Ultrasound monitoring

National Guideline Centre (UK)

Ultrasound monitoring

Rheumatoid arthritis in adults: diagnosis and management

Evidence review I

NICE Guideline, No. 100

Authors

National Guideline Centre (UK).

London: National Institute for Health and Care Excellence (NICE); 2018 Jul.

ISBN-13: 978-1-4731-3003-6

1. Ultrasound monitoring

1.1. Review questions

In adults with rheumatoid arthritis (RA), what is the added value of monitoring disease activity with ultrasound?

In adults with poor prognosis rheumatoid arthritis, what is the added value of monitoring disease activity with ultrasound?

1.2. Introduction

Structural damage can happen quickly in rheumatoid arthritis if inflammation is not efficiently suppressed. The widespread use of strategies that aim for clinical remission or low disease activity has significantly improved the prognosis of rheumatoid arthritis. However, progressive bone erosion and relapses can still occur even in clinical remission.

Ultrasound can detect subclinical synovitis, but it is not known whether the use of ultrasound as part of routine monitoring results in improved patient outcomes.

1.3. PICO table

For full details, see the review protocol in Appendix A.

Table 1

PICO characteristics of clinical effectivenss review.

Table 2

PICO characteristics of prognostic question.

This review sought to investigate clinical assessment plus ultrasound using 2 components. Firstly the review sought out randomised cotrolled trials comparing monitoring with clinical assessment combined with ultrasound versus monitoring via clinical assessment alone. The outcomes would give a comparison of the clinical affectiveness of the monitoring mthods.

The second component assessed the prognostic value of monitoring to predict the outcomes of interest. The prognostic factors of interest encompassed clinical assessment and ultrasound through measurement of disease activity and ultrasound variables. Multivariate analysis was utilised to assess whether single factors involved in the assessment were independently associated with the outcomes of interest. Factors such as tender joint count, swollen joint count, pain, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and anti-CCP are measures utilised in disease assessment so they have been reported as factors in the evidence.

1.4. Methods and process

This evidence review was developed using the methods and process described in Developing NICE guidelines: the manual.[ref to be added] Methods specific to this review question are described in the review protocol in appendix A.

Declarations of interest were recorded according to NICE’s 2014 conflicts of interest policy.

1.5. Clinical evidence

1.5.1. Included studies

A search was conducted for randomised controlled trials and systematic reviews of these study types in the first instance. However as evidence was limited, prospective prognostic cohort studies were also searched for.

One randomised controlled trial and 5 prognostic studies were included in the review; they are summarised in Table 3 and Table 4 below. Evidence from these studies is summarised in the clinical evidence summaries below (see Table 6, Table 7, Table 8, Table 9, Table 10 and Table 11).

See also the study selection flow chart in appendix C, study evidence tables in appendix D, forest plots in appendix E and GRADE tables in appendix H.

1.5.2. Excluded studies

See the excluded studies list in appendix I.

1.5.3. Summary of clinical studies included in the evidence review

Table 3

Summary of randomised controlled trials included in the evidence review.

Table 4

Summary of prospective cohort prognostic studies included in the evidence review.

See appendix D for full evidence tables.

1.5.4. Quality assessment of clinical studies included in the evidence review

1.5.4.1. RCTs

Table 5

Clinical evidence summary: clinical assessment and ultrasound versus clinical assessment alone.

1.5.4.2. Prognostic studies

Table 6

Clinical evidence summary - Outcome: MRI erosive progression (dichotomous – at 1 year).

Table 7

Clinical evidence summary - Outcome: Disease flare (increase in disease activity requiring an initiation, change or increase in therapy based on DAS28; dichotomous – at 1 year).

Table 8

Clinical evidence summary - Outcome: Relapse (dichotomous – at 1 year; DAS28-ESR>2.6 following a period of clinical remission).

Table 9

Clinical evidence summary - Outcome: Remission (DAS28-CRP4v <2.6; dichotomous – at 1 year).

Table 10

Clinical evidence summary - Outcome: Remission (DAS44-CRP4v <1.6; dichotomous – at 1 year).

Table 11

Clinical evidence summary - Outcome: Function (HAQ score; continuous – 1 year after prognostic variables were measured).

See appendix F for full GRADE tables.

1.6. Economic evidence

1.6.1. Included studies

No relevant health economic studies were identified.

1.6.2. Excluded studies

No health economic studies that were relevant to this question were excluded due to assessment of limited applicability or methodological limitations.

See also the health economic study selection flow chart in appendix G.

1.6.3. Unit costs

The unit costs of rheumatology appointments and of unbundled diagnostic ultrasound imaging are provided below for guidance.

Table 12

Cost of outpatient rheumatology appointments.

Table 13

Cost of ultrasound.

1.7. Resource costs

The recommendations made in this review are not expected to have a substantial impact on resources.

1.8. Evidence statements

1.8.1. Clinical evidence statements

Evidence from 1 RCT showed no clinically important difference between monitoring with or without ultrasound in terms of disease activity, quality of life, function, remission, pain or withdrawal due to adverse events. Monitoring with ultrasound showed a small benefit in terms of lower radiological progression and fewer withdrawals from the trial due to willingness to participate; however, there was considerable uncertainty in the direction of these effects, limiting the ability to draw firm conclusions (1 to 2 years, moderate quality, n=230).

Evidence from 5 prospective cohort studies with prognostic analysis collectively reporting on 6 different outcomes at 1 year was highly inconsistent. Ultrasound grey scale inflammation was reported by 1 study (n=84, high to very low quality) to be independently associated with subsequent MRI erosive progression, but was not found to be independently associated with remission (1 study, n=217, very low quality) or function (1 study, n=93, low to very low quality). Synovial hypertrophy was found to be independently associated with a reduced risk of relapse. Power Doppler (PD) measures were independently associated with disease flare in 1 study (n=126, low to very low quality), in 2 studies (n=185 and 217, low to very low quality). The association between PD and the relapse or function was present for some PD measures but not others, two studies found no independent association between PD and remission (n=217, very low quality) or function (n=185) (low to very low quality). No single ultrasound factor was found to consistently predict the outcomes utilised by the studies included in the review.

1.8.2. Health economic evidence statements

No relevant economic evaluations were identified.

1.9. The committee’s discussion of the evidence

1.9.1. Interpreting the evidence

1.9.1.1. The outcomes that matter most

Ultrasound is used to monitor disease activity in addition to clinical assessment; therefore, the most critical outcome was agreed to be the DAS. Other critical outcomes were agreed as quality of life and function.

The important outcomes were agreed as the number of people in remission, and low disease activity, using DAS thresholds. The committee agreed that data reported in this format is not as informative as continuous DAS data but still gives an indication of symptom relief and disease activity improvement. Other important outcomes were the number of people experiencing a relapse, flare, a change in planned management at time of testing, or withdrew from or adhered to trial, as well as the level of pain and radiographic progression.

For most outcomes, 12-month data was sought apart from radiographic progression where the longest reported time point was reported. Outcomes of change in planned management at the time of testing and withdrawal from trial data from the duration of the entire trial was of interest.

No data were available for the outcomes of low disease activity and change in planned management at the time of testing.

1.9.1.2. The quality of the evidence

The review included a single randomised controlled trial (RCT). The evidence was moderate quality for all of the critical outcomes (change in DAS, change in Rheumatoid Arthritis Impact of Disease Score (RAID), and change in quality of life (EQ-5D)) as well as the important outcomes of change in radiological progression and change in pain. The evidence was generally at high risk of bias due to the absence of blinding in the study and the subjective nature of the outcomes reported; only radiographic progression was at low risk of bias.

Further evidence was available from 5 prognostic studies, but this was generally of low to very low quality and could not be pooled as each study reported different outcomes. The majority of evidence was considered to be at very serious risk of bias. The committee discussed 1 study that reported that 52% of participants were lost to follow up or excluded from the analysis due to their outcome data being incomplete without explanation for the missing data. Many of the other studies had high levels of participants lost to follow up, or failed to report missing data at all. This, combined with low quality, reduced the committee’s certainty in the results despite the studies meeting the inclusion criteria.

Another limitation was that many studies failed to report key aspects of their statistical methods. For many of the outcomes, there were small numbers of participants and low numbers of events, resulting in wide confidence intervals, meaning there was considerable uncertainty as to whether the factor was associated with better or poorer outcomes. The impact of these limitations of the evidence was that the committee agreed they could not place much weight on the data from the prognostic studies. No studies were found that looked at people with poor prognostic factors alone or sperately presented their data..

1.9.1.3. Benefits and harms

The data from the RCT provided evidence that ultrasound made no clinical difference for any of the critical outcomes (disease activity score, RAID score and quality of life) when compared to monitoring without the use of ultrasound. Most of the important outcomes (DAS remission, pain and withdrawal due to adverse events) also failed to show a clinical difference between the groups. The outcomes which did show limited benefit with the use of ultrasound were associated with considerable uncertainty and were inconsistent with the majority of the data that informed the review. The committee therefore placed little weight on the evidence for these outcomes in their deliberations.

The committee discussed the findings from the prognostic studies. The committee could not reconcile the highly inconsistent findings between the outcomes and even between different ultrasound measures for the same outcome. For example, given the association seen between grey scale inflammation and MRI erosive progression, the committee were surprised to see no association between the same factor and the outcomes of remission and function.

The committee agreed that given the limited data (1 small study for each outcome), the low to very low evidence quality, and the inconsistent results across the outcomes, little weight should be placed on the prognostic data in determining the value of ultrasound in monitoring rheumatoid arthritis. The committee agreed that RCT data was the best way to establish the true added value of monitoring rheumatoid arthritis using ultrasound. In the presence of the clear RCT findings, the committee placed little weight on the (inconsistent, inconclusive) results of the non-randomised prognostic studies.

Overall, the committee agreed that there was no evidence that ultrasound added value over monitoring disease activity clinically for the majority of rheumatoid arthritis patients. As a result, the committee agreed that for most people with rheumatoid arthritis, clinical assessment performs well and there was no reason to recommend the use of ultrasound as it does not provide additional information that would change management or outcomes.

The committee decided that the evidence did not support the routine use of ultrasound in monitoring the majority of people with rheumatoid arthritis and made a recommendation accordingly.

The committee agreed, however, that there may be a proportion of people who might benefit from ultrasound assessment, but these populations were not defined in any of the included studies. These might be people with rheumatoid arthritis where decisions have to be made about escalating treatment, and in whom:

the clinician perceives a difference between the clinical examination and the disease activity score (for example, where no clinical synovitis is apparent but other markers of disease activity such as inflammatory markers or pain are high); or
clinical examination is unreliable or uncertain (for example, the evaluation of synovial swelling is affected by other co-existent factors such as obesity or oedema).

The committee noted that the included studies did not solely reflect the potential rheumatoid arthritis populationsof interest, as stated above. Therefore, the committee agreed to make a research recommendation to determine whether ultrasound assessment would add value to standard clinical monitoring in the specific RA populations.

1.9.2. Cost effectiveness and resource use

No health economic studies were identified. The unit cost of ultrasound (£55 per ultrasound) was presented to the committee to aid the consideration of cost-effectiveness. The committee noted that, in some areas ultrasound monitoring is carried out in the rheumatology department and in other areas it is referred to the radiology department. The unit cost presented to the committee was deemed to reflect the cost of ultrasound within a radiology department appropriately.

The committee discussed the potential economic benefits of ultrasound monitoring in a subset of people. The committee noted that in this subset of people in whom ultrasound monitoring could help to identify remission, treatment could be tapered off, and there could be a reduction in the use of DMARDs. This could potentially offset the cost of monitoring or even save costs to the NHS. The committee conceded that no evidence is currently available to support this.

The clinical evidence did not support the routine use of ultrasound in monitoring the majority of people with rheumatoid arthritis, and the committee made a recommendation accordingly. As routine use of ultrasound for monitoring is used in some rheumatology departments in the NHS, it is anticipated that this recommendation should reduce the overall use of ultrasound and therefore moderately reduce costs to the NHS.

1.9.3. Other factors the committee took into account

The committee discussed that results seen from ultrasound can be meaningful for people with rheumatoid arthritis. The patient representatives on the committee explained that ultrasound enables patients to visualise their disease activity, instead of only been given a score (for example, DAS). This may be reflected by data from the RCT which showed that more people continued to be willing to participate in the ultrasound treatment arm compared to the clinical monitoring only arm (though the committee again noted the imprecision of this effect estimate). In some circumstances, this visualisation of disease activity may be important and may improve patient outcomes, by encouraging medication adherence and facilitating agreement to treatment escalation where necessary. However, the committee agreed that in the presence of evidence that including ultrasound as part of regular monitoring does not improve clinical outcomes, its routine use could not be justified. Further research should help to clarify the circumstances where ultrasound assessment may be clinically and cost effective in rheumatoid arthritis.

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Appendices

Appendix A. Review protocols

Table 14. Review protocol: Use of ultrasound monitoring in rheumatoid arthritis (PDF, 190K)

Table 15. Health economic review protocol (PDF, 152K)

Appendix B. Literature search strategies

The literature searches for this review are detailed below and complied with the methodology outlined in Developing NICE guidelines: the manual 2014, updated 2017. https://www.nice.org.uk/guidance/pmg20/resources/developing-nice-guidelines-the-manual-pdf-72286708700869

For more detailed information, please see the Methodology Review.

B.1. Clinical search literature search strategy

Searches were constructed using a PICO framework where population (P) terms were combined with Intervention (I) and in some cases Comparison (C) terms. Outcomes (O) are rarely used in search strategies for interventions as these concepts may not be well described in title, abstract or indexes and therefore difficult to retrieve. Search filters were applied to the search where appropriate.

Table 16. Database date parameters and filters used

Medline (Ovid) search terms

Embase (Ovid) search terms

Cochrane Library (Wiley) search terms

B.2. Health Economics literature search strategy

Health economic evidence was identified by conducting a broad search relating to rheumatoid arthritis population in NHS Economic Evaluation Database (NHS EED – this ceased to be updated after March 2015) and the Health Technology Assessment database (HTA) with no date restrictions. NHS EED and HTA databases are hosted by the Centre for Research and Dissemination (CRD). Additional searches were run on Medline and Embase for health economics studies.

Table 17. Database date parameters and filters used

Medline (Ovid) search terms

Embase (Ovid) search terms

NHS EED and HTA (CRD) search terms

Appendix C. Clinical evidence selection

Figure 1. Flow chart of clinical study selection for the review of ultrasound monitoring

Appendix D. Clinical evidence tables

D.1. Randomised controlled trials (PDF, 216K)

D.2. Prognostic studies (PDF, 210K)

Appendix E. Forest plots

E.1. Randomised controlled trial: Clinical assessment and ultrasound versus clinical assessment alone

Figure 2. Change in Disease activity score (DAS28)

Figure 3. Change in function (RAID score)

Figure 4. Change in Quality of life (EQ-5D)

Figure 5. Remission (DAS<1.6)

Figure 6. Change in pain (VAS)

Figure 7. Withdrawal from trial due to “no longer willing”

Figure 8. Withdrawal from trial due to adverse events

E.2. Prognostic studies: Effect of clinical and US prognostic factors on various outcomes

Note: All prognostic factors are displayed on the forest plots even where odds ratios were not reported, as these factors were considered by the studies. Where a study has its results listed as ‘Not estimable’ for a specific factor, that factor was not independently associated with the outcome following multivariable analysis.

Figure 9. Clinical and US prognostic factors for MRI erosive progression (dichotomous; at 1 year)

Figure 10. Clinical and US prognostic factors for disease flare (increase in disease activity requiring an initiation, change or increase in therapy based on DAS28; dichotomous – at 1 year)

Figure 11. Clinical and US prognostic factors for relapse (DAS28-ESR>2.6 following a period of clinical remission; dichotomous – at 1 year)

Figure 12. Clinical and US prognostic factors for remission (DAS28-CRP4v <2.6; dichotomous – at1 year)

Figure 13. Clinical and US prognostic factors for remission (DAS44-CRP4v <1.6; dichotomous – at1 year)

Appendix F. GRADE tables

Appendix H. Health economic evidence tables

None.

Appendix I. Excluded studies

I.1. Excluded clinical studies

Table 25. Studies excluded from the clinical review

I.2. Excluded health economic studies

Table 26. Studies excluded from the health economic review

Appendix J. Research recommendations

J.1. Ultrasound to assess disease activity (monitoring) where clinical examination is inconsistent or inconclusive

Research question: What is the clinical and cost effectiveness of using ultrasound to monitor disease in adults with RA when/where clinical examination is inconclusive or inconsistent with other signs of disease activity?

Why this is important:

Rheumatoid arthritis is a chronic inflammatory condition which requires regular review of disease activity to enable relevant adjustments in management accordingly to achieve a target of remission or low disease activity.

While some people in clinical remission have been found to have subclinical inflammation or erosions on ultrasound examination, randomised controlled evidence does not support using ultrasound for this routine monitoring of RA. However, ultrasound may be useful in assessing disease activity in a narrower subgroup of people with RA; specifically, when clinical examination is inconclusive or is inconsistent with other signs of disease activity (for example, pain or markers of inflammation). Reliable research on the added value of ultrasound in assessing disease activity as part of a monitoring strategy in these subgroups is absent.

If clinical examination is unreliable or uncertain in this subgroup, it will be challenging for healthcare professionals to make a valid clinical assessment and thus apply a treat to target approach and make appropriate management decisions.

In addition, where there is inconsistency between the clinical examination and the disease activity score, it may be unclear if the person has subclinical inflammatory synovitis or more of a widespread pain syndrome, which is not inflammatory. These states require very different treatments, so it is important to define them accurately.

Criteria for selecting high-priority research recommendations

Table

Population: Adults with RA in whom clinical examination is inconclusive or is inconsistent with other signs of disease activity Intervention(s): Treatment adjusted throughultrasound assessment plus usual monitoring assessments

Final

Evidence review

Developed by the National Guideline Centre, hosted by the Royal College of Physicians

The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or service users. The recommendations in this guideline are not mandatory and the guideline does not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and, where appropriate, their carer or guardian.

Local commissioners and providers have a responsibility to enable the guideline to be applied when individual health professionals and their patients or service users wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with compliance with those duties.

NICE guidelines cover health and care in England. Decisions on how they apply in other UK countries are made by ministers in the Welsh Government, Scottish Government, and Northern Ireland Executive. All NICE guidance is subject to regular review and may be updated or withdrawn.

Bookshelf ID: NBK577152PMID: 35129933

Table 1PICO characteristics of clinical effectivenss review

Population	Adults with rheumatoid arthritis Studies in adults with poor prognostic factors, patients in remission, and patients with early disease (< 1 year) will be presented separately
Interventions	Clinical assessment plus ultrasound assssment
Comparison	Clinical assessment alone
Outcomes	CRITICAL Disease Activity Score (continuous) at 12 months Quality of life (continuous) at 12 months Function (continuous) at 12 months IMPORTANT Remission (dichotomous) at 12 months Low disease activity (dichotomous) at 12 months Relapse (dichotomous) at 12 months Flare (dichotomous) at 12 months Pain (continuous) at 12 months Radiographic progression (continuous) at 12 months Change in planned management at time of testing (dichotomous) over duration of trial Withdrawal from trial / adherence to strategy (dichotomous) over duration of trial
Study design	Randomised controlled trials (RCTs) Systematic Review / Network Meta-Analysis of RCTs

Table 2PICO characteristics of prognostic question

Population	Adults with RA. Studies in adults with poor prognostic factors, patients in remission, and patients with early disease (< 1 year) will be presented separately.
Prognostic factor(s)	Prognostic factors: Ultrasound findings (for example: synovitis, persistent effusion, tendon injuries, synovitis, Doppler flow, tethering of the tendons, ligament, tenosynovitis, erosions) Disease activity
Outcome(s)	Disease Activity Score (continuous) Quality of life (continuous) Function (continuous) Remission (dichotomous) Low disease activity (dichotomous) Relapse (dichotomous) Flare (dichotomous) Pain (continuous) Radiographic progression (continuous) Change in planned management at time of testing (dichotomous) Withdrawal from trial / adherence to strategy (dichotomous)
Study design	Prospective cohort studies (prognostic) Systematic reviews of the above

Table 3Summary of randomised controlled trials included in the evidence review

Study

Intervention and comparison

Population

Outcomes

Comments

Haavardsh olm 2016²⁵

Monitoring of treat-to-target tight control regime using clinical assessment and ultrasound versus monitoring using clinical assessment alone (usual care).

US Group:

Target was clinical remission (DAS <1.6 and no swollen joints) and no power Doppler (PD) signal in any of the joints assessed.

Control group:

Target was clinical remission (DAS < 1.6 and no swollen joints).

Adults aged 18-75 years with early RA

n=238

Disease activity score
Rheumatoid Arthritis Impact of Disease (RAID) score
Quality of life (EQ-5D)
Remission
Pain
Radiological progression
Withdrawal from trial due to “no longer willing”
Withdrawal from trial due to adverse events

Participants in both groups were treated according to the same fixed treatment algorithm, adhering to a treat-to-target strategy with DMARD escalation therapy if target was not met. US results could be used by clinicians to overrule DAS-based target decisions if indicated.

Table 4Summary of prospective cohort prognostic studies included in the evidence review

Study	Population	Analysis	Prognostic variable(s)	Confounders	Outcome	Limitations
Boyesen 2011⁵; Haavar dsholm 2008²⁶	Adults with early rheumatoid arthritis (<1 year) n = 84	Stepwise multiple logistic regression	USGS¹ inflammation, DAS28, anti-CCP+, SvdH score²	All prognostic variables plus an additional eleven clinical, biomarker and demographic variables	Magnetic resonance imaging (MRI) erosive progression	Low risk of bias
Geng 2016²³	Adults with rheumatoid arthritis in clinical remission n = 126	Multivariable logistic regression	DAS28-ESR³, PD⁴>0, PD total score and SH⁵ total score	Additional variables included in univariate analysis not known	Relapse (DAS28-ESR > 2.6)	Very high risk of bias (outcome measurement – blinding not reported; statistical analysis and reporting – univariate analysis (UVA) analysis not reported and multivariate analysis (MVA) model unclear).
Horton 2016³²	Adults with rheumatoid arthritis (DAS28-CRP4v ≥2.6) n = 217	Multivariable logistic regression	TJC28⁶, SJC28⁷, CRP⁸ mg/L, patient VASglobal disease assessment (components of DAS28-CRP), total USGS¹ score on US, total PD⁴ activity (PDA) score	All prognostic variables plus an additional eleven clinical, biomarker and demographic variables	Remission: both DAS28-CRP4v < 2.6 and DAS44-CRP4v < 1.6	Very high risk of bias (study attrition – 52% patients lost to follow up or excluded; outcome measurement – blinding not reported; statistical analysis and reporting – only included variables in MVA if p < 0.05 in UVA, may have missed important variables).
Saleem 2012⁶⁰	Adults with rheumatoid arthritis in remission (no flares in the last 6 months, stable treatment) n = 93	Multiple binary logistic regression	PD⁴ present, remission (DAS28<2.6)	All prognostic variables plus health assessment questionnaire disability index (HAQ-DI)	Disease flare	Very high risk of bias (study attrition- no information on drop-outs; prognostic factor measurement- crudemeasurement; study confounding- few possible confounders accounted for)
Zavada 2017⁷⁶	Adults with early or established rheumatoid arthritis n = 185	Multiple logistic regression	Previous DAS28-CRP⁸ and previous US assessment (GSsynSS⁹, PDsynSS¹⁰, GStenSS¹¹, PDtenSS¹², erosion score (ES)	All prognostic variables plus previous HAQ	HAQ score (after measuring prognostic variables)	High risk of bias (study attrition- missing data unclear) Serious indirectness (MVA model looks at associations between different time points rather than baseline to 12 months)

1: Ultrasound grey-scale

2: Sharp van der Heijde score

3: Erythrocyte sedimentation rate

4: Power Doppler

5: synovial hypertrophy

6: Tender joint count of 28 joints

7: Swollen joint count of 28 joints

8: C-reactive protein

9: Grey-scale synovitis sum score

10: Power Doppler synovitis sum score

11: Grey-scale tenosynovitis sum score

12: Power Doppler tenosynovitis sum score

Table 5Clinical evidence summary: clinical assessment and ultrasound versus clinical assessment alone

Outcomes

No of Participants (studies) Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

Anticipated absolute effects

Risk with Control

Risk difference with Monitoring including ultrasound (95% CI)

Disease Activity Score

Change in DAS28. Scale from: 0 to 9.4.

230

(1 study)

12 months

MODERATE¹

due to risk of bias

The mean change in Disease Activity Score in the control groups was −2.4

The mean change in Disease Activity Score in the intervention groups was

0 higher

(0.35 lower to 0.35 higher)

Function

Change in rheumatoid arthritis impact of disease (RAID) score. Scale from: 0 to 10.

230

(1 study)

12 months

MODERATE¹

due to risk of bias

The mean change in rheumatoid arthritis impact of disease score in the control groups was −2.4

The mean change in rheumatoid arthritis impact of disease score in the intervention groups was

0.2 lower

(0.76 lower to 0.36 higher)

Quality of life

Change in EQ-5D. Scale from: −0.59 to 1.

230

(1 study)

12 months

MODERATE¹

due to risk of bias

The mean change in quality of life in the control groups was 0.25

The mean change in quality of life in the intervention groups was

0.03 higher

(0.04 lower to 0.1 higher)

Remission

DAS <1.6

230

(1 study)

12 months

LOW¹^,²

due to risk of bias, imprecision

RR 0.89

(0.75 to 1.06)

723 per 1000

80 fewer per 1000

(from 181 fewer to 43 more)

Pain

Change in VAS. Scale from: 0 to 100.

230

(1 study)

12 months

MODERATE¹

due to risk of bias

The mean change in pain in the control groups was −29.2

The mean change in pain in the intervention groups was

3.3 lower

(10.16 lower to 3.56 higher)

Radiological progression

Change in Sharp score. Scale from: 0 to 448.

230

(1 study)

24 months

MODERATE³

The median (interquartile range - IQR) change in Sharp score in the control group was 1.5 (0.5-3.0)

The median change in Sharp score in the intervention groups was

0.5 lower⁴ (median (IQR): 1.0 (0-2.5)

Withdrawal from trial due to “no longer willing”

211

(1 study)

24 months

VERY LOW¹^,²

due to risk of bias, imprecision

RR 0.4

(0.08 to 2)

48 per 1000

29 fewer per 1000

(from 44 fewer to 48 more)

Withdrawal from trial due to adverse events

215

(1 study)

24 months

VERY LOW¹^,²

due to risk of bias, imprecision

RR 1.15

(0.36 to 3.64)

48 per 1000

7 more per 1000

(from 30 fewer to 126 more)

1: Downgraded by 1 increment if the majority of the evidence was at high risk of bias, and downgraded by 2 increments if the majority of the evidence was at very high risk of bias

2: Downgraded by 1 increment if the confidence interval crossed one MID or by 2 increments if the confidence interval crossed both MIDs

3: Imprecision could not be assessed because non-parametric statistics were reported. The confidence interval is relatively wide.

4: Confidence intervals not calculated due to non-parametric statistics

Table 6Clinical evidence summary - Outcome: MRI erosive progression (dichotomous – at 1 year)

Risk factor for predicting MRI erosive progression	Number of studies	Effect (95% CI)	Imprecision³	GRADE Quality
USGS² inflammation (<0.5 vs ≥0.5)	1 (n=84)	Adjusted OR: 2.01 (1.14-3.53)	none	HIGH
DAS28	1 (n=84)	Not independently associated with the outcome following multivariable analysis.	n/a	n/a
Anti-CCP+	1 (n=84)	Not independently associated with the outcome following multivariable analysis.	n/a	n/a
Sharp van der Heijde score	1 (n=84)	Not independently associated with the outcome following multivariable analysis.	n/a	n/a

: n/a: unable to assess as data not reported (factor not independently associated with the outcome following multivariable analysis)

2: USGS: Ultrasound grey-scale

3: If the 95% CI did not cross the null line then no serious imprecision was recorded. If the 95% CI crossed the null line then serious imprecision was recorded.

Table 7Clinical evidence summary - Outcome: Disease flare (increase in disease activity requiring an initiation, change or increase in therapy based on DAS28; dichotomous – at 1 year)

Risk factor for predicting disease flare	Number of studies	Effect (95% CI)	Imprecision²	GRADE Quality
Remission (DAS28<2.6)	1 (n=93)	Adjusted OR: 2.71 (0.73-10.14)	serious	VERY LOW
PD¹ present	1 (n=93)	Adjusted OR: 7.57 (1.75-32.76)	none	LOW

1: Power Doppler

2: If the 95% CI did not cross the null line then no serious imprecision was recorded. If the 95% CI crossed the null line then serious imprecision was recorded.

Table 8Clinical evidence summary - Outcome: Relapse (dichotomous – at 1 year; DAS28-ESR>2.6 following a period of clinical remission)

Risk factor for predicting relapse	Number of studies	Effect (95% CI)	Imprecision⁴	GRADE Quality
PD²>0	1 (n=126)	Adjusted OR: 8.8 (2.7 – 28.4)	none	LOW
PD² total score	1 (n=126)	Adjusted OR: 1.4 (0.9 – 2.0)	serious	VERY LOW
SH³ total score	1 (n=126)	Adjusted OR: 0.7 (0.5 – 1.0)	serious	VERY LOW
DAS28-ESR	1 (n=126)	Data unavailable¹	not assessed	not assessed

1: Variable was independently associated with the outcome but data is not presented here as it was incorrectly reported by the authors.

2: Power Doppler

3: Synovial hypertrophy

4: If the 95% CI did not cross the null line then no serious imprecision was recorded. If the 95% CI crossed the null line then serious imprecision was recorded.

Table 9Clinical evidence summary - Outcome: Remission (DAS28-CRP4v <2.6; dichotomous – at 1 year)

Risk factor for predicting remission	Number of studies	Effect (95% CI)	Imprecision⁶	GRADE Quality
CRP¹ mg/l	1 (n=217)	Not independently associated with the outcome following multivariable analysis.	n/a	n/a
Patient VAS global disease assessment	1 (n=217)	Adjusted OR: 0.98 (0.95 – 1.00)	serious	VERY LOW
SJC28²	1 (n=217)	Not independently associated with the outcome following multivariable analysis.	n/a	n/a
TJC28³	1 (n=217)	Adjusted OR: 0.93 (0.85 – 1.02)	serious	VERY LOW
Total USGS⁴ score on US	1 (n=217)	Not independently associated with the outcome following multivariable analysis.	n/a	n/a
Total PDA⁵ score on US	1 (n=217)	Not independently associated with the outcome following multivariable analysis.	n/a	n/a

: n/a: unable to assess as data not reported (factor not independently associated with the outcome following multivariable analysis)

1: C-reactive protein

2: Tender joint count of 28 joints

3: Swollen joint count of 28 joints

4: Ultrasound grey-scale

5: Power Doppler Activity

6: If the 95% CI did not cross the null line then no serious imprecision was recorded. If the 95% CI crossed the null line then serious imprecision was recorded.

Table 10Clinical evidence summary - Outcome: Remission (DAS44-CRP4v <1.6; dichotomous – at 1 year)

Risk factor for predicting remission	Number of studies	Effect (95% CI)	Imprecision⁶	GRADE Quality
CRP¹ mg/l	1 (n=217)	Not independently associated with the outcome following multivariable analysis.	n/a	n/a
Patient VAS global disease assessment	1 (n=217)	Not independently associated with the outcome following multivariable analysis.	n/a	n/a
SJC28²	1 (n=217)	Not independently associated with the outcome following multivariable analysis.	n/a	n/a
TJC28³	1 (n=217)	Adjusted OR: 0.88 (0.79 – 0.98)	none	LOW
Total USGS⁴ score	1 (n=217)	Not independently associated with the outcome following multivariable analysis.	n/a	n/a
Total PDA⁵ score on US	1 (n=217)	Not independently associated with the outcome following multivariable analysis.	n/a	n/a

: n/a: unable to assess as data not reported (factor not independently associated with the outcome following multivariable analysis)

1: C-reactive protein

2: Tender joint count of 28 joints

3: Swollen joint count of 28 joints

4: Ultrasound grey-scale

5: Power Doppler Activity

6: If the 95% CI did not cross the null line then no serious imprecision was recorded. If the 95% CI crossed the null line then serious imprecision was recorded.

Table 11Clinical evidence summary - Outcome: Function (HAQ score; continuous – 1 year after prognostic variables were measured)

Risk factor for predicting function (at 12 months)	Number of studies	Effect (95% CI)	Imprecision⁵	GRADE Quality
Previous DAS28-CRP	1 (n=185)	Coefficient: 0.161 (0.113 to 0.208)	none	LOW
Previous GSsynSS²	1 (n=185)	Coefficient: −0.004 (−0.019 to 0.010)	serious	VERY LOW
Previous PDsynSS¹	1 (n=185)	Coefficient: −0.021 (−0.040 to −0.002)	none	LOW
Previous GStenSS³	1 (n=185)	Coefficient: 0.000 (−0.085 to 0.085)	serious	VERY LOW
Previous PDtenSS⁴	1 (n=185)	Coefficient: −0.015 (−0.078 to 0.048)	serious	VERY LOW
Previous erosion score	1 (n=185)	Coefficient: 0.012 (−0.022 to 0.046)	serious	VERY LOW

1: Power Doppler synovitis sum score

2: Grey-scale synovitissum score

3: Grey-scale tenosynovitis sum score

4: Power Doppler tenosynovitis sum score

5: If the 95% CI did not cross the null line then no serious imprecision was recorded. If the 95% CI crossed the null line then serious imprecision was recorded.

Table 12Cost of outpatient rheumatology appointments

Currency Code	Currency Description	No. of attendances	National Average Unit Cost
Consultant led
WF01A	Non-Admitted Face to Face Attendance, Follow-Up	1,223,574	£137
WF01B	Non-Admitted Face to Face Attendance, First	311,626	£220
WF02A	Multi-professional Non-Admitted Face to Face Attendance, Follow-Up	7,357	£218
WF02B	Multi-professional Non-Admitted Face to Face Attendance, First	4,219	£246
Non-consultant led
WF01A	Non-Admitted Face to Face Attendance, Follow-Up	250,578	£87
WF01B	Non-Admitted Face to Face Attendance, First	59,478	£146
WF02A	Multi-professional Non-Admitted Face to Face Attendance, Follow-Up	928	£106
WF02B	Multi-professional Non-Admitted Face to Face Attendance, First	366	£114

: Source: NHS Reference costs, 2015-2016³

Table 13Cost of ultrasound

Department Description^(a)	Currency Code	Currency Description	No. of examinations	National Average Unit Cost
Direct Access	RD40Z	Ultrasound Scan with duration of less than 20 minutes, without contrast	1,905,598	£51
Direct Access	RD41Z	Ultrasound Scan with duration of less than 20 minutes, with contrast	43,644	£39
Direct Access	RD42Z	Ultrasound Scan with duration of 20 minutes and over, without contrast	463,721	£60
Direct Access	RD43Z	Ultrasound Scan with duration of 20 minutes and over, with contrast	23,462	£52
Direct Access	RD44Z	Ultrasound Scan, Mobile or Intraoperative Procedures, with duration of less than 20 minutes	31,126	£42
Direct Access	RD45Z	Ultrasound Scan, Mobile or Intraoperative Procedures, with duration of 20 to 40 minutes	22,770	£99
Outpatient	RD40Z	Ultrasound Scan with duration of less than 20 minutes, without contrast	1,993,859	£55
Outpatient	RD41Z	Ultrasound Scan with duration of less than 20 minutes, with contrast	48,731	£52
Outpatient	RD42Z	Ultrasound Scan with duration of 20 minutes and over, without contrast	519,666	£66
Outpatient	RD43Z	Ultrasound Scan with duration of 20 minutes and over, with contrast	20,377	£66
Outpatient	RD44Z	Ultrasound Scan, Mobile or Intraoperative Procedures, with duration of less than 20 minutes	28,758	£55
Outpatient	RD45Z	Ultrasound Scan, Mobile or Intraoperative Procedures, with duration of 20 to 40 minutes	64,212	£89
Other	RD40Z	Ultrasound Scan with duration of less than 20 minutes, without contrast	18,468	£56
Other	RD42Z	Ultrasound Scan with duration of 20 minutes and over, without contrast	3,556	£88
Weighted average				£55

: Source: NHS Reference costs, 2015-2016³

(a): Direct access services are provided independently of an admission or outpatient attendance because a patient is referred by a GP for a test or self-refers.

Table 16Database date parameters and filters used

Database

Dates searched

Search filter used

Medline (Ovid)

1946 – 09 October 2017

Exclusions

Embase (Ovid)

1974 – 09 October 2017

Exclusions

The Cochrane Library (Wiley)

Cochrane Reviews to 2017

Issue 10 of 12

CENTRAL to 2017 Issue 9 of 12

DARE, and NHSEED to 2015

Issue 2 of 4

HTA to 2016 Issue 4 of 4

None

Medline (Ovid) search terms

1.	exp Arthritis, Rheumatoid/
2.	(rheumatoid adj2 (arthritis or arthrosis)).ti,ab.
3.	(caplan* adj2 syndrome).ti,ab.
4.	(felty* adj2 syndrome).ti,ab.
5.	(rheumatoid adj2 factor).ti,ab.
6.	((inflammatory or idiopathic) adj2 arthritis).ti,ab.
7.	“inflammatory polyarthritis”.ti,ab.
8.	or/1-7
9.	limit 8 to English language
10.	letter/
11.	editorial/
12.	news/
13.	exp historical article/
14.	Anecdotes as Topic/
15.	comment/
16.	case report/
17.	(letter or comment*).ti.
18.	or/10-17
19.	randomized controlled trial/ or random*.ti,ab.
20.	18 not 19
21.	animals/ not humans/
22.	Animals, Laboratory/
23.	exp Animal Experimentation/
24.	exp Models, Animal/
25.	exp Rodentia/
26.	(rat or rats or mouse or mice).ti.
27.	or/20-26
28.	9 not 27
29.	exp Ultrasonography/
30.	(ultrasound* or ultrason* or echograph* or echotomograph* or doppler).ti,ab.
31.	29 or 30
32.	28 and 31

Embase (Ovid) search terms

1.	exp *rheumatoid arthritis/
2.	(rheumatoid adj2 (arthritis or arthrosis)).ti,ab.
3.	(caplan* adj2 syndrome).ti,ab.
4.	(felty* adj2 syndrome).ti,ab.
5.	(rheumatoid adj2 factor).ti,ab.
6.	((inflammatory or idiopathic) adj2 arthritis).ti,ab.
7.	“inflammatory polyarthritis”.ti,ab.
8.	or/1-7
9.	limit 8 to English language
10.	letter.pt. or letter/
11.	note.pt.
12.	editorial.pt.
13.	case report/ or case study/
14.	(letter or comment*).ti.
15.	or/10-14
16.	randomized controlled trial/ or random*.ti,ab.
17.	15 not 16
18.	animal/ not human/
19.	nonhuman/
20.	exp Animal Experiment/
21.	exp Experimental Animal/
22.	animal model/
23.	exp Rodent/
24.	(rat or rats or mouse or mice).ti.
25.	or/17-24
26.	9 not 25
27.	exp *echography/
28.	(ultrasound* or ultrason* or echograph* or echotomograph* or doppler).ti,ab.
29.	27 or 28
30.	26 and 29

Cochrane Library (Wiley) search terms

#1.	[mh “Arthritis, Rheumatoid”]
#2.	(rheumatoid near/2 (arthritis or arthrosis)):ti,ab
#3.	(caplan* near/2 syndrome):ti,ab
#4.	(felty* near/2 syndrome):ti,ab
#5.	(rheumatoid near/2 factor):ti,ab
#6.	((inflammatory or idiopathic) near/2 arthritis):ti,ab
#7.	inflammatory polyarthritis:ti,ab
#8.	(or #1-#7)
#9.	[mh Ultrasonography]
#10.	(ultrasound* or ultrason* or echograph* or echotomograph* or doppler):ti,ab
#11.	#9 or #10
#12.	#8 and #11

Table 17Database date parameters and filters used

Database

Dates searched

Search filter used

Medline

2014 – 06 October 2017

Exclusions

Health economics studies

Embase

2014 – 06 October 2017

Exclusions

Health economics studies

Centre for Research and Dissemination (CRD)

HTA - 2001 – 06 October 2017

NHSEED - 2001 – 31 March 2015

None

Medline (Ovid) search terms

1.	exp Arthritis, Rheumatoid/
2.	(rheumatoid adj2 (arthritis or arthrosis)).ti,ab.
3.	(caplan* adj2 syndrome).ti,ab.
4.	(felty* adj2 syndrome).ti,ab.
5.	(rheumatoid adj2 factor).ti,ab.
6.	((inflammatory or idiopathic) adj2 arthritis).ti,ab.
7.	“inflammatory polyarthritis”.ti,ab.
8.	or/1-7
9.	limit 8 to English language
10.	letter/
11.	editorial/
12.	news/
13.	exp historical article/
14.	Anecdotes as Topic/
15.	comment/
16.	case report/
17.	(letter or comment*).ti.
18.	or/10-17
19.	randomized controlled trial/ or random*.ti,ab.
20.	18 not 19
21.	animals/ not humans/
22.	Animals, Laboratory/
23.	exp animal experiment/
24.	exp animal model/
25.	exp Rodentia/
26.	(rat or rats or mouse or mice).ti.
27.	or/20-26
28.	9 not 27
29.	Economics/
30.	Value of life/
31.	exp “Costs and Cost Analysis”/
32.	exp Economics, Hospital/
33.	exp Economics, Medical/
34.	Economics, Nursing/
35.	Economics, Pharmaceutical/
36.	exp “Fees and Charges”/
37.	exp Budgets/
38.	budget*.ti,ab.
39.	cost*.ti.
40.	(economic* or pharmaco?economic*).ti.
41.	(price* or pricing*).ti,ab.
42.	(cost* adj2 (effective* or utilit* or benefit* or minimi* or unit* or estimat* or variable*)).ab.
43.	(financ* or fee or fees).ti,ab.
44.	(value adj2 (money or monetary)).ti,ab.
45.	or/29-44
46.	exp models, economic/
47.	*Models, Theoretical/
48.	*Models, Organizational/
49.	markov chains/
50.	monte carlo method/
51.	exp Decision Theory/
52.	(markov* or monte carlo).ti,ab.
53.	econom* model*.ti,ab.
54.	(decision* adj2 (tree* or analy* or model*)).ti,ab.
55.	or/46-54
56.	28 and (45 or 55)

Embase (Ovid) search terms

1.	exp *rheumatoid arthritis/
2.	(rheumatoid adj2 (arthritis or arthrosis)).ti,ab.
3.	(caplan* adj2 syndrome).ti,ab.
4.	(felty* adj2 syndrome).ti,ab.
5.	(rheumatoid adj2 factor).ti,ab.
6.	((inflammatory or idiopathic) adj2 arthritis).ti,ab.
7.	“inflammatory polyarthritis”.ti,ab.
8.	or/1-7
9.	limit 8 to English language
10.	letter.pt. or letter/
11.	note.pt.
12.	editorial.pt.
13.	case report/ or case study/
14.	(letter or comment*).ti.
15.	or/10-14
16.	randomized controlled trial/ or random*.ti,ab.
17.	15 not 16
18.	animal/ not human/
19.	nonhuman/
20.	exp Animal Experiment/
21.	exp Experimental Animal/
22.	animal model/
23.	exp Rodent/
24.	(rat or rats or mouse or mice).ti.
25.	or/17-24
26.	9 not 25
27.	statistical model/
28.	exp economic aspect/
29.	27 and 28
30.	*theoretical model/
31.	*nonbiological model/
32.	stochastic model/
33.	decision theory/
34.	decision tree/
35.	monte carlo method/
36.	(markov* or monte carlo).ti,ab.
37.	econom* model*.ti,ab.
38.	(decision* adj2 (tree* or analy* or model*)).ti,ab.
39.	or/29-38
40.	*health economics/
41.	exp *economic evaluation/
42.	exp *health care cost/
43.	exp *fee/
44.	budget/
45.	funding/
46.	budget*.ti,ab.
47.	cost*.ti.
48.	(economic* or pharmaco?economic*).ti.
49.	(price* or pricing*).ti,ab.
50.	(cost* adj2 (effective* or utilit* or benefit* or minimi* or unit* or estimat* or variable*)).ab.
51.	(financ* or fee or fees).ti,ab.
52.	(value adj2 (money or monetary)).ti,ab.
53.	or/40-52
54.	26 and (39 or 53)

NHS EED and HTA (CRD) search terms

#1.	MeSH DESCRIPTOR Arthritis, Rheumatoid EXPLODE ALL TREES
#2.	((rheumatoid adj2 (arthritis or arthrosis)))
#3.	((caplan* adj2 syndrome))
#4.	((felty* adj2 syndrome))
#5.	((rheumatoid adj2 factor))
#6.	(((inflammatory or idiopathic) adj2 arthritis))
#7.	(“inflammatory polyarthritis”)
#8.	#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7

Figure 1Flow chart of clinical study selection for the review of ultrasound monitoring

Figure 2Change in Disease activity score (DAS28)

Figure 3Change in function (RAID score)

Figure 4Change in Quality of life (EQ-5D)

Figure 5Remission (DAS<1.6)

Figure 6Change in pain (VAS)

Figure 7Withdrawal from trial due to “no longer willing”

Figure 8Withdrawal from trial due to adverse events

Figure 9Clinical and US prognostic factors for MRI erosive progression (dichotomous; at 1 year)

Figure 10Clinical and US prognostic factors for disease flare (increase in disease activity requiring an initiation, change or increase in therapy based on DAS28; dichotomous – at 1 year)

Figure 11Clinical and US prognostic factors for relapse (DAS28-ESR>2.6 following a period of clinical remission; dichotomous – at 1 year)

Note: DAS28-ESR was independently associated with the outcome but data is not presented here as it was incorrectly reported by the authors.

Figure 12Clinical and US prognostic factors for remission (DAS28-CRP4v <2.6; dichotomous – at1 year)

Figure 13Clinical and US prognostic factors for remission (DAS44-CRP4v <1.6; dichotomous – at1 year)

Figure 14Flow chart of economic study selection for the guideline

* Non-relevant population, intervention, comparison, design or setting; non-English language

Table 25Studies excluded from the clinical review

Reference	Reason for exclusion
Aydin 2017¹	Unobtainable
Backhaus 2013²	Analyses not adjusted for confounders
Bellis 2016⁴	cross-sectional study, no follow-up
Brown 2008⁶	Analyses not adjusted for confounders
Bugatti 2016⁷	no relevant outcomes
Bugatti 2012⁸	Analyses not adjusted for all key confounders; outcome is indirect
Bugatti 2012⁵⁰	see above
Cavet 2009⁹	Unclear if analyses are adjusted for confounders; incomplete reporting of results
Chen 2017¹⁰	Analyses not adjusted for key confounders
Cheung 2016¹²	Key confounders for the outcome (radiographic progression) not considered in analysis
Cheung 2014¹¹	no regression analysis; no anti-CCP measured
Christensen 2016¹³	Study duration only 4 months
D’Agostino 2016¹⁴	Analyses not adjusted for confounders
D’Agostino 2017¹⁵	narrative review
Dale 2016¹⁷	mixed study population of RA and UA (breakdown unknown)
Dale 2014¹⁶	mixed study population of RA and UA (breakdown unknown)
Dougados 2012¹⁸	no regression analysis; no anti-CCP measured
Dougados 2013¹⁹	no regression analysis; no anti-CCP measured
El Miedany 2016²⁰	results incompletely reported
Fukae 2017²¹	Analyses not adjusted for key confounders
Gartner 2015²²	analyses not adjusted for confounders
Hammer 2017²⁷	no regression analysis
Han 2016²⁸	systematic review
Harman 2015³⁰	Analyses not adjusted for confounders
Harman 2015²⁹	multivariate analysis model does not include factors of interest
Hirata 2017³¹	Incorrect study design
Horton 2017³³	No relevant outcomes
Hurnakova 2015³⁵	cross-sectional study
Hurnakova 2016³⁴	Incorrect study design
Iagnocco 2015³⁶	Analyses not adjusted for key confounders; outcomes incompletely reported
Ikeda 2007³⁷	Analyses not adjusted for confounders
Ikeda 2013³⁹	Study looked at ultrasound alone not in combination with clinical assessment
Ikeda 2012³⁸	see above
Ivanac 2015⁴⁰	Study looked at ultrasound alone not in combination with clinical assessment
Janta 2016⁴¹	Analyses not adjusted for key confounders; results incomplete
Jeka 2017⁴²	no regression analysis
Jindal 2017⁴³	Unobtainable
Kakavouli 2015⁴⁴	single case study
Kamel 2017⁴⁵	No relevant outcomes
Kawashiri 2017⁴⁶	retrospective study
Kirino 2015⁴⁷	retrospective study
Komarova 2015⁴⁸	Incorrect study design
Luz 2016⁴⁹	Analyses not adjusted for key confounders
Manzo 2012⁵⁰	shouldn’t have been ordered - exclude from EXCLUSION TABLE
Naredo 2007⁵¹	Analyses not adjusted for confounders
Naredo 2008⁵²	no anti-CCP and no baseline erosions measured
Osipyants 2013⁵⁴	not enough information on analyses (conference abstract)
Osipyants 2013⁵⁵	not enough information on analyses (conference abstract)
Ramírez García 2014⁵⁶	Adjustment for confounders unclear; incomplete reporting of results
Rees 2007⁵⁷	no regression analysis
Reynolds 2009⁵⁸	no regression analysis
Rosa 2016⁵⁹	cross-sectional study; analyses not adjusted for key confounders
Scire 2009⁶¹	mixed patient population (either RA or undifferentiated polyarthritis)
Sreerangaiah 2016⁶²	results incompletely presented; unclear if analyses was adjusted for key confounders
Takase-Minegishi 2017⁶³	Systematic review: references checked
Tan 2016⁶⁴	no regression analysis
Taylor 2004⁶⁵	Unclear if analyses are adjusted for confounders; incomplete reporting of results
Tokai 2015⁶⁶	Analyses not adjusted for key confounders
Toyota 2016⁶⁷	Unobtainable
Valor 2016⁶⁸	Incorrect study design
Van der ven 2017⁶⁹	No relevant outcomes
Vlad 2015⁷⁰	Analyses not adjusted for key confounders
Vreju 2016⁷¹	Key confounders for the outcome not considered in analysis
Wakefield 2007⁷²	Analyses not adjusted for confounders
Yamada 2016⁷³	Unobtainable
Yoshimi 2013⁷⁵	no regression analysis; no anti-CCP measured
Yoshimi 2014⁷⁴	no regression analysis; no anti-CCP measured
Zhao 2017⁷⁷	Literature review

Table 26Studies excluded from the health economic review

Reference	Reason for exclusion
None

PICO question	Population: Adults with RA in whom clinical examination is inconclusive or is inconsistent with other signs of disease activity Intervention(s): Treatment adjusted throughultrasound assessment plus usual monitoring assessments Comparison: Treatment adjusted through standard monitoring assessments alone Outcome(s): Disease activity, numbers in remission, numbers with low disease activity, quality of life, function and pain, radiographic progression
Importance to patients or the population	If ultrasound can be used to provide healthcare professionals with additional information on disease activity when standard monitoring assessments are inconclusive, this would enable more informed management decisions to be made. By enabling accurate assessment, ultrasound may facilitate appropriate treatment adjustment to achieve the agreed target and improve prognosis. People with RA may therefore have improvements in clinical status, symptoms and quality of life and avoid receiving inappropriate therapies. Ultrasound is a very simple non-invasive investigation, which is valued by people with RA as it enables them to visualise their disease activity. This in itself may also improve outcomes, by encouraging medication adherence and facilitating agreement to treatment escalation where necessary.
Relevance to NICE guidance	Current NICE guidance recommends against using US for routine monitoring of disease activity. This research would aim to identify whether there is an important subset of people with RA who would benefit.
Relevance to the NHS	If ultrasound was found to be clinically and cost effective in assessing disease activity in certain subgroups of people with RA, its use may increase in those groups of people. Although there may be additional training requirements for rheumatologists or other members of the MDT and upfront costs to supply the equipment, if the use of ultrasound for monitoring is found to enable a more appropriate management strategy, this may be cost neutral or even cost saving through better management of RA.
National priorities	N/A
Current evidence base	Randomised controlled evidence in the evidence review reported in chapter I showed no benefit of ultrasound to routine monitoring of disease activity in people with RA. Evidence looking at the association between ultrasound findings and subsequent poor outcomes were of generally low to very low quality and their findings were inconsistent and inconclusive and insufficient to inform a recommendation. Therefore a recommendation was made against the use of ultrasound for routine monitoring for all people with RA. No RCTs were available in the particular subgroups identified in this research question – namely people with RA in whom clinical examination is inconclusive or is inconsistent with other signs of disease activity.
Equality	Ultrasound may be of benefit where synovitis is difficult to assess in case of obesity or extensive deformities.
Study design	Randomised controlled trial comparing treatment adjusted through clinical assessment plus ultrasound, with treatment adjusted through clinical assessment alone. Inclusion criteria would be people with RA in whom clinical examination is inconclusive or is inconsistent with other signs of disease activity, as described above. This could be cluster randomised to aid feasibility by increasing recruitment potential. Trial duration: at least 1 year
Feasibility	The main issue would be to ensure cross-site agreement on US scoring and technique, and therefore this should be considered and pre-specified in the trial protocol.
Other comments	This is an important question appropriate for funding from several potential sources. Ultrasound is currently being used in an ad hoc way with substantial variation in practice around the country. If it is shown to be of added value in particular subgroups of patients, it has the potential to improve the application of the current treat to target strategy in a focussed way.
Importance	High: the research is essential to inform future updates of key recommendations in the guideline.

Ultrasound monitoring

Authors

1. Ultrasound monitoring

1.1. Review questions

1.2. Introduction

1.3. PICO table

1.4. Methods and process

1.5. Clinical evidence

1.5.1. Included studies

1.5.2. Excluded studies

1.5.3. Summary of clinical studies included in the evidence review

1.5.4. Quality assessment of clinical studies included in the evidence review

1.5.4.1. RCTs

1.5.4.2. Prognostic studies

1.6. Economic evidence

1.6.1. Included studies

1.6.2. Excluded studies

1.6.3. Unit costs

1.7. Resource costs

1.8. Evidence statements

1.8.1. Clinical evidence statements

1.8.2. Health economic evidence statements

1.9. The committee’s discussion of the evidence

1.9.1. Interpreting the evidence

1.9.1.1. The outcomes that matter most

1.9.1.2. The quality of the evidence

1.9.1.3. Benefits and harms

1.9.2. Cost effectiveness and resource use

1.9.3. Other factors the committee took into account

References

Appendices

Appendix A. Review protocols

Appendix B. Literature search strategies

B.1. Clinical search literature search strategy

B.2. Health Economics literature search strategy

Appendix C. Clinical evidence selection

Appendix D. Clinical evidence tables

Appendix E. Forest plots

E.1. Randomised controlled trial: Clinical assessment and ultrasound versus clinical assessment alone

E.2. Prognostic studies: Effect of clinical and US prognostic factors on various outcomes

Appendix F. GRADE tables

F.1. Randomised controlled trials

F.2. Prognostic studies

Appendix G. Health economic evidence selection

Appendix H. Health economic evidence tables

Appendix I. Excluded studies

I.1. Excluded clinical studies

I.2. Excluded health economic studies

Appendix J. Research recommendations

J.1. Ultrasound to assess disease activity (monitoring) where clinical examination is inconsistent or inconclusive

Criteria for selecting high-priority research recommendations

Table 1PICO characteristics of clinical effectivenss review

Table 2PICO characteristics of prognostic question

Table 3Summary of randomised controlled trials included in the evidence review

Table 4Summary of prospective cohort prognostic studies included in the evidence review

Table 5Clinical evidence summary: clinical assessment and ultrasound versus clinical assessment alone

Table 6Clinical evidence summary - Outcome: MRI erosive progression (dichotomous – at 1 year)

Table 7Clinical evidence summary - Outcome: Disease flare (increase in disease activity requiring an initiation, change or increase in therapy based on DAS28; dichotomous – at 1 year)

Table 8Clinical evidence summary - Outcome: Relapse (dichotomous – at 1 year; DAS28-ESR>2.6 following a period of clinical remission)

Table 9Clinical evidence summary - Outcome: Remission (DAS28-CRP4v <2.6; dichotomous – at 1 year)

Table 10Clinical evidence summary - Outcome: Remission (DAS44-CRP4v <1.6; dichotomous – at 1 year)

Table 11Clinical evidence summary - Outcome: Function (HAQ score; continuous – 1 year after prognostic variables were measured)

Table 12Cost of outpatient rheumatology appointments

Table 13Cost of ultrasound

Table 16Database date parameters and filters used

Medline (Ovid) search terms

Embase (Ovid) search terms

Cochrane Library (Wiley) search terms

Table 17Database date parameters and filters used

Medline (Ovid) search terms

Embase (Ovid) search terms

NHS EED and HTA (CRD) search terms

Figure 1Flow chart of clinical study selection for the review of ultrasound monitoring

Figure 2Change in Disease activity score (DAS28)

Figure 3Change in function (RAID score)

Figure 4Change in Quality of life (EQ-5D)

Figure 5Remission (DAS<1.6)

Figure 6Change in pain (VAS)

Figure 7Withdrawal from trial due to “no longer willing”

Figure 8Withdrawal from trial due to adverse events