Kasem AliSliman R, Regev S, Ghanim B, Hamad Saied M
Seminars in arthritis and rheumatism •
PFAPA (periodic fever, aphthous stomatitis, pharyngitis, adenitis) syndrome is the most common periodic fever disorder in children, causing recurrent debilitating episodes that impose a substantial burden on children and their families. Current therapeutic approaches primarily rely on corticosteroid administration, which provides rapid symptom resolution but fails to address the underlying inflammatory cascade, prevent future attacks, and carries the risk of side effects. To determine the therapeutic efficacy of colchicine prophylaxis in reducing attack frequency and extending disease-free intervals in PFAPA patients, compared to standard of care management alone. This retrospective cohort study included 55 pediatric PFAPA patients, 15 receiving colchicine prophylaxis, and 40 controls managed with standard care alone. The primary outcome was the change in inter-attack interval duration from baseline study completion. Secondary analyses examined treatment response by FMF genetic status and survival analysis for time to next attack. Both groups showed comparable baseline characteristics, except higher FMF mutation prevalence in the colchicine group (73.3% vs. 27.5%, P = 0.002). Patients receiving colchicine experienced a dramatic improvement in inter-attack intervals (median change: 60 days, IQR: 51) compared with controls (median change: 0 days, IQR: 0; P < 0.001). Colchicine's therapeutic benefit was consistent regardless of FMF genetic status. Colchicine prophylaxis significantly reduces PFAPA attack frequency, with therapeutic benefits that are independent of FMF genetic status. These findings support colchicine as an effective first-line prophylactic treatment for PFAPA patients with frequent episodes or families concerned about frequent steroid use, representing a paradigm shift from reactive to preventive management.
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.
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.
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.
Gattorno M, Caorsi R, Meini A, Cattalini M, Federici S , et al.
Pediatrics •
To analyze whether there were clinical differences between genetically positive and negative patients fulfilling periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome criteria and to test the accuracy of the Gaslini diagnostic score for identifying patients with PFAPA syndrome with higher probabilities of carrying relevant mutations in genes associated with periodic fevers. Complete clinical and genetic information was available for 393 children with periodic fever; 82 had positive genetic test results, 75 had incomplete genetic test results, and 236 had negative results for MVK, TNFRSF1A, and MEFV mutations. Current diagnostic criteria for PFAPA syndrome were applied. Of 393 children, 210 satisfied PFAPA syndrome criteria; 43 carried diagnostic mutations (mevalonate kinase deficiency: n = 33; tumor necrosis factor receptor-associated periodic syndrome: n = 3; familial Mediterranean fever: n = 7), 37 displayed low-penetrance mutations or incomplete genotypes, and 130 demonstrated negative genetic testing results. Genetically positive patients had higher frequencies of abdominal pain and diarrhea (P < .001), vomiting (P = .006), and cutaneous rash and arthralgia (P = .01). Genetically negative patients had a higher frequency of exudative pharyngitis (P = .010). Genetically undetermined patients showed the same pattern of symptom frequency as genetically negative patients. The Gaslini diagnostic score was able to identify 91% of genetically positive patients correctly, with a global accuracy of 66%. The Gaslini diagnostic score represents a useful tool to identify patients meeting PFAPA syndrome criteria and at low risk of carrying relevant mutations in genes associated with periodic fevers.
Identification of the genes involved in hereditary periodic fever syndromes has led to the recognition of a new pathophysiological category, the autoinflammatory disorders. The main non-hereditary autoinflammatory disease in childhood is systemic juvenile idiopathic arthritis (sJIA), others being the chronic infantile neurological cutaneous arthropathy (CINCA) syndrome and the periodic fever, aphthous stomatitis, pharyngitis and adenopathy (PFAPA) syndrome. Familial Mediterranean fever (FMF) has been traced to mutations in the MEFV gene. Mutations in the MVK gene, encoding the enzyme mevalonate kinase, cause the hyper-IgD periodic fever syndrome (HIDS). The tumour necrosis factor(TNF)-receptor-associated periodic syndromes (TRAPS) have been linked to mutations in theTNFRSF1A gene, encoding a TNF-alpha receptor, and the CIAS1 gene is mutated in familial cold autoinflammatory syndrome. We discuss how this knowledge has influenced diagnosis and treatment of these rare genetic disorders and how it might change our approach to the more common rheumatic diseases.