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The aim of this study was to analyze the relationship between the serum levels of soluble transferrin receptor (sTfR) and interleukin 4 (IL-4), and the disease activity and organ manifestations in SLE patients. We studied 200 SLE patients and 50 controls. We analyzed disease activity, organ involvement, serum sTfR, IL-4 and interleukin-6 (IL-6) levels, and antinuclear and antiphospholipid antibody profiles. The median serum levels of sTfR (<i>p</i> > 0.000001) and IL-4 (<i>p</i> < 0.00001) were higher in the study group than in the controls. SLE patients, compared to the controls, had significantly lower HGB levels (<i>p</i> < 0.0001), a lower iron concentration (<i>p</i> = 0.008), a lower value of total iron-binding capacity (TIBC) (<i>p</i> = 0.03), and lower counts of RBC (<i>p</i> = 0.004), HCT (<i>p</i> = 0.0004), PLT (<i>p</i> = 0.04), neutrophil (<i>p</i> = 0.04), and lymphocyte (<i>p</i> < 0.0001). Serum sTfR levels were negatively correlated with lymphocyte (<i>p</i> = 0.0005), HGB (<i>p</i> = 0.0001) and HCT (<i>p</i> = 0.008), and positively correlated with IL-4 (<i>p</i> = 0.01). Elevated serum sTfR > 2.14 mg/dL was associated with an increased risk of myocardial infarction (OR: 10.6 95 CI 2.71–464.78; <i>p</i> = 0.001), ischemic heart disease (OR: 3.25 95 CI 1.02–10.40; <i>p</i> = 0.04), lung manifestations (OR: 4.48 95 CI 1.44–13.94; <i>p</i> = 0.01), and hematological manifestations (OR: 2.07 95 CI 1.13–3.79; <i>p</i> = 0.01), and with a reduced risk of neuropsychiatric manifestations (OR: 0.42 95 CI 0.22–0.80; <i>p</i> = 0.008). Serum IL-4 was negatively correlated with CRP (<i>p</i> = 0.003), and elevated serum IL-4 levels > 0.17 mg/L were associated with a reduced risk of mucocutaneous manifestations (OR: 0.48 95 CI 0.26–0.90; <i>p</i> = 0.02). In SLE patients, elevated serum levels of sTfR were associated with an increased risk of cardiovascular, pulmonary, and hematological manifestations, and with a decreased risk of neuropsychiatric manifestations. In contrast, elevated serum IL-4 levels were associated with a decreased risk of mucocutaneous manifestations.