Increased pretreatment serum IFN-β/α ratio predicts non-response to tumour necrosis factor α inhibition in rheumatoid arthritis

Theresa Wampler Muskardin, Priyanka Vashisht, Jessica M. Dorschner, Mark A. Jensen, Beverly S. Chrabot, Marlena Kern, Jeffrey R. Curtis, Maria I. Danila, Stacey S. Cofield, Nancy Shadick, Peter A. Nigrovic, E. William St Clair, Clifton O. Bingham, Richard Furie, William Robinson, Mark Genovese, Christopher C. Striebich, James R. O'Dell, Geoffrey M. Thiele, Larry W. Moreland & 4 others Marc Levesque, S. Louis Bridges, Peter K. Gregersen, Timothy B. Niewold

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

OBJECTIVE: Studies suggest that circulating type I interferon (IFN) may predict response to biological agents in rheumatoid arthritis (RA). Prediction of response prior to initiating therapy would represent a major advancement.

METHODS: We studied sera from a test set of 32 patients with RA from the Auto-immune Biomarkers Collaborative Network Consortium and a validation set of 92 patients with RA from the Treatment Efficacy and Toxicity in Rheumatoid Arthritis Database and Repository registry. The test set included those with good response or no response to tumour necrosis factor (TNF) inhibitors at 14 weeks by European League Against Rheumatism criteria. The validation set included subjects with good, moderate or no response at 12 weeks. Total serum type I IFN activity, IFN-α and IFN-β activity were measured using a functional reporter cell assay.

RESULTS: In the test set, an increased ratio of IFN-β to IFN-α (IFN-β/α activity ratio) in pretreatment serum associated with lack of response to TNF inhibition (p=0.013). Anti-cyclic citrullinated peptide antibody titre and class of TNF inhibitor did not influence this relationship. A receiver-operator curve supported a ratio of 1.3 as the optimal cut-off. In the validation set, subjects with an IFN-β/α activity ratio >1.3 were significantly more likely to have non-response than good response (OR=6.67, p=0.018). The test had 77% specificity and 45% sensitivity for prediction of non-response compared with moderate or good response. Meta-analysis of test and validation sets confirmed strong predictive capacity of IFN-β/α activity ratio (p=0.005).

CONCLUSIONS: Increased pretreatment serum IFN-β/α ratio strongly associated with non-response to TNF inhibition. This study supports further investigation of serum type I IFN in predicting outcome of TNF inhibition in RA.

Original languageEnglish (US)
Pages (from-to)1757-1762
Number of pages6
JournalAnnals of the Rheumatic Diseases
Volume75
Issue number10
DOIs
StatePublished - Oct 1 2016

Fingerprint

Interferons
Rheumatoid Arthritis
Tumor Necrosis Factor-alpha
Serum
Interferon Type I
Immunoglobulin Isotypes
Biological Factors
Biomarkers
Toxicity
Registries
Meta-Analysis
Assays
Databases
Sensitivity and Specificity
Antibodies

Keywords

  • Cytokines
  • Rheumatoid Arthritis
  • TNF-alpha
  • Treatment

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Wampler Muskardin, T., Vashisht, P., Dorschner, J. M., Jensen, M. A., Chrabot, B. S., Kern, M., ... Niewold, T. B. (2016). Increased pretreatment serum IFN-β/α ratio predicts non-response to tumour necrosis factor α inhibition in rheumatoid arthritis. Annals of the Rheumatic Diseases, 75(10), 1757-1762. https://doi.org/10.1136/annrheumdis-2015-208001

Increased pretreatment serum IFN-β/α ratio predicts non-response to tumour necrosis factor α inhibition in rheumatoid arthritis. / Wampler Muskardin, Theresa; Vashisht, Priyanka; Dorschner, Jessica M.; Jensen, Mark A.; Chrabot, Beverly S.; Kern, Marlena; Curtis, Jeffrey R.; Danila, Maria I.; Cofield, Stacey S.; Shadick, Nancy; Nigrovic, Peter A.; St Clair, E. William; Bingham, Clifton O.; Furie, Richard; Robinson, William; Genovese, Mark; Striebich, Christopher C.; O'Dell, James R.; Thiele, Geoffrey M.; Moreland, Larry W.; Levesque, Marc; Bridges, S. Louis; Gregersen, Peter K.; Niewold, Timothy B.

In: Annals of the Rheumatic Diseases, Vol. 75, No. 10, 01.10.2016, p. 1757-1762.

Research output: Contribution to journalArticle

Wampler Muskardin, T, Vashisht, P, Dorschner, JM, Jensen, MA, Chrabot, BS, Kern, M, Curtis, JR, Danila, MI, Cofield, SS, Shadick, N, Nigrovic, PA, St Clair, EW, Bingham, CO, Furie, R, Robinson, W, Genovese, M, Striebich, CC, O'Dell, JR, Thiele, GM, Moreland, LW, Levesque, M, Bridges, SL, Gregersen, PK & Niewold, TB 2016, 'Increased pretreatment serum IFN-β/α ratio predicts non-response to tumour necrosis factor α inhibition in rheumatoid arthritis', Annals of the Rheumatic Diseases, vol. 75, no. 10, pp. 1757-1762. https://doi.org/10.1136/annrheumdis-2015-208001
Wampler Muskardin, Theresa ; Vashisht, Priyanka ; Dorschner, Jessica M. ; Jensen, Mark A. ; Chrabot, Beverly S. ; Kern, Marlena ; Curtis, Jeffrey R. ; Danila, Maria I. ; Cofield, Stacey S. ; Shadick, Nancy ; Nigrovic, Peter A. ; St Clair, E. William ; Bingham, Clifton O. ; Furie, Richard ; Robinson, William ; Genovese, Mark ; Striebich, Christopher C. ; O'Dell, James R. ; Thiele, Geoffrey M. ; Moreland, Larry W. ; Levesque, Marc ; Bridges, S. Louis ; Gregersen, Peter K. ; Niewold, Timothy B. / Increased pretreatment serum IFN-β/α ratio predicts non-response to tumour necrosis factor α inhibition in rheumatoid arthritis. In: Annals of the Rheumatic Diseases. 2016 ; Vol. 75, No. 10. pp. 1757-1762.
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abstract = "OBJECTIVE: Studies suggest that circulating type I interferon (IFN) may predict response to biological agents in rheumatoid arthritis (RA). Prediction of response prior to initiating therapy would represent a major advancement.METHODS: We studied sera from a test set of 32 patients with RA from the Auto-immune Biomarkers Collaborative Network Consortium and a validation set of 92 patients with RA from the Treatment Efficacy and Toxicity in Rheumatoid Arthritis Database and Repository registry. The test set included those with good response or no response to tumour necrosis factor (TNF) inhibitors at 14 weeks by European League Against Rheumatism criteria. The validation set included subjects with good, moderate or no response at 12 weeks. Total serum type I IFN activity, IFN-α and IFN-β activity were measured using a functional reporter cell assay.RESULTS: In the test set, an increased ratio of IFN-β to IFN-α (IFN-β/α activity ratio) in pretreatment serum associated with lack of response to TNF inhibition (p=0.013). Anti-cyclic citrullinated peptide antibody titre and class of TNF inhibitor did not influence this relationship. A receiver-operator curve supported a ratio of 1.3 as the optimal cut-off. In the validation set, subjects with an IFN-β/α activity ratio >1.3 were significantly more likely to have non-response than good response (OR=6.67, p=0.018). The test had 77{\%} specificity and 45{\%} sensitivity for prediction of non-response compared with moderate or good response. Meta-analysis of test and validation sets confirmed strong predictive capacity of IFN-β/α activity ratio (p=0.005).CONCLUSIONS: Increased pretreatment serum IFN-β/α ratio strongly associated with non-response to TNF inhibition. This study supports further investigation of serum type I IFN in predicting outcome of TNF inhibition in RA.",
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T1 - Increased pretreatment serum IFN-β/α ratio predicts non-response to tumour necrosis factor α inhibition in rheumatoid arthritis

AU - Wampler Muskardin, Theresa

AU - Vashisht, Priyanka

AU - Dorschner, Jessica M.

AU - Jensen, Mark A.

AU - Chrabot, Beverly S.

AU - Kern, Marlena

AU - Curtis, Jeffrey R.

AU - Danila, Maria I.

AU - Cofield, Stacey S.

AU - Shadick, Nancy

AU - Nigrovic, Peter A.

AU - St Clair, E. William

AU - Bingham, Clifton O.

AU - Furie, Richard

AU - Robinson, William

AU - Genovese, Mark

AU - Striebich, Christopher C.

AU - O'Dell, James R.

AU - Thiele, Geoffrey M.

AU - Moreland, Larry W.

AU - Levesque, Marc

AU - Bridges, S. Louis

AU - Gregersen, Peter K.

AU - Niewold, Timothy B.

PY - 2016/10/1

Y1 - 2016/10/1

N2 - OBJECTIVE: Studies suggest that circulating type I interferon (IFN) may predict response to biological agents in rheumatoid arthritis (RA). Prediction of response prior to initiating therapy would represent a major advancement.METHODS: We studied sera from a test set of 32 patients with RA from the Auto-immune Biomarkers Collaborative Network Consortium and a validation set of 92 patients with RA from the Treatment Efficacy and Toxicity in Rheumatoid Arthritis Database and Repository registry. The test set included those with good response or no response to tumour necrosis factor (TNF) inhibitors at 14 weeks by European League Against Rheumatism criteria. The validation set included subjects with good, moderate or no response at 12 weeks. Total serum type I IFN activity, IFN-α and IFN-β activity were measured using a functional reporter cell assay.RESULTS: In the test set, an increased ratio of IFN-β to IFN-α (IFN-β/α activity ratio) in pretreatment serum associated with lack of response to TNF inhibition (p=0.013). Anti-cyclic citrullinated peptide antibody titre and class of TNF inhibitor did not influence this relationship. A receiver-operator curve supported a ratio of 1.3 as the optimal cut-off. In the validation set, subjects with an IFN-β/α activity ratio >1.3 were significantly more likely to have non-response than good response (OR=6.67, p=0.018). The test had 77% specificity and 45% sensitivity for prediction of non-response compared with moderate or good response. Meta-analysis of test and validation sets confirmed strong predictive capacity of IFN-β/α activity ratio (p=0.005).CONCLUSIONS: Increased pretreatment serum IFN-β/α ratio strongly associated with non-response to TNF inhibition. This study supports further investigation of serum type I IFN in predicting outcome of TNF inhibition in RA.

AB - OBJECTIVE: Studies suggest that circulating type I interferon (IFN) may predict response to biological agents in rheumatoid arthritis (RA). Prediction of response prior to initiating therapy would represent a major advancement.METHODS: We studied sera from a test set of 32 patients with RA from the Auto-immune Biomarkers Collaborative Network Consortium and a validation set of 92 patients with RA from the Treatment Efficacy and Toxicity in Rheumatoid Arthritis Database and Repository registry. The test set included those with good response or no response to tumour necrosis factor (TNF) inhibitors at 14 weeks by European League Against Rheumatism criteria. The validation set included subjects with good, moderate or no response at 12 weeks. Total serum type I IFN activity, IFN-α and IFN-β activity were measured using a functional reporter cell assay.RESULTS: In the test set, an increased ratio of IFN-β to IFN-α (IFN-β/α activity ratio) in pretreatment serum associated with lack of response to TNF inhibition (p=0.013). Anti-cyclic citrullinated peptide antibody titre and class of TNF inhibitor did not influence this relationship. A receiver-operator curve supported a ratio of 1.3 as the optimal cut-off. In the validation set, subjects with an IFN-β/α activity ratio >1.3 were significantly more likely to have non-response than good response (OR=6.67, p=0.018). The test had 77% specificity and 45% sensitivity for prediction of non-response compared with moderate or good response. Meta-analysis of test and validation sets confirmed strong predictive capacity of IFN-β/α activity ratio (p=0.005).CONCLUSIONS: Increased pretreatment serum IFN-β/α ratio strongly associated with non-response to TNF inhibition. This study supports further investigation of serum type I IFN in predicting outcome of TNF inhibition in RA.

KW - Cytokines

KW - Rheumatoid Arthritis

KW - TNF-alpha

KW - Treatment

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