High titers of both rheumatoid factor and anti-CCP antibodies at baseline in patients with rheumatoid arthritis are associated with increased circulating baseline TNF level, low drug levels, and reduced clinical responses: A post hoc analysis of the RISING study

Tsutomu Takeuchi, Nobuyuki Miyasaka, Takashi Inui, Toshiro Yano, Toru Yoshinari, Tohru Abe, Takao Koike

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11 Citations (Scopus)

Abstract

Background: Although both rheumatoid factor (RF) and anticyclic citrullinated peptide antibodies (anti-CCP) are useful for diagnosing rheumatoid arthritis (RA), the impact of these autoantibodies on the efficacy of tumor necrosis factor (TNF) inhibitors has been controversial. The aim of this post hoc analysis of a randomized double-blind study (the RISING study) was to investigate the influences of RF and anti-CCP on the clinical response to infliximab in patients with RA. Methods: Methotrexate-refractory patients with RA received 3 mg/kg of infliximab from weeks 0 to 6 and then 3, 6, or 10 mg/kg every 8 weeks from weeks 14 to 46. In this post hoc analysis, patients were stratified into three classes on the basis of baseline RF/anti-CCP titers: "low/low-C" (RF < 55 IU/ml, anti-CCP < 42 U/ml), "high/high-C" (RF ≥ 160 IU/ml, anti-CCP ≥ 100 U/ml), and "middle-C" (neither low/low-C nor high/high-C). Baseline plasma TNF level, serum infliximab level, and disease activity were compared between the three classes. Results: Baseline RF and anti-CCP titers showed significant correlations with baseline TNF and infliximab levels in weeks 2-14. Comparison of the three classes showed that baseline TNF level was lowest in the low/low-C group and highest in the high/high-C group (median 0.73 versus 1.15 pg/ml), that infliximab levels at week 14 were highest in the low/low-C group and lowest in the high/high-C group (median 1.0 versus 0.1 μg/ml), and that Disease Activity Score in 28 joints based on C-reactive protein at week 14 was lowest in the low/low-C group and highest in the high/high-C group (median 3.17 versus 3.82). A similar correlation was observed at week 54 in the 3 mg/kg dosing group, but not in the 6 or 10 mg/kg group. Significant decreases in both RF and anti-CCP were observed during infliximab treatment. Conclusions: RF/anti-CCP titers correlated with TNF level. This might explain the association of RF/anti-CCP with infliximab level and clinical response in patients with RA. Baseline RF/anti-CCP titers may serve as indices that aid infliximab treatment. Trial registration: ClinicalTrials.gov, NCT00691028. Retrospectively registered on 3 June 2008.

Original languageEnglish
Article number194
JournalArthritis Research and Therapy
Volume19
Issue number1
DOIs
Publication statusPublished - 2017 Sep 2

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Rheumatoid Factor
Rheumatoid Arthritis
Tumor Necrosis Factor-alpha
Peptides
Antibodies
Pharmaceutical Preparations
Infliximab
Double-Blind Method
Methotrexate
C-Reactive Protein
Autoantibodies
Joints

Keywords

  • Anticyclic citrullinated peptide antibodies
  • Clinical response
  • Infliximab
  • Pharmacokinetics
  • Prediction
  • Rheumatoid arthritis
  • Rheumatoid factor

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology

Cite this

@article{396c57fc499a42e28f09713187073fc6,
title = "High titers of both rheumatoid factor and anti-CCP antibodies at baseline in patients with rheumatoid arthritis are associated with increased circulating baseline TNF level, low drug levels, and reduced clinical responses: A post hoc analysis of the RISING study",
abstract = "Background: Although both rheumatoid factor (RF) and anticyclic citrullinated peptide antibodies (anti-CCP) are useful for diagnosing rheumatoid arthritis (RA), the impact of these autoantibodies on the efficacy of tumor necrosis factor (TNF) inhibitors has been controversial. The aim of this post hoc analysis of a randomized double-blind study (the RISING study) was to investigate the influences of RF and anti-CCP on the clinical response to infliximab in patients with RA. Methods: Methotrexate-refractory patients with RA received 3 mg/kg of infliximab from weeks 0 to 6 and then 3, 6, or 10 mg/kg every 8 weeks from weeks 14 to 46. In this post hoc analysis, patients were stratified into three classes on the basis of baseline RF/anti-CCP titers: {"}low/low-C{"} (RF < 55 IU/ml, anti-CCP < 42 U/ml), {"}high/high-C{"} (RF ≥ 160 IU/ml, anti-CCP ≥ 100 U/ml), and {"}middle-C{"} (neither low/low-C nor high/high-C). Baseline plasma TNF level, serum infliximab level, and disease activity were compared between the three classes. Results: Baseline RF and anti-CCP titers showed significant correlations with baseline TNF and infliximab levels in weeks 2-14. Comparison of the three classes showed that baseline TNF level was lowest in the low/low-C group and highest in the high/high-C group (median 0.73 versus 1.15 pg/ml), that infliximab levels at week 14 were highest in the low/low-C group and lowest in the high/high-C group (median 1.0 versus 0.1 μg/ml), and that Disease Activity Score in 28 joints based on C-reactive protein at week 14 was lowest in the low/low-C group and highest in the high/high-C group (median 3.17 versus 3.82). A similar correlation was observed at week 54 in the 3 mg/kg dosing group, but not in the 6 or 10 mg/kg group. Significant decreases in both RF and anti-CCP were observed during infliximab treatment. Conclusions: RF/anti-CCP titers correlated with TNF level. This might explain the association of RF/anti-CCP with infliximab level and clinical response in patients with RA. Baseline RF/anti-CCP titers may serve as indices that aid infliximab treatment. Trial registration: ClinicalTrials.gov, NCT00691028. Retrospectively registered on 3 June 2008.",
keywords = "Anticyclic citrullinated peptide antibodies, Clinical response, Infliximab, Pharmacokinetics, Prediction, Rheumatoid arthritis, Rheumatoid factor",
author = "Tsutomu Takeuchi and Nobuyuki Miyasaka and Takashi Inui and Toshiro Yano and Toru Yoshinari and Tohru Abe and Takao Koike",
year = "2017",
month = "9",
day = "2",
doi = "10.1186/s13075-017-1401-2",
language = "English",
volume = "19",
journal = "Arthritis Research and Therapy",
issn = "1478-6354",
publisher = "BioMed Central",
number = "1",

}

TY - JOUR

T1 - High titers of both rheumatoid factor and anti-CCP antibodies at baseline in patients with rheumatoid arthritis are associated with increased circulating baseline TNF level, low drug levels, and reduced clinical responses

T2 - A post hoc analysis of the RISING study

AU - Takeuchi, Tsutomu

AU - Miyasaka, Nobuyuki

AU - Inui, Takashi

AU - Yano, Toshiro

AU - Yoshinari, Toru

AU - Abe, Tohru

AU - Koike, Takao

PY - 2017/9/2

Y1 - 2017/9/2

N2 - Background: Although both rheumatoid factor (RF) and anticyclic citrullinated peptide antibodies (anti-CCP) are useful for diagnosing rheumatoid arthritis (RA), the impact of these autoantibodies on the efficacy of tumor necrosis factor (TNF) inhibitors has been controversial. The aim of this post hoc analysis of a randomized double-blind study (the RISING study) was to investigate the influences of RF and anti-CCP on the clinical response to infliximab in patients with RA. Methods: Methotrexate-refractory patients with RA received 3 mg/kg of infliximab from weeks 0 to 6 and then 3, 6, or 10 mg/kg every 8 weeks from weeks 14 to 46. In this post hoc analysis, patients were stratified into three classes on the basis of baseline RF/anti-CCP titers: "low/low-C" (RF < 55 IU/ml, anti-CCP < 42 U/ml), "high/high-C" (RF ≥ 160 IU/ml, anti-CCP ≥ 100 U/ml), and "middle-C" (neither low/low-C nor high/high-C). Baseline plasma TNF level, serum infliximab level, and disease activity were compared between the three classes. Results: Baseline RF and anti-CCP titers showed significant correlations with baseline TNF and infliximab levels in weeks 2-14. Comparison of the three classes showed that baseline TNF level was lowest in the low/low-C group and highest in the high/high-C group (median 0.73 versus 1.15 pg/ml), that infliximab levels at week 14 were highest in the low/low-C group and lowest in the high/high-C group (median 1.0 versus 0.1 μg/ml), and that Disease Activity Score in 28 joints based on C-reactive protein at week 14 was lowest in the low/low-C group and highest in the high/high-C group (median 3.17 versus 3.82). A similar correlation was observed at week 54 in the 3 mg/kg dosing group, but not in the 6 or 10 mg/kg group. Significant decreases in both RF and anti-CCP were observed during infliximab treatment. Conclusions: RF/anti-CCP titers correlated with TNF level. This might explain the association of RF/anti-CCP with infliximab level and clinical response in patients with RA. Baseline RF/anti-CCP titers may serve as indices that aid infliximab treatment. Trial registration: ClinicalTrials.gov, NCT00691028. Retrospectively registered on 3 June 2008.

AB - Background: Although both rheumatoid factor (RF) and anticyclic citrullinated peptide antibodies (anti-CCP) are useful for diagnosing rheumatoid arthritis (RA), the impact of these autoantibodies on the efficacy of tumor necrosis factor (TNF) inhibitors has been controversial. The aim of this post hoc analysis of a randomized double-blind study (the RISING study) was to investigate the influences of RF and anti-CCP on the clinical response to infliximab in patients with RA. Methods: Methotrexate-refractory patients with RA received 3 mg/kg of infliximab from weeks 0 to 6 and then 3, 6, or 10 mg/kg every 8 weeks from weeks 14 to 46. In this post hoc analysis, patients were stratified into three classes on the basis of baseline RF/anti-CCP titers: "low/low-C" (RF < 55 IU/ml, anti-CCP < 42 U/ml), "high/high-C" (RF ≥ 160 IU/ml, anti-CCP ≥ 100 U/ml), and "middle-C" (neither low/low-C nor high/high-C). Baseline plasma TNF level, serum infliximab level, and disease activity were compared between the three classes. Results: Baseline RF and anti-CCP titers showed significant correlations with baseline TNF and infliximab levels in weeks 2-14. Comparison of the three classes showed that baseline TNF level was lowest in the low/low-C group and highest in the high/high-C group (median 0.73 versus 1.15 pg/ml), that infliximab levels at week 14 were highest in the low/low-C group and lowest in the high/high-C group (median 1.0 versus 0.1 μg/ml), and that Disease Activity Score in 28 joints based on C-reactive protein at week 14 was lowest in the low/low-C group and highest in the high/high-C group (median 3.17 versus 3.82). A similar correlation was observed at week 54 in the 3 mg/kg dosing group, but not in the 6 or 10 mg/kg group. Significant decreases in both RF and anti-CCP were observed during infliximab treatment. Conclusions: RF/anti-CCP titers correlated with TNF level. This might explain the association of RF/anti-CCP with infliximab level and clinical response in patients with RA. Baseline RF/anti-CCP titers may serve as indices that aid infliximab treatment. Trial registration: ClinicalTrials.gov, NCT00691028. Retrospectively registered on 3 June 2008.

KW - Anticyclic citrullinated peptide antibodies

KW - Clinical response

KW - Infliximab

KW - Pharmacokinetics

KW - Prediction

KW - Rheumatoid arthritis

KW - Rheumatoid factor

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U2 - 10.1186/s13075-017-1401-2

DO - 10.1186/s13075-017-1401-2

M3 - Article

C2 - 28865493

AN - SCOPUS:85028630920

VL - 19

JO - Arthritis Research and Therapy

JF - Arthritis Research and Therapy

SN - 1478-6354

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M1 - 194

ER -