ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 2216

Muscle Type I Interferon Gene Expression May Predict Therapeutic Responses to Rituximab in Myositis Patients

Kanneboyina Nagaraju1,2, Svetlana Ghimbovschi3, Sree Rayavarapu2,4, Aditi Phadke4, Lisa G Rider5, Eric Hoffman2,4 and Frederick W. Miller6, 1Research Center for Genetic Medicine, Children’s National Medical Center, Washington DC, DC, 2Department of Integrative Systems Biology, The George Washington University, Washington, DC, 3Research Center for Genetic Medicine, Children's National Medical Center, Washington DC, WA, 4Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC, 5Environmental Autoimmunity Group, Program of Clinical Research, National Institute of Environmental Health Sciences, National Institutes of Health, US Department of Health and Human Services, Bethesda, MD, 6Environmental Autoimmunity Group, NIEHS, NIH, Bethesda, MD

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords:

Session Information

Title: Muscle Biology, Myositis and Myopathies: Immunological Aspects of Inflammatory Myopathy

Session Type: Abstract Submissions (ACR)

Background/Purpose

To identify muscle gene expression patterns that predict rituximab responses and assess the effects of rituximab on muscle gene expression in polymyositis (PM) and dermatomyositis (DM). 

Methods

In an attempt to understand the molecular mechanism of response and non-response to rituximab therapy, we performed Affymetrix gene expression array analyses on muscle biopsies taken before and after rituximab therapy from eight PM and two DM patients in the Rituximab in Myositis study.  We also analyzed selected muscle-infiltrating cell phenotypes in these biopsies by immunohistochemical staining. Partek and Ingenuity pathway analyses were used to identify gene pathways and networks.

Results

Microarray analysis of gene expression changes in the skeletal muscle of myositis patients before and after rituximab treatment showed differential expression of innate immune and inflammatory genes. Supervised hierarchical clustering analysis of these genes resulted in myeloid clusters (clusters 1 and 2) and non-myeloid clusters (cluster 3-5). Myeloid clusters include cluster 1(STAT4, SDC1, ITGB8, MAVS, RFX3, IFNAR2, IRF4, UBA7, and IFRD1) cluster 2 (ICAM1, IRF1, CASP2, SIGLEC1, CD68, and IFI44). Non-myeloid clusters include predominantly type 1IFN genes (cluster 3 (CD19, IFI35, IFNA1, MX2, UBE2L6, LY6E, XAF1, SP110), cluster 4 (OAS1, USP18, ISG15, IFIT5, MEG3, RTP4, MX1, OAS3, and IFNA2), and cluster 5 (OAS2, OASL, IFIT3, IFIT2 and IFNB1). Type 1 Interferon (IFN) signature genes were expressed at higher levels at baseline in the skeletal muscle of rituximab responders than in non-responders. These genes are known to have immunomodulatory effects on the infiltrating immune cells as well as skeletal muscle.   Also, IFN signature genes were significantly down-regulated post-treatment in patients who had a clinical response when compared to non-responder patients.  The decrease in the type I IFN signature following administration of rituximab may be associated with the decreases in muscle-infiltrating CD19+ B cells and CD68+ macrophages in responders. Further, analysis of muscle-infiltrating CD138-positive plasma cells showed an increase in non-responder patients. 

Conclusion

Our study confirms that myeloid and type 1 IFN signatures are important in myositis pathogenesis and rituximab treatment alters these signatures. Our findings also suggest that high levels of muscle type I IFN gene expression predict responses to rituximab in PM/DM and that rituximab responders also have a greater decrease in the expression of these genes. These data add further evidence to recent studies defining the type I IFN signature as both a predictor of therapeutic responses and a biomarker of myositis disease activity.

Disclosure:

K. Nagaraju,
None;

S. Ghimbovschi,
None;

S. Rayavarapu,
None;

A. Phadke,
None;

L. G. Rider,

NIAMS-NIH,

9,

NIEHS-NIH,

9;

E. Hoffman,
None;

F. W. Miller,

NIEHS-NIH,

2,

NIAMS-NIH,

2.

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