Skip to main content
SpringerLink
Log in

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

  • Review Article
  • Published:
Clinical Rheumatology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Marshall GS, Edwards KM, Butler J, Lawton AR (1987) Syndrome of periodic fever, pharyngitis, and aphthous stomatitis. J Pediatr 110:43–46

    Article  CAS  PubMed  Google Scholar 

  2. Rigante D (2009) Autoinflammatory syndromes behind the scenes of recurrent fevers in children. Med Sci Monit 15:179–187

    Google Scholar 

  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 30:269–271

    PubMed  Google Scholar 

  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 36:463–468

    Article  PubMed  Google Scholar 

  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 5:165–171

    Article  CAS  Google Scholar 

  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 19:444–447

    Google Scholar 

  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 33:650–652

    Article  PubMed  Google Scholar 

  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 5:10200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Manthiram K, Nesbitt E, Morgan T, Edwards K (2016) Family history in periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA) syndrome. Pediatrics 138:e20154572

    Article  PubMed  PubMed Central  Google Scholar 

  10. Rigante D (2017) A systematic approach to autoinflammatory syndromes: a spelling booklet for the beginner. Expert Rev Clin Immunol 13:571–597

    Article  CAS  PubMed  Google Scholar 

  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 108:7148–7153

    Article  PubMed  PubMed Central  Google Scholar 

  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 131:1635–1643

    Article  CAS  PubMed  Google Scholar 

  13. Dagan E, Gershoni-Baruch R, Khatib I, Mori A, Brik R (2010) MEFV, TNF1rA, CARD15 and NLRP3 mutation analysis in PFAPA. Rheumatol Int 30:633–636

    Article  CAS  PubMed  Google Scholar 

  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 198:2063–2069

    Article  CAS  PubMed  Google Scholar 

  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 37:883–889

    Article  PubMed  Google Scholar 

  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. 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 31:980–987

    PubMed  Google Scholar 

  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 2015:570418

    Article  CAS  Google Scholar 

  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 24:598–602

    PubMed  PubMed Central  Google Scholar 

  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 72:678–685

    Article  Google Scholar 

  21. Federici S, Gattorno M (2014) A practical approach to the diagnosis of autoinflammatory diseases in childhood. Best Pract Res Clin Rheumatol 28:263–276

    Article  PubMed  Google Scholar 

  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 27:78–82

    Article  PubMed  Google Scholar 

  23. Feder HM, Salazar JC (2010) A clinical review of 105 patients with PFAPA (a periodic fever syndrome). Acta Paediatr 99:178–184

    CAS  PubMed  Google Scholar 

  24. Padeh S (2005) Periodic fever syndromes. Pediatr Clin N Am 52:577–609

    Article  Google Scholar 

  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 24:1–13

    PubMed  Google Scholar 

  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 159:958–964

    Article  PubMed  Google Scholar 

  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 10:173–178

    CAS  PubMed  Google Scholar 

  28. Lachmann HJ (2017) Periodic fever syndromes. Best Pract Res Clin Rheumatol 31:596–609

    Article  PubMed  Google Scholar 

  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 45:471–474

    Article  CAS  PubMed  Google Scholar 

  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 59:655–660

    Article  CAS  PubMed  Google Scholar 

  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 83:406–411

    Article  CAS  PubMed  Google Scholar 

  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 105:1140–1151

    Article  PubMed  PubMed Central  Google Scholar 

  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 18:261–264

    Article  PubMed  PubMed Central  Google Scholar 

  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 58:687–689

    Article  PubMed  Google Scholar 

  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 26:286–287

    Article  PubMed  Google Scholar 

  36. Thomas KT, Feder HM Jr, Lawton AR, Edwards KM (1999) Periodic fever syndrome in children. J Pediatr 135:15–21

    Article  CAS  PubMed  Google Scholar 

  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 135:548–553

    Article  PubMed  Google Scholar 

  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 135:98–101

    Article  CAS  PubMed  Google Scholar 

  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 126:1146–1149

    Article  CAS  PubMed  Google Scholar 

  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 31:472–475

    Article  PubMed  Google Scholar 

  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:A4452

    PubMed  Google Scholar 

  42. Licameli G, Lawton M, Kenna M, Dedeoglu F (2012) Long-term surgical outcomes of adenotonsillectomy for PFAPA syndrome. Arch Otolaryngol Head Neck Surg 138:902–906

    Article  PubMed  Google Scholar 

  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 102:187–192

    Article  PubMed  Google Scholar 

  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 129:670–673

    Article  PubMed  Google Scholar 

  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 70:1841–1845

    Article  CAS  PubMed  Google Scholar 

  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 74:1203–1208

    Article  PubMed  Google Scholar 

  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 32:156–159

    Google Scholar 

  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 36:270–274

    Article  PubMed  Google Scholar 

  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 151:289–292

    Article  CAS  PubMed  Google Scholar 

  50. Spalding SJ, Hashkes PJ (2008) The role of tonsillectomy in management of periodic fever, aphthous stomatitis, pharyngitis, and adenopathy: unanswered questions. J Pediatr 152:742–743

    Article  PubMed  Google Scholar 

  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 179:172–177

    Article  PubMed  Google Scholar 

  52. Garavello W, Romagnoli M, Gaini RM (2009) Effectiveness of adenotonsillectomy in PFAPA syndrome: a randomized study. J Pediatr 155:250–253

    Article  PubMed  Google Scholar 

  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:CD008669

    Google Scholar 

  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 18:3

    Article  PubMed  PubMed Central  Google Scholar 

  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. 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 192:253–255

    Article  PubMed  Google Scholar 

  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 20:1050–1051

    Article  PubMed  Google Scholar 

  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 8:21–28

    Google Scholar 

  59. Marque M, Guillot B, Bessis D (2007) Thalidomide for treatment of PFAPA syndrome. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 103:306–307

    Article  PubMed  Google Scholar 

  60. Pinto A, Lindemeyer RG, Sollecito TP (2007) Thalidomide in PFAPA syndrome. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 103:307

    Article  Google Scholar 

  61. Mahamid M, Agbaria K, Mahamid A, Nseir W (2013) Vitamin D linked to PFAPA syndrome. Int J Pediatr Otorhinolaryngol 77:362–364

    Article  PubMed  Google Scholar 

  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 78:964–968

    Article  PubMed  Google Scholar 

  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 12:363–364

    Article  PubMed  Google Scholar 

  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 67:219–226

    CAS  PubMed  Google Scholar 

  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 5:222

    Google Scholar 

  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 13:132

    Article  PubMed  PubMed Central  Google Scholar 

  67. Rigante D (2018) A developing portrait of hereditary periodic fevers in childhood. Expert Opin Orphan Drugs 6:47–55

    Article  Google Scholar 

  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 2013:485103

    Article  PubMed  PubMed Central  Google Scholar 

  69. Rigante D (2018) New mosaic tiles in childhood hereditary autoinflammatory disorders. Immunol Lett 193:67–76

    Article  CAS  PubMed  Google Scholar 

  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) 68:1859–1865

    Article  Google Scholar 

  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 8:1018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Pediatrics, University of Siena, Siena, Italy

    Carla Gaggiano & Salvatore Grosso

  2. Institute of Pediatrics, Università Cattolica Sacro Cuore, Rome, Italy

    Donato Rigante

  3. Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy

    Donato Rigante

  4. Research Center of Systemic Autoinflammatory Diseases and Behçet’s Disease and Rheumatology-Ophthalmology Collaborative Uveitis Center, Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy

    Jurgen Sota & Luca Cantarini

  5. Policlinico “Le Scotte”, Viale Bracci 1, 53100, Siena, Italy

    Luca Cantarini

Authors
  1. Carla Gaggiano
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Donato Rigante
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jurgen Sota
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Salvatore Grosso
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Luca Cantarini
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Luca Cantarini.

Ethics declarations

Disclosures

None.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gaggiano, C., Rigante, D., Sota, J. et al. Treatment options for periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome in children and adults: a narrative review. Clin Rheumatol 38, 11–17 (2019). https://doi.org/10.1007/s10067-018-4361-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10067-018-4361-2

Keywords

Search

Navigation