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
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.
| Study | Full text retrieved? | Study Type | Sample Size | Treatment Duration | Control Groups | Setting |
|---|---|---|---|---|---|---|
| M. Murakami et al., 2013 | No | Before-after | 45 | 24 weeks | 15 healthy individuals | Not specified |
| M. Scarsi et al., 2014 | No | Before-after | 24 | ≥6 months (6-12 month follow-up) | 16 healthy controls | Not specified |
| M. Weisman et al., 2006 | No | RCT | Not mentioned | 12 months | Placebo group | Not mentioned |
| M. Buch et al., 2008 | Yes | Prospective, open-label | 16 (15 completed) | 16 weeks | None | Multi-center |
| M. Scarsi et al., 2013 | No | Before-after | 24 | ≥6 months (6-12 month follow-up) | 16 healthy donors | Not specified |
| M. Alenazy et al., 2021 | Yes | Before-after | 31 | ≥6 months (average 13 months) | 31 RA patients on other treatments, 30 healthy controls | Single-center |
| L. Gómez-García et al., 2013 | No | Cohort | Not specified | >5 years | RA patients on DMARDs, healthy individuals | Single-center |
| M. Borisova et al., 2017 | No | Before-after | 44 | 24 weeks (assessed every 12 weeks) | 16 healthy individuals | Not mentioned |
| M. Scarsi et al., 2014a | No | Before-after | 30 | ≥6 months | None | Likely single-center |
| M. Scarsi et al., 2013a | No | Cohort | 42 | ≥6 months (6-12 month follow-up) | Not mentioned | Likely single-center |
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 |
| 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. 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
| 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.