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Gray zone in the spectrum of autoinflammatory diseases: familial Mediterranean fever accompanying periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome: single-center experience

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Abstract

Despite the advanced knowledge concerning autoinflammatory diseases (AID), more data regarding the optimal treatment options and outcomes of the children who met the criteria of more than one AID are required. This study aimed to describe the demographic and clinical characteristics of children from familial Mediterranean fever (FMF)-endemic countries who meet both the FMF and the periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome criteria. Moreover, we aimed to measure the response rates to colchicine and tonsillectomy and evaluate the factors affecting the colchicine response in these patients. The study was conducted at pediatric rheumatology tertiary centre. A total of 131 patients (58 females; 73 males) who met both the modified Marshall and pediatric FMF criteria were included. The median age at onset was 18 months (1–77 months), and the mean age at diagnosis was 47 ± 21.88 months. The median interval between episodes was 21 (7–90) days. The median disease duration was 46 (6–128) months. Consanguineous marriage was detected in 17 (13%) of the patients. The most common clinical finding was fever (100%), followed by exudative pharyngitis (88.5%), abdominal pain (86.3%), arthralgia (61.8%), stomatitis (51.1%), adenitis (42%), myalgia (28.7%), chest pain (16%), maculopapular rash (12.2%), arthritis (8.4%), and erysipelas-like rash (4.6%). MEFV gene variants were identified in 106 (80.9%) patients. The most common variants were M694V heterozygous (29%). We found that patients with tonsillopharyngitis, aphthous stomatitis, and PFAPA family history were more likely to be colchicine-resistant and tonsillectomy responsive, while those with exon 10 MEFV gene mutations were more prone to have a favorable response to colchicine.

     Conclusion: PFAPA syndrome patients with exon 10 MEFV gene mutation, showing typical FMF symptoms, should be treated with colchicine, even after tonsillectomy. In multivariate analysis, PFAPA family history and lack of exon 10 MEFV gene mutations were independent risk factors for colchicine resistance. Thus, tonsillectomy may be recommended as a possible treatment option for these patients. It has yet to be clarified when colchicine treatment will be discontinued in patients whose attacks ceased after tonsillectomy that was performed due to colchicine unresponsiveness.

What is Known:

• A certain number of patients with periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome concomitantly fulfill the familial Mediterranean fever (FMF) criteria.

• While colchicine is proposed as a first treatment choice in familial Mediterranean fever (FMF), corticosteroids are recommended as a first-line treatment in PFAPA syndrome patients.

What is New:

• In patients with concomitant PFAPA syndrome and FMF, PFAPA family history and lack of exon 10 MEFV gene mutation are predictive factors of colchicine resistance.

• The presence of exon 10 MEFV gene mutations in patients with concomitant FMF and PFAPA syndrome has a favourable effect on response to colchicine treatment.

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Data availability

All data relevant to the study are included in the article.

Abbreviations

AID:

Autoinflammatory diseases

FMF:

Familial Mediterranean fever

MEFV:

Mediterranean fever

PFAPA:

Periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome

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Authors and Affiliations

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

    Elif Kilic Konte, Fatih Haslak, Mehmet Yildiz, Neslihan Gucuyener, Ipek Ulkersoy, Aybuke Gunalp, Esma Aslan, Amra Adrovic, Sezgin Sahin, Kenan Barut & Ozgur Kasapcopur

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  1. Elif Kilic Konte
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Contributions

EKK, FH, NY, IU, AG, EA, MY, AA, SS, KB, and OK were responsible for data collection and analysis. EKK, FH, NY, IU, AG, and EA contributed to the writing of the manuscript. MY, AA, SS, KB, and OK reviewed and revised the manuscript. EKK had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: OK. Acquisition, analysis, or interpretation of data: all authors.

Corresponding author

Correspondence to Ozgur Kasapcopur.

Ethics declarations

Ethics approval

The study was approved by Istanbul University-Cerrahpasa Institutional Review Board (07.05.2020–59984).

Informed consent

Written informed consent was obtained from all the participants in this study, and no identifying information of any participant was included in this paper.

Competing interests

The authors declare no competing interests.

The patient and public involvement statement

Patients or the public were not involved in the design, or conduct, or reporting, or dissemination plans of our research.

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Communicated by Tobias Tenenbaum

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Prepublication note: Our paper was not published as a pre-print.

Previous presentation: The data from this study were presented as an oral presentation at Turkish Pediatric Rheumatology Congress; on March 15–18, 2023, in Antalya, Turkey (through the Turkish Society of Pediatric Rheumatology; Abstract: SS-28).

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Konte, E.K., Haslak, F., Yildiz, M. et al. Gray zone in the spectrum of autoinflammatory diseases: familial Mediterranean fever accompanying periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome: single-center experience. Eur J Pediatr 182, 5473–5482 (2023). https://doi.org/10.1007/s00431-023-05209-4

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