Ja-Young Jeon

Cytokine IL-6 and IL-10 as biomarkers in systemic lupus erythematosus.

There is a great deal of interest in the identification of biomarkers that are closely associated with disease activity in systemic lupus erythematosus (SLE), but few biomarkers have been validated. Cytokines play an important role in the pathogenesis of SLE. Therefore, we evaluated the levels of cytokines and their possible association with disease activity. In the present study, we found that the SLE patients had higher IL-6, IL-10, IL-12, and IFN-γ levels, but lower IL-2, than normal controls. Serum IL-6 level was significantly elevated in active SLE patients and correlated with the SLE activity index (SLEDAI), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). Serum IL-10 level was also significantly elevated in active SLE patients and revealed positive correlation with SLEDAI and anti-double-stranded DNA (dsDNA) titer and negative correlation with C3, C4, and lymphocyte counts. No significant differences in the levels of cytokines were observed between SLE patients with nephritis and those without nephritis. These data suggest that IL-6 and IL-10 may be a useful biomarker for disease activity in SLE.

C-reactive Protein Is a More Sensitive and Specific Marker for Diagnosing Bacterial Infections in Systemic Lupus Erythematosus Compared to S100A8/A9 and Procalcitonin

Objective. C-reactive protein (CRP), S100A8/A9, and procalcitonin have been suggested as markers of infection in patients with systemic lupus erythematosus (SLE). We investigated the clinical significance of these factors for indication of infection in SLE. Methods. Blood samples were prospectively collected from 34 patients with SLE who had bacterial infections and 39 patients with SLE who had disease flares and no evidence of infection. A second set of serum samples was collected after the infections or flares were resolved. Results. CRP levels of SLE patients with infections were higher than those with flares [5.9 mg/dl (IQR 2.42, 10.53) vs 0.06 mg/dl (IQR 0.03, 0.15), p < 0.001] and decreased after the infection was resolved. S100A8/A9 and procalcitonin levels of SLE patients with infection were also higher [4.69 μg/ml (IQR 2.25, 12.07) vs 1.07 (IQR 0.49, 3.05) (p < 0.001) and 0 ng/ml (IQR 0–0.38) vs 0 (0–0) (p < 0.001), respectively]; these levels were also reduced once the infection disappeared. In the receiver-operating characteristics analysis of CRP, S100A8/A9, and procalcitonin, the area under the curve was 0.966 (95% CI 0.925–1.007), 0.732 (95% CI 0.61–0.854), and 0.667 (95% CI 0.534–0.799), respectively. CRP indicated the presence of an infection with a sensitivity of 100% and a specificity of 90%, with a cutoff value of 1.35 mg/dl. Conclusion. Our data suggest that CRP is the most sensitive and specific marker for diagnosing bacterial infections in SLE.

Serum S100A8/A9, But Not Follistatin-like Protein 1 and Interleukin 18, May Be a Useful Biomarker of Disease Activity in Adult-onset Still’s Disease

Objective. S100A8/A9, follistatin-like protein 1, and interleukin 18 (IL-18) have been suggested as biomarkers of disease activity in patients with systemic juvenile idiopathic arthritis or adult-onset Still’s disease (AOSD). We investigated the clinical significance of these factors in AOSD. Methods. Blood samples were collected from 36 patients with AOSD, 40 patients with rheumatoid arthritis (RA), and 33 healthy controls. Of the patients with AOSD, followup samples were collected from 16 patients after resolution of disease activity. Results. Serum levels of S100A8/A9 (11.77 ± 8.84 μg/ml) in AOSD patients were higher than those in RA patients (3.53 ± 3.43 μg/ml; p < 0.001) and controls (2.49 ± 1.83 μg/ml; p < 0.001). Follistatin-like protein 1 levels in AOSD were not different from those in RA and controls. IL-18 levels in AOSD (7560.3 ± 7577.6 pg/ml) were higher than those in RA (217.7 ± 292.1 pg/ml; p < 0.001) and controls (139.2 ± 86.2 pg/ml; p < 0.001). The sensitivity and specificity of IL-18 for diagnosing AOSD was highest with a cutoff value of 366.1 pg/ml. Serum S100A8/A9 correlated with leukocyte count, erythrocyte sedimentation rate, C-reactive protein, ferritin, and systemic disease score; however, IL-18 correlated only with ferritin and systemic disease score. S100A8/A9 was decreased after disease activity was resolved in followup of AOSD patients (9.96 ± 7.35 μg/ml in active AOSD vs 3.6 ± 4.77 μg/ml in resolved cases; p = 0.001). The change of S100A8/A9 was well correlated with that of systemic disease score. Conclusion. The data suggest that serum S100A8/A9 may be a useful biomarker for evaluating disease activity in patients with AOSD.

Interleukin 6 Gene Polymorphisms Are Associated with Systemic Lupus Erythematosus in Koreans

Objective. Interleukin 6 (IL-6) gene polymorphisms are known to play a role in chronic inflammatory disorders. We searched for polymorphisms in the IL-6 gene and described their pathogenic role in Korean patients with systemic lupus erythematosus (SLE). Methods. Genomic DNA was extracted from 151 patients with SLE and 151 controls, and about 1.4 kb-sized IL-6 genes located between promoter region and exon 2 region were amplified by polymerase chain reaction. The promoter activity was analyzed by luciferase reporter assay in Hep3B cells and HeLa cells. Results. We identified 4 single-nucleotide polymorphisms (SNP; −572 C > G, −278 A > C in the promoter, and 330 T > G, and 334 A > T in exon 2) and a −373 AnTn tract polymorphism in the IL-6 gene. The genotype frequency, −373 A10T11, −278 C, and 334 T allele were significantly associated with SLE (p < 0.001, p = 0.03 and p = 0.005, respectively). Patients with SLE carrying the −572 G allele had anti-dsDNA more frequently (p = 0.007). In addition, thrombocytopenia was significantly more common in patients carrying the −278 C allele (p = 0.006). In the haplotype analysis, patients with SLE had more frequently haplotype HT3 (CA10T11ATA, dominant model, p = 0.012) that was associated with arthritis, leukopenia, anti-dsDNA, and hypocomplementemia. Promoter reporter structures carrying the −278 C allele displayed significantly higher promoter activity than the −278 A allele in Hep3B cells (p < 0.001) and HeLa cells (p < 0.001). Conclusion. These data suggest that IL-6 gene polymorphisms are associated with disease susceptibility and phenotype of SLE. In addition, promoter polymorphisms may be involved in regulation of IL-6 expression.

Serum S100A12 May Be a Useful Biomarker of Disease Activity in Adult-onset Still’s Disease

Objective. S100A12 and soluble receptor for advanced glycation endproducts (sRAGE) have been suggested as biomarkers of disease activity in patients with systemic juvenile idiopathic arthritis. We investigated the clinical significance of these markers in adult-onset Still’s disease (AOSD). Methods. Blood samples were collected from 37 patients with active AOSD and 38 healthy controls (HC). Of the patients with AOSD, followup samples were collected from 19 patients after resolution of disease activity. Results. Serum S100A12 (547.9 ± 148.4 ng/ml) in patients with AOSD was higher than those of HC (272.3 ± 133 ng/ml, p < 0.001). The sRAGE levels of AOSD (514.1 ± 273.6 pg/ml) were lower than those of HC (850.3 ± 405.8 pg/ml, p < 0.001). Serum S100A12 correlated with serum sRAGE (r = −0.228, p = 0.049). Serum S100A12 correlated with erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), ferritin, and systemic score, whereas sRAGE did not correlate with any disease activity markers. In addition, the level of S100A12 was decreased after disease activity was resolved in followed-up patients with AOSD (505.7 ± 161.3 ng/ml vs 361.3 ± 162.5 ng/ml, p = 0.01). Further, the change of S100A12 was well correlated with that of ESR, CRP, and systemic score. Conclusion. S100A12 levels showed strong correlations with known disease activity markers such as ESR, CRP, ferritin, and systemic score. In the followup patients with AOSD, most patients showed decreased S100A12 levels after resolution of disease activity. These results suggest that serum S100A12 can be a reliable clinical marker for monitoring disease activity and treatment response.

Beta2-Microglobulin Can Be a Disease Activity Marker in Systemic Lupus Erythematosus

Background:To investigate the clinical significance of beta2-microglobulin in Korean patients with systemic lupus erythematosus (SLE). Methods:Blood samples were collected from patients with SLE (n = 100) and normal healthy controls (n = 50). The level of beta2-microglobulin was investigated by enzyme-linked immunosorbent assay. Serial samples from SLE patients were collected at 4.2 ± 2.6 months after first sampling. Results:The beta2-microglobulin levels of the SLE patients (2.64 ± 0.11 &mgr;g/mL) were higher than the normal controls (2.14 ± 0.04 &mgr;g/mL, P < 0.001). The patients with SLE with serositis, oral ulcer, or lupus nephritis had significantly higher beta2-microglobulin levels than those without, respectively. A significant correlation was found between the beta2-microglobulin level and each of anti-dsDNA antibody, hemoglobin, complement, and SLE Disease Activity Index. In sequential sampling of patients with SLE, a positive correlation was found between the change of the SLE Disease Activity Index and the change of the beta2-microglobulin levels. Conclusions:These data suggest that the measurement of beta2-microglobulin seem to be a useful addition to the laboratory tests that can help in assessment of disease activity of SLE.

The antichromatin antibodies can be useful as a diagnostic tool and disease activity marker of systemic lupus erythematosus in Koreans

We have investigated the clinical utility of antichromatin antibodies for the diagnosis of SLE and as a marker of disease activity in Korean SLE patients. Blood samples were collected from SLE patients, lupus syndrome patients having only two or three of ACR classification criteria for SLE and normal controls. The level of antichromatin antibody was measured by enzyme linked immunosorbent assay and expressed as arbitrary unit. The antichromatin antibody levels of the SLE and lupus syndrome patients were higher than NC. The antichromatin antibody levels were significant higher in SLE patients with arthritis. A significant correlation was found between the level of antichromatin antibodies and each of anti-dsDNA antibody, leukopenia, complement and SLEDAI. The change of antichromatin antibody levels showed a positive correlation with the change of SLEDAI in serial samples. These data suggest that the antichromatin antibodies appear to be a useful laboratory test that can help in the diagnosis and assessment of SLE.

Circulating hsa-miR-30e-5p, hsa-miR-92a-3p, and hsa-miR-223-3p may be novel biomarkers in systemic lupus erythematosus.

MicroRNAs (miRNAs) are short, non‐coding RNAs that regulate gene expression at the post‐transcriptional level, which can be measured in cells, tissues, and body fluids including plasma. Differences in miRNA expression levels suggest an epigenetic mechanism and changed expression levels are emerging as a novel biomarker for various diseases. We attempted to identify circulating miRNAs associated with susceptibility to systemic lupus erythematosus (SLE) in the Korean population and elucidate their significance for clinical phenotype. An expression profiling analysis using miRNA polymerase chain reaction (PCR) array was conducted with pooled miRNA from 10 patients with SLE and 10 healthy controls (HCs). Nine miRNAs were differentially expressed between the SLE and HC. To verify this, we performed quantitative PCR for various miRNA from SLE patients (n = 70) and HCs (n = 40). The hsa‐miR‐30e‐5p, hsa‐miR‐92a‐3p, and hsa‐miR‐223‐3p were significantly up‐regulated in plasma of SLE patients (P = 0.048, P = 0.039, and P = 0.046, respectively). Especially, the hsa‐miR‐223‐3p was significantly associated with oral ulcer (P < 0.001) and lupus anticoagulant (P = 0.031). Thus, plasma hsa‐miR‐30e‐5p, hsa‐miR‐92a‐3p, and hsa‐miR‐223‐3p may be promising novel biomarkers in the diagnosis and clinical manifestation of SLE.

Salivary cortisol levels, but not salivary α‐amylase levels, are elevated in patients with rheumatoid arthritis irrespective of depression

Stress is recognized as an important factor in the etiology of rheumatoid arthritis (RA). Therefore, we explored multiple aspects of stress in RA patients.

Autoantibodies to C-reactive protein in incomplete lupus and systemic lupus erythematosus.

Objective Anti-C-reactive protein (CRP) antibodies have been described in patients with systemic lupus erythematosus (SLE). We investigated the potential of the anti-CRP antibody as a marker for disease activity in SLE patients and as a predictor of progression to SLE in patients with incomplete lupus. Methods Immunoglobulin G anti-CRP antibody levels were measured using an enzyme-linked immunosorbent assay. Results Patients with incomplete lupus exhibited clinical and immunologic characteristics different from those in SLE patients: no serositis and alopecia, more common oral ulcers and arthritis, lower disease activity index, lower positivity for antinuclear and anti–double-strand DNA antibodies, and higher complement levels. Anti-CRP antibody levels were higher in SLE patients (35.6 [35.1] AU) than in patients with incomplete lupus (23.1 [25.8] AU, P = 0.016) and normal controls (21.0 [14.3] AU, P < 0.001). Anti-CRP antibody was significantly higher in SLE patients with arthritis and correlated with disease activity markers, including antichromatin antibody. However, no difference in anti-CRP antibody levels was observed between patients with incomplete lupus that progressed to SLE and those whose did not. Conclusion These data suggest that anti-CRP antibodies can neither be used as biomarkers in SLE nor predict SLE progression in patients with incomplete lupus.