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. More on methods

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
• n = 10

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: Does the study include participants with rheumatoid arthritis diagnosed according to established criteria (ACR 1987, ACR/EULAR 2010, or physician diagnosis)?
• Abatacept Intervention: Is abatacept administered as the main therapeutic intervention (either as monotherapy or combination therapy) in this study?
• Cytokine Measurements: Does the study measure at least one cytokine level with quantitative data (serum, plasma, or synovial fluid) at both baseline and at least one post-treatment timepoint?
• Human Study: Is this a study conducted in human participants (not an in vitro or animal study)?
• Adult Population: Does the study focus on adult participants (≥18 years old) rather than exclusively on juvenile or pediatric RA populations?
• Study Design: Is this study a randomized controlled trial, observational study, systematic review, or meta-analysis (not a case report or case series)?
• RA-Specific Data: Does the study provide RA-specific cytokine data (either exclusively RA population or separate analysis for RA patients) rather than focusing solely on clinical outcomes without cytokine measurements?
• Publication Status: Is this a published full-text study (not a conference abstract or unpublished study)?

We considered all screening questions together and made a holistic judgement about whether to screen in each paper.

Data extraction

We asked a large language model to extract each data column below from each paper. We gave the model the extraction instructions shown below for each column.

• Study Design:

Extract study design and sample characteristics for abatacept treatment in RA patients, including:

• Study type (RCT, cohort, before-after, etc.)

  • Sample size of RA patients receiving abatacept
  • Study duration and follow-up periods
  • Control groups (if any)
  • Setting (single-center, multi-center)

• Patient Characteristics:

Extract baseline characteristics of RA patients receiving abatacept treatment, including:

• Age and gender distribution

  • RA disease duration
  • Baseline disease activity (DAS28, CRP, etc.)
  • Prior treatments (DMARDs, biologics)
  • ACPA/RF status
  • Inclusion/exclusion criteria relevant to cytokine analysis

• Abatacept Treatment:

Extract details about abatacept treatment regimen and clinical response, including:

• Dose and administration schedule

  • Treatment duration at time of cytokine measurement
  • Concomitant medications (methotrexate, other DMARDs)
  • Clinical response criteria used (EULAR, ACR)
  • Proportion of patients with good vs. poor clinical response

• Cytokines Measured:

Extract comprehensive list of all cytokines measured in RA patients receiving abatacept, including:

• Specific cytokine names (TNF-α, IL-2, IFN-γ, IL-17, IL-6, IL-4, IL-10, etc.)

  • Classification (Th1, Th2, Th17, pro-inflammatory, anti-inflammatory)
  • Whether measured in serum/plasma or cellular production
  • Sample sizes for each cytokine measurement

• Cytokine Changes:

Extract quantitative data on cytokine changes from baseline to post-abatacept treatment, including:

• Baseline values (mean/median with ranges or SD)

  • Post-treatment values at each timepoint (6 months, 12 months, etc.)
  • Direction of change (increase/decrease)
  • Magnitude of change (fold change, percentage change, effect size)
  • Statistical significance (p-values, confidence intervals)
  • Which cytokines showed the largest magnitude changes

• Measurement Methods:

Extract methodology for cytokine assessment in abatacept-treated RA patients, including:

• Assay types (ELISA, flow cytometry, multiplex, RT-qPCR)

  • Whether measuring serum/plasma levels vs. cellular production
  • Stimulation conditions for cellular assays (PMA/ionomycin, etc.)
  • Cell types analyzed (CD4+, CD8+, PBMC)
  • Timepoints of measurement relative to abatacept dosing

• Clinical Correlations:

Extract relationships between cytokine changes and clinical outcomes in abatacept-treated RA patients, including:

• Correlations between cytokine changes and disease activity improvement (DAS28, CRP changes)
  • Differences in cytokine responses between clinical responders vs. non-responders
  • Associations with specific clinical measures (joint counts, inflammatory markers)
  • Whether cytokine normalization occurred relative to healthy controls
  • Predictive value of cytokine changes for treatment response

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. M. Murakami et al. found that IL-6 levels correlated significantly with disease activity markers including CRP and MMP-3 at baseline, and that changes in IL-6 levels correlated significantly with changes in CRP, DAS28-CRP, and MMP-3. Similarly, 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, 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). IL-17-producing CD8+ T cells showed similar patterns, decreasing from 1.2% (0.7-1.8) to 1.0 (0.6-1.3) at 6 months (p=0.035).

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). These changes were statistically significant only in patients achieving good EULAR clinical responses, not in non-responders.

M. Alenazy et al. measured serum IL-17 levels and found a significant decrease (p=0.0013), though specific quantitative values were not provided in the abstract.

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. M. Scarsi et al. (2013a) reported that IFN-γ-producing CD8+ T cells decreased from 70 (45-166) cells/μl to 55 (43-82) cells/μl at 6 months (p=0.036), representing an approximately 21.4% decrease. Another study by M. Scarsi et al. (2014) confirmed decreases in IFN-γ-producing CD8+ T cells after 6 months (p=0.033), though specific quantitative values were not provided.

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. M. Weisman et al. reported smaller reductions in TNF-α compared to other biomarkers in the abatacept 10 mg/kg group versus placebo, though specific values were not provided. M. Buch et al. noted trends toward reduction in TNF-α gene expression but did not quantify the magnitude.

IP-10 decreased significantly in M. Borisova et al.’s study, from baseline levels of 21 (12.9-49.8) pg/mL to 14 (7.5-28) pg/mL at 24 weeks (p=0.007), representing an approximate 33% reduction. This reduction correlated significantly with decreased DAS28 (r=0.32, p<0.05).

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. Specific quantitative values for these changes were not provided.

IL-22 serum levels showed no significant change with abatacept treatment, with median levels decreasing from 38.3 (7.7-93.0) pg/mL to 33.8 (11.1-74.8) pg/mL at 6 months (p=0.56).

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

1. M. Murakami et al. (2013). SAT0121 Changes in Cytokine Profiles in Rheumatoid Arthritis Patients During Abatacept Treatment. Annals of the Rheumatic Diseases
2. M. Scarsi et al. (2014). Reduction of peripheral blood T cells producing IFN-γ and IL-17 after therapy with abatacept for rheumatoid arthritis. Clinical and Experimental Rheumatology
3. M. Weisman et al. (2006). Reduction of inflammatory biomarker response by abatacept in treatment of rheumatoid arthritis. Journal of Rheumatology
4. M. Buch et al. (2008). Mode of action of abatacept in rheumatoid arthritis patients having failed tumour necrosis factor blockade: a histological, gene expression and dynamic magnetic resonance imaging pilot study. Annals of the Rheumatic Diseases
5. M. Alenazy et al. (2021). Abatacept enhances blood regulatory B cells of rheumatoid arthritis patients to a level that associates with disease remittance. Scientific Reports