Arthritis & Rheumatism, Volume 60,
October 2009 Abstract Supplement

The 2009 ACR/ARHP Annual Scientific Meeting
Philadelphia October 16-21, 2009.


A Systems Biology Analysis of PFAPA Syndrome Reveals a Distinct Disease Entity with Interferon-Inducible Protein 10 (IP-10) and Interleukin-1 (IL-1) as Novel Links for Pathogenesis and Therapy

Stojanov1,  Silvia, Lapidus1,  Sivia, Chitkara1,  Puja, Feder2,  Henry, Salazar2,  Juan C., Ward1,  Michael M., Colbert1,  Robert A.

NIAMS/NIH, Bethesda, MD
University of Connecticut Health Sciences Center/Connecticut Children's Medical Center, Hartford, CT
duPont Hospital for Children/Thomas Jefferson University, Wilmington, DE
NIAID/NIH, Bethesda, MD

Purpose:

Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) attacks are associated with an aberrant cytokine profile, suggesting a dysregulated innate and adaptive immune response. Using a systems biology approach we attempted to shed more insights into pathogenesis and treatment.

Method:

We collected blood samples from three pediatric cohorts: PFAPA patients whose genetic testing excluded hereditary periodic fevers (HPFs) during flares and asymptomatic intervals (N=21), healthy controls (N=21), and HPF patients with flare (N=12). We performed analyses using whole blood microarray, quantitative PCR (qRT-PCR), serum cytokines, and lymphocyte immunophenotyping.

Results:

Principal component analysis of the overall mRNA expression revealed that PFAPA flares were remarkably distinct from asymptomatic intervals and HPF flares. Genes that were significantly overexpressed in PFAPA attacks compared to inactive PFAPA included interferon-induced (IP-10) and IL-1-related (IL-1B, CASP1), as well as complement (C1QB, C2, SERPING1) genes, whereas T cell-associated transcripts (CD3, CD8B) were downregulated. Leukocytosis with neutrophilia and monocytosis during PFAPA flares was accompanied by a relative reduction of T lymphocytes. Serum IP-10, a chemokine for activated T lymphocytes, was significantly increased during flares and correlated with a decrease in circulating CD4+/CD25+ lymphocytes (Spearman r =-0.8257, p = 0.0001). Serum G-CSF, IL-18, IL-6 and MIP-1b were significantly elevated during PFAPA flares, with IP-10 and G-CSF being the strongest flare predictors. Based on our results, two patients were treated with the IL-1 receptor antagonist, anakinra, during febrile attacks with a prompt clinical response.

Conclusion:

Gene expression profiling revealed PFAPA as a distinct entity from HPFs. The overexpression of complement genes suggests an infectious trigger with a strong IP-10, and IL-1/IL-18-mediated response of the innate immune system. Activation and probable recruitment of T cells to peripheral tissues underline the involvement of the adaptive immunity in the pathogenesis of PFAPA, with IP-10 as a potential new biomarker. Preliminary results of the clinical response in two patients support IL-1 inhibition for treatment of PFAPA attacks.

To cite this abstract, please use the following information:
Stojanov, Silvia, Lapidus, Sivia, Chitkara, Puja, Feder, Henry, Salazar, Juan C., Ward, Michael M., et al; A Systems Biology Analysis of PFAPA Syndrome Reveals a Distinct Disease Entity with Interferon-Inducible Protein 10 (IP-10) and Interleukin-1 (IL-1) as Novel Links for Pathogenesis and Therapy [abstract]. Arthritis Rheum 2009;60 Suppl 10 :621
DOI: 10.1002/art.25701

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