Lilla Soós

Accelerated Atherosclerosis in Rheumatoid Arthritis

Abstract:  Cardiovascular disease is a leading cause of mortality in rheumatoid arthritis (RA). Endothelial dysfunction often precedes manifest atherosclerosis. Both traditional, Framingham risk factors and inflammation‐associated factors are involved in RA‐associated atherosclerosis. Among imaging techniques, the early determination of common carotid intima‐media thickness (ccIMT), flow‐mediated vasodilation (FMD), and nitroglycerine‐mediated vasodilation (NMD) may be useful to determine atherosclerosis and endothelial dysfunction. We and others found increased ccIMT and impaired FMD in RA patients. Among immunological and metabolic laboratory markers, anticyclic citrullinated peptide (anti‐CCP) antibodies, IgM rheumatoid factor, circulating immune complexes, pro‐inflammatory cytokines including tumor necrosis factor‐α (TNF‐α) and interleukin‐6 (IL‐6), Th0/Th1 T cells, homocysteine, dyslipidemia, decreased folate and vitamin B12 production, and impaired paraoxonase activity may all be involved in the development of vascular disease in RA. The early diagnosis of endothelial dysfunction and atherosclerosis, active immunosuppressive treatment, the use of drugs that control atherosclerosis, changes in sedentary lifestyle, and the close follow‐up of RA patients may help to minimize cardiovascular risk in these individuals.

Anti-Citrullinated Protein Antibodies in Rheumatoid Arthritis: As Good as it Gets?

Anti-citrullinated protein antibodies (ACPAs) have recently emerged as sensitive and specific serological markers of rheumatoid arthritis (RA), providing superior alternative of the rheumatoid factor (RF) test in the laboratory diagnostics of RA. The first members of this autoantibody family were anti-perinuclear factor (APF) and anti-keratin antibodies (AKA). It became evident that both APF and AKA recognize citrullinated epitopes of filaggrin. Citrullination is a post-translational modification of arginine by deimination, physiologically occurring during apoptosis, inflammation or keratinization. The presence of several citrullinated proteins has been demonstrated in the RA synovium. The identification of citrullinated epitopes as targets for anti-filaggrin antibodies led to the development of the first and later second generation anti-cyclic citrullinated peptide (anti-CCP) antibody assays. The widely used anti-CCP2 assays have high diagnostic sensitivity and specificity, and they also show important predictive and prognostic value in RA. The anti-Sa antibody has been identified a decade ago; however, recent studies confirmed that anti-Sa is directed against citrullinated vimentin, hence it is a new member of the family of ACPAs. The newly developed anti-mutated citrullinated vimentin (anti-MCV) assay has similar diagnostic performance than the anti-CCP2 ELISA; however, the diagnostic spectrum of the anti-MCV test is somewhat different from that of anti-CCP2. It’s especially useful in the diagnosis of RA in RF and anti-CCP2 seronegative patients. The combined application of anti-CCP2 and anti-MCV assays can improve the laboratory diagnostics of RA. The family of ACPAs is expected to expand; there is an increasing need for developing new diagnostic strategies after careful evaluation of the characteristics of the available assays.

New classification of the shared epitope in rheumatoid arthritis: impact on the production of various anti-citrullinated protein antibodies

OBJECTIVE HLA-DR [shared epitope (SE)] alleles have recently been re-classified into S1, S2, S3P and S3D groups. S2 and S3P have been associated with increased risk for RA. We assessed the impact of S1, S2, S3P and S3D alleles on anti-citrullinated protein antibody (ACPA) production. Instead of comparing allele-carriers to non-carriers, we studied each allele group individually, using the X/X (non-SE) genotype as reference. METHODS Serum and genomic DNA samples of 91 RA patients and 78 healthy controls were obtained. Various ACPAs and IgM RF were determined by ELISA. HLA-DRB1 genotyping and subtyping was performed by PCR. HLA-DRB1 alleles were re-classified as described above. Correlations between SE and ACPAs were determined. RESULTS Not only S2 and S3P, but, to a lesser extent, S1 and S3D alleles also predisposed to anti-cyclic citrullinated peptide (CCP) production (P < 0.0001, P = 0.004, P = 0.01 and P = 0.027, respectively), with the following hierarchy of association: S2+S3P > S1+S3D > X/X. Similar associations were observed for anti-citrullinated vimentin. Anti-citrullinated fibrinogen (CF) exerted a different association pattern with the strongest correlation with S1 alleles [odds ratio (OR) 16.00; P = 0.05]. In addition, HLA-DRB1*15 alleles may represent a special predisposing effect for anti-CF antibody production. Finally, in this study, RF production was associated only with the HLA-DRB1*0401 SE allele (P = 0.04). CONCLUSIONS Our approach of comparing individual S allele carriers with X/X genotype patients allowed us to perform unequivocal analyses and demonstrate new associations. Thus, novel subgroups of RA could be identified with potential relevance for prognosis and therapy.

Increased production of the soluble tumor-associated antigens CA19-9, CA125, and CA15-3 in rheumatoid arthritis: Potential adhesion molecules in synovial inflammation?

Abstract:  Some tumor‐associated antigens (TAAs) are expressed on inflammatory cells. We previously detected carcinoembryonic antigen (CEA; CD66) in the rheumatoid (RA) synovium. The production of CEA, CA19‐9, CA125, and CA15.3, may be increased in patients with RA, scleroderma, lupus, and Sjögrens syndrome (SS). Some of these TAAs contain sialylated carbohydrate motifs and they are involved in tumor‐associated cell adhesion and metastasis. We assessed levels of TAAs in the sera of RA patients and healthy subjects. Serum TAA levels were correlated with disease markers including serum rheumatoid factor (RF), C‐reactive protein (CRP), and anti‐CCP antibody levels, DAS28, age disease duration. TAAs including CEA, CA15‐3, CA72‐4, CA125, and CA19‐9, and neuron‐specific enolase (NSE) were assessed by immunoassay in the sera of 75 patients with RA and 50 age‐ and sex‐matched healthy controls. Normal upper limits for these TAAs were 3.4 μg/L, 25 kU/L, 6.9 kU/L, 35 kU/L, 34 kU/L, and 16.3 μg/L, respectively. There were significantly more RA patients showing abnormally high levels of CA125 (10.8% versus 7.1%), CA19‐9 (8.1% versus 0%), and CA15‐3 (17.6% versus 14.3%) in comparison to controls (P < 0.05). The mean absolute serum levels of CA125 (23.9 ± 1.8 versus 16.8 ± 2.2 kU/L) and CA19‐9 (14.2 ± 1.2 versus 10.5 ± 1.6 kU/L) were also significantly higher in RA compared to controls (P < 0.05). Among RA patients, serum CEA showed significant correlation with RF (r= 0.270; P < 0.05). None of the assessed TAAs showed any correlation with CRP, anti‐CCP, DAS28, age or disease duration. The concentration of some TAAs may be elevated in the sera of patients with established RA in comparison to healthy subjects. CEA, CA19‐9, CA125, and CA15‐3 contain carbohydrate motifs and thus they may be involved in synovitis‐associated adhesive events. Furthermore, some TAAs, such as CEA, may also correlate with prognostic factors, such as serum RF levels.

Associations of HLA-shared epitope, anti-citrullinated peptide antibodies and lifestyle-related factors in Hungarian patients with rheumatoid arthritis: data from the first Central-Eastern European cohort.

Joint Bone Spine - In Press.Proof corrected by the author Available online since mardi 5 juillet 2011