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Table 1. Clinical characteristics of the study population in the 2016-2018 KURAMA cohort
35
n=224
2016
2017
2018
The positivity of
44.2
43.3
45.5
53.5
50.9
52.4
DAS28-CRP
2.09 ± 0.81
2.10 ± 0.81
1.94 ± 0.73
DAS28-ESR
2.64 ± 0.96
2.66 ± 0.99
2.43 ± 0.97
Anti-CCP antibody,
266.0 ± 444.7
355.6 ± 566.3
403.5 ± 772.1
anti-cit-OPN
antibody, %
The positive rate of
anti-cit-OPN
antibody in anti CCP
antibody positive
patient, %
U/mL
36
The rate of anti-CCP 77.8
77.7
78.0
119.7 ± 240.4
120.6 ± 264.4
130.1 ± 296.0
77.7
80.0
78.6
CRP, mg/dL
0.36 ± 0.74
0.36 ± 0.64
0.38 ± 0.73
ESR 1h, mm/h
20.6 ± 16.3
21.1 ± 16.7
20.3 ± 17.6
ptVAS, 0-100mm
22.3 ± 21.8
22.9 ± 21.8
23.0 ± 22.6
The use of PSL, %
22.8
22.3
22.3
PSL dose, mg/day
3.78 ± 4.16
3.29 ± 2.10
3.31 ± 1.73
The use of MTX, %
75.0
74.6
73.7
antibody positive, %
Rheumatoid factor,
IU/mL
The rate of
rheumatoid factor
positive, %
37
MTX dose, mg/week 7.37 ± 3.13
7.50 ± 3.16
7.47 ± 3.28
The use of biologic
52.2
54.5
50.9
DMARDs, %
CRP, C-reactive protein; C, reactive protein; ESR, erythrocyte sedimentation rate; CCP,
cyclic citrullinated peptide; VAS, visual analogue scale; PSL, prednisolone; MTX,
methotrexate; DMARDs, disease-modifying antirheumatic drugs.
38
Figure legends
Fig. 1 Positivity of autoantigen in sera of patients with rheumatoid arthritis (RA).
A Serum IgG antibodies against osteopontin (OPN), fibronectin (FN), tenascin -C (TNC), enolase (-ENO), bone sialoprotein (BSP), type 2 collagen (Col II), vimentin (Vim), and
fibrinogen (Fgn) were quantified by enzyme-linked immunosorbent assay (ELISA).
B Antibodies against citrullinated osteopontin (cit-OPN), citrullinated fibronectin (cit-FN),
citrullinated tenascin-C (cit-TNC), citrullinated -enolase (cit--ENO), citrullinated bone
sialoprotein (cit-BSP), citrullinated type 2 collagen (cit-Col II), citrullinated vimentin (citVim), and citrullinated fibrinogen (cit-Fgn) were tested. Serum samples from 30 RA patients
and 7 healthy donors were used. The dashed line indicates the cutoff, defined as the mean
plus two standard deviations (SDs), and the positivity of each antibody in RA patients is
shown.
Fig. 2 IgG from RA patients’ sera with anti-cit-OPN autoantibodies enhanced binding
39
of fibroblast-like synoviocyte (FLSs) with OPN.
A The 96-well plates were coated with OPN. FLSs were transferred to protein -coated plates
and incubated at 37 °C for 120 min with pooled IgG from anti-cit-OPN positive RA patients
or anti-cit-OPN negative RA patients. After washing, the number of cells was estimated using
a 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay.
B Quantification of the five different donors.
Data are shown as mean ± SEM from the aggregate data. * p < 0.05 and ** p < 0.01 by
Tukey–Kramer test.
Fig. 3 OPN induced IL-6 and MMP production in TNF-stimulated FLSs and IgG from
patients with anti-OPN antibody increased their production
A RT-qPCR analysis of inflammatory genes (normalized relative to GAPDH mRNA). FLSs
were stimulated with TNF (5 ng/ml) and OPN, cit-OPN, Col II, -ENO, or Vim for 24 h.
Data represent the mean ± SEM of triplicates from one representative experiment of three
independent donors.
B Proliferation of FLSs. The FLSs were incubated with OPN or cit-OPN for one week. The
40
number of cells was quantified using the MTT assay. Results are presented as the mean ± SD
from three independent donors.
C FLSs were stimulated with TNF (5 ng/ml) and OPN for 24 h. IgG from anti-cit-OPN
positive RA patients or anti-cit-OPN negative RA patients were added simultaneously. Data
represent the mean ± SEM of 10 independent donors.Data are shown as the mean ± SEM. *
p < 0.05 and ** p < 0.01 by Tukey-Kramer test (B) or Mann–Whitney's U test (C).
Fig. 4 Anti-cit-OPN antibody aggravate inflammatory arthritis.
A Arthritis in DBA/1 mice immunized with ovalbumin or citrullinated osteopontin was
induced by intraperitoneal injection of KBxN serum.
B Time course of changes in the arthritis severity score and joint swelling
C,D Histologic sections from the ankle stained with hematoxylin and eosin staining C and
assessed for the histologic synovitis scores D. (n= 4-7 from two independent experiments)
E Arthritis in SKG mice immunized with ovalbumin or citrullinated osteopontin was induced
by mannan.
F Time course of changes in the arthritis severity score and joint swelling.
41
G,H Histological sections from the ankle stained with hematoxylin and eosin G and
assessed for histological synovitis scores H. (n = 6, from two independent experiments)
All data are shown as the mean ± SEM. * p < 0.05 and *** p < 0.001 by Holm–Sidak test (B,
F) or Mann–Whitney's U test (D, H).
Fig. 5 Survival rate of anti-rheumatic drugs between RA patients with and without anticit-OPN antibodies.
A Positivity of anti-cit-OPN antibody from RA sera collected over 3 consecutive years,
measured by ELISA.
B Relationship between serum anti-CCP antibody and anti-cit-OPN antibody using stored
serum in the 2016 cohort.
C Survival rate of TNF inhibitors due to lack of efficacy between RA patients with and
without anti-cit-OPN antibodies in the 2016 cohort. Patients in whom TNF inhibitors were
discontinued within 90 days were excluded.
D Survival rate of CTLA4-Ig due to lack of efficacy between RA patients with and without
anti-cit-OPN antibodies. Patients in whom the drug was discontinued within 90 days were
42
excluded.
43
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