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

Paper search

We performed a semantic search across over 138 million academic papers from the Elicit search engine, which includes all of Semantic Scholar and OpenAlex.

We ran this query: “Which cytokines (e.g., TNF-α, IL-2, IFN-γ) change most with abatacept treatment in RA?” The search returned 200 total results from Elicit. We retrieved 200 papers most relevant to the query for screening.

Screening

We screened in sources based on their abstracts that met these criteria:

• RA Population: Inclusion of rheumatoid arthritis diagnosed participants.
• Abatacept Intervention: Abatacept as the main therapeutic intervention.
• Cytokine Measurements: Measurement of at least one cytokine level.
• Human Study: Conducted in human participants.
• Adult Population: Focus on adult participants (≥18 years).
• Study Design: Randomized controlled trial, observational study, etc.
• RA-Specific Data: Provision of RA-specific cytokine data.
• Publication Status: Full-text published study.

Data extraction

We asked a large language model to extract each data column below from each paper:

• Study Design:

  • Study type, sample size of RA patients receiving abatacept, study duration, follow-up periods, control groups, and setting.

• Patient Characteristics:

  • Age, gender distribution, disease duration, baseline disease activity, prior treatments, ACPA/RF status.

• Abatacept Treatment:

  • Dose and administration schedule, treatment duration, concomitant medications, clinical response criteria used.

• Cytokines Measured:

  • List of cytokines measured, classification, and measurement types.

• Cytokine Changes:

  • Quantitative data on cytokine changes, including baseline values, post-treatment values, direction of change, magnitude of change, and statistical significance.

• Measurement Methods:

  • Assay types, measurement types and conditions, cell types analyzed, and timepoints.

• Clinical Correlations:

  • Relationship between cytokine changes and clinical outcomes.

Results

Characteristics of included studies

All 10 included studies employed before-after or cohort designs, with treatment durations ranging from 16 weeks to over 5 years.

Patient populations were relatively homogeneous across studies. Patients were predominantly female with mean ages ranging from 46.9 to 55 years, a disease duration of median 2 years to 10 years, and high baseline disease activity, with DAS28 scores ranging from 5.2 to 7.1. Clinical response rates were favorable with 60-86% of patients achieving good or moderate EULAR responses.

Cytokines measured across studies

Studies employed various methodological approaches to cytokine assessment: plasma or serum levels were measured using ELISA, multiplex assays; cellular cytokine production was assessed via flow cytometry.

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). 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.

Changes in IL-6 levels correlated strongly with clinical improvement. M. Borisova et al. reported that lowering of IL-6 levels was significantly associated with decreases in DAS28 (r=0.5, p<0.05).

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

IL-17 demonstrated substantial reductions, particularly in clinical responders. M. Scarsi et al. reported significant decreases in IL-17-producing CD4+ T cells after 6-12 months. The magnitude of IL-17 reduction correlated with clinical improvement.

IFN-γ showed moderate but significant reductions

IFN-γ demonstrated moderate reductions with significant decreases reported in gene expression and cellular production.

Other pro-inflammatory cytokines showed variable responses

TNF-α showed only modest reductions with few studies quantifying the exact changes.

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 moderate reductions in IFN-γ. TNF-α showed only modest reductions. Anti-inflammatory cytokines IL-35 and IFN-β increased significantly with treatment.

References

• M. Murakami et al., 2013
• M. Scarsi et al., 2014
• M. Weisman et al., 2006
• M. Buch et al., 2008
• M. Alenazy et al., 2021