Gharra A, Amarilyo G, Harel L, Levinsky Y, Tal R , et al.
Orphanet journal of rare diseases •
To characterize the clinical presentation of PFAPA and the response to treatment in an ethnic subgroup- Druze and analyze the differences compared to other ethnic groups. Retrospective data were collected from medical records of patients with PFAPA attending 2 pediatric tertiary medical centers in Israel between March 2014-December 2022. Patients with concomitant familial Mediterranean fever were excluded. Ethnicity was categorized as Mediterranean, non-Mediterranean, multiethnic and Druze. Of 386 patients with PFAPA, 52 (13.5%) were with a corresponding FMF diagnosis (PFAPA/FMF) information was lacking regarding FMF status in 9 (2.3%) patients and 8 (2.1%) patients were excluded because of poor follow-up. The study included 317 PFAPA patients, 178 (56.2%) of which were of Mediterranean descent (Sephardic Jews or Israeli Arabs), 87 (27.4%) were multiethnic, 19 (6%) were of non-Mediterranean descent (all Ashkenazi Jews), and 33 (10.4%) were of Druze ethnicity. No noteworthy differences in age of onset or age of diagnosis were found among ethnic groups. Clinical presentation analysis revealed statistical significance ( = 0.025) of the prevalence of abdominal pain across ethnic groups. No significance association was found regarding other symptoms including pharyngitis, adenitis, aphthous, myalgia, arthralgia, rash, and headache. Additionally, no significant association was observed between the response to treatment and ethnic group. Genetic testing was performed in 127 (40%) patients, no significant association was shown between number of mutations and ethnic origin. The clinical presentation of PFAPA in patients of Druze ethnicity is not significantly different from other ethnic groups in Israel. This finding fails to support the hypothesis that PFAPA is on the Behҫet spectrum. The online version contains supplementary material available at 10.1186/s13023-026-04278-6.
Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery •
To compare surgical versus medical treatment approaches for periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome. PubMed, Embase, Web of Science, and Cochrane. We followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses-Network Meta-analyses checklist. Two authors independently reviewed the studies. Inclusion criteria comprised randomized controlled trials and cohort studies. Non-English studies, along with case series and review articles, were excluded. The primary outcome was the incidence of persistent symptoms following surgery, compared to medical treatment. Secondary outcomes included complications. The search identified 693 publications. After applying the inclusion and exclusion criteria, nine studies were included (three randomized controlled trials and six cohort studies), comprising a total of 691 patients (256 [37%] females, mean age: 2.97 years, and interquartile range: 2.3-3.3). Patients were treated with either tonsillectomy (n = 201), intracapsular tonsillectomy (IT, n = 24), or medical treatment (n = 466). Surgery was associated with a higher likelihood of symptom resolution compared to medical treatment (odds ratio [OR]: 11.7, 95% CI: 2.14-63.94). However, heterogeneity was observed across studies (I = 80.8%, P < .01). A sensitivity analysis was performed, including randomized controlled trials. Both tonsillectomy (OR: 34.15, 95% CI: 3.77-308.95) and IT (OR: 21, 95% CI: 1.5-293.25) were associated with a greater likelihood of symptom resolution. The pooled complication rate was 6.6%, with a higher incidence in patients who underwent tonsillectomy versus IT (46/201 vs 0/24, P = .008). The pooled rate of symptom recurrence was 13.6% in patients following tonsillectomy and 37.5% in IT. Surgical management of PFAPA with tonsillectomy was superior to medical treatment. Tonsillectomy resulted in a lower recurrence rate of symptoms compared to IT, with a comparable incidence of complications to existing literature. However, given the limited number of patients in the IT group, these findings should be interpreted with caution, and further randomized studies are warranted.
Broide M, Levinsky Y, Tal R, Harel L, Shoham S , et al.
Pediatric rheumatology online journal •
Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is the most common periodic fever syndrome in children; by definition, episodes occur every 2 to 8 weeks. However, in a subset of our patients, we noticed a higher frequency of attacks, of less than 2 weeks, which we refer to as extreme PFAPA (ePFAPA). This group consisted of patients who were extreme upon presentation of PFAPA, and those who became extreme after initiation of abortive corticosteroid treatment. We aimed to characterize demographic and clinical features of ePFAPA, including the two groups, and to compare them to patients with non-extreme PFAPA (nPFAPA). The medical records of 365 patients with PFAPA who attended Schneider Children's Medical Center of Israel from March 2014 to April 2021 were reviewed. Patients with concomitant familial Mediterranean fever were excluded. Characteristics of the ePFAPA (including subgroups) and nPFAPA groups were compared using Wilcoxon rank sum, Pearson's chi-squared, and Fisher's exact tests. Forty-seven patients (12.9%) were identified as having ePFAPA. Among patients with ePFAPA, compared to patients with nPFAPA, the median (interquartile range) age at disease onset was earlier: 1.5 years (0.7-2.5) vs. 2.5 years (1.5-4.0), P < 0.001; and diagnosis was younger: 2.6 years (2.0-3.6) vs. 4.5 years (3.0-6.2), P < 0.001. A higher proportion of patients with ePFAPA than nPFAPA were treated with colchicine prophylaxis (53% vs. 19%, P < 0.001), but symptoms and signs during flares did not differ significantly between these groups. Demographic and clinical characteristics were similar between patients with ePFAPA from presentation of PFAPA (22, 47% of those with ePFAPA) and ePFAPA from after corticosteroid treatment. About half the patients categorized with ePFAPA syndrome already had extreme features upon presentation. Patients with ePFAPA compared to nPFAPA presented and were diagnosed at an earlier age.
Butbul Aviel Y, Harel L, Abu Rumi M, Brik R, Hezkelo N , et al.
The Journal of pediatrics •
To describe a cohort of pediatric patients diagnosed with periodic fever aphthous stomatitis, pharyngitis and adenitis (PFAPA) and familial Mediterranean fever (FMF) and compare them with children diagnosed solely with PFAPA (sPFAPA). Clinical, laboratory, and genetic data of all pediatric patients diagnosed with sPFAPA or PFAPA/FMF were retrospectively collected from 2 primary Israeli medical referral centers and compared. Of 270 patients with PFAPA, more than one-half were of Mediterranean ancestry. Among patients with PFAPA, 51 (18.9%) also were diagnosed with FMF (PFAPA/FMF). Genetic data on the 9 most common MEFV variants were available for 45 children (88%) in the PFAPA/FMF group. Two variants were found in 15 children (33.3 %), 1 variant was found 27 patients (60%), and 3 patients (6.6%) had no variants. Abdominal pain, myalgia, and arthralgia each were more commonly reported in the PFAPA/FMF group compared with the sPFAPA group (90% vs 49% [P < .0001]; 46% vs 23% [P = .02]; and 30% vs 17% [P = .049], respectively). Colchicine was more commonly prescribed for the PFAPA/FMF group compared with the sPFAPA group (82% vs 29%; P < .0001), but alleviation of PFAPA symptoms with colchicine was similar between groups (75% vs 63%; P = .23). We show a strong association between 2 common autoinflammatory syndromes, PFAPA and FMF, in patients from Mediterranean ancestry. Clinicians should be aware that presentation of 1 disease may clinically evolve into another. The association between PFAPA and FMF poses the question similar pathogenesis and genetic influence of the MEFV gene on PFAPA.
Vanoni F, Caorsi R, Aeby S, Cochard M, Antón J , et al.
Pediatric rheumatology online journal •
Diagnosis of Periodic Fever, Aphthous stomatitis, Pharyngitis and Cervical Adenitis (PFAPA) syndrome is currently based on the modified Marshall's criteria, but no validated evidence based classification criteria for PFAPA has been established so far. A multistep process, based on the Delphi and Nominal Group Technique was conducted. After 2 rounds of e-mail Delphi survey involving 21 experts in autoinflammation we obtained a list of variables that were discussed in an International Consensus Conference. Variables reaching the 80% of consensus between participants were included in the new classification criteria. In the second phase the new classification criteria and the modified Marshall's criteria were applied on a cohort of 80 pediatric PFAPA patients to compare their performance. The Delphi Survey was sent to 22 participants, 21 accepted to participate. Thirty variables were obtained from the survey and have been discussed at the Consensus Conference. Through the Nominal Group Technique we obtained a new set of classification criteria. These criteria were more restrictive in respect to the modified Marshall's criteria when applied on our cohort of patients. Our work led us to identify a new set of classification criteria for PFAPA syndrome, but they resulted to be too restrictive to be applied in daily clinical practice for the diagnosis of PFAPA.
Butbul Aviel Y, Tatour S, Gershoni Baruch R, Brik R
Seminars in arthritis and rheumatism •
To evaluate the efficacy of colchicine in reducing the frequency of attacks in patients with PFAPA. We conducted a 6-month open label, randomized, controlled study among patients with PFAPA who attend the Pediatric Rheumatology Clinic at the Rambam Medical Center in Israel. A total of 18 patients aged4 -11 years (males:females ratio = 11:7) were randomized into a control group (I, 10 children) and a study group (II, 8 children). Group I was followed for 6 months without any intervention, and group II was initially followed for 3 months and was thereafter treated with colchicine for 3 additional months, according to standard regimen. During the 6-month period of the study the patients and their physician recorded all the episodes of PFAPA in a constructed log. DNA analyses for the 5 common FMF mutations in Israel were performed in 17 out of the 18 patients. The number of episodes during the first 3 months was similar in both groups (group I 3.2 ± 1.5, group II 4.9 ± 2.3; p ≤ 0.12). Group II had significantly less PFAPA attacks in the second period while on colchicine therapy (4.9 ± 2.3 vs. 1.6 ± 1.2; p ≤ 0.01), in opposition to group I, where no difference in the number of attacks was noted between the first and second period of follow-up (3.2 ± 1.5 vs. 2.7 ± 1.5; p = 0.33). Of the 17 patients tested, 8 were carriers for FMF mutations (2 in group I and 6 in group II). Colchicine prophylaxis seems to be effective in reducing the number of attacks in PFAPA.
Federici S, Sormani MP, Ozen S, Lachmann HJ, Amaryan G , et al.
Annals of the rheumatic diseases •
The objective of this work was to develop and validate a set of clinical criteria for the classification of patients affected by periodic fevers. Patients with inherited periodic fevers (familial Mediterranean fever (FMF); mevalonate kinase deficiency (MKD); tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS); cryopyrin-associated periodic syndromes (CAPS)) enrolled in the Eurofever Registry up until March 2013 were evaluated. Patients with periodic fever, aphthosis, pharyngitis and adenitis (PFAPA) syndrome were used as negative controls. For each genetic disease, patients were considered to be 'gold standard' on the basis of the presence of a confirmatory genetic analysis. Clinical criteria were formulated on the basis of univariate and multivariate analysis in an initial group of patients (training set) and validated in an independent set of patients (validation set). A total of 1215 consecutive patients with periodic fevers were identified, and 518 gold standard patients (291 FMF, 74 MKD, 86 TRAPS, 67 CAPS) and 199 patients with PFAPA as disease controls were evaluated. The univariate and multivariate analyses identified a number of clinical variables that correlated independently with each disease, and four provisional classification scores were created. Cut-off values of the classification scores were chosen using receiver operating characteristic curve analysis as those giving the highest sensitivity and specificity. The classification scores were then tested in an independent set of patients (validation set) with an area under the curve of 0.98 for FMF, 0.95 for TRAPS, 0.96 for MKD, and 0.99 for CAPS. In conclusion, evidence-based provisional clinical criteria with high sensitivity and specificity for the clinical classification of patients with inherited periodic fevers have been developed.
Dagan E, Gershoni-Baruch R, Khatib I, Mori A, Brik R
Rheumatology international •
PFAPA is a periodic fever disease, of unknown etiology, characterized by aphthous stomatitis, pharyngitis and cervical adenitis. To inquire whether genes implicated in other auto-inflammatory diseases might be involved in its pathogenesis, predominant mutations in the genes causing familial Mediterranean fever, TNF receptor-associated periodic fever syndrome, Crohn's disease and Muckel-Wells syndrome were analyzed in PFAPA patients. Patients (n = 57) with PFAPA, according to previously published criteria were recruited, at the Meyer Children Hospital during 2006-2007. Clinical information was complemented during physicians-parents encounter. Predominant mutations in MEFV, TNF1rA, CARD15/NOD2 and NLRP3 genes were tested. Mean age at diagnosis was 30.64 +/- 16.4 months. Boys (n = 33; 58%) were diagnosed earlier than girls (n = 21; 42%) at 26.18 +/- 13.83 and 36.41 +/- 18.32 months, respectively (P = 0.05). Fifteen patients (27%) carried an MEFV mutation; two patients (3.6%) a CARD15 mutation, one patient (1.8%) a variance in TNF1rA and another had both an MEFV and a CARD15 mutation. Clinical symptoms were equally manifested in carriers and non-carriers. The high carrier rate of MEFV mutations in our PFAPA cases compares well with that of the general population in Israel. It is debated whether MEFV mutations, when mediated by the presence of additional modifiers, may expose a transient fever condition, namely PFAPA.
