytosis or Macrophage Activation Syndrome","volume":"2","author":"Mehta","year":"2020","journal-title":"Lancet Rheumatol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1016\/j.semarthrit.2020.12.007","article-title":"Understanding of Cytokines and Targeted Therapy in Macrophage Activation Syndrome","volume":"51","author":"Tang","year":"2021","journal-title":"Semin Arthritis Rheum"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2020-217470","article-title":"Monocyte and Bone Marrow Macrophage Transcriptional Phenotypes in Systemic Juvenile Idiopathic Arthritis Reveal TRIM8 as a Mediator of IFN-Gamma Hyper-Responsiveness and Risk for Macrophage Activation Syndrome","volume":"80","author":"Schulert","year":"2020","journal-title":"Ann Rheum Dis"},{"key":"B9","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1136\/annrheumdis-2020-217139","article-title":"EULAR Points to Consider for the Diagnosis and Management of Rheumatic Immune-Related Adverse Events Due to Cancer Immunotherapy With Checkpoint Inhibitors","volume":"80","author":"Kostine","year":"2021","journal-title":"Ann Rheum Dis"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2019-216599","article-title":"Machine Learning Algorithms Reveal Unique Gene Expression Profiles in Muscle Biopsies From Patients With Different Types of Myositis","volume":"79","author":"Pinal-Fernandez","year":"2020","journal-title":"Ann Rheum Dis"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keab001","article-title":"High Early Mortality in Idiopathic Inflammatory Myopathies: Results From the Inception Cohort at a Tertiary Care Center in Northern India","volume":"60","author":"Mehta","year":"2021","journal-title":"Rheumatol (Oxford)"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1007\/s00296-020-04590-9","article-title":"Macrophage Activation Syndrome in Adult Dermatomyositis: A Case-Based Review","volume":"40","author":"Kishida","year":"2020","journal-title":"Rheumatol Int"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.190542","article-title":"Hemophagocytic Lymphohistiocytosis: Prevalence, Risk Factors, Outcome, and Outcome-Related Factors in Adult Idiopathic Inflammatory Myopathies","volume":"47","author":"Liang","year":"2020","journal-title":"J Rheumatol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1080\/10428194.2017.1379079","article-title":"PET-CT in AML-Related Hemophagocytic Lymphohistiocytosis","volume":"59","author":"Boddu","year":"2018","journal-title":"Leuk Lymphoma"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpeds.2021.02.008","article-title":"Sudden Hypotension and Increased Serum Interferon-Gamma and Interleukin-10 Predict Early Macrophage Activation Syndrome in Patients With Systemic Juvenile Idiopathic Arthritis","volume":"235","author":"Guo","year":"2021","journal-title":"J Pediatr"},{"key":"B16","doi-asserted-by":"publisher","first-page":"99","DOI":"10.3899\/jrheum.181222","article-title":"Effect of Treatment on Imaging, Clinical, and Serologic Assessments of Disease Activity in Large-Vessel Vasculitis","volume":"47","author":"Banerjee","year":"2020","journal-title":"J Rheumatol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1007\/s11926-019-0864-3","article-title":"PET Scan: Nuclear Medicine Imaging in Myositis","volume":"21","author":"Selva-O\u2019Callaghan","year":"2019","journal-title":"Curr Rheumatol Rep"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keq133","article-title":"Distinct Cytokine Profiles of Systemic-Onset Juvenile Idiopathic Arthritis-Associated Macrophage Activation Syndrome With Particular Emphasis on the Role of Interleukin-18 in its Pathogenesis","volume":"49","author":"Shimizu","year":"2010","journal-title":"Rheumatol (Oxford)"},{"key":"B19","doi-asserted-by":"publisher","first-page":"e90","DOI":"10.1136\/annrheumdis-2017-212774","article-title":"Performance of the 2017 European League Against Rheumatism\/American College of Rheumatology Classification Criteria for Adult and Juvenile Idiopathic Inflammatory Myopathies in Clinical Practice","volume":"77","author":"Hocevar","year":"2018","journal-title":"Ann Rheum Dis"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/kez185","article-title":"Successful Classification of Macrophage-Mannose Receptor CD206 in Severity of Anti-MDA5 Antibody Positive Dermatomyositis Associated ILD","volume":"58","author":"Horiike","year":"2019","journal-title":"Rheumatol (Oxford)"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.rmed.2016.10.019","article-title":"Comprehensive Assessment of Myositis-Specific Autoantibodies in Polymyositis\/Dermatomyositis-Associated Interstitial Lung Disease","volume":"121","author":"Hozumi","year":"2016","journal-title":"Respir Med"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/kex188","article-title":"Clinical Characteristics and Change in the Antibody Titres of Patients With Anti-MDA5 Antibody-Positive Inflammatory Myositis","volume":"56","author":"Abe","year":"2017","journal-title":"Rheumatol (Oxford)"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.200941","article-title":"Efficacy of Moderately Dosed Etoposide in Macrophage Activation Syndrome-Hemophagocytic Lymphohistiocytosis","volume":"48","author":"Horne","year":"2021","journal-title":"J Rheumatol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1007\/s00277-013-1906-y","article-title":"Clinical Implication of F-18 FDG PET\/CT in Patients With Secondary Hemophagocytic Lymphohistiocytosis","volume":"93","author":"Kim","year":"2014","journal-title":"Ann Hematol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/ket112","article-title":"[18f]FDG Uptake in Proximal Muscles Assessed by PET\/CT Reflects Both Global and Local Muscular Inflammation and Provides Useful Information in the Management of Patients With Polymyositis\/Dermatomyositis","volume":"52","author":"Tanaka","year":"2013","journal-title":"Rheumatol (Oxford)"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(13)61048-X","article-title":"Adult Haemophagocytic Syndrome","volume":"383","author":"Ramos-Casals","year":"2014","journal-title":"Lancet"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1007\/s00259-020-05103-3","article-title":"Assessing Immune Organs on (18)F-FDG PET\/CT Imaging for Therapy Monitoring of Immune Checkpoint Inhibitors: Inter-Observer Variability, Prognostic Value and Evolution During the Treatment Course of Melanoma Patients","volume":"48","author":"Prigent","year":"2021","journal-title":"Eur J Nucl Med Mol Imaging"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1038\/cmi.2011.47","article-title":"Bone Marrow and the Control of Immunity","volume":"9","author":"Zhao","year":"2012","journal-title":"Cell Mol Immunol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.00119","article-title":"The Immunology of Macrophage Activation Syndrome","volume":"10","author":"Crayne","year":"2019","journal-title":"Front Immunol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.chest.2015.11.004","article-title":"Pulmonary Involvement in Patients With Hemophagocytic Lymphohistiocytosis","volume":"149","author":"Seguin","year":"2016","journal-title":"Chest"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2020-218048","article-title":"Lung Involvement in Macrophage Activation Syndrome and Severe COVID-19: Results From a Cross-Sectional Study to Assess Clinical, Laboratory and Artificial Intelligence-Radiological Differences","volume":"79","author":"Ruscitti","year":"2020","journal-title":"Ann Rheum Dis"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1002\/art.41075","article-title":"Proinflammatory Histidyl-Transfer RNA Synthetase-Specific CD4+ T Cells in the Blood and Lungs of Patients With Idiopathic Inflammatory Myopathies","volume":"72","author":"Galindo-Feria","year":"2020","journal-title":"Arthritis Rheumatol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.02764","article-title":"Dynamics of Colon Monocyte and Macrophage Activation During Colitis","volume":"9","author":"Jones","year":"2018","journal-title":"Front Immunol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-019-0415-0","article-title":"Targeting Immune Cell Circuits and Trafficking in Inflammatory Bowel Disease","volume":"20","author":"Neurath","year":"2019","journal-title":"Nat Immunol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1007\/s12519-019-00299-3","article-title":"Dilemmas in Diagnosis and Management of Hemophagocytic Lymphohistiocytosis in Children","volume":"16","author":"Xu","year":"2020","journal-title":"World J Pediatr"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcrc.2017.02.018","article-title":"Cytokine Profiles as Novel Diagnostic Markers of Epstein-Barr Virus-Associated Hemophagocytic Lymphohistiocytosis in Children","volume":"39","author":"Han","year":"2017","journal-title":"J Crit Care"},{"key":"B37","article-title":"Analysis of Cytokine Risk Factors in the Early Death of Patients With Secondary Phagocytic Lymphocytic Histiocytosis","volume":"13","author":"Li","year":"2021","journal-title":"Am J Transl Res"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.03089","article-title":"Natural Killer Cells in Systemic Autoinflammatory Diseases: A Focus on Systemic Juvenile Idiopathic Arthritis and Macrophage Activation Syndrome","volume":"10","author":"Vandenhaute","year":"2019","journal-title":"Front Immunol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2020007930","article-title":"JAK Inhibition for Murine HLH Requires Complete Blockade of IFNg Signaling and is Limited by Toxicity of JAK2 Inhibition","volume":"138","author":"Chaturvedi","year":"2021","journal-title":"Blood"},{"key":"B40","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1186\/s12890-020-01226-3","article-title":"Serum Levels of Interleukins and S100A8\/A9 Correlate With Clinical Severity in Patients With Dermatomyositis-Associated Interstitial Lung Disease","volume":"20","author":"Lou","year":"2020","journal-title":"BMC Pulm Med"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/kez301","article-title":"Exploration of Pathomechanism Using Comprehensive Analysis of Serum Cytokines in Polymyositis\/Dermatomyositis-Interstitial Lung Disease","volume":"59","author":"Matsuda","year":"2020","journal-title":"Rheumatol (Oxford)"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2003.017715","article-title":"Altered Cytokine Expression of Peripheral Blood Lymphocytes in Polymyositis and Dermatomyositis","volume":"64","author":"Aleksza","year":"2005","journal-title":"Ann Rheum Dis"},{"key":"B43","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1186\/s13075-018-1737-2","article-title":"Relevance of Interferon-Gamma in Pathogenesis of Life-Threatening Rapidly Progressive Interstitial Lung Disease in Patients With Dermatomyositis","volume":"20","author":"Ishikawa","year":"2018","journal-title":"Arthritis Res Ther"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1097\/BOR.0000000000000526","article-title":"Systemic Juvenile Idiopathic Arthritis and Macrophage Activation Syndrome: Update on Pathogenesis and Treatment","volume":"30","author":"Yasin","year":"2018","journal-title":"Curr Opin Rheumatol"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1007\/s00296-019-04398-2","article-title":"Clinical Spectrum and Therapeutics in Canadian Patients With Anti-Melanoma Differentiation-Associated Gene 5 (MDA5)-Positive Dermatomyositis: A Case-Based Review","volume":"39","author":"Huang","year":"2019","journal-title":"Rheumatol Int"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/j.semarthrit.2020.10.014","article-title":"Myositis-Specific and Myositis-Associated Autoantibodies in a Large Indian Cohort of Inflammatory Myositis","volume":"51","author":"Gupta","year":"2021","journal-title":"Semin Arthritis Rheum"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1016\/j.semarthrit.2020.03.007","article-title":"Recommendations for the Treatment of Anti-Melanoma Differentiation-Associated Gene 5-Positive Dermatomyositis-Associated Rapidly Progressive Interstitial Lung Disease","volume":"50","author":"Romero-Bueno","year":"2020","journal-title":"Semin Arthritis Rheum"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1155\/2020\/7948095","article-title":"Increased Levels of Soluble CD206 Associated With Rapidly Progressive Interstitial Lung Disease in Patients With Dermatomyositis","volume":"2020","author":"Shen","year":"2020","journal-title":"Mediators Inflammation"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keaa034","article-title":"Clinical Significance of Radiological Patterns of HRCT and Their Association With Macrophage Activation in Dermatomyositis","volume":"59","author":"Zuo","year":"2020","journal-title":"Rheumatol (Oxford)"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keab371","article-title":"Antiviral Proinflammatory Phenotype of Monocytes in Anti-MDA5 Antibody-Associated Interstitial Lung Disease","author":"Gono","year":"2021","journal-title":"Rheumatol (Oxford)"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.180825","article-title":"Clinical Significance of Serum Chitotriosidase Level in Anti-MDA5 Antibody-Positive Dermatomyositis-Associated Interstitial Lung Disease","volume":"46","author":"Fujisawa","year":"2019","journal-title":"J Rheumatol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.745211\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,18]],"date-time":"2021-11-18T07:12:56Z","timestamp":1637219576000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.745211\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,18]]},"references-count":51,"alternative-id":["10.3389\/fimmu.2021.745211"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.745211","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,18]]},"article-number":"745211"}}