Dipasquale RF, Sinopoli P, Adessi S, Pascuzzo A, Gallizzi R
European journal of pediatrics •
We examined associations between clinical features at first paediatric rheumatology assessment and eventual benign/self-limited (Group 1) versus systemic/chronic (Group 2) diagnostic categories in children referred for recurrent oral aphthosis. We retrospectively studied 404 children evaluated from 2010 to 2024. Baseline clinical variables were documented at the first rheumatology visit before final diagnosis; follow-up assessments were performed every 3-6 months. Eight prespecified clinical features entered multivariable logistic regression. Firth and diagnosis-exclusion sensitivity analyses addressed sparse data and diagnostic-composition bias. CRP/ESR and HLA-B51 were analysed separately. The cohort included 198 males (49.0%) and 206 females (51.0%); age at symptom onset ranged from 2 months to 15 years. Group 1 included 267 patients, and Group 2 included 137. Recurrent fever (aOR, 0.25; 95% CI, 0.12-0.49) and tonsillitis/pharyngitis (aOR, 0.17; 95% CI, 0.09-0.32) were associated with lower odds of Group 2, whereas genital aphthosis was associated with higher odds (aOR, 13.08; 95% CI, 3.04-56.32). After simultaneous exclusion of PFAPA and Behçet disease spectrum diagnoses, the fever/pharyngitis associations were attenuated, and the genital aphthosis estimate became uninformative because of sparse data, while arthralgia/arthritis remained positively associated. Elevated CRP/ESR was not independently associated with Group 2; HLA-B51 positivity was more frequent in Group 2 among selectively tested patients.  In children referred for recurrent oral aphthosis, recurrent fever and pharyngitis were mainly associated with benign/self-limited diagnoses, whereas genital aphthosis was mainly associated with systemic/chronic diagnoses. These associations were largely driven by PFAPA and Behçet spectrum disease, respectively. Articular involvement showed the most consistent positive association across sensitivity analyses. These findings are descriptive, not a validated diagnostic prediction tool. • Oral aphthae are common and non-specific in childhood. • Associated symptoms guide diagnostic work-up and follow-up. • PFAPA-characteristic features clustered with benign/self-limited diagnoses; genital aphthosis with systemic/chronic diagnoses. • After PFAPA/Behçet spectrum exclusion, these signals attenuated; articular involvement was the most consistent positive association.
Dipasquale RF, Sinopoli P, Mendicino A, Gallizzi R
European journal of pediatrics •
Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) is the most common periodic fever syndrome in children. On-demand corticosteroids stop attacks but may shorten fever-free intervals. This systematic review assessed the effectiveness of daily colchicine prophylaxis in pediatric PFAPA. Furthermore, MEFV status association with colchicine efficacy has been explored. PubMed, Scopus, and Web of Science were systematically searched from inception to 6 November 2025 to identify trials and observational studies presenting participants with a diagnosis of PFAPA, colchicine prophylaxis as interventions, and attack frequency/attack-free interval as outcomes. All eligible records identified up to that date were screened. Colchicine reduced attack frequency, lengthened attack-free intervals, and lowered steroid use, with benefits often within 1 month. A short randomized comparison showed similar 3-month efficacy to cimetidine. Adverse events were mostly mild gastrointestinal; discontinuations were uncommon. MEFV variants as predictors of response remain uncertain. Current evidence supports colchicine as an efficacy and generally well-tolerated preventive option. • PFAPA is the most common periodic fever in children. On-demand corticosteroids stop attacks but may shorten symptom-free intervals; preventive options include cimetidine, selective tonsillectomy, and biologics. • Colchicine modulates innate immunity and it is effective in familial Mediterranean fever; MEFV variants occur in a subset of PFAPA, supporting interest in repurposing. • Continuous colchicine reduced attack frequency, prolonged attack-free intervals, and lowered steroid use; adverse events were mostly mild gastrointestinal, with few treatment discontinuations. • Clinical improvement often appeared by about 1 month and stabilized by 3 months; this supports early reassessment to adjust dose or change therapy. MEFV is not clearly associated.
Spagnolo A, Mileto V, Civino A, Maggio MC, Risso P , et al.
Frontiers in pediatrics •
Periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome (PFAPA) is the most common cause of periodic fever in childhood. Although PFAPA is generally a self-limited condition, it can have negative impact on child's and parents' quality of life and family functioning. Our primary aim was to assess the potential effectiveness of Streptococcus Salivarius K12 (SSK12) in preventing febrile attacks in PFAPA patients. Secondary objectives included evaluating the effectiveness of SSK12 in mitigating the severity of febrile episodes seen as a statistically significant reduction in the episode duration, highest fever temperature reached during fever, in the frequency of each associated symptom, calculated in the six months before and after the start of therapy. A total of 117 patients with PFAPA were evaluated using Marshall's criteria, modified by Thomas et al. and according to Eurofever/PRINTO classification criteria, aged 6 months to 9 years, with a median age at the onset of the disease of 2 years, treated with SSK12, since January 2021 to January 2023. Data were collected retrospectively. Before using SS K12, febrile episodes recurred on average every 26.1 ± 11.5 days, with a febrile episode duration of 4.1 ± 1.4 days. The highest fever temperature during the episode was 39.8 ± 0.7 °C. After six months of SS K12, febrile episodes recurred on average every 70 ± 53,1 days ( value <0.01), the mean lenght of febrile episodes was 3.3 ± 1.6 ( value <0.01) and the highest fever temperature reached during the febrile episode was 39.1 ± 1.1 °C ( value <0.01). We also documented a reduction in the frequency of exudative pharyngotonsillitis present in 72 vs. 103 patients ( value <0.01), oral aphthosis present in 47 vs. 80 patients ( value <0.01), lateral cervical lymphadenopathy in 45 vs. 83 ( value <0.01). Erythematous pharyngotonsillitis decreased in frequency but it was not statistically significant. The results of our study indicate that the use of SS K12 could be beneficial in decreasing febrile episodes related to PFAPA syndrome and its associated symptoms, potentially improving the quality of life in pediatric patients and decreasing the need for additional pharmacological therapies.
Gerritsma AM, Sutera D, Cantarini L, Cattalini M, Lachmann HJ , et al.
Clinical and experimental rheumatology •
To describe the clinical phenotype and response to treatment of autoinflammatory disease (AID) patients with the TNFRSF1A-pR92Q variant compared to patients with tumour necrosis factor receptor-associated periodic syndrome (TRAPS) due to pathogenic mutations in the same gene and patients diagnosed with other recurrent fever syndromes including periodic fever with aphthous stomatitis, pharyngitis, and adenitis (PFAPA) and syndrome of undefined recurrent fever (SURF). Clinical data from pR92Q variant associated AID, classical TRAPS, PFAPA and SURF patients were obtained from the Eurofever registry, an international, multicentre registry enabling retrospective collection of data on AID patients. In this study, 361 patients were enrolled, including 77 pR92Q variant, 72 classical TRAPS, 152 PFAPA and 60 SURF patients. pR92Q carriers had an older age of disease onset than classical TRAPS and PFAPA patients. Compared to pR92Q variant patients, classical TRAPS patients had more relatives affected and were more likely to have migratory rash and AA-amyloidosis. Despite several differences in disease characteristics and symptoms between pR92Q variant and PFAPA patients, part of the pR92Q variant patients experienced PFAPA-like symptoms. pR92Q variant and SURF patients showed a comparable clinical phenotype. No major differences were observed in response to treatment between the four patient groups. Steroids were most often prescribed and effective in the majority of patients. Patients with AID carrying the TNFRSF1A-pR92Q variant behave more like SURF patients and differ from patients diagnosed with classical TRAPS and PFAPA in clinical phenotype. Hence, they should no longer be diagnosed as having TRAPS and management should differ accordingly.
