Association between seropositivity and discontinuation of tumor necrosis factor inhibitors due to ineffectiveness in rheumatoid arthritis

Ogawa, Yoshikazu; Takahashi, N.; Kaneko, Atsushi; Hirano, Yuji; Kanayama, Yasuhide; Yabe, Yuichiro; Oguchi, Takeshi; Fujibayashi, Takayoshi; Takagi, Hideki; Hanabayashi, Masahiro; Funahashi, Koji; Hayashi, Masatoshi; Tsuboi, Seiji; Asai, Shuji; Asai, Nobuyuki; Matsumoto, Takuya; Sobue, Yasumori; Ishiguro, Naoki; Kojima, Toshihisa

doi:10.1007/s10067-019-04626-x

Cited by 14 publications

(17 citation statements)

References 30 publications

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“…Moreover, autoantibody-negative RA patients have a better treatment response compared to autoantibody-positive RA patients when given similar therapies [ 21 ]. In accordance with previous literature, we found a shortened biological survival due to inefficacy or adverse events in RF-positive RA patients but also the inability to taper TNF inhibitors after reaching remission in ACPA-positive RA patients [ 22 ]. This reconfirms the fact that autoantibody positivity is associated with worse outcomes and indicates that RA can be subdivided into autoantibody-positive and autoantibody-negative RA.…”

Section: Discussionsupporting

confidence: 92%

Factors that influence biological survival in rheumatoid arthritis: results of a real-world academic cohort from the Netherlands

et al. 2021

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We aim to explore real-world biological survival stratified for discontinuation reason and determine its influenceability in rheumatoid arthritis (RA) patients. Data from the local pharmacy database and patient records of a university hospital in the Netherlands were used. RA patients who started a biological between 2000 and 2020 were included. Data on age, anti-citrullinated protein antibody (ACPA) and rheumatoid factor (RF) status, presence of erosions, gender, body mass index, time to first biological, biological survival time, use of csDMARDs, and discontinuation reasons were collected. Of the included 318 patients, 12% started their first biological within 6 months after diagnosis. The median time to first biological was 3.6 years (95% CI, 1.0–7.2). The median survival of the first- and second-line biological was respectively 1.7 years (95% CI, 1.3–2.2) and 0.8 years (95% CI, 0.5–1.0) (p = 0.0001). Discontinuation reasons for the first-line biological were ineffectiveness (47%), adverse events (17%), remission (16%), pregnancy (30%), or patient preference (10%). Multivariable Cox regression analyses for discontinuation due to inefficacy or adverse events showed that concomitant use of csDMARDs (HR = 1.32, p < 0.001) positively while RF positivity negatively (HR = 0.82, p = 0.03) influenced biological survival. ACPA positivity was associated with the inability to discontinue biologicals after achieving remission (HR = 1.43, p = 0.023). Second-line TNF inhibitor survival was similar between patients with a primary and secondary non-response on the first-line TNF inhibitor (HR = 1.28, p = 0.34). Biological survival diminishes with the number of biologicals used. Biological survival is prolonged if patients use csDMARDs. RF was negatively associated with biological survival. ACPA was negatively associated with the inability to discontinue biologicals after achieving remission. Therefore, tailoring treatment based upon autoantibody status might be the first step towards personalized medicine in RA. Key Points• Prolonged biological survival is a surrogate for treatment effectiveness; however, an increasing amount of patients will taper treatment due to remission, and factors influencing biological survival based on separate reasons for discontinuation have not been explored.• We found that combining a biological DMARD with a conventional synthetic DMARD increases biological DMARD survival. Rheumatoid factor is negatively associated with biological survival. Anti-citrullinated protein antibody is negatively associated with the inability to discontinue the biological when remission was reached.• The first step towards personalized medicine might be tailoring of treatment based upon autoantibody status.

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Section: Discussionsupporting

confidence: 92%

Factors that influence biological survival in rheumatoid arthritis: results of a real-world academic cohort from the Netherlands

et al. 2021

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“…Our subgroup analysis of patients with ACPA and RF seropositivity were also consistent with other studies: observational studies have shown higher persistence on abatacept and lower persistence on TNFis among patients with ACPA and RF seropositivity. 32,33 These studies conclude higher persistence could be the result of better effectiveness of abatacept, or lower effectiveness of TNFis, in this population, which would also align with our findings that more patients discontinued TNFis than abatacept due to disease progression among this subgroup.…”

Section: Discussionsupporting

confidence: 88%

Persistence with Early-Line Abatacept versus Tumor Necrosis Factor-Inhibitors for Rheumatoid Arthritis Complicated by Poor Prognostic Factors

Han

Lobo

Broder

et al. 2021

JHEOR

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Background: Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by joint swelling and destruction that leads to severe disability. There are no clear guidelines regarding the order of therapies. Gathering data on treatment patterns outside of a clinical trial setting can provide useful context for clinicians. Objectives: To assess real-world treatment persistence in early-line abatacept versus tumor necrosis factor-inhibitors (TNFi) treated patients with RA complicated by poor prognostic factors (including anti-cyclic citrullinated peptide antibodies [ACPA] and rheumatoid factor [RF] seropositivity). Methods: We performed a multi-center retrospective medical record review. Adult patients with RA complicated by poor prognostic factors were treated with either abatacept or TNFis as the first biologic treatment at the clinic. Poor prognostic factors included ACPA+, RF+, increased C-reactive protein levels, elevated erythrocyte sedimentation rate levels, or presence of joint erosions. We report 12-month treatment persistence, time to discontinuation, reasons for discontinuation, and risk of discontinuation between patients on abatacept versus TNFi. Select results among the subgroup of ACPA+ and/or RF+ patients are presented. Results: Data on 265 patients (100 abatacept, 165 TNFis) were collected. At 12 months, 83% of abatacept patients were persistent versus 66.1% of TNFi patients (P=0.003). Median time to discontinuation was 1423 days for abatacept versus 690 days for TNFis (P=0.014). In adjusted analyses, abatacept patients had a lower risk of discontinuing index treatment due to disease progression (0.3 [95% confidence interval (CI): 0.1-0.6], P=0.001). Among the subgroup of ACPA+ and/or RF+ patients (55 abatacept, 108 TNFis), unadjusted 12-month treatment persistence was greater (83.6% versus 64.8%, P=0.012) and median time to discontinuation was longer (961 days versus 581 days, P=0.048) in abatacept versus TNFi patients. Discussion: Patients with RA complicated by poor prognostic factors taking abatacept, including the subgroup of patients with ACPA and RF seropositivity, had statistically significantly higher 12-month treatment persistence and a longer time to discontinuation than patients on TNFis. Conclusions: In a real-world setting, RA patients treated with abatacept were more likely to stay on treatment longer and had a lower risk of discontinuation than patients treated with TNFis.

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“…According to the blood presence of autoantibodies, RA is classified as seropositive or seronegative. The presence of these autoantibodies would confer to the disease a higher degree of inflammation, which results in a more aggressive and joint erosive condition for the patients who show higher disease activity, as well as worse prognosis and an accelerated progression of the disease ( 5 , 6 , 19 ).…”

Section: Discussionmentioning

confidence: 99%

“…This joint inflammation triggered by B cells is partly mediated by soluble cytokines, such as IL6, APRIL, or BAFF, which promote B cell activation and differentiation into short-lived plasma cells, producing autoantibodies as rheumatoid factor (RF) or anti-citrullinated protein antibodies (ACPA) ( 4 ). Furthermore, serum autoantibodies have been correlated with a higher disease activity ( 5 , 6 ), which has been associated with an increase of TNFi clearance due to the inflammatory sink that would lead to an early drug administration stopping ( 7 , 8 ). In this line, some studies have pointed out that the autoantibody seropositive status, mainly due to RF or ACPA, may be influencing the survival of TNFi as well as blood TNFi levels ( 9 , 10 ).…”

Section: Introductionmentioning

confidence: 99%

Methotrexate Reduces the Probability of Discontinuation of TNF Inhibitors in Seropositive Patients With Rheumatoid Arthritis. A Real-World Data Analysis

et al. 2021

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Tumor necrosis factor inhibitors (TNFi) are widely used for the treatment of patients with rheumatoid arthritis (RA), however a considerable percentage of patients discontinued the therapy. The aim of this study is to explore real-world TNFi survival, stratified for seropositivity, and to determine the factors that may influence it. This is a retrospective, observational and longitudinal study, using real-world data of patients, who started their first TNFi therapy between 1999 and 2018 from the RA-PAZ cohort. Patients were considered seropositive if they showed positive serum levels of either RF, ACPA, or both. Treatment survival was analyzed using Kaplan-Meier curves, and Cox proportional hazards models were used to compare the risks of TNFi discontinuation for seronegative and seropositive patients. Of the included 250 patients, 213 (85%) were seropositive. Results showed that TNFi survival did not depend on seropositivity status. However, median survival time was significant longer for seropositive patients who received concomitant MTX compared to patients who did not receive it (median [95% CI]: 3.3 yr. [2.3–4.2] vs. 2.6 yr. [1.7–3.6], respectively; p = 0.008). Furthermore, seropositive patients who received concomitant MTX were 49% less likely to discontinue TNFi therapy than patients who did not receive it (HR: 0.51; 95% CI: 0.35–0.74). In addition, we found that in seropositive patients, the use of prednisone throughout the TNFi treatment was associated with a higher likelihood of therapy discontinuation (OR: 2.30; 95% CI: 1.01–5.23). In conclusion, these data provide evidence to support the use of concomitant MTX in seropositive patients to prolong the effectiveness and the survival of the TNFi therapy. Moreover, the co-administration of prednisone in seropositive patients receiving TNFi was highly associated with TNFi discontinuation.

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Association between seropositivity and discontinuation of tumor necrosis factor inhibitors due to ineffectiveness in rheumatoid arthritis

Cited by 14 publications

References 30 publications

Factors that influence biological survival in rheumatoid arthritis: results of a real-world academic cohort from the Netherlands

Factors that influence biological survival in rheumatoid arthritis: results of a real-world academic cohort from the Netherlands

Persistence with Early-Line Abatacept versus Tumor Necrosis Factor-Inhibitors for Rheumatoid Arthritis Complicated by Poor Prognostic Factors

Methotrexate Reduces the Probability of Discontinuation of TNF Inhibitors in Seropositive Patients With Rheumatoid Arthritis. A Real-World Data Analysis

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