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Clinical Rheumatology

, Volume 38, Issue 1, pp 11–17 | Cite as

Treatment options for periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome in children and adults: a narrative review

  • Carla Gaggiano
  • Donato Rigante
  • Jurgen Sota
  • Salvatore Grosso
  • Luca CantariniEmail author
Review Article

Abstract

Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is the most frequent non-hereditary autoinflammatory disorder in childhood: Its onset is usually observed before 5 years, though reports regarding adulthood are increasing. The pathogenesis of the syndrome is not completely understood, but a multifactorial origin, probably based on a polygenic pattern of susceptibility, is the most probable rational pathogenetic hypothesis. Treatment of PFAPA syndrome relies on the administration of low-dose corticosteroids, which promptly abort flares but cannot prevent subsequent disease episodes over time. Tonsillectomy with or without adenoidectomy has proved to be successful in some pediatric patients, as proven by different studies. On the other hand, colchicine, cimetidine, nonsteroidal anti-inflammatory drugs, and interleukin-1 inhibitors have shown efficacy, which require further definite confirmations. This review is aimed at summarizing all the recent evidence about treatment options available for PFAPA syndrome both in pediatric and adult patients.

Keywords

Aphthous stomatitis Autoinflammation Cimetidine Colchicine Corticosteroids Familial Mediterranean fever Innovative biotechnologies Interleukin-1 MEFV Nonsteroidal anti-inflammatory drugs Periodic fever Personalized medicine Pharyngitis and cervical adenitis (PFAPA) syndrome Tonsillectomy 

Notes

Compliance with ethical standards

Disclosures

None.

References

  1. 1.
    Marshall GS, Edwards KM, Butler J, Lawton AR (1987) Syndrome of periodic fever, pharyngitis, and aphthous stomatitis. J Pediatr 110:43–46CrossRefGoogle Scholar
  2. 2.
    Rigante D (2009) Autoinflammatory syndromes behind the scenes of recurrent fevers in children. Med Sci Monit 15:179–187Google Scholar
  3. 3.
    Cantarini L, Vitale A, Bartolomei B, Galeazzi M, Rigante D (2012) Diagnosis of PFAPA syndrome applied to a cohort of 17 adults with unexplained recurrent fevers. Clin Exp Rheumatol 30:269–271Google Scholar
  4. 4.
    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
  5. 5.
    Gentileschi S, Vitale A, Frediani B, Galeazzi M, Rigante D, Cantarini L (2017) Challenges and new horizons in the periodic fever, aphthous stomatitis, pharingitis and adenitis (PFAPA) syndrome. Expert Opin Orphan Drugs 5:165–171CrossRefGoogle Scholar
  6. 6.
    Rigante D, Gentileschi S, Vitale A, Tarantino G, Cantarini L (2017) Evolving frontiers in the treatment of periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis (PFAPA) syndrome. Isr Med Ass J 19:444–447Google Scholar
  7. 7.
    Esposito S, Bianchini S, Fattizzo M, Baggi E, Marchisio P, Rigante D (2014) The enigma of periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome. Pediatr Infect Dis J 33:650–652CrossRefGoogle Scholar
  8. 8.
    Di Gioia S, Bedoni N, von Scheven-Gête A, Vanoni F, Superti-Furga A, Hofer M, Rivolta C (2015) Analysis of the genetic basis of periodic fever with aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome. Sci Rep 5:10200CrossRefGoogle Scholar
  9. 9.
    Manthiram K, Nesbitt E, Morgan T, Edwards K (2016) Family history in periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA) syndrome. Pediatrics 138:e20154572CrossRefGoogle Scholar
  10. 10.
    Rigante D (2017) A systematic approach to autoinflammatory syndromes: a spelling booklet for the beginner. Expert Rev Clin Immunol 13:571–597CrossRefGoogle Scholar
  11. 11.
    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 U S A 108:7148–7153CrossRefGoogle Scholar
  12. 12.
    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
  13. 13.
    Dagan E, Gershoni-Baruch R, Khatib I, Mori A, Brik R (2010) MEFV, TNF1rA, CARD15 and NLRP3 mutation analysis in PFAPA. Rheumatol Int 30:633–636CrossRefGoogle Scholar
  14. 14.
    Cheung MS, Theodoropoulou K, Lugrin J, Martinon F, Busso N, Hofer M (2017) Periodic fever with aphthous stomatitis, pharyngitis, and cervical adenitis syndrome is associated with CARD8 variant unable to bind the NLRP3 inflammasome. J Immunol 198:2063–2069CrossRefGoogle Scholar
  15. 15.
    Manthiram K, Li SC, Hausmann JS, Amarilyo G, Barron K, Kim H, Nativ S, Lionetti G, Zeft A, Goldsmith D, Kimberlin D, Edwards K, Dedeoglu F, Lapidus S, Childhood Arthritis and Rheumatology Research Alliance (CARRA) PFAPA Subcommittee (2017) Physicians’ perspectives on the diagnosis and management of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome. Rheumatol Int 37:883–889CrossRefGoogle Scholar
  16. 16.
    Ibáñez Alcalde MLM, Caldevilla Asenjo L, Calvo Rey C, García-Mon Marañés F, Blázquez Gamero D, Saavedra Lozano J, Navarro Gómez ML, Hernández-Sampelayo Matos T, Santos Sebastián M (2017) Characteristics and disease course in a cohort of children with PFAPA syndrome in the community of Madrid. Spain Reumatol Clin.  https://doi.org/10.1016/j.reuma.2017.10.015
  17. 17.
    Król P, Böhm M, Sula V, Dytrych P, Katra R, Nemcová D, Dolezalová P (2013) PFAPA syndrome: clinical characteristics and treatment outcomes in a large single-centre cohort. Clin Exp Rheumatol 31:980–987Google Scholar
  18. 18.
    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
  19. 19.
    Mehregan FF, Ziaee V, Ahmadinejad Z, Tahghighi F, Sabouni F, Moradinejad MH (2014) Periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome in Iranian children first report of Iranian periodic fever and autoinflammatory registry (IPFAIR). Iran J Pediatr 24:598–602Google Scholar
  20. 20.
    Ter Haar N, Lachmann H, Özen S, Woo P, Uziel Y, Modesto C, Koné-Paut I, Cantarini L, Insalaco A, Neven B, Hofer M, Rigante D, Al-Mayouf S, Touitou I, Gallizzi R, Papadopoulou-Alataki E, Martino S, Kuemmerle-Deschner J, Obici L, Iagaru N, Simon A, Nielsen S, Martini A, Ruperto N, Gattorno M, Frenkel J, Paediatric Rheumatology International Trials Organisation (PRINTO) and the Eurofever/Eurotraps Projects (2013) Treatment of autoinflammatory diseases: results from the Eurofever registry and a literature review. Ann Rheum Dis 72:678–685CrossRefGoogle Scholar
  21. 21.
    Federici S, Gattorno M (2014) A practical approach to the diagnosis of autoinflammatory diseases in childhood. Best Pract Res Clin Rheumatol 28:263–276CrossRefGoogle Scholar
  22. 22.
    Celiksoy MH, Ogur G, Yaman E, Abur U, Fazla S, Sancak R, Yildiran A (2016) Could familial Mediterranean fever gene mutations be related to PFAPA syndrome? Pediatr Allergy Immunol 27:78–82CrossRefGoogle Scholar
  23. 23.
    Feder HM, Salazar JC (2010) A clinical review of 105 patients with PFAPA (a periodic fever syndrome). Acta Paediatr 99:178–184Google Scholar
  24. 24.
    Padeh S (2005) Periodic fever syndromes. Pediatr Clin N Am 52:577–609CrossRefGoogle Scholar
  25. 25.
    Ahmadinejad Z, Mansori S, Ziaee V, Alijani N, Aghighi Y, Parvaneh N, Mordinejad MH (2014) Periodic fever: a review on clinical, management and guideline for Iranian patients—part I. Iran J Pediatr 24:1–13Google Scholar
  26. 26.
    Wurster VM, Carlucci JG, Feder HM Jr, Edwards KM (2011) Long-term follow-up of children with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis syndrome. J Pediatr 159:958–964CrossRefGoogle Scholar
  27. 27.
    Rigante D, La Torraca I, Avallone L, Pugliese AL, Gaspari S, Stabile A (2006) The pharmacological basis of treatment with colchicine in children with familial Mediterranean fever. Eur Rev Med Pharmacol Sci 10:173–178Google Scholar
  28. 28.
    Lachmann HJ (2017) Periodic fever syndromes. Best Pract Res Clin Rheumatol 31:596–609CrossRefGoogle Scholar
  29. 29.
    Butbul Aviel Y, Tatour S, Gershoni Baruch R, Brik R (2016) Colchicine as a therapeutic option in periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis (PFAPA) syndrome. Semin Arthritis Rheum 45:471–474CrossRefGoogle Scholar
  30. 30.
    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
  31. 31.
    Dusser P, Hentgen V, Neven B, Koné-Paut I (2016) Is colchicine an effective treatment in periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis (PFAPA) syndrome? Joint Bone Spine 83:406–411CrossRefGoogle Scholar
  32. 32.
    Wekell P, Karlsson A, Berg S, Fasth A (2016) Review of autoinflammatory diseases, with a special focus on periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome. Acta Paediatr 105:1140–1151CrossRefGoogle Scholar
  33. 33.
    Yasuura S, Harada Y (2017) A case of adult-onset periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome in Japan. J Gen Fam Med 18:261–264CrossRefGoogle Scholar
  34. 34.
    Taniguchi K, Ono N, Sakai T, Ichiyama Y, Uemichi K (2016) Response to cimetidine in a 1-year-old child with PFAPA syndrome. Turk J Pediatr 58:687–689CrossRefGoogle Scholar
  35. 35.
    Kutsuna S, Ohmagari N, Tanizaki R, Hagino N, Nishikomori R, Ujiie M, Takeshita N, Hayakawa K, Kato Y, Kanagawa S (2016) The first case of adult-onset PFAPA syndrome in Japan. Mod Rheumatol 26:286–287CrossRefGoogle Scholar
  36. 36.
    Thomas KT, Feder HM Jr, Lawton AR, Edwards KM (1999) Periodic fever syndrome in children. J Pediatr 135:15–21CrossRefGoogle Scholar
  37. 37.
    Pignataro L, Torretta S, Pietrogrande MC, Dellepiane RM, Pavesi P, Bossi A, Drago L, Capaccio P (2009) Outcome of tonsillectomy in selected patients with PFAPA syndrome. Arch Otolaryngol Head Neck Surg 135:548–553CrossRefGoogle Scholar
  38. 38.
    Padeh S, Brezniak N, Zemer D, Pras E, Livneh A, Langevitz P, Migdal A, Pras M, Passwell JH (1999) Periodic fever, aphthous stomatitis, pharyngitis, and adenopathy syndrome: clinical characteristics and outcome. J Pediatr 135:98–101CrossRefGoogle Scholar
  39. 39.
    Dahn KA, Glode MP, Chan KH (2000) Periodic fever and pharyngitis in young children: a new disease for the otolaryngologist? Arch Otolaryngol Head Neck Surg 126:1146–1149CrossRefGoogle Scholar
  40. 40.
    Peridis S, Koudoumnakis E, Theodoridis A, Stefanaki K, Helmis G, Houlakis M (2010) Surgical outcomes and histology findings after tonsillectomy in children with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis syndrome. Am J Otolaryngol 31:472–475CrossRefGoogle Scholar
  41. 41.
    Kyvsgaard N, Mikkelsen T, Korsholm J, Veirum JE, Herlin T (2012) Periodic fever associated with aphthous stomatitis, pharyngitis and cervical adenitis. Dan Med J 59:A4452Google Scholar
  42. 42.
    Licameli G, Lawton M, Kenna M, Dedeoglu F (2012) Long-term surgical outcomes of adenotonsillectomy for PFAPA syndrome. Arch Otolaryngol Head Neck Surg 138:902–906CrossRefGoogle Scholar
  43. 43.
    Førsvoll J, Kristoffersen EK, Øymar K (2013) Incidence, clinical characteristics and outcome in Norwegian children with periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome; a population-based study. Acta Paediatr 102:187–192CrossRefGoogle Scholar
  44. 44.
    Parikh SR, Reiter ER, Kenna MA, Roberson D (2003) Utility of tonsillectomy in 2 patients with the syndrome of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis. Arch Otolaryngol Head Neck Surg 129:670–673CrossRefGoogle Scholar
  45. 45.
    Leong SC, Karkos PD, Apostolidou MT (2006) Is there a role for the otolaryngologist in PFAPA syndrome? A systematic review. Int J Pediatr Otorhinolaryngol 70:1841–1845CrossRefGoogle Scholar
  46. 46.
    Peridis S, Pilgrim G, Koudoumnakis E, Athanasopoulos I, Houlakis M, Parpounas K (2010) PFAPA syndrome in children: a meta-analysis on surgical versus medical treatment. Int J Pediatr Otorhinolaryngol 74:1203–1208CrossRefGoogle Scholar
  47. 47.
    Vigo G, Martini G, Zoppi S, Vittadello F, Zulian F (2014) Tonsillectomy efficacy in children with PFAPA syndrome is comparable to the standard medical treatment: a long-term observational study. Clin Exp Rheumatol 32:156–159Google Scholar
  48. 48.
    Erdogan F, Kulak K, Öztürk O, İpek İÖ, Ceran Ö, Seven H (2016) Surgery vs medical treatment in the management of PFAPA syndrome: a comparative trial. Paediatr Int Child Health 36:270–274CrossRefGoogle Scholar
  49. 49.
    Renko M, Salo E, Putto-Laurila A, Saxen H, Mattila PS, Luotonen J, Ruuskanen O, Uhari M (2007) A randomized, controlled trial of tonsillectomy in periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome. J Pediatr 151:289–292CrossRefGoogle Scholar
  50. 50.
    Spalding SJ, Hashkes PJ (2008) The role of tonsillectomy in management of periodic fever, aphthous stomatitis, pharyngitis, and adenopathy: unanswered questions. J Pediatr 152:742–743CrossRefGoogle Scholar
  51. 51.
    Lantto U, Koivunen P, Tapiainen T, Renko M (2016) Long-term outcome of classic and incomplete PFAPA (periodic fever, aphthous stomatitis, pharyngitis, and adenitis) syndrome after tonsillectomy. J Pediatr 179:172–177CrossRefGoogle Scholar
  52. 52.
    Garavello W, Romagnoli M, Gaini RM (2009) Effectiveness of adenotonsillectomy in PFAPA syndrome: a randomized study. J Pediatr 155:250–253CrossRefGoogle Scholar
  53. 53.
    Burton MJ, Pollard AJ, Ramsden JD, Chong LY, Venekamp RP (2014) Tonsillectomy for periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome (PFAPA). Cochrane Database Syst Rev 9:CD008669Google Scholar
  54. 54.
    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 18:3CrossRefGoogle Scholar
  55. 55.
    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
  56. 56.
    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
  57. 57.
    Lopalco G, Rigante D, Vitale A, Caso F, Iannone F, Cantarini L (2017) Canakinumab efficacy in refractory adult-onset PFAPA syndrome. Int J Rheum Dis 20:1050–1051CrossRefGoogle Scholar
  58. 58.
    Hasan S, Saeed S, Rai A, Kumar A, Choudhary P, Panigrahi R, Sahu PK (2018) Thalidomide: clinical implications in oral mucosal lesions—an update. Ann Med Health Sci Res 8:21–28Google Scholar
  59. 59.
    Marque M, Guillot B, Bessis D (2007) Thalidomide for treatment of PFAPA syndrome. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 103:306–307CrossRefGoogle Scholar
  60. 60.
    Pinto A, Lindemeyer RG, Sollecito TP (2007) Thalidomide in PFAPA syndrome. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 103:307CrossRefGoogle Scholar
  61. 61.
    Mahamid M, Agbaria K, Mahamid A, Nseir W (2013) Vitamin D linked to PFAPA syndrome. Int J Pediatr Otorhinolaryngol 77:362–364CrossRefGoogle Scholar
  62. 62.
    Stagi S, Bertini F, Rigante D, Falcini F (2014) Vitamin D levels and effects of vitamin D replacement in children with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome. Int J Pediatr Otorhinolaryngol 78:964–968CrossRefGoogle Scholar
  63. 63.
    Rico Rodes A, Sabrido Bermúdez G, Llombart Vidal A, Alcalá Minagorre PJ (2016) Periodic fever, aphtous stomatitis, pharyngitis and adenopathy syndrome and vitamin D: a possible treatment option? Reumatol Clin 12:363–364CrossRefGoogle Scholar
  64. 64.
    Buongiorno A, Pierossi N (2015) Effectiveness of pidotimod in combination with bacterial lysates in the treatment of the PFAPA (periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis) syndrome. Minerva Pediatr 67:219–226Google Scholar
  65. 65.
    Di Pierro F, Campana A, Panatta ML, Antenucci V, De Vincentiis G (2016) The use of Streptococcus salivarius K12 in attenuating PFAPA syndrome. A pilot study. Altern Integr Med 5:222Google Scholar
  66. 66.
    Grimwood C, Koné-Paut I, Piram M, Rossi-Semerano L, Hentgen V (2018) Health-related quality of life in children with PFAPA syndrome. Orphanet J Rare Dis 13:132CrossRefGoogle Scholar
  67. 67.
    Rigante D (2018) A developing portrait of hereditary periodic fevers in childhood. Expert Opin Orphan Drugs 6:47–55CrossRefGoogle Scholar
  68. 68.
    Rigante D, Frediani B, Galeazzi M, Cantarini L (2013) From the Mediterranean to the sea of Japan: the transcontinental odyssey of autoinflammatory diseases. Biomed Res Int 2013:485103CrossRefGoogle Scholar
  69. 69.
    Rigante D (2018) New mosaic tiles in childhood hereditary autoinflammatory disorders. Immunol Lett 193:67–76CrossRefGoogle Scholar
  70. 70.
    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
  71. 71.
    Cantarini L, Vitale A, Sicignano LL, Emmi G, Verrecchia E, Patisso I, Cerrito L, Fabiani C, Cevenini G, Frediani B, Galeazzi M, Rigante D, Manna R (2017) Diagnostic criteria for adult-onset periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome. Front Immunol 8:1018CrossRefGoogle Scholar

Copyright information

© International League of Associations for Rheumatology (ILAR) 2018

Authors and Affiliations

  1. 1.Institute of PediatricsUniversity of SienaSienaItaly
  2. 2.Institute of PediatricsUniversità Cattolica Sacro CuoreRomeItaly
  3. 3.Fondazione Policlinico Universitario A. Gemelli IRCCSRomeItaly
  4. 4.Research Center of Systemic Autoinflammatory Diseases and Behçet’s Disease and Rheumatology-Ophthalmology Collaborative Uveitis Center, Department of Medical Sciences, Surgery and NeurosciencesUniversity of SienaSienaItaly
  5. 5.Policlinico “Le Scotte”SienaItaly

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