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Autoinflammatory disorders
Original research
Still’s disease continuum from childhood to elderly: data from the international AIDA Network Still’s disease registry
  1. Antonio Vitale1,2,
  2. Valeria Caggiano1,2,
  3. Giuseppe Lopalco3,
  4. Henrique A Mayrink Giardini4,
  5. Francesco Ciccia5,
  6. Ibrahim A Almaghlouth6,7,
  7. Piero Ruscitti8,
  8. Petros P Sfikakis9,
  9. Abdurrahman Tufan10,
  10. Lorenzo Dagna11,12,
  11. Roberto Giacomelli13,14,
  12. Andrea Hinojosa-Azaola15,
  13. Gafaar Ragab16,17,
  14. Haner Direskeneli18,
  15. Lampros Fotis19,
  16. Jurgen Sota1,2,
  17. Florenzo Iannone3,
  18. Maria Morrone3,
  19. Isabele Parente de Brito Antonelli4,
  20. Marilia Ambiel Dagostin4,
  21. Daniela Iacono5,
  22. Martina Patrone5,
  23. Kazi Asfina7,
  24. Fehaid Alanazi6,
  25. Ilenia Di Cola8,
  26. Carla Gaggiano1,2,
  27. Maria G Tektonidou9,
  28. Riza Can Kardas10,
  29. Hamit Kucuk10,
  30. Corrado Campochiaro11,12,
  31. Alessandro Tomelleri11,12,
  32. Luca Navarini13,14,
  33. Onorina Berardicurti13,14,
  34. Eduardo Martín-Nares15,
  35. Jiram Torres-Ruiz15,
  36. Ayman Abdel-Monem Ahmed Mahmoud16,
  37. Fatma Alibaz-Oner18,
  38. Katerina Kourtesi19,
  39. Maria Tarsia2,20,
  40. Paolo Sfriso21,
  41. Joanna Makowska22,
  42. Marcello Govoni23,
  43. Francesco La Torre24,
  44. Maria Cristina Maggio25,
  45. Sara Monti26,27,
  46. Emanuela Del Giudice28,
  47. Giacomo Emmi29,30,
  48. Elena Bartoloni31,
  49. José Hernández-Rodríguez32,
  50. Verónica Gómez-Caverzaschi32,
  51. Armin Maier33,
  52. Gabriele Simonini34,
  53. Annamaria Iagnocco35,
  54. Giovanni Conti36,
  55. Alma Nunzia Olivieri37,
  56. Amato De Paulis38,39,
  57. Alberto Lo Gullo40,
  58. Ombretta Viapiana41,
  59. Ewa Wiesik-Szewczyk42,
  60. Sukran Erten43,
  61. Benson Ogunjimi44,45,46,47,
  62. Francesco Carubbi48,
  63. Samar Tharwat49,50,
  64. Katerina Laskari51,
  65. Stefania Costi52,
  66. Paola Triggianese53,54,
  67. Anastasios Karamanakos55,
  68. Alessandro Conforti56,
  69. Micol Frassi57,
  70. Gian Domenico Sebastiani58,
  71. Antonio Gidaro59,
  72. Angela Mauro60,
  73. Alberto Balistreri61,
  74. Claudia Fabiani2,62,
  75. Bruno Frediani1,2 and
  76. Luca Cantarini1,2
  1. 1Department of Medical Sciences, Surgery and Neurosciences, Research Center of Systemic Autoinflammatory Diseases and Behçet's Disease Clinic, University of Siena, Siena, Italy
  2. 2Azienda Ospedaliero-Universitaria Senese [European Reference Network (ERN) for Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases (RITA) Center], Azienda Ospedaliero-Universitaria Senese, Siena, Italy
  3. 3Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J) Policlinic Hospital, University of Bari, Bari, Italy
  4. 4Rheumatology Division, Faculdade de Medicina, Hospital das Clínicas, Universidade de Sao Paulo, Sao Paulo, Brazil
  5. 5Department of Precision Medicine, Università degli Studi della Campania Luigi Vanvitelli, Napoli, Italy
  6. 6Rheumatology Unit, Department of Medicine, College of Medicine, King Saud University, Riyadh, Saudi Arabia
  7. 7College of Medicine Research Center, College of Medicine, King Saud University, Riyadh, Saudi Arabia
  8. 8Rheumatology Unit, Department of Biotechnological and Applied Clinical Sciences, Università degli Studi dell'Aquila, L'Aquila, Italy
  9. 9Joint Academic Rheumatology Program, Medical School, National and Kapodistrian, University of Athens, Athens, Greece
  10. 10Department of Internal Medicine, Division of Rheumatology, Gazi University, Ankara, Turkey
  11. 11Division of Immunology, Transplants and Infectious Diseases, Università Vita-Salute San Raffaele, Milan, Italy
  12. 12Unit of Immunology, Rheumatology, Allergy and Rare Diseases, IRCCS Ospedale San Raffaele, Milan, Italy
  13. 13Clinical and research section of Rheumatology and Clinical Immunology, Fondazione Policlinico Campus Bio-Medico, Rome, Italy
  14. 14Rheumatology, Immunology and Clinical Medicine Unit, Department of Medicine, University of Rome “Campus Biomedico” School of Medicine, Rome, Italy
  15. 15Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición, Mexico City, Mexico
  16. 16Internal Medicine Department, Rheumatology and Clinical Immunology Unit, Cairo University, Giza, Egypt
  17. 17Faculty of Medicine, Newgiza University, 6th of October City, Egypt
  18. 18Department of Internal Medicine, Division of Rheumatology, Marmara University, School of Medicine, Istanbul, Turkey
  19. 19Department of Pediatrics, Attikon General Hospital, National and Kapodistrian University of Athens, Athens, Greece
  20. 20Clinical Pediatrics, Department of Molecular Medicine and Development, University of Siena, Siena, Italy
  21. 21Rheumatology Unit, Department of Medicine, University of Padua, Padua, Italy
  22. 22Department of Rheumatology, Medical University of Lodz, Lodz, Poland
  23. 23Rheumatology Unit, Department of Medical Sciences, Azienda Ospedaliero-Universitaria S. Anna-Ferrara, University of Ferrara, Ferrara, Italy
  24. 24Department of Pediatrics, Pediatric Rheumatology Center, Giovanni XXIII Pediatric Hospital, University of Bari Aldo Moro, Bari, Italy
  25. 25University Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE) "G. D'Alessandro", University of Palermo, Palermo, Italy
  26. 26Department of Internal Medicine and Therapeutics, University of Pavia; early Arthritis Clinic, IRCCS Policlinico S. Matteo Foundation, Pavia, Italy
  27. 27Division of Rheumatology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
  28. 28Pediatric and Neonatology Unit, Department of Maternal Infantile and Urological Sciences, University of Rome La Sapienza, Rome, Italy
  29. 29Department of Experimental and Clinical Medicine, University of Florence, Firenze, Italy
  30. 30Centre for Inflammatory Diseases, Department of Medicine, Monash Medical Centre, Monash University, Clayton, VIC, Australia
  31. 31Rheumatology Unit, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
  32. 32Department of Autoimmune Diseases, Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Hospital Clínic of Barcelona [European Reference Network (ERN) for Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases (RITA) Center], University of Barcelona, Barcelona, Spain
  33. 33Rheumatology Unit, Department of Medicine, Central Hospital of Bolzano, Bolzano, Italy
  34. 34NEUROFARBA Department, Rheumatology Unit, Meyer Children's Hospital IRCCS, University of Florence, Firenze, Italy
  35. 35Academic Rheumatology Centre, Dipartimento Scienze Cliniche e Biologiche, Università degli Studi di Torino, Torino, Italy
  36. 36Pediatric Nephrology and Rheumatology Unit, Azienda Ospedaliera Universitaria (AOU), "G. Martino", Messina, Italy
  37. 37Department of Woman, Child and of General and Specialized Surgery, University of Campania Luigi Vanvitelli, Napoli, Italy
  38. 38Department of Translational Medical Sciences, Section of Clinical Immunology, University of Naples Federico II, Napoli, Italy
  39. 39Center for Basic and Clinical Immunology Research (CISI), WAO Center of Excellence, University of Naples Federico II, Naples, Italy
  40. 40Unit of Rheumatology, Department of Medicine, ARNAS Garibaldi Hospital, Catania, Italy
  41. 41Rheumatology Unit, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
  42. 42Department of Internal Medicine, Pneumonology, Allergology and Clinical Immunology, Central Clinical Hospital of the Ministry of National Defense, Poland Ministry of Interior and Administration, Warszawa, Poland
  43. 43Department of Rheumatology, Faculty of Medicine Ankara City Hospital, Ankara Yildirim Beyazit Universitesi, Ankara, Turkey
  44. 44Department of Paediatrics, University Hospital Antwerp, Edegem, Belgium
  45. 45Antwerp Unit for Data Analysis and Computation in Immunology and Sequencing, University of Antwerp, Antwerp, Belgium
  46. 46Antwerp Center for Translational Immunology and Virology, Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium
  47. 47Center for Health Economics Research and Modeling Infectious Diseases, Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium
  48. 48Department 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
  49. 49Rheumatology and Immunology Unit, Internal Medicine Department, Mansoura University, Mansoura, Egypt
  50. 50Department of Internal Medicine, Faculty of Medicine, Horus University, New Damietta, Egypt
  51. 51Joint Academic Rheumatology Program, National and Kapodistrian University of Athens Medical School, Athens, Greece
  52. 52Department of Clinical Sciences and Community Health, Research Center for Adult and Pediatric Rheumatic Diseases, University of Milan, Milano, Italy
  53. 53Rheumatology, Allergology and Clinical Immunology, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
  54. 54PhD in Immunology, Molecular Medicine and Applied Biotechnology, University of Rome Tor Vergata, Rome, Italy
  55. 55Joint Academic Rheumatology Program, First Department of Propaedeutic and Internal Medicine, National and Kapodistrian University of Athens, Athens, Greece
  56. 56U.O.Medicina Generale, Ospedale San Paolo di Civitavecchia, ASL Roma 4, Civitavecchia, Rome, Italy
  57. 57Rheumatology and Clinical Immunology, Spedali Civili and Department of Clinical and Experimental Sciences, [European Reference Network (ERN) for Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases (RITA) Center], University of Brescia, Brescia, Italy
  58. 58UOC di Reumatologia, Azienda Ospedaliera San Camillo Forlanini, Roma, Italy
  59. 59Department of Biomedical and Clinical Sciences Luigi Sacco, Luigi Sacco Hospital, University of Milan, Milan, Italy
  60. 60Pediatric Unit, Fatebenefratelli Hospital, Milan, Milan
  61. 61Bioengineering and Biomedical Data Science Lab, Department of Medical Biotechnologies, University of Siena, Siena, Italy
  62. 62Ophthalmology Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy
  1. Correspondence to Dr Luca Cantarini; cantariniluca{at}hotmail.com; Dr Antonio Vitale; vitale.reumatologia{at}gmail.com

Abstract

Objective Still’s disease is more frequently observed in the paediatric context, but a delayed onset is not exceptional both in the adulthood and in the elderly. However, whether paediatric-onset, adult-onset and elderly-onset Still’s disease represent expressions of the same disease continuum or different clinical entities is still a matter of controversy. The aim of this study is to search for any differences in demographic, clinical features and response to treatment between pediatric-onset, adult-onset and elderly-onset Still’s disease.

Methods Subjects included in this study were drawn from the International AutoInflammatory Disease Alliance Network registry for patients with Still’s disease.

Results A total of 411 patients suffering from Still’s disease were enrolled; the disease occurred in the childhood in 65 (15.8%) patients, in the adult 314 (76.4%) patients and in the elderly in 32 (7.8%) patients. No statistically significant differences at post-hoc analysis were observed in demographic features of the disease between pediatric-onset, adult-onset and elderly-onset Still’s disease. The salmon-coloured skin rash (p=0.004), arthritis (p=0.009) and abdominal pain (p=0.007) resulted significantly more frequent among paediatric patients than in adult cases, while pleuritis (p=0.015) and arthralgia (p<0.0001) were significantly more frequent among elderly-onset patients compared with paediatric-onset subjects. Regarding laboratory data, thrombocytosis was significantly more frequent among paediatric patients onset compared with adult-onset subjects (p<0.0001), while thrombocytopenia was more frequent among elderly-onset patients although statistical significance was only bordered. No substantial differences were observed in the response to treatments.

Conclusions Despite some minor difference between groups, overall, demographic, clinical, laboratory and treatments aspects of Still’s disease were similarly observed in patients at all ages. This supports that pediatric-onset, adult-onset and elderly-onset Still’s disease is the same clinical condition arising in different ages.

  • Still's Disease, Adult-Onset
  • Epidemiology
  • Child

Data availability statement

Data are available upon reasonable request. All data relevant to the study are included in the article.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/rmdopen-2023-003578

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    WHAT IS ALREADY KNOWN ON THIS TOPIC

    • An overlap between adult-onset and pediatric-onset Still’s disease has been increasingly suggested.

    WHAT THIS STUDY ADDS

    • This study identifies only minor differences in demographic, clinical and laboratory features of patients with Still’s disease disregarding the age at disease onset.

    HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

    • This study provides more evidence about the overlapping clinical and laboratory Still’s disease manifestations across the age at the disease onset.

    Introduction

    Still’s disease is a rare systemic polygenic autoinflammatory condition of unknown aetiology involving several environmental, genetic and immunological factors.1 It has been more frequently described in the paediatric context, but a delayed onset is not exceptional both in the adulthood and in the elderly.2–4

    Preliminary laboratory studies show that Still’s disease has similar pathogenesis disregarding the age at disease onset.5–8 Similarly, most of clinical and laboratory features, along with the response to anti-interleukin (IL)-1 agents, are similarly observed in paediatric and adult-onset disease.9–11 Therefore, it has been suggested that pediatric-onset and adult-onset diseases are the same clinical entity occurring at different periods of life; however, this topic is still a matter of controversy.

    An additional topic to investigate is whether subjects with a very late disease onset represent a clinical condition belonging to the same disease continuum or a further disease phenotype with own disease features. In this work, we aimed to investigate any significant difference in demographic, clinical and laboratory features of paediatric-onset, adult-onset and elderly-onset Still’s disease, along with differences in the response to the most frequently employed treatments in such patients.

    Materials and methods

    Patients included in this study were drawn from the International AutoInflammatory Disease Alliance (AIDA) Network registry for patients with Still’s disease12 at March 2023.

    All patients were diagnosed with Still’s disease, classified according to the internationally accepted criteria: Yamaguchi and/or Fautrel for adult patients13 14 and the International League of Associations for Rheumatology (ILAR) and/or the Paediatric Rheumatology INternational Trials Organisation (PRINTO) criteria for patients aged<16 years.15 16

    The objective of this study is to search for any differences between patients with pediatric-onset, adult-onset and elderly-onset Still’s disease. With this aim, patients recruited in the International AIDA Network registry for patients with Still’s disease were distinguished into three groups according to the different age at disease onset. Specifically, patients complaining of the onset of symptoms by 16 years of age were included in the pediatric-onset group; the adult-onset group included patients with Still’s disease onset between 16 and 60 years of age, as previously described.17 18 Patients with onset of symptoms from the age of 60 years were included in the elderly group. Figure 1 represents the flow diagram with patients’ segregation into the three different study groups. The figure also illustrates the fulfilment of the more widely used classification criteria in childhood and adulthood.

    Figure 1
    Figure 1

    Flow diagram showcasing the distribution of the enrolled AIDA patients into the three study groups (pediatric-onset, adult-onset and elderly-onset patients) and the fulfilment of classification criteria used before and after the age of 16 (ILAR criteria,15 PRINTO criteria,16 Yamaguchi criteria,13 Fautrel criteria14). AIDA, AutoInflammatory Disease Alliance, ILAR, International League of Associations for Rheumatology; PRINTO, Pediatric Rheumatology International Trials Organization.

    Clinical and laboratory data resulted statistically significant among the three study groups were further analysed by comparing pediatric-onset patients, young adults (16–39 years), adults (40–59 years) and elderly-onset of Still’s disease. This further patients distinction was aimed at assessing any possible similarities and differences between the paediatric and young adult group as well as the adult group with elderly-onset patients. The endpoint of the study consisted in the identification of any statistically significant difference between the three groups regarding demographic, clinical and laboratory variables observed from the disease onset to the last follow-up assessment. Moreover, statistically significant differences were searched among groups regarding the response to the more frequently employed treatment approaches in all the three study groups.

    Disease duration was defined as the time elapsing between the onset of symptoms and the diagnosis of Still’s disease. Disease course was distinguished into monocyclic, polycyclic and chronic articular according to Cush et al, with the monocyclic and the polycyclic courses being characterised by a prevalent systemic inflammatory involvement and the latter consisting of a more prevalent musculoskeletal affection with a less prominent systemic inflammation. The monocyclic course typically resolves within 12 months from the start of symptoms, while the polycyclic course lasts longer, with intercritical quiescence.19 Continuous fever referred to a fever course with temperature remaining above normal throughout the day, with a constant fashion; remittent fever was defined for patients with temperature remaining above normal throughout the day, but with fluctuations; transient fever was referred to temperature elevated for several hours with intervals characterised by temperature dropping back to normal; undulant fever refers to a fever course resembling Brucellosis (with no evidence of infection). Liver involvement was defined as occurrence of hepatomegaly and/or signs of hepatic failure and/or hepatitis and or increase in hepatic liver enzymes. Arthritis was meant as the presence of articular inflammation in one site (monarthritis), from two to four joints (oligoarthritis) or more than four joints (polyarthritis). Cardiac involvement included endocarditis, myocarditis, arrhythmias and cardiac tamponade. Vascular involvement included stroke, critical limb-threatening ischaemia, rupture of abdominal aortic aneurysm, rupture of an intracranial aneurysm, bowel infarction, pulmonary embolism and deep vein thrombosis. Regarding treatment outcomes, complete response was defined as the resolution of all disease-related clinical manifestations, with decrease to normal values of all laboratory inflammatory parameters. Partial response was defined as persistence of clinical manifestations with remarkable decrease in their severity, as reported by patients, with inflammatory laboratory parameters normalised or only slightly increased. Failure was meant as persistence of fever-associated clinical manifestations and/or no decrease of laboratory inflammatory markers. A relapse was defined as reappearance of Still’s disease related clinical manifestations during the course of treatment. Macrophage activation syndrome (MAS) was classified according to 2016 criteria developed for systemic juvenile idiopathic arthritis and/or the HLH-2004 criteria and/or the HScore.20–22 Pleuritis was diagnosed through a combination of clinical and radiological elements; thoracentesis was performed only when required for clinical reasons.

    Laboratory findings, included blood count, C reactive protein (CRP), erythrocyte sedimentation rate, serum levels of ferritin, thrombocytosis, hypergammaglobulinaemia and lactate dehydrogenase, were investigated at the time of disease onset. The reference ranges depended on the laboratory of the recruiting centres.

    All patients or parents (or legal guardian) signed the informed consent to participate to the AIDA project.

    Regarding statistical computations, descriptive statistics included mean, standard deviation (SD), range, median and interquartile range (IQR), as required. Data distribution was evaluated by the Shapiro-Wilk test. Global computations were performed using the analysis of variance test or the Kruskal-Wallis test for quantitative data, as required by data distribution; the χ2 test was used for qualitative data. Post-hoc analysis was performed with the t-test or the Mann-Whitney test for quantitative data and with χ2 test or with the Fisher exact test according to the frequency counts and the expected frequencies. Bonferroni correction was applied for multiple comparisons and Yates correction was applied to χ2 test, when required. Significance level was set at 95% (p<0.05); p values were two tailed in all cases. Statistical analysis was plotted through the RStudio software, V.4.3.0.

    Results

    We enrolled 411 patients diagnosed with Still’s disease. The disease onset occurred in the childhood in 65 (15.8%) patients, in the adult 314 (76.4%) patients and in the elderly in 32 (7.8%) patients. The ethnicity was as follows: Caucasian in 300 (73%) cases; Arab in 40 (9.7%) cases; Hispanic in 19 (4.6%) cases; Black in 7 (1.7%) cases; Asian in 2 (0.5%) cases; Jewish and Native American in 1 case; in 41 cases ethnicity was not provided. Yamaguchi’s criteria13 were met in 236 (75.2%) adult patients and in 24 (74%) subjects with elderly disease onset (p=1.0); adult and elderly patients fulfilled Fautrel’s criteria14 in, respectively, 183 (58.3%) and 16 (50%) cases (p=0.46). For patients aged<16 years, PRINTO criteria16 were fulfilled in 55 (84.6%) subjects and ILAR criteria15 were met in 39 (60%) paediatric cases.

    Table 1 summarises demographic features of patients enrolled. Undulant fever was reported more frequently among patients with adult (p=0.0003) and elderly onset (p=0.0009). Conversely, a global statistically significant difference was observed among groups in the disease duration at diagnosis and in the frequency of the chronic articular disease course, but with no statistically significant difference at post-hoc analysis.

    View this table:
    Table 1

    Demographic and clinical features of patients enrolled, according to the age at disease onset

    Table 2 describes the frequency of Still’s disease clinical features in the three study groups. The salmon-coloured skin rash (p=0.004) and abdominal pain (p=0.007) resulted significantly more frequent among patients with Still’s disease with pediatric onset than those with adult onset, while no significant differences were observed with elderly-onset patients. Pleuritis (p=0.015) and arthralgia (p<0.0001) were significantly more frequent among elderly-onset patients compared with pediatric-onset subjects. Arthritis was significantly more frequent in pediatric-onset patients than among adult-onset patients (p=0.009); nevertheless, no differences were observed in the number of joints involved, as the frequency of monarthritis, oligoarthritis and polyarthritis did not differ among groups in a significant fashion. A global statistically significant difference was observed in the MAS frequency, but with no significance at post-hoc analysis.

    View this table:
    Table 2

    Frequency of clinical features related to Still’s disease among patients with pediatric, adult and elderly onset

    Table 3 provides laboratory data distinguished according to the age at Still’s disease onset. Thrombocytosis was significantly more frequent among pediatric-onset patients compared with adult-onset subjects (p<0.0001), while thrombocytopenia was more frequent among elderly-onset patients although statistical significance was only bordered. The frequency of increased lactate dehydrogenase showed a global statistical significance with no post-hoc statistically significant differences among groups.

    View this table:
    Table 3

    Laboratory data reported in the first inflammatory episode among patients with pediatric onset, adult onset and elderly onset

    Table 4 includes clinical and laboratory features resulted to differ in a statistically significant fashion between pediatric-onset, adult-onset and elderly-onset patients. These variables were further analysed after a distinction of adult patients into young adults (16–39 years) and adults (40–59 years). Salmon-coloured skin rash was less frequently encountered among young adults, reaching statistical significance towards paediatric patients; pleuritis was less frequent in the paediatric group, with a statistically significant difference when compared with adults; thrombocytosis was more frequent in the paediatric group, reaching statistical significance towards both young adults and adults.

    View this table:
    Table 4

    Clinical and laboratory features found to significantly discriminate pediatric, adult and elderly patients were reanalysed distinguishing adult patients into two further groups, that are young adults (aged 16–39) and adults (aged 40–59)

    Methotrexate (MTX), leflunomide, cyclosporine A, sulfasalazine and azathioprine were the conventional disease-modifying antirheumatic drugs (cDMARDs) used in this cohort of patients. Figure 2 represents their frequencies in the three groups of patients. MTX resulted significantly less frequent in paediatric patients compared with adults (p=0.002) and elderly (p=0.0001) patients.

    Figure 2
    Figure 2

    Frequency of use of the different conventional disease-modifying antirheumatic drugs (cDMARDs) in the different groups (pediatric-onset, adult-onset and elderly-onset patients).

    Regarding response to treatment, the response to MTX used as monotherapy did not differ significantly among groups. The frequency of failure was characterised by a global significance towards a higher frequency in the paediatric group; however, no statistical significance was obtained at post-hoc analysis between paediatric-onset and adult-onset cases (p=0.07) and between paediatric and elderly cases (p=0.13).

    Table 5 describes the response to biotechnological agents employed as monotherapy in the three groups of patients; no differences were observed in the response according to the different age at onset, except for the frequency of patients experiencing relapses during tocilizumab treatment, which was significantly more frequent among patients with pediatric-onset compared with adult-onset subjects (p=0.008).

    View this table:
    Table 5

    Treatment outcome to biotechnological agents employed in pediatric-onset, adult-onset and elderly-onset patients in terms of frequency of complete and partial response, treatment failure, number of patients experiencing relapses during treatment and frequency of treatment discontinuation due to lack or loss of efficacy and long-term disease remission

    Table 6 reports treatment outcome to biotechnological agents combined with MTX in the three groups of patients. No statistically significant differences were observed in the treatment response among paediatric, adult and elderly cases.

    View this table:
    Table 6

    Treatment outcome to biotechnological agents employed in combination with methotrexate in pediatric-onset, adult-onset and elderly-onset cases

    Tumour necrosis factor (TNF) inhibitors administered as monotherapy in this cohort were etanercept (ETN) (n=3), infliximab (IFX) (n=2) in the paediatric group; IFX (n=9), ETN (n=6), adalimumab (ADA) (n=2), golimumab (GOL) (n=1), certolizumab pegol (n=1) among adults; ETN (n=1) in elderly cases. The TNF inhibitors combined with MTX were ETN (n=1) in paediatric cases, IFX (n=3),ETN (n=1), ADA (n=1), GOL (n=1) in adult cases; no TNF inhibitor combined with MTX were used in elderly cases. Figure 3 describes the long-term drug survival for biotechnological agents used in the three age groups.

    Figure 3
    Figure 3

    Kaplan-Meier curves with p values obtained with the Log-rank test. The drug survival was assessed in the three age groups (pediatric, adult and elderly onset) for anakinra (A), canakinumab (B), tocilizumab (C), and tumour necrosis factor (TNF) inhibitors.

    At start of biotechnological treatments, oral corticosteroids were used in 23/65 (35.4%) pediatric-onset cases, in 125/314 (39.8%) adult patients, and in 10/32 (31.3%) elderly-onset subjects (p=0.55). At the last follow-up visit, systemic corticosteroids were still employed in 4/23 (17.4%) pediatric-onset patients, 29/125 (23.2%) adult subjects and 1/10 (10%) patient in elderly-onset group (p=0.67).

    Discussion

    Still’s disease is a pathological condition capable of arising at any age.2–4 Nevertheless, Still’s disease is more widely studied in paediatric and early adulthood settings, while it is more rarely found in older age. Although rarer to meet, Still’s disease in the elderly is not an exceptional diagnosis and needs to be more deeply investigated in order to assess any differences and peculiarities with respect to paediatric and early adult-onset patients. On the other side, an increasing number of laboratory and clinical evidence supports that paediatric-onset and adult-onset Still’s disease represent the same condition arising in different ages.5–8 Despite this, further evidence supporting overlap between paediatric form of disease and adult-onset disease is still needed.

    Looking at past literature, patients with elderly onset showed a higher prevalence in females,2 a lower frequency of the typical Still’s disease symptoms, including salmon-coloured skin rash, sore throat, lymphadenopathy, splenomegaly and a higher frequency of pleuritis.4 17 23 Pericarditis was also identified more frequently among elderly-onset patients, with age predicting the development of serositis and parenchymal lung disease.18 Data about complications including MAS and disseminated intravascular coagulation are inconsistent, with some authors describing a higher frequency2 4 17 and other an equal frequency24 25 in adult patients when compared with cases with earlier onset. Similarly, serum ferritin levels were reported higher in the elderly group,25 but in some cases with no statistical significance.18 24 Leucocytosis was reported more frequently among elderly-onset cases in one study.18

    Our results disclosed a higher frequency of pleuritis, pericarditis, lung parenchymal involvement and a slight reduced frequency of salmon-coloured skin rash, splenomegaly, lymphadenopathy and the polycyclic disease course in the elderly group. However, except for pleuritis, none of these clinical features met statistical significance. In particular, pleuritis was significantly more frequent in the elderly group compared with the pediatric-onset group, while no statistical difference was observed between the elderly group and adult-onset group. The higher frequency of pleuritis in later age is also confirmed when adult patients were subdivided into young adults and adults; actually, pleuritis was significantly more frequent among patients aged 40–59 years than in paediatric patients. The frequency of pleuritis was similar in the elderly group and among patients aged between 40 and 59 (roughly 18%), but significance towards the paediatric group was obtained only among the latter due to the smaller sample size of elderly-onset patients. In addition, arthralgia but not arthritis resulted significantly more frequently in the elderly group than in the paediatric group.

    A higher risk of relapses4 25 and a less frequent drug-free remission17 have been previously reported in the elderly group; in the present study, no statistically significant difference was observed between the elderly-onset group ant the other two groups in terms of response to therapy, number of patients undergoing relapses during treatment with MTX, biotechnological agents used alone or in combination with MTX. These findings seem to contradict previous experience,4 17 25 but this could be related to the relatively low number of patients treated with each therapeutic approach and to the specific outcomes investigated.

    As a whole, we identified much less differences between patients with elderly Still’s disease onset and the other patients’ groups. Consequently, based on our findings, we do not confirm the presence of a specific subset of patients characterised by an elderly disease onset with distinctive clinical features; however, we confirm that typical Still’s disease clinical characteristics may be less frequent in such cases, but not to the extent of defining an atypical clinical picture. This could be related to the more conservative statistical approach used in this study, ensuring specific results at the expense of sensitivity.

    Looking at differences between the pediatric-onset group and adult-onset Still’s disease patients, a few differences have been highlighted. In particular, undulant fever course was never reported in the paediatric group, while the salmon-coloured skin rash, arthritis and abdominal pain were significantly more frequent among patients with the pediatric-disease onset. Surprisingly, while paediatric patients were more exposed to salmon-coloured skin rash, this manifestation resulted less frequent in young adults aged 16–39 rather than in adults aged 40–59 and elderly subjects.

    The higher frequency of arthritis in the paediatric group could be related to the wide use of ILAR criteria to classify Still’s disease in the paediatric context, which requires the presence of arthritis as a mandatory item.15 MAS was more frequent in the paediatric disease group, but with no statistically significant difference. From a laboratory perspective, thrombocytosis was significantly more frequent among paediatric patients. Again, the lack of statistical significance towards the elderly group is caused by the limited sample size of patients aged>60. Ruscitti et al have recently published a similar article aimed at assessing differences between pediatric-onset and adult-onset disease. Their results showed several significant differences capable of highlighting remarkable disparities in the prevalence of many clinical manifestations, especially those typically related to Still’s disease diagnosis.26 Comparing our data with those reported by Ruscitti et al, this discrepancy is widely related to the remarkably higher frequency of sore throat, lymphadenopathy, splenomegaly, pericarditis, myalgia, and leukocytosis in our cohort of paediatric patients.26 Actually, our clinical findings are similar to that reported by Neau et al, who identified a similar clinical presentation between paediatric and adult groups, except for sore throat and myalgia, which were more frequent in adults in their study.27 Neau et al27 identified a statistically significant difference between paediatric and adult-onset groups in the CRP and serum ferritin levels. In this regard, ferritin levels have been distinguished between adult and elderly cases in our non-paediatric patients, probably affecting the difference between paediatric and adult groups.

    The wide age of onset may contribute to the disease heterogeneity; thus, based on its clinical relevance, this feature has been used in deriving diverse patient clusters in Still’s disease by data mining techniques.25 28 Furthermore, although many findings support the hypothesis of pediatric and adult onset of Still’s disease being a continuum of the same continuum condition, additional issues in adults may impact their prognosis, such as smoking habit, comorbidities and ageing-related frailty.18 29–31

    Excluding the number of patients experiencing disease relapses during tocilizumab therapy, no differences were observed in the treatment outcome to biotechnological agents used either as monotherapy or combined with MTX and/or glucocorticoids. Similarly, no differences were observed in the drug retention rate of the different IL targeting agents used in this study. Altogether, these findings support a similar response to currently employed treatment approaches and, consequently, a unique clinical continuum including both pediatric-onset and adult-onset Still’s disease.

    The main limitation of the study is in the relatively low number of elderly-onset cases, which is quite comparable to that previously reported in other studies. Also, the number of cases with a poor treatment outcome in the three groups was low due to the high effectiveness of therapies. This has made statistics less powerful in assessing therapeutic differences between groups. Noteworthy, no deaths have been reported in the registry so far. This could conceal a selection bias, as investigators may have omitted the recruitment of deceased patients. Moreover, response to treatments was relegated to biotechnological agents and to combination treatment between cDMARDs and biologics. This decision was taken in order to avoid a bias related to a different use of cDMARDs as monotherapy between paediatricians and physicians dealing with Still’s disease. Indeed, any difference would have reflected a different perspective between physicians rather than a pathophysiological difference among groups. Despite these limitations, this is the first study aimed at assessing Still’s disease subdividing patients into three groups according with the age at disease onset, in order to identify any differences in this continuum of patients.

    In conclusion, the present study highlights only minor differences among groups in both demographic, clinical, laboratory and treatments aspects of Still’s disease. This supports that paediatric-onset, adult-onset and elderly-onset Still’s disease could be the same clinical condition arising in different ages; however, genetic and molecular assessments should be performed on the same age groups to confirm findings observed from a clinical and laboratory perspective.

    Data availability statement

    Data are available upon reasonable request. All data relevant to the study are included in the article.

    Ethics statements

    Patient consent for publication

    Ethics approval

    This study involves human participants and was approved by Azienda Ospedaliero Universitaria Senese, Siena, Italy (AIDA Project; Ref. N. 14951). Participants gave informed consent to participate in the study before taking part.

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    Footnotes

    • AV and VC contributed equally.

    • Contributors All the authors substantially contributed to the conception or design of the work, the acquisition and interpretation of data and critically revised the paper. All the authors approved the final version and agreed to be responsible for all the aspects of the work. In addition, AV and VC wrote the first draft of the manuscript and performed the preliminary data analysis and interpretation; VC, GL, HG, FC, IAA, PR, PPS, AT, LD, RG, AHA, GR, HD, LF, JS, FI, MM, IPDBA, MAD,DI, MP, KA, FA, IDC, CG, MGT, RCK, HK, CC, AT, LN, OB, EMN, JTR, AAMAM, FAO, KK, MT, PS, JM, MG, FLT, MCM, SM, EDG, GE, EB, JHR, VGC, AM, GS, AI, GC, ANO, ADP, ALG, OV, EWS, SE, BO, FC, ST, KL, SC, PT, AK, AC, MF, GDS, AG, AM, CF and BF were involved in the study according to their active role in enrolling patients in the AIDA Network Still’s disease Registry by May 2023; AB is also the bioengineer involved in the technical management of the platform and registries; LC took care of the final revision of the manuscript and accounted for AIDA Registries Coordinator. LC is also the guarantor of the overall content.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.