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Suppression of Serum Interferon‐γ Levels as a Potential Measure of Response to Ustekinumab Treatment in Patients With Systemic Lupus Erythematosus

OBJECTIVE: In a previously reported phase II randomized, placebo‐controlled, interventional trial, we demonstrated that treatment with ustekinumab, an anti–interleukin‐12 (IL‐12)/IL‐23 p40 neutralizing monoclonal antibody, improved global and organ‐specific measures of disease activity in patients w...

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Autores principales: Cesaroni, Matteo, Seridi, Loqmane, Loza, Matthew J., Schreiter, Jessica, Sweet, Kristen, Franks, Carol, Ma, Keying, Orillion, Ashley, Campbell, Kim, M. Gordon, Robert, Branigan, Patrick, Lipsky, Peter, van Vollenhoven, Ronald, Hahn, Bevra H., Tsokos, George C., Chevrier, Marc, Rose, Shawn, Baribaud, Frédéric, Jordan, Jarrat
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986128/
https://www.ncbi.nlm.nih.gov/pubmed/33010188
http://dx.doi.org/10.1002/art.41547
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author Cesaroni, Matteo
Seridi, Loqmane
Loza, Matthew J.
Schreiter, Jessica
Sweet, Kristen
Franks, Carol
Ma, Keying
Orillion, Ashley
Campbell, Kim
M. Gordon, Robert
Branigan, Patrick
Lipsky, Peter
van Vollenhoven, Ronald
Hahn, Bevra H.
Tsokos, George C.
Chevrier, Marc
Rose, Shawn
Baribaud, Frédéric
Jordan, Jarrat
author_facet Cesaroni, Matteo
Seridi, Loqmane
Loza, Matthew J.
Schreiter, Jessica
Sweet, Kristen
Franks, Carol
Ma, Keying
Orillion, Ashley
Campbell, Kim
M. Gordon, Robert
Branigan, Patrick
Lipsky, Peter
van Vollenhoven, Ronald
Hahn, Bevra H.
Tsokos, George C.
Chevrier, Marc
Rose, Shawn
Baribaud, Frédéric
Jordan, Jarrat
author_sort Cesaroni, Matteo
collection PubMed
description OBJECTIVE: In a previously reported phase II randomized, placebo‐controlled, interventional trial, we demonstrated that treatment with ustekinumab, an anti–interleukin‐12 (IL‐12)/IL‐23 p40 neutralizing monoclonal antibody, improved global and organ‐specific measures of disease activity in patients with active systemic lupus erythematosus (SLE). Utilizing the biomarker data from this phase II clinical study, we sought to determine whether modulation of the expression of IL‐12, IL‐23, or both cytokines by ustekinumab is associated with clinical efficacy in patients with SLE. METHODS: This phase II randomized, placebo‐controlled study enrolled 102 patients with autoantibody‐positive SLE whose disease remained active despite standard‐of‐care therapy. Patients were randomized at a 3:2 ratio to receive ~6 mg/kg ustekinumab intravenously or placebo at week 0, followed by subcutaneous injections of 90 mg ustekinumab or placebo every 8 weeks, with placebo crossover to 90 mg ustekinumab every 8 weeks. The SLE Responder Index 4 (SRI‐4) at week 24 was used to determine which patients could be classified as ustekinumab responders and which could be classified as nonresponders. In addition to measurements of p40 and IL‐23, serum levels of interferon‐γ (IFNγ), IL‐17A, IL‐17F, and IL‐22, as a proxy for the IL‐12 and IL‐23 pathways, were quantified by immunoassay. RESULTS: Changes in the serum levels of IL‐17A, IL‐17F, and IL‐22 at different time points after treatment were not consistently significantly associated with an SRI‐4 clinical response to ustekinumab in patients with SLE. In contrast, an SRI‐4 response to ustekinumab was significantly associated (P < 0.01) with durable reductions in the serum IFNγ protein levels at several time points relative to baseline, which was not observed in ustekinumab nonresponders or patients who received placebo. CONCLUSION: While not diminishing a potential role of IL‐23, these serum biomarker assessments indicate that IL‐12 blockade has an important role in the mechanism of action of ustekinumab treatment in patients with SLE.
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spelling pubmed-79861282021-03-25 Suppression of Serum Interferon‐γ Levels as a Potential Measure of Response to Ustekinumab Treatment in Patients With Systemic Lupus Erythematosus Cesaroni, Matteo Seridi, Loqmane Loza, Matthew J. Schreiter, Jessica Sweet, Kristen Franks, Carol Ma, Keying Orillion, Ashley Campbell, Kim M. Gordon, Robert Branigan, Patrick Lipsky, Peter van Vollenhoven, Ronald Hahn, Bevra H. Tsokos, George C. Chevrier, Marc Rose, Shawn Baribaud, Frédéric Jordan, Jarrat Arthritis Rheumatol Systemic Lupus Erythematosus OBJECTIVE: In a previously reported phase II randomized, placebo‐controlled, interventional trial, we demonstrated that treatment with ustekinumab, an anti–interleukin‐12 (IL‐12)/IL‐23 p40 neutralizing monoclonal antibody, improved global and organ‐specific measures of disease activity in patients with active systemic lupus erythematosus (SLE). Utilizing the biomarker data from this phase II clinical study, we sought to determine whether modulation of the expression of IL‐12, IL‐23, or both cytokines by ustekinumab is associated with clinical efficacy in patients with SLE. METHODS: This phase II randomized, placebo‐controlled study enrolled 102 patients with autoantibody‐positive SLE whose disease remained active despite standard‐of‐care therapy. Patients were randomized at a 3:2 ratio to receive ~6 mg/kg ustekinumab intravenously or placebo at week 0, followed by subcutaneous injections of 90 mg ustekinumab or placebo every 8 weeks, with placebo crossover to 90 mg ustekinumab every 8 weeks. The SLE Responder Index 4 (SRI‐4) at week 24 was used to determine which patients could be classified as ustekinumab responders and which could be classified as nonresponders. In addition to measurements of p40 and IL‐23, serum levels of interferon‐γ (IFNγ), IL‐17A, IL‐17F, and IL‐22, as a proxy for the IL‐12 and IL‐23 pathways, were quantified by immunoassay. RESULTS: Changes in the serum levels of IL‐17A, IL‐17F, and IL‐22 at different time points after treatment were not consistently significantly associated with an SRI‐4 clinical response to ustekinumab in patients with SLE. In contrast, an SRI‐4 response to ustekinumab was significantly associated (P < 0.01) with durable reductions in the serum IFNγ protein levels at several time points relative to baseline, which was not observed in ustekinumab nonresponders or patients who received placebo. CONCLUSION: While not diminishing a potential role of IL‐23, these serum biomarker assessments indicate that IL‐12 blockade has an important role in the mechanism of action of ustekinumab treatment in patients with SLE. John Wiley and Sons Inc. 2021-02-01 2021-03 /pmc/articles/PMC7986128/ /pubmed/33010188 http://dx.doi.org/10.1002/art.41547 Text en © 2020 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Systemic Lupus Erythematosus
Cesaroni, Matteo
Seridi, Loqmane
Loza, Matthew J.
Schreiter, Jessica
Sweet, Kristen
Franks, Carol
Ma, Keying
Orillion, Ashley
Campbell, Kim
M. Gordon, Robert
Branigan, Patrick
Lipsky, Peter
van Vollenhoven, Ronald
Hahn, Bevra H.
Tsokos, George C.
Chevrier, Marc
Rose, Shawn
Baribaud, Frédéric
Jordan, Jarrat
Suppression of Serum Interferon‐γ Levels as a Potential Measure of Response to Ustekinumab Treatment in Patients With Systemic Lupus Erythematosus
title Suppression of Serum Interferon‐γ Levels as a Potential Measure of Response to Ustekinumab Treatment in Patients With Systemic Lupus Erythematosus
title_full Suppression of Serum Interferon‐γ Levels as a Potential Measure of Response to Ustekinumab Treatment in Patients With Systemic Lupus Erythematosus
title_fullStr Suppression of Serum Interferon‐γ Levels as a Potential Measure of Response to Ustekinumab Treatment in Patients With Systemic Lupus Erythematosus
title_full_unstemmed Suppression of Serum Interferon‐γ Levels as a Potential Measure of Response to Ustekinumab Treatment in Patients With Systemic Lupus Erythematosus
title_short Suppression of Serum Interferon‐γ Levels as a Potential Measure of Response to Ustekinumab Treatment in Patients With Systemic Lupus Erythematosus
title_sort suppression of serum interferon‐γ levels as a potential measure of response to ustekinumab treatment in patients with systemic lupus erythematosus
topic Systemic Lupus Erythematosus
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986128/
https://www.ncbi.nlm.nih.gov/pubmed/33010188
http://dx.doi.org/10.1002/art.41547
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