Ophthalmology · Medical Literature
Association of IL-6 and IL-17 with thyroid eye disease.
Abstract
Thyroid Eye Disease (TED) is the most common extrathyroidal manifestation of Graves' disease. Interleukin-6 (IL-6) and interleukin-17 (IL-17) have been implicated in its pathogenesis, but individual study results remain inconsistent. However, existing findings on IL-6 and IL-17 levels in the serum or tears of TED patients remain inconsistent. This meta-analysis aimed to statistically evaluate the level of IL-6 and IL-17 in patients with TED. A systematic literature search was conducted across five electronic databases (PubMed, Web of Science, Elsevier Science Direct, Wiley Online Library, and CNKI). The search strategy targeted the terms "Thyroid Eye Disease" in conjunction with "Interleukin-6" or "Interleukin-17" in title and abstract fields. Results are presented as standardized mean differences (SMD) with 95% confidence intervals (CI). This meta-analysis demonstrated significantly elevated levels of both IL-6 and IL-17 in patients with TED compared to controls. Pooled estimates showed a substantial increase in IL-6 (SMD: 1.68; 95% CI: 0.83-2.53), with substantial heterogeneity. Similarly, IL-17 levels were markedly higher in TED patients overall (SMD: 1.78; 95% CI: 1.18-2.37). Furthermore, patients with active TED exhibited significantly higher IL-6 and IL-17 levels than those with inactive disease. To our knowledge, this meta-analysis is a large-scale systematic evaluation of IL-6 and IL-17 levels in patients with TED. These findings describe the circulating cytokine profile in the studied population and may inform future hypothesis-driven research. https://www.crd.york.ac.uk/PROSPERO/view/CRD420261277844, identifier CRD420261277844.
Clinical relevance
Are circulating or tear levels of interleukin-6 (IL-6) and interleukin-17 (IL-17) significantly elevated in patients with thyroid eye disease (TED) compared to controls, and do these levels differ according to disease activity status or sample type? __SNAPSHOT__ {"studyDesign":"Systematic review with meta-analysis","setting":"Multi-database literature synthesis; affiliated institution: Department of Ophthalmology, Second Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang, China","sampleSize":"not reported in abstract (number of included studies and total participants not specified in available abstract text; authors describe this as a 'large-scale systematic evaluation')","population":"Patients with a diagnosis of thyroid eye disease (Graves' orbitopathy) compared to non-TED controls; cytokine measurements obtained from serum or tear samples; subgroups stratified by disease activity (active vs. inactive TED) and sample type (serum vs. tears)","intervention":"Measurement of IL-6 and IL-17 levels in serum or tear fluid of TED patients","comparator":"Non-TED controls (specific control population characteristics not detailed in available abstract)","primaryOutcome":"Pooled standardized mean difference (SMD) in IL-6 and IL-17 levels between TED patients and controls","followUp":"not applicable (cross-sectional comparisons pooled from included studies)","fundingSource":"not reported"}
Key findings
The meta-analysis demonstrated significantly elevated levels of both IL-6 and IL-17 in TED patients compared to controls. For IL-6, the pooled SMD was 1.68 (95% CI: 0.83–2.53), indicating a large effect size by conventional thresholds, but with substantial heterogeneity across included studies. For IL-17, the pooled SMD was 1.78 (95% CI: 1.18–2.37), also a large effect, again with substantial heterogeneity. Subgroup analyses by sample type found that IL-6 elevations were present in both serum (SMD: 1.90; 95% CI: 0.66–3.14; I²=97.5%) and tear samples (SMD: 1.19; 95% CI: 0.79–1.59; I²=45.8%); IL-17 elevations were similarly present in serum (SMD: 1.94; 95% CI: 1.08–2.80; I²=94%) and tears (SMD: 1.42; 95% CI: 0.74–2.10; I²=84.1%). Patients with active TED exhibited significantly higher IL-6 and IL-17 levels than those with inactive disease. Meta-regression identified disease activity and sample type as significant contributors to heterogeneity (p<0.05), whereas publication year, geographic region, mean age, and sample size were not significant contributors. I²values for serum IL-6 and serum IL-17 exceed 90%, indicating very high between-study variability that substantially undermines precision of the pooled estimates. P-values for the primary pooled estimates were not explicitly reported in the available abstract. NNT/NNH are not applicable to this biomarker association study. No adverse events are applicable to this observational meta-analysis.
Practice implications
This meta-analysis provides pooled evidence that IL-6 and IL-17 are elevated in TED patients relative to controls across both serum and tear compartments, with the signal persisting in subgroup analyses. The finding that active TED is associated with higher cytokine levels compared to inactive disease is consistent with the known role of IL-6 in driving Th17 differentiation and orbital fibroblast activation, and with the identification of pathogenic Th17 cells as a dominant T-helper subset within the TED orbit. However, several important caveats limit clinical translation: (1) The extremely high I² values for serum analyses (97.5% for IL-6, 94% for IL-17) indicate that most variance in results is between-study rather than within-study, making the pooled SMD estimates unreliable as precise quantitative summaries. (2) The study establishes association, not causation; it cannot determine whether cytokine elevations drive disease activity or are an epiphenomenon of it. (3) The study does not establish clinical decision thresholds, diagnostic cut-points, or prognostic utility for either biomarker. (4) Patients with varying thyroid function status, treatment exposure, and disease staging were pooled without uniform standardization, limiting comparability. (5) Only an abstract was available for review; full methodology, individual study characteristics, risk-of-bias assessments, and publication bias analyses cannot be independently evaluated. (6) Generalizability is uncertain given the predominance of studies likely sourced from East Asian populations (CNKI database included). These findings are most applicable to pathophysiological understanding and hypothesis generation for future cytokine-targeting trials, rather than to routine clinical biomarker use. The failed phase III trial of secukinumab (anti-IL-17A) in TED should temper enthusiasm about translating elevated IL-17 association data directly into therapeutic benefit. __LIMITATIONS__ Very high between-study heterogeneity (I²>90% for serum IL-6 and serum IL-17) substantially undermines reliability of pooled point estimates despite statistically significant confidence intervals that exclude zero.,Inclusion of CNKI (Chinese-language database) alongside English-language databases may introduce population homogeneity skewed toward East Asian cohorts, limiting global generalizability.,Disease activity, thyroid function status, prior treatment, and cytokine assay methodology varied across included studies and were incompletely standardized — all identified as potential heterogeneity drivers.,Meta-regression could not fully explain residual heterogeneity; unidentified confounders (e.g., smoking status, concomitant medications, duration of TED) likely contribute.,The study uses surrogate biomarker endpoints (cytokine levels); no clinical outcomes (visual acuity, proptosis, Clinical Activity Score response) are linked to cytokine levels in this analysis.,Number of included studies and total patient-level sample size are not reported in the available abstract, preventing assessment of statistical power and precision.,Cross-sectional design of constituent studies precludes causal inference or temporal assessment of cytokine dynamics.,Only the abstract was available for this summary; full risk-of-bias evaluation, funnel plot analysis for publication bias, and sensitivity analyses could not be independently verified.,Funding source is not reported, preventing assessment of potential conflicts of interest.,The failed phase III secukinumab trial in TED (NCT04737330, terminated early) is an important external context suggesting that elevated IL-17 association does not automatically translate to therapeutic benefit from IL-17 blockade. __BOTTOM_LINE_CATEGORY__ promising_but_preliminary __BOTTOM_LINE__ This meta-analysis confirms statistically significant elevations of both IL-6 and IL-17 in TED patients versus controls across serum and tear compartments, with larger effect sizes in active versus inactive disease; however, extremely high between-study heterogeneity (I²>90% for serum analyses) substantially limits confidence in the pooled estimates. These findings reinforce the pathophysiological relevance of the IL-6/Th17/IL-17 axis in TED but do not establish clinical biomarker thresholds or support a change in diagnostic or therapeutic practice. Clinicians should interpret these results as hypothesis-generating context for future biomarker and interventional research, not as evidence to guide routine cytokine measurement or cytokine-targeted treatment selection.