A multi-biomarker disease activity score for monitoring rheumatoid arthritis

Figures & data

Figure 1 Description of the multi-step process used in determination of the MBDA score algorithm.

Note: Numbers in column represent number of patients (in some instances, patients might contribute to more than one visit).
Abbreviations: BRASS, Brigham and Women’s RA Sequential Study; CAMERA, Computer Assisted Management in Early RA; InFoRM, Index for RA Measurement-Crescendo Bioscience Study; Leiden, Leiden Early Arthritis Cohort; MBDA, multi-biomarker disease activity; OKC, Oklahoma City Community Cohort; DAS28, 28-joint disease activity score; CRP, C-reactive protein; RA, rheumatoid arthritis; DA, disease activity.

Table 1 Clinical characteristics of patients based on classification of disease activity by multi-biomarker disease activity score in validation studies

	n	TJC28 (mean)	SJC28 (mean)	PG (mean)	Median CRP level (mg/L)	DAS28-CRP (mean)
Seropositive validation
Low: ≤29	51	3.9	3.0	29	1.4	2.65
Moderate: >29 to 44	66	8.3	5.9	42	4.9	3.92
High: >44	113	12.0	9.1	48	17.0	5.01
Seronegative validation
Low: ≤29	54	3.6	5.7	27	0.7	2.81
Moderate: >29 to 44	46	5.4	7.2	41	3.9	3.73
High: >44	41	9.8	11.0	52	15.0	4.98

Note: Reprinted from Curtis JR, van der Helm-van Mil AH, Knevel R, et al. Validation of a novel multi-biomarker test to assess rheumatoid arthritis disease activity. Arthritis Care Res (Hoboken). 2012;64(12):1794–1803, copyright © 2012, with permission from John Wiley and Sons.²⁰

Abbreviations: CRP, C-reactive protein; DAS28, 28-joint disease activity score; PG, patient global assessment; SJC28, 28-joint swollen joint count; TJC28, 28-joint tender joint count.

Table 2 Cross-sectional correlations with additional clinical disease activity measures for the MBDA score and CRP^a

Biomarker measure	Clinical measure	Pearson’s correlation	P-value	n
Seropositive validation
MBDA score	SDAI	0.55	<0.001	148
MBDA score	CDAI	0.48	<0.001	148
CRP	CDAI	0.44	<0.001	148
MBDA score	RAPID3	0.47	<0.001	92
CRP	RAPID3	0.37	<0.001	92
Seronegative performance
MBDA score	SDAI	0.29	<0.001	139
MBDA score	CDAI	0.21	0.02	139
CRP	CDAI	0.20	0.02	139
MBDA score	RAPID3	0.26	0.003	127
CRP	RAPID3	0.26	0.003	127

Note:

a CRP was log-transformed prior to analysis because Pearson’s correlation assumes normally distributed data. Reprinted from Curtis JR, van der Helm-van Mil AH, Knevel R, et al. Validation of a novel multi-biomarker test to assess rheumatoid arthritis disease activity. Arthritis Care Res (Hoboken). 2012;64(12):1794–1803, copyright © 2012, with permission from John Wiley and Sons.²⁰

Abbreviations: CDAI, clinical disease activity index; CRP, C-reactive protein; MBDA, multi-biomarker disease activity; RAPID3, Routine Assessment of Patient Index Data 3; SDAI, simple disease activity index.

Figure 2 Relationship between the MBDA score and clinical disease activity indices. Correlation and linear regression of MBDA score with DAS28-ESR (A), SDAI (B), and CDAI (C).

Note: Hirata S, Dirven L, Shen Y, et al. A multi-biomarker score measures rheumatoid arthritis disease activity in the BeSt study. Rheumatology. 2013(7);52:1202–1207, by permission of Oxford University Press.²⁴
Abbreviations: CDAI, clinical disease activity index; DAS28, 28-joint disease activity score; ESR, erythrocyte sedimentation rate; MBDA, multi-biomarker disease activity; SDAI, simple disease activity index.

Table 3 Ratios of median disease activity measures^a between RA patients with and without common comorbidities

Comorbidity	n (%)	CRP	CDAI	DAS28-CRP	MBDA score
Hypertension	223 (44)	0.98	1.32^b	1.14^b	1.05
Osteoarthritis^c	172 (34)	0.88	1.17	1.13	1.05
Osteoporotic bone fractures	131 (26)	0.91	1.05	1.02	1.05
Degenerative joint disease^c	113 (22)	1.20	1.18	1.11^b	1.07
Diabetes	73 (14)	1.01	1.09	1.04	1.07^b
Asthma	50 (10)	1.28	1.11	1.05	1.05

Notes:

a Values close to 1.0 indicate that the measurement or test is not affected by the comorbidity;

b nominal P<0.05 adjusted for age and sex; when adjusted for multiple comparisons, none was statistically significant;

c osteoarthritis and degenerative joint disease were listed as separate conditions on the case report forms. Reprinted from Centola M, Cavet G, Shen Y, et al. Development of a multi-biomarker disease activity test for rheumatoid arthritis. PLoS One. 2013;8(4):e60635.¹⁹

Abbreviations: CDAI, clinical disease activity index; CRP, C-reactive protein; DAS28, 28-joint disease activity score; MBDA, multi-biomarker disease activity; RA, rheumatoid arthritis.

Figure 3 MBDA scores by treatment arm and time point.

Notes: For each treatment strategy (ie, intensive tight control MTX-based [n=39] and conventional MTX-based [n=15] treatment strategy), the results of the MBDA score are shown at baseline and after 6 months of treatment. Only results of patients with MBDA score at baseline and 6 months are shown. Reproduced from Bakker MF, Cavet G, Jacobs JW, et al. Performance of a multi-biomarker score measuring rheumatoid arthritis disease activity in the CAMERA tight control study. Ann Rheum Dis. 2012;71(10):1692–1697, copyright © 2012, with permission from BMJ Publishing Group Ltd.²¹
Abbreviations: MBDA, multi-biomarker disease activity; MTX, methotrexate.

Figure 4 Changes (Δ) in MBDA score by EULAR response at week 52.

Notes: Box and whisker plot of ΔMBDA score from baseline to 52 weeks after initiation of TNF inhibitor treatment in patients with no, moderate, and good treatment response at 52 weeks as defined by EULAR criteria. Statistical significance of the difference between the responder groups was assessed by Wilcoxon’s rank-sum test. Thick horizontal line indicates the median; box indicates the interquartile range (IQR); and whiskers indicate the most extreme points within 1.5 times the IQR from the limits of the box. Hirata S, Li W, Defranoux N, et al. A multi-biomarker disease activity score tracks clinical response consistently in patients with rheumatoid arthritis treated with different anti-tumor necrosis factor therapies: A retrospective observational study. Mod Rheumatol. 2015;25(3):344–349, copyright © 2014, Informa Healthcare.²⁷ Reproduced with permission of Informa Healthcare.
Abbreviations: BL, baseline; EULAR, European League Against Rheumatism; IQR, interquartile range; MBDA, multi-biomarker disease activity; TNF, tumor necrosis factor.

Figure 5 Probability plots of radiographic progression at year 1 for high, moderate, and low disease activity patient (n=235) grouped according to baseline MBDA (A), CRP (B), DAS28 (C), and ESR (D).

Notes: Each black circle represents a patient with low disease activity, the red triangle indicates moderate disease activity, and the blue square indicates high disease activity. Horizontal dashed line represents ΔSHS =5 from baseline to 1 year, above which the change is considered as rapid radiographic progression (ΔSHS >5). Reproduced from Hambardzumyan K, Bolce R, Saevarsdottir S, et al. Pretreatment multi-biomarker disease activity score and radiographic progression in early RA: results from the SWEFOT trial. Ann Rheum Dis. 2015;74(6):1102–1109, copyright © 2014, with permission from BMJ Publishing Group Ltd.³⁰
Abbreviations: CRP, C-reactive protein; DA, disease activity; DAS28, 28-joint disease activity score; ESR, erythrocyte sedimentation rate; MBDA, multi-biomarker disease activity; SHS, Sharp-van der Heijde score.

Table S1 Twelve biomarkers reflect the heterogeneity of RA

Biomarker	Biomarker category	Primary role
VCAM-1	Adhesion molecules	Cellular influx and tissue expansion
EGF, VEGF-A	Growth factors	Cellular influx and tissue expansion
IL-6, TNF-R1	Cytokine-related proteins	Local inflammation and destruction
MMP-1, MMP-3	Matrix metalloproteinases	Cartilage degradation and joint damage
YKL-40	Skeletal-related proteins	Stromal activity and regulation (fibroblasts, chondrocytes, vascular cells)
Leptin, resistin	Hormones	Systemic inflammatory response
SAA, CRP	Acute-phase proteins	Systemic inflammatory response

Abbreviations: CRP, C-reactive protein; EGF, epidermal growth factor; IL-6, interleukin 6; MMP, matrix metalloproteinase; SAA, serum amyloid A; TNF-R1, tumor necrosis factor alpha receptor 1A; VCAM-1, vascular cell adhesion molecule 1; VEGF-A, vascular endothelial growth factor A; YKL-40, human cartilage glycoprotein 39; RA, rheumatoid arthritis.

Curtis JR, van der Helm-van Mil AH, Knevel R, et al. validation of a novel multibiomarker test to assess rheumatoid arthritis disease activity. Arthritis Care Res (Hoboken). 2012;64(12):1794–1803.

 PubMed Web of Science ®Google Scholar

Hirata S, Dirven L, Shen Y, et al. A multi-biomarker score measures rheumatoid arthritis disease activity in the BeSt study. Rheumatology (Oxford). 2013(7);52:1202–1207.

 Google Scholar

Centola M, Cavet G, Shen Y, et al. Development of a multi-biomarker disease activity test for rheumatoid arthritis. PLoS One. 2013;8(4):e60635.

 PubMed Web of Science ®Google Scholar

Bakker MF, Cavet G, Jacobs JW, et al. Performance of a multi-biomarker score measuring rheumatoid arthritis disease activity in the CAMERA tight control study. Ann Rheum Dis. 2012;71(10):1692–1697.

 PubMed Web of Science ®Google Scholar

Hirata S, Li W, Defranoux N, et al. A multi-biomarker disease activity score tracks clinical response consistently in patients with rheumatoid arthritis treated with different anti-tumor necrosis factor therapies: A retrospective observational study. Mod Rheumatol. 2015;25(3):344–349.

 PubMed Web of Science ®Google Scholar

Hambardzumyan K, Bolce R, Saevarsdottir S, et al. Pretreatment multi-biomarker disease activity score and radiographic progression in early RA: results from the SWEFOT trial. Ann Rheum Dis. 2015; 74(6):1102–1109.

 PubMed Web of Science ®Google Scholar