Advertisement

Rheumatology International

, Volume 39, Issue 1, pp 29–36 | Cite as

Familial Mediterranean fever and periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome: shared features and main differences

  • Amra Adrovic
  • Sezgin Sahin
  • Kenan Barut
  • Ozgur Kasapcopur
Review
  • 358 Downloads

Abstract

Autoinflammatory diseases are characterized by fever attacks of varying durations, associated with variety of symptoms including abdominal pain, lymphadenopathy, polyserositis, arthritis, etc. Despite the diversity of the clinical presentation, there are some common features that make the differential diagnosis of the autoinflammatory diseases challenging. Familial Mediterranean fever (FMF) is the most commonly seen autoinflammatory conditions, followed by syndrome associated with periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA). In this review, we aim to evaluate disease characteristics that make a diagnosis of FMF and PFAPA challenging, especially in a regions endemic for FMF. The ethnicity of patient, the regularity of the disease attacks, and the involvement of the upper respiratory systems and symphonies could be helpful in differential diagnosis. Current data from the literature suggest the use of biological agents as an alternative for patients with FMF and PFAPA who are non-responder classic treatment options. More controlled studies are needed to evaluate the efficacy and safety of this strategy.

Keywords

Familial Mediterranean fever PFAPA syndrome Colchicine Recurrent fever Anti-interleukin-1 agents 

Notes

Author contributions

OK made a design of the paper. AA, SS, and KB provided the search of the literature and wrote the paper. OK and KB made a critical evaluation of the data collection and interpretation. SS designed a figure. All of the authors additionally revised the final version of the manuscript.

Funding

This review was not funded by any person or corporation.

Compliance with ethical standards

Conflict of interest

Author Amra Adrovic declares that she has no conflict of interest. Author Sezgin Sahin declares that he has no conflict of interest. Author Kenan Barut declares that she has no conflict of interest. Author Ozgur Kasapcopur declares that he has receiving advisory board and speaker fees from Novartis.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

References

  1. 1.
    Sag E, Bilginer Y, Ozen S (2017) Autoinflammatory diseases with periodic fevers. Curr Rheumatol Rep 19:41CrossRefGoogle Scholar
  2. 2.
    Pehlivan E, Adrovic A, Sahin S, Barut K, Kul Cınar O, Kasapcopur O (2018) PFAPA syndrome in a population with endemic familial Mediterranean fever. J Pediatr 192:253–255CrossRefGoogle Scholar
  3. 3.
    Pepper RJ, Lachmann HJ (2016) Autoinflammatory syndromes in children. Indian J Pediatr 83:242–247CrossRefGoogle Scholar
  4. 4.
    Gasparyan AY, Ayvazyan L, Blackmore H, Kitas GD (2011) Writing a narrative biomedical review: considerations for authors, peer reviewers, and editors. Rheumatol Int 31:1409–1417CrossRefGoogle Scholar
  5. 5.
    Barut K, Sahin S, Adrovic A, Sinoplu AB, Yucel G, Pamuk G, Aydın AK, Dasdemir S, Turanlı ET, Buyru N, Kasapcopur O (2018) Familial Mediterranean fever in childhood: a single center experience. Rheumatol Int 38:67–74CrossRefGoogle Scholar
  6. 6.
    Ozen S, Bilginer Y (2014) A clinical guide to autoinflammatory diseases: familial Mediterranean fever and next-of-kin. Nat Rev Rheumatol 10:135–147CrossRefGoogle Scholar
  7. 7.
    Booth DR, Gillmore JD, Lachmann HJ, Booth SE, Bybee A, Soyturk M, Akar S, Pepys MB, Tunca M, Hawkins PN (2000) The genetic basis of autosomal dominant familial Mediterranean fever. QJM 93:217–221CrossRefGoogle Scholar
  8. 8.
    Xu H, Yang J, Gao W, Li L, Li P, Zhang L, Gong YN, Peng X, Xi JJ, Chen S, Wang F, Shao F (2014) Innate immune sensing of bacterial modifications of Rho GTPases by the Pyrin inflammasome. Nature 513:237–241CrossRefGoogle Scholar
  9. 9.
    Park YH, Wood G, Kastner DL, Chae JJ (2016) Pyrin inflammasome activation and RhoA signaling in the autoinflammatory diseases FMF and HIDS. Nat Immunol 17:914–921CrossRefGoogle Scholar
  10. 10.
    Yalcinkaya F, Ozen S, Ozcakar ZB, Aktay N, Cakar N, Duzova A, Kasapcopur O, Elhan AH, Doganay B, Ekim M, Kara N, Uncu N, Bakkaloglu A (2009) A new set of criteria for the diagnosis of familial Mediterranean fever in childhood. Rheumatology 48:395–398CrossRefGoogle Scholar
  11. 11.
    Sönmez HE, Batu ED, Demir S, Bilginer Y, Özen S (2017) Comparison of patients with familial Mediterranean fever accompanied with sacroiliitis and patients with juvenile spondyloarthropathy. Clin Exp Rheumatol 35(Suppl 108):124–127Google Scholar
  12. 12.
    Ozçakar ZB, Yalçinkaya F, Cakar N, Acar B, Kasapçopur O, Ugüten D, Soy D, Kara N, Uncu N, Arisoy N, Ekim M (2008) MEFV mutations modify the clinical presentation of Henoch–Schönlein purpura. J Rheumatol 35:2427–2429CrossRefGoogle Scholar
  13. 13.
    Yalçinkaya F, Ozçakar ZB, Kasapçopur O, Oztürk A, Akar N, Bakkaloğlu A, Arisoy N, Ekim M, Ozen S (2007) Prevalence of the MEFV gene mutations in childhood polyarteritis nodosa. J Pediatr 151:675–678CrossRefGoogle Scholar
  14. 14.
    Korkmaz C, Ozdogan H, Kasapçopur O, Yazici H (2002) Acute phase response in familial Mediterranean fever. Ann Rheum Dis 61:79–81CrossRefGoogle Scholar
  15. 15.
    Gul A, Ozdogan H, Erer B, Ugurlu S, Kasapcopur O, Davis N, Sevgi S (2015) Efficacy and safety of canakinumab in adolescents and adults with colchicine-resistant familial Mediterranean fever. Arthritis Res Ther 17:243CrossRefGoogle Scholar
  16. 16.
    Sozeri B, Kasapcopur O (2015) Biological agents in familial Mediterranean fever focusing on colchicine resistance and amyloidosis. Curr Med Chem 22:1986–1991CrossRefGoogle Scholar
  17. 17.
    Kallinich T, Haffner D, Niehues T, Huss K, Lainka E, Neudorf U, Schaefer C, Stojanov S, Timmann C, Keitzer R, Ozdogan H, Ozen S (2007) Colchicine use in children and adolescents with familial Mediterranean fever: literature review and consensus statement. Pediatrics 119:e474–e483CrossRefGoogle Scholar
  18. 18.
    Özçakar ZB, Özdel S, Yılmaz S, Kurt-Şükür ED, Ekim M, Yalçınkaya F (2016) Anti-IL 1 treatment in familial Mediterranean fever and related amyloidosis. Clin Rheumatol 35:441–446CrossRefGoogle Scholar
  19. 19.
    Ozen S, Demirkaya E, Duzova A, Erdogan O, Erken E, Gul A, Kasapcopur O, Kasifoglu T, Kisacik B, Ozdogan H, Tunca M, Acikel C, FMF Arthritis Vasculitis and Orphan Disease Research in Pediatric Rheumatology (FAVOR), Turkish FMF Study Group (2014) FMF50: a score for assessing outcome in familial Mediterranean fever. Ann Rheum Dis 73:897–901CrossRefGoogle Scholar
  20. 20.
    De Benedetti F, Gattorno M, Anton J, Ben-Chetrit E, Frenkel J, Hoffman HM, Koné-Paut I, Lachmann HJ, Ozen S, Simon A, Zeft A, Calvo Penades I, Moutschen M, Quartier P, Kasapcopur O, Shcherbina A, Hofer M, Hashkes PJ, Van der Hilst J, Hara R, Bujan-Rivas S, Constantin T, Gul A, Livneh A, Brogan P, Cattalini M, Obici L, Lheritier K, Speziale A, Junge G (2018) Canakinumab for the treatment of autoinflammatory recurrent fever syndromes. N Engl J Med 378:1908–1919CrossRefGoogle Scholar
  21. 21.
    Harel L, Hashkes PJ, Lapidus S, Edwards KM, Padeh S, Gattorno M, Marshall GS (2018) The first international conference on periodic fever, aphthous stomatitis, pharyngitis, adenitis syndrome. J Pediatr 193:265–274CrossRefGoogle Scholar
  22. 22.
    Vitale A, Orlando I, Lopalco G, Emmi G, Cattalini M, Frediani B, Galeazzi M, Iannone F, Rigante D, Cantarini L (2016) Demographic, clinical and therapeutic findings in a monocentric cohort of adult patients with suspected PFAPA syndrome. Clin Exp Rheumatol 34:77–81Google Scholar
  23. 23.
    Rigante D, Vitale A, Natale MF, Lopalco G, Andreozzi L, Frediani B, D’Errico F, Iannone F, Cantarini L (2017) A comprehensive comparison between pediatric and adult patients with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenopathy (PFAPA) syndrome. Clin Rheumatol 36:463–468CrossRefGoogle Scholar
  24. 24.
    Cattalini M, Soliani M, Rigante D, Lopalco G, Iannone F, Galeazzi M, Cantarini L (2015) Basic characteristics of adults with periodic fever, aphthous stomatitis, pharyngitis, and adenopathy syndrome in comparison with the typical pediatric expression of disease. Mediat Inflamm 2015:570418CrossRefGoogle Scholar
  25. 25.
    Førsvoll J, Øymar K (2018) The role of tonsillectomy in the periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome; a literature review. BMC Ear Nose Throat Disord 22:18:3CrossRefGoogle Scholar
  26. 26.
    Stojanov S, Lapidus S, Chitkara P, Feder H, Salazar JC, Fleisher TA, Brown MR, Edwards KM, Ward MM, Colbert RA, Sun HW, Wood GM, Barham BK, Jones A, Aksentijevich I, Goldbach-Mansky R, Athreya B, Barron KS, Kastner DL (2011) Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) is a disorder of innate immunity and Th1 activation responsive to IL-1 blockade. Proc Natl Acad Sci USA 108:7148–7153CrossRefGoogle Scholar
  27. 27.
    Kolly L, Busso N, von Scheven-Gete A, Bagnoud N, Moix I, Holzinger D, Simon G, Ives A, Guarda G, So A, Morris MA, Hofer M (2013) Periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis syndrome is linked to dysregulated monocyte IL-1β production. J Allergy Clin Immunol 131:1635–1643CrossRefGoogle Scholar
  28. 28.
    Yamagami K, Nakamura T, Nakamura R, Hanioka Y, Seki K, Chiba H, Kobayashi K, Agematsu K (2017) Famillial Mediterranean fever with P369S/R408Q exon 3 varian in pyrin presenting as symptoms of PFAPA. Mod Rheumatol 27:356–359CrossRefGoogle Scholar
  29. 29.
    Berkun Y, Levy R, Hurwitz A, Meir-Harel M, Lidar M, Livneh A, Padeh S (2011) The familial Mediterranean fever gene as a modifier of periodic fever, aphthous stomatitis, pharyngitis, and adenopathy syndrome. Semin Arthritis Rheum 40:467–472CrossRefGoogle Scholar
  30. 30.
    Taniuchi S, Nishikomori R, Iharada A, Tuji S, Heike T, Kaneko K (2013) MEFV variants in patients with PFAPA syndrome in Japan. Open Rheumatol J 19:7:22–25CrossRefGoogle Scholar
  31. 31.
    Perko D, Debeljak M, Toplak N, Avčin T (2015) Clinical features and genetic background of the periodic Fever syndrome with aphthous stomatitis, pharyngitis, and adenitis: a single center longitudinal study of 81 patients. Mediat Inflamm 2015:293417CrossRefGoogle Scholar
  32. 32.
    Batu ED, Kara Eroğlu F, Tsoukas P, Hausmann JS, Bilginer Y, Kenna MA, Licameli GR, Fuhlbrigge RC, Özen S, Dedeoğlu F (2016) Periodic fever, aphthosis, pharyngitis, and adenitis syndrome: analysis of patients from two geographic areas. Arthritis Care Res (Hoboken) 68:1859–1865CrossRefGoogle Scholar
  33. 33.
    Marshall GS, Edwards KM, Lawton AR (1989) PFAPA syndrome. Pediatr Infect Dis J 8:658–659CrossRefGoogle Scholar
  34. 34.
    Thomas KT, Feder HM, Lawton AR, Edwards KM (1999) Periodic fever in children. J Pediatr 135:15–21CrossRefGoogle Scholar
  35. 35.
    Feder HM, Salazar JC (2010) A clinical review of 105 patients with PFAPA (a periodic fever syndrome). Acta Paediatr 99:178–184Google Scholar
  36. 36.
    Marshall GS, Edwards KM, Butler J, Lawton AR (1987) Syndrome of periodic fever, pharyngitis, and aphthous stomatitis. J Pediatr 110:43–46CrossRefGoogle Scholar
  37. 37.
    Federici S, Sormani MP, Ozen S, Lachmann HJ, Amaryan G, Woo P, Koné-Paut I, Dewarrat N, Cantarini L, Insalaco A, Uziel Y, Rigante D, Quartier P, Demirkaya E, Herlin T, Meini A, Fabio G, Kallinich T, Martino S, Butbul AY, Olivieri A, Kuemmerle-Deschner J, Neven B, Simon A, Ozdogan H, Touitou I, Frenkel J, Hofer M, Martini A, Ruperto N, Gattorno M, Paediatric Rheumatology International Trials Organisation (PRINTO), Eurofever Project (2015) Evidence-based provisional clinical classification criteria for autoinflammatory periodic fevers. Ann Rheum Dis 74:799–805CrossRefGoogle Scholar
  38. 38.
    Aktas O, Aytuluk HG, Caliskan SK, Erdur O, Cirik AA (2017) Long-term follow-up of tonsillectomy efficacy in children with PFAPA syndrome. Braz J Otorhinolaryngol.  https://doi.org/10.1016/j.bjorl.2017.10.012 Google Scholar
  39. 39.
    Gunes M, Cekic S, Kilic SS (2017) Is colchicine more effective to prevent periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis episodes in Mediterranean fever gene variants? Pediatr Int 59:655–660CrossRefGoogle Scholar
  40. 40.
    Dusser P, Hentgen V, Neven B, Koné-Paut I (2016) Is colchicine an effective treatment in periodic fever, aphtous stomatitis, pharyngitis, cervical adenitis (PFAPA) syndrome? Jt Bone Spine 83:406–411CrossRefGoogle Scholar
  41. 41.
    Igante D, Gentileschi S, Vitale A, Tarantino G, Cantarini L (2017) Evolving frontiers in the treatment of periodic fever, aphthous stomatitis, pharyngitis, cervical aphthous stomatitis, pharyngitis, cervical adenitis (PFAPA) syndrome. Isr Med Assoc J 19:444–447Google Scholar
  42. 42.
    Yamagami K, Nakamura T, Nakamura R, Hanioka Y, Seki K, Chiba H, Kobayashi K, Agematsu K (2017) Familial Mediterranean fever with P369S/R408Q exon3 variant in pyrin presenting as symptoms of PFAPA. Mod Rheumatol 27:356–359CrossRefGoogle Scholar
  43. 43.
    Salehzadeh F, Vahedi M, Hosseini-Asl S, Jahangiri S, Habibzadeh S, Hosseini-Khotbesara M (2014) PFAPA and 12 common MEFV gene mutations our clinical experience. Iran J Pediatr 24:64–68Google Scholar
  44. 44.
    Taniuchi S, Nishikomori R, Iharada A, Tuji S, Heike T, Kaneko K (2013) MEFV variants in patients with PFAPA syndrome in Japan. Open Rheumatol J 9:7:22–25CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Pediatric Rheumatology, Cerrahpasa Medical SchoolIstanbul UniversityIstanbulTurkey

Personalised recommendations