Observational Study

. 2023 Nov;9(4):e003419.

doi: 10.1136/rmdopen-2023-003419.

Derivation and validation of four patient clusters in Still's disease, results from GIRRCS AOSD-study group and AIDA Network Still Disease Registry

Piero Ruscitti¹, Francesco Masedu², Antonio Vitale^{3

4}, Ilenia Di Cola², Valeria Caggiano^{3

4}, Claudia Di Muzio², Paola Cipriani², Marco Valenti², Onorina Berardicurti^{5

6}, Luca Navarini^{5

6}, Daniela Iacono⁷, Ilenia Pantano⁷, Daniele Mauro⁷, Francesco Ciccia⁷, Silvia Rossi⁸, Ludovico De Stefano⁸, Sara Monti⁸, Serena Bugatti⁸, Carlomaurizio Montecucco⁸, Francesco Caso⁹, Luisa Costa⁹, Marcella Prete¹⁰, Federico Perosa¹⁰, Annamaria Iagnocco¹¹, Fabiola Atzeni¹², Giuliana Guggino¹³, Henrique Giardini¹⁴, Isabele Parente de Brito Antonelli¹⁴, Ibrahim A Almaghlouth^{15

16}, Kazi Asfina^{15

16}, Haner Direskeneli¹⁷, Fatma Alibaz-Oner¹⁷, Gizem Sevik¹⁷, Abdurrahman Tufan¹⁸, Petros P Sfikakis¹⁹, Francesco La Torre²⁰, Andrea Hinojosa-Azaola²¹, Eduardo Martín-Nares²¹, Jiram Torres-Ruiz²¹, Gafaar Ragab^{22

23}, Maria Cristina Maggio²⁴, Joanna Makowska²⁵, Emanuela Del Giudice²⁶, Elena Bartoloni²⁷, Giacomo Emmi^{28

29}, Marcello Govoni³⁰, Alberto Lo Gullo³¹, Giuseppe Lopalco³², Gabriele Simonini³³, Lampros Fotis³⁴, Benson Ogunjimi^{35

36

37

38}, Samar Tharwat^{39

40}, Bruno Frediani^{3

4}, Armin Maier⁴¹, Francesco Carubbi⁴², Lorenzo Dagna^{43

44}, Sukran Erten⁴⁵, Antonio Gidaro⁴⁶, José Hernández-Rodríguez⁴⁷, Paolo Sfriso⁴⁸, Claudia Fabiani⁴⁹, Roberto Giacomelli^{5

6}, Luca Cantarini^{3

4}

Affiliations

¹ Rheumatology Unit, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy piero.ruscitti@univaq.it.
² Rheumatology Unit, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy.
³ UOC Reumatologia, Azienda Ospedaliero-Universitaria Senese, ERN-RITA Center, Siena, Italy.
⁴ Department of Medical Sciences, Surgery and Neurosciences, Research Center of Systemic Autoinflammatory Diseases and Behçet's Disease Clinic University of Siena, Siena, Italy.
⁵ Rheumatology and Clinical Immunology, Department of Medicine, University of Rome "Campus Biomedico", School of Medicine, Rome, Italy.
⁶ Clinical and Research Section of Rheumatology and Clinical Immunology, Fondazione Policlinico Campus Bio-Medico, Rome, Italy.
⁷ Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy.
⁸ Rheumatology Department, Istituto di ricovero e cura a carattere scientifico Policlinico S. Matteo Fondazione, University of Pavia, Pavia, Italy.
⁹ Rheumatology Unit, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy.
¹⁰ Rheumatic and Systemic Autoimmune Diseases Unit, Department of Interdisciplinary Medicine (DIM), University of Bari Medical School, Bari, Italy.
¹¹ Academic Rheumatology Centre, Ospedale Mauriziano - Dipartimento Scienze Cliniche e Biologiche, Università degli Studi di Torino, Turin, Italy.
¹² Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.
¹³ Rheumatology Section, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University Hospital P. Giaccone, Palermo, Italy.
¹⁴ Rheumatology Division, Faculdade de Medicina, Hospital das Clínicas, Universidade de São Paulo, São Paulo, Brazil.
¹⁵ Rheumatology Unit, Department of Medicine, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
¹⁶ College of Medicine Research Center, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
¹⁷ Department of Internal Medicine, Division of Rheumatology, Marmara University, School of Medicine, Istanbul, Turkey.
¹⁸ Division of Rheumatology, Department of Internal Medicine, Gazi University Faculty of Medicine, Ankara, Turkey.
¹⁹ Joint Academic Rheumatology Program, National and Kapodistrian University of Athens Medical School, Athens, Greece.
²⁰ Clinical Pediatrics, University of Bari, Bari, Italy.
²¹ Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas Y Nutrición Salvador Zubirán, Mexico City, Mexico.
²² Internal Medicine Department, Rheumatology and Clinical Immunology Unit, Faculty of Medicine, Cairo University, Giza, Egypt.
²³ Faculty of Medicine, Newgiza University, 6th of October City, Egypt.
²⁴ University Department Pro.Sa.M.I. "G. D'Alessandro", University of Palermo, Palermo, Italy.
²⁵ Department of Rheumatology, Medical University of Lodz, Łódź, Poland.
²⁶ Pediatric and Neonatology Unit, Department of Maternal Infantile and Urological Sciences, Sapienza, University of Rome, Polo Pontino, Latina, Italy.
²⁷ Department of Medicine and Surgery, MED/16- Rheumatology, Università degli studi di Perugia, P.zza Università, Perugia, Italy.
²⁸ Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
²⁹ Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Melbourne, Victoria, Australia.
³⁰ Rheumatology Unit, Department of Medical Sciences, Azienda Ospedaliero-Universitaria S. Anna - Ferrara, University of Ferrara, Ferrara, Italy.
³¹ UOSD Reumatologia ARNAS Garibaldi, Catania, Italy.
³² Rheumatology Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.
³³ NEUROFARBA Department, Rheumatology Unit, Meyer Children's University Hospital, University of Florence, Firenze, Italy.
³⁴ Third Department of Paediatrics, National and Kapodistrian University of Athens, General University Hospital "Attikon", Athens, Greece.
³⁵ Antwerp Unit for Data Analysis and Computation in Immunology and Sequencing, University of Antwerp, Antwerp, Belgium.
³⁶ Antwerp Center for Translational Immunology and Virology, Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium.
³⁷ Department of Paediatrics, Antwerp University Hospital, Antwerp, Belgium.
³⁸ Center for Health Economics Research and Modeling Infectious Diseases, Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium.
³⁹ Rheumatology and Immunology Unit, Internal Medicine Department, Mansoura University, Mansoura, Egypt.
⁴⁰ Department of Internal Medicine, Faculty of Medicine, Horus University, New Damietta, Egypt.
⁴¹ Rheumatology Unit, Department of Medicine, Central Hospital of Bolzano, Bolzano, Italy.
⁴² Department of Life, Health & Environmental Sciences and Internal Medicine and Nephrology Unit, Department of Medicine, University of L'Aquila and ASL Avezzano-Sulmona-L'Aquila, San Salvatore Hospital, L'Aquila, Italy.
⁴³ Unit of Immunology, Rheumatology, Allergy and Rare Diseases, IRCCS San Raffaele Hospital, Milan, Italy.
⁴⁴ Vita-Salute San Raffaele University, Milan, Italy.
⁴⁵ Department of Rheumatology, Faculty of Medicine Ankara City Hospital, Ankara Yıldırım Beyazıt University, Ankara, Turkey.
⁴⁶ Department of Biomedical and Clinical Sciences Luigi Sacco, Luigi Sacco Hospital, University of Milan, Milan, Italy.
⁴⁷ Vasculitis Research Unit and Autoinflammatory Diseases Clinical Unit, Department of Autoimmune Diseases, Hospital Clinic of Barcelona, IDIBAPS, University of Barcelona, [European Reference Network (ERN) for Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases (RITA) Center], Barcelona, Spain.
⁴⁸ Rheumatology Unit, Department of Medicine (DIMED), University of Padova, Padova, Italy.
⁴⁹ Ophthalmology Unit, Department of Medicine, Surgery and Neurosciences, University of Siena and Azienda Ospedaliero-Universitaria Senese [European Reference Network (ERN) for Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases (RITA) Center], Siena, Italy.

PMID: 37989322
PMCID: PMC10660445
DOI: 10.1136/rmdopen-2023-003419

Observational Study

Derivation and validation of four patient clusters in Still's disease, results from GIRRCS AOSD-study group and AIDA Network Still Disease Registry

Piero Ruscitti et al. RMD Open. 2023 Nov.

. 2023 Nov;9(4):e003419.

doi: 10.1136/rmdopen-2023-003419.

Authors

Affiliations

¹ Rheumatology Unit, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy piero.ruscitti@univaq.it.
² Rheumatology Unit, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy.
³ UOC Reumatologia, Azienda Ospedaliero-Universitaria Senese, ERN-RITA Center, Siena, Italy.
⁴ Department of Medical Sciences, Surgery and Neurosciences, Research Center of Systemic Autoinflammatory Diseases and Behçet's Disease Clinic University of Siena, Siena, Italy.
⁵ Rheumatology and Clinical Immunology, Department of Medicine, University of Rome "Campus Biomedico", School of Medicine, Rome, Italy.
⁶ Clinical and Research Section of Rheumatology and Clinical Immunology, Fondazione Policlinico Campus Bio-Medico, Rome, Italy.
⁷ Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy.
⁸ Rheumatology Department, Istituto di ricovero e cura a carattere scientifico Policlinico S. Matteo Fondazione, University of Pavia, Pavia, Italy.
⁹ Rheumatology Unit, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy.
¹⁰ Rheumatic and Systemic Autoimmune Diseases Unit, Department of Interdisciplinary Medicine (DIM), University of Bari Medical School, Bari, Italy.
¹¹ Academic Rheumatology Centre, Ospedale Mauriziano - Dipartimento Scienze Cliniche e Biologiche, Università degli Studi di Torino, Turin, Italy.
¹² Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.
¹³ Rheumatology Section, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University Hospital P. Giaccone, Palermo, Italy.
¹⁴ Rheumatology Division, Faculdade de Medicina, Hospital das Clínicas, Universidade de São Paulo, São Paulo, Brazil.
¹⁵ Rheumatology Unit, Department of Medicine, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
¹⁶ College of Medicine Research Center, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
¹⁷ Department of Internal Medicine, Division of Rheumatology, Marmara University, School of Medicine, Istanbul, Turkey.
¹⁸ Division of Rheumatology, Department of Internal Medicine, Gazi University Faculty of Medicine, Ankara, Turkey.
¹⁹ Joint Academic Rheumatology Program, National and Kapodistrian University of Athens Medical School, Athens, Greece.
²⁰ Clinical Pediatrics, University of Bari, Bari, Italy.
²¹ Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas Y Nutrición Salvador Zubirán, Mexico City, Mexico.
²² Internal Medicine Department, Rheumatology and Clinical Immunology Unit, Faculty of Medicine, Cairo University, Giza, Egypt.
²³ Faculty of Medicine, Newgiza University, 6th of October City, Egypt.
²⁴ University Department Pro.Sa.M.I. "G. D'Alessandro", University of Palermo, Palermo, Italy.
²⁵ Department of Rheumatology, Medical University of Lodz, Łódź, Poland.
²⁶ Pediatric and Neonatology Unit, Department of Maternal Infantile and Urological Sciences, Sapienza, University of Rome, Polo Pontino, Latina, Italy.
²⁷ Department of Medicine and Surgery, MED/16- Rheumatology, Università degli studi di Perugia, P.zza Università, Perugia, Italy.
²⁸ Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
²⁹ Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Melbourne, Victoria, Australia.
³⁰ Rheumatology Unit, Department of Medical Sciences, Azienda Ospedaliero-Universitaria S. Anna - Ferrara, University of Ferrara, Ferrara, Italy.
³¹ UOSD Reumatologia ARNAS Garibaldi, Catania, Italy.
³² Rheumatology Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.
³³ NEUROFARBA Department, Rheumatology Unit, Meyer Children's University Hospital, University of Florence, Firenze, Italy.
³⁴ Third Department of Paediatrics, National and Kapodistrian University of Athens, General University Hospital "Attikon", Athens, Greece.
³⁵ Antwerp Unit for Data Analysis and Computation in Immunology and Sequencing, University of Antwerp, Antwerp, Belgium.
³⁶ Antwerp Center for Translational Immunology and Virology, Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium.
³⁷ Department of Paediatrics, Antwerp University Hospital, Antwerp, Belgium.
³⁸ Center for Health Economics Research and Modeling Infectious Diseases, Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium.
³⁹ Rheumatology and Immunology Unit, Internal Medicine Department, Mansoura University, Mansoura, Egypt.
⁴⁰ Department of Internal Medicine, Faculty of Medicine, Horus University, New Damietta, Egypt.
⁴¹ Rheumatology Unit, Department of Medicine, Central Hospital of Bolzano, Bolzano, Italy.
⁴² Department of Life, Health & Environmental Sciences and Internal Medicine and Nephrology Unit, Department of Medicine, University of L'Aquila and ASL Avezzano-Sulmona-L'Aquila, San Salvatore Hospital, L'Aquila, Italy.
⁴³ Unit of Immunology, Rheumatology, Allergy and Rare Diseases, IRCCS San Raffaele Hospital, Milan, Italy.
⁴⁴ Vita-Salute San Raffaele University, Milan, Italy.
⁴⁵ Department of Rheumatology, Faculty of Medicine Ankara City Hospital, Ankara Yıldırım Beyazıt University, Ankara, Turkey.
⁴⁶ Department of Biomedical and Clinical Sciences Luigi Sacco, Luigi Sacco Hospital, University of Milan, Milan, Italy.
⁴⁷ Vasculitis Research Unit and Autoinflammatory Diseases Clinical Unit, Department of Autoimmune Diseases, Hospital Clinic of Barcelona, IDIBAPS, University of Barcelona, [European Reference Network (ERN) for Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases (RITA) Center], Barcelona, Spain.
⁴⁸ Rheumatology Unit, Department of Medicine (DIMED), University of Padova, Padova, Italy.
⁴⁹ Ophthalmology Unit, Department of Medicine, Surgery and Neurosciences, University of Siena and Azienda Ospedaliero-Universitaria Senese [European Reference Network (ERN) for Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases (RITA) Center], Siena, Italy.

PMID: 37989322
PMCID: PMC10660445
DOI: 10.1136/rmdopen-2023-003419

Abstract

Background: Different patient clusters were preliminarily suggested to dissect the clinical heterogeneity in Still's disease. Thus, we aimed at deriving and validating disease clusters in a multicentre, observational, prospective study to stratify these patients.

Methods: Patients included in GIRRCS AOSD-study group and AIDA Network Still Disease Registry were assessed if variables for cluster analysis were available (age, systemic score, erythrocyte sedimentation rate (ESR), C reactive protein (CRP) and ferritin). K-means algorithm with Euclidean metric and Elbow plot were used to derive an adequate number of clusters.

Results: K-means clustering assessment provided four clusters based on means standardised according to z-scores on 349 patients. All clusters mainly presented fever, skin rash and joint involvement. Cluster 1 was composed by 115 patients distinguished by lower values of age and characterised by skin rash myalgia, sore throat and splenomegaly. Cluster 2 included 128 patients identified by lower levels of ESR, ferritin and systemic score; multiorgan manifestations were less frequently observed. Cluster 3 comprised 31 patients categorised by higher levels of CRP and ferritin, they were characterised by fever and joint involvement. Cluster 4 contained 75 patients derived by higher values of age and systemic score. Myalgia, sore throat, liver involvement and life-threatening complications, leading to a high mortality rate, were observed in these patients.

Conclusions: Four patient clusters in Still's disease may be recognised by a multidimensional characterisation ('Juvenile/Transitional', 'Uncomplicated', 'Hyperferritinemic' and 'Catastrophic'). Of interest, cluster 4 was burdened by an increased rate of life-threatening complications and mortality, suggesting a more severe patient group.

Keywords: Arthritis; Arthritis, Juvenile; Still's Disease, Adult-Onset.

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Conflict of interest statement

Competing interests: None declared.

References

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Derivation and validation of four patient clusters in Still's disease, results from GIRRCS AOSD-study group and AIDA Network Still Disease Registry

Affiliations

Derivation and validation of four patient clusters in Still's disease, results from GIRRCS AOSD-study group and AIDA Network Still Disease Registry

Authors

Affiliations

Abstract

Conflict of interest statement

References

Publication types

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Medical

Research Materials

Miscellaneous