Circulating Fibroblast Growth Factor-21 Levels in Rheumatoid Arthritis: Associations With Disease Characteristics, Body Composition, and Physical Functioning

Abstract

Objective: This study evaluated associations between fibroblast growth factor (FGF)-21, an adipokine associated with metabolic stress, and adverse longitudinal changes in body composition and physical functioning in patients with rheumatoid arthritis (RA).

Methods: At baseline and follow-up, patients with RA aged 18-70 years completed whole-body dual-energy X-ray absorptiometry and peripheral quantitative computed tomography to quantify lean mass, fat mass, and muscle density. Dynamometry assessed muscle strength at the hand and knee, and physical functioning was measured with the Health Assessment Questionnaire (HAQ) and the Short Physical Performance Battery (SPPB). FGF-21 and inflammatory cytokines were measured at baseline. Linear and logistic regression analyses assessed associations between FGF-21 levels and both body composition and physical functioning over time.

Results: There were 113 patients with RA enrolled, and 84 (74%) returned for follow-up at a median of 2.68 years. At baseline, FGF-21 was associated with age, smoking, methotrexate use, adiposity, and inflammatory cytokines: tumor necrosis factor receptor type I, YKL-40, vascular endothelial growth factor (VEGF), and resistin. The highest FGF-21 quartile was associated with worse SPPB and HAQ. Higher baseline FGF-21 levels (per 1 SD) were associated with worsening in muscle density and area Z-scores (β -0.06, 95% CI -0.12 to 0.008, P = 0.08; and β -0.05, 95% CI -0.10 to 0.006, P = 0.08, respectively) and a greater probability of a clinically meaningful worsening of HAQ (OR 2.37, 95% CI 1.21-4.64, P = 0.01). The fourth FGF-21 quartile was associated with worsening of SPPB (β -0.57, 95% CI -1.04 to -0.09, P = 0.02).

Conclusion: FGF-21 levels are associated with obesity and inflammatory cytokines, and with worsening in physical functioning in RA. These data support the hypothesis that FGF-21 can identify patients at risk of functional decline.

Keywords: biomarkers; body composition; disease activity; fibroblast growth factor 21; physical functioning; rheumatoid arthritis.

Figure 1.

Association between Cytokines and Inflammatory Markers and FGF-21 Levels. Graph shows regression coefficients from models regressing FGF-21 levels on each factor. Bars show 95% CI. FGF-21 and all factor levels were converted to standardized scores to allow for direct comparisons. Right-hand coefficients (triangle) for each marker are adjusted for age, gender, visceral fat area, current smoking, and methotrexate use (all at baseline). N=106 (unadjusted model) and 104 (adjusted) for TNF-RI, YKL-40, VEGF, Resistin, CRP, Leptin, VCAM-1, IL-6, SAA, EGF, MMP1, and MMP3. N=111 (unadjusted model) and 109 (adjusted) for ESR. N=113 (unadjusted model) and 111 (adjusted) for TNF, IFN, IL-1, and Adiponectin.

Figure 2.

Probability of a Clinically Meaningful Negative Change in Selected Measures at Second Visit, by Baseline FGF-21 Z-Score. *= p value <0.05. Models include adjustments for age, gender, visceral fat area, current smoking, and methotrexate use (all at baseline). Clinically meaningful worsening was defined as follows, or as patient death before visit (N for each regression is listed as well):

1. HAQ: increased by 0.2 (N=89)

2. SPPB: decreased by 1 (N=51)

3. Extension and flexion strength: decreased by 10% (N=78, 78)

4. Grip strength: decreased by 6.5 kg (N=86)

5. Muscle density and muscle area z-score: decreased by 0.5 (N=82, 76)