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

Abstract

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.

Family History in Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA) Syndrome

“…Although the pathogenesis of PFAPA is unknown, it is considered an autoinflammatory syndrome due to its episodic nature and periodicity, activation of innate immune pathways during flares, and rapid improvement with corticosteroid administration. 15 If recurrent pharyngitis and aphthous stomatitis share a common pathogenesis with PFAPA in these families, these disease entities may also be autoinflammatory in some individuals. This finding also suggests that some patients with recurrent stereotypical episodes of pharyngitis at frequencies lower than expected for PFAPA may have autoinflammatory pharyngitis and not repeated infectious pharyngitis as typically diagnosed.…”

Gene expression profiles in febrile children with defined viral and bacterial infection

“…Circulating blood leukocytes react to pathogens by recognizing pathogen-specific molecular patterns through pattern recognition receptors leading to up-or down-regulation of the expression of host genes associated with immune functions (2,3), with differential activation of host transcriptional programs with different pathogens (4). Thus, host blood transcriptional profiles and representative biomarkers may be powerful tools for categorizing infection (5).…”

“…In addition, specific blood transcriptional signatures were defined in adult volunteers challenged with specific respiratory viruses (11). Analysis of host transcriptional profiles has also been applied to the diagnosis of inflammatory and hematological diseases (12)(13)(14)(15), including the identification of potential biomarkers for specific disease entities (5).…”

Oral manifestations of systemic disease

“…Unlike RAS this disorder tends to spontaneously remit in the teenage years. 21 Other autoinflammatory diseases (that is, periodic fevers) such as familial Mediterranean fever (FMF) may also sometimes give rise to superficial oral ulceration. 22 Ulceration similar to RAS, but without the same periodicity, can be a feature of anaemia of almost any cause.…”