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

Authors

Silvia Stojanov, National Institute of Arthritis and Musculoskeletal and Skin Diseases
Sivia Lapidus, National Institute of Arthritis and Musculoskeletal and Skin Diseases
Puja Chitkara, National Institute of Arthritis and Musculoskeletal and Skin Diseases
Henry Feder, University of Connecticut Health Sciences Center
Juan C Salazar, University of Connecticut Health Sciences Center
Thomas A Fleisher, Clinical Center Department of Laboratory Medicine
Margaret R Brown, Clinical Center Department of Laboratory Medicine
Kathryn M Edwards, Vanderbilt University School of Medicine
Michael M Ward, National Institute of Arthritis and Musculoskeletal and Skin Diseases
Robert A Colbert, National Institute of Arthritis and Musculoskeletal and Skin Diseases
Hong-Wei Sun, National Institute of Arthritis and Musculoskeletal and Skin Diseases
Geryl M Wood, National Institute of Arthritis and Musculoskeletal and Skin Diseases
Beverly K Barham, National Institute of Arthritis and Musculoskeletal and Skin Diseases
Anne Jones, National Institute of Arthritis and Musculoskeletal and Skin Diseases
Ivona Aksentijevich, National Institute of Arthritis and Musculoskeletal and Skin Diseases
Raphaela Goldbach-Mansky, National Institute of Arthritis and Musculoskeletal and Skin Diseases
Balu Athreya, Thomas Jefferson UniversityFollow
Karyl S Barron, National Institute of Allergy and Infectious Diseases
Daniel L Kastner, National Institute of Arthritis and Musculoskeletal and Skin Diseases

Document Type

Article

Publication Date

4-26-2011

Comments

This article has been peer reviewed. It was published in Proceedings of the Natural Academy of Sciences of the United States of America.

Volume 108, Issue 7, April 2011, Pages 7148-7153.

The published version is available at DOI: 10.1073/pnas.1103681108 . Copyright © National Academy of Sciences

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.

Recommended Citation

Stojanov, Silvia; Lapidus, Sivia; Chitkara, Puja; Feder, Henry; Salazar, Juan C; Fleisher, Thomas A; Brown, Margaret R; Edwards, Kathryn M; Ward, Michael M; Colbert, Robert A; Sun, Hong-Wei; Wood, Geryl M; Barham, Beverly K; Jones, Anne; Aksentijevich, Ivona; Goldbach-Mansky, Raphaela; Athreya, Balu; Barron, Karyl S; and Kastner, Daniel L, "Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) is a disorder of innate immunity and Th1 activation responsive to IL-1 blockade." (2011). Department of Pediatrics Faculty Papers. Paper 39.
https://jdc.jefferson.edu/pedsfp/39

PubMed ID

21478439