Elicit: Cytokine Response to Abatacept in RA
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
- 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?”
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)?
Data extraction
The extraction of data was carried out with respect to multiple facets related to study design, patient characteristics, abatacept treatment details, cytokines measured, cytokine changes, measurement methods, and clinical correlations.
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.
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.
| Cytokine | Studies Measuring | Classification | Measurement Type |
|---|---|---|---|
| IL-6 | M. Murakami et al., 2013; M. Weisman et al., 2006; M. Buch et al., 2008; L. Gómez-García et al., 2013; M. Borisova et al., 2017 | Pro-inflammatory | Plasma/serum; gene expression |
| IL-17 | M. Murakami et al., 2013; M. Scarsi et al., 2014; M. Scarsi et al., 2013; M. Alenazy et al., 2021; L. Gómez-García et al., 2013; M. Borisova et al., 2017; M. Scarsi et al., 2014a; M. Scarsi et al., 2013a | Th17 | Plasma/serum; cellular production |
| IFN-γ | M. Murakami et al., 2013; M. Scarsi et al., 2014; M. Buch et al., 2008; M. Scarsi et al., 2013; L. Gómez-García et al., 2013; M. Scarsi et al., 2013a | Th1 | Plasma/serum; cellular production; gene expression |
| TNF-α | M. Murakami et al., 2013; M. Weisman et al., 2006; M. Buch et al., 2008; L. Gómez-García et al., 2013; M. Borisova et al., 2017 | Pro-inflammatory | Serum; gene expression |
| IL-2 | M. Murakami et al., 2013 | Th1 | Plasma |
| IL-4 | M. Murakami et al., 2013 | Th2 | Plasma |
| IL-10 | M. Murakami et al., 2013; M. Alenazy et al., 2021 | Th2; anti-inflammatory | Plasma/serum |
| Soluble IL-2 receptor | M. Weisman et al., 2006 | Not specified | Serum |
| IL-1β | M. Buch et al., 2008; M. Alenazy et al., 2021; L. Gómez-García et al., 2013; M. Borisova et al., 2017 | Pro-inflammatory | Serum; gene expression |
| IL-35 | M. Alenazy et al., 2021 | Anti-inflammatory | Serum |
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. 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.
IFN-γ showed moderate but significant reductions
IFN-γ demonstrated moderate reductions across multiple studies.
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.
Anti-inflammatory cytokines increased with treatment
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).
Summary table of cytokine changes
| Cytokine | Study | Baseline | Post-treatment | Change | p-value |
|---|---|---|---|---|---|
| IL-6 | M. Murakami et al., 2013 | 24.9±20.5 pg/mL | 11.5±7.7 pg/mL (24 weeks) | -54% | <0.001 |
| IL-6 | M. Borisova et al., 2017 | 2.4 (1.1-6.4) pg/mL | 1.29 (0.9-2.2) pg/mL (24 weeks) | -46% | 0.0006 |
| IFN-γ (gene) | M. Buch et al., 2008 | Not specified | Not specified | -52% (95% CI -73 to -15) | <0.05 |
| IFN-γ (cellular) | M. Scarsi et al., 2013a | 70 (45-166) cells/μl | 55 (43-82) cells/μl (6 months) | -21.4% | 0.036 |
| IL-17 (cellular, CD4+) | M. Scarsi et al., 2013a | 19 (12-23) cells/μl | 9 (4-16) cells/μl (6 months) | -52.6% | 0.017 |
| IL-17 (% CD4+) | M. Scarsi et al., 2013 | 1.1% (0.4-2.0) | 0.3% (0.2-0.5) (12 months) | -73% | 0.005 |
| IL-17 (% CD8+) | M. Scarsi et al., 2013 | 1.2% (0.7-1.8) | 1.0 (0.6-1.3) (6 months) | -17% | 0.035 |
| IL-17 (serum) | M. Alenazy et al., 2021 | Not specified | Not specified | Decreased | 0.0013 |
| IP-10 | M. Borisova et al., 2017 | 21 (12.9-49.8) pg/mL | 14 (7.5-28) pg/mL (24 weeks) | -33% | 0.007 |
| IL-22 | M. Scarsi et al., 2014a | 38.3 (7.7-93.0) pg/mL | 33.8 (11.1-74.8) pg/mL (6 months) | -12% | 0.56 (NS) |
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.