What is the added value of ultrasound joint examination for monitoring synovitis in rheumatoid arthritis and can it be used to guide treatment decisions? A systematic review and cost-effectiveness analysis

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Chapter 1 Background

Chapter 2 Definition of the decision problem

Chapter 3 Assessment of ultrasound studies

Results

Quantity and quality of research available

A total of 2724 records were identified from the electronic databases following deletion of duplicate records.

Eight guidelines were identified through grey literature searching. 9,24,28,30,46,75–77 Eight systematic reviews of relevance to the decision problem were also identified. 25,29,45,50,85–88 Guidelines were published on US in rheumatology by the ACR,46 Arthritis Research UK30 and EULAR,75 which also published guidelines on imaging in RA. 28 Guidelines on the management of RA were published by NICE9,77 and the Scottish Intercollegiate Guidelines Network. 76 Reviews were published on the use of US in inflammatory arthritis29,85–87 or US for use in RA including the detection of synovitis and defining remission. 24,25,45,50,88 The bibliographies of these guidelines and reviews were searched to identify studies meeting the review inclusion criteria, identifying an additional 26 records. This led to a total of 2750 records being screened.

The study selection process is provided in Figure 1. At title and abstract sift, 2596 records were excluded. The 63 records excluded at full paper sift are presented with reasons for exclusion in Appendix 4.

FIGURE 1.

Flow diagram of study inclusion.

A total of 75 articles53,55,68,69,89–158 describing 58 studies were included in the review; following the searches but prior to publication of this report, one of the studies identified as ongoing by the searches (ARCTIC) was published as an abstract. 79 Data extraction forms for these included studies are provided in Appendix 5.

Study quality assessment forms for the included studies are provided in Appendix 6.

Ten89–98 of the 58 included studies were reported as abstracts only and so limited details were available.

Of the 58 studies included, diagnosis of RA was reported as being confirmed using the ACR or EULAR classification criteria for RA, either the 2010 criteria11 or an earlier version,8 in all except nine studies. 89,90,92–96,98,99

An established US scoring system was referenced in all but nine89,91,94,95,100–104 of the 58 included studies. According to the hierarchy of evidence published by Merlin et al. ,159 diagnostic accuracy studies are of higher quality if they are blinded and recruit consecutive patients and prospective cohort studies are of higher quality than other forms of prognostic studies. Of 33 studies53,92,96,102–116,118–132 reporting diagnostic accuracy or detection rates of synovitis, 13102–104,107,109–111,113–115,118,119,124 were blinded comparisons of consecutive patients. Of 15 studies of prognosis,55,69,97,98,113,134,135,137–144 all but one,138 an ancillary study to a RCT, were prospective cohort studies.

Studies reporting the detection of synovitis are described in Appendix 7 (see Tables 138–140). Diagnostic data were extracted from 37 publications53,68,92,96,99,102–132,146 reporting on 33 studies. One of these studies113,146 also provided prognostic data.

For most of the studies providing diagnostic data (see Appendix 7, Table 138), CE had a high specificity and low sensitivity when using PDUS or GSUS as the reference standard. This indicates some agreement between CE and US, with US detecting synovitis in some joints that CE did not detect and only a few cases in which CE detected synovitis and US did not. This agrees with the higher detected rates of synovitis for US over CE (see Appendix 7, Table 139) reported in the majority of studies.

However, five studies found lower rates of detection of synovitis with US than with CE. 106,115,123,125,130 Also, there were mixed results in three studies, with higher detection rates for GSUS than for CE but lower detection rates for PDUS than for CE in two studies108,119 and lower detection rates for PDUS than for CE for metacarpophalangeal (MCP) joints but higher detection rates for PDUS than for CE for proximal interphalangeal (PIP) and wrist joints in one study. 131

The five studies106,115,123,125,130 that found lower rates of detection with US than with CE were some of the older trials; however, there were other trials from the early 2000s that did not report this finding and so this cannot explain the difference between these trials and trials finding a higher rate of detection with US than with CE. Study quality did not explain the differences between the study results, although one of the studies reporting a lower rate of detection with US than with CE had a small sample size (n = 6), and the differences did not appear to be caused by the US scoring system used (0–1 vs. 0–3 or 0–4; see Table 3).

It may be that the types of joint examined could explain the differences between the study results. Of the studies finding lower rates of detection with US than with CE, three studies106,115,130 investigated ankle and/or foot joints and one study123 included metatarsophalangeal (MTP) joints; however, this study also assessed PIP and MCP joints, which have been shown to have higher rates of detection of synovitis using US than using CE. 125 This agrees with one within-study comparison of joints, which reported that CE had a lower sensitivity for MTP joints than for MCP or PIP joints. 160 However, heterogeneity between other studies, suggesting that US is less useful for foot and ankle joints than for wrist and hand joints, means that there is uncertainty in the findings.

The detection of subclinical synovitis would be useful only if clinically relevant, as investigated using prognostic studies.

Prognostic data were extracted from 23 publications55,56,69,97,98,100,113,134–139,141–148,150,151 reporting on 15 studies. One of these studies was an ancillary study to a RCT. 138 The other studies were prospective cohort studies in which a cohort of patients was assessed at baseline with US and with CE and was then followed up to assess the association of these baseline measures with a given outcome. Prognostic data are provided in Tables 6–8.

Treatment data were extracted from 16 publications89–91,93–95,100,101,139,152–157 reporting on 13 studies. Following the searches but prior to publication of this report, one of the studies identified as ongoing (ARCTIC) was published as an abstract. 79 This abstract was included to provide treatment data, meaning that 14 studies in total provided data relating to treatment. Six of these were prospective cohort studies that measured the association of an outcome at follow-up with the US and CE variables measured at baseline93,101 or US and CE variables measured after 4 months of treatment139 or at the time of treatment discontinuation or tapering. 95,155,156 One study reported data from a prospective cohort in which baseline US and CE variables were tested for association with an outcome taken from a RCT of RA treatment. 95,132 Two studies were RCTs comparing treatment strategies with or without US. 79,154 One of these RCTs154 also provided data on treatment decisions. Treatment decisions were also investigated using observational data. 89–91,94,152 Treatment data are provided in Tables 9–14.

Meta-analyses were not performed because of heterogeneity in the type of US used, US scoring systems used (see Table 3), joints assessed, clinical comparators (type of examination; use of composite clinical scoring), outcome measures and follow-up times.

Assessment of prognostic studies

Heterogeneity of trials precluded meta-analysis. Therefore, no summary estimates of effect were available, which is a limitation of the review. Significance values refer to the association of baseline US and CE measures with later outcome measures. Radiographic progression measures are of importance to patients as they reflect structural damage, which is associated with loss of function over time. Other outcomes assessed are of importance to patients as they reflect disease activity and function. Studies investigated whether or not baseline measures could be predictive of later outcomes, rather than directly comparing different baseline measures. As well as heterogeneity of outcome measures, studies differed in the statistics reported to assess the association of baseline US and CE measures with clinical outcome at follow-up, including Spearman correlations (R) and odds ratios (ORs) (univariate analysis unless otherwise stated).

Two studies113,134 reported the sensitivity of US and CE measures to predict progression (Table 4). These were prospective cohort studies in which patients were tested with US and underwent CE at baseline and were then followed up and evaluated for the outcome measures of progression. Boyesen and Haavardsholm134 used a measure of GSUS inflammation based on synovitis and tenosynovitis and found that this US measure had a similar sensitivity for predicting erosive progression as MRI at 12 months, indicating that the majority of patients with a high US score, or high DAS, relapsed. This measure of GSUS inflammation134 had a higher specificity than DAS28 (although neither US nor DAS28 had high specificity) for predicting erosive progression as measured by MRI at 12 months, indicating that more patients with a low GSUS score than a low DAS did not progress. Ikeda et al. 113 found that GSUS, PDUS and Disease Activity Score 28 joints using C-reactive protein (DAS28-CRP; see Table 1) had similar sensitivities for predicting radiographic progression at 24 weeks (see Table 4). GSUS had a lower specificity than PDUS and DAS28 for predicting radiographic progression. 113 This study subgrouped patients by recently retrieved treatment and found that in MTX-treated patients (n = 16) and TCZ-treated patients (n = 17) PDUS had higher specificity than DAS28-CRP, but that specificities were similar in TNFi-treated patients (n = 24) (see Appendix 5). Both of these studies were prospective cohort studies, at level II in the study quality hierarchy, although the study by Ikeda et al. 113 was a better-quality and more rigorous study given that blinding was unclear in the study by Boyesen and Haavardsholm134 (see Appendix 8).

TABLE 4 - Sensitivity and clinical prognosis

CI, confidence interval; mTSS, modified total Sharp score; NR, not reported; RAMRIS, rheumatoid arthritis magnetic resonance imaging scoring system.

Composite score of synovitis and tenosynovitis.

Cut-off values not reported.

vdHSS.

Study	Population	Outcome	Patients with outcome, n (%)	US measure	Sensitivity (95% CI), %	Specificity (95% CI), %	Clinical measure	Sensitivity, %	Specificity, %
Boyesen 2011134	79 patients, dominant wrist	MRI erosive progression at 12 months (≥ 1-unit increase in RAMRIS)	53 (67.1)	GSUS inflammation score cut-off values < 0.5 vs. ≥ 0.5a	79 (NR)	55 (NR)	DAS28 remission/low vs. moderate/highb	74 (NR)	21 (NR)
Ikeda 2013113	57 patients, 28 joints of DAS28	Radiographic progression (mTSS) at 24 weeksc	21 (36.8)	Total GSUS score cut-off values of < 62	56 (NR)	57 (NR)	DAS28-CRP cut-off of < 9.0	64 (NR)	81 (NR)
				Total PDUS score cut-off values of < 21	69 (NR)	76 (NR)

Eleven studies (with 14 publications55,69,97,113,134–136,138–141,144,148,150) reported an association of US and CE prognostic factors with radiographic progression/erosion (Table 5). These were prospective cohort studies in which patients were tested with US and underwent CE at baseline and were then followed up and evaluated for the outcome measures of progression.

TABLE 5 - Correlation of US and CE with prognosis: radiographic progression

CI, confidence interval; gVAS, general visual analogue scale; JSN, joint space narrowing; MMP-3, matrix metalloproteinase 3; mTSS, modified total Sharp score; NR, not reported; NS, non-significant radiographic progression; PD, power doppler; RAMRIS, rheumatoid arthritis magnetic resonance imaging scoring system; SD, standard deviation; US7, ultrasound 7 score.

≥ 1-unit increase in 1-year RAMRIS erosive change.

Composite score of synovitis and tenosynovitis.

CE measures were not included in the stepwise regression analysis as they did not reach statistical significance. Multivariate analysis included GSUS, bone marrow oedema, gender and age.

Genant-mTSS.

vdHSS.

Occurrence or worsening of erosion or JSN.

0 = no synovitis; 1 = doubtful synovitis; 2 = obvious and moderate synovitis; 3 = obvious and important synovitis.

Grey-scale USJCAS (ultrasonographic joint count for active synovitis).

Power Doppler USJIPD (ultrasonographic joint index for power Doppler signal).

Multivariate analysis included time-integrated PDUS, rheumatoid factor, CRP and ESR.

Measured by US, graded from 0 to 3.

Study	Population	Joints	Follow-up	Outcome	Type of US	Correlation of US synovitis with outcome	Type of CE	Correlation of CE with outcome
Backhaus 201369	453 patients	US7 score	12 months	Bone erosion (US7 erosion sum score)	US7 synovitis sum score in GSUS	R ± SD: 0.140 ± 0.038 (95% CI 0.066 to 0.215; p < 0.001)	DAS28, ESR, CRP	R ± SD: DAS28 of 0.621 ± 0.141 (95% CI 0.345 to 0.898; p < 0.001); ESR 0.008 ± 0.010 (95% CI −0.011 to 0.027; p = 0.399); CRP 0.001 ± 0.009 (95% CI −0.017 to 0.018; p = 0.945)
					US7 synovitis score in PDUS	R ± SD: 0.099 ± 0.051 (95% CI −0.001 to 0.200; p = 0.053)
Boyesen 2011134	84 patients	Dominant wrist	1 year	MRI erosive progressiona	GSUS (univariate analysis)b	OR 2.15 (95% CI 1.23 to 3.75; p = 0.01)	DAS28 (univariate analysis)	OR 1.15 [95% CI 0.80 to 1.64; p = 0.46 (NS)]
					GSUS (multivariate analysis)b,c	OR 2.01 (95% CI 1.14 to 3.53; p = 0.02)	ESR (univariate analysis)	OR 1.02 [95% CI 0.98 to 1.06; p = 0.29 (NS)]
					GSUS synovitis (radiocarpal joint assessed in the dorsal midline)	OR 7.2 (95% CI 0.9 to 61.0; p = NS)	CRP (univariate analysis)	OR 1.04 [95% CI 0.98 to 1.10; p = 0.16 (NS)]
Brown 2008135 (same study as Ikeda 2007136)	90 patients in clinical remission	Dominant hand MCP joint and wrist	12 months	Progressive radiographic damage (both hands and feet)d	PDUS signal	OR 12.21 (95% CI 3.34 to 44.73; p < 0.001)	Painful joint count	OR 3.32 (95% CI 0.39 to 28.30; p = 0.273)
					GSUS synovial hypertrophy	OR 1.92 (95% CI 0.49 to 7.54; p = 0.350)	TJC	OR 2.17 (95% CI 0.26 to 18.10; p = 0.473)
							SJC	OR 1.69 (95% CI 0.43 to 6.67; p = 0.457)
Ikeda 2007136 (same study as Brown 2008135)	107 patients in remission (clinician assessed) on DMARDs	Dominant hand MCP and wrist	12 months	Radiographic progression (direct assessment of individual joints)	GSUS synovial hypertrophy score	Mann–Whitney U-test p = 0.027	Painful joints	Chi-squared test p = 0.284
					PDUS score	p < 0.001 (in asymptomatic joints only p = 0.002)	Tender joints	p = 0.389
					Increased PDUS signal	Likelihood ratio 7.02, chi-squared test p = 0.037	Swollen joints	p = 0.417
Cavet 2009138	24 patients	10 MCP joints100	110 weeks	Radiographic progressione	GSUS synovial thickening	R = 0.59 (p-value NR)	Biomarkers (93 serum proteins) at 6 weeks (multivariate model)	Significant correlation R = 0.79 (p-value NR)
					Power Doppler area)	R = 0.77 (p-value NR)
Dougados 2013139,149	59 patients	MCP (×10), PIP (×10), wrist (×2) and MTP (×10) joints	2 years	Radiological progressionf	GSUS (0 vs. 1–3)	OR 1.64 (95% CI 1.08 to 2.47)	Clinical synovitisg	0 vs. 1–3: OR 2.08 (95% CI 1.39 to 3.11; p < 0.001); 0–1 vs. 2–3: OR 1.64 (95% CI 1.14 to 2.36; p = 0.008)
					GSUS (0–1 vs. 2–3)	OR 1.91 (95% CI 1.18 to 3.10)	Tender joints	OR 1.53 (95% CI 1.02 to 2.29; p = 0.04)
					PDUS 0 vs. 1–3	OR 1.80 (95% CI 1.20 to 2.71; p = 0.005)	Tender joints with clinical synovitis	OR 1.89 (95% CI 1.25 to 2.85; p = 0.002)
					PDUS 0–1 vs. 2–3	OR 1.36 (95% CI 0.78 to 2.38; p = 0.278)
Ikeda 2013113	57 patients (MTX, n = 16; TNFi, n = 24; TCZ, n = 17)	Finger, wrist, elbow, shoulder and knee	24 weeks	Radiographic damagee	GSUS (cumulative total GSUS score)	R = 0.062; p = 0.649 (MTX, r = 0.210, p = 0.436; TNFi, r = 0.027, p = 0.900; TCZ, r = 0.492, p = 0.179)	Cumulative DAS28-CRP	R = 0.342, p = 0.009 (MTX, r = 0.487, p = 0.056; TNFi, r = 0.308, p = 0.144; TCZ, r = 0.369, p = 0.145)
					PDUS (cumulative total PDUS score)	R = 0.357; p = 0.006 (MTX, r = 0.679, p = 0.004; TNFi, r = 0.153, p = 0.476; TCZ, r = 0.353, p = 0.165)
Naredo 200755	42 RA patients starting DMARDs (38 patients followed up to 1 year)	28 joints	1 year	Total radiographic score progression (radiographic erosion score and JSN score)e	Joint count for GSUSh	GSUS r = 0.61; p < 0.001	SJC, TJC, DAS28, HAQ, ESR, CRP	SJC, r = 0.46, p < 0.01; TJC, r = 0.36, p < 0.05; DAS28, r = 0.40, p < 0.05; HAQ, r = 0.36, p < 0.05; ESR/CRP, NS
					Joint count for PDUS signali	PDUS r = 0.59; p < 0.001
Naredo 2008140	278 patients with complete data (of 367 RA patients starting TNFis)	86 intra-articular and periarticular sites in 28 joints	1 year	Total radiographic score progression (radiographic erosion score and JSN score);e multivariate analysisj	Time integrated values of US joint count for PDUS signal	Total radiographic score (R = 0.59) significant; erosion score (R = 0.64) significant; JSN score NS	ESR, CRP	Total radiographic score: ESR (R = 0.59) significant; ESR for erosion or JSN score NS; baseline CRP level weak predictive value for JSN score progression (R = 0.2); CRP NS for erosion and total scores
Osipyants 201397,150	35 patients	Wrists	1 year	Radiographic progression (mTSS)e	PDUS signals of residual inflammation of the wrists at 6 months	Significantly correlated (r = 0.696; p = 0.011); mTSS at 1 year significantly higher [93 (range 56–131) vs. 32.5 (range 19.5–83) units; p < 0.04] in patients with middle- or high-active PDUS signals (n = 27) (SJC > 1, PDUS > 1) than in cases with lower imaging activity or the absence of the PD signals (n = 8) at 6 months	SJC	Non-significantly lower radiographic progression over 1 year in those with SJC ≤ 1 [55 (range 31–116) vs. 88.5 (range 55–130); p < 0.205] than in those with SJC > 1 (n = 25)
Reynolds 2009141	25 patients (providing data at the 2-year follow-up of 40 patients recruited)	MCP and PIP joints	2 years	Erosion progressionk	GSUS and PDUS	Mann–Whitney U-test synovial score (0–3) NS; mean synovial thickness (cm) NS; pre-contrast PDUS score (0–3) NS; post-contrast PDUS score (0–3) NS	ESR	NS
Yoshimi 2013144	22 RA patients in clinical remission (of 31 recruited)	Bilateral wrists and all of the MCP and PIP joints	2 years	Radiographic progressione	Total PDUS score	Total PDUS score significantly higher in patients with radiographic progression than in patients without (6.00 ± 6.44 vs. 0.87 ± 1.15; p = 0.0011)	SJC, DAS28, gVAS and the serum levels of ESR, CRP and MMP-3	Significant differences in SJC (0.33 ± 0.79 vs. 1.29 ± 0.70; p = 0.0040) and DAS28-ESR (p = 0.0010) and DAS28-CRP (p = 0.041) between the radiographic progression group and the non-progression group. Borderline significance for TJC (p = 0.054). No significant difference in other clinical parameters (gVAS and the serum levels of ESR, CRP and MMP-3) between the radiographic progression group and the non-progression group
					Total GSUS score	No significant difference in the total GSUS score, (12.6 ± 12.4 vs. 8.80 ± 5.78; p = 0.57), between the radiographic progression group and the non-progression group

Of the 11 studies, seven55,69,113,138–140,144 found that US and at least one of the clinical measures investigated could significantly predict radiographic progression, most of which were of high quality (with the exception of two studies69,138 in which blinding was unclear). Three studies found that US could significantly predict radiographic progression whereas the clinical comparator could not (DAS28-ESR/ESR/CRP;134 joint counts;135 SJC97), two97,134 of which were less rigorous in terms of study quality, with blinding being unclear. One study141 found that neither US nor the clinical comparator (ESR) was significantly associated with later progression; this study was more rigorous in terms of study quality. All of the studies were prospective cohort studies, at level II in the study quality hierarchy, with the exception of one study,138 which was an ancillary study to a RCT (see Appendix 8).

The majority of the studies reported a significant correlation between US and radiographic progression, using GSUS55,69,134–136,138,139,148 or PDUS;55,69,97,113,134–136,138–140,144,148 most of these studies were rigorous in terms of study quality, with four less rigorous studies in which blinding was unclear. 69,97,134,138

In some cases, GSUS was not significantly correlated with radiographic progression whereas PDUS was (see Table 5). There was no significant correlation with radiological progression for GSUS in the study by Ikeda et al. ,113 which did not find improved sensitivity or specificity above those for DAS28-CRP at 24 weeks (see Table 4). This study also found that PDUS was significantly correlated with radiological progression in the MTX-treated subgroup but not in bDMARD-treated patients.

Grey-scale ultrasound was not significantly correlated with radiographic progression in a study of 22 patients in clinical remission whereas there was a significant correlation between PDUS and radiographic progression. 144 One study135,136 found that PDUS was significantly associated with later radiographic outcomes. Another study of 25 patients found that neither GSUS nor PDUS was significantly correlated with erosion progression at 2 years’ follow-up. 141

Some studies reported a significant association of CE with radiographic progression (see Table 5). DAS28 was significantly correlated with radiographic progression in four studies,55,69,113,144 although not in the study by Boyesen and Haavardsholm134 nor in the bDMARD subsets in the study by Ikeda et al. 113 HAQ score was significantly correlated with radiographic progression in the only study reporting this outcome. 55 ESR and CRP did not significantly correlate with radiographic progression,55,69,134,141,144 with the exception of the study by Naredo et al. ,140 which found that ESR and total radiographic score progression were significantly associated. Biomarkers (serum proteins) were significantly correlated with modified total Sharp score (mTSS) in the only study reporting this comparator. 138

Swollen joint count and TJC were significantly correlated with radiographic progression in three studies55,139,144 but not in two studies97,135,136 and painful joint count was not significantly correlated with radiographic progression in one study. 135,136

Power Doppler ultrasound was significantly associated with radiographic progression in 10 studies in which it was measured. Associations reported as ORs were as follows: OR 12.21 [95% confidence interval (CI) 3.34 to 44.73; p < 0.001]135 and OR 1.80 (95% CI 1.20 to 2.71; p = 0.005). 139 Associations reported at correlation coefficients were as follows: r = 0.099 (p = 0.05);69 r = 0.357 (p = 0.006);113 r = 0.59 (p < 0.001);55 r = 0.696 (p = 0.011);97 r = 0.59 (p-value not reported);140 and r = 0.77 (p-value not reported). 138 Mann–Whitney U-test results reported were p < 0.001136 and p = 0.0011. 144

One study141 reported a non-significant association of baseline PDUS with the outcome measure. This different result could not be explained by study quality or the joints assessed and, although the authors suggested that the scoring system used was not as sensitive as that used in other studies, other studies that used semiquantitative scores found significant associations. This study did differ from most in that the outcome of erosion was measured by US. The other study that used US to measure the end point was the study reporting borderline significance for association. 69

Grey-scale ultrasound was significantly associated with radiographic progression in six studies. Significant associations reported were as follows: Mann–Whitney U-test p = 0.027,136 r = 0.140 (p < 0.001),69 r = 0.61 (p < 0.001),55 OR 2.15 (95% CI 1.23 to 3.75; p = 0.01)134 and OR 2.08 (95% CI 1.39 to 3.11). 139 A moderate correlation was found between GSUS and radiographic progression in one study. 138 GSUS was not significantly associated with radiographic progression in three studies: OR 1.92 (95% CI 0.49 to 7.54; p = 0.350);135 R = 0.062 (p = 0.649);113 and Mann–Whitney U-test non-significant. 141 One of these studies113 had a shorter follow-up time (24 weeks) than the others, but the other two studies135,141 with non-significant associations had similar follow-up times to the studies finding significant associations. These two studies135,141 were two of the older studies included in the review, which may indicate a difference in the US machines used; however, because of the heterogeneity between studies, it is uncertain why these studies differed from those reporting a significant association. The difference between studies reporting significant associations and studies reporting non-significant associations could not be explained by study quality, joints assessed or how the end point was measured.

The DAS28 joints was significantly correlated with radiographic progression in one study measuring progression using the ultrasound 7 score (US7) score (r = 0.621, p < 0.001)69 and three studies measuring progression using the mTSS [r = 0.342, p = 0.009;113 r = 0.40, p < 0.05;55 and p = 0.0010 (DAS28-ESR) and p = 0.041 (DAS28-CRP) (only p-values reported)144]. DAS28 was not significantly correlated in one study measuring MRI erosive progression. 134 Given heterogeneity between trials, it is uncertain whether outcome measure was the factor explaining the difference between trials finding a significant association, or not, between DAS28 and later radiographic progression.

Other outcomes

Studies reporting outcomes other than radiographic progression (measures of disease activity) are shown in Table 6. These were prospective cohort studies in which patients were tested with US and underwent CE at baseline and were then followed up and evaluated for outcome measures of disease activity. All studies used measures in the baseline CE that were not the same as the outcome measure at follow-up (although some studies additionally reported assessment of the outcome measure at baseline (DAS28 and HAQ score;55 components of the composite outcome measure145).

TABLE 6 - Correlation of US and CE with prognosis outcomes other than radiographic progression

CXCL13, chemokine (C-X-C motif) ligand 13; HAQ-DI, Health Assessment Questionnaire Disability Index; NS, non-significant; PGA, patient global assessment; RAQoL, Rheumatoid Arthritis Quality of Life; TGFβ1, transforming growth factor beta 1.

Multivariable analysis included US joint count, PDUS > 0, DAS, SJC and steroid use.

Grey-scale USJCAS (ultrasonographic joint count for active synovitis).

Power Doppler USJIPD (ultrasonographic joint index for power Doppler signal).

Logistic regression included PDUS, ESR and TGFβ1.

Study	Population	Joints	Follow-up	Outcome	Type of US	Correlation of US synovitis with outcome	Type of CE	Correlation of CE with outcome
Scirè 2009137 (same study as Bugatti 2012147)	43 patients achieving clinical remission	Bilateral shoulder, elbow, wrist, MCP, PIP, sternoclavicular, acromioclavicular, knee, ankle and MTP joints	6 months	Clinical relapse	US joint count > 2 (multivariable)a	OR 4.6 (95% CI 0.4 to 49.5; NS)	SJC > 1	OR 0.6 (95% CI 0.1 to 5.5)
					PDUS > 0	OR 12.8 (95% CI 1.6, 103.5; p < 0.05)	DAS28 of > 1.1	OR 9 (95% CI 0.7 to 110.3)
Bugatti 2012147 (same study as Scirè 2009137)	161 patients with early RA	Hands	12 months	Low disease activity (i.e. a DAS of < 2.4)	PDUS synovitis scored (0–3)	OR 0.94 [0.31 to 2.83; p = 0.91 (NS)]	Serum levels of the chemokine CXCL13	NS
Naredo 200755	42 patients with RA starting DMARDs (38 followed up for 1 year)	28 joints	1 year	DAS28	Joint count for GSUSb	GSUS r = 0.63; p < 0.001	SJC, TJC, DAS28, HAQ, ESR, CRP	DAS28, r = 0.75, p < 0.001; HAQ; r = 0.66, p < 0.001; TJC, r = 0.50, p < 0.01; SJC; r = 0.45, p < 0.01; ESR/CRP, r = 0.49, p < 0.01
					Joint count for PDUS signalc	PDUS r = 0.63; p < 0.001
				HAQ	Joint count for GSUSb	GSUS NS	SJC, TJC, DAS28, HAQ, ESR, CRP	HAQ, r = 0.82, p < 0.001; DAS28; r = 0.49, p < 0.01; TJC, r = 0.50, p < 0.01; SJC NS; ESR NS
					Joint count for PDUS signalc	PDUS NS
Osipyants 201397,150	35	Wrists	6 months	HAQ	PDUS	Significant (r = –0.821; p = 0.003)	DAS28-CRP, SDAI	Association with baseline DAS28 or SDAI NS. Subgroup [disease duration < 2 years (n = 9)]: HAQ score at 6 months correlated with baseline DAS28-CRP (r = 0.705, p = 0.02) and SDAI (r = 0.678, p = 0.03)
Ramirez García 201498	28	Knees and hands (wrists, MCP, PIP flexor and extensor tendons of the hand)	12 months	Relapse from clinical remission (i.e. a DAS28 of < 2.6)	PDUS	p = 0.034; logistic regression model OR 6.18d	ESR, TGFβ1	ESR, p = 0.046; TGFβ1, p = 0.082
Saleem 2012142	93 RA patients in clinical remission as determined by their treating rheumatologist	Hand and wrist	12 months	Flare – defined as any increase in disease activity requiring a change in therapy [24/93 (26%)]	PDUS and GSUS	PDUS (unadjusted OR 4.08, 95% CI 1.26 to 13.19; p = 0.014); GSUS score was not significantly associated (p = 0.658)	HAQ-DI, TJC, SJC, RAQoL, CRP, DAS28, SDAI	HAQ-DI per 0.1 unit OR 1.27 (95% CI 1.07 to 1.52; p = 0.006). RAQol OR 1.10 (95% CI 1.01 to 1.20; p = 0.036). Other variables were NS: SJC, p = 0.690; TJC, p = 0.827; CRP, p = 0.308; DAS28 remission, p = 0.499; SDAI remission, p = 0.616
Wakefield 2007143	10	Bilateral glenohumeral, elbow, wrist, MCP, PIP, knee, tibiotalar, midtarsal and MTP joints	46 weeks	Time to clinical remission	GSUS score	R = –0.221 (NS)	Baseline DAS28	r = 0.627; p = 0.071 (NS trend)
					PDUS score	R = –0.289 (NS)
Yoshimi 2014145	22 patient with RA in clinical remission (of 31 recruited)	Bilateral wrists and all of the MCP and PIP joints	2 years	Remission, defined by ACR/EULAR Boolean criteria; score of ≤ 1 for all of TJC, SJC, CRP and PGA components	PDUS total score	p = 0.020	DAS28-CRP, DAS28-ESR, SJC, TJC, CRP, ESR	NS for all: DAS28-CRP, p = 0.76; DAS28-ESR; p = 0.38; SJC; p = 0.060; TJC, p = 1.00; CRP, p = 0.17; ESR, p = 0.39
					GSUS total score	p = 0.020

In three cases, US and at least one clinical comparator measure were associated with the later outcome [ESR,98 Health Assessment Questionnaire Disability Index (HAQ-DI)142 and DAS55]. Three studies found that US was significantly associated with the later outcome but the clinical comparator was not (DAS28-CRP or SDAI;97 DAS28-CRP, DAS28-ESR, SJC, TJC, CRP and ESR;145 and SJC and DAS28137). In the study by Naredo et al. ,55 the clinical comparator DAS28 was associated with the later HAQ outcome, but the US joint count of 28 joints was not. The authors suggested that their results may differ from those of other studies because early RA patients were used in their study and, at this point of disease, functional status is related to inflammatory activity more than residual structural damage.

Low disease activity (i.e. a DAS of < 2.4) at 1 year was not significantly correlated with PDUS or the biomarker chemokine (C-X-C motif) ligand 13 (CXCL13). 147

The Disease Activity Score 28 joints at 1 year was significantly correlated with GSUS and PDUS and HAQ, SJC, TJC and ESR/CRP. 55 Relapse from clinical remission (i.e. of DAS28 of < 2.6) was significantly correlated with PDUS and ESR but not transforming growth factor beta 1 (TGFβ1). 98 Relapse (i.e. a DAS of ≥ 1.6) at 6 months was significantly correlated with PDUS, SJC and DAS but not GSUS. 137 Time to clinical remission (DAS28 of < 2.6) was not significantly correlated with GSUS, PDUS or DAS28 at baseline in a study of 10 patients. 143

Remission, defined by ACR/EULAR Boolean criteria [score of ≤ 1 for all of the TJC, SJC, CRP and patient global assessment components], at 2 years was significantly correlated with PDUS and GSUS, but not with the clinical comparators DAS28, SJC, TJC, CRP or ESR. 145

Flare, defined as any increase in disease activity requiring a change in therapy, at 12 months was significantly correlated with PDUS, HAQ and Rheumatoid Arthritis Quality of Life (RAQoL), but not with GSUS, SJC, TJC, CRP, DAS28 or SDAI. 142

Two studies investigated HAQ, one of which found that HAQ score at 1 year of follow-up was not significantly correlated with GSUS, PDUS, SJC, or ESR, but was with DAS28 and TJC. 55 One study97 found that HAQ score at 6 months was significantly correlated with PDUS, but not with DAS28 or SDAI (DAS28 and SDAI were significantly correlated in the subgroup with a disease duration of < 2 years but there were only nine patients in this subgroup).

Treatment studies

Treatment response or strategies

Nine studies79,93,95,100,101,139,154–156 reported data relating to treatment response or strategies. RA was reported as being diagnosed by 2010 ACR/EULAR criteria11 in two studies154,155 and by pre-2010 ACR/EULAR criteria8 in four studies;100,101,139,156 the criteria used were not reported in two studies. 93,95 Established semiquantitative scoring systems were used by Dougados et al. ,139 Inanc et al. ,93 Naredo et al. 156 (scoring system published by Wakefield51), Iwamoto et al. 155 (scoring system published by Naredo et al. 140) and Dale et al. 154 (scoring system published by Szkudlarek et al. 52). The heterogeneity of the trials precluded meta-analysis. Therefore, no summary estimates of effect are available, which is a limitation of the review. Significance values referred to the association of baseline US and CE measures with treatment measures (such as treatment persistence or response to treatment tapering). These measures could be of importance to patients in so far as they can be used to refine treatment.

Ultrasound was compared with CE as potential predictors of treatment persistence or response (Table 7). The study by Ellegaard et al. 101 investigated patients starting TNFi treatment to determine whether or not treatment persistence at 1 year of follow-up was associated with US and clinical measures [TJC, SJC, CRP, visual analogue scale (VAS), HAQ and DAS28]. This was a prospective cohort study in which patients were tested with US and underwent CE at baseline and were then followed up and evaluated to investigate the ability of these factors to predict treatment adherence, defined as patients remaining on TNFi therapy at the 1-year follow-up. Among US measures, the square root of the US Doppler colour fraction (USDCF), a measure of hyperaemia, was the only measure that significantly predicted TNFi continuation (p = 0.008). None of the clinical measures assessed, including SJC, TJC, DAS28 and CRP, was significantly associated with treatment persistence. 101 In the study by Inanc et al. 93, when considering EULAR response compared with no response after 3 months, baseline PDUS (p = 0.029) and GSUS (p = 0.020) differed significantly between responders and non-responders. This was a prospective cohort study in which patients were tested with US and underwent CE at baseline and were then followed up and evaluated to investigate the association with EULAR response at 3 months’ follow-up. Two of the clinical measures assessed also significantly differentiated between responders and non-responders [pain VAS (p = 0.009) and SJC (p = 0.05)], whereas other clinical measures (DAS28, TJC, ESR and CRP) did not. 93

TABLE 7 - Treatment persistence or response

NR, not reported; NS, not significant.

Other US measures not significant.

Multivariate analysis included extra-articular involvement, pain VAS and sum score of baseline PDUS.

Study	Population	Joints	Follow-up	Outcome	US type	US association with outcome	CE association with outcome
Ellegaard 2011101	109 patients starting TNFis (ADA, ETN or IFX)	Wrist (most affected)	1 year (n = 69 with US follow-up)	Treatment persistence (continued with TNFi)	USDCF square roota	Treatment persistence vs. dropouts because of lack of efficacy, p = 0.024; treatment persistence vs. all dropouts, p = 0.008	Treatment persistence vs. dropouts because of lack of efficacy (all NS): TJC, p = 0.86; SJC, p = 0.98; CRP, p = 0.86; VAS (patient global), p = 0.08; HAQ, p = 0.416; DAS28, p = 0.943. Treatment persistence vs. all dropouts (all NS): TJC, p = 0.321; SJC, p = 0.486; CRP, p = 0.453; VAS (patient global), p = 0.240; HAQ, p = 0.098; DAS28, p = 0.375
Inanc 201493	43 patients starting TNFis (drugs NR)	28 joints according to EULAR guideline	3 months	EULAR no response vs. response	PDUS	p = 0.029	Pain VAS, p = 0.009; SJC, p = 0.05; other clinical measures NS (DAS28, p = 0.90; TJC, p = 0.12; HAQ, p = 0.31; ESR, p = 0.61; CRP, p = 0.98)
					GSUS	p = 0.020
				EULAR good/moderate response (multivariate analysis)b	PDUS	OR 0.88 (95% CI 0.68 to 0.94; p = 0.04)	NR
					GSUS	NS

Patients with persistent synovitis measured by GSUS or PDUS (Table 8), after 4 months of bDMARD treatment, were significantly more likely to have radiological progression at 2 years’ follow-up. 139 The study by Dougados et al. 139 was a prospective cohort study in which 4 months of biological therapy were prescribed, with further follow-up up to 2 years. The association of lack of response to treatment at 4 months, measured by US or CE using a semiquantitative scoring system, with radiological progression at 2 years was assessed. For persistent synovitis as measured by CE, this did not reach significance. 139 Taylor et al. 100 reported prognostic data from a study that was part of a RCT comparing MTX plus IFX with MTX plus placebo in aggressive early RA. Baseline US and CRP were tested for association with radiological progression at 54 weeks. US could significantly predict radiological progression in MTX plus placebo-treated patients (p = 0.020), but not in IFX plus MTX-treated patients (p = 0.479). 100 However, there were only 12 patients in each group in this study. Baseline CRP did not significantly predict progression in either treatment group. 100

TABLE 8 - Progression and treatment response

PBO, placebo.

vdHSS.

Occurrence or worsening of erosion or joint space narrowing.

Study	Population	Follow-up duration	Joints	Outcome	Type of US	US association with outcome	Type of CE	CE association with outcome
Taylor 2004100	24 (IFX + MTX, n = 12; MTX + PBO, n = 12)	54 weeks	Hands and feet	Radiological progression at 54 weeksa	Baseline synovial thickness	MTX + PBO, r = 0.69, p = 0.020; IFX + MTX, r = –0.23, p = 0.479 (NS)	Baseline CRP	MTX + PBO, r = 0.58, p = 0.077; IFX + MTX, r = 0.19, p = 0.562
					Baseline synovial vascularity	MTX + PBO, r = 0.78, p = 0.005; IFX + MTX, r = –0.28, p = 0.372 (NS)
Dougados 2013139	59 (ETN, n = 34; ADA, n = 23; IFX, n = 2)	2 years	Wrist, MCP, PIP and MTP joints	Radiological progressionb	GSUS (> 0 on scale from 0 to 3), persistent synovitis after 4 months of treatment	OR 3.14 (95% CI 1.50 to 6.55; p = 0.002)	CE synovitis (> 0 on scale 0–3) persistent synovitis after 4 months of treatment	OR 1.70 (95% CI 0.93 to 3.12; p = 0.086)
					PDUS (> 0 on scale from 0 to 3), persistent synovitis after 4 months of treatment	OR 2.79 (95% CI 1.19 to 6.56; p = 0.019)

One prospective cohort study with 6 months’ follow-up155 reported the ability of US and CE to predict relapse following discontinuation of bDMARD (TNFi or TCZ) treatment (Table 9). GSUS- and PDUS-detected synovitis at the time of treatment discontinuation (total GSUS score of ≥ 14, total PDUS score of ≥ 3) had higher positive predictive values (PPVs) than DAS28 (≥ 1.5) for predicting relapse within 6 months. Relapse was defined as a DAS28 of > 3.2 in conjunction with escalation of anti-rheumatic treatment. Using these cut-off points patients were more likely to relapse if they had high GSUS (p = 0.007) or PDUS (p = 0.001) scores, but this was not the case for high DAS28 (p = 0.297). Few patients with high US scores did not relapse (GSUS, n = 2/10, PDUS, n = 1/9), but several patients with high DAS28 did not relapse (n = 15/28). However, negative predictive values (NPVs) were similar for GSUS, PDUS and DAS28 as most patients with scores below the cut-off point for US or DAS did not relapse.

TABLE 9 - Accuracy of US to predict relapse following discontinuation of treatment

NR, not reported.

Cut-off points determined by receiver operating characteristic (ROC) curve analysis.

Study	Population	Follow-up	Joints	Outcome measure	US typea	US PPV (95% CI), %	US NPV (95% CI), %	US sensitivity(95% CI), %	US specificity(95% CI), %	CE typea	DAS28 PPV, %	DAS28 NPV, %	DAS28 sensitivity, %	DAS28 specificity, %
Iwamoto 2014155	40 patients in clinical remission who had discontinued bDMARDs	6 months	134 synovial sites in 40 joints	Relapse DAS28 of > 3.2 and anti-rheumatic treatment escalated	GSUS cut-off point ≥ 14 (n = 10)	80 (NR)	73 (NR)	50 (NR)	92 (NR)	DAS28 cut-off point ≥ 1.5 (n = 28)	46	75	81	38
					PDUS cut-off point ≥ 3 (n = 9)	89 (NR)	74 (NR)	50 (NR)	96 (NR)	DAS28 cut-off point < 1.5 (n = 12)	25	NR	NR	NR

This study155 also compared the median values of several variables for patients with and without relapse (Table 10); the total GSUS score differed significantly between the groups (p = 0.005), as did the total PDUS score (p = 0.002), whereas clinical variables (DAS28, SDAI, CDAI and HAQ) did not. Two other prospective cohort studies95,156 investigated the association of outcomes with US assessment or CE at the time of treatment discontinuation or tapering (see Table 10).

TABLE 10 - Tapering and treatment discontinuation

NR, not reported, NS, not significant.

Remission: DAS28 of < 2.6.

Remission: CDAI of < 2.8.

Multivariate analysis included number of DMARDs, anti-cyclic citrullinated peptide antibody level, mean DAS28-CRP and median total PDUS score.

A DAS28 of < 2.6 or a SDAI of < 3.3.

Multivariate analysis included baseline DAS28 and the global index for Doppler synovitis (DSI) for 42 joints, 12 joints and wrist–MCP–ankle–MTP.

Study	Population	Follow-up	Joints	Outcome	US type	US association with outcome	CE association with outcome
Iwamoto 2014155	42 RA patients in clinical remission, discontinued biological therapya	6 months	134 synovial sites in 40 joints	Relapse (i.e. a DAS28 of > 3.2) and anti-rheumatic treatment escalated	Total GSUS score	p = 0.005	All NS: DAS28-ESR, p = 0.609; DAS28-CRP, p = 0.389; SDAI, p = 0.180; CDAI, p = 0.275; HAQ-DI, p = 0.721
					Total PDUS score	p = 0.002
Luengroongroj 201595	32 RA patients in clinical remission on DMARD(s), about to stop or reduce doseb	3 months	NR	Disease flare (arthritis symptoms and signs detected)	PDUS (median total score)	Univariate analysis: OR 2.14 (95% CI 1.13 to 4.05) (significant; p-value NR). Multivariate analysis:c NS (trend); OR 3.06, (95% CI 0.95 to 9.84; p = 0.06)	Number of DMARDs: univariate analysis – OR 5.88 (95% CI 1.12 to 30.88) (significant); in multivariate analysis NS. DAS28-CRP: NS by univariate or multivariate analysis
Naredo 2015156,157	77 RA patients in sustained clinical remissiond	12 months (n = 35, 45.5%, tapering failure at 12 months)	42 (including hands and feet)	bDMARD tapering failure (increase in bDMARD doses and/or the presence of clinical disease activity according to both DAS28 and SDAI criteria)	PDUS global index for Doppler synovitis (DSI) calculated	Significant associations: higher DSI (p < 0.0005); and DSI > 0 (p < 0.0005) at baseline. Multivariate analysis: DSI > 0 (OR 29.92, 95% CI 6.81 to 131.40; p < 0.0005)	Significant associations: longer duration of RA (p = 0.009), higher number of previous synthetic DMARDs (p = 0.003), higher DAS28 (p = 0.011), higher SDAI (p = 0.003) at baseline. Multivariate analysis: DAS28 of ≥ 2.2 (OR 5.81, 95% CI 1.62 to 20.93; p = 0.007). Other clinical variables (duration of remission) were not significant predictors in multiple regression analysis
					GSUS	GSUS was not a significant predictor of tapering failure in the multiple regression analysise

A study of patients in clinical remission with a reducing dose of bDMARDS156 found that PDUS could significantly predict tapering failure (p < 0.0005), defined as an increase in bDMARD dose and/or the presence of clinical disease activity according to both DAS28 and SDAI criteria (see Table 10), whereas GSUS was not significantly associated with tapering failure. Some clinical variables could also significantly predict tapering failure, namely DAS28 (p = 0.011) and SDAI (p = 0.003). 156 In a study of patients in clinical remission discontinuing or tapering DMARDS (bDMARDs or cDMARDs not specified),95 PDUS significantly predicted disease flare (p = 0.06 by multivariate analysis) (see Table 10), as did the number of DMARDs taken at baseline, whereas DAS28 did not.

One RCT154 investigated treatment strategies with and without US (Table 11). In this study, patients were given the same treatment for 3 months and then either step-up DMARD escalation strategies guided by DAS28 alone (n = 57) (target = DAS28 of < 3.2) or step-up DMARD escalation strategies guided by DAS28 plus PDUS assessment of a limited joint set (n = 53) (target = PDUS signal in one or fewer joints). Dale et al. 154 found that, at 18 months, significantly more patients in the group receiving PDUS had attained Disease Activity Score 44 joints (DAS44) remission (p = 0.046). Since drafting this report, the full results of this study have been published. 78 At 18 months’ follow-up, significantly more patients in the group receiving PDUS had attained DAS44 remission (p = 0.03) (see Table 11). However, for the two co-primary end points, change from baseline in DAS44 and rheumatoid arthritis magnetic resonance imaging scoring system (RAMRIS) erosion score, there was no significant between-group difference (p = 0.72 and p = 0.33, respectively). A preliminary publication of the ARCTIC study results,79 identified post search, also investigated treatment strategies with and without US in a randomised comparison (see Table 11). The primary end point (a DAS of < 1.6 and no swollen joints at 16, 20 and 24 months and no progression in vdHSS between 16 and 24 months) was reached by 26 patients in the US strategy group and 21 in the control group, with no significant difference between the groups.

TABLE 11 - Treatment strategies with and without US

IQR, interquartile range; NR, not reported.

Only one patient did not meet 2010 ACR/EULAR RA classification criteria. 11

Study	Population	Follow-up duration	Outcome	US treatment strategy group	Clinical treatment strategy group	Comparison
Dale 2013154 (TaSER)	110 early RA patients randomised to 3 months of the same treatment and then step-up DMARD escalation strategies guided by either DAS28 alone (n = 57) (target: DAS28 of < 3.2) or DAS28 + PDUS assessment of a limited joint set (n = 53) (target: PDUS signal in one or fewer joints)	18 months	DAS44 remission (i.e. a DAS44 of < 1.6)	Strategy PDUS and DAS28: significant improvement in DAS44 (mean change −2.76, 95% CI −0.84 to 0.33; p = 0.39). DAS44 remission: 33% at 3 months, 65% at 18 months	Strategy DAS28: significant improvement in DAS44 (mean change in DAS44 −2.51, 95% CI NR). DAS44 remission: 43% at 3 months, 44% at 18 months	After 18 months, more patients in the PDUS group had attained DAS44 remission (p = 0.046) (at 3 months, difference was not significant: p = 0.32)
Dale 201678 (TaSER)	111 RA or undifferentiated arthritis patientsa	18 months	DAS44 remission (i.e. a DAS44 of < 1.6)	(n = 54) DAS44 remission: 35 (66%)	(n = 57) DAS44 remission: 25 (43%)	DAS44 remission (p = 0.03)
			Mean change in DAS44	–2.69 (significant improvement)	–2.58 (significant improvement)	Non-significant difference between groups (p = 0.72)
			Median (IQR) change in RAMRIS erosion score	0.5 (0.0–1.0)	1.0 (0.0–2.0)	Non-significant difference between groups (p = 0.33)
Haavardsholm 201579 (ARCTIC)	130 early RA patients	24 months	Primary end point was a DAS of < 1.6, a SJC44 of < 1 and a ΔvdHSS of < 0.5 between 16 and 24 months	(n = 118) Strategy PDUS and GSUS and DAS: 26 (22.0%)	(n = 112) Strategy DAS: 21 (18.8%)	p = 0.54
			DAS remission (i.e. a DAS of < 1.6)	80 (67.8%)	75 (67.0%)	p = 0.89
			Median (IQR) change in vdHSS total score between 0 and 24 months	1.0 (0–2.5)	1.5 (0.5–3.0)	p = 0.09
			Median (IQR) change in vdHSS erosion score between 0 and 24 months	0.5 (0–1.5)	1.0 (0.5–2.0)	p = 0.04

For both randomised trials (TaSER and ARCTIC), there was no significant difference in primary end point between the clinical strategy group and the strategy group based on US and clinical measures. Both trials found a significant advantage of the strategy including US for one of the secondary outcomes (DAS remission in the TaSER study and erosion score in the ARCTIC study), but not for the other secondary outcomes (ACR core set variables in the TaSER study; CDAI or SDAI remission or EULAR response in the ARCTIC study). This suggests that adding US to a DAS-based strategy is not beneficial after 18–24 months. It is uncertain whether this is because of a genuine lack of improvement caused by the US strategy or because of other factors. Both trials included early RA patients only and PDUS (the ARCTIC study also used GSUS) and have some incorporation bias in terms of the clinical strategy and primary outcome being DAS related (although in the TaSER study the strategy used DAS28 and one of the co-primary outcomes was DAS44 and in the ARCTIC study the primary outcome was a composite measure of remission that included DAS).

Treatment decisions

Six studies89–91,94,152,153 reported on the use of US in addition to clinical measures and the impact on treatment decisions (Table 12). These were fairly small studies, with sample sizes ranging from 1789 to 10994 (see Appendix 8). Four studies89,90,94,153 took place in rheumatology clinics in the UK, one152 was from the USA and one91 was from France. Four studies89–91,152 did not report the source of funding, although three89–91 of these stated that the authors had no conflicts of interest. Two studies94,153 were supported by pharmaceutical companies. Dale et al. 153 stated that neither of their funders had any role in the design, performance, analysis, interpretation or reporting of the study.

TABLE 12 - Use of US in addition to CE alone and impact on treatment decisions

NR, not reported.

Study	Source of funding	Population, number of patients	Setting	US and treatment decisions
Bhamra 201489	NR	17	Nuffield Orthopaedic Hospital Emergency Rheumatology Clinic, UK	In 15/17 (88%) patients, treatment escalation was directly influenced by GSUS findings
Ceponis 2014152	NR	51	San Diego Health System, CA, USA	US use modified the bDMARD and/or cDMARD used in seven cases, but did not affect the overall treatment plan (p > 0.15) or overall cDMARD (p < 0.062) or bDMARD use (p > 1.0). Use of US increased physicians’ confidence (p < 0.0005) and patients reported that their confidence in physicians’ medical decisions had increased (88.4% of cases)
Ciurtin 201390	NR	39	Department of Rheumatology, University College Hospital, London, UK	Study identified 9/39 (23%) RA patients with active synovitis with a positive Doppler signal that prompted a change of treatment
Dale 2014153,161 (TaSER)	Chief Scientist’s Office, Scottish Executive, and Pfizer UK	53	Three Glasgow teaching hospital sites, UK	On 120 occasions (29%), GSUS findings contradicted the DAS28 and led to modified treatment decisions
Gandjbakhch 200891	NR	52	University rheumatology centre, Paris, France	US results caused a change in treatment in 13% of patients. Confidence of the clinician, measured using a VAS (0–100), increased by 11 points (95% CI 5.9 to 16.9 points) following US (p < 0.001)
Kelly 201394	AbbVie	109	Four secondary care rheumatology clinics: two in London, one in Southampton and one in Antrim, UK	The US-monitored group (n = 54) had a significantly shorter time to initiation of DMARDs (1.45 vs. 2.38 months) than the non-US group (n = 55) (t-test, p = 0.02)

When the percentage of treatment decisions modified by the additional use of US was reported, this ranged from 13% to 88% of cases89–91,153 (for studies based in the UK the percentages were 23%,90 29%153 and 88%89).

One study89 examined treatment decisions in clinician-evaluated patients by survey and found that 15 out of 17 (88%) treatment escalations were influenced by the addition of US. Of two observational studies, one91 found that US (in addition to CE and DAS28) influenced treatment decisions in only 7 out of 52 (13%) patients; however, clinician confidence was significantly improved following US (p < 0.001). The other observational study94 found a significant difference in time to initiation of DMARDs (p = 0.02) (the US-monitored group had a shorter time to initiation than the group undergoing clinical evaluation alone) (see Table 12). Two studies investigated the utility of routine US and reported a change in treatment following US in 9 out of 39 (23%) patients with clinician-evaluated synovitis90 and a modification of the bDMARD or cDMARD used in 7 out of 51 patients (compared with clinical evaluation of swollen joints and CDAI);152 clinician confidence was also significantly improved following US (p < 0.0005) in one of the studies. 152 A study of treatment strategy153 reported that, on 120 occasions (29%), GSUS findings contradicted the DAS28 and led to modified treatment decisions (see Table 12).

Survey

A survey of UK rheumatology units (see Appendix 1) with 31 respondents suggested that US is already being used in some units for modifying treatment decisions in RA. Twenty respondents (65%) said that they used US for monitoring synovitis. Additionally, one respondent said that their unit planned to use US in the future. Survey respondents were self-selecting and so the sample may have been biased. Only 31 responses were received by the end of February 2016 and the small sample size is a limitation of the survey.

Chapter 4 Assessment of cost-effectiveness

Results

The cost-effectiveness of ultrasound monitoring in patients who have been stable on biological disease-modifying anti-rheumatic drugs and for whom the clinician is contemplating reducing the dose of biological disease-modifying anti-rheumatic drug

The average reduction in bDMARD use that would be required for a strategy of US monitoring to be cost neutral was calculated. This was 2.46% (£226.62/£9200). The levels of drug reduction and serious infections avoided at which US is at the threshold of cost-effectiveness are shown in Figure 2.

FIGURE 2.

The average levels of bDMARD drug reduction and serious infections avoided that result in a cost per QALY gained of £20,000 and £30,000 for the use of US in monitoring synovitis.

The cost-effectiveness of ultrasound monitoring in patients who have been stable on conventional disease-modifying anti-rheumatic drugs and for whom the clinician is contemplating reducing the dose of conventional disease-modifying anti-rheumatic drug

The average reduction in cDMARD use that would be required for a strategy of US monitoring to be cost neutral was calculated. It was not possible to recoup the assumed costs of US (£227) with reduced use of either intensive cDMARDs (£218 per annum) or MTX (£39 per annum). However, the levels of drug reduction and serious infections avoided at which US is at the threshold of cost-effectiveness are shown in Figure 3.

FIGURE 3.

The average levels of intensive cDMARD drug reduction and serious infections avoided that result in a cost per QALY gained of £20,000 and £30,000 for the use of US in monitoring synovitis.

The cost-effectiveness of ultrasound monitoring in patients who appear to have disease progression despite biological disease-modifying anti-rheumatic drug treatment and for whom the clinician is contemplating amending treatment

This analysis was not formally conducted as there was insufficient evidence to provide any robust assessment. The likely impact of a change in treatment for a patient on bDMARDs will vary depending on the current treatment and on whether or not the disease was progressing.

At the time of writing, NICE guidance41 recommended that patients progressing from first-line bDMARDs should receive RTX in combination with MTX as it is cheaper than other bDMARDs and has a similar efficacy. 23 As such, the immediate impact of a patient moving to RTX would be a cost saving, regardless of whether or not the disease was progressing and regardless of any US result. However, a potential treatment option has been exhausted, which may have longer-term impacts if the disease had not progressed at the time of the switch to RTX, but began progressing on subsequent treatments. It is unclear to what extent the decision to move to RTX would be influenced by the use of US to monitor synovitis.

In contrast, if a patient was on full-dose TCZ following RTX treatment, at the point that the clinician was contemplating amending treatment, current NICE guidance would allow no further bDMARDs. It is unclear to what extent the knowledge of underlying synovitis would influence a clinician’s decision to amend treatment. The threshold proportion of patients who could be moved onto RTX from their initial bDMARD, at which point the savings in bDMARD acquisition cost would offset the costs of US monitoring, has been calculated. This threshold value, assuming a cost per year of £4900 for RTX, would be £226.62/(£9200 – £4900), which is 5.3%. The components of this formula are the annual costs of US monitoring and the annual costs associated with bDMARDs and RTX.

If a patient was on a reduced-dose bDMARD because of previous tapering then the use of US to decide whether or not to increase the dose is easier to model, although the answer would be dependent on the assumed increase in dose. It has earlier been shown that the assumed costs of US per year equate to 2.46% of the annual costs of bDMARDs. The proportion of patients who would not need an increase in dose because of the information provided by US for a strategy of monitoring with US to be cost neutral can be calculated as £226.62/[assumed increase in bDMARD dose (as a percentage of the full dose) × £9200].

Thus, if a dose increase of 33% of the full dose was contemplated, the threshold proportion of patients who do not need to be treated would be £226.62/(33% × £9200), which is equal to 7.4%.

The cost-effectiveness of ultrasound monitoring in patients who appear to have disease progression despite conventional disease-modifying anti-rheumatic drug treatment and for whom the clinician is contemplating amending treatment

This analysis has again been divided into those patients on intensive cDMARDs and those on MTX alone. It has been assumed that those on MTX alone would progress to an intensive cDMARD strategy, whereas those on intensive cDMARDs would move to a bDMARD. The thresholds for patients on intensive cDMARDs are shown in Figure 4 and the thresholds for those on MTX alone are shown in Figure 5. Assuming no changes in serious infections the threshold value was 2.52% for those not progressing to bDMARDs; the threshold value could not be attained for those not progressing to intensive cDMARDs.

FIGURE 4.

The average levels of reduction in patients moving to bDMARDs and serious infections avoided that result in a cost per QALY gained of £20,000 and £30,000 for the use of US in monitoring synovitis.

FIGURE 5.

The average levels of reduction in patients moving to intensive cDMARDs and serious infections avoided that result in a cost per QALY gained of £20,000 and £30,000 for the use of US in monitoring synovitis.

When a patient is on a reduced dose of intensive cDMARDs or MTX because of previous tapering, the threshold for the proportion of patients at which monitoring with US becomes cost neutral can be calculated in a similar manner to that illustrated for patients on bDMARDs who have received tapered medication and the clinician is contemplating increasing the dose.

Sensitivity analysis

Sensitivity analysis was undertaken assuming that the number of US scans required per patient to monitor synovitis ranged from one per year to 12 per year. The cost of a scan was assumed constant at £56.66.

Figure 6 provides data relating to the analyses in which the treatment dose was being tapered. It was calculated that, even if a scan was provided on a monthly basis, this approach would be cost neutral if the average decrease in bDMARD costs was 7.39%. This value was 15.99% for intensive cDMARDs. In contrast, for patients on intensive cDMARDs, even when only one scan was performed per year a reduction in drug costs of 26% would be needed to make US cost neutral.

FIGURE 6.

Sensitivity analysis relating reduction in drug-related costs to the assumed number of US scans undertaken per year.

Further sensitivity analysis was undertaken looking at the percentage reduction in the cost of bDMARDs, assuming lower prices than the £9200 assumed in the base case. The motivation for this sensitivity analysis was the fact that biosimilars have entered the market. This sensitivity analysis is shown in Figure 7.

FIGURE 7.

Sensitivity analysis relating percentage reduction in bDMARD acquisition costs to the assumed price of bDMARDs.

It is seen that, as the price of bDMARDs approaches 50% of the price assumed in the base case, a 5% reduction in bDMARD use would still be sufficient to make monitoring with US cost saving.

Additional sensitivity analysis was conducted to assess the impact of the increased costs associated with use of subcutaneous MTX, which was assumed to cost £798.71 per annum more than oral MTX.

The results for the tapering analyses when assuming costs associated with subcutaneous MTX are provided in Figures 8–11. The reduction in drug costs at which the use of US became cost neutral were 2.27% for patients on bDMARDs, 22.9% for those on intensive cDMARDs and 27.04% for patients on subcutaneous MTX alone.

FIGURE 8.

The average levels of bDMARD drug reduction and serious infections avoided that result in a cost per QALY gained of £20,000 and £30,000 for the use of US in monitoring synovitis assuming the use of subcutaneous MTX.

FIGURE 9.

The average levels of intensive cDMARD drug reduction and serious infections avoided that result in a cost per QALY gained of £20,000 and £30,000 for the use of US in monitoring synovitis assuming the use of subcutaneous MTX.

FIGURE 10.

The average levels of MTX drug reduction and serious infections avoided that result in a cost per QALY gained of £20,000 and £30,000 for the use of US in monitoring synovitis assuming the use of subcutaneous MTX.

FIGURE 11.

Sensitivity analyses relating reduction in drug-related costs to the assumed number of US scans undertaken per year assuming the use of subcutaneous MTX.

Chapter 5 Assessment of factors relevant to the NHS and other parties

Evidence identified for this report appears to indicate that monitoring synovitis with US could potentially be cost-effective given the possibility of tapering of DMARDs or inappropriate escalation of treatment. There are a number of potential implications for NHS resources. If monitoring of synovitis becomes more widespread (and there are a number of unknowns, for example US use may vary according to the apparent clinical level of disease activity), depending on the number of US scans undertaken per year, there may be a need for more sonographers. Such increased resources would also depend on drivers outside the scope of this report. US has clinical advantages beyond the monitoring of inflammatory arthritis, both for diagnosis (e.g. for a proportion of patients with suspected inflammatory arthritis, enabling earlier intervention) and for guiding the accurate placement of needles for therapeutic injection. All of this has implications for US access in both rheumatology and radiology departments. This also raises issues regarding timely and equal access to US.

Chapter 6 Discussion

Chapter 7 Conclusions

Little evidence matched the decision problem. However, this systematic review found correlational evidence that US-detected synovitis was significantly associated with later radiographic progression. PDUS-detected synovitis also significantly predicted DAS28, ACR/EULAR remission and flare. Studies suggested that US was superior to CE alone in predicting response to treatment tapering or discontinuation. Studies varied with regard to interventions, comparators and outcomes, precluding meta-analysis and meaning that there is uncertainty in the available evidence. With regard to treatment strategies, studies were not all consistent with regard to the statistical significance of the benefit of US. Only two RCTs were identified and the addition of US to DAS-based strategies did not significantly influence the primary end points, although one of these RCTs significantly favoured the addition of US for the outcome of attaining DAS remission. It is uncertain whether the lack of significant influence on the primary end point is due to a genuine lack of improvement caused by the US strategy or other factors such as joint counts and types of US used within studies. Small studies suggested that US was used in treatment decisions and could increase physician confidence in those decisions. A small survey of UK rheumatology units suggested that US is already being used in some units for modifying treatment decisions in RA. Most studies relied on one-off US measurements at baseline; however, the two RCTs employed US serially as part of treatment strategies.

The purposefully simplistic modelling undertaken shows that there is potential for the monitoring of synovitis with US to be cost-effective, although there remains considerable uncertainty around this conclusion.

Acknowledgements

We would like to thank Mike Holmes [School of Health and Related Research (ScHARR), University of Sheffield] for help with sifting the cost-effectiveness searches, Eva Kaltenthaler and Paul Tappenden (ScHARR) for providing comments on the draft report and Gill Rooney (Programme Manager, ScHARR) for providing administrative support and preparing and formatting the report.

We would like to thank the patient advisor who contributed to the report and the National Rheumatoid Arthritis Society (NRAS) who provided names of patients who were willing to be involved in the project. We would like to thank the BSR for providing input into the survey to investigate how US was being used in practice and for publicising it to UK rheumatology units.

This report was commissioned by the National Institute for Health Research (NIHR) HTA programme. The views expressed in this report are those of the authors and not necessarily those of the NIHR HTA programme.

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Appendix 1 Survey

There were few publications regarding US and its use in treatment decisions (see Chapter 1). A survey was conducted of UK rheumatology units to investigate how US was being used in practice to influence therapy. The BSR publicised the survey to UK rheumatology units. Additionally, the BSR requested that respondents be questioned about the use of US in the diagnosis of RA.

The survey was available to clinicians from December 2015 to February 2016.

Only 31 responses were received by the end of February 2016. Survey respondents were self-selecting and so the sample may have been biased.

Appendix 2 Patient involvement

The National Rheumatoid Arthritis Society were contacted about patient involvement in the study. It provided the names of two patients with RA who were willing to be contacted about being involved. Both patients were sent a draft of the plain English summary and were asked to provide feedback. The full report was available to provide further information. The two patients were also invited to provide comments regarding the patient experience of US and suggestions for future research priorities.

One patient did not respond. The other patient provided feedback on the plain English summary and contributed text on the patient experience of US. This feedback was helpful and was deemed to improve the accessibility of the plain English summary to a lay audience. The text of the plain English summary was amended in accordance with the patient’s suggestions. The background section of the report was amended based on information provided by the patient advisor on the patient experience of US.

Appendix 3 Literature search strategies

There were three phases of searches: (1) initial searches to identify key words, (2) the phase 1 scoping searches and (3) the phase 2 comprehensive searches. The scoping searches were conducted to determine whether or not evidence was available on US for monitoring synovitis in RA and, therefore, whether or not phase 2 of the project could be justified and whether or not any cost-effectiveness analyses could be conducted.

The phase 1 searches identified diagnostic accuracy and prognostic studies relevant to the monitoring of synovitis by US and so comprehensive searches for the diagnostic, prognostic and treatment effectiveness section of the project were conducted as planned. However, the phase 1 scoping searches revealed a lack of data to populate the planned cost-effectiveness model. Following advice from the clinical advisors and consultation with the NIHR HTA programme, it was decided that an analysis of the costs and benefits associated with US would be of value to the clinical community. However, attempting to achieve this using the model that informed the recent NICE multiple technology appraisal40 was not deemed sensible as this contained many elements that would be unnecessary when focusing on current decision problem and would add uncertainty to the results. Therefore, a simpler model was constructed, which was subject to sensitivity analyses and threshold analyses.

Appendix 4 Excluded studies

Table 20 shows the studies excluded at full-text sift, with reasons for exclusion.

Appendix 5 Data extraction tables

For calculations of diagnostic accuracy, US was counted as the reference standard and the accuracy of the clinical comparator was assessed using sensitivity (i.e. the proportion of TPs) and specificity (i.e. the proportion of TNs). Sensitivity is calculated as the number of TPs divided by the sum of the TPs and FNs; specificity is calculated as the number of TNs divided by the sum of the TNs and FPs.