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. 2021 Jan 29;7(1):e001511. doi: 10.1136/rmdopen-2020-001511

Table 3.

Concise summary of papers on the assessment of inflammatory activity at patient level

Papers/design Replicated diagnostic tests (*: n) Reference standards (*: n)† Results RoB:*
Composite indices as reference standard    
54 papers (4 SLRs (*14/22/7/14), 46 CS, 2CS‡, 2 CC)22–29 34 35 37–40 43–50 52–58 61–65 68–80 82–88
RA patients:

  • General RA population, n=9686+ NR

  • Suspected of or diagnosed with RA, n=40

  • Established RA, n=46

  • ACPA positive, n=72

  • Active RA, n=40

  • With musculoskeletal symptoms, n=27

  • With at least one painful or swollen joint, n=42

  • With knee effusion, n=30

  • With at least one joint amenable to biopsy, n=15

  • Who were referred for examination of hands and feet, n=46

 Biomarkers:
MBDA score (2: 3936); miR-146a (1 SLR: 638); ACPA (8: 568); Neutrophile lymphocyte ratio (3: 523); Platelet lymphocyte ratio (2: 421); Leptin (6: 404); IL-6 (4: 373); VEGF (5: 344); MMP-3 (2: 173); IL-17 (2: 121+NR); TNF(a) (2: 185); RF (2: 165); Fibrinogen (2: 152); Resistin (2: 141); IL-2 (2: 111); IL-4 (2: 111); IL-10 (2: 111)


Imaging (sum scores):
US all types (9: 2060+NR): US GS (2: 57), US PD (5: 646);
OST measures (3: 171)		 DAS28 (51: 8656+NR); CDAI (7: 4186); SDAI (6: 4140); Composite score, not further specified (1: 1307) Following replicated diagnostic tests with DAS28 as reference standard:

  • MBDA score: pooled r=0.41 (s, 1 SLR); r=0.52 (s, 1 CS)

    • SLR concludes: ‘The MBDA demonstrates moderate convergent validity with DAS28-CRP and DAS28-ESR, but weaker correlations with SDAI, CDAI, and RAPID3.’

  • miR-146a: pooled r=0.434 (s)

    • SLR concludes: ‘Circulating and synovial tissue/fluid miR-146a levels are high in patients with RA, and circulating miR-146a levels positively correlate with ESR.’

  • IL-17: pooled r=0.335 (s, 1 SLR); r=0.373 (s, 1 CS)

    • SLR concludes: ‘Circulating IL-17 level is related to the disease activity of RA.’

  • ACPA: r=-0.126–0.437 (s in *2; ns in *6)

  • Neutrophile lymphocyte ratio: r=0.192–0.345 (s in *1; ns in *1)

  • Platelet lymphocyte ratio: r=0.22–0.352 (s, *2)

  • Leptin: r=-0.111–0.513 (s in *4; ns in *2)

  • IL-6: r=0.31–0.409 (s, *4)

  • VEGF: r=0.10–0.6527 (s, in *2; ns in *3)

  • MMP-3: r=0.30–0.674 (s, *3)

  • TNF(a): r=-0.01–0.213 (s in *1; ns in *1))

  • RF: r=0.265–0.3 (s, *2)

  • Fibrinogen: r=0.373–0.55 (s, *2)

  • Resistin: r=0.403–0.44 (s, *2)

  • IL-2: r=-0.08–−0.005 (ns, *2)

  • IL-4: r=-0.004–0.191 (ns, *2)

  • IL-10: r=-0.11–0.226 (ns, *2)




Following replicated imaging measures with composite index as reference standard:

  • US (all types): r=0.03, 0.40–0.70 (s in *7; NR in *2)

  • US (GS): r=0.251–0.70 (s, *2)

  • US (PD): r=0.5043–0.72 (s in *5; ns in *1)

  • OST measure: r=0.06–0.42 (s in *2; ns in *1)


SLR concludes: ‘Ultrasonography can be regarded as a valuable tool for globally examining the extent of synovitis in RA. However, it is presently difficult to determine a minimal number of joints to be included in a global ultrasonography score. Further validation of proposed scores is needed.’		 L: 5
M: 43
 H: 6
Clinical assessment as reference standard      
20 papers (17 CS, 2 CS‡, 1 CC)24 26–30 35 43 47 52 57 63 65 66 68 72 74 75 82 88
RA patients:

  • General population, n=1002

  • ACPA positive, n=72

  • Established RA, n=46

  • With knee effusion, n=30

  • With at least one joint amenable to biopsy, n=15

  • With at least one painful or swollen joint, n=42

 Biomarkers:
IL-6 (2: 205); VEGF (2: 205); ACPA (3: 181); Leptin (2: 87)


Imaging (sum scores):
US (5: 299); OST measure (2: 109)		 SJC28/32/66 (19: 1170); TJC 28/32/66 (20: 1207) Following diagnostic tests with SJC as reference standard:

  • IL-6: r=0.39–0.41 (s, *2)

  • VEGF: r=0.13–0.14 (ns, *2)

  • ACPA: r=−0.051 (ns, *3)

  • Leptin: r=−0.046 (ns, *1)

  • US: r=0.3270–0.78 (s, *4)

  • OST measure: r=0.30–0.50 (s, *2)




Following diagnostic tests with TJC as reference standard:

  • IL-6: r=0.09–0.14 (ns, *2)

  • VEGF: r=-0.03–0.15 (ns, *2)

  • ACPA: r=0–0.144 (ns, *3)

  • Leptin: r=0.072–0.59 (s in *1; ns in *2)

  • US: r=0.25–0.65 (s, *4)

  • OST measure: r=-0.02–0.25 (s in *1; ns in *1)



 H: 20
Imaging as reference standard    
12 papers (1 SLR (*14), 8 CS, 2 CS‡, 1 CC)25 26 35 38 40 47 59 72 74 75 83 88
RA patients:

  • General population, n=1795

  • Who were referred for examination of hands and feet (n=46)

  • With at least one painful or swollen joint, n=42

 Biomarkers:
IL-6 (2: 207); VEGF (3: 277)


Imaging (sum scores):
US (4: 110+NR);
OST measures (2: 109)		 US (11: 1865); MRI (2: 1325) Following diagnostic tests with US as reference standard:

  • IL-6: r=0.23–0.49 (s in *2; ns in *1)

  • VEGF: r=-0.10–0.4824 (s in *2; ns in *1)

  • US (PD in six joints vs PD in 12 joints): r=0.03–0.935 (s in *3; ns in *1)

  • OST measure: r=0.54–0.64 (s, *2)


SLR concludes: ‘Ultrasonography can be regarded as a valuable tool for globally examining the extent of synovitis in RA. However, it is presently difficult to determine a minimal number of joints to be included in a global ultrasonography score. Further validation of proposed scores is needed.’		 M: 2
H: 10

*Number of studies.

†For the general established RA population, validated composite disease activity indices (eg, DAS28 or CDAI) were deemed as appropriate to assess the presence of inflammatory activity at patient level. In patients in whom there is explicit doubt about the presence of inflammatory activity, the traditional measures are not trustworthy. Therefore, in studies assessing this population we considered scores based on established imaging measures as a more appropriate reference standard.

‡Abstract.

ACPA, anticitrullinated protein antibody; CC, case control; CDAI, Clinical Disease Activity Index; CS, cross-sectional; DAS28, Disease Activity Score Assessing 28 joints; ESR, erythrocyte sedimentation rate; GS, Grey scale; H, high (red); IL, interleukin; L, low (green); M, moderate (yellow); MBDA, multi-biomarker disease activity; miRNA, micro RNA; MMP-3, matrix metalloproteinase-3; NR, not reported; ns, not significant; OST, optical spectral transmission; PD, power Doppler; RA, rheumatoid arthritis; RF, rheumatoid factor; RoB, risk of bias; SDAI, Simplified Disease Activity Index; SJC, swollen joint count; SLR, systematic literature review; TJC, tender joint count; TNF, tumour necrosis factor; US, ultrasonography; VEGF, vascular endothelial growth factor.