Inflammasome and immune disorders (187)
Autoimmune and Inflammatory Disorders Research (153)
Kawasaki Disease and Coronary Complications (72)
Adolescent and Pediatric Healthcare (49)
Systemic Lupus Erythematosus Research (43)
Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is the most frequent periodic fever syndrome in non-Mediterranean children, usually manifesting before the age of 5 years. It is characterized by clockwork episodes of fever lasting 3-7 days, accompanied by aphthous stomatitis, pharyngitis, and/or cervical adenitis. Typically, patients with PFAPA are generally well between episodes and exhibit normal growth and development. Although PFAPA often resolves spontaneously, its recurrent nature can significantly impact quality of life, and symptoms may persist into adulthood. This narrative review aimed to consolidate current knowledge on PFAPA epidemiology, pathogenesis, clinical presentation, diagnostic considerations, and therapeutic options. A structured literature search was performed using PubMed, Cochrane Library, and Scopus, focusing on relevant articles specifically addressing PFAPA. Increasing evidence suggests multifactorial pathogenesis involving innate immune dysregulation, activation of the NLRP3 inflammasome, and Th1-driven inflammation. Genetic analysis studies suggest a polygenic inheritance of PFAPA, linking it to immune pathways shared with familial Mediterranean fever and Behçet's disease. Diagnosis remains clinical, though genetic testing may be warranted in specific cases. Management strategies vary owing to the absence of standardized guidelines. Oral corticosteroids are highly effective for acute episodes but may shorten the interval between flares. Among preventive therapies, colchicine appears to reduce attack frequency, although evidence of its efficacy is limited, while tonsillectomy is often considered curative but recommended for patients with refractory disease or when there is a concurrent otolaryngologic indication. Further research is needed to refine diagnostic criteria and optimize treatment strategies, ultimately improving patients' and caregivers' quality of life.
Gattorno M, Hofer M, Federici S, Vanoni F, Bovis F , et al.
Annals of the rheumatic diseases •
Different diagnostic and classification criteria are available for hereditary recurrent fevers (HRF)-familial Mediterranean fever (FMF), tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS), mevalonate kinase deficiency (MKD) and cryopyrin-associated periodic syndromes (CAPS)-and for the non-hereditary, periodic fever, aphthosis, pharyngitis and adenitis (PFAPA). We aimed to develop and validate new evidence-based classification criteria for HRF/PFAPA. Step 1: selection of clinical, laboratory and genetic candidate variables; step 2: classification of 360 random patients from the Eurofever Registry by a panel of 25 clinicians and 8 geneticists blinded to patients' diagnosis (consensus ≥80%); step 3: statistical analysis for the selection of the best candidate classification criteria; step 4: nominal group technique consensus conference with 33 panellists for the discussion and selection of the final classification criteria; step 5: cross-sectional validation of the novel criteria. The panellists achieved consensus to classify 281 of 360 (78%) patients (32 CAPS, 36 FMF, 56 MKD, 37 PFAPA, 39 TRAPS, 81 undefined recurrent fever). Consensus was reached for two sets of criteria for each HRF, one including genetic and clinical variables, the other with clinical variables only, plus new criteria for PFAPA. The four HRF criteria demonstrated sensitivity of 0.94-1 and specificity of 0.95-1; for PFAPA, criteria sensitivity and specificity were 0.97 and 0.93, respectively. Validation of these criteria in an independent data set of 1018 patients shows a high accuracy (from 0.81 to 0.98). Eurofever proposes a novel set of validated classification criteria for HRF and PFAPA with high sensitivity and specificity.
Grimwood C, Kone-Paut I, Piram M, Rossi-Semerano L, Hentgen V
Orphanet journal of rare diseases •
Conventionally, PFAPA syndrome is considered as a benign disease compared to other recurrent fevers because it completely passes before adulthood. However, in our clinical practice, fever episodes have a huge impact on daily activities. Observational cohort study using the Pediatric Quality of Life Inventory (PedsQL™ 4.0) Generic Core and Fatigue Scales. PedsQL™ uses a modular approach to measure the HRQOL in children with acute and chronic health conditions. We used pediatric FMF patients as the control group. We included 33 children with PFAPA and compared them to 27 FMF patients matched for age: preschool-age children (2 to 7 years) and school-age children and youths (8 to18 years). PedsQL™ self-reported scores of children with PFAPA were systematically lower than those of FMF peers for general quality of life and physical and psychosocial functioning (significant only in the preschool-age group). PedsQL™ self-reported fatigue scores of children with PFAPA were significantly lower than those of FMF peers for both preschoolers and school-age children and youths. Parent proxy-reports were not significantly different, even though scores were systematically lower for the parents of PFAPA children. Our study demonstrates, for the first time, that the wellbeing of PFAPA children is poor, with a major impact on psychosocial functioning and increased fatigue. The quality of life of PFAPA children appears to be even lower than that of FMF patients, for whom a lower than normal HRQOL has already been demonstrated.
Konukbay D, Gattorno M, Yildiz D, Frenkel J, Acikel C , et al.
Clinical and experimental rheumatology •
To develop and test a new multidimensional questionnaire for assessment of children with auto-inflammatory disease (AID) such as FMF, PFAPA, HIDS, TRAPS in standard clinical care. The juvenile auto-inflammatory disease multidimensional assessment report (JAIMAR) includes 16 parent or patient-centered measures and four dimensions that assess functional status, pain, therapeutic compliance and health-related quality of life (physical, social, school, emotional status) with disease outcome. It is proposed for use as both a proxy-report and a patient self-report, with the suggested age range of 8-18 years for use as a self-report. 250 children with FMF were included in the study. Total of 179 forms were filled up by parents and patients, and 71 forms were filled up by parents having children less than 8 years. Completing and scoring the JAIMAR can be done in 15 minutes. For the JAIMAR's dimensions, the Cronbach's alpha coefficient for internal consistency was between 0.507-0.998. There was a significant and a positive correlation between the test-retest scale scores (ICC=0.607-0.966). Concerning construct validity, all factors loadings were above 0.30. For the criterion validity, the correlation level between each dimension and the related scale ranged from medium (r=0.329, p<0.0001) to large (r=0.894, p<0.0001). The parents' proxy-reported and children's self-reported data were outstandingly concordant (r=0.770-0.989). The development of the JAIMAR introduces a new and multi-dimensional approach in paediatric rheumatology practice. It is a new tool for children with auto-inflammatory dis-ease and it may help enhance their quality of care.
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.