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Extended report
In silico validation of the Autoinflammatory Disease Damage Index
  1. Nienke M ter Haar1,2,
  2. Amber Laetitia Justine van Delft3,
  3. Kim Valerie Annink3,
  4. Henk van Stel3,
  5. Sulaiman M Al-Mayouf4,
  6. Gayane Amaryan5,
  7. Jordi Anton6,
  8. Karyl S Barron7,
  9. Susanne Benseler8,
  10. Paul A Brogan9,
  11. Luca Cantarini10,
  12. Marco Cattalini11,
  13. Alexis-Virgil Cochino12,
  14. Fabrizio de Benedetti13,
  15. Fatma Dedeoglu14,
  16. Adriana Almeida de Jesus15,
  17. Erkan Demirkaya16,
  18. Pavla Dolezalova17,
  19. Karen L Durrant18,
  20. Giovanna Fabio19,
  21. Romina Gallizzi20,
  22. Raphaela Goldbach-Mansky15,
  23. Eric Hachulla21,
  24. Veronique Hentgen22,
  25. Troels Herlin23,
  26. Michaël Hofer24,25,
  27. Hal M Hoffman26,
  28. Antonella Insalaco27,
  29. Annette F Jansson28,29,
  30. Tilmann Kallinich28,
  31. Isabelle Kone-Paut30,
  32. Anna Kozlova31,
  33. Jasmin Beate Kuemmerle-Deschner32,
  34. Helen J Lachmann33,
  35. Ronald M Laxer34,
  36. Alberto Martini35,
  37. Susan Nielsen36,
  38. Irina Nikishina37,
  39. Amanda K Ombrello38,
  40. Seza Özen39,
  41. Efimia Papadopoulou-Alataki40,
  42. Pierre Quartier41,
  43. Donato Rigante42,
  44. Ricardo Russo43,
  45. Anna Simon44,
  46. Maria Trachana45,
  47. Yosef Uziel46,
  48. Angelo Ravelli47,
  49. Grant Schulert48,49,
  50. Marco Gattorno47,
  51. Joost Frenkel3
  1. 1Laboratory for Translational Immunology, University Medical Centre Utrecht, Utrecht, The Netherlands
  2. 2Department of Paediatric Immunology and Rheumatology, University Medical Centre Utrecht, Utrecht, The Netherlands
  3. 3Department of Paediatrics, Universitair Medisch Centrum Utrecht–Locatie Wilhelmina Kinderziekenhuis, Utrecht, The Netherlands
  4. 4Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
  5. 5National Paediatric Centre for Familial Mediterranean Fever and Gastroenterology Service, Arabkir Medical Centre–Institute of Child and Adolescent Health, Yerevan, Armenia
  6. 6Paediatric Rheumatology Unit, Hospital Sant Joan de Déu, Barcelona, Spain
  7. 7Division of Intramural Research and National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
  8. 8Departments of Paediatrics and Rheumatology, Alberta Children’s Hospital, Calgary, Alberta, Canada
  9. 9Department of Infection, Inflammation and Rheumatology, University College London Institute of Child Health, London, UK
  10. 10Rheumatology Unit, Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy
  11. 11Paediatric Clinic, University of Brescia and Spedali Civili di Brescia, Brescia, Italy
  12. 12Department of Paediatrics, National Institute for Mother and Child Health Alessandrescu-Rusescu, Bucharest, Romania
  13. 13Division of Rheumatology, Ospedale Pediatrico Bambino Gesù, Rome, Italy
  14. 14Rheumatology Program, Division of Immunology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
  15. 15Translational Autoinflammatory Disease Section, NIAMS/NIH, Bethesda, Maryland, USA
  16. 16Western University Children’s Hospital, London Health Sciences Centre, London, UK
  17. 17Department of Paediatrics and Adolescent Medicine, Charles University, General University Hospital, Praha, Czech Republic
  18. 18Autoinflammatory Alliance, San Francisco, California, USA
  19. 19Department of Internal Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
  20. 20Department of Paediatric Rheumatology, AOUG Martino, Messina, Italy
  21. 21Département de Médecine Interne et Immunologie Clinique, Université de Lille, Lille, France
  22. 22Reference Centre for Autoinflammatory Diseases (CEREMAI), Versailles Hospital, Le Chesnay, France
  23. 23Departmentof Paediatrics, Aarhus University Hospital, Aarhus, Denmark
  24. 24Department of Paediatric Rheumatology, University of Lausanne, Lausanne, Switzerland
  25. 25Departmentof Paediatric Rheumatology, University Hospital of Geneva, Geneva, Switzerland
  26. 26Department of Paediatrics, University of California, San Diego, California, USA
  27. 27Dipartimento di Medicina Pediatrica, IRCCS Ospedale Pediatrico Bambino Gesù, Roma, Italy
  28. 28Paediatric Pneumology and Immunology and Interdisciplinary Centre for Social Paediatrics, Charite University Medicine Berlin, Berlin, Germany
  29. 29Department of Rheumatology and Immunology, Dr von Hauner Children’s Hospital, Ludwig-Maximilians-University, Munich, Germany
  30. 30Department of Paediatric Rheumatology and CEREMAI, Bicêtre Hospital, APHP, University of Paris Sud, Paris, France
  31. 31Department of Immunology, Federal Research and Clinical Centre for Paediatric Haematology, Oncology and Immunology, Moscow, Russian Federation
  32. 32Division of Pediatric Rheumatology, Department of Pediatrics, University Hospital Tübingen, Tübingen, Germany
  33. 33Division of Medicine, University College London, London, UK
  34. 34Department of Paediatrics and Medicine, University of Toronto and the Hospital for Sick Children, Toronto, Ontario, Canada
  35. 35Direzione Scientifica, Istituto Giannina Gaslini, Genova, Liguria, Italy
  36. 36Paediatric Rheumatology Unit 4272, Rigshospitalet, Copenhagen, Denmark
  37. 37Department of Paediatric Rheumatic Diseases, VA Nasonova Research Institute of Rheumatology, Moscow, Russian Federation
  38. 38Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA
  39. 39Pediatric Rheumatology, Hacettepe University, Ankara, Turkey
  40. 40Fourth Department of Pediatrics, Aristotle University of Thessaloniki, Thessaloniki, Greece
  41. 41Department of Paediatric Immunology–Hematology and Rheumatology Unit and IMAGINE Institute, Institution Necker-Enfants Malades Hospital and Paris Descartes University, Paris, Île-de-France, France
  42. 42Institute of Paediatrics, Fondazione Policlinico Universitario A Gemelli, Università Cattolica Sacro Cuore, Rome, Italy
  43. 43Servicio de Inmunología/Reumatología, Hospital de Pediatria Juan P Garrahan, Buenos Aires, Argentina
  44. 44Department of General Internal Medicine, Radboud Expertise Centre for Immunodeficiency and Autoinflammation, Radboud University Medical Centre, Nijmegen, The Netherlands
  45. 45Paediatric Immunology and Rheumatology Referral Centre, First Paediatric Clinic, Aristotle University of Thessaloniki, Thessaloniki, Greece
  46. 46Department of Paediatrics, Meir Medical Centre, Kfar Saba, Israel
  47. 47Institution Università degli Studi di Genova and G Gaslini Institute, Genova, Italy
  48. 48Division of Rheumatology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
  49. 49Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio, USA
  1. Correspondence to Dr Joost Frenkel, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht 3508 AB, The Netherlands; j.frenkel{at}


Introduction Autoinflammatory diseases can cause irreversible tissue damage due to systemic inflammation. Recently, the Autoinflammatory Disease Damage Index (ADDI) was developed. The ADDI is the first instrument to quantify damage in familial Mediterranean fever, cryopyrin-associated periodic syndromes, mevalonate kinase deficiency and tumour necrosis factor receptor-associated periodic syndrome. The aim of this study was to validate this tool for its intended use in a clinical/research setting.

Methods The ADDI was scored on paper clinical cases by at least three physicians per case, independently of each other. Face and content validity were assessed by requesting comments on the ADDI. Reliability was tested by calculating the intraclass correlation coefficient (ICC) using an ‘observer-nested-within-subject’ design. Construct validity was determined by correlating the ADDI score to the Physician Global Assessment (PGA) of damage and disease activity. Redundancy of individual items was determined with Cronbach’s alpha.

Results The ADDI was validated on a total of 110 paper clinical cases by 37 experts in autoinflammatory diseases. This yielded an ICC of 0.84 (95% CI 0.78 to 0.89). The ADDI score correlated strongly with PGA-damage (r=0.92, 95% CI 0.88 to 0.95) and was not strongly influenced by disease activity (r=0.395, 95% CI 0.21 to 0.55). After comments from disease experts, some item definitions were refined. The interitem correlation in all different categories was lower than 0.7, indicating that there was no redundancy between individual damage items.

Conclusion The ADDI is a reliable and valid instrument to quantify damage in individual patients and can be used to compare disease outcomes in clinical studies.

  • inflammation
  • fever syndromes
  • familial Mediterranean fever

Statistics from


  • Handling editor Josef S Smolen

  • Contributors NMtH, ALJvD, KVA and JF designed the study, created the patient cases and wrote the manuscript. HvS contributed to the study design and analysis. KLD represented the patient’s perspective. SMAM, GA, JA, KSB, SB, PAB, LC, MC, AVC, FdB, FD, AAdJ, ED, PD, KLD, GF, RG, RGM, EH, VH, TH, MH, HMH, AI, AFJ, TK, IKP, AK, JBKD, HJL, RML, AM, SN, IN, AKO, SO, EPA, PQ, DR, RR, AS, MT, YU, AR, GS, MG and JF provided patient cases and (except for JF) scored the ADDI on the rewritten case scenarios. All authors have read and approved the manuscript.

  • Funding The project was supported by ERANET-PRIOMEDCHILD RaDiCEA Project No 40-41800-98-007. The Eurofever Registry was funded by the Executive Agency for Health and Consumers (EAHC, Project No 2007332). The consensus meeting was supported by an unrestricted grant by Novartis Pharma.

  • Disclaimer Novartis Pharma did not have any influence on the selection of participants or on the content of the ADDI/consensus meeting or the reporting of the findings.

  • Competing interests Novartis Pharma financially supported meetings with the methodologist. PAB: consultancy/speaking fees from Novartis, Roche, SOBI, UCB. FdB: Novartis, Novimmune, Hoffmann-La Roche, SOBI, AbbVie. LC: speaker’s fee from Novartis and SOBI. MC: consultancy fees for Novartis, SOBI and Abbvie. KLD: consultancy work for SOBI and Novartis; donations, honorariums and unrestricted grants have been received by the Autoinflammatory Alliance from SOBI, Novartis and Regeneron. RG: consultant for Abbvie. RGM: study support from SOBI, Novartis, Regeneron. VH: honorariums and educational grants from Novartis; honorariums from SOBI. MH: consultant for Novartis. HMH: consultant for Novartis and SOBI; speaker for Novartis. TK: research grant by Novartis; speaker’s bureau by Roche, BMS, Novartis and SOBI. JKD: consultant/speaker for Novartis and SOBI, and has received grant support from SOBI and Novartis. RML: ad board and consultant for Abbvie and Novartis. PQ: investigator, consultant and speaker’s bureau for Novartis and SOBI. MG: consultant for and unrestricted grants to Eurofever and speaker’s fee from SOBI and Novartis. YU: grant/research support from Novartis; consultant for Novartis; speaker’s bureau of Abbvie, Neopharm, Novartis, Roche. JF: consultant for Novartis. GS: consulting fees for Novartis. FD: attended to Novartis advisory board meeting.

  • Patient consent Not required.

  • Ethics approval Local IRB of each participating centre granted approval to enter patient data in the Eurofever Registry. The present study is a validation of the ADDI; development of the ADDI was approved by the IRB of UMC Utrecht.

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

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