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.

Conflict of interest statement

Consent for publication

Not applicable.

Competing interests

TT has received grant support, consultant’s fees, and/or lecture fees from AbbVie GK, Asahi Kasei Medical, Asahi Kasei Pharma, Astellas Pharma, AstraZeneca K.K., AYUMI Pharmaceutical, Bristol-Myers K.K., Celltrion, Chugai Pharmaceutical, Daiichi Sankyo, Eisai, Eli Lilly Japan, Janssen Pharmaceutical K.K., Merck Serono, Mitsubishi Tanabe Pharma, Nippon Kayaku, Nippon Shinyaku, Novartis Pharma K.K., Pfizer Japan, Taisho Toyama Pharmaceutical, Takeda Pharmaceutical, and Teijin Pharma. TI, TYano, and TYoshinari are employees of Mitsubishi Tanabe Pharma. TK has received consultant’s fees and/or lecture fees from AbbVie GK, Astellas Pharma, Bristol-Myers K.K., Chugai Pharmaceutical, Daiichi Sankyo, Eisai, Eli Lilly Japan, Mitsubishi Tanabe Pharma, Pfizer Japan, Santen Pharmaceutical, Taisho Toyama Pharmaceutical, Teijin Pharma, and UCB Japan. NM and TA declare that they have no competing interests.

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Figures

Fig. 1

a, b Serum infliximab level and disease activity at week 54 in three stratified classes. Differences among three classes stratified on the basis of rheumatoid factor and anti-cyclic citrullinated peptide antibodies at week 0 in serum infliximab (IFX) level at week 54 (a) and with disease activity at week 54 b were evaluated by Kruskal-Wallis test. Disease activity was evaluated using Disease Activity Score in 28 joints based on C-reactive protein with the following REM cutoff levels: < 2.3, LDA ≥ 2.3 but < 2.7, MDA ≥ 2.7 but ≤ 4.1, and HDA > 4.1 [22]. HDA High disease activity, LDA Low disease activity without clinical remission, MDA Moderate disease activity, REM Clinical remission