Kastner DL

Features Associated with Response to Tonsillectomy in Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis Syndrome in Children.

To identify clinical features associated with response to tonsillectomy among children with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome and to determine optimal management of children with continued episodes after tonsillectomy. Patients with PFAPA seen at Vanderbilt University Children's Hospital and the National Institutes of Health (NIH) who underwent tonsillectomy were enrolled and queried regarding symptoms before and after surgery. Ninety-seven subjects with PFAPA (43 Vanderbilt, 54 NIH) were followed for a median of 49 months following tonsillectomy. Nearly half of participants reported complete resolution of PFAPA episodes (65% at Vanderbilt and 35% at NIH), while 25% had less severe or frequent episodes, 23% had a period of remission with recurrence, and 4% had no change in episodes. By logistic regression, factors associated with a full response to tonsillectomy were episode resolution with glucocorticoid treatment, presence of exudative pharyngitis, absence of rash, and absence of arthralgia/myalgia during pre-tonsillectomy PFAPA flares. Among those requiring treatment for persistent flares post-tonsillectomy, 15/19 (79%) reported improvement with cimetidine or famotidine prophylaxis. Tonsillectomy remains effective in improving PFAPA flares in most patients. However, unique episode features prior to tonsillectomy appear to be clinical predictors of response to tonsillectomy. Histamine receptor 2 antagonists like cimetidine were effective prophylactic agents for refractory cases post-tonsillectomy. Patients with incomplete response to tonsillectomy may represent a subset of PFAPA with unique factors affecting their pathogenesis.

The systemic autoinflammatory diseases: Coming of age with the human genome.

Common genetic susceptibility loci link PFAPA syndrome, Behçet's disease, and recurrent aphthous stomatitis.

Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is the most common periodic fever syndrome in children. The disease appears to cluster in families, but the pathogenesis is unknown. We queried two European-American cohorts and one Turkish cohort (total = 231) of individuals with PFAPA for common variants previously associated with two other oropharyngeal ulcerative disorders, Behçet's disease and recurrent aphthous stomatitis. In a metaanalysis, we found that a variant upstream of (rs17753641) is strongly associated with PFAPA (OR 2.13, = 6 × 10). We demonstrated that monocytes from individuals who are heterozygous or homozygous for this risk allele produce significantly higher levels of IL-12p70 upon IFN-γ and LPS stimulation than those from individuals without the risk allele. We also found that variants near , , and were significant susceptibility loci for PFAPA, suggesting that the pathogenesis of PFAPA involves abnormal antigen-presenting cell function and T cell activity and polarization, thereby implicating both innate and adaptive immune responses at the oropharyngeal mucosa. Our results illustrate genetic similarities among recurrent aphthous stomatitis, PFAPA, and Behçet's disease, placing these disorders on a common spectrum, with recurrent aphthous stomatitis on the mild end, Behçet's disease on the severe end, and PFAPA intermediate. We propose naming these disorders Behçet's spectrum disorders to highlight their relationship. alleles may be factors that influence phenotypes along this spectrum as we found new class I and II associations for PFAPA distinct from Behçet's disease and recurrent aphthous stomatitis.

Classification criteria for autoinflammatory recurrent fevers.

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.

Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) is a disorder of innate immunity and Th1 activation responsive to IL-1 blockade.

The syndrome of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) is the most common periodic fever disease in children. However, the pathogenesis is unknown. Using a systems biology approach we analyzed blood samples from PFAPA patients whose genetic testing excluded hereditary periodic fevers (HPFs), and from healthy children and pediatric HPF patients. Gene expression profiling could clearly distinguish PFAPA flares from asymptomatic intervals, HPF flares, and healthy controls. During PFAPA attacks, complement (C1QB, C2, SERPING1), IL-1-related (IL-1B, IL-1RN, CASP1, IL18RAP), and IFN-induced (AIM2, IP-10/CXCL10) genes were significantly overexpressed, but T cell-associated transcripts (CD3, CD8B) were down-regulated. On the protein level, PFAPA flares were accompanied by significantly increased serum levels of chemokines for activated T lymphocytes (IP-10/CXCL10, MIG/CXCL9), G-CSF, and proinflammatory cytokines (IL-18, IL-6). PFAPA flares also manifested a relative lymphopenia. Activated CD4(+)/CD25(+) T-lymphocyte counts correlated negatively with serum concentrations of IP-10/CXCL10, whereas CD4(+)/HLA-DR(+) T lymphocyte counts correlated positively with serum concentrations of the counterregulatory IL-1 receptor antagonist. Based on the evidence for IL-1β activation in PFAPA flares, we treated five PFAPA patients with a recombinant IL-1 receptor antagonist. All patients showed a prompt clinical and IP-10/CXCL10 response. Our data suggest an environmentally triggered activation of complement and IL-1β/-18 during PFAPA flares, with induction of Th1-chemokines and subsequent retention of activated T cells in peripheral tissues. IL-1 inhibition may thus be beneficial for treatment of PFAPA attacks, with IP-10/CXCL10 serving as a potential biomarker.