The enzymes α-2,6-sialyltransferase 1 (ST6Gal1), neuraminidase 1 (Neu1), α-2,3-sialyltransferase 1 (ST3Gal1), and neuraminidase 3 (Neu3) are known to affect immune cell function. However, it is not ...known whether the levels of these enzymes relate to remission definitions or differentiate American College of Rheumatology (ACR), European League Against Rheumatism (EULAR), and Simplified Disease Activity Index (SDAI) responses in patients with rheumatoid arthritis (RA). We measured the ST6Gal1, Neu1, ST3Gal1, and Neu3 levels of B cells and monocytes in RA patients and correlated the cells’ enzyme levels/ratios with the improvement in the ACR, EULAR and SDAI responses and with the two remission definitions. The difference in the B-cell Neu1 levels differed between the ACR 70% improvement and non-improvement groups (p = 0.043), between the EULAR good major response (improvement) and non-good response groups (p = 0.014), and also between the SDAI 50% or 70% improvement and non-improvement groups (p = 0.001 and 0.018, respectively). The same held true when the RA patients were classified by positive rheumatoid factor or the use of biologics. The B-cell Neu1 levels significantly indicated 2005 modified American Rheumatism Association and 2011 ACR/EULAR remission definitions (area under the curve (AUC) = 0.674 with p = 0.001, and AUC = 0.682 with p < 0.001, respectively) in contrast to the CRP and ESR (all AUCs < 0.420). We suggest that B-cell Neu1 is superior for discriminating ACR, EULAR, and SDAI improvement and is good for predicting two kinds of remission definitions.
Objective
To study the association of α2,6-sialic acid (SIA) content in serum IgG anti-dsDNA with human systemic lupus erythematosus disease activity index (SLEDAI) and the effect of sialylated and ...desialylated (deSIA) IgG anti-dsDNA on lupus B cells.
Methods
Blood from lupus patients was collected to determine the ratio of SIA in isolated IgG anti-dsDNA over serum IgG anti-dsDNA (SIA/IgG anti-dsDNA) ratios, which were plotted against SLEDAI using a receiver-operating-characteristics curve. Lupus B cells were cultured in vitro with chimeric sialylated IgG anti-dsDNA and its deSIA form. Culture supernatants were assayed for anti-inflammatory IL-10 and SIA/IgG anti-dsDNA ratios, which were compared among different pre-treatment groups using t-tests.
Results
The area-under-the-curve (AUC) for anti-dsDNA levels against SLEDAI was 0.791 positively (95% confidence interval C.I.: 0.699–0.884) and SIA/IgG anti-dsDNA ratios against SLEDAI yielded an AUC of 0.705 inversely (95% C.I: 0.601–0.809): not significantly different. SIA/IgG anti-dsDNA ratios discriminated significantly between patients without and patients with proteinuria (p = .046). SIA/IgG anti-dsDNA ratios correlated significantly and positively with serum C3c and C4 levels. Pre-treatment with IgG anti-dsDNA and its immune complexes (dsDNA/IgG anti-dsDNA IC) induced higher IL-10 from lupus B cells than medium pre-treatment (most p < .01 from day 2 to day 5 culture). DeSIA IgG anti-dsDNA IC induced lower IL-10 (p < .05) and lower SIA/IgG anti-dsDNA ratios (p < .001) from lupus B cells than medium and dsDNA pre-treatment.
Conclusion
α2,6-SIA/IgG anti-dsDNA ratios inversely forecasted SLEDAI scores. Possible mechanisms may be due to the different effects of sialylated and deSIA IgG anti-dsDNA on lupus B cells in terms of IL-10 secretion and SIA/IgG anti-dsDNA ratios.
Allopurinol, a commonly prescribed medication for gout and hyperuricemia, is a frequent cause of severe cutaneous adverse reactions (SCAR), which include the drug hypersensitivity syndrome, ...Stevens-Johnson syndrome, and toxic epidermal necrolysis. The adverse events are unpredictable and carry significant morbidity and mortality. To identify genetic markers for allopurinol-SCAR, we carried out a case-control association study. We enrolled 51 patients with allopurinol-SCAR and 228 control individuals (135 allopurinol-tolerant subjects and 93 healthy subjects from the general population), and genotyped for 823 SNPs in genes related to drug metabolism and immune response. The initial screen revealed strong association between allopurinol-SCAR and SNPs in the MHC region, including BAT3 (encoding HLA-B associated transcript 3), MSH5 (mutS homolog 5), and MICB (MHC class I polypeptide-related sequence B) ($P<10^{-7}$). We then determined the alleles of HLA loci A, B, C, and DRB1. The HLA-B*5801 allele was present in all (100%) 51 patients with allopurinol-SCAR, but only in 20 (15%) of 135 tolerant patients odds ratio 580.3 (95% confidence interval, 34.4-9780.9); corrected P value=4.7× 10-24 and in 19 (20%) of 93 of healthy subjects 393.51 (23.23-6665.26); corrected P value=8.1× 10-18. HLA alleles A*3303, Cw*0302, and DRB1*0301 were in linkage disequilibrium and formed an extended haplotype with HLA-B*5801. Our results indicated that allopurinol-SCAR is strongly associated with a genetic predisposition in Han Chinese. In particular, HLA-B*5801 allele is an important genetic risk factor for this life-threatening condition.
We attempted to determine whether the level of enzymes sialyltransferase (ST) and neuraminidase (Neu) and sialic acid (SIA) in patients with systemic lupus erythematosus (SLE) correlates with the SLE ...Disease Activity Index (SLEDAI) and in patients with rheumatoid arthritis (RA) correlates with the Disease Activity Score28 (DAS28).
We examined cell-surface levels of ST6Gal-1, Neu1, ST3Gal-1, Neu3, α-2,6-SIA, and α-2,3-SIA by using fluorescent anti-enzyme antibodies, fluorescent-conjugated Sambucus nigra lectin, and fluorescent-conjugated Maackia amurensis lectin on blood cells in SLE and RA patients and assessed correlations of these levels with SLEDAI and with DAS28. Areas under the curve (AUC) were calculated for different variables against SLEDAI.
The B-cell ST3Gal-1/Neu3 ratio positively correlated with SLEDAI scores (ρ = 0.409 and P = 0.002, statistically significant after Bonferroni' correction for multiple analyses.). It was supported by the inverse correlation of B-cell Neu3 levels with SLEDAI scores (ρ = -0.264, P = 0.048). The B-cell ST3Gal-1/Neu3 ratio against SLEDAI yielded an AUC of 0.689, which was comparable to that of anti-dsDNA levels at 0.635. In contrast, both ST3Gal-1 and Neu3 levels of RA B cells (r = 0.376, P = 0.013; r = 0.425, P = 0.005, respectively) correlated positively with high disease-activity DAS28 scores.
B-cell ST3Gal-1/Neu3 ratios in SLE and B-cell ST3Gal-1 and Neu3 levels in RA with high disease-activity DAS28 scores correlated with disease activity measures and may be useful in monitoring disease activities.
This prospective one-year follow-up study was conducted from 835 visits in 178 rheumatoid arthritis (RA) patients. Tender-/swollen-joint count, Health Assessment Questionnaire Disability Index ...(HAQ-DI), Disease Activity Score 28-ESR (DAS28-ESR), DAS28-CRP, Simplified Disease Activity Index (SDAI) and DAS28-monocyte chemotactic protein-1 (DAS28-MCP-1) scores were obtained every 3 months. Radiographs of hands and feet were acquired at baseline and one year. We evaluated the correlation and accuracy of activity scores in predicting remission, HAQ-DI changes and radiographic changes. DAS28-MCP-1 correlated strongly with DAS28-ESR, DAS28-CRP and SDAI scores (0.830, 0.899 and 0.931, respectively, with all P < 0.001). Score changes of DAS28-MCP-1 were comparable to those of DAS28-ESR, DAS28-CRP and SDAI in predicting changes in HAQ-DI and bone erosion. DAS28-MCP-1 (<2.2) was better than DAS28-ESR (<2.6) in indicating modified American Rheumatism Association remission and 2011 American College of Rheumatology/European League Against Rheumatism remission (75.61% vs. 36.99% and 81.71% vs. 49.13%, respectively) with odds ratios of 5.28 and 4.62 (both P < 0.001), respectively. We compared DAS28-MCP-1 with SDAI (≦3.3) in indicating remission with odds ratios of 2.63 (P = 0.002) and 0.98, respectively (and DAS28-MCP-1 with DAS28-CRP < 2.5: 1.33 and 0.92). Therefore, DAS28-MCP-1 is useful as an alternative in assessing RA activity.
It is not clear whether immunoregulatory cytokines and cells are associated with Disease Activity Score 28 (DAS28) scores and ultrasound grades/scores. Here, we investigated the relationships between ...immunoregulatory cytokines or cells and different DAS28 scores or ultrasound grades/scores in patients with rheumatoid arthritis (RA). This study enrolled 50 RA patients (with 147 visits) who had remission/low/moderate DAS28-ESR scores (92% in remission and low disease activity) at baseline. Blood was collected and an ultrasound was performed three times in a year. Percentages of regulatory B cells and T regulatory type 1 cells and M2 macrophage numbers in the blood were examined. Plasma levels of 10 immunoregulatory cytokines IL-4, IL-5, IL-9, IL-10, IL-13, IL-27, IL-35, TGF-β1, sTNF-R1, and sTNF-R2 and monocyte chemotactic protein-1 (MCP-1) were assessed using ELISA assay. The correlations of cytokines and cells with different DAS28 scores and ultrasound grades were investigated, and cytokines and cells were compared between different categories of DAS28 scores and ultrasound grades. Plasma TGF-β1 levels were higher in the DAS28-ESR < 2.6 (remission) subgroup than in the DAS28-ESR ≥ 2.6 (nonremission) subgroup (p = 0.037). However, plasma TGF-β1 levels were higher in the high ultrasound grade subgroup than those in the low ultrasound grade subgroup (p = 0.007). The number of M2 macrophages was lower in the DAS28-MCP-1 < 2.2 subgroup than in the DAS28-MCP-1 ≥ 2.2 subgroup (p = 0.036). The levels of TGF-β1, sTNF-R2, IL-10, and IL-27 were higher in patients with high ultrasound grades than in those with low ultrasound grades. IL-27 was also higher in the nonremission DAS28-ESR subgroup than the remission one (p = 0.025). Moreover, sTNF-R1 levels in the 2011 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) remission subgroup were significantly lower than in the 2011 ACR/EULAR nonremission subgroup (p = 0.007). This trend was reflected in that lower sTNF-R1 levels correlated with low DAS28-MCP-1 scores (rho = 0.222, p = 0.007). We conclude that high plasma TGF-β1 levels indicate the DAS28-ESR remission (<2.6) subgroup and the high ultrasound grade subgroup. IL-27 probably connects the nonremission DAS28-ESR to high ultrasound grades. Low sTNF-R1 levels probably link low DAS28-MCP-1 scores with the 2011 ACR/EULAR remission subgroup. It suggests that incongruent immuno-inflammatory abnormalities exist between DAS28 scores and ultrasound grades, and are also dissimilar among various DAS28-formula categories. Therefore, this study may provide a basis for further research into individual cytokines and immunoregulatory cells behind each DAS28 formula and ultrasound grades/scores.
We assessed blood pentraxin 3 (PTX3) and macrophage chemotactic factor-1 (MCP-1) levels as indicators of disease activity in rheumatoid arthritis (RA) patients, because data on disease activity score ...28 (DAS28)-erythrocyte sedimentation rate (ESR) and DAS28-C-reactive protein (CRP) are still imperfect.
In 111 patients with RA, we examined longitudinal and cross-sectional correlations of blood PTX3, MCP-1, CRP, and ESR levels with measures of clinical arthritic activity, namely, swollen joint count (SJC), tender joint count (TJC), visual analog scale for general health (GH), DAS28, and adapted DAS28-MCP-1.
Blood MCP-1, but not PTX3, was significantly correlated with SJC, TJC, DAS28, and DAS28-CRP. DAS28-MCP-1 was strongly correlated with DAS28 (r = 0.984, P<0.001) and DAS28-CRP (r = 0.971, P<0.001), and modestly correlated with CRP (r = 0.350, P<0.001), and ESR (r = 0.386, P<0.001). Similarly, the duration of arthritic symptoms, but not sex, was significantly correlated with variables of arthritic activity. In particular, DAS28-MCP-1 significantly correlated with DAS28 during a 6-month period (r = 0.944, P<0.001; r = 0.951, P<0.001; r = 0.862, P<0.001; and r = 0.865, P<0.001 for month 0, 1, 3, and 6, respectively).
Blood MCP-1 and adapted DAS28-MCP-1, but not blood PTX3, may be useful in monitoring RA activity.
We decided to study the association of monocyte α-2,3-sialyltransferase 1 (ST3Gal-1), neuraminidase-3 (Neu3), α-2,6-sialyltransferase 1 (ST6Gal-1), and neuraminidase-1 (Neu1) levels with disease ...activity score 28 (DAS28) in human rheumatoid arthritis (RA), considering that mouse monocytes' sialic acid (SIA) levels relate to their phagocytosis and IgG binding ability.
ST3Gal-1, Neu3, ST6Gal-1, Neu1, α-2,3-SIA, and α-2,6-SIA levels on RA peripheral blood monocytes, T cells, and polymorphonuclear cells were determined by using fluorochrome-conjugated anti-cell-specific marker antibodies and fluorochrome-conjugated anti-enzyme antibodies. Simple correlation and linear regression were used to correlate enzyme levels with DAS28.
RA monocyte ST3Gal-1 and Neu3 levels correlated with DAS28 in patients having DAS28 >5.1 (r = 0.469, p = 0.002; r = 0.410, p = 0.006, respectively). When multivariable analysis was performed for erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and SIA-related enzyme levels in different cell types as independent variables with DAS28 as a dependent variable, monocyte ST3Gal-1 levels correlated with DAS28 (p = 0.009) but not ESR and CRP in patients having DAS28 >5.1 (both p ≥ 0.292). RA monocyte ST3Gal-1 levels correlated with DAS28 (p = 0.010) and with ESR (p < 0.001) at month 0 when applied to all RA patients including both remission and nonremission groups in multivariable analysis. The latter findings persisted longitudinally at month 3.
Monocyte ST3Gal-1 and Neu3 levels correlated longitudinally with DAS28 by two different methods suggest that monocyte ST3Gal-1 and Neu3 levels may be used as biomarkers to monitor RA disease activity.
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