Sialic-Acid-Related Enzymes of B Cells and Monocytes as Novel Markers to Discriminate Improvement Categories and to Fulfill Two Remission Definitions in Rheumatoid Arthritis

Abstract

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.

Keywords: B cells; Sialyltransferases; improvement criteria for RA; monocytes; neuraminidases; remission definitions for RA.

Figure 1

Comparisons of the difference of monocyte and B-cell enzyme levels/ratios between various ACR improvements and their non-improvements. (A) The B-cell Neu1 difference (M0 − M3) fulfilled the ACR 70% improvement criteria (n = 23), compared with those not fulfilled (n = 67), p = 0.043. (B) The monocyte Neu3 difference (M0 − M12) fulfilled the ACR 20% improvement criteria (n = 65), compared with those not fulfilled (n = 6), p = 0.037. (C) The B-cell ST6 difference (M0 − M12) fulfilled the ACR 20% improvement criteria (n = 62), compared with those not fulfilled (n = 5), p = 0.050. (D) The monocyte ST3/Neu3 ratio difference (M0 − M12) fulfilled the ACR 70% improvement criteria (n = 26), compared with those not fulfilled (n = 38), p = 0.042. All comparisons were analysed using the Mann–Whitney U test.

Figure 2

Comparisons of the difference of monocyte and B-cell enzyme levels/ratios between various ACR improvements and their non-improvements in RA patients with positive rheumatoid factor. (A) The B-cell Neu1 difference (M0 − M3) fulfilled the ACR 70% improvement criteria (n = 21), compared with those not fulfilled (n = 53), p = 0.041. (B) The B-cell ST6 difference (M0 − M3) fulfilled the ACR 70% improvement criteria (n = 21), compared with those not fulfilled (n = 50), p = 0.022; that of the B-cell ST6 difference yielded p = 0.024 (ACR 50%, M0 − M12). (C) The monocyte Neu3 difference (M0 − M12) fulfilled the ACR 20% improvement criteria (n = 67), compared with those not fulfilled (n = 8), p = 0.029; that of the monocyte ST6/Neu1 ratio difference rendered p = 0.007 (ACR 70%, M0 − M12); that of the monocyte ST6 difference yielded p = 0.019 (ACR 50%, M0 − M15). (D) The B-cell ST3 difference (M0 − M3) fulfilled the ACR 70% improvement criteria (n = 21), compared with those not fulfilled (n = 49), p = 0.013; that of the B-cell ST3 difference provided p = 0.046 (ACR 50%, M0 − M12); that of the B-cell Neu 3 difference yielded p = 0.015 (ACR 70%, M0 − M3). All comparisons were analysed using the Mann–Whitney U test.

Figure 3

Comparisons of the difference of monocyte and B-cell enzyme levels/ratios between various ACR improvements and their non-improvements in RA patients with positive anti-CCP antibodies. (A) The B-cell ST6 difference (M0 − M12) fulfilled the ACR 70% improvement (n = 75) criteria, compared with those not fulfilled (n = 6), p = 0.030. (B) The monocyte ST6 difference gave p = 0.039 for ACR 70% improvement (n = 50) vs. non-improvement (n = 31) (M0 − M15). (C) The monocyte ST3/Neu3 ratio difference rendered p = 0.036 for ACR 70% improvement (n = 33) vs. non-improvement (n = 41) (M0 − M12). All comparisons were analysed using the Mann–Whitney U test.

Figure 4

Comparisons of the difference of monocyte and B-cell enzyme levels/ratios between various ACR improvements and their non-improvements in RA patients with use of biologics. (A) The B-cell Neu1 difference (M0 − M3) fulfilled the ACR 50% improvement criteria (n = 26), compared with those not fulfilled (n = 16), p = 0.029. (B) The B-cell ST6/Neu1 ratio difference (M0 − M3) fulfilled the ACR 50% improvement (n = 21), compared with those not fulfilled (n = 15) gave p = 0.037. (C) The monocyte ST6/Neu1 ratio difference (M0 − M3) fulfilled the ACR 20% improvement (n = 31), compared with those not fulfilled (n = 6), p = 0.009. (D) The monocyte ST3/Neu3 ratio difference (M0 − M12) fulfilled the ACR 70% improvement (n = 10), compared with those not fulfilled (n = 27), p = 0.028. All comparisons were analysed using the Mann–Whitney U test.

Figure 5

Comparison of the B-cell Neu1 level and DAS28 scores between baseline and later months. The B-cell Neu1 level was significantly lower in (A) month 12 (n = 72) and (B) month 15 (n = 48) than month 0 (n = 100) (p = 0.009 and <0.001, respectively). DAS28-ESR scores were significantly lower in (C) month 12 and (D) month 15 than month 0 (p < 0.001 and <0.001, respectively). DAS28-MCP-1 scores were significantly lower in (E) month 12 and (F) month 15 than month 0 (p < 0.001 and <0.001, respectively). All comparisons were analysed using the Mann–Whitney U test.