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Abstract Number: 2836

Measurement of Interferon Alpha Expression Using Multiple Methodologies Identifies a Signature in a Subgroup of Connective Tissue Disease Patients with Haematological Abnormalities

John A. Reynolds1,2, Tracy A. Briggs3, Gillian Rice4, Ellen Bruce1, Sahena Haque5, Eoghan McCarthy1, Ariane L. Herrick2,6, Hector Chinoy2,6, Darragh Duffy7, Yanick J Crow8, Benjamin Parker2,9 and Ian N. Bruce1,2, 1NIHR Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom, 2Centre for Musculoskeletal Research, Division of Musculoskeletal and Dermatological Sciences, The University of Manchester, Manchester, United Kingdom, 3Institute of Human Development, University of Manchester, Manchester, United Kingdom, 4Manchester Academic Health Science Centre, Institute of Human Development, University of Manchester, Manchester, United Kingdom, 5Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester, United Kingdom, 6Department of Rheumatology, Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, Salford, United Kingdom, 7Institut Pasteur, Paris, Paris, France, 8Institut Imagine, Paris, Paris, France, 9NIHR Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, United Kingdom

Meeting: 2018 ACR/ARHP Annual Meeting

Keywords: connective tissue diseases and interferons

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Session Information

Date: Tuesday, October 23, 2018

Title: 5T090 ACR Abstract: SLE–Clinical III: Translational Aspects (2832–2837)

Session Type: ACR Concurrent Abstract Session

Session Time: 2:30PM-4:00PM

Background/Purpose:

Interferon alpha (IFNα) is an inflammatory cytokine implicated in the development and persistence of autoimmunity.  Although IFNα expression is increased in a subgroup of SLE patients its role in other connective tissue diseases (CTDs) is less clear.  We aimed to characterise the IFNα signature across CTDs using 3 methods and determine whether in this mixed cohort we could identify common associations with clinical and laboratory features.

Methods:

Patients with at least 1 CTD clinical feature and at least 1 autoantibody were recruited.  Detailed clinical assessment was conducted and whole blood collected for RNA analysis and plasma for IFNα protein measurement by single molecule assay (SIMOA).

Interferon-stimulated gene (ISG) and nucleic acid receptors (NAR) expression was measured in whole blood using RT-qPCR.  The ISG score was calculated as the mean expression of 6 ISGs (IFI27, IFI44L, IFIT1, ISG15, RSAD2, SIGLEC1) relative to HPRT1 and 18s.  The ISG score was classed as positive (ISG+) or negative (ISG-) using the mean +2 SD of healthy controls.  6 NARs were measured: DDX58, MB21D1, TMEM173, TLR3, TLR7 and TLR9.  Expression of 30 ISGs was also explored using the NanoString customer designed codesets in a subgroup of patients.

Results:

We recruited 164 patients covering 6 diseases; SLE, Sjogren’s syndrome (SS), undifferentiated and mixed CTD (UCTD, MCTD), inflammatory myopathy (IIM) and systemic sclerosis (SSc).  63/164 (38%) of patients were ISG+ (figure).  NanoString (27 patients) and was strongly correlated with the IFN score (r=0.96).  Similarly 39/93 (41%) had plasma IFNα protein levels <10fg/ml (correlation for the 2 methods, r=0.83, p<0.001).

There were no differences in mucocutaneous or internal organ involvement between ISG+ and ISG- patients.  ISG+ patients had increased prevalence of rheumatoid factor, anti-Sm and -chromatin antibodies after adjusting for disease type. 

ISG+ patients had increased frequency of ever having a haematological disorder (as per the ACR SLE criteria) and in models adjusted for disease type, lower lymphocyte and neutrophil counts.

Expression of TLR7, TLR9, DDX58, MB21D1 and TMEM173 (but not TLR3) was increased in CTD compared to HC (all p<0.001).  Only DDX58 was positively associated with the ISG score (r=0.6556) and was increased in patients who were anti-ENA or anti-chromatin positive.  Anti-Ro was associated with reduced expression of all NARs (except DDX58); this association remained after adjustment for age, gender, disease group and ISG score.

Conclusion:

IFNα is increased in a subgroup of CTD patients but more strongly associates with haematological abnormalities than any disease subtype.   Increased NAR expression does not correlate with increased IFNα suggesting that the drivers of IFNα may be multifactorial.  The identification of this high-IFN subset of patients within a CTD cohort supports a pathology-based approach to treatment.

Figure


Disclosure: J. A. Reynolds, None; T. A. Briggs, None; G. Rice, None; E. Bruce, None; S. Haque, None; E. McCarthy, None; A. L. Herrick, Actelion, 2,Medical Research Council (MRC), 2; H. Chinoy, None; D. Duffy, None; Y. J. Crow, None; B. Parker, None; I. N. Bruce, Sanofi Genzyme, 2.

To cite this abstract in AMA style:

Reynolds JA, Briggs TA, Rice G, Bruce E, Haque S, McCarthy E, Herrick AL, Chinoy H, Duffy D, Crow YJ, Parker B, Bruce IN. Measurement of Interferon Alpha Expression Using Multiple Methodologies Identifies a Signature in a Subgroup of Connective Tissue Disease Patients with Haematological Abnormalities [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 9). https://acrabstracts.org/abstract/measurement-of-interferon-alpha-expression-using-multiple-methodologies-identifies-a-signature-in-a-subgroup-of-connective-tissue-disease-patients-with-haematological-abnormalities/. Accessed .
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