Publisher Correction: Metabolites of type I, II, III, and IV collagen may serve as markers of disease activity in axial spondyloarthritis.

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Metabolites of type I, II, III, and IV collagen may serve as markers of disease activity in axial spondyloarthritis.

Local inflammation in axial spondyloarthritis (axSpA) leads to the release of collagen metabolites from the disease-affected tissue. We investigated whether collagen metabolites were associated with disease activity and could distinguish non-radiographic(nr)-axSpA from ankylosing spondylitis (AS). A total of 193 axSpA patients (nr-axSpA, n = 121 and AS, n = 72) and asymptomatic controls (n = 100) were included. Serum levels of metalloproteinase (MMP)-degraded collagen type I (C1M), type II (C2M), type III (C3M) and type IV (C4M2) were quantified by enzyme-linked immunosorbent assay (ELISA). All metabolites were higher in axSpA than in controls (all p < 0.001). Serum levels of C1M, C3M, and C4M2 were increased in AS compared to nr-axSpA (43.4 ng/mL vs. 34.6; p < 0.001, 15.4 vs. 12.8; p = 0.001, and 27.8 vs. 22.4; p < 0.001). The best metabolite to differentiate between axSpA and controls was C3M (AUC 0.95; specificity 92.0, sensitivity 83.4). C1M correlated with ASDAS-CRP in nr-axSpA (ρ = 0.37; p < 0.001) and AS (ρ = 0.57; p < 0.001). C1M, C3M, and C4M2 were associated with ASDAS-CRP in AS and nr-axSpA after adjustment for age, gender, and disease duration. Serum levels of collagen metabolites were significantly higher in AS and nr-axSpA than in controls. Moreover, the present study indicates that collagen metabolites reflect disease activity and are useful biomarkers of axSpA.

Metabolites of C-reactive protein and vimentin are associated with disease activity of axial spondyloarthritis.

OBJECTIVES: Non-radiographic (nr-axSpA) and radiographic (AS) forms of axial spondyloarthritis (axSpA) share clinical features, but have different radiographic patterns. Radiographic progression is not associated with the current disease activity biomarkers. We investigated a matrix metalloproteinase mediated metabolite of C-reactive protein (CRPM) and two biomarkers of citrullinated vimentin (VICM and anti-MCV) as novel biomarkers of disease activity. METHODS: AxSpA patients (n=121 nr-axSpA and n=72 AS) were characterised by activity (AS disease activity score with CRP [ASDAS-CRP], Bath AS disease activity index [BASDAI] and functional index [BASFI]), radiographic scores and quality of life questionnaires. CRPM, VICM and anti-MCV levels were analysed by ELISA in serum. Asymptomatic controls (n=100) were used as reference. Multiple regression investigated association with disease activity and diagnostic potential. RESULTS: CRPM and VICM levels were increased in AS compared to nr-axSpA (11.9nM vs. 10.2nM, p<0.001 and 4.92nM vs. 3.77nM, p=0.0025). Anti-MCV was similar in both axSpA subgroups, but lowered in controls. In nr-axSpA, CRPM correlated with CRP (ρ=0.33, p<0.001) and VICM (ρ=0.29, p=0.001); in AS, VICM correlated with CRP (ρ=0.34, p=0.0032) and ESR (ρ=0.38, p<0.001). ASDAS-CRP correlated with CRPM and anti-MCV, but when adjusting for CRP the correlation only remained with CRPM. CRPM and VICM separated the subgroups with odds ratios of 1.19 and 1.10 adjusted for age, gender, BMI, and disease duration. VICM lost significance when adjusting for CRP. CONCLUSIONS: CRPM was associated with disease activity in axSpA, and CRPM and VICM separated the axSpA groups. This study indicates that serological biomarkers may be novel biomarkers in axSpA.

Circulating cytokine pattern and factors describing rheumatoid arthritis: IL-15 as one of the biomarkers for RA?

The aim of study was to examine relationship among levels of cytokines (IL-6, IL-13, IL-15, TNF-α) and chemokine (IL-8), production of autoantibodies, radiographic progression, and factors describing rheumatoid arthritis (RA). A total of 156 RA patients according to ACR criteria, and 55 control subjects were recruited into study. We observed higher levels of IL-15 within RA patients compared to healthy controls. Correlations among cytokine levels and the measures of rheumatoid factors, anti-CCP, measures of disease activity, and radiographic progression were observed. We conclude that IL-15 level in circulation could serve as one of the biomarkers for RA detection.

RANTES, MCP-1 chemokines and factors describing rheumatoid arthritis.

The MCP-1/CCL2 as well as RANTES/CCL5 chemokines are potent chemoattractants involved in immunoregulatory and inflammatory processes of rheumatoid arthritis. Recent studies demonstrated elevated levels of MCP-1 and RANTES in plasma, synovial fluid, and the synovial tissue of patients with RA. To examine the relationship among MCP-1 and RANTES single nucleotide polymorphisms and circulating levels and rheumatoid arthritis (RA), a total of 156 RA patients and 125 controls were recruited into the study. An association of -855 C/G MCP-1 polymorphism to IgM RF within the RA patients was observed. The lowest circulating levels of RANTES were observed in the AA variant of RANTES -403 G/A polymorphism. Furthermore, an association of -403 AA variant to circulating levels of IL-15 and IL-10 was found. No associations of factors describing rheumatoid arthritis (RFs, ANA, anti-CCP-positive/negative, DAS 28 score and number of swollen joints) with MCP-1 levels, genotype distribution, allelic frequencies and/or frequencies of haplotypes composed of all three studied polymorphisms in promoter region of MCP-1, and RANTES polymorphism were observed. We conclude that the RANTES promoter polymorphism is associated to circulating levels of RANTES, IL15 and IL10. However, our findings suggest that polymorphisms in the MCP-1 and RANTES gene promoters do not contribute significantly to the interindividual RA susceptibility and/or severity in Caucasians.

Association of polymorphisms in interleukin-10 gene promoter with autoantibody production in patients with rheumatoid arthritis.

Interleukin-10 (IL-10) is a major anti-inflammatory cytokine that plays a crucial role in the regulation of the immune system. Allelic polymorphisms in the IL-10 gene promoter may contribute to the regulation of autoantibody production. To examine the association between both individuals IL-10 single nucleotide polymorphisms and the production of autoantibodies and the radiographic progression of rheumatoid arthritis (RA), a total of 144 RA patients were recruited into the study. We found significant differences in genotype distribution of the -1082G/A polymorphism between IgG, IgA, and IgM rheumatoid factor(RF)-positive/negative RA patients. We also found significant differences in allelic frequencies of the -3575T/A, -819C/T, and -592A/C polymorphisms between anticyclic citrullinated peptide (anti-CCP)-positive/negative RA patients. The haplotype TGAATA was found to be less frequent within anti-CCP-positive RA patients. Results obtained in this study provide evidence of an association between polymorphisms in IL-10 gene promoter and the production of autoantibodies in RA patients.

Association of the -1082 G/A promoter polymorphism of interleukin-10 gene with the autoantibodies production in patients with rheumatoid arthritis.

Interleukin-10 (IL-10) is an immunoregulatory cytokine, usually considered to mediate the downregulation of the inflammatory response in rheumatoid arthritis (RA). Some effects of IL-10 are not anti-inflammatory; for example, the activation of B cells to promote autoantibody production. Allelic polymorphisms located in the promoter region of the IL-10 gene may contribute to the regulation of autoantibodies production. To examine the putative association between the -1082 G/A polymorphism in the promoter region of the IL-10 gene and the susceptibility to disease onset and severity of RA, a total of 144 patients with RA diagnosed according to the revised criteria of the American College of Rheumatology for RA were consecutively recruited into the study. Radiographic progression of RA was scored according to the Sharp/van der Heijde method. Serum levels of rheumatoid factors (RFs) were measured by enzyme-linked immunosorbent assay. Polymerase chain reaction amplification was used for the analysis of the promoter polymorphism of the IL-10 gene. We observed significant differences in genotype distribution of the -1082 G/A polymorphism between IgM RF, IgA RF, and IgG RF positive/negative subgroups of RA patients, with higher prevalence of the GG genotype within IgM RF (Pg = 0.006), IgA RF (Pg = 0.05), and IgG RF (Pg = 0.007) negative RA patients. Results obtained in this study provide the evidence of an association between the -1082 G/A polymorphism in the IL-10 gene promoter and the production of RFs in RA patients.

Polymorphism in the tumor necrosis factor-alpha gene promoter is associated with severity of rheumatoid arthritis in the Czech population.

Rheumatoid arthritis (RA) is a model of multigenic inflammatory disorder in which tumor necrosis factor-alpha (TNF-alpha) plays an important role. Genetic factors may be implicated in the susceptibility to disease initiation as well as in severity of disease course. Elevated levels of TNF-alpha in the plasma and synovial fluid from RA patients may be associated with polymorphisms in the promoter region of the TNF-alpha gene. The aim of this study was to elucidate putative association between the -308 G/A polymorphism in the promoter region of the TNF-alpha gene and susceptibility to onset and severity of RA. A total of 130 RA patients and a control group of 150 healthy subjects with similar age and sex distribution were available for the study. All patients fulfilled the American College of Rheumatology revised criteria for RA. RA patients had a disease duration of at least 2 years. Radiographs of both hands of all RA patients were scored with the Steinbrocker method. There were 15 patients of stage I (nonerosive form) of RA and 114 patients of stages II-IV (erosive form). To assess the RA patient's functional ability, the Health Assessment Questionnaire (HAQ) was used. The -308 G/A promoter polymorphism of the TNF-alpha gene was detected by polymerase chain reaction and restriction fragment length polymorphism analysis. No differences in genotype distribution and allelic frequences of -308 G/A TNF-alpha promoter polymorphism have been found between RA patients and the control group. Significant differences have been observed within the RA group divided according to the radiographic progression of disease based on the Steinbrocker radiographic score and functional ability (HAQ). These results suggest an association of the -308 G/A polymorphism of the TNF-alpha gene with the severity of RA.

Association of the 5A/6A promoter polymorphism of the MMP-3 gene with the radiographic progression of rheumatoid arthritis.

Matrix metalloproteinases (MMPs) as a family of zinc-dependent endopeptidases have been involved in remodeling the extracellular matrix (ECM) in rheumatoid arthritis (RA). In RA patients synovial fluid and serum include enhanced levels of MMP-3. The 5A/6A polymorphism in the MMP-3 gene promoter can contribute to the severity of RA on account of a higher promoter activity of the 5A allele in vitro. The aim of the study was to associate the 5A/6A polymorphism of the MMP-3 gene with radiographic progression of RA. A total of 128 RA patients according to the ACR criteria were available for the study. Radiographs of both hands, obtained from all RA patients, were scored using the modified Sharp/van der Heijde method and the Steinbrocker method. The total Sharp score (TSS) and the annual radiographic progression rate (TSS/year) were calculated. Significant association with the 5A/6A polymorphism was found between patients with TSS/year 1.00 in allelic frequencies (Pa = 0.046) and also in genotype distribution (Pg = 0.04). Compared to other genotypes the prevalence of 5A/5A genotype was lower within patients with TSS/year