Assistance Publique – Hôpitaux de Paris

Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis (PFAPA) Syndrome in Children-From Pathogenesis to Treatment Strategies: A Comprehensive Review.

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.

Symptom course of PFAPA syndrome.

Periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome is the most common cause of autoinflammatory periodic fever in children. It is generally considered to be a self-limiting condition that resolves spontaneously over time. To evaluate age and delay to recovery of patients with PFAPA syndrome. We retrospectively reviewed the medical records of patients diagnosed with PFAPA syndrome at the Versailles Hospital (Paris, France) and included in the Juvenile Inflammatory Rheumatism (JIR) cohort between 2016 and February 2023. Recovery was defined as the absence of any febrile PFAPA episode in the past year. Patients with either no reported febrile episode or insufficient information on fever status over the last 12 months were contacted by telephone. 209 patients with PFAPA syndrome were included. Overall, 56 (27%) patients experienced resolution of periodic fever, 119 (57%) were still active and 34 (16%) patients were lost to follow-up. Among recovered patients, the median duration of symptoms was 5.43 years (Q1-Q3: 2.97–8.65) and the median age at last febrile episode was 8.34 years (Q1-Q3: 5.44–10.24). Of the 119 patients with persistent fever, 10 patients were initially declared cured but relapsed. In patients whose fever resolved, most experienced their last febrile episode before adolescence. The identification of relapses after at least 12 months without a febrile episode raises questions about the definition of recovery.

Unravelling the clinical heterogeneity of undefined recurrent fever over time in the European registries on Autoinflammation.

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.

Do we need the PFAPA syndrome in adults with non-monogenic periodic fevers?

Validation of the new classification criteria for hereditary recurrent fever in an independent cohort: experience from the JIR Cohort Database.

The new classification criteria for the hereditary recurrent fever (HRF) syndrome [cryopyrin-associated periodic syndrome (CAPS), TNF-α receptor-associated periodic syndrome (TRAPS), FMF and mevalonate kinase deficiency] have been published recently. These criteria define two core sets of criteria for each HRF: mixed criteria, including genetic and clinical variables, and clinical criteria, relying on clinical variables only. Our aim was to validate the criteria for HRF in an independent cohort, the JIR Cohort database, an international repository of systemic inflammatory diseases. We enrolled patients with HRF, periodic fever, adenitis, pharyngitis and aphthous stomatitis syndrome (PFAPA) and syndrome of undefined recurrent fever (SURF). A score ranging from zero to two was attributed to their respective genotypes: zero (no mutation), one (non-confirmatory genotype) or two (confirmatory genotype). The criteria were applied to all patients based on genotype scoring. The treating physician's diagnosis served as the gold standard for the determination of specificity. We included 455 patients. The classification criteria showed excellent specificity for CAPS and TRAPS (98% specificity each), fair specificity for FMF (88%), but poor specificity for mevalonate kinase deficiency (58%). Sub-analysis showed excellent accuracy of the mixed criteria for all four HRFs. Misclassification was mainly attributable to clinical criteria sets, with false-positive patients in all four HRF clinical criteria sets. This study represents the final validation step of the HRF classification criteria as recommended by the ACR. Genetic data appear to be necessary to classify patients with HRF correctly.

AA amyloidosis revealing mevalonate kinase deficiency: A report of 20 cases including two new French cases and a comprehensive review of literature.

Mevalonate kinase deficiency (MKD) is a rare autosomal recessive autoinflammatory disease that can lead to an inflammatory A amyloidosis (AA). To study the occurrence of AA in MKD patients we performed a systemic review of the literature and described two novel patients. Amyloidosis occurred in 20 MKD patients, renal impairment being always the revealing symptom of AA. Although an accurate prevalence estimation is not possible since exact MKD prevalence is unknown, AA seems rare in MKD (about 6% if we estimate MKD prevalence at 300 patients worldwide). MVK gene study, available in 18 out of the 20 patients, confirmed two pathogenic mutations in all tested individuals. The most frequent genotype was V377I/I268T (n = 9/18). Retrospective search of clinical signs of MKD established, in all patients carrying MVK pathogenic mutations, a disease onset within the first four years of life. Nephrotic syndrome (n = 15), end-stage renal failure (n = 5) or both (n = 8) pointed out kidney amyloidosis. The youngest patient with renal amyloidosis was a European four-year-old girl previously misdiagnosed with PFAPA syndrome. Five patients died of AA amyloidosis despite the use of a biotherapy for two of them; kidney transplant was performed in nine individuals. Colchicine was not effective in any patient. Anti-interleukin-1 anakinra (n = 8), anti TNF etanercept (n = 7) and anti-interleukin 6 tocilizumab (n = 5) treatments were partially effective. Inflammatory A amyloidosis, a rare complication of MKD, can cause death or necessitate kidney transplantation. Early diagnosis and cytokine blocking biotherapy using anti-IL1, anti-TNF or anti-IL6 agents are required to prevent terminal renal failure.

Autoinflammatory diseases: State of the art.

Autoinflammatory diseases are characterized by innate immunity abnormalities. In autoinflammatory diseases (AID), inflammatory blood biomarkers are elevated during crisis without infection and usually without autoantibodies. The first 4 described AID were familial Mediterranean fever, cryopyrin-associated periodic fever syndrome (CAPS) or NLRP3-associated autoinflammatory disease (NRLP3-AID), mevalonate kinase deficiency (MKD) and TNFRSF1A-receptor associated periodic fever syndrome (TRAPS). Since their description 20 years ago, and with the progresses of genetic analysis, many new diseases have been discovered; some with recurrent fever, others with predominant cutaneous symptoms or even immune deficiency. After describing the 4 historical recurrent fevers, some polygenic inflammatory diseases will also be shortly described such as Still disease and periodic fever with adenitis, pharyngitis and aphtous (PFAPA) syndrome. To better explore AID, some key anamnesis features are crucial such as the family tree, the age at onset, crisis length and organs involved in the clinical symptoms. An acute phase response is mandatory in crisis.

Towards a new set of classification criteria for PFAPA syndrome.

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.

Is colchicine an effective treatment in periodic fever, aphtous stomatitis, pharyngitis, cervical adenitis (PFAPA) syndrome?

PFAPA syndrome is the most frequent periodic fever syndrome in non-Mediterranean patients. The pathogenesis is unclear and the treatment is purely symptomatic and not standardized. The aim of this study was to assess colchicine's efficacy as prophylactic treatment in PFAPA syndrome and to identify factors able to predict response to treatment. We performed a retrospective, multicentric, cohort study of PFAPA patients under colchicine prophylaxis. PFAPA diagnosis was established according to Feder's criteria. Medical records were reviewed and analyzed for demographic, clinical and laboratory data. We distinguished one responder's group, defined as patients who had no more or twice fewer crises under colchicine and another one of non-responders. Subgroup analyses were performed using non-parametric Mann-Whitney test for quantitative data and calculating odds ratio and confidence interval for qualitative data. Difference between the two groups was considered significant for P-value<0.05 or a confidence interval different from 1. Twenty children, 65% of whom were boys, were analyzed. Their mean age at disease onset was 2.3±1.5 years. Among the nine responder patients, five were MEFV (71%) heterozygotes: M694V mutation in four and V726A once. Heterozygous MEFV gene mutation tended to be more frequent in the responders group (71% versus 43%; OR=0.3 [0.03-2.7]). Non-responder patients had more chronic fatigue (82% versus 33%; OR=9 [1,14-71]) and had more oral aphtosis (82% versus 11%; OR=36 [1,7-141]) than the responders ones. Although not significant, colchicine treatment appeared more effective in patients with less complete PFAPA phenotype and MEFV heterozygosity.

Performance of Different Diagnostic Criteria for Familial Mediterranean Fever in Children with Periodic Fevers: Results from a Multicenter International Registry.

Our aims were to validate the pediatric diagnostic criteria in a large international registry and to compare them with the performance of previous criteria for the diagnosis of familial Mediterranean fever (FMF). Pediatric patients with FMF from the Eurofever registry were used for the validation of the existing criteria. The other periodic fevers served as controls: mevalonate kinase deficiency (MKD), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), cryopyrin-associated periodic syndrome (CAPS), aphthous stomatitis, pharyngitis, adenitis syndrome (PFAPA), and undefined periodic fever from the same registry. The performances of Tel Hashomer, Livneh, and the Yalcinkaya-Ozen criteria were assessed. The FMF group included 339 patients. The control group consisted of 377 patients (53 TRAPS, 45 MKD, 32 CAPS, 160 PFAPA, 87 undefined periodic fevers). Patients with FMF were correctly diagnosed using the Yalcinkaya-Ozen criteria with a sensitivity rate of 87.4% and a specificity rate of 40.7%. On the other hand, Tel Hashomer and Livneh criteria displayed a sensitivity of 45.0 and 77.3%, respectively. Both of the latter criteria displayed a better specificity than the Yalcinkaya-Ozen criteria: 97.2 and 41.1% for the Tel Hashomer and Livneh criteria, respectively. The overall accuracy for the Yalcinkaya-Ozen criteria was 65 and 69.6% (using 2 and 3 criteria), respectively. Ethnicity and residence had no effect on the performance of the Yalcinkaya-Ozen criteria. The Yalcinkaya-Ozen criteria yielded a better sensitivity than the other criteria in this international cohort of patients and thus can be used as a tool for FMF diagnosis in pediatric patients from either the European or eastern Mediterranean region. However, the specificity was lower than the previously suggested adult criteria.

Evidence-based provisional clinical classification criteria for autoinflammatory periodic fevers.

The objective of this work was to develop and validate a set of clinical criteria for the classification of patients affected by periodic fevers. Patients with inherited periodic fevers (familial Mediterranean fever (FMF); mevalonate kinase deficiency (MKD); tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS); cryopyrin-associated periodic syndromes (CAPS)) enrolled in the Eurofever Registry up until March 2013 were evaluated. Patients with periodic fever, aphthosis, pharyngitis and adenitis (PFAPA) syndrome were used as negative controls. For each genetic disease, patients were considered to be 'gold standard' on the basis of the presence of a confirmatory genetic analysis. Clinical criteria were formulated on the basis of univariate and multivariate analysis in an initial group of patients (training set) and validated in an independent set of patients (validation set). A total of 1215 consecutive patients with periodic fevers were identified, and 518 gold standard patients (291 FMF, 74 MKD, 86 TRAPS, 67 CAPS) and 199 patients with PFAPA as disease controls were evaluated. The univariate and multivariate analyses identified a number of clinical variables that correlated independently with each disease, and four provisional classification scores were created. Cut-off values of the classification scores were chosen using receiver operating characteristic curve analysis as those giving the highest sensitivity and specificity. The classification scores were then tested in an independent set of patients (validation set) with an area under the curve of 0.98 for FMF, 0.95 for TRAPS, 0.96 for MKD, and 0.99 for CAPS. In conclusion, evidence-based provisional clinical criteria with high sensitivity and specificity for the clinical classification of patients with inherited periodic fevers have been developed.