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Independent risk factors for resolution of periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome within 4 years after the disease onset

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Abstract

Background/Objective

Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome is a polygenic disease with unknown etiology. In this retrospective cohort study, we aimed to evaluate the risk factors for the resolution of PFAPA syndrome within 4 years after the onset.

Methods

In total, 466 patients with PFAPA syndrome that are being followed up our department were included into the study. Between May 2020 and September 2020, medical charts of the patients were reviewed retrospectively.

Results

The median age of the patients at the time of the study and at disease onset were 8.6 (2.9–20.5; IQR 6.9–10.6) years and 18 (1–84; IQR 11-31) months. On univariate analysis age at disease onset (p = 0.003), positive family history of PFAPA syndrome (p = 0.04), absence of myalgia (p = 0.04), and absence of headache (p = 0.003) were all associated with the resolution of PFAPA syndrome within 4 years after the onset. Multivariate logistic regression analysis revealed that age at disease onset (OR 1.04, 95% CI 1.01–1.07, p = 0.002), positive family history of PFAPA syndrome (OR 2.69, 95% CI 1.12–6.48, p = 0.02), and absence of headache (OR 0.2, 95% CI 0.05–0.74, p = 0.01) were independent risk factors for the resolution of PFAPA syndrome within 4 years after the onset.

Conclusion

We report later age of disease onset, positive family history of PFAPA syndrome, and absence of headache as independent risk factors for resolution of PFAPA syndrome within 4 years after the onset.

Key points:

• Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome is a multifactorial disease with unknown etiology.

• Although, PFAPA syndrome usually resolves within 3–5 years after the disease onset, it can persist for years and even continue into adulthood. With our current knowledge, there is no clue to predict which patients will have a long disease course and which patients will not.

• Later age of disease onset, positive family history of PFAPA syndrome and absence of headache as independent risk factors for resolution of PFAPA syndrome within 4 years after the onset.

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Referances

  1. Yıldız M, Haşlak F, Adrovic A, Barut K, Kasapçopur Ö (2020) Autoinflammatory Diseases in Childhood. Balkan Med J 37(5):236–246. https://doi.org/10.4274/balkanmedj.galenos.2020.2020.4.82

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Adrovic A, Sahin S, Barut K, Kasapcopur O (2019) Familial Mediterranean fever and periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome: shared features and main differences. Rheumatol Int 39(1):29–36. https://doi.org/10.1007/s00296-018-4105-2

    Article  PubMed  Google Scholar 

  3. Yamahara K, Egawa Y, Lee K, Nakashima N, Ikegami S (2019) A case of adult-onset periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome responsive to tonsillectomy in Japan. Case Rep Otolaryngol 2019:1746180. https://doi.org/10.1155/2019/1746180

    Article  PubMed  PubMed Central  Google Scholar 

  4. Tsukadaira A, Takeuchi Y, Watanabe K, Tsukamoto K, Okubo Y, Agematsu K (2020) An adult case of periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome developed in childhood and diagnosed after progress more than 30 years Arerugi. Allergy 69(1):53–58. https://doi.org/10.15036/arerugi.69.53

    Article  PubMed  Google Scholar 

  5. 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(2):463–468. https://doi.org/10.1007/s10067-016-3317-7

    Article  PubMed  Google Scholar 

  6. Hofer M (2020) Why and How Should We Treat Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis (PFAPA) Syndrome? Paediatr Drugs 22(3):243–250. https://doi.org/10.1007/s40272-020-00393-4

    Article  PubMed  Google Scholar 

  7. Thomas KT, Feder HM Jr, Lawton AR, Edwards KM (1999) Periodic fever syndrome in children. J Pediatr 135(1):15–21. https://doi.org/10.1016/s0022-3476(99)70321-5

    Article  CAS  PubMed  Google Scholar 

  8. Batu ED (2019) Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome: main features and an algorithm for clinical practice. Rheumatol Int 39(6):957–970. https://doi.org/10.1007/s00296-019-04257-0

    Article  CAS  PubMed  Google Scholar 

  9. Ali NS, Sartori-Valinotti JC, Bruce AJ (2016) Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome. Clin Dermatol 34(4):482–486. https://doi.org/10.1016/j.clindermatol.2016.02.021

    Article  PubMed  Google Scholar 

  10. Manthiram K, Correa H, Boyd K, Roland J, Edwards K (2018) Unique histologic features of tonsils from patients with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome. Clin Rheumatol 37(5):1309–1317. https://doi.org/10.1007/s10067-017-3773-8

    Article  PubMed  Google Scholar 

  11. Vanoni F, Theodoropoulou K, Hofer M (2016) PFAPA syndrome: a review on treatment and outcome. Pediatr Rheumatol Online J 14(1):38. https://doi.org/10.1186/s12969-016-0101-9

    Article  PubMed  PubMed Central  Google Scholar 

  12. 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 (Oslo, Norway : 1992) 102(2):187–192. https://doi.org/10.1111/apa.12069

    Article  Google Scholar 

  13. Gaggiano C, Rigante D, Sota J, Grosso S, Cantarini L (2019) Treatment options for periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome in children and adults: a narrative review. Clin Rheumatol 38(1):11–17. https://doi.org/10.1007/s10067-018-4361-2

    Article  PubMed  Google Scholar 

  14. 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(4):471–474. https://doi.org/10.1016/j.semarthrit.2015.07.005

    Article  CAS  PubMed  Google Scholar 

  15. Pehlivan E, Adrovic A, Sahin S, Barut K, Kul Cinar O, Kasapcopur O (2018) PFAPA syndrome in a population with endemic familial Mediterranean fever. J Pediatr 192:253–255. https://doi.org/10.1016/j.jpeds.2017.08.078

    Article  PubMed  Google Scholar 

  16. 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(6):655–660. https://doi.org/10.1111/ped.13265

    Article  CAS  PubMed  Google Scholar 

  17. Dusser P, Hentgen V, Neven B, Kone-Paut I (2016) Is colchicine an effective treatment in periodic fever, aphtous stomatitis, pharyngitis, cervical adenitis (PFAPA) syndrome? Joint Bone Spine Revue du Rhumatisme 83(4):406–411. https://doi.org/10.1016/j.jbspin.2015.08.017

    Article  CAS  Google Scholar 

  18. 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(3):289–292. https://doi.org/10.1016/j.jpeds.2007.03.015

    Article  CAS  PubMed  Google Scholar 

  19. Licameli G, Lawton M, Kenna M, Dedeoglu F (2012) Long-term surgical outcomes of adenotonsillectomy for PFAPA syndrome. Arch Otolaryngol--Head Neck Surg 138(10):902–906. https://doi.org/10.1001/2013.jamaoto.313

    Article  PubMed  Google Scholar 

  20. Manthiram K, Nesbitt E, Morgan T, Edwards KM (2016) Family History in Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA) Syndrome. Pediatrics 138(3). https://doi.org/10.1542/peds.2015-4572

  21. Cochard M, Clet J, Le L, Pillet P, Onrubia X, Gueron T, Faouzi M, Hofer M (2010) PFAPA syndrome is not a sporadic disease. Rheumatology (Oxford, England) 49(10):1984–1987. https://doi.org/10.1093/rheumatology/keq187

    Article  Google Scholar 

  22. Butbul Aviel Y, Harel L, Abu Rumi M, Brik R, Hezkelo N, Ohana O, Amarilyo G (2019) Familial Mediterranean fever is commonly diagnosed in children in Israel with periodic fever aphthous stomatitis, pharyngitis, and adenitis syndrome. J Pediatr 204:270–274. https://doi.org/10.1016/j.jpeds.2018.08.080

    Article  PubMed  Google Scholar 

  23. 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(4 Suppl 84):S156–S159

    PubMed  Google Scholar 

  24. Gattorno M, Caorsi R, Meini A, Cattalini M, Federici S, Zulian F, Cortis E, Calcagno G, Tommasini A, Consolini R, Simonini G, Pelagatti MA, Baldi M, Ceccherini I, Plebani A, Frenkel J, Sormani MP, Martini A (2009) Differentiating PFAPA syndrome from monogenic periodic fevers. Pediatrics 124(4):e721–e728. https://doi.org/10.1542/peds.2009-0088

    Article  PubMed  Google Scholar 

  25. 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(1):98–101. https://doi.org/10.1016/s0022-3476(99)70335-5

    Article  CAS  PubMed  Google Scholar 

  26. 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 2015:293417. https://doi.org/10.1155/2015/293417

    Article  Google Scholar 

  27. 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(5):467–472. https://doi.org/10.1016/j.semarthrit.2010.06.009

    Article  PubMed  Google Scholar 

  28. 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 7:22–25. https://doi.org/10.2174/1874312901307010022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Federici S, Calcagno G, Finetti M, Gallizzi R, Meini A, Vitale A, Caroli F, Cattalini M, Caorsi R, Zulian F, Tommasini A, Insalaco A, Sormani MP, Baldi M, Ceccherini I, Martini A, Gattorno M (2012) Clinical impact of MEFV mutations in children with periodic fever in a prevalent western European Caucasian population. Ann Rheum Dis 71(12):1961–1965. https://doi.org/10.1136/annrheumdis-2011-200977

    Article  PubMed  Google Scholar 

  30. Yilmaz E, Ozen S, Balci B, Duzova A, Topaloglu R, Besbas N, Saatci U, Bakkaloglu A, Ozguc M (2001) Mutation frequency of Familial Mediterranean Fever and evidence for a high carrier rate in the Turkish population. Eur J Hum Genet 9(7):553–555. https://doi.org/10.1038/sj.ejhg.5200674

    Article  CAS  PubMed  Google Scholar 

  31. 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 68(12):1859–1865. https://doi.org/10.1002/acr.22901

    Article  Google Scholar 

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Authors and Affiliations

  1. Department of Pediatric Rheumatology, Cerrahpasa Medical School, Istanbul University-Cerrahpasa, Istanbul, Turkey

    Mehmet Yildiz, Fatih Haslak, Amra Adrovic, Neslihan Gucuyener, Ipek Ulkersoy, Oya Koker, Sezgin Sahin, Gulcin Unlu, Kenan Barut & Ozgur Kasapcopur

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  1. Mehmet Yildiz
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Correspondence to Ozgur Kasapcopur.

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The study was approved by Istanbul University-Cerrahpasa Institutional Review Board (83045809-604.01.02)

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Yildiz, M., Haslak, F., Adrovic, A. et al. Independent risk factors for resolution of periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome within 4 years after the disease onset. Clin Rheumatol 40, 1959–1965 (2021). https://doi.org/10.1007/s10067-020-05466-w

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