Vyzhga Y, Wittkowski H, Hentgen V, Georgin-Lavialle S, Theodoropoulou A , et al.
Pediatric rheumatology online journal •
Systemic autoinflammatory disorders (SAIDs) represent a growing spectrum of diseases characterized by dysregulation of the innate immune system. The most common pediatric autoinflammatory fever syndrome, Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA), has well defined clinical diagnostic criteria, but there is a subset of patients who do not meet these criteria and are classified as undefined autoinflammatory diseases (uAID). This project, endorsed by PRES, supported by the EMERGE fellowship program, aimed to analyze the evolution of symptoms in recurrent fevers without molecular diagnosis in the context of undifferentiated AIDs, focusing on PFAPA and syndrome of undifferentiated recurrent fever (SURF), using data from European AID registries. Data of patients with PFAPA, SURF and uSAID were collected from 3 registries including detailed epidemiological, demographic and clinical data, results of the genetic testing and additional laboratory investigations with retrospective application of the modified Marshall and PRINTO/Eurofever classification criteria on the cohort of PFAPA patients and preliminary SURF criteria on uSAID/SURF patients. Clinical presentation of PFAPA is variable and some patients did not fit the conventional PFAPA criteria and exhibit different symptoms. Some patients did not meet the criteria for either PFAPA or SURF, highlighting the heterogeneity within these groups. The study also explored potential overlaps between PFAPA and SURF/uAID, revealing that some patients exhibited symptoms characteristic of both conditions, emphasizing the need for more precise classification criteria. Patients with recurrent fevers without molecular diagnoses represent a clinically heterogeneous group. Improved classification criteria are needed for both PFAPA and SURF/uAID to accurately identify and manage these patients, ultimately improving clinical outcomes.
Kapustova L, Banovcin P, Bobcakova A, Jurkova Malicherova E, Kapustova D , et al.
Frontiers in immunology •
Periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome (PFAPA) is the most frequent periodic fever syndrome in children. Its pathogenesis is still unknown, but some disease-modifying factors were observed. Several medications were tested for the long-term prophylaxis of inflammatory flares; however, none are standardly used. This prospective clinical trial enrolled 142 children (71 girls, 50%) meeting diagnostic criteria for PFAPA syndrome. We analysed selected clinical characteristics and compared laboratory parameters during the flare and attack-free period (at least two weeks after the attack). Moreover, we assessed the possible therapeutic effect of ketotifen on the duration of attack free-periods and clinical picture. The mean age of patients was 6.81 ± 3.03 years and the mean age of onset of symptoms was 2.31 ± 2.02 years. No significant differences were observed between genders.We recorded a positive family history for PFAPA in 31.69% of patients. Attacks lasted for 2.8 ± 1.2 days, with intervals between attacks of 4 ± 1 weeks. We administered ketotifen in 111 (77.8%) patients, and a positive effect was observed in 86 (77.5%) of patients. We observed prolonged attack-free intervals in patients treated with ketotifen (14.7 ± 8.9 days in comparison with 4.4 ± 1.9 days before the treatment; p<0.001). The used dose of ketotifen was 0.08 ± 0.01 mg/kg/day. Mild side effects were observed in four patients (restlessness, irritability, agitation and constipation). Our data supports the use of ketotifen for long-term prophylaxis in children with PFAPA syndrome with positive effects on the attenuation of disease activity and the prolongation of attack-free periods. Further well-designed studies should confirm the preliminary data.
Kovacs L, Hlavatá A, Baldovič M, Paulovicova E, Dallos T , et al.
Neuro endocrinology letters •
The periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome appears to be more common than generally appreciated and should be differentiated from hereditary periodic fever syndromes, particularly from mevalonate kinase deficiency (MKD). 14 unrelated patients (7 males, 7 females) met clinical criteria for both the PFAPA syndrome and MKD. Immunoglobulin D (IgD) levels, mevalonic aciduria and mevalonate kinase (MVK) genotype was determined in all patients. Children experienced their first febrile episode at the age of 24.5±5.9 months (mean±SD), the clinical diagnosis of PFAPA syndrome was established with delay at 42.7±11.7 months. The duration of febrile episodes was 3.4±0.2 days, the asymptomatic interval between them lasted 5.4±0.9 weeks. Accompanying symptoms included pharyngitis (92.8%), cervical lymphadenitis (85.7%), aphthous stomatitis (21.4%), arthralgia (14.3%) and skin erythema (35.7%). Neither mevalonic aciduria nor MVK gene mutations were found in any of the subjects, however, unexpectedly, increased plasma IgD (322.2±29.2 U/l) levels were detected in all patients. Raised IgD levels may represent a non-specific epiphenomenon, which frequently accompanies PFAPA syndrome as well as MKD. Because of the overlapping clinical and laboratory features, genetic testing of the MVK gene is indicated to differentiate these two conditions, if clinical criteria for both are fulfilled.
