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Target for monitoring
Evidence review D
NICE Guideline, No. 100
National Guideline Centre (UK).
1. Target for monitoring
1.1. Review question: In adults with rheumatoid arthritis, what is the best target to use when monitoring disease activity (remission or low disease activity)?
1.2. Introduction
Current consensus amongst the rheumatology community is that a treat-to-target strategy should be used when treating people with rheumatoid arthritis (RA) with DMARDs. A treat-to-target strategy is a strategy that defines a treatment target (such as remission or low disease activity) and applies tight control (for example, monthly visits and respective treatment adjustment) to reach this target. The treatment strategy often follows a protocol for treatment adaptions depending on the disease activity level and degree of response to treatment.
The 2009 NICE guideline: Rheumatoid arthritis in adults: management9 suggested a treat-to-target approach in the recommendations that said to measure inflammatory markers and disease activity monthly “until treatment has controlled the disease to a level previously agreed with the person with RA”. However, the committee agreed that the evidence for a treat-to-target strategy should be reviewed, to make this recommendation clearer and more direct if supported by the evidence.
The committee also agreed that greater clarity was needed on how frequently people with rheumatoid arthritis should be monitored, as there was currently variation in practice and some uncertainty about how frequent monitoring should be in different groups of people with rheumatoid arthritis with varying degrees of disease activity. However, the frequency of monitoring review excluded an update of the annual review recommended in the previous guideline, as it is an essential and well-established practice and therefore was not included within the scope of this update.
Three interrelated evidence reviews were conducted to answer the following key questions in this area:
- Is treat-to-target more effective than usual care?
- If so, should the treatment target be low disease activity or remission?
- How often should people be monitored, outside of the annual review?
1.3. PICO table
For full details, see the review protocol in appendix A.
Table 1
PICO characteristics of review question.
1.4. Methods and process
This evidence review was developed using the methods and process described in Developing NICE guidelines: the manual.1 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 randomised controlled trials comparing remission with low disease activity as targets in monitoring RA.
No relevant clinical studies were identified.
See also the study selection flow chart in appendix C.
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
No relevant clinical studies were identified.
1.5.4. Quality assessment of clinical studies included in the evidence review
No relevant clinical studies were identified.
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
Table 2
UK costs of healthcare professional visits.
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
No relevant clinical studies were identified.
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
The critical outcomes were agreed to be the Disease Activity Score (DAS), quality of life and function for all 3 reviews.
Pain, radiographic progression, fatigue and the number of people who withdrew from the trial were agreed to be important outcomes for all 3 reviews. The treat-to-target review and the frequency of monitoring review also specified the number of people achieving remission and low disease activity, using DAS thresholds, as important outcomes. The committee agreed that data reported in this format are not as informative as continuous DAS data but still give an indication of symptom relief and disease activity improvement. Disease activity data in this dichotomous format were not considered informative for the review of whether low disease activity or remission was the better target given the question posed by the review.
In the treat-to-target review, no data were available for the outcome of fatigue. For the frequency of monitoring review, no data were available for any of the disease activity outcomes, quality of life or fatigue.
No studies were identified for the review of remission compared with low disease activity as a treatment target.
1.9.1.2. The quality of the evidence
Treat-to-target versus usual care
Five studies were included in the review of treat-to-target versus usual care. The quality of the evidence was varied, ranging from moderate to very low quality, with the majority of the outcomes graded either low or very low quality. A lack of blinding was a source of risk of bias in all of the included studies. Some studies also poorly reported aspects of their design such as how they randomised participants, concealed allocation, and dealt with missing data, which affected the quality rating. For those outcomes where the data was reported by only 1 or 2 trials, the confidence intervals tended to be wide which meant there was some uncertainty about whether the treat-to-target strategy was more effective than usual care.
Importantly, there was substantial inconsistency in the magnitude of the benefit of treat-to-target across the studies and between different treat-to-target arms within studies, which also affected the quality of the evidence for most outcomes (DAS, HAQ, remission, low disease activity, pain, and study discontinuation). It was not possible to conduct formal subgroup analysis to see if this explained the heterogeneity, as there were too few studies in each subgroup category. However, the committee discussed the possible reasons for these differing results. The committee noted the great variation in the design of the studies, particularly around the disease duration of participants (which ranged from less than 1 year in 1 study, to a median of 6-7 years in another study), the nature of the target used in the intervention arm (whether a DAS-based target was used), and whether or not either or both study arms used a protocol-driven treatment strategy (some studies did not use a protocol in either arm, other studies used a protocol in both arms and some studies compared a protocol in the intervention arm to usual care without a protocol).
The committee agreed that it was not possible to establish definitively which of these factors (if any) might explain the differences in the magnitude of the effect between the studies. However, the committee noted that while there was some inconsistency in the magnitude of the benefit of treat-to-target in improving disease activity, function and pain, in general the majority of evidence across outcomes favoured treat-to-target over usual care. The few results that did suggest a benefit of usual care were generally from the non- DAS-based target arms of 2 studies (which used targets of zero swollen joint count and matrix metalloproteinase 3 levels). The results of the DAS-based target arms of those studies favoured the intervention arm, consistent with the other study results.
Remission or low disease activity as the target
No evidence was identified comparing the targets of remission or low disease activity. Recommendations were therefore informed by GC consensus opinion.
Frequency of monitoring
One study was included in the review of different monitoring frequencies. This study compared patient-initiated rapid access with traditionally scheduled reviews every 3 to 6 months. All of the evidence was assessed to be very low quality. Lack of blinding, along with relatively high rates of missing data and limited information about how this was dealt with in the analysis contributed to the risk of bias. It was also unclear what was measured at each review and whether the minimum requirements as specified in the review protocol were satisfied (assessment of the joints for swelling and measurement of inflammatory markers), which further weakened the evidence. The evidence was also assessed to be indirect to that specified in the protocol due to the variation in the frequency of reviews in the control group, and the population being a mix of people with stable and unstable disease.
No studies were found comparing any other frequencies of monitoring.
People at risk of poor outcomes
People with a poor prognosis were pre-specified as a separate stratum in the protocols for the review of remission versus low disease activity as a target and the review of frequency of monitoring. People with a poor prognosis were considered to be those with one or more of the key prognostic factors identified in a separate review, which were anti-CCP positive status and the presence of erosions at baseline. No evidence was found in this subgroup of people for either question.
1.9.1.3. Benefits and harms
Treat-to-target versus usual care
The committee agreed that the evidence for the treat-to-target versus usual care review suggested that a treat-to-target approach was more effective than usual care. The committee acknowledged the limitations of the evidence base described above, but were persuaded by the consistency of the overall findings of a clinically important benefit in favour of treat-to-target across almost all of the outcomes. The committee acknowledged that the more frequent appointments usually required with treat-to-target management could, for some people, be difficult to combine with full time work, although this would depend on the individual. The committee were reassured by the evidence that not only did treat-to-target appear to be more clinically effective than usual care, study discontinuation rates tended to be lower in people receiving treat-to-target care, even though the frequency of monitoring in the treat-to-target groups was often higher and so the burden on people attending the appointments greater.
In further support of treat-to-target despite the differences in the included studies, the committee agreed that one included study most closely reflected the treat-to-target and usual care approaches used in clinical practice in England, whereas some of the other included studies used more unusual designs. This study was the only study that utilised more frequent monitoring and a protocol-driven treatment strategy in the intervention group, compared with less frequent visits and treatment at the discretion of treating doctor in the usual care group. The committee noted that this trial found consistent and substantial benefits of treat-to-target approach over usual care, which further reinforced their view that treat-to-target was more effective than usual care. In addition, the committee noted that many of the included studies in the separate evidence review of DMARD treatment, which reported positive outcomes for people with rheumatoid arthritis, were strategy trials that employed a treat-to-target approach. This provided further indirect evidence of the importance of treating-to-target to achieve good outcomes for people with rheumatoid arthritis.
The committee unanimously agreed that a treat-to-target approach to managing rheumatoid arthritis was essential to achieving rapid and sustained disease control and was the cornerstone of modern rheumatology practice. The lay members of the committee strongly emphasised the difference made to the lives of people with rheumatoid arthritis when a treat-to-target approach is implemented. Without a treat-to-target approach, people with rheumatoid arthritis risk being left in a moderate disease activity state, and these disease levels will have a significant impact on their daily life. If implemented appropriately, a treat-to-target approach should also avoid many people with rheumatoid arthritis having high disease activity levels warranting biologic DMARD treatment in the future. Although the quality of evidence from this review was not of high quality, the GC agreed that the importance of this recommendation in clinical practice, combined with this evidence and the indirect evidence from other reviews where the strategy was employed, all supported a strong recommendation for all people with rheumatoid arthritis.
Remission or low disease activity as the target
Having agreed that a treat-to-target approach is beneficial, the committee discussed what the disease activity target should be. The committee discussed the existing recommendation, which did not specify a target, and agreed that although no evidence was identified for this review, it was important to specify a target to ensure that people were fully treated and achieved the best possible outcomes and understood the goal of the treatment.
In the absence of available evidence the committee discussed which of the 2 targets was most appropriate based on their experience and expertise. The committee agreed that the aim should always be to control disease activity to the lowest possible level, but that this would depend on the individual as in some people, treatment will not be able to achieve very low targets. The committee decided by consensus that remission (for example, DAS28 less than 2.6) is the ideal target for most people with rheumatoid arthritis, but for people who were unable to achieve this target despite a treat-to-target approach with appropriate escalation, low disease activity (for example, DAS28 less than 3.2) would be acceptable as this is more achievable for some people and agreed as a good outcome if remission can’t be achieved. The committee noted that remission and low disease activity can be measured using various composite scoring measures. The committee were of the view that the most appropriate measures were validated scoring systems that incorporated inflammatory markers and a swollen joint count. Such measures include DAS, DAS28 and SDAI.
In order to treat-to-target using a target of remission or low disease activity, it is essential that a disease activity score such as the DAS28 is measured at each visit. The committee acknowledged that the DAS28 can be calculated using either ESR or CRP (both inflammatory markers), but agreed that current consensus is that CRP is subject to less variability as it is a direct measure of inflammatory protein. Hence, CRP is generally the preferred measure for people treated with conventional DMARDs. Therefore, the committee agreed to maintain the previous recommendation to measure CRP and disease activity using a composite score such as DAS28.
Frequency of monitoring
The committee discussed how frequently people should be monitored (a) while their disease is active as part of a treat-to-target approach, (b) after they have achieved the treatment target, and (c) once they have maintained disease activity below the treatment target for a period of time and their disease is considered well-controlled.
No evidence was identified specifically looking at how often people with active disease should be monitored. The committee noted that the previous guideline recommended monthly monitoring for people with active disease. The committee also considered the monitoring regimens in the studies included in the treat-to-target review. These varied between studies, however, the study considered to be the most applicable evidence (discussed above) employed monthly monitoring in the treat-to-target arm, compared with three monthly in the usual care arm. The committee agreed by consensus that monthly review of people with active disease remained the most appropriate monitoring frequency as part of the treat-to-target approach. Monthly monitoring in active disease was considered necessary in order to escalate DMARD doses, to consider the need for short-term glucocorticoids while waiting for DMARDs to take effect, to establish whether people were tolerating the drug and assess side effects, and to provide support and encourage adherence. Any more frequent was considered to be unnecessary from both an effectiveness and resource impact perspective, and would increase the burden for people with RA.
The committee discussed how frequently people should be monitored once their disease was below the target activity level of remission or low disease activity. The committee discussed the previous guideline recommendation, which was to provide appointments at a frequency and location suitable to [the person’s] needs. The committee agreed that this should be more specific if possible, to improve consistency and avoid under or over monitoring of this group of people. It was agreed by consensus that a review appointment should be considered 6 months after a person achieves the treatment target, to assess whether the disease control has been maintained.
The committee discussed whether people with sustained disease levels below the treatment target required regular monitoring between annual reviews in the absence of worsening symptoms or deterioration (annual reviews were not updated in this guideline). The committee considered the study included in the frequency of monitoring review to be somewhat applicable to this situation, as it enrolled participants with long term, established disease. The evidence suggested that patient-initiated rapid access (median 8 reviews over 6 years) was no less effective than traditionally scheduled medical review every 3-6 months (median 13 reviews over 6 years) in this group of people with rheumatoid arthritis. The committee acknowledged the limitations of this evidence (discussed above), but agreed it reflected their experience that regular scheduled appointments (over and above an annual review) were not necessary in people with well-controlled disease.
Overall, the committee agreed that once people with rheumatoid arthritis had achieved the treatment target, and this was sustained at a 6 month follow-up appointment, there was no need for additional routine appointments to be scheduled other than the annual review. However, the committee emphasised the importance of all people with rheumatoid arthritis having rapid access to specialist care for disease flares, and the need for ongoing drug monitoring. The committee agreed this was addressed by the existing recommendations on rapid access, which had not been reviewed in the update, with some amendments to the wording to improve clarity.
People at risk of poor outcomes
The committee agreed that there was no evidence suggesting people with a poor prognosis should be managed any differently to the general rheumatoid arthritis population, in terms of the treatment target or the frequency of monitoring. The committee agreed that the standard recommendations regarding treatment-to-target with monthly monitoring should ensure that people with a poor prognosis receive effective treatment of their disease.
1.9.2. Cost effectiveness and resource use
For the treat-to-target review, 2 economic evaluations were identified, comparing a treat-to-target approach to usual care (Nair 2015, Grigor 2004). Nair 2015 was a cost–utility analysis based on a cohort of people with early RA. This evaluation used clinical effectiveness data from the CAMERA trial, which was also included in the clinical review for treat-to-target. Analysis within this study identified treat-to-target to be cost effective, and in fact cost saving compared to usual practice (being less costly and more effective). The treat-to-target strategy resulted in less medical consumption and improved quality of life due to better DAS28/HAQ; however, drug costs were higher. The committee noted the relatively short time horizon of the study and questioned the ability of the study to capture the long-term cost benefits associated with the treat-to-target approach. The second analysis (Grigor 2004) was a cost–consequences analysis based on the TICORA RCT (same paper) which was also included in the clinical review. This analysis also found that treat-to-target was less costly and more effective than usual care. No analysis of uncertainty was conducted however; confidence intervals indicate that there is some uncertainty in both the costs and outcomes. The committee considered these confidence intervals and concluded that at a minimum treat-to-target was likely to be cost neutral.
Based on the clinical and economic evidence reviewed, the committee concluded that treat-to-target appeared to improve outcomes at no additional cost. As treat-to-target is already considered current practice and was recommended in the previous guideline, it is not anticipated that this recommendation will have a substantial resource impact.
No health economic studies were identified regarding the frequency of monitoring or the target for monitoring. Unit costs were provided for rheumatologist consultations to aid the consideration of cost effectiveness. The committee considered the potential economic impact of increasing frequency of monitoring from monthly to fortnightly and agreed that this would have a substantial impact on NHS resources and that there was no clinical evidence to support it. The committee agreed to keep the previous recommendation of monthly monitoring based on the clinical evidence reviewed. The committee noted that monthly visits may not have been implemented nationwide and this is reflected in a survey of the 2009 guideline implementation in the Midlands (25–62% receiving monthly monitoring). If this is reflective of practice across the country, this recommendation will likely involve a change in practice in many clinics around the country and may have a resource impact. Although there was no direct health economic evidence for the frequency of monitoring, the Grigor 2004 and Nair 2015 treat-to-target economic analyses suggested that even with more frequent visits (monthly versus every 3 months), a treat-to-target approach was cost saving. Finally, the committee noted that these monthly visits are often conducted by a nurse specialist rather than a consultant. The unit costs of different healthcare professionals were presented to the committee and it was noted that the cost of a nurse consultation would be less expensive than that of a consultant.
Regarding the target, aiming for low disease activity or remission is considered unlikely to have a resource impact. With either target, the individual will require ongoing monitoring and treatment adjustment, both of which have cost implications that are unlikely to differ depending on the target.
The committee made a recommendation to consider a review appointment within 6 months of stabilising. This recommendation was made based on expert opinion and consensus. The committee considered that this recommendation might reduce unwarranted variation in follow-up across the country as the prior recommendation may have led to unnecessary consultations for some or others receiving no follow-up.
References
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Appendices
Appendix A. Review protocols
Table 3. Review protocol: Which target to monitor in rheumatoid arthritis? (PDF, 165K)
Table 4. Health economic review protocol (PDF, 147K)
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.
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.
Appendix C. Clinical evidence selection
Appendix D. Clinical evidence tables
No relevant clinical studies were identified.
Appendix E. Forest plots
No relevant clinical studies were identified.
Appendix F. GRADE tables
No relevant clinical studies were identified.
Appendix G. Health economic evidence selection
Figure 2. Flow chart of economic study selection for the guideline
Appendix H. Health economic evidence tables
No relevant economic studies were identified.
Appendix I. Excluded studies
I.1. Excluded clinical studies
I.2. Excluded health economic studies
Final
Intervention 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.
- Review Frequency of monitoring: Rheumatoid arthritis in adults: diagnosis and management: Evidence review E[ 2018]Review Frequency of monitoring: Rheumatoid arthritis in adults: diagnosis and management: Evidence review ENational Guideline Centre (UK). 2018 Jul
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