Inflammasome and immune disorders (33)
Autoimmune and Inflammatory Disorders Research (28)
Rheumatoid Arthritis Research and Therapies (12)
Systemic Lupus Erythematosus Research (7)
Vasculitis and related conditions (6)
Veres T, Amarilyo G, Abu Ahmad S, Abu Rumi M, Brik R , et al.
Frontiers in pediatrics •
Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA) is the most common periodic fever syndrome in the pediatric population, yet its pathogenesis is unknown. PFAPA was believed to be sporadic but family clustering has been widely observed. To identify demographic and clinical differences between patients with PFAPA and a positive family history (FH+) as compared to those with no family history (FH-). In a database comprising demographic and clinical data of 273 pediatric PFAPA patients treated at two tertiary centers in Israel, 31 (14.3%) had FH+. Data from patients with FH+ were compared to data from those with FH-. Furthermore, family members (FMs) of those with FH+ were contacted via telephone for more demographic and clinical details. The FH+ group as compared to the FH- group had more myalgia (56 vs. 19%, respectively, = 0.001), headaches (32 vs. 2%, respectively, = 0.016), and a higher carrier frequency of M694V mutation (54% vs. 25%, respectively, = 0.05). Colchicine was seen to be a more beneficial treatment for the FH+ group as compared to the FH- group; however, with no statistical significance ( = 0.096). FMs displayed almost identical characteristics to patients in the FH+ group except for greater arthralgia during flares (64 vs. 23%, respectively, = 0.008), and compared to the FH- group they had more oral aphthae (68 vs. 43%, respectively, = 0.002), myalgia/arthralgia (64 vs. 19%/16%, respectively, < 0.0001), and higher rates of FH of Familial Mediterranean fever (FMF) (45 vs.15%, respectively, = 0.003). Our findings suggest that patients with a FH+ likely experience a different subset of disease with higher frequency of family history of FMF, arthralgia, myalgia, and might have a better response to colchicine compared to FH-. Colchicine prophylaxis for PFAPA should be considered in FH+.
Amarilyo G, Harel L, Abu Ahmad S, Abu Rumi M, Brik R , et al.
The Journal of pediatrics •
To evaluate the ethnic distribution of Israeli patients with the syndrome of periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA). The medical records of patients with PFAPA attending 2 pediatric tertiary medical centers in Israel from March 2014 to March 2019 were retrospectively reviewed. Patients with concomitant familial Mediterranean fever were excluded. Ethnicity was categorized as Mediterranean, non-Mediterranean, and multiethnic. Findings were compared with patients with asthma under treatment at the same medical centers during the same period. The cohort included 303 patients with PFAPA and 475 with asthma. Among the patients with PFAPA, 178 (58.7%) were of Mediterranean descent (Sephardic Jews or Israeli Arabs), 96 (33.0%) were multiethnic, and 17 (5.8%) were of non-Mediterranean descent (all Ashkenazi Jews). Patients with PFAPA had a significantly higher likelihood of being of Mediterranean descent than the patients with asthma (58.7% vs 35.8%; P < .0001). The Mediterranean PFAPA subgroup had a significantly earlier disease onset than the non-Mediterranean subgroup (2.75 ± 1.7 vs 3.78 ± 1.9 years, P < .04) and were younger at disease diagnosis (4.77 ± 2.3 vs 6.27 ± 2.9 years, P < .04). PFAPA was significantly more common in patients of Mediterranean than non-Mediterranean descent. Further studies are needed to determine the genetic background of these findings.
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.
Hofer M, Pillet P, Cochard MM, Berg S, Krol P , et al.
Rheumatology (Oxford, England) •
The aims of this study were to describe the clinical features of periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) and identify distinct phenotypes in a large cohort of patients from different countries. We established a web-based multicentre cohort through an international collaboration within the periodic fevers working party of the Pediatric Rheumatology European Society (PReS). The inclusion criterion was a diagnosis of PFAPA given by an experienced paediatric rheumatologist participating in an international working group on periodic fever syndromes. Of the 301 patients included from the 15 centres, 271 had pharyngitis, 236 cervical adenitis, 171 oral aphthosis and 132 with all three clinical features. A total of 228 patients presented with additional symptoms (131 gastrointestinal symptoms, 86 arthralgias and/or myalgias, 36 skin rashes, 8 neurological symptoms). Thirty-one patients had disease onset after 5 years and they reported more additional symptoms. A positive family history for recurrent fever or recurrent tonsillitis was found in 81 patients (26.9%). Genetic testing for monogenic periodic fever syndromes was performed on 111 patients, who reported fewer occurrences of oral aphthosis or additional symptoms. Twenty-four patients reported symptoms (oral aphthosis and malaise) outside the flares. The CRP was >50 mg/l in the majority (131/190) of the patients tested during the fever. We describe the largest cohort of PFAPA patients presented so far. We confirm that PFAPA may present with varied clinical manifestations and we show the limitations of the commonly used diagnostic criteria. Based on detailed analysis of this cohort, a consensus definition of PFAPA with better-defined criteria should be proposed.
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.