Glucose-6-Phosphate Isomerase Is Associated with Disease Activity and Declines in Response to Infliximab Treatment in Rheumatoid Arthritis
Introduction
Rheumatoid arthritis (RA) is a chronic systemic autoimmune disorder characterized by synovial inflammation, leading to joint destruction, disability, and reduced quality of life. While the pathogenesis of RA involves complex interactions between genetic, environmental, and immune factors, autoantibodies and inflammatory cytokines play pivotal roles in disease progression. Tumor necrosis factor (TNF) inhibitors, such as infliximab, have revolutionized RA treatment by targeting inflammatory pathways. However, a significant proportion of patients exhibit inadequate responses to TNF inhibitors or lose therapeutic efficacy over time. Identifying biomarkers predictive of treatment response remains a critical unmet need in RA management.
Glucose-6-phosphate isomerase (GPI), an enzyme central to glycolysis and gluconeogenesis, has emerged as a multifunctional protein with extracellular cytokine-like activity. Preclinical studies demonstrate that GPI immunization induces arthritis in mice, while GPI overexpression stimulates synovial fibroblast proliferation and inflammatory cytokine secretion. Elevated serum GPI levels in RA patients further suggest its role in disease pathogenesis. This study evaluates the clinical relevance of serum GPI as a biomarker for RA disease activity and its utility in predicting responses to infliximab therapy.
Methods
A prospective cohort of 62 RA patients with inadequate responses to methotrexate (MTX) (≥10 mg/week for ≥3 months) was enrolled at Peking University People’s Hospital from July 2016 to July 2018. Patients received infliximab (3 mg/kg intravenously at weeks 0, 2, and 6, followed by 8-week intervals) alongside stable MTX therapy. Clinical assessments and serum sampling were conducted at baseline and week 18.
Disease activity was quantified using the Disease Activity Score in 28 joints (DAS28-ESR), incorporating tender joint count (TJC), swollen joint count (SJC), erythrocyte sedimentation rate (ESR), and patient global assessment (visual analog scale). Patients were stratified into remission (DAS28 ≤2.6), low (2.6<DAS28 ≤3.2), moderate (3.25.1) disease activity categories. Treatment response was defined using European League Against Rheumatism (EULAR) criteria. Radiographic joint damage was assessed via the modified Sharp/van der Heijde score (SHS), including erosion (ERO) and joint space narrowing (JSN) sub-scores.
Serum GPI concentrations were measured using enzyme-linked immunosorbent assay (ELISA) (Shanghai Beijia Biochemical Sciences Co., Ltd.), with positivity defined as >0.2 mg/L. Statistical analyses included Spearman correlation, Mann-Whitney U tests, and Wilcoxon signed-rank tests, with significance set at P<0.05.
Results
Baseline Patient Characteristics
The cohort comprised 62 RA patients (71% female; median age 64 years [IQR 49–75]). At baseline, 79% (49/62) were GPI-positive. Median disease duration was 9 months (IQR 3.75–15.25), with high disease activity (DAS28 >5.1) observed in 54.8% of patients. Median CRP and ESR levels were 41.9 mg/L (IQR 17.8–49.2) and 75.0 mm/h (IQR 53.8–91.3), respectively. Rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibodies were present in 71% (44/62) and 79% (49/62) of patients, respectively.
GPI Correlation with Clinical Parameters
Serum GPI levels positively correlated with DAS28 (r=0.6840, P<0.001), SJC (r=0.4248, P=0.001), TJC (r=0.6701, P<0.001), and CRP (r=0.2706, P=0.033) (Figures 1 and 2). Patients with high disease activity (DAS28 >5.1) exhibited significantly higher GPI levels compared to those with lower disease activity (P=0.035). No correlations were observed between GPI and ESR, RF, anti-CCP, or immunoglobulins (IgA, IgG, IgM) (Figure 2D–I).
GPI-positive patients had higher median TJC (10 [IQR 4–21.5] vs. 0 [IQR 0–2.5], P<0.001) and SJC (6 [IQR 2–17] vs. 1 [IQR 0–5], P=0.009) than GPI-negative patients (Table 2). Smoking prevalence was higher in GPI-negative patients (46.2% vs. 16.3%, P=0.022).
GPI and Radiographic Progression
No significant associations were found between baseline GPI levels and radiographic scores (SHS: r=0.0554, P=0.693; ERO: r=0.1101, P=0.429; JSN: r=-0.0065, P=0.966) (Figure 3).
GPI Dynamics During Infliximab Therapy
Infliximab treatment significantly reduced DAS28 scores from baseline to week 18 (median ΔDAS28=-2.15 [IQR -3.20–-1.10], P<0.001) (Figure 4A). GPI-positive patients showed greater DAS28 improvement than GPI-negative patients (P<0.001) (Figure 4B). Serum GPI levels declined markedly post-treatment (median ΔGPI=-0.52 mg/L [IQR -0.95–-0.15], P<0.001) (Figure 4C), with baseline GPI levels correlating strongly with DAS28 improvement (r=0.6102, P<0.001) (Figure 4D).
Discussion
This study establishes serum GPI as a clinically relevant biomarker in RA, correlating with disease activity and therapeutic response to infliximab. The strong association between GPI and DAS28, SJC, TJC, and CRP underscores its role in reflecting synovial inflammation. GPI’s decline following infliximab therapy highlights its potential utility in monitoring treatment efficacy, particularly in MTX-inadequate responders.
The mechanistic link between GPI and RA pathogenesis may involve its dual enzymatic and cytokine-like functions. Preclinical models show GPI-induced synovitis and fibroblast activation, consistent with its pro-inflammatory role in RA. The lack of correlation between GPI and radiographic scores suggests that GPI primarily reflects inflammatory activity rather than structural damage, aligning with prior observations that synovitis and joint destruction may follow distinct pathways.
Notably, GPI-positive patients exhibited robust responses to infliximab, emphasizing its predictive value. The greater DAS28 improvement in these patients may stem from GPI’s involvement in TNF-α-driven pathways, which are targeted by infliximab. The observed smoking disparity (higher in GPI-negative patients) warrants further investigation, as smoking is a known risk factor for autoantibody-positive RA.
Limitations and Future Directions
The study’s small sample size and heterogeneous disease durations limit generalizability. Short-term follow-up precluded assessment of long-term radiographic progression. Prospective studies with larger cohorts are needed to validate GPI as a prognostic marker and explore its pathogenic mechanisms.
Conclusion
Serum GPI is a promising biomarker for evaluating RA disease activity and predicting therapeutic responses to infliximab. Its dynamic correlation with clinical improvement supports its integration into RA management strategies, enabling personalized treatment approaches.
DOI
https://doi.org/10.1097/CM9.0000000000000750
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