Cytokine Response to Abatacept in RA

Which cytokines (e.g., TNF-α, IL-2, IFN-γ) change most with abatacept treatment in RA?

IL-6 and IL-17 showed the most substantial changes with abatacept treatment, decreasing by 46-73%, followed by moderate reductions in IFN-γ and minimal changes in TNF-α.

Abstract

Ten studies evaluated cytokine changes following abatacept treatment in RA patients, employing before-after or cohort designs with treatment durations ranging from 16 weeks to over 5 years. Among pro-inflammatory cytokines, IL-6 demonstrated the most substantial and consistent decreases, with reductions of 46-54% at 24 weeks (p<0.001). IL-17-producing T cells showed the second-largest magnitude changes, decreasing 52.6-73% in clinical responders at 6-12 months (p≤0.017), with levels normalizing to those of healthy controls. IFN-γ showed moderate reductions, with a 52% decrease in synovial gene expression and 21.4% decrease in cellular production. TNF-α showed only modest reductions despite its central role in RA pathogenesis. Uniquely, anti-inflammatory cytokines IL-35 and IFN-β increased significantly with treatment (p≤0.0013). Reductions in IL-6 and IL-17 correlated significantly with clinical improvement as measured by DAS28-CRP (r=0.477-0.5, p<0.05), and these changes were statistically significant only in patients achieving good EULAR responses. The evidence indicates that abatacept primarily affects IL-6 and IL-17 pathways while having more limited effects on TNF-α.

Methods

We analyzed 10 sources from an initial pool of 200, using 8 screening criteria. Each paper was reviewed for 7 key aspects that mattered most to the research question.

Records from Elicit search

• n = 200

• Papers screened using: RA Population, Abatacept Intervention, Cytokine Measurements, Human Study, Adult Population, Study Design, RA-Specific Data, Publication Status

• n = 200 Papers screened out

• n = 190 Papers included for extraction

Results

Characteristics of included studies

All 10 included studies employed before-after or cohort designs to evaluate cytokine changes following abatacept treatment in RA patients, with treatment durations ranging from 16 weeks to over 5 years.

Patient populations were relatively homogeneous across studies. Where reported, patients were predominantly female with mean ages ranging from 46.9 to 55 years. Disease duration varied from a median of 2 years to 10 years. Baseline disease activity was generally high, with DAS28 scores ranging from 5.2 to 7.1 where reported. Most patients had failed prior DMARD or biologic therapy. Seropositivity rates were high, with 75-84.4% being RF-positive and/or ACPA-positive. Clinical response rates were favorable across studies. Good or moderate EULAR responses were achieved in 60-86% of patients, with 52-71% achieving clinical remission or good response.

Cytokines measured across studies

Studies employed varied methodological approaches to cytokine assessment. Plasma or serum levels were measured using ELISA, multiplex assays, or MicroVue immunoassay. Cellular cytokine production was assessed via flow cytometry with intracellular staining following in vitro stimulation with PMA/ionomycin. One study used RT-qPCR to measure cytokine gene expression in synovial tissue.

Effects of abatacept on cytokine levels

IL-6 showed the most consistent and substantial reductions

IL-6 emerged as the cytokine with the most consistent and substantial reductions across studies. M. Murakami et al. reported that baseline IL-6 levels were significantly elevated in RA patients compared to healthy individuals (24.9±20.5 vs 7.1±4.0 pg/mL, p<0.001) regardless of ACPA status. Following 24 weeks of abatacept treatment, IL-6 levels decreased significantly (24.9±20.5 to 11.5±7.7 pg/mL, p<0.001), representing an approximate 54% reduction. M. Borisova et al. confirmed these findings in a separate cohort, reporting baseline IL-6 levels of 2.4 (1.1-6.4) pg/mL that decreased to 1.29 (0.9-2.2) pg/mL after 24 weeks (p=0.0006), representing an approximate 46% reduction. Changes in IL-6 levels correlated strongly with clinical improvement.

IL-17-producing T cells showed marked reductions, particularly in clinical responders

IL-17 demonstrated substantial reductions, though primarily measured as cellular production rather than serum levels. M. Scarsi et al. (2013a) reported the most dramatic changes in clinical responders, with IL-17-producing CD4+ T cells decreasing from 19 (12-23) cells/μl to 9 (4-16) cells/μl after 6 months (p=0.017), representing an approximately 52.6% decrease. The same group reported in another study that IL-17-producing CD4+ T cells decreased from 1.1% (0.4-2.0) to 0.3% (0.2-0.5) of CD4+ T cells at 12 months (p=0.005). Importantly, these reductions in IL-17-producing T cells normalized to levels comparable with healthy controls. The magnitude of IL-17 reduction correlated with clinical improvement, with the reduction in IL-17-producing CD4+ T cells correlating with decreased DAS28-CRP scores (r=0.477, p=0.039).

IFN-γ showed moderate but significant reductions

IFN-γ demonstrated moderate reductions across multiple studies. M. Buch et al. reported a 52% reduction in IFN-γ gene expression in synovial tissue (95% CI -73 to -15, p<0.05), representing the largest magnitude change for this cytokine. This reduction correlated with MRI improvements in synovial inflammation. Cellular production of IFN-γ showed more modest changes.

Other pro-inflammatory cytokines showed variable responses

TNF-α, despite being a key pro-inflammatory cytokine in RA pathogenesis, showed only modest reductions with abatacept.

Th1 and Th2 cytokines (IL-2, IL-4, IL-10) showed decreases in plasma levels following abatacept treatment, though the proportions of Th1 and Th2 cells did not change.

Anti-inflammatory cytokines increased with treatment

Uniquely, M. Alenazy et al. reported significant increases in anti-inflammatory cytokines. Serum IL-35 levels increased significantly (p=0.0013), as did IFN-β levels (p=0.0008). These increases accompanied enhanced blood levels of IL-35+IL-10+ regulatory B cells, which were higher in patients achieving remission (DAS28-CRP <2.6) compared to those who did not (p=0.0173). IL-10 levels themselves did not change significantly (p=0.8922).

Summary table of cytokine changes

Among pro-inflammatory cytokines, IL-6 demonstrated the most substantial and consistent decreases (46-54% reductions), followed by IL-17-producing cells (52.6-73% reductions in responders) and IFN-γ (21.4-52% reductions depending on measurement method). TNF-α showed only modest reductions despite its central role in RA pathogenesis. Anti-inflammatory cytokines IL-35 and IFN-β uniquely increased with treatment, suggesting abatacept may enhance regulatory mechanisms in addition to suppressing pro-inflammatory pathways.

References

M. Murakami, T. Matsutani, M. Sekiguchi, K. Matsui, M. Kitano, and 22 more (2013)
M. Scarsi, C. Zanotti, M. Chiarini, L. Imberti, S. Piantoni, and 3 more (2014)
M. Weisman, P. Durez, D. Hallegua, R. Aranda, J. Becker, and 4 more (2006)
M. Buch, David L. Boyle, S. Rosengren, B. Saleem, R. Reece, and 8 more (2008)
M. Scarsi, C. Zanotti, M. Chiarini, S. Piantoni, L. Imberti, and 6 more (2013)
M. Alenazy, Fatemeh Saheb Sharif‐Askari, M. Omair, Mohammad S El-Wetidy, M. Omair, and 5 more (2021)
L. Gómez-García, C. Ramírez-Assad, A. Vargas, F. Massó, F. Sánchez-Muñoz, and 3 more (2013)
M. Borisova, G. Lukina, Y. Sigidin, E. Luchihina, D. Karateev, and 5 more (2017)
M. Scarsi, E. Colombo, S. Piantoni, R. Ottaviani, F. Allegri, and 2 more (2014)
M. Scarsi, S. Piantoni, M. Chiarini, C. Zanotti, L. Imberti, and 2 more (2013)