Molecular signatures in systemic lupus erythematosus: distinction between disease flare and infection

The clinical scenario of a febrile, acutely ill, immunocompromised patient with immunocompromised lupus remains challenging despite advances in technology and improved understanding of pathogenic mechanisms. Infection is a major contributor to morbidity and mortality in systemic lupus erythematosus (SLE); infection-related hospitalisation rates range from 10% to 35%1–4 and mortality rates range from 29% to 53%.5 ,6 The disease itself and most treatment strategies are immunosuppressive, rendering patients with SLE more susceptible to severe infection with common organisms and opportunistic pathogens. Both infection and lupus flare can incite clinically indistinguishable inflammatory responses. Consequently, appropriate therapy may be delayed or patients are treated for both conditions while awaiting results of time-consuming investigations for bacterial and viral infections. The potential consequences of treating infection with immunosuppression are obvious and may contribute to the high mortality rates. Antibiotics given unnecessarily also have potential toxicities. A biomarker that would accurately and rapidly differentiate between flare and infection would provide an extremely valuable guide to more directed, precise therapy, likely leading to significantly decreased morbidity and mortality. Microarray technology offers an unbiased, systems biology approach to study the expression level of thousands of genes simultaneously and genome-wide transcriptional studies have emerged as a powerful investigational tool to study complex diseases as well as infection.7 The objective of this exploratory study was to use whole blood gene expression profiling to identify specific RNA expression profiles that would differentiate systemic inflammation related to SLE disease flare from infection in acutely ill patients with lupus. We hypothesised that the molecular signature associated with active disease and no infection in patients with SLE will differ from the molecular signature in patients with SLE with infection. Comparison groups consisted of SLE subjects with inactive disease and healthy controls. ### Study design Blood samples for microarray analysis were obtained from two …

[1]  C. Băicuș,et al.  Is there still a place for erythrocyte sedimentation rate and C-reactive protein in systemic lupus erythematosus? , 2016, Lupus.

[2]  J. Paulson,et al.  Siglec-mediated regulation of immune cell function in disease , 2014, Nature Reviews Immunology.

[3]  Laurent Chiche,et al.  Mortality Associated With Systemic Lupus Erythematosus in France Assessed by Multiple‐Cause‐of‐Death Analysis , 2014, Arthritis & rheumatology.

[4]  C. Parks,et al.  Elevated C-reactive protein and self-reported disease activity in systemic lupus erythematosus , 2014, Lupus.

[5]  S. Sato,et al.  The Friend leukaemia virus integration 1 (Fli‐1) transcription factor affects lupus nephritis development by regulating inflammatory cell infiltration into the kidney , 2014, Clinical and experimental immunology.

[6]  P. Gregersen,et al.  Editorial: The Power of a Modular Approach to Transcriptional Analysis , 2014, Arthritis & rheumatology.

[7]  Virginia Pascual,et al.  Modular Transcriptional Repertoire Analyses of Adults With Systemic Lupus Erythematosus Reveal Distinct Type I and Type II Interferon Signatures , 2014, Arthritis & rheumatology.

[8]  P. Nietert,et al.  Reducing FLI1 Levels in the MRL/lpr Lupus Mouse Model Impacts T Cell Function by Modulating Glycosphingolipid Metabolism , 2013, PloS one.

[9]  L. Rönnblom,et al.  The interferon signature in autoimmune diseases , 2013, Current opinion in rheumatology.

[10]  G. Dougan,et al.  Host Responses to Melioidosis and Tuberculosis Are Both Dominated by Interferon-Mediated Signaling , 2013, PloS one.

[11]  Alexander Hoischen,et al.  Functional genomics identifies type I interferon pathway as central for host defense against Candida albicans , 2013, Nature Communications.

[12]  G. Gilkeson,et al.  Fli-1 transcription factor affects glomerulonephritis development by regulating expression of monocyte chemoattractant protein-1 in endothelial cells in the kidney. , 2012, Clinical immunology.

[13]  M. Urowitz,et al.  International consensus for a definition of disease flare in lupus , 2011, Lupus.

[14]  Stephen J. Huang,et al.  Genome-wide transcription profiling of human sepsis: a systematic review , 2010, Critical care.

[15]  G. Gilkeson,et al.  A GA microsatellite in the Fli1 promoter modulates gene expression and is associated with systemic lupus erythematosus patients without nephritis , 2010, Arthritis research & therapy.

[16]  D. Gladman,et al.  Prolonged Serologically Active Clinically Quiescent Systemic Lupus Erythematosus: Frequency and Outcome , 2010, The Journal of Rheumatology.

[17]  Virginia Pascual,et al.  An Interferon-Inducible Neutrophil-Driven Blood Transcriptional Signature in Human Tuberculosis , 2010, Nature.

[18]  M. Amria,et al.  The mouse and human Fli1 genes are similarly regulated by Ets factors in T cells , 2010, Genes and Immunity.

[19]  J. Hoffmann.  Neutrophil CD64: a diagnostic marker for infection and sepsis , 2009, Clinical chemistry and laboratory medicine.

[20]  Ian W. Dawes,et al.  Gene-expression profiling of peripheral blood mononuclear cells in sepsis* , 2009, Critical care medicine.

[21]  Virginia Pascual,et al.  A modular analysis framework for blood genomics studies: application to systemic lupus erythematosus. , 2008, Immunity.

[22]  Pan Du,et al.  lumi: a pipeline for processing Illumina microarray , 2008, Bioinform..

[23]  Steven B. Johnson,et al.  Gene Expression Profiles Differentiate Between Sterile SIRS and Early Sepsis , 2007, Annals of surgery.

[24]  J. Banchereau,et al.  Gene expression patterns in blood leukocytes discriminate patients with acute infections. , 2007, Blood.

[25]  G. Stormo,et al.  Molecular Diagnostics in Sepsis: From Bedside to Bench , 2006, Journal of the American College of Surgeons.

[26]  M. Crow.  Interferon pathway activation in systemic lupus erythematosus , 2005, Current rheumatology reports.

[27]  M. Peterson,et al.  Activation of the interferon-alpha pathway identifies a subgroup of systemic lupus erythematosus patients with distinct serologic features and active disease. , 2005, Arthritis and rheumatism.

[28]  G. Gilkeson,et al.  Decreased Expression of the Ets Family Transcription Factor Fli-1 Markedly Prolongs Survival and Significantly Reduces Renal Disease in MRL/lpr Mice1 , 2004, The Journal of Immunology.

[29]  D. Gladman,et al.  The American College of Rheumatology response criteria for systemic lupus erythematosus clinical trials: measures of overall disease activity. , 2004, Arthritis and rheumatism.

[30]  U. Sibelius,et al.  Neutrophil CD177 (NB1 gp, HNA‐2a) expression is increased in severe bacterial infections and polycythaemia vera , 2004, British journal of haematology.

[31]  E. Bamgboye,et al.  Outcome of patients with systemic lupus erythematosus in intensive care unit , 2004, Lupus.

[32]  Gordon K Smyth,et al.  Linear Models and Empirical Bayes Methods for Assessing Differential Expression in Microarray Experiments , 2004, Statistical applications in genetics and molecular biology.

[33]  N. Arden,et al.  Hospitalization of individuals with systemic lupus erythematosus: characteristics and predictors of outcome , 2003, Lupus.

[34]  Virginia Pascual,et al.  Interferon and Granulopoiesis Signatures in Systemic Lupus Erythematosus Blood , 2003, The Journal of experimental medicine.

[35]  G. Karypis,et al.  Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[36]  L. Rönnblom,et al.  Systemic lupus erythematosus and the type I interferon system , 2003, Arthritis research & therapy.

[37]  D. Wilkinson.  Gene Expression Patterns , 2002, Brain Research.

[38]  D. Gladman,et al.  The nature and outcome of infection in systemic lupus erythematosus , 2002, Lupus.

[39]  A. Fraga,et al.  Infections in outpatients with systemic lupus erythematosus: a prospective study , 2001, Lupus.

[40]  Mimi Y. Kim,et al.  Classification and definition of major flares in SLE clinical trials , 1999, Lupus.

[41]  Caroline Gordon,et al.  The American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes. , 1999, Arthritis and rheumatism.

[42]  T. Satoh,et al.  Clinical and laboratory features of lupus patients with complicating pulmonary disease. , 1999, Respiratory medicine.

[43]  S. Ansell,et al.  Study of critically ill patients with systemic lupus erythematosus. , 1996, Critical care medicine.

[44]  A. Bernstein,et al.  An immunological renal disease in transgenic mice that overexpress Fli-1, a member of the ets family of transcription factor genes , 1995, Molecular and cellular biology.

[45]  D. Sackett,et al.  Derivation of the SLEDAI. A disease activity index for lupus patients. The Committee on Prognosis Studies in SLE. , 1992, Arthritis and rheumatism.

[46]  J. Eberwine,et al.  Amplified RNA synthesized from limited quantities of heterogeneous cDNA. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[47]  H. Moutsopoulos,et al.  High C-reactive protein response in lupus polyarthritis. , 1983, Clinical and experimental rheumatology.