Clinical Approach to the Diagnosis of Autoinflammatory Diseases

  • Philip J. HashkesEmail author
  • Karyl S. Barron
  • Ronald M. Laxer


In this chapter, we present the clinical approach to patients with a suspected autoinflammatory syndrome. We describe a systematic approach to the history, physical examination, system involvement and laboratory testing and offer an algorithm on investigative pathways for these patients. We discuss the various diagnostic criteria currently used for specific autoinflammatory diseases. Finally, we propose an approach, including empiric treatment and management, to the many patients with suspected autoinflammatory syndromes who remain undiagnosed, despite a comprehensive work-up, including genetic testing.


Autoinflammatory syndrome Diagnosis Management Diagnostic criteria 



Aicardi-Goutières syndrome


Autoinflammatory diseases activity index


Adaptor related protein complex 1 sigma 3 subunit


Autoinflammation and PLAID


Cryopyrin-associated periodic syndromes


Caspase activation and recruitment domain


Chronic non-bacterial osteomyelitis


Deficiency of adenosine deaminase 2


Deficiency of the IL-1 receptor antagonist


Deficiency of the IL-36 receptor antagonist (generalized pustular psoriasis)


Familial cold autoinflammatory syndrome


Familial Mediterranean fever


Inflammatory bowel disease




Macrophage activation syndrome


Mevalonate kinase deficiency


Muckle-Wells syndrome


Nucleotide-binding oligomerization (NOD), leucine rich repeats and CARD domain containing


Nucleotide-binding domain, leucine-rich repeat, and pyrin domain containing


Neonatal-onset multisystem inflammatory disease


Pyrin-associated autoinflammation with neutrophilic dermatosis


Pyogenic sterile arthritis, pyoderma gangrenosum, and acne


Periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis


Periodic fever, immunodeficiency and thrombocytopenia


PLCγ2-associated antibody deficiency and immune dysregulation


Proline-serine-threonine phosphatase-interacting protein 1


Synovitis, acne, pustulosis, hyperostosis and osteitis


STING-associated vasculopathy with onset in infancy


Sideroblastic anemia, immunodeficiency, fevers, and developmental delay


Systemic juvenile idiopathic arthritis


Tumor necrosis factor


Tumor necrosis factor receptor-associated periodic syndrome


  1. 1.
    Masters SL, Simon A, Aksentijevich I, Kastner DL. Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease. Annu Rev Immunol. 2009;27:621–68.CrossRefGoogle Scholar
  2. 2.
    Barron K, Kastner D. Periodic fever syndromes and other inherited autoinflammatory diseases. In: Petty RE, Laxer RM, Lindsley CB, Wedderburn LR, editors. Textbook of pediatric rheumatology. 7th ed. Philadelphia, PA: Elsevier; 2014. p. 609–26.Google Scholar
  3. 3.
    Gattorno M, Sormani MP, D’Osualdo A, et al. A diagnostic score for molecular analysis of hereditary autoinflammatory syndromes with periodic fever in children. Arthritis Rheum. 2008;58:1823–32.CrossRefGoogle Scholar
  4. 4.
    Federici L, Rittore-Domingo C, Kone-Paut I, et al. A decision tree for genetic diagnosis of hereditary periodic fevers in unselected patients. Ann Rheum Dis. 2006;65:1427–32.CrossRefGoogle Scholar
  5. 5.
    Gattorno M, Caorsi R, Meini A, et al. Differentiating PFAPA syndrome from monogenic periodic fevers. Pediatrics. 2009;124:e721–8.CrossRefGoogle Scholar
  6. 6.
    Livneh A, Langevitz P, Zemer D, et al. Criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum. 1997;40:1879–85.CrossRefGoogle Scholar
  7. 7.
    Yalçinkaya F, Ozen S, Ozçakar ZB, et al. A new set of criteria for the diagnosis of familial Mediterranean fever in childhood. Rheumatology (Oxford). 2009;48:395–8.CrossRefGoogle Scholar
  8. 8.
    Kondi A, Hentgen V, Piram M, Letierce A, Guillaume-Czitrom S, Koné-Paut I. Validation of the new paediatric criteria for the diagnosis of familial Mediterranean fever: data from a mixed population of 100 children from the French reference centre for auto-inflammatory disorders. Rheumatology (Oxford). 2010;49:2200–3.CrossRefGoogle Scholar
  9. 9.
    Ozçakar ZB, Yalçınkaya F, Cakar N, et al. Application of the new pediatric criteria and Tel Hashomer criteria in heterozygous patients with clinical features of FMF. Eur J Pediatr. 2011;170:1055–7.CrossRefGoogle Scholar
  10. 10.
    Demirkaya E, Saglam C, Turker T, et al. Paediatric Rheumatology International Trials Organisations (PRINTO) Eurofever Project. Performance of different diagnostic criteria for familial Mediterranean fever in children with periodic fevers: results from a multicenter international registry. J Rheumatol. 2016;43:154–60.CrossRefGoogle Scholar
  11. 11.
    International Team for the Revision of the International Criteria for Behçet’s Disease (ITR-ICBD). The International Criteria for Behçet’s Disease (ICBD): a collaborative study of 27 countries on the sensitivity and specificity of the new criteria. J Eur Acad Dermatol Venereol. 2014;28:338–47.Google Scholar
  12. 12.
    Koné-Paut I, Shahram F, Darce-Bello M, et al. Consensus classification criteria for paediatric Behçet’s disease from a prospective observational cohort: PEDBD. Ann Rheum Dis. 2016;75:958–64.CrossRefGoogle Scholar
  13. 13.
    Federici S, Sormani MP, Ozen S, et al. Paediatric Rheumatology International Trials Organisation (PRINTO) and Eurofever Project. Evidence-based provisional clinical classification criteria for autoinflammatory periodic fevers. Ann Rheum Dis. 2015;74:799–805.CrossRefGoogle Scholar
  14. 14.
    Kuemmerle-Deschner JB, Ozen S, Tyrrell PN, et al. Diagnostic criteria for cryopyrin-associated periodic syndrome (CAPS). Ann Rheum Dis. 2017;76:942–7.CrossRefGoogle Scholar
  15. 15.
    Drenth JP, van der Meer JW. Hereditary periodic fever. N Engl J Med. 2001;345:1748–57.CrossRefGoogle Scholar
  16. 16.
    John C, Gilsdorf J. Recurrent fever in children. Pediatr Infect Dis J. 2002;21:1071–7.CrossRefGoogle Scholar
  17. 17.
    Long SS. Distinguishing among prolonged, recurrent, and periodic fever syndromes: approach of a pediatric infectious diseases subspecialist. Pediatr Clin N Am. 2005;52:811–35.CrossRefGoogle Scholar
  18. 18.
    Zeft AS, Spalding SJ. Autoinflammatory syndromes: fever is not always a sign of infection. Cleve Clin J Med. 2012;79:569–81.CrossRefGoogle Scholar
  19. 19.
    Hashkes PJ, Toker O. Autoinflammatory syndromes. Pediatr Clin N Am. 2012;59:447–70.CrossRefGoogle Scholar
  20. 20.
    Federici S, Gattorno M. A practical approach to the diagnosis of autoinflammatory diseases in childhood. Best Pract Res Clin Rheumatol. 2014;28:263–76.CrossRefGoogle Scholar
  21. 21.
    Lidar M, Giat E. An up-to-date approach to a patient with a suspected autoinflammatory disease. Rambam Maimonides Med J. 2017;30:1.Google Scholar
  22. 22.
    Jamilloux Y, Belot A, Magnotti F, et al. Geoepidemiology and immunologic features of autoinflammatory diseases: a comprehensive review. Clin Rev Allergy Immunol. 2018;54:454–79.CrossRefGoogle Scholar
  23. 23.
    Vitale A, Rigante D, Lucherini OM, et al. The diagnostic evaluation of patients with a suspected hereditary periodic fever syndrome: experience from a referral center in Italy. Intern Emerg Med. 2017;12:605–11.CrossRefGoogle Scholar
  24. 24.
    Hashkes PJ. Profile of a pediatric rheumatology practice in Israel. Clin Exp Rheumatol. 2003;21:123–8.PubMedGoogle Scholar
  25. 25.
    Lidar M, Tokov I, Chetrit A, Zaks N, Langevitz P, Livneh A. Diagnosis delay in familial Mediterranean fever (FMF): social and gender gaps disclosed. Clin Exp Rheumatol. 2005;23:357–63.PubMedGoogle Scholar
  26. 26.
    Berody S, Galeotti C, Koné-Paut I, Piram M. A retrospective survey of patients’s journey before the diagnosis of mevalonate kinase deficiency. Joint Bone Spine. 2015;82:240–4.CrossRefGoogle Scholar
  27. 27.
    Ozen S, Kuemmerle-Deschner JB, Cimaz R, et al. International retrospective chart review of treatment patterns in severe familial Mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome, and mevalonate kinase deficiency/hyperimmunoglobulinemia D syndrome. Arthritis Care Res (Hoboken). 2017;69:578–86.CrossRefGoogle Scholar
  28. 28.
    Piram M, Koné-Paut I, Lachmann HJ, et al. Validation of the auto-inflammatory diseases activity index (AIDAI) for hereditary recurrent fever syndromes. Ann Rheum Dis. 2014;73:2168–73.CrossRefGoogle Scholar
  29. 29.
    Manthiram K, Nesbitt E, Morgan T, Edwards KM. Family history in periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA) syndrome. Pediatrics. 2016;138:e20154572.CrossRefGoogle Scholar
  30. 30.
    Manthiram K, Li SC, Hausmann JS, et al. Childhood Arthritis and Rheumatology Research Alliance (CARRA) PFAPA Subcommittee. Physicians’ perspectives on the diagnosis and management of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome. Rheumatol Int. 2017;37:883–9.CrossRefGoogle Scholar
  31. 31.
    Harrison SR, McGonagle D, Nizam S, et al. Anakinra as a diagnostic challenge and treatment option for systemic autoinflammatory disorders of undefined etiology. JCI Insight. 2016;1:e86336.CrossRefGoogle Scholar
  32. 32.
    Padeh S, Livneh A, Pras E, et al. Familial Mediterranean Fever in the first two years of life: a unique phenotype of disease in evolution. J Pediatr. 2010;156:985–9.CrossRefGoogle Scholar
  33. 33.
    Moreira A, Torres B, Peruzzo J, Mota A, Eyerich K, Ring J. Skin symptoms as diagnostic clue for autoinflammatory diseases. An Bras Dermatol. 2017;92:72–80.CrossRefGoogle Scholar
  34. 34.
    Abramson JS, Givner LB, Thompson JN. Possible role of tonsillectomy and adenoidectomy in children with recurrent fever and tonsillopharyngitis. Pediatr Infect Dis J. 1989;8:119–20.PubMedGoogle Scholar
  35. 35.
    Licameli G, Jeffrey J, Luz J, Jones D, Kenna M. Effect of adenotonsillectomy in PFAPA syndrome. Arch Otolaryngol Head Neck Surg. 2008;134:136–40.CrossRefGoogle Scholar
  36. 36.
    Dusser P, Hentgen V, Neven B, Koné-Paut I. Is colchicine an effective treatment in periodic fever, aphtous stomatitis, pharyngitis, cervical adentitis (PFAPA) syndrome? Joint Bone Spine. 2016;83:406–11.CrossRefGoogle Scholar
  37. 37.
    Aggarwal R, Ringold S, Khanna D, et al. Distinctions between diagnostic and classification criteria. Arthritis Care Res (Hoboken). 2015;67:891–7.CrossRefGoogle Scholar
  38. 38.
    Sohar E, Gafni J, Pras M, Heller H. Familial Mediterranean fever. A survey of 470 cases and review of the literature. Am J Med. 1967;43:227–53.CrossRefGoogle Scholar
  39. 39.
    Butbul Aviel Y, Tatour S, Gershoni Baruch R, Brik R. Colchicine as a therapeutic option in periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis (PFAPA) syndrome. Semin Arthritis Rheum. 2016;45:471–4.CrossRefGoogle Scholar
  40. 40.
    Gunes M, Cekic S, Kilic SS. Is colchicine more effective to prevent periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis episodes in Mediterranean fever gene variants? Pediatr Int. 2017;59:655–60.CrossRefGoogle Scholar
  41. 41.
    Marshall GS, Edwards KM, Butler J, Lawton AR. Syndrome of periodic fever, pharyngitis, and aphthous stomatitis. J Pediatr. 1987;110:43–6.CrossRefGoogle Scholar
  42. 42.
    Marshall GS, Edwards KM, Lawton AR. PFAPA syndrome. Pediatr Infect Dis J. 1989;8:658–9.CrossRefGoogle Scholar
  43. 43.
    Thomas KT, Feder HM Jr, Lawton AR, Edwards KM. Periodic fever syndrome in children. J Pediatr. 1999;135:15–21.CrossRefGoogle Scholar
  44. 44.
    Berkun Y, Levy R, Hurwitz A, et al. The familial Mediterranean fever gene as a modifier of periodic fever, aphthous stomatitis and adenopathy syndrome. Semin Arthritis Rheum. 2011;40:467–72.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Philip J. Hashkes
    • 1
    Email author
  • Karyl S. Barron
    • 2
  • Ronald M. Laxer
    • 3
  1. 1.Pediatric Rheumatology UnitShaare Zedek Medical Center and Hebrew UniversityJerusalemIsrael
  2. 2.National Institute of Allergy and Infectious Diseases, National Institutes of HealthBethesdaUSA
  3. 3.Department Paediatrics, Division of RheumatologyThe Hospital for Sick Children and University of TorontoTorontoCanada

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