
==== Front
Eur J Pediatr
Eur J Pediatr
European Journal of Pediatrics
0340-6199
1432-1076
Springer Berlin Heidelberg Berlin/Heidelberg

39085658
5703
10.1007/s00431-024-05703-3
Research
Exploring factors for predicting colchicine responsiveness in children with PFAPA
http://orcid.org/0000-0003-2641-4140
Özaslan Zeynep zeynepgozaluludag@gmail.com

1
http://orcid.org/0009-0000-8676-7197
Şen Abdulvahap 2
http://orcid.org/0000-0002-4283-0921
Uçar Sıla Atamyıldız 3
http://orcid.org/0000-0002-1034-6406
Çakan Mustafa 4
http://orcid.org/0000-0003-2774-9591
Sanisoğlu Bengisu 5
http://orcid.org/0009-0000-9947-8298
Kaya Feray 6
http://orcid.org/0000-0003-2575-6309
Otar Yener Gülçin 7
http://orcid.org/0000-0001-9801-925X
Demir Ferhat 8
http://orcid.org/0000-0002-1386-4575
Tanatar Ayşe 9
http://orcid.org/0000-0001-5602-4595
Özdel Semanur 2
http://orcid.org/0000-0003-0466-0228
Öztürk Kübra 6
http://orcid.org/0000-0002-2122-6952
Şahin Nihal 1
http://orcid.org/0000-0002-9186-3068
Sönmez Hafize Emine 1
http://orcid.org/0000-0003-3594-7387
Aktay Ayaz Nuray 5
http://orcid.org/0000-0002-5079-5644
Sözeri Betül 3
1 https://ror.org/0411seq30 grid.411105.0 0000 0001 0691 9040 Department of Pediatric Rheumatology, Faculty of Medicine, MD, Kocaeli University, Kocaeli, Turkey
2 Department of Pediatric Rheumatology, Ankara Etlik City Hospital, Ankara, Turkey
3 grid.417018.b 0000 0004 0419 1887 Department of Pediatric Rheumatology, Health Sciences University, Umraniye Training and Research Hospital, Istanbul, Turkey
4 grid.417395.d 0000 0004 0419 2062 Department of Pediatric Rheumatology, Zeynep Kamil Training and Research Hospital, Istanbul, Turkey
5 https://ror.org/03a5qrr21 grid.9601.e 0000 0001 2166 6619 Department of Pediatrics, Department of Pediatric Rheumatology, İstanbul University, Istanbul, Turkey
6 https://ror.org/05j1qpr59 grid.411776.2 0000 0004 0454 921X Department of Pediatric Rheumatology, İstanbul Medeniyet University, İstanbul, Turkey
7 https://ror.org/00czdkn85 grid.508364.c Department of Pediatric Rheumatology, Eskişehir City Hospital, Eskişehir, Turkey
8 https://ror.org/05g2amy04 grid.413290.d 0000 0004 0643 2189 Department of Pediatric Rheumatology, Acıbadem Ataşehir Hospital, Istanbul, Turkey
9 Department of Pediatric Rheumatology, Gaziantep City Hospital, Gaziantep, Turkey
Communicated by Tobias Tenenbaum

31 7 2024
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2024
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© The Author(s) 2024
2024
https://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis syndrome (PFAPA) are the most common autoinflammatory syndromes in children. This study aimed to evaluate the clinical and laboratory parameters that may predict colchicine responsiveness.This retrospective, multicenter, cross-sectional study involved nine pediatric rheumatology centers from our country., The patients diagnosed with PFAPA were compared on the basis of their responses to colchicine. In the 806 (42.3% female 57.7% male) patients, the most common clinical findings were fever (100%), exudative tonsillitis (86.5%), pharyngitis (80.9%), and aphthous stomatitis (50.5%). The mean attack frequency was 13.5 ± 6.8 attacks per year lasting for a mean of 3.9 ± 1.1 days. Colchicine treatment was attempted in 519 (64.4%) patients, with 419 (80.7%) showing a favorable response. In patients who underwent MEFV gene analysis (70.8%), the most common variant was M694V heterozygous (16.8%). The presence of pharyngitis (p = 0.03, 95% CI 0.885 to 0.994), the presence of arthralgia (p = 0.04, 95% CI 0.169 to 0.958), and having more frequent attacks (p = 0.001, 95% CI 0.028 to 0.748) were found to be associated with colchicine unresponsiveness, whereas the carriage of the M694V variant (p = 0.001, 95% CI 0.065 to 0.242) was associated with colchicine responsiveness.

Conclusion: This study identified the presence of pharyngitis, arthralgia, and increased attack frequency in patients with PFAPA as factors predicting colchicine unresponsiveness, whereas the carriage of the M694V variant emerged as a predictor of colchicine responsiveness. Predicting colchicine response at disease onset may facilitate a more effective management of PFAPA. What is Known:

• Colchicine treatment can be used in the prophylaxis of PFAPA disease.

• Having the MEFV variant is the most commonly known factor in predicting response to colchicine.

	
What is New:

• The presence of pharyngitis or arthralgia, and more frequent attacks in PFAPA disease were found to be independently associated with colchicine unresponsiveness.

• Carrying the M694V variant was identified as the sole factor predicting colchicine responsiveness.

	

Keywords

PFAPA
Colchicine
Treatment response
MEFV
University of KocaeliOpen access funding provided by the Scientific and Technological Research Council of Türkiye (TÜBİTAK).

issue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2024
==== Body
pmcIntroduction

Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis syndrome (PFAPA) are the most common autoinflammatory periodic fever syndromes in children. The precise prevalence and etiology of PFAPA are currently unknown; however, a study conducted in Scandinavia estimated the incidence to be 2.3 per 10,000 children [1]. In preschool-aged children, PFAPA is characterized by recurrent episodes of high fever lasting 3–7 days and occurring every 2–8 weeks. Diagnosis is often delayed because of the lack of specific laboratory findings for the disease, leading to variations in treatment approaches [2, 3]. A typical PFAPA episode presents with fever, pharyngitis, oral aphthous lesions, and cervical lymphadenitis. During attacks, abdominal pain, arthralgia, arthritis, headache, rash, diarrhea, and vomiting may also be present [4]. In addition, 60% of patients may experience prodromal symptoms such as fatigue. As the child grows, the frequency and duration of episodes typically decrease, and PFAPA commonly resolves within a few years [1–3].

During PFAPA episodes, patients and their families often experience heightened anxiety, leading to a notable decline in their quality of life. Treatment achieves complete remission of the disease or at least reduce disease activity, thereby positively impacting patients and families. The objective is to restore a satisfactory quality of life and promote uninterrupted child development, especially concerning normal school performance. Commonly used treatment strategies for PFAPA include antipyretics during episodes, corticosteroids for abortive treatment, colchicine or cimetidine for prophylaxis, and tonsillectomy as a surgical option [5].

Intermittent single doses of steroids can be used during PFAPA attacks [5, 6]. Nevertheless, it may increase the frequency of attacks. In such cases, the regular administration of colchicine is an alternative therapeutic approach. Colchicine, a compound derived from plants, exerts its anti-inflammatory effects by binding to tubulins, thereby impeding the assembly and polymerization of microtubules. It may be employed prophylactically to reduce the frequency of PFAPA attacks in children, with studies demonstrating a decrease in attack frequency following regular colchicine treatment [6, 7]. Understanding the factors that influence colchicine response in PFAPA syndrome is crucial for effective patient management. This study aimed to evaluate whether specific parameters can predict colchicine response by analyzing the clinical, genetic, and laboratory characteristics of patients with PFAPA.

Methods

This study is retrospective, multicenter and cross-sectional study. Nine pediatric rheumatology referral centers from our country were enrolled in the study. The patients diagnosed with PFAPA between January 2019 and January 2024 were enrolled it. A total of 806 patients with PFAPA were included in the study. The diagnosis of PFAPA syndrome was made according to the Eurofever/PRINTO classification criteria [2]. Patients who meet the diagnosis of FMF according to Yalçınkaya and Özen criteria or meet the diagnostic criteria of any of monogenic autoinflammatory diseases were excluded.

Steroid responsiveness was determined by the resolution of the disease episode within 6 h after a single dose of steroid administration during the disease attack. Patients whose disease episodes ceased or became less frequent after colchicine treatment were classified as "colchicine responsive" [8]. The disease was considered to have ceased if the patient did not experience an attack for at least 1 year. Patients who were treated with colchicine among all PFAPA patients were divided into two groups as colchicine responsive and colchicine non-responsive.

Demographic data, laboratory findings, Mediterranean FeVer (MEFV) gene analysis, parameters such as fever episodes, associated symptoms, effectiveness of various therapies (including glucocorticoids, colchicine, tonsillectomy, and/or adenotonsillectomy), and age at the time of surgery were documented from the patient’s medical records.

Data from all centers were entered into a common Excel worksheet. Duplicate entries were removed, and the final version was transferred to SPSS software for analysis.

Statistical analysis

Statistical analyses were conducted using the SPSS software version 21. The variables were assessed using visual (histogram and probability plots) and analytical methods (Kolmogorov–Smirnov) to determine their distribution. Descriptive analysis data are presented as mean ± standard deviation or median (minimum–maximum) where appropriate. Categorical variables were compared using the chi-square test or Fisher’s exact test, as appropriate. The Student’s T-test or Mann–Whitney U-test was used to compare continuous data between the two groups. Variables with a p-value of ≤ 0.05 in univariate analysis were entered into a logistic regression analysis to identify independent predictors of colchicine resistance. Model fit was assessed using Hosmer–Lemeshow goodness-of-fit statistics. A significance level of 5% was used. Risk scores for each selected variable were weighted based on β coefficients (‘x’ = log of the OR) in the final model.

Results

A total of 806 patients were enrolled in the study. Of them, 341 (42.3%) were female and 465 (57.7%) were male. The median current age of the patients was 68 (17–180) months. The median age at diagnosis and symptom onset were 44 (9–140) and 24 (3–120) months, respectively.

Fever was the most common clinical finding, reported in all 806 (100%) patients, followed by exudative tonsillitis in 697 (86.5%), pharyngitis in 652 (80.9%), aphthous stomatitis in 407 (50.5%), cervical lymphadenopathy in 340 (42.2%), abdominal pain in 253 (31.4%), arthralgia in 191 (23.7%), headache in 34 (4.12%), and arthritis in 8 (1%) of the patients. The mean attack frequency was 13.5 ± 6.8 attacks per year with a mean of 3.9 ± 1.1 days. The mean interval time between attacks was 29 ± 14.6 days.

At the time of the attack, the median white blood cell count (WBC) was 12460 (6000–33540)/mm3, erythrocyte sedimentation rate (ESR) was 26 (20–120) mm/h, and C-reactive protein (CRP) was 56 (10–324) mg/dL.

Out of 659 (81.8%) patients who received steroids during attacks, 602 (91.3%) showed resolution of the febrile episode within 6 h. However, the attack frequency increased in 214 (32.4%) cases.

Colchicine treatment was attempted in 519 (64.4%) patients. Of these, 419 (80.7%) were colchicine-responsive, whereas 12 (2.3%) showed partial response. Tonsillectomy/adenoidectomy was advised in 134 (16.6%) patients and performed on 90 (11.2%) during follow-up. This resulted in the cessation of disease episodes in 74 (82.2%) patients who underwent the procedure.

MEFV gene sequencing was performed on 571 (70.8%) patients. Among them, the genetic mutation was not detected in 335 (58.1%) patients, whereas the most common variant was M694V heterozygote in 96 (16.8%) patients, followed by E148Q heterozygote in 52 (9.1%), V726A heterozygote in 20 (3.5%), and M680I heterozygote in 15 (2.6%) patients. The genetic test results are summarized in Table 1. One hundred forty (24.1%) carried exon 10 heterozygote variants, 62 (10.5%) carried non-exon 10 heterozygote variants, 9 (1.6%) carried exon 10/non-exon 10 compound heterozygote variants, 5 (0.08%) were non-exon 10 homozygous, 5 (0.08%) were non-exon 10/non-exon 10 compound heterozygotes, 3 (0.05%) were exon 10 compound heterozygotes, and 2 (0.03%) were exon 10 homozygous. The clinical and laboratory parameters of the patients were compared based on their responses to colchicine (Table 2). Table 1 Genetic test results of patients (n = 571)

Genetic variants	n (%)	
M694V/-	96 (16.8)	
E148Q/-	53 (9.2)	
V726A/-	20 (3.5)	
M680I/-	15 (2.6)	
K695R/-	6 (1.1)	
P369S/-	5 (0.8)	
E148Q/E148Q	4 (0.7)	
R761H/-	3 (0.5)	
R408Q/P369S	3 (0.5)	
M694V/E148Q	2 (0.3)	
V726A/E148Q	2 (0.3)	
I591T/-	2 (0.3)	
M694V/V726A	1 (0.17)	
M694V/S369A	1 (0.17)	
M694V/R408Q/P369S	1 (0.17)	
M694V/P369S	1 (0.17)	
M694V/M694V	1 (0.17)	
M694V/K695R	1 (0.17)	
M694V/K695R/K695R	1 (0.17)	
R408Q/E148Q/P369S	1 (0.17)	
P588P/P588P	1 (0.17)	
M680I / A744S	1 (0.17)	
F479L/-	1 (0.17)	
E148Q/P369S	1 (0.17)	
A744S/-	1 (0.17)	
Y471X/-	1 (0.17)	
V726A/R408Q	1 (0.17)	
Negative	345 (60.4)	
Total	571 (100)	

Table 2 Comparison of clinical and laboratory parameters based on colchicine-responsiveness in patients with PFAPA syndrome

	Colchicine responsive (n = 419)	Colchicine unresponsive (n = 88)	P
value	
Gender (Female/Male)	180 /239	40/48	0.66	
Age at symptom onset (months)	24 (3–120)	23.5 (5–72)	0.32	
Age at diagnosis (months)	42 (9–140)	37.5 (15–80)	0.24	
Fever, n (%)	419 (100)	88 (100)	NA	
Exudative tonsillitis, n (%)	365 (87.1)	77(87.5)	0.92	
Pharyngitis, n (%)	327 (78)	80 (90.9)	0.006	
Aphthous stomatitis, n (%)	210 (50.1)	51 (58)	0.18	
Cervical lymphadenopathy, n (%)	174 (41.5)	39 (44.3)	0.63	
Headache, n (%)	15 (3.6)	4 (4.5)	0.66	
Abdominal pain, n (%)	135 (32.3)	34 (38.6)	0.25	
Arthralgia, n (%)	97 (23.2)	30 (34.1)	0.03	
Arthritis, n (%)	3 (0.7)	2 (2.3)	0.17	
Attack frequency, per year	13.6 ± 7.1	16.1 ± 7.1	0.001	
Duration of attacks, day	4.1 ± 0.9	3.8 ± 1.1	0.001	
The interval time between attacks, days	28.4 ± 20	28.5 ± 12.1	0.18	
White blood count, mm3	13,000 (6000–32000)	13,205 (8500–33540)	0.44	
Erythrocyte sedimentation rate, mm/hr	26.5 (20–106)	32.5 (30–100)	0.23	
C reactive protein (CRP), mg/L	59.9 (10–274)	65.5 (8–256)	0.28	
Steroids, n (%)	360 (85.9)	78 (86.6)	0.49	
Responsive to steroids, n (%)	334 (92.5)	68 (87.2)	0.12	
Increased attack frequency with steroids, n (%)	126 (30.1)	37 (42)	0.09	
Tonsillectomy/adenoidectomy	15 (3.6)	36 (40.9)	 < 0.001	
MEFV variants				
Carrying exon 10 variants	123 (61.9)	17 (63)	0.367	
Carrying M694V variants	95 (20.2)	10 (6.9)	 < 0.001	

To identify independent predictors of colchicine response, all clinical and laboratory results were analyzed by univariate analysis. Those that were significant in the univariate analysis were included in the multivariate analysis. In a multivariate regression analysis, the presence of pharyngitis (p = 0.03, CI95% 0.885 to 0.994), the presence of arthralgia (p = 0.04, CI95% 0.169 to 0.958), and more frequent attacks (p = 0.001, CI95% 0.028 to 0.748) were found to be independently associated with colchicine unresponsiveness, while carrying the M694V variant (p = 0.001, CI95% 0.065 to 0.242) was the sole factor predicting colchicine responsiveness.

Discussion

There is no consensus on the optimal therapeutic strategy for PFAPA syndrome. The primary objective of treatment is to manage acute attacks and decrease their frequency. However, decisions regarding colchicine resistance and the potential necessity for tonsillectomy have predominantly relied on expert consensus, given the absence of an objective laboratory marker capable of interpreting and predicting the disease’s course. When determining the most suitable treatment strategy for patients with PFAPA, it is essential to carefully weigh the risks and benefits of each option and involve the family in the decision-making process. In this multicenter study involving a substantial sample size, we examined parameters for predicting the response to colchicine in patients with PFAPA, focusing on clinical and laboratory findings. Our findings indicate that the presence of pharyngitis, arthralgia, and more frequent attacks are predictive of colchicine resistance in PFAPA. In addition, we observed that the presence of the M694V variant carrier status significantly predicts colchicine sensitivity.

The demographic and clinical data of patients with PFAPA have been comprehensively examined in numerous prior studies. Consistent with previous findings, our study revealed a slight male predominance among patients with PFAPA, which was observed in both the colchicine-responsive and colchicine-resistant groups [1, 6, 9]. Various studies have consistently reported exudative pharyngitis, aphthous stomatitis, cervical lymphadenitis, and abdominal pain as the most frequently observed clinical findings in patients with PFAPA [6, 10–14]. Correspondingly, exudative tonsillitis, pharyngitis, aphthous stomatitis, and cervical lymphadenopathy were the most common symptoms during the attack in our cohort.

In various studies, the response rate to colchicine initiated for prophylaxis in PFAPA disease ranges between 45% and 95.1% [6, 11, 13, 15–18]. In our study, a colchicine response rate of 80.7% was observed, which is consistent with the literature. Konte et al. examined clinical factors predicting colchicine response and reported that the presence of tonsillopharyngitis and aphthous stomatitis is associated with a higher likelihood of colchicine resistance and response to tonsillectomy [14]. Our study revealed that the presence of pharyngitis and arthralgia were the only clinical findings associated with colchicine resistance. However, the presence of exudative tonsillitis, aphthous stomatitis, cervical lymphadenopathy, headache, and arthritis did not aid in predicting the response to colchicine.

PFAPA episodes typically last 3–7 days, most commonly around 4–5 days, with recurrences occurring every 14–60 days, often within 3 to 6 weeks [1, 6, 10, 14, 19]. In our study, although the average interval (28 days) between attacks did not differ between the colchicine-responsive and colchicine-unresponsive groups, the duration of attacks was significantly shorter (3.8 days vs 4.1 days, p = 0.001) and the annual attack frequency was lower (13.6 vs 16.1, p = 0.001) in the colchicine-responsive group than in the colchicine-unresponsive group.

In clinical practice, patients with PFAPA syndrome typically undergo genetic analysis targeting genes associated with monogenic autoinflammatory diseases, such as the MEFV gene, which is linked to familial Mediterranean fever (FMF). Previous studies have demonstrated that carrying MEFV variants may impact the clinical course and treatment responses in individuals with PFAPA [6, 7, 12, 13, 16, 18, 20–22]. For instance, Pehlivan et al. [12] showed that PFAPA patients with MEFV variants exhibited a better response to colchicine than those without MEFV variants (66% vs 33%, respectively, p = 0.003). Furthermore, a 6-month open-label, randomized, controlled study by Butbul et al. [7] showed a decrease in attack frequency in six out of eight patients who were started on colchicine and reported that five of these patients had MEFV mutations (heterozygous M694V in 3 and E148Q in 2). A multicenter study conducted in France analyzing 20 children with PFAPA syndrome demonstrated that nine patients responded to colchicine. Among these nine responders, MEFV mutations were detected in five patients (heterozygous M694V in 4 and V726A in 1). The study indicated that heterozygous MEFV variants were more common in the colchicine responder group but did not reach statistical significance [18]. Gunes et al. [6], in their study involving 400 PFAPA cases, conducted genetic analyses on 231 patients and identified heterozygous MEFV gene variants in 57 individuals. The most prevalent mutation was heterozygous M694V, which was observed in 23 (10%) patients. The present study found that the presence of the MEFV gene variant was significantly associated with a reduction in attack frequency (p = 0.003). Konte et al. [14] detected MEFV gene variants in 106 of 131 PFAPA patients (80.9%), with M694V heterozygous being the most common variant. They found that the presence of tonsillopharyngitis, aphthous stomatitis, and a family history of PFAPA were associated with colchicine resistance, whereas those with exon 10 MEFV gene mutations were more likely to respond favorably to colchicine. In contrast, Yener et al. [13] evaluated colchicine responsiveness in 157 patients with PFAPA syndrome and concluded that carrying an MEFV variant did not influence the response. In our study, MEFV gene sequencing was performed on 571 (70.8%) patients. The predominant MEFV variants identified were M694V at a frequency of 16.8%, E148Q at 9.1%, V726A at 3.5%, and M680I at 2.6%. Our analysis did not reveal any notable variance in colchicine response between patients harboring MEFV variants and those with exon 10 variants. Nevertheless, we observed a notably elevated rate of response to colchicine among patients carrying the M694V variant. The high prevalence of MEFV variants in patients with PFAPA may be explained at the high carrier rate in the healthy population [23].

The most significant limitation of this study was its retrospective design. However, it is strengthened by its large sample size and multicenter design. Another important limitation is the national focus, which precludes an examination of potential ethnic variations in the findings. The disease course may be influenced by environmental and epigenetic factors over time. Therefore, prospective studies may be more constructive in this regard.

In our study, the presence of pharyngitis or arthralgia and more frequent attacks were found to be independently associated with colchicine unresponsiveness, whereas carrying the M694V variant was the sole factor predicting colchicine responsiveness. In conclusion, genetic predisposition, clinical features, and disease course play critical roles in determining the response to colchicine, the cornerstone prophylactic treatment for PFAPA syndrome. Predicting whether colchicine will be beneficial is crucial for clinicians in managing patients diagnosed with PFAPA, informing families, and determining the timing of treatment options such as tonsillectomy.

Abbreviations

CRP C-reactive protein

ESR Erythrocyte sedimentation rate

FMF Familial Mediterranean fever

MEFV Mediterranean FeVer

PFAPA Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis syndrome

WBC White blood cell count

Acknowledgements

We sincerely thank Sibel Balcı for her great effort on statistical analysis.

Authors' Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by ZÖ, AŞ, SAU,MÇ,BS,FK,GOY,FD,AT,SÖ,KÖ,NŞ,HES,NAA,BS. The first draft of the manuscript was written by Zeynep Özaslan and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Funding

Open access funding provided by the Scientific and Technological Research Council of Türkiye (TÜBİTAK). The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Data Availability

The authors are pleased to share the data upon request.

Declarations

Ethical Approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of University Kocaeli (GOKAEK-2024/09.07).

Consent to participate

Informed consent was obtained from all individual participants included in the study.

Consent to publish

Not applicable.

Conflict of interest

The authors declare no competing interests.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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ReferencesQuery

1. Førsvoll J Kristoffersen EK Øymar K Incidence, clinical characteristics and outcome in Norwegian children with periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome; A population-based study Acta Paediatr Int J Paediatr 2013 102 2 187 192 10.1111/apa.12069
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 Int J Paediatr 102(2):187–192. 10.1111/apa.12069
2. Gattorno M Hofer M Federici S Classification criteria for autoinflammatory recurrent fevers Ann Rheum Dis 2019 78 8 1025 1032 10.1136/annrheumdis-2019-215048 31018962
Gattorno M, Hofer M, Federici S et al (2019) Classification criteria for autoinflammatory recurrent fevers. Ann Rheum Dis 78(8):1025–1032. 10.1136/annrheumdis-2019-21504831018962
3. Król P Böhm M Šula V PFAPA syndrome: clinical characteristics and treatment outcomes in a large single-centre Cohort Pediatrıc Rheumatology Periodic fever PFAPA Syndr Clin Exp Rheumatol 2013 31 6 980 987
Król P, Böhm M, Šula V et al (2013) PFAPA syndrome: clinical characteristics and treatment outcomes in a large single-centre Cohort Pediatrıc Rheumatology Periodic fever. PFAPA Syndr Clin Exp Rheumatol 31(6):980–987
4. Cantarini L Vitale A Sicignano LL Diagnostic criteria for adult-onset periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome Front Immunol 2017 8 1018 10.3389/fimmu.2017.01018 28970828
Cantarini L, Vitale A, Sicignano LL et al (2017) Diagnostic criteria for adult-onset periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome. Front Immunol 8:1018. 10.3389/fimmu.2017.0101828970828
5. Amarilyo G Rothman D Manthiram K Edwards KM Li SC Marshall GS Consensus treatment plans for periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome (PFAPA): A framework to evaluate treatment responses from the childhood arthritis and rheumatology research alliance (CARRA) PFAPA work group Pediatr Rheumatol 2020 18 1 1 7 10.1186/s12969-020-00424-x
Amarilyo G, Rothman D, Manthiram K, Edwards KM, Li SC, Marshall GS et al (2020) Consensus treatment plans for periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome (PFAPA): A framework to evaluate treatment responses from the childhood arthritis and rheumatology research alliance (CARRA) PFAPA work group. Pediatr Rheumatol 18(1):1–7. 10.1186/s12969-020-00424-x
6. Gunes M Cekic S Kilic SS Is colchicine more effective to prevent periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis episodes in Mediterranean fever gene variants? Pediatr Int 2017 59 6 655 660 10.1111/ped.13265 28207965
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. 10.1111/ped.1326528207965
7. Butbul Aviel Y Tatour S Gershoni Baruch R Brik R Colchicine as a therapeutic option in periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis (PFAPA) syndrome Semin Arthritis Rheum 2016 45 4 471 474 10.1016/j.semarthrit.2015.07.005 26315860
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. 10.1016/j.semarthrit.2015.07.00526315860
8. Amarilyo G Rothman D Manthiram K Consensus treatment plans for periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome (PFAPA): A framework to evaluate treatment responses from the childhood arthritis and rheumatology research alliance (CARRA) PFAPA work group Pediatr Rheumatol 2020 18 1 1 7 10.1186/s12969-020-00424-x
Amarilyo G, Rothman D, Manthiram K et al (2020) Consensus treatment plans for periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome (PFAPA): A framework to evaluate treatment responses from the childhood arthritis and rheumatology research alliance (CARRA) PFAPA work group. Pediatr Rheumatol 18(1):1–7. 10.1186/s12969-020-00424-x
9. Hofer M Pillet P Cochard MM International periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis syndrome cohort: Description of distinct phenotypes in 301 patients Rheumatology 2014 53 6 1125 1129 10.1093/rheumatology/ket460 24505122
Hofer M, Pillet P, Cochard MM et al (2014) International periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis syndrome cohort: Description of distinct phenotypes in 301 patients. Rheumatology 53(6):1125–1129. 10.1093/rheumatology/ket46024505122
10. Batu ED Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome: main features and an algorithm for clinical practice Rheumatol Int 2019 39 957 70 10.1007/s00296-019-04257-0 30798384
Batu ED (2019) Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome: main features and an algorithm for clinical practice. Rheumatol Int 39:957–70. 10.1007/s00296-019-04257-030798384
11. Celiksoy MH Ogur G Yaman E Could familial Mediterranean fever gene mutations be related to PFAPA syndrome? Pediatr Allergy Immunol 2016 27 1 78 82 10.1111/pai.12490 26360812
Celiksoy MH, Ogur G, Yaman E et al (2016) Could familial Mediterranean fever gene mutations be related to PFAPA syndrome? Pediatr Allergy Immunol 27(1):78–82. 10.1111/pai.1249026360812
12. Pehlivan E Adrovic A Sahin S Barut K Kul Cınar O Kasapcopur O PFAPA Syndrome in a population with endemic famil ial Mediterranean fever J Pediatr 2018 192 253 255 10.1016/j.jpeds.2017.08.078 29031862
Pehlivan E, Adrovic A, Sahin S, Barut K, Kul Cınar O (2018) Kasapcopur O PFAPA Syndrome in a population with endemic famil ial Mediterranean fever. J Pediatr 192:253–255. 10.1016/j.jpeds.2017.08.07829031862
13. Otar Yener G Aktaş İ Altıntaş Meşe C Çakan M Does having MEFV gene sequence variants affect the clinical course and colchicine response in children with PFAPA syndrome? Eur J Pediatr 2023 182 1 411 417 10.1007/s00431-022-04709-z 36376520
Otar Yener G, Aktaş İ, Altıntaş Meşe C, Çakan M (2023) Does having MEFV gene sequence variants affect the clinical course and colchicine response in children with PFAPA syndrome? Eur J Pediatr 182(1):411–417. 10.1007/s00431-022-04709-z36376520
14. Konte EK Haslak F Yildiz M 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 2023 182 12 5473 5482 10.1007/s00431-023-05209-4 37777601
Konte EK, Haslak F, Yildiz M et al (2023) 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(12):5473–5482. 10.1007/s00431-023-05209-437777601
15. Amarilyo G Harel L Abu Ahmad S Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenitis Syndrome – Is It Related to Ethnicity? An Israeli Multicenter Cohort Study J Pediatr 2020 227 268 273 10.1016/j.jpeds.2020.08.033 32805260
Amarilyo G, Harel L, Abu Ahmad S et al (2020) Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenitis Syndrome – Is It Related to Ethnicity? An Israeli Multicenter Cohort Study. J Pediatr 227:268–273. 10.1016/j.jpeds.2020.08.03332805260
16. Butbul Aviel Y Harel L Abu Rumi M Familial Mediterranean Fever Is Commonly Diagnosed in Children in Israel with Periodic Fever Aphthous Stomatitis, Pharyngitis, and Adenitis Syndrome J Pediatr 2019 204 270 274 10.1016/j.jpeds.2018.08.080 30361059
Butbul Aviel Y, Harel L, Abu Rumi M et al (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. 10.1016/j.jpeds.2018.08.08030361059
17. Batu ED Kara Eroğlu F Tsoukas P Periodic Fever, Aphthosis, Pharyngitis, and Adenitis Syndrome: Analysis of Patients From Two Geographic Areas Arthritis Care Res (Hoboken) 2016 68 12 1859 1865 10.1002/acr.22901 27059542
Batu ED, Kara Eroğlu F, Tsoukas P et al (2016) Periodic Fever, Aphthosis, Pharyngitis, and Adenitis Syndrome: Analysis of Patients From Two Geographic Areas. Arthritis Care Res (Hoboken) 68(12):1859–1865. 10.1002/acr.2290127059542
18. Dusser P Hentgen V Neven B Koné-Paut I Is colchicine an effective treatment in periodic fever, aphtous stomatitis, pharyngitis, cervical adenitis (PFAPA) syndrome? Jt Bone Spine 2016 83 4 406 411 10.1016/j.jbspin.2015.08.017
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(4):406–411. 10.1016/j.jbspin.2015.08.017
19. Thomas KT Feder HM Jr Lawton AR Edwards KM Periodic fever syndrome in children J Pediatr 1999 135 1 15 21 10.1016/s0022-3476(99)70321-5 10393598
Thomas KT, Feder HM Jr, Lawton AR, Edwards KM (1999) Periodic fever syndrome in children. J Pediatr 135(1):15–21. 10.1016/s0022-3476(99)70321-510393598
20. Öztürk K Coşkuner T Baglan E Real-Life Data From the Largest Pediatric Familial Mediterranean Fever Cohort Front Pediatr 2022 9 805919 10.3389/fped.2021.805919 35127599
Öztürk K, Coşkuner T, Baglan E et al (2022) Real-Life Data From the Largest Pediatric Familial Mediterranean Fever Cohort. Front Pediatr 9:805919. 10.3389/fped.2021.80591935127599
21. Adrovic A Sahin S Barut K Kasapcopur O Familial Mediterranean fever and periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome: shared features and main differences. Vol. 39 Rheumat Int 2019 39 29 36 10.1007/s00296-018-4105-2
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. Vol. 39. Rheumat Int 39:29–36. 10.1007/s00296-018-4105-2
22. Kolly L Busso N Von Scheven-Gete A Periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis syndrome is linked to dysregulated monocyte IL-1β production J Allergy Clin Immunol 2013 131 6 1635 1643 10.1016/j.jaci.2012.07.043 23006543
Kolly L, Busso N, Von Scheven-Gete A et al (2013) Periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis syndrome is linked to dysregulated monocyte IL-1β production. J Allergy Clin Immunol 131(6):1635–1643. 10.1016/j.jaci.2012.07.04323006543
23. Yilmaz E Ozen S Balci B Mutation frequency of Familial Mediterranean Fever and evidence for a high carrier rate in the Turkish population Eur J Hum Genet 2001 9 7 553 555 10.1038/sj.ejhg.5200674 11464248
Yilmaz E, Ozen S, Balci B et al (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. 10.1038/sj.ejhg.520067411464248
