Intensive therapy for moderate established rheumatoid arthritis: the TITRATE research programme

Overview

Rheumatoid arthritis is an immunologically driven long-term condition. Its key features are persistent synovitis of the joints, systemic inflammation and autoantibodies, such as rheumatoid factor. 1–3 RA affects 0.5–1% of adults in high-income countries, although there is considerable variation between countries and populations. 4–6 It particularly involves women and older adults. Its annual incidence is 5–50 per 100,000 people. 6–8 Uncontrolled active RA results in substantial physical disability and poor quality of life,9,10 which are often associated with loss of work and high medical and social costs. 11–13

Management

Rheumatoid arthritis is usually managed in the UK by multidisciplinary teams that comprise rheumatologists, nurses, physiotherapists, occupational therapists and other health-care professionals. The multidisciplinary teams provide education, medication, psychological support, exercise and joint protection. There is substantial variability in the nature of these teams,14 and the evidence supporting the different approaches they use also varies. 15,16 Surgical intervention may be required for end-stage joint damage. 17

Treatment focuses on the control of joint inflammation and the prevention of disease progression using disease-modifying antirheumatic drugs (DMARDs). 18 These reduce synovitis and systemic inflammation in the short term and physical disability and erosive progression in the long term. DMARDs can be categorised into several groups. We have classified them as conventional DMARDs, biologics and new orally acting Janus kinase (JAK) inhibitors. Together with short-term steroids, they are the key drug treatments for RA.

Methotrexate is the dominant conventional DMARD. 19–21 Other currently prescribed conventional DMARDs include sulfasalazine, leflunomide and hydroxychloroquine. Some patients are treated by combining two or more conventional DMARDs. Such intensive combination treatment is constrained by concerns about adverse event risks. 22,23

Biologics are used when RA is not controlled by conventional DMARDs. 24–28 They include the tumour necrosis factor inhibitors (TNFis) rituximab, abatacept and tocilizumab. All biologics are highly effective in reducing joint inflammation. They are usually combined with methotrexate or another conventional DMARD to increase efficacy and reduce the formation of blocking antibodies that could reduce their efficacy. Their use is limited by their high costs, although the advent of biosimilars is likely to reduce their costs. 29 Despite often achieving substantial reductions in disease activity, biologics are not curative. New oral drugs for RA, the JAK inhibitors, have a similar position to biologics in the treatment paradigm. 30

Steroids (glucocorticoids) are used in the short term to reduce joint inflammation. However, their long-term use is not recommended because of their side effects. 31 RA patients also receive various symptomatic treatments, including non-steroidal anti-inflammatory drugs and analgesics. 32,33 These are not usually given to control the disease process.

Clinical guidelines

There are many clinical guidelines for RA, including English guidelines from the National Institute for Health and Care Excellence (NICE), which outline its overall management. 34 High-cost treatments, such as the biologics, have specific NICE Health Technology Appraisals that recommend when they should be used. 35 The various guidelines have not resolved how best to manage patients with moderately active RA.

Treat to target

There is substantial evidence that disease outcomes are optimal when patients with active RA receive intensive managements to achieve predefined targets, particularly disease remission. 36,37 The evidence supporting treat to target is strongest in early active RA.

Patient load

The long-term management of RA dominates specialist rheumatology services. The 2016 national audit of early arthritis enrolled > 5000 patients, most of whom had RA. Inflammatory arthritis accounts for 40–60% of rheumatology follow-up visits. English Hospital Episode Statistics data show that there were more than 1,300,000 rheumatology outpatient follow-ups in 2017/18,38 and it is likely that a substantial proportion of these would have been for RA, potentially in the region of 300,000–600,000 outpatient follow-ups. The 2009 report from the National Audit Office estimated that 580,000 English adults had RA, with 26,000 new diagnoses each year. 39

Costs

Rheumatoid arthritis has substantial financial impacts for the NHS and the whole UK. The National Audit Office estimated that NHS costs were £560M per year and work-related disability costs were another £1800M per year. 39 Most costs are incurred by patients with high disability levels. Early intensive management targeted at remission should reduce future disability and, therefore, decrease costs. Biologic drug costs, which currently exceed £1B per year, continue to increase. 40

Need for research

The 2009 NICE guidance41 identified several unresolved questions that have been directly addressed in the TITRATE programme. Crucial issues included (1) the optimal management of patients with moderate disease activity, (2) the impact of enhancing remission rates on reducing future disability and (3) the role of self-management and the support patients need to use it.

Although more clinical guidelines have been published since 2009, including updated NICE guidance,41 and much new research has been undertaken, these questions remain important and unresolved.

Pathogenic heterogeneity

Rheumatoid arthritis may not be one disease. Instead, it may represent a final common pathway for several inflammatory joint diseases that vary by antibody profiles and clinical features. 42–45 Consequently, individualised management strategies are needed.

Effective treatments strategies

Both conventional DMARDs and biologics are effective treatments in active RA. However, there are uncertainties about their benefits and costs. In particular, there is debate about the relative value of combinations of conventional DMARDs compared with biologics. 46–49

Intensive management

Strategy trials have shown that combining treatments, such as conventional DMARDs, short-term steroids and, in some trials, biologics, optimise clinical outcomes. 37,50,51 Such strategy trials justify adopting treat-to-target approaches. However, there are uncertainties about the impact of intensive management on established RA patients with moderate disease activity.

Aim

The overall aim of the TITRATE programme was to assess the evidence that outcomes improve in patients with established RA who have moderate disease activity when they receive intensive management.

Objectives

There were three objectives. These were to:

1. define how to deliver intensive therapy to patients with moderate established RA

2. establish the clinical effectiveness and cost-effectiveness of intensive therapy in treatment of moderate established RA in a clinical trial

3. evaluate existing evidence supporting such intensive management in observational studies and completed trials.

Each of these objectives was studied in one of the workstreams. The first, second and third objectives were studied in workstreams A, B and C, respectively.

Changes in rheumatoid arthritis management and outcomes

Rheumatoid arthritis management and outcomes continually evolve, and there is considerable evidence that RA is becoming better controlled or less severe. 56–66 We therefore examined changes in disease activity, disability and treatment intensities in observational studies in routine practice settings in recent years. We examined changes in erosive progression in a systematic review of long-term observational studies52 that measured this outcome. We had to take this approach for erosive progression because X-ray damage is not quantified in routine practice.

Clinical management guidelines

Expert guidance about managing RA also evolves. 67,68 We therefore systematically reviewed published clinical guidelines on RA management to identify current recommendations on disease assessments and intensive management (both of which are crucial for the TITRATE strategy).

Trial evidence supporting intensive management

The evidence base for intensive management of RA is also expanding. 69 We therefore undertook two systematic reviews in the area. The first systematic review focused on remissions with all intensive managements and the second systematic review assessed the clinical effectiveness and cost-effectiveness of treat-to-target strategies.

Clinical evidence for treating moderately active rheumatoid arthritis intensively

The TITRATE programme reflects two concepts. First, patients with moderate RA and persisting disease activity are likely to have substantial ongoing disability, and observational evidence supports this perspective. 17 Second, if patients with moderate disease activity subsequently achieve remission, then they will have less disability, but there is little definitive evidence for this perspective. We evaluated both assumptions by analysing an observational study and two trials. Our aim was to ensure that evidence existed in favour of treating moderate RA intensively.

Observational studies

One observational study combined four cross-sectional surveys undertaken in two adjacent specialist units from 1996 to 2014 (three surveys had previously been published70–72). The studies each enrolled 189–520 patients (see Appendix 1, Table 27, for details of these patients). Overall, 1324 patients were studied. The patients in each survey were similar: 76–80% were female, their mean age was 58–60 years and their mean disease duration was 9–10 years. No particular treatment strategy was followed.

The other observational study was a longitudinal cohort study established in 2005 at Guy’s Hospital (London, UK). It involved most of the RA patients who were managed in another specialist centre until 2015. The study enrolled 1693 patients. Seventy-five per cent of the patients were female and their mean age was 55 years and mean disease duration was 11 years at entry to study (details of these patients are given in Appendix 1, Table 28). Patients were managed intensively using a treat-to-target approach. The longitudinal observational study included 752 patients, who were followed over ≥ 3 years.

Clinical trials

The CARDERA (Combination Anti-Rheumatic Drugs in Early Rheumatoid Arthritis) trial, which lasted 24 months, enrolled 467 patients, and complete end-point data were available in 379 patients. 73 The TACIT (Tumour Necrosis Factor Inhibitors Against Combination Intensive Therapy) trial, which lasted 12 months, enrolled 208 patients, and complete end-point data were available in 179 patients. 74 Details of these patients are given in Appendix 1, Table 31.

Clinical assessments

We assessed disease activity using the Disease Activity Score for 28 joints based on the erythrocyte sedimentation rate (DAS28-ESR)75 and disability using the Health Assessment Questionnaire (HAQ). 76 Further details are given in Appendix 2.

Systematic reviews

Four systematic reviews assessed:

• erosive progression in long-term observational studies

• clinical guidelines for managing RA

• intensive managements and remission

• the clinical effectiveness and cost-effectiveness of treat-to-target strategies.

Full details of these systematic reviews are given in the supplementary online material, including PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow diagrams (see Report Supplementary Material 1, Figure 1), and details of the included studies (see Report Supplementary Material 1, Tables 1–5).

Statistical analyses

Data were analysed descriptively using means, standard deviations (SDs) and 95% confidence intervals (CIs) or medians and interquartile ranges (IQRs). The longitudinal observational study used mixed models to examine the changes in DAS28-ESR over time.

The systematic review of erosive damage used Larsen77 and Sharp–van der Heijde scores78 to estimate annual rates of change in a linear regression model. The systematic review of intensive management and remissions used meta-analysis with RevMan 5.3 (The Cochrane Collaboration, The Nordic Cochrane Centre, Copenhagen, Denmark) to report relative risks in random-effects models,79 using Cochrane’s chi-squared test to assess between-study heterogeneity and quantify I² statistics. 80 The other systematic reviews were descriptive and further details are given in Appendix 3.

Clinical studies of changes in disease activity and disability

Both observational studies showed that there have been considerable reductions in disease activity levels and increases in treatment intensities over the last two decades.

The first observational study, involving four cross-sectional surveys between 1996–7 and 2012–14, showed substantial decreases in mean DAS28-ESR scores (Figure 2). In 1996/7, mean DAS28-ESR scores were 5.2 (95% CI 5.0 to 5.4) and they decreased to 3.7 (95% CI 3.6 to 3.8) by 2012/14. DAS28-ESR remissions increased from 8% to 28%. The main treatment change was increased biologics use. None was used before 2000, but by 2012/14 biologics were used in 32% patients. Despite reductions in disease activity and increases in biologics use, disability levels were stable. In 1996/7, mean HAQ score was 1.30 (95% CI 1.08 to 1.52), and in 2012/14 it was 1.32 (95% CI 1.25 to 1.39).

FIGURE 2.

Changes in DAS28-ESR over time. (a) Cross-sectional surveys; and (b) longitudinal study.

The second observational study, which comprised a longitudinal cohort study from 2005 to 2015, also showed that mean DAS28-ESR scores had decreased (see Figure 2). In 2005, the mean DAS28-ESR score was 4.1 (95% CI 3.9 to 4.3), and by 2015 it was 3.6 (95% CI 3.3 to 3.8). DAS28-ESR remissions increased from 18% to 27%. The main treatment change was increased biologics use. Biologics were prescribed for 19% of patients in 2005 and 42% of patients in 2015. The mean HAQ scores fell from 1.38 (95% CI 1.26 to 1.50) in 2005 to 1.19 (95% CI 1.04 to 1.34) in 2015.

Systematic review of changes in the progression of erosive damage

We identified 28 studies reporting RA radiological progression, and 10 studies, reported in nine papers,81–89 had sufficient data for meta-analysis. These 10 studies recruited patients from 1965 to 2000 and followed them for 5–20 years. Of 1121 patients, 73 had baseline radiological data. Five of the studies recruited from 1965 to 198981–85 and the other five studies recruited from 1990 to 2000. 85–89

Baseline radiographic scores were similar in pre- and post-1990 studies (with a mean maximum damage of 2.01% and 2.03%, respectively). The annual rate of erosive change was higher in pre-1990 studies (mean 1.50%, 95% CI 1.08% to 1.92%) than in post-1990 studies (mean 0.68%, 95% CI 0.47% to 0.90%) and the difference was significant (p < 0.05) after adjusting for scoring methods. These changes are summarised in Figure 3.

FIGURE 3.

Initial damage and annual rate of damage in pre- and post-1990 cohorts. Means and 95% CIs are shown. (a) Initial; and (b) annual progression.

Systematic review of clinical management guidelines

We identified 22 guidelines36,90–110 (three were for early RA,99,105,107 one for established RA98 and 18 for all disease durations36,90–97,100–104,106,108–110). They were compiled by rheumatologists with variable patient involvement and contributions from nurses, allied health professionals and other experts. All guidelines dealt with drug therapies (11 guidelines covered diagnosis and 13 guidelines covered non-drug treatments).

Twenty guidelines36,90–98,100–105,107–110 recommended remission as the treatment target, and 16 guidelines36,90–97,102–104,107–110 recommended low disease activity as an alternative. Two guidelines98,106 recommended suppressing joint inflammation without defining what it implies. These recommendations are summarised in Figure 4. Remission was defined in various ways. DAS28-ESR remission was recommended in 13 guidelines,90,92–95,97,101,102,104,107–110 Simple Disease Activity Index (SDAI) in nine guidelines,36,92,95–97,102–104,108 Clinical Disease Activity Index (CDAI) in seven guidelines92,95,97,102,104,108,109 and American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) Boolean in seven guidelines. 36,92,95,97,103,104,109 Six guidelines did not recommend any specific remission criteria. 91,96,98–100,105,106

FIGURE 4.

Remission assessments and treatment targets in RA guidelines.

All guidelines36,90–110 recommend treating active RA. There was less unanimity about treating moderately active disease. Thirteen guidelines91,92,94–97,100,102–105,107,108 included definite recommendations about treating moderate disease, four guidelines36,90,101,109 gave implied guidance about treating moderate disease by indicating what treatment policies were needed until patients achieved remission and five guidelines93,98,99,106,110 made no recommendations.

Systematic review of trials of remissions with intensive management

We identified 53 trials reporting remissions. 74,111–162 Forty-eight trials111–132,134–139,142,143,145–162 were superiority trials in which an intensive management strategy was compared with a less intensive strategy, six trials74,128,133,140,141,144 were head-to-head trials comparing combination DMARDs with biologic treatments and one trial was in both groups. 128

In superiority studies, 3013 of 11,259 patients achieved remission with intensive management, compared with 1211 of 8493 control patients. Meta-analysis of the 53 comparisons showed a significant benefit for intensive management [risk ratio (RR) 2.23, 95% CI 1.90 to 2.61]. Intensive management increased remissions in early RA (23 comparisons; RR 1.5, 95% CI 1.38 to 1.76) and established RA (29 comparisons; RR 4.21, 95% CI 2.92 to 6.07). All intensive strategies (i.e. combination DMARDs, biologics, and JAK inhibitors) increased remissions. These effects are shown in Figure 5.

FIGURE 5.

Effectiveness in superiority and head-to-head trials assessed by random RRs. (a) Superiority trials; and (b) head-to-head trials.

In the six head-to-head trials,74,128,133,140,141,144 317 of 787 patients achieved remission with biologics, compared with 229 of 671 patients receiving combination DMARD therapies. There was no difference between treatment strategies (RR 1.06, 95% CI 0.93 to 1.21). These effects are shown in Figure 5.

Remission frequencies differed in early and established RA. In early RA, 49% of patients had remissions with intensive management compared with 34% of control patients (RR 1.05, 95% CI 0.88 to 1.24). In established RA, 19% patients had remissions with intensive management compared with 6% of control patients (RR 1.21, 95% CI 0.88 to 1.68).

Systematic review of trials supporting using treat to target

We identified 41 papers49,113,128,129,141,148,153,155,163–195 reporting 16 relevant trials. Six trials129,158,171,179,186,190 compared treat to target with usual care, six trials49,113,128,177,183,185 compared different treatment protocols, two trials141,172 compared different treatment targets and two trials153,160 had other comparisons of conventional with intensive therapy. As the trials were too heterogeneous for meta-analysis, we undertook a narrative analysis. Details of the impact of treat-to-target strategies on remission in studies with controls receiving conventional treatment is shown in Table 1.

Four of six trials comparing treat to target with usual care reported remissions and all found more remissions with intensive management. Differences were clinically and statistically significant in three trials,129,179,186 but the differences were considered meaningful in the STREAM (Strategies in Early Arthritis Management) trial. 158 Two trials171,190 comparing treat to target with usual care reported only low disease activity states. One trial171 found a significant difference and the other trial190 did not.

The six trials49,113,128,177,183,185 that compared treatment protocols all reported remissions. Two trials113,177 included conventionally treated controls and found significantly more remissions with intensive managements. Five49,128,183,185 of these trials compared different intensive management regimens and found no significant differences in remissions between regimens. One of these trials [Behandel–Strategieën (BeSt)128] included a conventionally treated group that had fewer remissions, although the difference was not significant.

Two trials141,172 compared targets in patients receiving different intensive management regimens. Both trials141,172 found no significant difference between groups. Finally, two trials153,160 that did not fit into the previous categories had conventionally treated controls and reported more remissions with intensive managements. The difference was significant in one trial,160 but not in the other. 153

Twelve trials reported harms. Deaths were reported in seven trials. 49,113,128,129,141,183,186 There were no deaths in three trials and 11 deaths in the other four trials (three deaths in two standard care arms and eight deaths in 10 intensive management arms). Serious adverse events were reported in eight trials. 49,113,128,141,158,177,185,186 Overall, 11% patients had a serious event (12% of patients receiving intensive management and 9% of patients receiving standard care).

Two studies129,153 reported cost-effectiveness. In one study,129 treat to target dominated usual care and in the other study153 step-up combination treatments were cost-effective. In 5 of the 16 studies158,172,179,183,185 included in the clinical effectiveness review, no cost-effectiveness conclusion could be reached, and in one study49 no conclusion could be drawn in the case of patients designated as low risk. In the remaining 10 studies,113,128,129,141,153,160,171,177,186,190 and among patients identified as high risk in one study,49 cost-effectiveness was inferred. In most cases, treat to target is likely to be cost-effective, except where biological treatment in early disease is used initially. No conclusions could be drawn for established RA, as there were too few studies to assess benefit.

Clinical studies of treating moderately active rheumatoid arthritis intensively

The impact of achieving remission on subsequent disease activity and disability, particularly in moderate disease patients, was studied in 752 patients in a longitudinal observational study followed for ≥ 3 years and in secondary analyses of early and established RA trials.

The frequency of moderately active disease at baseline in the 752 patients in the observational study and at 6 months in the 558 patients in the trials was substantial. It varied from 39% to 45% of patients (Table 2). In all three studies, moderate disease patients were the largest group in terms of disease activity levels. The mean end-point DAS28-ESR scores in these patients after 1–3 years’ follow-up varied between 3.5 and 4.2, and their end-point mean HAQ scores varied between 1.3 and 1.5.

Dividing patients with initial/6-month moderate RA into those who subsequently had one or more DAS28-ESR remissions and those who did not (Figure 6) shows two things. First, those patients who achieved one or more remissions had lower subsequent mean DAS28-ESR scores than patients who did not. Second, mean HAQ scores were lower in patients who achieved one or more remissions.

FIGURE 6.

Changes in DAS28-ESR and HAQ score in moderate RA patients. Patients divided by none or one or more remissions. (a) DAS28-ESR – observational; (b) DAS28-ESR – TACIT trial;74 (c) DAS28-ESR – CARDERA trial;73 (d) HAQ – observational; (e) HAQ – TACIT trial;74 and (f) HAQ – CARDERA trial. 73

Evaluating these changes in detail (see Table 2) showed that 18–48% of patients with initial/6-month moderate disease achieved one or more episodes of remission during the period of follow-up. The patients with one or more remissions had significantly lower end-point mean DAS28-ESR scores in all studies and significantly lower end-point mean HAQ scores in two studies (i.e. the observational study and the CARDERA trial73). In the other study (i.e. the TACIT trial74), end-point mean HAQ scores were lower in patients who achieved one or more remissions, but the difference was not significant. In patients with initially moderate disease, treatment intensities were comparable in patients with and without subsequent remissions (Figure 7).

FIGURE 7.

Changes in DMARD and biologic prescribing in patients with initial moderate disease activity in the observational study. Patients are divided by whether they had one or more remissions during follow-up. (a) DMARD monotherapy; (b) DMARD combination; and (c) biologics.

Patients studied

It is likely that patient inclusion and follow-up strategies in observational studies have changed over time. In particular, patients with milder disease may have attended more frequently in recent years. Such changes in patient care could explain some or all of the reductions in disease activity we observed. It is also possible that the clinical phenotype of RA has evolved, with milder disease increasing in frequency. However, a recent analysis of English early RA patients since 1990 does not suggest that there have been major changes in RA clinical phenotypes. 196

Assessing benefits and risks

The assessment of remission and the duration of treatment varied in the trials of intensive management in the systematic review. This variation created unavoidable complexities when combining data from studies. When there are many studies, as occurred in the comparison of all intensive managements, combining heterogeneous data appears reasonable. However, when there are few studies, as occurred in comparisons of treat-to-target strategies, it is best avoided.

Evidence about the benefits of intensive management are almost entirely based on clinician-defined outcomes, such as changes in disease activity (e.g. remissions, reductions in disability and erosive damage). The extent to which patients consider intensive management to be beneficial is largely unknown. Patients can have different perspectives to clinicians. 197–199

One final and important issue is that we did not assess the potential of intensive management to harm patients in detail. In routine practice settings, it is particularly difficult to assess harms because they are not reported in any organised way. Nevertheless, we found no evidence of intensive management substantially increasing adverse events. Published systematic reviews of intensive management, predominantly using biological treatments, have also not found any substantial increases in adverse events with more intensive treatment regimens. 23,200,201

Treatments

There is no internationally agreed definition of what constitutes intensive management in RA. The numbers and types of treatments used, the time frames over which they are increased and the frequencies at which patients are assessed vary across studies. The absence of definite agreement makes it difficult to compare the benefits of intensive management.

Generally agreed areas

There is extensive evidence that intensive management in RA patients increases the frequency of remissions. One consequence has been that the use of intensive management is supported in all clinical guidelines. Another consequence has been that, over the last two decades, the intensity of treatment has increased in routine practice settings. This change has been reported in other settings. 67,202–204 Associated with the increased use of intensive managements have been reductions in overall disease activity levels and increases in the frequency of remissions. These findings have also been reported by others. 57,60 In addition, erosive progression has lessened substantially for an even longer period, and this is most likely a consequence of increased treatment intensity together with earlier diagnosis and treatment, although it remains a relevant outcome measure. This finding has also been identified in other studies and reviews. 59,205

Continuing uncertainties

There is considerable support from expert opinion in clinical guidelines for treating moderate RA intensively. We also found, in our analysis of observational data and trials, that remissions are associated with overall reductions in disease activity levels in patients with moderate disease activity. Although there is some evidence that reducing disease activity improves disability in patients with moderate RA, our results were not conclusive and further work is needed to resolve this important question.

It is also not possible to be certain that achieving remission in patients with moderate RA in our observational study and in secondary analyses of completed clinical trials was a result of the intensity of their treatment. This uncertainty can be resolved only in a prospective clinical trial that directly tests this hypothesis.

Treatment targets

Targets must balance the ideal with the practical. Stringent targets may deliver optimal outcomes in some individuals, but achieve fewer overall benefits than more readily achievable targets. The TITRATE programme adopted DAS28-ESR remission as its primary target because it is the most widely used composite remission assessment. There is also extensive evidence that achieving DAS28-ESR remission optimises health-related quality of life and function and minimises radiological damage. 211–215 Sustained remission over time is particularly important because it is associated with better outcomes than remission at a single time point. 216,217 We collected components of other composite measures to compare their value as targets during intensive management.

In this section, we evaluated four aspects of treatment targets: (1) comparisons of sustained remission (persistent remission after 6 months’ treatment) and point DAS28-ESR remission and low disease activity, (2) the impact of lesser improvements in DAS28-ESR, (3) limitations of DAS28-ESR in comparison to other composite assessments and (4) associations of DAS28-ESR components with health-related quality of life.

We focused on these aspects of treatment targets, as they are important and we had access to relevant observational and trial data. We could not examine all indices, as some of the necessary data are not collected in routine care settings or our published trials. As C-reactive protein (CRP) levels and physicians’ global assessments are not usually measured in routine practice in England, we could not study the SDAI. 218

Simple baseline outcome predictors

Using baseline measures to predict clinical outcomes may help routine practice. We therefore assessed the value of simple four-point scores, HAQ scores alone and mental health status.

We selected these areas on the basis of what was practical and likely to be used in clinical practice. There was a case to assess rheumatoid factor and subtypes and other autoantibodies in predicting RA outcomes,81,219,220 but these were not used in the observational studies and trials that we could access.

Observational studies

We further studied the observational longitudinal cohort study established in 2005 at Guy’s Hospital. The study focused on 752 patients followed over ≥ 3 years. Details of these patients are given in Appendix 1, Table 28. We also studied 155 early RA patients who completed 12 months’ follow-up with clinical data at 0, 6 and 12 months in an observational study [Early Rheumatoid Arthritis Network (ERAN)]. Details of these patients are given in Appendix 1. We selected these studies because they involved patients treated in recent years. More historical studies were not used because patients received far less intensive management.

We also evaluated a compilation of single time point observational studies of outpatients with RA. 72,221–223 The patients included 747 European white RA patients, 197 black African/Caribbean British patients and 430 Arab patients seen in rheumatology clinics in Saudi Arabia. No specific treatment policies were followed in these patients. Details of these patients are given in Appendix 1, Table 29.

Clinical trials

We further evaluated the 379 patients completing the 24-month CARDERA trial73 and the 179 patients completing the TACIT trial. 74 We also evaluated patients with established RA in the OPTTIRA (Optimizing Treatment with Tumour Necrosis Factor Inhibitors In Rheumatoid Arthritis) trial. 224 The OPTTIRA trial, which lasted 6 months, enrolled 103 patients, and complete end-point data were available in 97 patients. Details of these patients are given in Appendix 1, Table 31.

Clinical assessments

We assessed disease activity using DAS28-ESR, CDAI and Routine Assessment of Patient Index Data 3 (RAPID3), disability using the HAQ, and health-related quality of life using EuroQol-5 Dimensions (EQ-5D) and the Short Form questionnaire-36 items (SF-36). 225–230

Further details are given in Appendix 2.

Statistical analyses

Data were analysed descriptively using means, SDs and 95% CIs or medians and IQRs for non-normally distributed data. Other tests included chi-squared tests, assessments of sensitivity and specificity, t-tests, regression analyses, Spearman’s correlations and multiple linear regression methods. Further details are given in Appendix 3.

Treatment targets: DAS28-ESR and disability

The relationships between remission and low disease activity with disability and quality of life were studied in early and established RA trials and an observational cohort. In these patients, both sustained remission and sustained low disease activity were relatively uncommon. Between 5% and 9% of patients had sustained remissions and 9–16% of patients had sustained low disease activity. More patients had remission and low disease activity at single time points. Between 35% and 58% of patients had an episode of remission and between 49% and 74% of patients had an episode of low disease activity.

Disease Activity Score for 28 joints based on ESR scores varied substantially after patients had achieved an episode of remission. End-point DAS28-ESR scores (at 12 and 24 months in TACIT and CARDERA trials,73,74 and at final assessment in the observational study) in patients achieving an episode of remission showed that 53–61% of patients were still in remission, 9–18% of patients had low disease activity, 21–22% of patients had moderate disease activity and 4–8% of patients had high disease activity. These findings are shown in Figure 8.

FIGURE 8.

End-point DAS28-ESR category after attaining point remission.

Individual patients showed marked levels of variation in their subsequent DAS28-ESR scores following attaining remission. The extent of this within-individual variability was similar across all three cohorts. Figure 9 shows DAS28-ESR scores for all patients following attaining remission in the longitudinal observations study in patients with at least five subsequent DAS28-ESR measures.

FIGURE 9.

Within-individual variability in DAS28-ESR scores after remission for patients in the longitudinal observational study. DAS28-ESR scores for each individual patient following an episode of remission are plotted, provided there were at least five subsequent DAS28-ESR measures. Reprinted from Seminars in Arthritis and Rheumatism, Volume 49, Scott IC, Ibrahim F, Panayi G, Cope AP, Garrood T, Vincent A, et al. The frequency of remission and low disease activity in patients with rheumatoid arthritis, and their ability to identify people with low disability and normal quality of life, pp. 20–6, Copyright 2019, with permission from Elsevier. 210

Reprinted from Seminars in Arthritis and Rheumatism, Volume 49, Scott IC, Ibrahim F, Panayi G, Cope AP, Garrood T, Vincent A, et al. The frequency of remission and low disease activity in patients with rheumatoid arthritis, and their ability to identify people with low disability and normal quality of life, pp. 20–6, Copyright 2019, with permission from Elsevier. 210

Sustained and point remissions had varying impacts on end-point low disability and normal EQ-5D scores (Table 3). Sustained remissions were most specific for low disability (97–98%) and normal EQ-5D (93–97%), but lacked sensitivity (low disability: 19–29%; normal EQ-5D: 19–36%). Point remission gave a better balance between sensitivity and specificity (low disability: specificity 50–78% and sensitivity 68–89%; normal EQ-5D: specificity 42–72% and sensitivity 70–93%).

Attaining sustained low disease activity was also highly specific for low disability (92–96%) and normal EQ-5D (86–94%), but lacked sensitivity (low disability: 26–41%; normal EQ-5D: 33–41%). Low disease activity at any point was highly sensitive (low disability: sensitivity 87–97%; normal EQ-5D: sensitivity 87–100%), but had only moderate specificity (low disability: specificity 31–63%; normal EQ-5D: specificity 25–58%).

Treatment targets: optimal responses in DAS28-ESR scores

An alternative way of assessing the inter-relationship between DAS28-ESR scores, disability and quality of life was examining the impact of EULAR responses in clinical trial settings. This approach was taken in another study208 that evaluated the impacts of moderate and good EULAR responses on changes in HAQ scores at the end points of early and established RA trials.

Moderate EULAR responders’ mean HAQ scores decreased by 0.39 and 0.33 in the CARDERA and TACIT trials, respectively. 73,74 In contrast, EULAR good responders had reductions of 0.88 and 0.64, respectively. In both trials, the difference between moderate and good responders exceeded the minimum clinically important difference for HAQ scores (0.22). The differences in mean reductions of 0.49 and 0.30 between moderate and good responders were significant (p < 0.01, unpaired t-test).

There were similar findings for EQ-5D scores. In moderate EULAR responders, EQ-5D scores increased by 0.18 and 0.15. In good EULAR responders, EQ-5D scores increased by 0.30 in both trials. The differences (0.12 and 0.15) between moderate and good responders also exceeded the minimum clinically important difference, which is generally considered to be 0.07, and were significant (p < 0.01, unpaired t test).

In addition, the frequencies of large and minimal improvements in disability and quality of life were assessed in these patients (Figure 10). With HAQ scores between 41% and 18%, good EULAR responders had large decreases in HAQ score (> 1.00) in early and established RA. However, only 13% and 9% of moderate EULAR responders had such reductions. By contrast, only 21% and 20% of good EULAR responders had minimal changes in HAQ score (> 0.22), compared with 37% and 43% of moderate EULAR responders.

FIGURE 10.

Changes in HAQ score in moderate and good EULAR responders. In early and established RA trials (CARDERA trial73 and TACIT trial,74 respectively). Shows per cent of patients with substantial (> 1.00) and minimal changes (< 0.22). Adapted with permission from Mian et al. 208 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/. The figure includes minor additions and formatting changes to the original figure.

Adapted with permission from Mian et al. 208 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/. The figure includes minor additions and formatting changes to the original figure.

Treatment targets: DAS28-ESR and alternative assessments

The inter-relationships between the four components of DAS28-ESR scores were assessed over the four disease activity levels: (1) remission, (2) low disease activity, (3) moderate disease activity and (4) high disease activity. Initially, these inter-relationships were assessed in an observational study of 747 European white patients. This analysis showed that ESRs contributed most to mean DAS28-ESR scores at all activity levels. However, their contribution was greatest in remission, when ESRs accounted for 70% of DAS28-ESR scores. The contribution of ESR decreased to 40% of DAS28-ESR scores in active disease. In contrast, the contributions of tender joint count to overall DAS28-ESR scores declined as DAS28-ESR fell. Swollen joint counts and patient global assessments showed small stable contributions to DAS28-ESR scores over all disease activity levels.

These findings were replicated in two further observational studies of 197 black African/Caribbean British patients223 and 430 Arab patients. 222 They were also replicated in three clinical trials (i.e. CARDERA,73 TACIT74 and OPTTIRA224) that involved 97–369 patients. Figure 11 shows the contributions of ESR and tender joint counts to DAS28-ESR disease activity levels in all six of these observational studies and trials.

FIGURE 11.

Contributions of different components to activity scores in different states of disease activity. Tender joints and ESR in DAS28 in data from six studies72–74,221–224 and components CDAI and RAPID3 in data from the CARDERA trial. 73 (a) DAS28 tender joints; (b) CDAI all components; (c) DAS28-ESR; and (d) RAPID3 all components.

Two other composite scores – CDAI and RAPID3 – were studied in a comparative manner in one early RA trial (i.e. the CARDERA trial73). These alternative composite scores showed different patterns of variation across disease activity levels, which is also shown in Figure 11. With the CDAI, patient and assessor global assessments dominated in remission and swollen and tender joint counts dominated in active disease. With RAPID3, patient global score, pain score and HAQ score made relatively stable contributions to the overall score across all activity levels.

Treatment targets: DAS28-ESR and health-related quality of life

The association between different components of the DAS28-ESR and health-related quality of life was assessed using the SF-36. The inter-relationships were evaluated in clinical trials of 672 patients with early and established RA.

Linear regression models, which included all four DAS28-ESR components, examined the relationships to SF-36 physical component score (PCS) and mental component score (MCS). The regression models were adjusted for treatment, age, sex and disease duration. The regression models found significant correlations between patient global scores and both SF-36 summary scores in early and established RA (Table 4). Other components of DAS28-ESR had significant correlations in early RA patients, but did not have significant correlations in established RA patients.

Predictive factors: simple four-point scores

The first approach to predicting RA outcomes involved developing and testing a simple predictive score using data that are regularly collected in routine care settings. It focused on predicting persisting active RA. The score was developed in an observational study (ERAN),206 using 155 early RA patients who completed 12 months’ follow-up and had clinical data at 0, 6 and 12 months. Regression modelling identified three main predictors for persisting active disease: (1) tender joint counts, (2) HAQ scores and (3) ESR. Each of these predictors was then dichotomised (six or more tender joint counts, HAQ score of ≥ 1.0 and an ESR of ≥ 20 mm/hour) to give a four-point score. This index predicted persisting active disease (i.e. a DAS28-ESR score of > 3.2) at 6 and 12 months during follow-up in ERAN.

The value of this four-point score was then assessed in clinical trials in 558 patients with early and established RA. In the early RA trial, only 20% of patients with no predictors had persistent active disease, whereas 80% of patients with all three predictors had persistent active disease (Figure 12). This relationship was significant (p < 0.01). There was a similar relationship in the established RA trial, although this was weaker because none of the patients in the established RA trial had no initial predictive factors. In these patients, 20% of patients with one predictive factor had persistent active disease, compared with 60% of patients with all three predictors (p = 0.05).

FIGURE 12.

Simplified predictors of persistently active disease in trial patients.

Predictive factors: high baseline Health Assessment Questionnaire score as an outcome predictor

A second approach to predicting outcomes used initial HAQ scores alone. The value of baseline HAQ scores in predicting outcomes was assessed in 558 patients in early and established RA trials73,74 and 752 patients followed over ≥ 3 years in the observational study.

In both trials,73,74 patients with low baseline HAQ scores (≤ 1.50) had significantly more good EULAR responses (both p = 0.013) and significantly lower final mean DAS28-ESR scores (both p > 0.001) than patients with high baseline HAQ scores (> 1.50). These differences are shown in Figure 13. In the observational study, patients with low baseline HAQ scores had significantly lower overall mean DAS28-ESR scores (p < 0.001). In both trials, patients with high initial HAQ scores (> 1.50) had the largest end-point decreases in HAQ score if they achieved good EULAR responses. The observational study showed the same pattern.

FIGURE 13.

Initial high and low HAQ scores and changes in HAQ score in EULAR good responders. Mean and standard errors are shown.

Sequential changes in DAS28-ESR scores in both trials73,74 and the observational study showed that patients with low baseline HAQ scores had lower mean DAS28-ESR scores at all subsequent follow-up time points (Figure 14). The pattern of response was similar in all three groups, although the difference in DAS28-ESR scores attributed to baseline HAQ was larger in the early RA trial73 than in the established RA trial. 74

FIGURE 14.

Sequential changes in mean DAS28-ESR scores in patients with high (> 1.50) and low (≤ 1.50) baseline HAQ scores. Standard errors are shown. (a) Early RA trial;73 (b) established RA trial;74 and (c) observational study.

The relationship between baseline HAQ scores, subsequent remissions during treatment and changes in HAQ scores with treatment are shown in Table 5. The analysis shows two main things. First, patients with high baseline HAQ scores had significantly fewer remissions. Second, when remissions occurred, especially several remissions, the changes in HAQ scores were greatest in patients with high baseline HAQ.

Predictive factors: anxiety and depression

The final approach to predicting outcomes assessed the impact of anxiety and depression using EQ-5D, which were related to outcomes in 379 patients in an early RA trial73 using linear regression models.

In unadjusted regression models, patients with moderate and high levels of depression and anxiety at baseline had higher HAQ and DAS28-ESR scores over time and at the trial end point. After adjusting for age, sex, disease duration, time, treatment type, baseline HAQ and DAS28-ESR scores and rheumatoid factor status, there were no longer between-group differences for HAQ score (Table 6). However, there continued to be a significant relationship between high levels of depression and anxiety at baseline and higher end-point DAS28-ESR scores.

At the trial end point, 80 (21%) patients had remissions (i.e. DAS-28 scores < 2.6). Patients with moderate levels of depression and anxiety at baseline had fewer clinical remissions than patients with no depression and anxiety at baseline [odds ratio (OR) 0.50, 95% CI 0.29 to 0.88; p = 0.02]. Patients with high levels of depression and anxiety symptoms at baseline also had reduced odds of reaching remission; however, this comparison was not significant (OR 0.77, 95% CI 0.25 to 2.33; p = 0.64). This is likely to reflect the small number of patients with extreme symptoms at baseline (n = 24), reducing the power to find a significant effect because of an imprecise estimate.

Secondary analyses of existing data

Most studies in this section were post hoc analyses of existing data. They did not address prespecified hypotheses. As a consequence, caution is needed interpreting their significance.

Rheumatoid factor and other autoantibodies

The prognostic studies did not consider the impact of rheumatoid factor isotypes or anti-citrullinated peptide antibodies. These are recognised response predictors that, together with smoking status, are linked to rheumatoid factor positivity. 231–234 However, as autoantibodies are measured in many different ways across centres, it is impractical to use them in current clinical practice studies. Smoking status is also not usually recorded in routine clinical practice.

Diagnostic criteria and intensive management strategies

Rheumatoid arthritis patients in all studies assessed were enrolled before the introduction of new diagnostic criteria for the classification of RA. There is evidence that these new criteria change the patients classified as having RA, particularly patients with seronegative disease. 45,235–238 The TITRATE trial uses the most recent criteria and it would have been a mistake not to do so. This change makes it difficult to relate historical findings exactly to new data.

The trials studied did not involve the same intensive management strategies used in the TITRATE programme and the impact of changing treatment in patients who did not achieve sustained remissions was not examined. These are general limitations with all trials involving intensive management strategies. 239–244

Duration of DAS28-ESR remission

We found that achieving sustained DAS28-ESR remission gave the greatest chance of minimising disability and maximising health-related quality of life; however, this was uncommon, reflecting international experience with sustained remission. 217,245–249 More patients benefited when the treatment target was to achieve DAS28-ESR remission at any time during follow-up.

End-point remission and low disease activity were both reasonable targets.

Other assessments of remission

Disease Activity Score for 28 joints based on ESR scores were dominated by the ESR at low levels and in remission. Other composite disease activity assessments, such as CDAI and RAPID3, show different patterns in their components as disease activity changes. However, there was no reason to favour one composite index over another. These findings reflect the ongoing debate about how best to use composite indices in assessing RA disease activity. 250–254 We also found that patient global assessment, a component of most composite measures, was most closely associated with patient-assessed health-related quality of life. Several other recent reports255–257 have highlighted the importance of patient global assessments in RA.

Simple outcome predictors

Poor outcomes were predicted by several simple baseline measures, including a simple four-point predictive score, initial HAQ score and the presence of anxiety and depression. The situation with the HAQ was complex, as the largest improvements with treatment were seen in patients who had high initial HAQ scores and then showed substantial clinical improvements and achieved remission. Other research has highlighted the relevance of baseline HAQ score258–261 and depression262–265 in predicting RA outcomes.

Qualitative study of patient expectations

We explored the views and expectations of patients with moderately active RA and their carers about intensive management strategies. Several previous reports have examined the views of patients with more active RA. 270–272

Patient handbook

We developed a patient handbook to support patients who received intensive management, and this reflects growing recognition of the importance of the involvement and shared decision-making of patients in their disease management. 273–277 Patients helped to identify relevant information and ensured that its content was acceptable and accessible.

Clinician training manual

We developed a training manual to support clinicians to deliver intensive management. During the development of the manual, we systematically reviewed the evidence for psychological approaches, in general, and motivational interviewing (MI) to incorporate psychological approaches to support patients receiving intensive management. Psychological interventions are likely to be beneficial as adjunctive treatments for pain, fatigue and psychological distress in RA. 278 Health-care professionals can be trained to deliver psychological interventions to support patients with common long-term disorders,279 and MI fits this niche. 280,281

Motivational interviewing was identified as a candidate psychological technique because the trial research questions focused on treat-to-target approaches. Stopping, starting and changing medications and doses is a behaviour. Therefore, the intervention required a behavioural approach to support discussions about medication, which could lead to assessment of motivation for behaviour change in routine care by specialist nurses. The clinical and research expertise of Jackie Sturt, the academic lead for the psychological intervention component, identified the potential of MI to deliver the required behavioural changes around medication changes. Researchers undertook a review of the evidence to understand whether or not MI had been used experimentally in RA and the ways in which MI had been used in long-term condition self-care behaviours in general. The wealth of evidence in many long-term conditions and the absence of evidence in RA confirmed our decision to use MI. We considered it a good fit from both the clinical and theoretical perspectives. In addition, we noted that there was no existing evidence base for its use in this population.

Other developmental activities

Two other developments did not require primary research: (1) to devise treatment plans to capture patients’ views about their treatments and (2) the development of training courses for clinicians to deliver intensive management.

Qualitative studies of patient expectations

Focus groups and one-to-one interviews were conducted with nine patients with RA and five carers from four rheumatology clinics in three London hospitals. Two non-English-speaking patients were included and were assisted by a professional translator. The groups and interviews were audio-recorded, transcribed and assessed using a framework analysis approach. 282 Details of the patients and carers are shown in Appendix 1, Table 32.

Audio-recordings were transcribed verbatim. Transcripts were analysed by the researcher (LP). A second rater (HL) appraised the emergent themes from the transcripts and consensus between both researchers was reached. The transcripts were analysed using a framework analysis approach. 283 The process of framework analysis involves a series of stages: (1) familiarisation, (2) identification of a thematic framework, (3) indexing, (4) charting and (5) mapping and interpretation.

A combined inductive–deductive approach was taken, as the study had some specific issues to explore; however, it still allowed space to discover participants’ views and concerns. The codes were based on an iterative process that incorporated both the research question and line-by-line analysis of two patient and two carer transcripts. The remaining data were indexed in a systematic way in accordance with the thematic framework. Where new codes were identified, previously indexed interview transcripts were re-read to ensure that all relevant data were coded. 283,284

Patient workshop

Handbook development was facilitated by an audio-recorded workshop that involved six patients, with another patient giving more feedback via e-mail. None had substantial prior knowledge of intensive management. The workshop transcript was analysed using thematic content analysis. 285

Systematic reviews

Two systematic reviews were undertaken, searching MEDLINE and other databases using predefined terms. The first assessed systematic reviews of psychological interventions in RA. The second assessed MI in musculoskeletal diseases. Full details of these systematic reviews are given in Report Supplementary Material 1 and 2, including a PRISMA flow diagram (see Report Supplementary Material 1, Figure 5) and details of the included studies (see Report Supplementary Material 1, Tables 6–8).

Patients’ and carers’ views and expectations

Patients’ and carers’ views about intensive management spanned several themes and are shown in Tables 7 and 8. One theme was treatment expectations (i.e. patients want to have improved physical symptoms, reduced pain, increased mobility and greater independence). A second theme was increased medication. Patients had varying views about taking more medication, subject to the stability and benefits of their current treatment regimens. Most patients did not receive drug combinations that fully controlled their RA and they were willing to try more intensive managements, despite concerns about potential side effects. Intensive management involved more frequent clinic appointments, but these were generally acceptable to patients and carers.

Tables 7 and 8 provide both positive and negative views, reflecting variation in participant responses. The findings identified that there was variation depending on individual circumstances.

Patients’ educational needs formed another theme. Some patients would readily take ‘whatever is prescribed’. Most wanted some information. A few preferred as much information as possible. An intervention needs to cater for all these requests. Continuity of care formed the final theme. Patients liked to see ‘their own’ rheumatologist and were concerned this specialist would ‘not know what has been happening’ when they saw different clinicians.

Development of the patient handbook: workshop for patients

Patients made several recommendations about the handbook content. They suggested that it include information on (1) the aims of intensive management, (2) its benefits above standard care and (3) the importance of patient’s active engagement with the trial.

The handbook included information about intensive management and what this would involve (e.g. monthly blood tests), including guidance on self-management (the contents of which were informed by the aims of the intervention) to help patients identify and work on key areas where they may be challenged (e.g. pain, fatigue, physical activity, medication adherence and low mood/anxiety).

Two researchers (SG and LP) collected information, for example current treatments for RA, intensive management in the TITRATE programme and self-management of life with RA. The information was gathered from evidence-based sources, including publications and current clinical guidelines, expertise from medical and allied health practitioners, and online sources from national charities National Rheumatoid Arthritis Society (NRAS) and Arthritis Research UK. The relevant information was then collated by one of the researchers (SG) into a draft handbook across nine sections. 268 Further details are given in Appendix 3.

Developing training manual: evidence for psychological support

Our systematic review of reviews on psychological support in RA identified eight relevant publications. 278,286–292 These systematic reviews all showed that psychological treatments resulted in significant improvements in functional disability, pain, fatigue, self-efficacy and coping in analyses of between 4 and 27 trials. The key findings are shown in Table 9. The effect sizes for these different interventions ranged from –0.09 for pain to 0.46 for coping.

Developing training manual: evidence for motivational interviewing

Our systematic review identified seven relevant studies,293–299 including one systematic review,294 two clinical trials,293,298 two pilot studies297,299 and two interventional studies. 295,296

The systematic review by Chilton et al. 294 evaluated five trials of MI for the treatment of pain, fibromyalgia and osteoporosis. Although, overall, its findings were inconclusive because of the heterogeneity of the studies involved, it included considerable evidence favouring the use of MI.

The other six original research studies,293,295–299 which comprised clinical trials, pilot studies and interventional studies, also all provided some evidence in favour of using MI in these patients. Three studies293,295,299 were most relevant to the TITRATE programme. First, the trial of Ang et al. 293 showed short-term benefits on physical activity and clinical outcomes from six MI sessions. The pilot study of Ferguson et al. 299 provided some evidence that MI improved adherence with treatment. Finally, the interventional study of De Gucht295 showed that patient education that involved MI resulted in increased physical activity.

Completed patient handbook and clinician training manual

Based on these studies and associated developmental work, the handbook and training manual were finalised and used throughout the TITRATE trial.

Other developmental work

Activities that did not require primary research were the creation of a treatment plan for individual patients and devising a 2-day training course for specialist nurses and other clinicians involved in intensive management in the TITRATE trial. The course involved group-based participative experiential workshops over 2 days. It incorporated psychological and behavioural approaches to deliver supportive care together with clinical assessment and pharmacological prescribing algorithms to ensure that patients were able to receive intensive management. These were supplemented by remote one-to-one support while practitioners delivered the TITRATE intervention to their first three patients.

Generalisability of patients’ views

The patients’ and carers’ perspectives in the qualitative study and in the development of the handbook might not be generalisable to all patients with moderate RA. Some patients might have very different perspectives, although focus groups allow insights into the wide range of views that participants had about a specific issue, as well as how they interacted in a more ‘naturalistic’ setting. 300,301

Limitations of evidence

Although the manual and training course for clinicians delivering intensive management were evidence based, they had to reflect a range of expert opinions on management in addition to evidence-based care. There are also complex issues in the assessment of patients’ perspectives. For example, as RA predominantly affects women, the views of men with RA may be overlooked. 302

Participants were given the option of taking part in a focus group or a semistructured interview (in-person or via telephone). The reason for this was to provide choice to participants, minimise participant burden and also accommodate those experiencing RA symptoms. Focus group and semistructured interview data were analysed in the same way. This is a limitation of the study, as semistructured interviews are more suited to exploring individual experiences and focus groups more exploratory research. Telephone interviews were advantageous in this study for participants who may not have had the time or ability to take part had the interview been in person.

Patients’ perspectives

Patients and carers had a range of views on intensive management. As they want improved physical symptoms and greater independence, most will try intensive management and accept the need for frequent appointments. However, they want sufficient information and continuity of care.

Supportive material

We developed a patient handbook and clinician training manual, which included patients’ views and the evidence about psychological interventions, and a training course for clinicians delivering intensive management. There is evidence that techniques such as MI can be used by clinicians after relatively brief training280 and that MI is relevant for patients with RA.

Design

This was an open-label 12-month pragmatic randomised multicentre, two-arm, parallel-group superiority trial.

Participants

Patients were recruited from 39 English rheumatology centres. Included patients were males and females aged > 18 years who met the 2010 RA classification criteria,309 had received at least 6 months’ treatment with conventional DMARDs, were currently receiving at least one DMARD, had moderate/intermediate disease activity (defined as a DAS28-ESR score of 3.2–5.1 with three or more swollen and/or tender joints out of 66/68 and at least one swollen joint) and who were able and willing to follow intensive management. Excluded patients included patients who had comorbidities that made intensive treatment inadvisable; in whom treatment with five or more DMARDs had failed; who had taken biologics; who had irreversible disability from extensive joint damage; who were women who were pregnant, breastfeeding or at risk of conceiving; who had recently been in another trial; or who were currently on an early RA pathway. 310

Interventions

Assessments

All measures were assessed at baseline and at 6 and 12 months, except radiographs, which were taken at baseline and at 12 months. In addition, psychosocial measures (i.e. mood, anxiety, health beliefs and illness perceptions) were measured at baseline. Individual assessments were combined in composite indices [i.e. DAS28-ESR, Disease Activity Score for 28 joints based on C-reactive protein levels (DAS28-CRP), SDAI and CDAI]. A record was made of DAS28-ESR low disease activity states (i.e. a score of ≤ 3.2). Further details are given in Appendix 2.

Primary outcome measure

The primary outcome measure was DAS28-ESR remission (i.e. a DAS28-ESR score of < 2.6) at 12 months. 212,312 Alternative remission definitions consisted were a DAS28-CRP score of < 2.6, a SDAI score of ≤ 3.3, a CDAI score of ≤ 2.8 and ACR/EULAR Boolean remission at 12 months. 212,218,313,314

Secondary outcome measures

Secondary outcome measures included tender joint counts (28 and 68 joints), swollen joint counts (28 and 66 joints), ESR, CRP level, patient global assessments on 100-mm visual analogue scales (VASs), assessor global assessments on 100-mm VASs, pain and fatigue on 100-mm VASs, the HAQ,228 EuroQol-5 Dimensions, five-level version (EQ-5D-5L), score,315 plain-film radiographs of the hands and feet (scored using a modified Larsen score)316 and adverse events.

Sample size calculation

The most relevant UK trial129 compared treat to target with standard care in active early RA. Sixteen per cent of patients receiving standard care had end-point Disease Activity Score (DAS) remission. 129 We assumed that standard care in the TITRATE trial would also lead to 16% of patients achieving end-point DAS28-ESR remissions. We proposed rejecting the null hypothesis (i.e. RA patients with intermediate disease activity on DMARDs have no more remission after 12 months of intensive management) if intensive management increased remission at 12 months by ≥ 15%. Demonstrating this difference with 5% significance and 90% power meant randomising 358 patients (179 patients per group). We ended recruitment, for organisational reasons, after 3 years and when 335 patients were randomised (i.e. 94% of the planned sample size).

Randomisation

Potentially eligible patients were screened and reasons for non-entry recorded. Consenting patients were individually randomised using block randomisation with randomly varying block sizes. Stratifying by site ensured prerandomisation allocation concealment. Patients were randomised to intensive management or standard care in a 1 : 1 ratio. All staff involved in the conduct of the trial were unaware of the allocation sequence.

Blinding

The TITRATE trial was un-blinded, as patient involvement in their intensive management made blinding impossible. Independent assessors uninvolved in managing trial patients undertook clinical assessments. No specific checks were made on their knowledge of patients’ treatments. Pain, fatigue, disability and quality of life were self-assessed by patients. Radiographic reading was blinded to treatment group.

Statistical methods

Baseline characteristics were summarised by randomisation group as means and SDs and frequencies and percentages (categorical variables).

Randomised patients who received treatment were assessed on an intention-to-treat (ITT) basis. All participants had complete observations at baseline. Missing data at follow-up were imputed regardless of the reason(s) that they were missing. For subjects with missing outcomes, the baseline outcomes and other explanatory covariates (i.e. treatment group, sex, age, ethnicity, NHS region and disease duration) were used to impute the missing outcome data using predictive mean matching (PMM) with five nearest neighbours, assuming that unobserved measurements were missing at random (see Appendix 3 for detailed imputation descriptions).

A logistic regression analysis was used to analyse the primary outcome of remission at 12 months. Univariate analyses were adjusted for NHS region (design variable). Multivariable analyses were adjusted for sex, ethnicity, age, NHS region and disease duration. Alternative remission definitions were analysed similar to the primary outcome measure. Linear regression evaluated change at 12 months for the continuous primary outcome (i.e. DAS28-ESR) and secondary outcome measures.

For primary and secondary analyses that involve longitudinal measurements, linear mixed models were used to estimate the effect of treatment. Working correlation matrices were unstructured, which is not unduly complicated given that measurements were taken at three time points. Interactions between time and treatment group were also assessed in these models.

Valid/robust estimates of the precision of effects were obtained through use of the information sandwich estimator for all analyses. The estimates for primary outcome were presented as ORs with 95% CIs for the effect of intensive management. Statistical significance was determined at the 5% level using a two-sided test throughout. Serious adverse events and adverse rates in the two treatment arms were compared using comparisons of two independent proportions. Finally, complete-case analyses were also undertaken, which evaluated patients who followed the protocol and received 12 months’ treatment. All analysis was carried out using Stata^® (StataCorp LP, College Station, TX, USA).

Patients and analyses

Patients

Between August 2014 and July 2017, a total of 1405 patients were invited to participate, 459 patients were screened and 335 patients were randomised and treated (Figure 15). Of the randomised patients, 303 of 335 (90%) patients provided a primary outcome measure at 12 months, including three patients who withdrew but agreed to medical review only. Thirty-two (10%) patients were lost to follow-up.

FIGURE 15.

A CONSORT (Consolidated Standards of Reporting Trials) flow diagram for the TITRATE trial. Reproduced with permission from Scott et al. 308 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/. The figure includes minor additions and formatting changes to the original figure.

Reproduced with permission from Scott et al. 308 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/. The figure includes minor additions and formatting changes to the original figure.

Primary outcome

Intensive management increased the frequency of DAS28-ESR remissions at 12 months compared with standard care. With intensive management, 32% (95% CI 25% to 40%) of patients had achieved remission, compared with 18% (95% CI 12% to 24%) of patients receiving standard care (Figure 16). Both unadjusted and adjusted logistic regression showed that these differences were significant (p < 0.01) and these differences are summarised in Table 12.

FIGURE 16.

Remission rates with intensive treatment and standard care.

Other remission criteria and low disease activity at 12 months

Clinical outcomes at 12 months

Clinical outcomes over 6 and 12 months

Longitudinal analyses assessed changes over both 6 and 12 months using mixed-effects models (see Table 13). Unadjusted and adjusted analyses showed significant differences between groups for DAS28-ESR, swollen joint counts for 66 joints, patient global assessments, fatigue and pain. The coefficients for fatigue between treatment groups were particularly large in the unadjusted (–15.7, 95% CI –21.3 to –10.1) and adjusted (–13.1, 95% CI –18.1 to –8.1) analyses.

Complete-case analyses

Harms

Fourteen patients receiving intensive management and 11 patients receiving standard care experienced one or more serious adverse events or died (Table 15). There was no significant difference in proportion of serious adverse events between treatment groups (RR 1.27, 95% CI 0.56 to 2.92). The three patients who died comprised two in the intensive management group and one in the standard care group. None of the deaths was considered to be treatment related. Other serious adverse events spanned a range of systems and there was no indication that any of the events were treatment related.

Overall, 132 patients (60 intensive management patients and 72 standard care patients) had 265 adverse events (114 in the intensive management group and 151 in the standard care group) (see Table 15). These events spanned a range of body systems. There was no evidence that intensive management increased the risk of an adverse event.

Strengths

The TITRATE trial had two strengths. First, it was a relatively large trial, involving almost 40 different specialist centres and a range of patients. Its findings are therefore likely to be robust. Second, the predicted and the actual outcomes were very similar, showing that it delivered the expected degree of improvements based on previous studies in early RA.

Limitations

The TITRATE trial also had a number of limitations. First, it did not compare the sustainability of remission between groups;216,317 however, to assess standard care patients more often than every 6 months would mean that they were no longer receiving standard care and, therefore, invalidating them as a control group. Second, the TITRATE trial lasted only 12 months. Ideally, strategy trials would last for several years; for example, 10-year results have now been reported for the BeSt strategy trial. 175 However, undertaking such long-term trials of intensive treatment strategies has organisational and funding complexities and could not be pursued in the TITRATE trial. Third, there is uncertainty as to which outcome is preferable. 318 ACR/EULAR Boolean remissions appear ideal but are not often achieved, whereas low DAS28-ESR scores may have fewer benefits but were achieved by almost half the patients receiving intensive management. In addition, although the TITRATE trial included a range of patient-reported outcome measures, the trial was designed before newer measures, such as the Rheumatoid Arthritis Impact of Disease (RAID) score, became widely used and patients’ perspectives on their outcomes may have provided important additional information. Fourth, intensive management is not effective in all patients. The TITRATE trial does not provide any information on how best to manage patients who did not respond to intensive management. Failure to respond to different forms of intensive treatment, particularly biological therapies, is increasingly recognised as being relatively common and a source of high health-care costs. 319–321 Fifth, the use of monthly sessions was planned when the trial was designed and patients did not have any particular input into deciding if this was an optimal time for assessing their progress or if less frequent assessments would be preferable. An additional issue is that some centres may use ultrasound assessments to evaluate joint inflammation in patients with moderate disease activity, although most centres do not take this approach.

One inevitable limitation of a treatment strategy trial, like the TITRATE trial, in which patients receive a range of different interventions, is the uncertainty about the extent to which different parts of the intervention contributed to the overall benefit of intensive management. Increasing conventional DMARDs, starting biological treatments and supportive management from the specialist nurses are all likely to have contributed. However, we do not know which of these was most important or if all were needed. Such challenges are commonplace in complex interventions. 322–324

Impact of intensive management on remission

The TITRATE trial shows that managing patients with established moderate RA who are receiving conventional DMARDs and who are being followed in specialist rheumatology clinics achieve more remission at the end of 12 months’ intensive management following a treat-to-target strategy compared with standard care. Five different remission criteria showed that intensive management was more effective than standard care. More patients also achieved low disease activity states with intensive management. Although we cannot entirely disentangle the contributions of drug therapy from support from the specialist nurses, the balance of evidence suggests that both contributed to achieving remission.

Other benefits of intensive management

The TITRATE trial also showed that when trained nurses provide holistic care in addition to adjusting drug therapy using treat-to-target approaches, it could help minimise symptoms, which is important to patients.

Safety of intensive management

There was no evidence that intensive management led to more adverse events or serious adverse events.

Extent of benefits

In the complete-case analyses, 32% of patients receiving intensive management achieved 12-month DAS28-ESR remissions and 46% of patients achieved low disease activity states. Achieving remission was associated with substantial improvements in disability and health-related quality of life. Patients receiving intensive management also had substantial improvements in fatigue and pain, and these changes were also most marked in patients achieving remission. Overall, these findings suggest that between one-third and a half of patients receiving intensive management achieved substantial benefits from this treatment approach.

Differences between strategies

Intensive management patients received more conventional DMARDs, more biologics and more steroid injections. They also had more changes in DMARD and biologic dose. However, the magnitude of these differences was relatively small. Biologic use is the most important example of the difference between strategies. With intensive management, 49 of 168 (29%) patients had 58 different biologics. With standard care, 24 of 167 (14%) patients had 26 biologics.

Costs

NHS resources were measured for each participant between baseline and final follow-up. This included medication costs, visits to health services and any social care and community support. Medication usage, the number of hospital visits and intensive management appointments were taken from trial records. NHS and PSS resources were self-reported by participants at 6 and 12 months, with the widely used and validated Client Service Receipt Inventory (CSRI) questionnaire. 326 It included questions related to time off work, which was used in sensitivity analysis.

Unit costs for all resources were obtained for the financial year 2018–19 from national sources. Medication use was taken from a form that collected current RA medication information over the trial. This included the duration of the medication (start date and end date of the medication), the dosage and the frequency of the medication. NHS unit costs for the medications were based on the drug tariff price reported in the British National Formulary (BNF)327 (see Appendix 5, Table 41). If the drug tariff price was not reported in the BNF, then we used the average NHS indicative price from all manufacturers of the medication. NHS and social services costs were from Unit Costs of Health and Social Care. 328

Total NHS costs and social services costs included medication, primary care, secondary care and social services contact. The unit costs are summarised in Appendix 5, Tables 41 and 42. Data on the use of secondary health-care service visits were collected by the research nurse at each centre based on forms designed to capture information on all hospital admissions and the frequency and type of intensive management sessions. Detail on the nature of the reported hospital admissions was not captured and we assumed the cost to be the cost of 1 hour with a rheumatologist. Intensive management sessions were excluded from reported hospital admissions to avoid double counting. The average costs of intensive management sessions were derived from bottom-up micro-costing based on the type of practitioner seen and the duration of the appointment (see Appendix 5, Table 44).

Primary care and social services contact were captured by the CSRI health resource questionnaire. The CSRI provides a 3-month recall and is measured at 6-month intervals. Linear interpolation was used to estimate the costs in the unobserved months. Participants were asked whether or not they had been in contact with a general practitioner (GP) (i.e. a visit to the GP, telephone call and/or GP home visit) and, if so, how many contacts they had had over the previous 3 months. This time was costed based on the average patient’s contact with a GP in the UK lasting 9.22 minutes. 328 Responses to questions on the CSRI relating to appointments with other NHS health-care workers (e.g. practice nurse, NHS physiotherapist, NHS occupational therapist) and social care workers (e.g. staff help at the participant’s home and appointments with social workers) were also recorded and staff time was costed per working hour (see Appendix 5, Table 44). Participants could also report any use of other health or social services, which was costed in a similar manner (i.e. a single working hour for staff on NHS band 5, £34) and included participants’ use of blood tests at walk-in centres, support from a mental health worker, visit to a memory clinic, installation of handrails and toilet seats, and appointments with podiatrists and orthopaedists.

Participants were asked if the NHS or social services paid for their transport to get to health-care appointments and the reported total was used for the cost of transport. The travel cost of staff to participants’ homes or to general practices for hospital-based staff was estimated as the sum of travel time and cost of transport. Travel time was assumed to be 15 minutes (i.e. one-quarter of the cost of a working hour), and we applied the NHS reimbursement rate for a 4-mile journey (i.e. 56 pence/mile, thus £2.24) for the cost of transport. Receipt of Meals on Wheels services was asked directly in the CSRI health resource questionnaire and costed for £4.40 per meal based on a 2018 national survey of the programme. 329

Indirect costs were defined as the production losses resulting from treatment when the participant was unable to return to normal activity. Information regarding participants’ recovery was collected in the CRSI questionnaire at 6 and 12 months. Individual participant costs comprised the amount of whole days or hours the individual has taken off work and the amount taken off by friends of relatives to care for them. Unit time costs were combined and costed using standard economic conventions (i.e. the human capital approach to estimating time costs) and Office for National Statistics data on UK median wages and working hours, and330 this gave a cost estimate of £92 for each day of work lost because of RA (see Appendix 5, Table 42).

The total cost to the NHS and PSS was computed by adding the estimated treatment and follow-up costs for each participant. There was no missing medication, primary care and PSS data. Missing data in the use of secondary health-care services were estimated with multiple imputation and the participant was included in the analysis. The sum of participants’ NHS, PSS and indirect costs was the societal cost of RA illness.

Health-related quality of life

The QALYs gained were estimated by applying the trapezium rule to estimate the area under the curve. QALYs were then adjusted for participants’ baseline level of utility using linear regression. Health utilities were derived from participant responses to the EQ-5D-5L at baseline and at 6 and 12 months. The EQ-5D-5L was designed in 2009 with the intention of improving the discriminative power of the instrument at levels of health near to full health, as compared with the widely used three-level version [EuroQol-5 Dimensions, three-level version (EQ-5D-3L)]. However, the position of NICE331 is that to have consistency with the current reference case analysis (which is based on EQ-5D-3L utility scores), and because of concerns raised about the validity of the EQ-5D-5L value set for England,332 the utility values should be established by mapping responses to the EQ-5D-5L descriptive system data onto the EQ-5D-3L valuation set using the mapping approach reported by Devlin et al. 333 We take this approach in the reference case. Sensitivity analysis will be undertaken with QALYs estimated using EQ-5D-5L responses and two alternative approaches for estimating EQ-5D-3L from responses to the EQ-5D-5L. 334 The mapping approaches were established based on two reference data sets of patients who completed the EQ-5D: (1) FORWARD (the National Databank for Rheumatic Diseases)334 and (2) a EuroQol Group-co-ordinated data collection study. 333,334 The EQ-5D-3L and EQ-5D-5L scores were estimated using the EQ-5D population tariffs that are based on the UK (EQ-5D-3L version) and England (EQ-5D-5L version) population responses. 333,335

Missing observations

Multiple imputation was used to create observations for missing data, which were assumed to be missing at random. Regardless of the possible reason outcomes were missing, we imputed missing values for the EQ-5D data (both EQ-5D-3L and EQ-5D-5L values) at 6 and 12 months, the number of clinical visits to the hospital and number of intensive management sessions. Missing values on the number of clinical visits to the hospital and number of intensive management sessions were dealt with in the same way as the EQ-5D. For each outcome, the method of imputation was PMM. 336 This approach imputes missing values by means of the five nearest neighbour donors, with distance based on the expected values of the missing variables. In our analysis, the expected values of missing variables were conditional on treatment group, sex, age, ethnicity, NHS region and health utility values at baseline. We then replaced each missing value with the mean value of 20 imputations created by the PMM approach (see Appendix 5, Table 43).

Economic outcomes

For each participant, we estimated total costs over the trial period and the QALYs gained. The mean differences between the two trial arms are presented with sample 95% CIs and bootstrapped bias-corrected 95% CIs. The cost and health information were combined in an estimate of incremental cost-effectiveness ratio (ICER) of intensive management compared with standard care. Non-parametric bootstrapping was used to generate CIs for the estimated mean incremental costs and effects and to summarise the uncertainty surrounding the ICERs. Uncertainty was visualised as a two-dimensional cost-effectiveness plane and as a cost-effectiveness acceptability curve, which reports the probability that the intervention is cost-effective for any given level of willingness to pay (WTP).

Sensitivity analysis

To further test the robustness of results derived from the base-case analysis, several deterministic sensitivity analyses were conducted. This included estimating an ICER with alternative approaches to establishing health utilities334 and a societal cost perspective that includes NHS and social services costs and productivity losses. 337 Such analyses examine the effect of estimated or uncertain parameters on the decision.

Subgroup analysis

To explore the sensitivity of the EQ-5D instrument to detect changes in remission, we summarise the mean QALY gain at 12 months for participants who achieved remission compared with those who did not. Remission is defined as a DAS28-ESR score of < 2.6 at 12 months.

To examine if there are subgroups of the population that respond differently to the intervention, we used regression analysis to explore associations of patient characteristics with the change in health utility score from baseline to 12 months. Logistic regression was used to examine which patient characteristics are associated with any improvement in EQ-5D-3L score at 12 months and, therefore, the dependent variable was 1 for participants who experienced any improvement at 12 months and zero otherwise. Ordinary least squares regressions explored which patient characteristics were associated with a change in the level of EQ-5D score (magnitude of the health gain) at 12 months and a separate regression explored these associations in the subgroup of patients who had achieved remission at 12 months. The regressions included as explanatory variables the region of health centre the participant receives RA treatment, sex, age, ethnicity, the duration of RA disease, intervention group and whether or not the patient moved to biologic medication during the trial. We also investigate the number of hospital visits, intensive management sessions and biologic use in participants who achieved remission compared with those who did not. The purpose of this analysis is to examine if more resources were used in patients who achieved and maintained remission, as this has implications for any future analysis that may wish to the extrapolate costs and health findings beyond the duration of this trial.

Duration of assessment

The costs and benefits of the intervention were not extrapolated beyond the trial period in a decision-analytic model to allow a lifetime estimate of expected costs and QALYs. Such a model would require time to loss of efficacy of intensive management sessions to determine the future treatment pathway for the patient populations once a switch from intensive DMARD therapy is estimated, including biologics if patients progress to severe RA.

Duration of treatment

It is plausible that the cost per QALY gained from the intervention would improve over a longer duration of treatment. We found that a key driver of improvement in health-related quality of life was whether or not patients achieved remission, and there is evidence that patients receiving intensive management who did not achieve remission within the trial period are more likely to have done had the trial lasted longer. The number of remissions were larger in the intensive management group and patients without remission had gains in health-related quality of life (mean gain in health utility of 0.024) that were not found in the standard care group (mean gain in utility of 0.0002). In addition, if patients in the intensive management group continue to achieve and maintain remission, then the costs of intensive management treatment would be expected to decrease because we found fewer hospital visits and biologic use in intensive management patients with remission than in patients without remission. This would serve to reduce the incremental costs between groups and improve the cost-effectiveness of the intervention. Therefore, the proportion of patients who move to biologics and the time it takes for them to move to biologics is expected to be key driver of costs and possibly health benefits in an extrapolation.

Overall health economic benefit

The ICER of intensive management compared with standard care was £43,972 and it decreased to £29,363 when a societal cost perspective was taken. Intensive management is therefore unlikely to be cost-effective at the threshold range of £20,000 to £30,000 per QALY, which is typically used by UK decision-makers when assessing short-term within-trial costs and benefits.

Longer-term perspectives

Resource constraints within the project prevented an economic evaluation beyond the 12-month follow-up period (outlined in the protocol as a potential tertiary analysis). This is needed in future research, as within-trial assessments underestimate the benefits of improved earlier treatment and potentially reduced biologic drug use over the longer term.

Baseline response predictors

We evaluated whether or not baseline response predictors would identify patients who showed limited responses to intensive management. We focused on predictors of DAS28-ESR remissions and improved fatigue scores, which were dominant clinical outcomes in the trial. Many previous studies have evaluated predictors of remission338–342 and fatigue343–348 in RA in trials and observational studies.

Analysis of non-responders

We also examined whether or not baseline factors identified patients who showed no improvement over 12 months (with decreases in DAS28-ESR of < 0.6 over 12 months). In addition, we assessed the extent to which non-responders showed some improvements in DAS28-ESR scores during treatment.

Response persistence

We undertook an 18-month follow-up assessment of patients receiving intensive management in the TITRATE trial, assessing the extent to which remissions and reductions in DAS28-ESR and fatigue were maintained after intensive management. Long-term follow-up of patients in RA intensive management trials has advantages,349 although these can be difficult to achieve.

Patients

We studied patients enrolled in the TITRATE trial. Studies of response predictors were confined to the 298 patients in whom 12-month DAS28-ESR and fatigue measures were present. Studies of response persistence were restricted to the 95 patients who were assessed at 18 months. Baseline assessments of these patients were similar from the overall group of patients recruited into the TITRATE trial. Details of these patients are shown in Appendix 4, Table 38.

Assessments

These were confined to the clinical assessments made in the TITRATE trial (see The TITRATE trial).

Statistical analyses

Data were analysed descriptively using means, SDs and 95% CIs or medians and IQRs. Predictors were assessed using logistic regression.

Baseline predictors of remissions at 12 months

Significant predictors on unadjusted logistic regression analyses comprised male sex, baseline DAS28-ESR, HAQ scores, body mass index (BMI) and receiving intensive management. These factors remained significant in adjusted analyses (Table 18). Factors unrelated to 12-month remissions included age, disease duration, pain, fatigue, Patient Health Questionnaire-9 items (PHQ-9), Generalised Anxiety Disorder-7 (GAD-7) and scores on the Beliefs About Medicines Questionnaire (BMQ).

Combining these predictors identified a group of 40 patients who were unlikely to achieve remission irrespective of the treatment they received. The subset of patients who were obese (i.e. had a BMI of > 30 kg/m²) and had high baseline HAQ scores (i.e. > 1.50) had few remissions. Only 1 in 17 (6%) patients receiving standard care and 3 in 23 (13%) patients receiving intensive management had remissions at 12 months (chi-squared 0.6; p > 0.05).

In contrast, the 124 patients with neither of these predictors had more remissions. Fifteen of 66 (23%) patients receiving standard care and 30 of 59 (51%) patients receiving intensive management achieved remissions at 12 months (chi-squared 9.5; p = 0.002).

Baseline predictors of 12 months improved fatigue

Significant predictors on unadjusted logistic regression analyses comprised baseline fatigue, BMI and intensive management (see Table 18). Factors unrelated to 12-month improved fatigue included sex, age, disease duration, DAS28-ESR, HAQ, pain, PHQ-9, GAD-7 and the BMQ.

Non-responder at 12 months

Significant baseline predictors of non-response at 12 months on unadjusted logistic regression analyses comprised BMI, the BMQ (general) and receiving intensive management. Unrelated factors included age, disease duration, DAS28-ESR, HAQ, pain, fatigue, PHQ-9 and GAD-7. These factors remained significant in adjusted analyses (see Table 18).

Changes in DAS28-ESR during follow-up in non-responders at 12 months

One hundred and two patients who received intensive treatment did not achieve 12-month remissions. In 99 of these patients, information was available about remissions occurring during their monthly monitoring visits. Fifty-one of these patients had no remissions during these visits and 48 patients had some remissions (16 patients had a single remission, 13 patients had two remissions and 19 patients had three or more remissions), with the maximum number of remissions being eight. Leaving aside 18 patients who withdrew before 12 months and three patients for whom monthly DAS28-ESR data were not available, there were three subgroups of patients receiving active treatment: (1) 48 patients achieved remissions at 12 months, (2) 48 patients had some remissions during treatment, but these were not sustained until 12 months, and (3) 51 patients had no remissions. These patients showed differing patterns of changes in their DAS28-ESR scores. Details are shown in Appendix 4, Figure 28.

Persistence of response

The 95 patients who had received intensive management in the TITRATE trial and had attended for follow-up at 18 months were divided into two groups on the basis of achieving remission in the trial. First, 48 patients had no or only one DAS28-ESR remission during intensive management and second, 47 patients had two or more DAS28-ESR remissions in this period (median 4 remissions; range 2–10 remissions).

Analysis of DAS28-ESR remissions at 6, 12 and 18 months showed a small decline in the overall frequency of remissions at 18 months, which was least in patients achieving two or more remissions during intensive management (Figure 19). There was also a gradual return in DAS28-ESR levels towards low or moderate levels, which was least in patients achieving two or more remissions (see Figure 19). There was a more marked return in fatigue over 18 months, although this is also least in patients achieving two or more remissions. There were also marked temporal variations in frequencies of different DAS28-ESR categories. Patients with initial moderate RA showed a wide range in activity levels during intensive management (Figure 20). In addition to achieving remission and low disease activity levels, up to 20% of patients had active disease (i.e. a DAS28-ESR score of > 5.1) during follow-up.

FIGURE 19.

Disease Activity Score for 28 joints based on ESR remissions, DAS28-ESR and fatigue. Mean scores over 18 months. (a) DAS28-ESR remissions; (b) mean DAS28-ESR; and (c) mean fatigue.

FIGURE 20.

Disease activity levels over 18 months with intensive management.

We also assessed changes in disease activity states in these patients at 12 and 18 months. This analysis showed considerable variability in the persistence of remission and low disease activity states in these patients, with many patients continuing to change between activity states. Details are shown in Appendix 4, Table 40.

Predictive factors

Identifying predictive factors in single trials is invariably limited by uncertainty about replication. As a consequence, caution is needed and further studies need to show similar findings before any certainty can be placed on our findings. These issues have been highlighted in publications from the PROGnosis RESearch Strategy (PROGRESS) Group. 350–353

Persistence of effect

Assessing what happens to a small subset of randomised patients after a trial has ended is invariably limited by the self-selected nature of the population involved and the limited duration of follow-up. The limitations of subgroup analyses in trials are well known. 354

Limited benefits of intensive management

Our analysis of baseline predictors suggested that some patients are unlikely to benefit from current intensive management, in particular those with a BMI > 30 kg/m². It is likely that other approaches are needed in these patients. The negative impact of obesity has been identified with many RA patients, but may not be extend across all biologic agents. 355,356

Duration of benefits

Intensive management is unlikely to have a permanent effect in RA. Six months after stopping treatment, many patients who had benefited from intensive management were beginning to show features of returning disease activity and higher levels of fatigue. When intensive management is successful, it is likely that ongoing similar treatment is required in the longer term.

Transitions over time

We went beyond investigating solely the state of remission and evaluated transitions between different disease activity states defined by the DAS28-ESR.

Disability over time

We described and characterised functional disability over time (using the HAQ) with a specific focus on the impact of erosive disease at baseline and the impact of time-varying disease activity on transitions between HAQ states.

Erosive damage

We investigated erosive disease, focusing on the impact of disease activity and disability at baseline on 1-year damage progression.

Patients

The REMIRA study recruited 152 adults with RA undergoing a treat-to-target management strategy for 12 months. Inclusion criteria comprised disease duration of ≤ 10 years, receiving stable doses of conventional DMARDs or biologics for > 6 months and DAS28-ESR scores of ≤ 3.2 for 1 month or longer before recruitment. Details of these patients are shown in Appendix 1, Table 30.

Assessments

Baseline data were collected on demographics, disease duration and current treatment. Three-monthly assessments comprised DAS28-ESR and its components (i.e. 28 tender joint count, 28 swollen joint count, patient global assessment and ESR), CRP levels, HAQ, EQ-5D, Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-F) for recording self-reported fatigue, and the Medical Outcomes Study SF-36 and its physical and mental subscales (PCS and MCS). 358–362

Posterioanterior radiographs of hands and feet at baseline and 12 months were used to define damage by radiographic erosions and damage progression by new erosions or worsening of existing erosions over 12 months.

Definition of disease states

Disease activity states were defined based on DAS28-ESR using the internationally agreed definition363 of a DAS28-ESR score of < 2.6 to indicate clinical remission, a DAS28-ESR score of 2.6–3.1 to indicate low disease activity, a DAS28-ESR score of 3.2–5.1 to indicate moderate disease activity and a DAS28-ESR score > 5.1 to indicate high disease activity.

Functional disability states were defined using the HAQ disability index categorised into four categories, (1) HAQ = 0, (2) HAQ = 0.1–0.49, (3) HAQ = 0.50–1.49 and (4) HAQ = 1.50–3.00, representing no functional disability, mild disability, moderate disability and severe disability, respectively. HAQ scores < 0.50 represent few difficulties (if any) in performing daily activities and scores > 1.50 reflect considerable difficulties or assistance required in performing daily activities. 364–367

Statistical methods

For modelling disease activity and functional disability over time, a multistate modelling approach368 based on Markov processes was adopted, as our interest lay in characterising the evolution of these disease processes as they transition between clinically meaningful disease states. In addition, multistate models naturally handle staged data where patients are under only intermittent observations. They allow the estimation of rates of transitions between the various states of disease activity or functional disability and easily incorporate the effects of covariates (both time-independent and time-dependent) on transition rates. Here, correlation among states of a patient at different assessments are directly modelled through the Markov assumption that the future evolution of the patient’s disease process depends only on his/her current disease state and not on his/her previous disease history.

For the disease activity process, we consider the three-state multistate model shown in Figure 21a, where direct transitions (forward and backwards) are allowed between adjacent states (i.e. between remission and low disease activity or between low disease activity and moderate to high disease activity). Direct transitions between remission and moderate to high disease activity are not allowed, although, as we model the disease activity process in continuous time, this simplifying assumption is not restrictive.

FIGURE 21.

Multistate diagrams for (a) disease activity states and (b) disability states.

For modelling physical functional disability, we adopt a four-state multistate model, as shown in Figure 21b, where, again, direct transitions are allowed only between adjacent states (i.e. between no disability and low disability, between low disability and moderate levels of disability, and between moderate and severe disability).

We examined the separate (univariate) and joint (multivariate) effects of select demographic and clinical variables on the transition rates in the models for both disease activity and disability. These covariates were incorporated into the models through the proportional hazards assumption. The variables considered were sex, age, ethnicity, erosive disease and treatment all at baseline, disease duration and either the HAQ score or DAS28-ESR score updated at each visit when considering either the disease activity multistate models or the disability multistate models, respectively. Damage progression was investigated through logistic regression models where only covariates measured at baseline were considered as predictors.

Baseline features

Over 85% of the cohort had low levels of disease activity or were in clinical remission at entry. None of the patients had high baseline levels of disease activity. Approximately 50% of the cohort had low levels or no disability at baseline. Erosive disease was observed to be present in 40% of the study sample (n = 67). Most patients were receiving stable doses of methotrexate for over 6 months prior to entry. Fifty-three per cent of patients were on two or more RA medications at baseline.

Characterisation of disease activity states over time

Figure 22a displays the longitudinal profiles of disease activity states for the 150 patients with at least two visits in which DAS28-ESR scores were recorded. Of these patients, 95 had DAS28-ESR scores recorded at all five visits and 44 (46%) of those were observed to have sustained remission (i.e. observed in remission at all five visits). Table 19 summarises the numbers and types of transitions in disease activity states that were observed over the 12-month follow-up period. Seventy-two patients were not observed to have made any transitions out of their initial state. Twenty-eight patients were observed to have made one transition (16 patients were observed to have deteriorated and 12 patients to have improved). Fifty patients were observed to have made two or more transitions, with the majority (92%) of patients observed to have a fluctuating course of both deteriorations and improvements.

FIGURE 22.

Longitudinal profiles of disease activity and disability over five visits. (a) Disease activity states; and (b) disability states. NA, not applicable.

On fitting the three-state multistate model (see Figure 21a) with no covariates to the disease activity states, we estimated that there would be 7.28 (95% CI 5.22 to 10.16) transitions per 100 person-months from the remission state to the low disease activity state, 36.81 (95% CI 26.30 to 51.51) transitions per 100 person-months from low disease activity back to remission, and 32.21 (95% CI 20.39 to 50.86) and 24.22 (95% CI 15.26 to 38.51) transitions per 100 person-months from low disease activity to moderate/high disease activity and moderate/high back to low disease activity, respectively. Based on these transition rates, we estimate that the mean time spent in the three states of remission, low disease activity and moderate to high disease activity before exiting are 13.74 (95% CI 9.85 to 19.17) months, 1.45 (95% CI 1.08 to 1.94) months and 4.12 (95% CI 2.60 to 6.55) months, respectively. Therefore, on average, once a person enters the remission states they spend over 12 months in this state before transitioning out under a treat-to-target management strategy. In contrast, a person spends very little time continuously in either the low or moderate/high disease activity states before exiting.

The results in Table 20 show the final multivariate multistate model when covariates are explored on various transition rates. We find that males have a higher transition rate out of low disease activity to moderate/high disease activity states than females. The rate of transition to remission (from low disease activity) is 3.2 (95% CI 1.2 to 6.6) times faster for males than for females, and a 1-unit increase in HAQ increases by 2.9-fold (95% CI 1.8- to 4.7-fold) the rate of transitioning out of remission.

Characterisation of functional disability over time

Figure 22b displays the longitudinal paths of disability states of the same 150 patients. The numbers of patients observed in the no disability, mild, moderate and severe disability states at first observed HAQ assessment were 64, 26, 49 and 11, respectively. Ninety-eight patients were observed to have HAQ measured at all five time points. Of these 98 patients, 23 (23.5%) remained disability free over all their visits (compared with 46.3% of patients who had five visits with DAS28-ESR measured being in sustained remission). Table 21 summarises the transition patterns in disability states that were observed over the 12-month follow-up period. Just under half of the 150 patients (n = 73) were observed to have not made any transitions out of their initial state. Twenty-five patients were observed to have made one transition (14 patients were observed to have deteriorated and 11 patients to have improved). Fifty-two patients were observed to have made two or more transitions and all but one patient were observed to have a fluctuating course of both deteriorations and improvements.

The results in Table 22 of fitting the final multivariate four-state multistate model provided evidence for the effects of disease duration, ethnicity and disease activity on transitions between various disability states. More precisely, we found that a 1-year increase in disease duration reduces the rates of transitioning both in and out of the no disability state by 0.8. The rate of transition to moderate disability from mild disability state increased 1.17-fold (95% CI 1.03 to 1.33) for every additional year of disease. Patients who were white had a slower rate of transitioning in and out of the no-disability state than non-white patients, and a 1-unit increase in DAS28-ESR score increased the transition rate from moderate to severe levels by around twofold (95% CI 1.24-fold to 3.92-fold). No evidence of effects of erosive disease and exposure to treatments at entry on the various transitions between disability states was found.

Damage progression

At 1-year follow-up, 71 of the 82 (86.6%) patients observed not to have erosive disease at baseline remained damage free and four patients were observed to have progressed. For the 67 patients with baseline erosive disease, 46 (68.7%) were observed not to have progressed further and 16 were observed to have further progression. There was clear statistical evidence, as expected, that the 1-year damage progression rate was higher in those patients with baseline erosive disease than in those without (p = 0.002).

The final multivariate logistic regression model investigating baseline predictors of 1-year damage progression identified ethnicity, disease activity and erosive disease at baseline as potentially important factors (Table 23). Patients who were white were found to have higher odds of damage progression (OR 9.47, 95% CI 1.11 to 80.47; p = 0.04) than non-white patients, patients with a higher DAS28-ESR score at baseline were more likely to progress than those with lower scores (OR 2.1, 95% CI 1.04 to 2.12 for a 1-unit higher DAS28-ESR score) and RA patients with erosive disease present at baseline were also at greater risk of progression (OR 7.3, 95% 2.08 to 25.59). No statistical evidence was found for an effect of physical functional disability on damage progression (p = 0.225) after accounting for ethnicity, disease activity and erosive disease at baseline.

Defining remission

There is no ideal definition of clinical remission. Even sustained clinical remission may not represent an underlying state of true biological remission. Although 44 patients in the REMIRA cohort had sustained remission over the 12 months, 5 of the 44 (11%) patients had damage progression after 1 year. Clinical remission may overlook subclinical synovitis and, consequently, true remission might be better characterised molecularly using laboratory markers.

Refractory disease

We found that 18 patients in the REMIRA cohort had moderate to high disease activity states at their last visit without ever showing any clinically meaningful improvement in their disease activity. These patients may represent a refractory group of patients who do not respond well to current therapies. However, our data also suggest that, once remission is achieved, patients under a treat-to-target strategy will tend to stay in remission for > 1 year, on average, before exiting this state of clinical disease quiescence.

Variability of remission

In the REMIRA cohort of 152 RA patients, we observed various patterns of disease activity and physical functional disability over 12 months. Forty-four patients were observed in sustained remission over all visits, whereas 23 patients were observed to be disability free at all visits and 14 patients were observed to have been both in sustained remission and disability free. Sizeable proportions of patients were observed to have a fluctuating disease course (30.7%, n = 46) and to have fluctuating levels of functional impairment (34%, n = 51). These fluctuating patterns may reflect the difficulty in controlling patients’ disease, even under a treat-to-target strategy.

Factors influencing transitions between disease states

We found that sex and levels of functional disability had an impact on the rate of transitions between disease activity states. In particular, males tended to have a higher rate of transitions out of low disease activity to moderate disease activity than females, although higher levels of disability increased the rate of transitioning out of the remission state. We also found that higher levels of disease activity increased the rate of transitioning from moderate to severe levels of disability and that ethnicity and disease duration also influenced the transition rates between disability states, in particular transitions in and out of the mild disability state.

Factors influencing erosive progression

As expected, the 1-year damage progression rate was higher in those patients with erosions at baseline. Ethnicity and disease activity at baseline were identified as possible predictors of damage progression. No evidence was found for functional disability as a predictor of 1-year damage progression in RA patients undergoing a treat-to-target strategy.

Patients’ and practitioners’ perspectives about the TITRATE trial

We explored patients’ and practitioners’ views on the feasibility and acceptability of intensive management and their experience of receiving and providing intensive management. There is considerable evidence that patients’ perspectives are important in trying to manage their long-term disorders, such as RA. 271,371–374

Broad-based perspectives

Patients discussed many aspects of their care during the TITRATE intensive management sessions, including emotional distress and treatment of pain and fatigue using self-management approaches. Practitioners provided emotional and self-management support to patients who learnt strategies to better manage symptoms. A study outside the TITRATE trial found that one other factor patients considered important was foot care; however, the TITRATE trial did not directly address this. There is substantial evidence that foot problems are particularly challenging in RA. 375–378 Two expert patients therefore led a survey of patients and clinic staff about foot care in RA.

Qualitative study to assess TITRATE trial management

Patients were recruited from the trial sites with no additional patient participant criteria to those of the trial. Fifteen patients (12 females and three males aged from 35 to 70 years) from 10 different clinics participated. Details of these patients are shown in Appendix 1, Table 33. Practitioners were those trained to deliver the TITRATE intensive management intervention who had delivered at least six sessions with the same patient. Sixteen practitioners (13 research nurses and three specialist nurses) from 13 rheumatology centres participated. Individual interviews were conducted with all patients and 13 practitioners. Eight interviews were face to face and 20 were via telephone. One focus group was held with three practitioners.

Separate semistructured topic guides were developed for patient and rheumatology practitioner participants. Initial topic guides were based on the research questions, constituent components of the intensive management intervention, and previous qualitative studies (e.g. Schoo et al. 379). The semistructured topic guides were discussed with the multidisciplinary research team and a departmental patient expert, who provided feedback on the suitability and relevance of the questions. Following the first two interviews, some small changes were made to the topic guides. These were based on how participants responded to the questions and the flow of the questions during the interviews. Further details are given in Appendix 3.

Foot health

A mixed-methods approach collected qualitative data from two focus groups of nine RA patients380 and quantitative data from 13 rheumatology team members from one site. The data were collected in a survey that had been piloted and assessed by two external clinicians and departmental patient experts living with RA for face and content validity using average congruence. 381 Further details of these patients and clinicians are given in Appendix 1.

Patients’ and practitioners’ perspectives

Assessments covered monthly appointments, the therapeutic relationship with the practitioner, increased medication, the patient handbook and shared treatment planning (Table 24).

Patient and practitioner data were analysed separately. Data were analysed using thematic analysis285 and iterative categorisation. 382 Iterative categorisation generates a clear audit trail with the data analysis, closely linked to the raw data, and involves four stages: (1) familiarisation through the reading of transcripts, (2) line-by-line coding to organise the data in preparation for analysis, (3) descriptive analysis that identifies themes and (4) interpretive analysis that explores patterns, inconsistencies and relates findings to existing knowledge.

Monthly appointments were acceptable to patients and practitioners. The benefits included (1) regular reviews of medication and (2) practitioners establishing close relationships with patients. Practitioners felt ‘fairly confident’ using MI techniques.

Therapeutic relationships with practitioners were important. Commonly reported goals included weight loss and exercise, closely followed by the management of fatigue, pain and regulation of sleep patterns. Patients described how they identified these areas with practitioners who ‘helped to organise them’ and ‘gently encouraged them’ to make changes. Practitioners’ monitoring and progress at subsequent intensive management sessions was considered helpful. Learning to pace was the most commonly reported self-management technique patients and practitioners worked on together, followed by gaining control over pain and fatigue.

Most patients said that their practitioner helped them to learn about their RA condition. Knowledge about RA and its treatments and what to expect from these is something patients found valuable. Areas mentioned specifically by patients included fatigue, pain and medication management.

Practitioners appreciated the option to offer biologics to patients with moderate RA. Most patients found that the optimised medication following monthly joint assessment helpful and side effects were generally resolved. Practitioners described the treatment algorithm as clear and easy to use. Nurses were able to seek advice from consultants about treatment changes.

The use of the patient handbook and shared treatment plans varied substantially. Practitioners described two categories of patients. Some patients would read the handbook carefully and bring the resource to the sessions and others did not show much interest in the material and did not use it.

Generalisability of patients’ and practitioners’ perspectives

Both practitioners and patients volunteered to take part in the interviews. It is possible that those who engaged more with the delivery or receipt of the intensive management intervention may have been more eager to participate. As patients in the qualitative study were largely elderly, retired and white, they were not fully representative of the RA population.

The assessment of foot health had to use a non-validated questionnaire and obtained retrospective views from clinicians because no questionnaire was available for this purpose. These methodological problems may have resulted in recall bias386 and reduced the generalisability of the findings. The perspectives of clinical staff were also restricted to clinicians practising in a single specialist unit.

What was missing from the TITRATE trial?

We do not know the extent to which the management approach in the TITRATE trial addressed all problems experienced by patients. We have highlighted the omission of foot care. Other issues that influence patients’ quality of life may have been overlooked in the management strategy.

Intensive management is feasible

We found that intensive management was acceptable to patients, whose feedback was positive. These findings reflect experience of patients in other comparable intensive treatment situations. 270,387,388 Patient participants found that increasing their medication was generally helpful. They also found that seeing the same practitioner at monthly intensive management sessions and the treatment support they provided were beneficial. Feedback from practitioners also showed that intensive management was feasible and that they could be trained to deliver it. Overall, these positive perspectives mirror the positive findings in the TITRATE trial.

Including lifestyle modification in routine care

Practitioners would like the opportunity to address lifestyle factors with patients in routine appointments. There is a strong case to examine the most practical and cost-effective way to train practitioners to adopt this approach in routine care settings. There is considerable support for such approaches in other settings. 344,389–392

Overlooking feet

Clinicians need to take into account foot symptoms when managing patients and avoid what has been termed ‘DAS blindness’369 (i.e. when consultations focus on components of the DAS28-ESR). Rheumatology clinic staff may need training in foot examination. Podiatry input should be part of the standard multidisciplinary care provided in RA, which was overlooked in the TITRATE trial, especially in view of the substantial evidence underlying the importance of foot care in RA. 393–398

Nurses and other practitioners giving intensive management

The work of rheumatology nurses to deliver intensive management raises several issues. These include the published evidence for the impact of nurses in the management of RA assessed by a systematic review, the number of rheumatology nurses involved in rheumatology identified in national surveys, and the experience and background of nurses and other practitioners who delivered intensive management in the TITRATE trial.

Rheumatoid arthritis portrayal by UK national newspapers

An important source of knowledge, beliefs and attitudes about illness is the mass media. 406 Research has established the often negative and emotive language utilised by journalists to report on long-term physical and psychological illnesses. Attempts to increase the use of intensive management in RA nationally are likely to be influenced by opinions outside the immediate specialist area, including its representation in the media. 247 We therefore examined how RA is portrayed in the UK popular press.

Fidelity of intervention delivery

Intensive management consultations were audio-recorded by rheumatology practitioners with patients’ consent. A 10% sample of all recorded consultations were assessed (this comprised 126 sessions). Fidelity assessment was conducted within a team of four researchers. Establishing inter-rater reliability was undertaken between July 2015 and February 2016. Rating of the treatment support delivery commenced in March 2016 and continued for 1 year.

Systematic review of nurses contributions

We searched MEDLINE using the terms ‘nursing’ and ‘rheumatoid arthritis’. The search was limited to English publications from January 2000 to August 2018. Further details are given in Report Supplementary Material 1 and 2, including a PRISMA flow diagram (see Report Supplementary Material 1, Figure 7), the studies included (see Report Supplementary Material 1, Table 9) and study quality (see Report Supplementary Material 1, Tables 10–13).

National data about nurse numbers

Data about rheumatology nurse numbers were obtained from surveys by the National Audit Office407 and National Clinical Audits. 408

Nurses and other practitioners involved in the TITRATE trial

The TITRATE team collected data about the professional backgrounds, experience and titles of all clinicians who delivered the intensive management during the 12-month trial.

Portrayal in newspapers

The study was patient led with the support by a social scientist. The LexisNexis^® [RELX (UK) Ltd, London, UK] online repository of print media was searched for articles from July 2011 to July 2016 that included RA in the headline and/or lead paragraph of 15 UK national non-specialist newspapers. Resultant articles were uploaded to NVivo (QSR International, Warrington, UK) and a realist perspective aided thematic analysis. 409 Further details are given in Report Supplementary Material 1, Tables 14 and 15.

Fidelity of intervention delivery

Seven assessments were undertaken to assess whether or not the technique was demonstrated (Table 25). Agreement of agenda between patient and nurse, the patient talking more than 60% of the time and the use of importance and confidence rulers were evidenced in only a minority of participants’ consultations. Those techniques that were clearly more instinctive, or easier for the intensive management nurses to learn and incorporate, were providing solicited information only, demonstrating listening skills and asking open questions.

Seven questions had graded answers indicating the degree to which a technique was used. These are shown in Table 25. Between 52% and 73% of assessed consultations did not demonstrate MI skill levels beyond grade 2 on the 0–4 scale. A high level of MI technique use was observed in 5–12% of consultations. The technique that nurses demonstrated most often at moderate or high fidelity levels was affirming the patient’s strengths and abilities [in 58 consultations (46%)]. Evoking and reinforcing change talk and identifying one main problem area were observed at moderate or high fidelity skill levels in 34 (27%) and 32 (25%) consultations, respectively. Conversely, exploring reasons for and against behaviour change and helping the patient identify barriers to and facilitators of behaviour change were observed at moderate and high fidelity in only 16 (13%) consultations.

Specialist nurses and other practitioners giving intensive management

Nurses and other practitioners involved in the TITRATE trial

From 2014 to 2017, TITRATE trial training was given to 100 clinicians from 39 NHS trusts (42 sites). Eighty-six participants were female, 14 were male and their mean age was 48 (range 28–72) years. The rheumatology experience of the participants varied, with a mean duration of 5 (range 0–30) years (59 participants had ≤ 4 years of experience) (Figure 24). The professional backgrounds of participants also varied: 85 participants were nurses, eight participants were other health professionals, six participants had medical backgrounds in non-consultant posts and one participant was an occupational therapist. There were marked differences in how the clinicians described their roles (Figure 25). Nurses were called rheumatology nurse, rheumatology nurse specialist, rheumatology clinical nurse specialist and rheumatology nurse practitioner. There were also considerable variations in their seniority, ranging from band 5 nurses to a modern matron.

FIGURE 24.

Rheumatology experience of TITRATE trial participants.

FIGURE 25.

Nurses and health-care professionals in training programme. SpN, specialist nurse; SpR, specialist registrar; ST3, year 3 of specialty training.

Portrayal by UK national newspapers

The LexisNexis search produced 413 newspaper articles, 147 of which met the inclusion criteria. Some newspapers published many articles on RA and others published few or none. Three themes were identified in the thematic analysis that conveyed how UK national newspapers used language to report on RA. These themes comprised (1) language used to describe RA, (2) language used to refer to those who live with RA and (3) language used to report on potential new treatments for RA.

In describing RA, ‘attack’ was the most cited term and was more likely to be used in the tabloid or middle market press than in the broadsheets. ‘Painful’, ‘crippling’, ‘agony’ and ‘incurable’ were also commonly used terms.

In describing people with RA, the term ‘sufferers’ had the most number of references across the entire data set of newspaper articles, and it was more likely to be found in the tabloid/middle market press than in broadsheets. ‘Patients’, ‘people’ and ‘victims’ were also commonly used terms.

The final theme, the way potential new drugs or medical technologies for RA are reported, showed that journalists often used the language of ‘hope’ to frame the discussion of potential treatments. ‘Hope’ was mainly used in the tabloid and middle market newspapers. Other terms included ‘breakthrough’, ‘ground-breaking’, ‘cure’ and even ‘miracle’ on one occasion.

Overall, newspaper articles drew on negative and emotionally laden language to convey the experience of RA. This approach was more apparent in the tabloid or middle market newspapers than in broadsheets. Neutral terms, such as ‘people’ and ‘individuals’, were used to describe those living with RA. However, they were often viewed by the popular press in a passive sense as ‘sufferers’ or ‘victims’. The media’s application of language in the context of potential new medical technologies or drugs for RA overwhelmingly stressed their positive effects. This is despite the fact that much of the scientific research highlighted in the printed press over the 5-year time frame of this study was still in development and often untested in humans.

Nature of intensive management

The treatment strategy in the TITRATE trial involved both increasing the intensity of treatment with DMARDs and biologics and supporting patients to manage their disease. Although some health-care practitioners may be most successful in increasing treatment, others may be most successful in providing supportive care. Not all practitioners may excel at all the different aspects of intensive management. This makes it challenging to judge their impact.

Variable rheumatology teams

There is extensive variation in the nature of specialist rheumatology teams across England. Some have large teams of nurses and other health-care practitioners. Others have very few staff. There is also extensive variation in the nature and experience of nurses. This variability makes it particularly difficult to assess what is available and what can be delivered locally.

Complexity of intervention

The fidelity assessments showed that nurses and health-care practitioners followed some but not all the approaches they were taught to use in the TITRATE trial. Training staff in the MI techniques followed in the TITRATE trial will require both time and commitment from their units.

Limited experience of specialist nurses

Most nurses delivering intensive management in the TITRATE trial had been involved in rheumatology for < 5 years. Whatever the benefits of using nurses to deliver specialist care, this level of experience of specialist nurses creates complexities in the delivery of expert care. Consultant rheumatologists, by comparison, have far more experience in the field. The challenges in training and supporting specialist nurses and other non-medical health-care professionals managing RA patients are widely understood. 428,429

Negative perspectives about rheumatoid arthritis

Media views about RA are not crucial for changing the way care is delivered. However, a persistent negative message about the disease as ‘crippling’ and patients being portrayed as ‘sufferers’ and ‘passive victims’430 is unhelpful in the promotion of intensive management approaches.

Intensive management in active rheumatoid arthritis

There is substantial evidence from previous trials that intensive management increases remissions in patients with active RA. There is no particular reason from the perspective of efficacy to favour one type of intensive management strategy over another. However, based on custom and practice and health economic considerations, there is a case to start with combinations of conventional DMARDs. This perspective is not universally shared. There is marked international variation in conventional DMARD use,48 and some groups report low persistence rates with combinations of conventional DMARDs compared with biologic combinations. 46,47,434

Intensive management in moderately active rheumatoid arthritis

The TITRATE trial showed that intensive management increases remissions in patients with moderate RA without increasing harms. The positive findings in the main trial were supported by the associated qualitative study of patients’ and clinicians’ views.

Using intensive management in routine care

The intensive management approach used in the TITRATE trial is acceptable to patients and clinical staff and is generalisable across English rheumatology clinics. Although it can be delivered in routine care, current NHS staff are working at full capacity, and implementing it nationally would have resource implications. There are unresolved uncertainties about how best to standardise nurse-delivered intensive management strategies in routine clinical settings. In addition, the way intensive management was used in the TITRATE trial primarily reflected clinicians’ perspectives. Patients may have somewhat different views on how it should best be used.

Other important findings

Intensive management, however, does not benefit all RA patients with established moderate disease. Previous trials and the findings in the TITRATE trial indicate that it usually benefits no more than half of RA patients. Ongoing active RA has negative clinical and social impacts on patients. 435,436 There is also uncertainty about the extent to which it provides care that is considered cost-effective within current perspectives on WTP thresholds in general437–439 and how this translates to RA. 29,440,441

Remission is the key target of intensive management. Although DAS28-ESR remissions have many complexities, they appear to be a reasonable and efficient target. When patients achieve DAS28-ESR remissions for more than a single occasion, they usually continue to have reasonably well-controlled RA for some considerable time.

The routine management of RA is continually evolving. Over the last two decades patients have received more intensive management and their disease activity levels have decreased. Current management resembles many components of the approach used in the TITRATE trial, although it neither achieves the same intensity of drug treatment nor receives the same extent of supportive care from specialist nurses.

Intensive management for patients with moderate rheumatoid arthritis

The positive findings from the TITRATE trial and associated research suggest that it is timely to manage some patients with moderate RA intensively. This approach is in line with the national and international guidance.

Biologics in moderate rheumatoid arthritis

The intensive management used in the TITRATE trial involved giving some patients biologics in line with current specialist guidance but outside what is currently agreed in NICE Technology Appraisal guidance for these drugs. This is an area of substantial change, as the introduction of biosimilars is currently reducing the acquisition costs of these drugs. 442–444 The TITRATE trial provides information to inform future national work in this field. It found that only a minority of patients needed these drugs over and above those meeting current guidance, which are both supportive of extending biologic use in this way. At the same time, there was no evidence in the TITRATE trial that biologics specifically contributed to the benefits of intensive management, and many patients who achieved remissions did not receive biologic drugs. Against this background, we appreciate that many elements are involved in developing national guidance and the findings from the TITRATE trial are only one factor to take into account. There is also a need to consider, in more detail, the cost-effectiveness of such an approach, as the TITRATE trial did not consider all aspects of the economic issues involved. Decisions about using relatively high-cost interventions for long-term disabling disorders like RA create complex ethics issues and it is important to take broad-based perspectives on the benefits not only to patients but also to society as a whole. Such considerations, although important, fall outside what conclusions can be reasonably be drawn by us as researchers in the field.

Regular assessments by nurses

Nurses and other health-care professionals played crucial roles in delivering intensive management in the TITRATE trial. A simplified version of the TITRATE training programme will be available for specialist units that wish to use it. A range of health-care professionals can deliver such care, and it may be possible to use telephone and digital interactions rather that needing all patients to attend clinics in person. Since our research was completed, the coronavirus pandemic changed the way clinical practice is delivered in England. Telephone and digital consultations have been widely adopted, and their impact on our findings needs careful consideration. Patient perceptions about the way their RA is assessed and managed are likely to be of particular relevance when refining how care is delivered. It may also be possible to assess patients at intervals other than monthly. Each specialist unit must decide how to deliver regular assessments by nurses and other staff based on national and international guidelines and a range of different sources of evidence, including studies such as the TITRATE trial. Not all patients require identical follow-up arrangements, and care needs to be individualised. There is also a case for undertaking further developmental work to further rationalise how intensive management is delivered. Simplifying the delivery of intensive management approaches will reduce their costs.

Impact of potential predictive factors outcome

The TITRATE trial showed that patients with a high BMI were unlikely to respond to intensive management, although whether the effect was due to obesity itself or reflective of a range of underlying associations is unknown There is a growing body of evidence from observational studies that a high BMI is associated with persisting active disease and poor outcomes. 355,445–447 The reasons for these associations and the implications for management need further investigation. However, such research needs to take into account a range of genetic, educational, behavioural and environmental risk factors, rather than focusing entirely on BMI. It is also likely that social factors will be of crucial importance in predicting responses, although this was not specifically addressed in our research. Patients from socioeconomically deprived backgrounds and those from some ethnic minorities may be more likely to have poor outcomes.

Broadening the approaches to minimising disability

Achieving remission reduced disability in the TITRATE trial, but many patients continued to have considerable disability. There was also evidence that high initial disability levels reduce response to intensive management and that, although disease activity levels have declined over the last two decades, there is less evidence that disability has also reduced. These various findings suggest that disability needs to be reduced in different ways over and above minimising disease activity levels. The best way to achieve this goal needs further research. Non-drug approaches, which were not part of the TITRATE trial, may be relevant. 448–450

Part of broadening approaches to minimising disability includes reconsidering how disease activity is assessed. Although we found that intensive management reduced disease activity in moderate RA, it did not have any impact on ESR or CRP levels. It is possible that alternative blood tests may be more appropriate in patients with moderate RA, and further work may help identify which, if any, of these provide useful data when monitoring treatment responses and how they can be used in conjunction with clinical data. 451–454 It is also possible that other approaches to assessing disease activity may be more informative (e.g. using patient self-assessments in association with digital consultations).

Explore the long-term cost-effectiveness of intensive management for patients with moderate rheumatoid arthritis

The clinical findings in the TITRATE trial strongly support using intensive management approaches for patients with moderately active established RA. In contrast, the economic analysis suggested that its costs fell above the thresholds usually accepted as affordable by the NHS. However, these economic assessments were restricted to the 12-month follow-up period in the trial. They did not take into account the benefits of improved earlier treatment and potentially reduced biologic drug use over the longer term. Extrapolation of the costs and benefits of the intervention could be carried out in a decision-analytic model to produce a lifetime estimate of expected costs and QALYs. One important issue is estimating the impact of the future treatment pathway for the patient populations once a switch from intensive DMARD therapy has occurred. This will include the costs of biologics if patients progress to severe RA and the time to loss of efficacy (which could be estimated from survival analysis of the within-trial data).

Equipping patients for intensive treatment

The patient handbook was developed with substantial PPI. First, it was supported by one focus group that involved six patients who live with RA from a single NHS hospital trust. Second, individual feedback was received from one departmental patient expert in close collaboration with two RA charities (the NRAS and Arthritis Research UK). Shared treatment plans, which are an associated part of the research, were developed with help from five patients and one carer from one hospital trust. The developmental work for the patients’ handbook and shared treatment plans has been described in one paper, which was published in 2017. 268 Two patients who were involved developing the handbook co-authored this publication.

Patients’ views on intensive treatment

Patients’ views on intensive treatment in the TITRATE programme before the trial commenced were evaluated through focus groups and one-to-one interviews with nine patients and five carers, and an additional two patients whose first language was not English. These patients and careers were from three different hospital trusts. The findings from the focus groups were published in 2016. 269 One patient co-authored this publication.

In 2017, the main focus has been an evaluation of the views of nurses and patients about their participation in the trial. Louise Prothero interviewed 13 MI practitioners from 20 different centres and a similar number of patients who participated in the active arm of the trial. The interview schedule for the patients was developed from the literature and in collaboration with one of our departmental expert patients so that the content of the questions were relevant and comprehensible to the participants. The research findings were published in 2019. 370

Input to research questions

The topic guide for the patient interviews was reviewed by a patient. Changes were made to key questions to make them more positive and understandable to patients.

Planning implementation

Four service users attended a planning meeting for implementing nurse training, together with 15 staff from national charities, health professionals and academic and clinic staff. The service users contributed substantially, based on their experiences attending nurse-led clinics. One author, a service user, agreed to co-author the report underpinning this initiative.

Foot health

A mixed-methods approach collected qualitative data from two focus groups of RA patients and quantitative data from rheumatology team members. The data were collected in a survey that had been piloted and assessed for face and content validity, using average congruence, by two external clinicians and departmental patient experts living with RA.

Rheumatoid arthritis portrayal by UK national newspapers

The mass media are an important source of knowledge, beliefs and attitudes about illness. A research team of academic staff and patients examined how RA is portrayed in the UK popular press. This was considered an important factor in influencing uptake of intensive management in routine clinical practice.

Supporting ongoing research

The workstream A team met 6-monthly to inform all co-applicants of the TITRATE programme about the progress of the research, including publications.

Qualitative studies

Several aspects of the research involved qualitative studies to evaluate patients’ perspectives about their management and preferred options for taking drugs and other treatments. These studies involved patients in both their designs and in their analysis. Without patient involvement, they would not have been possible.

Designing successful intensive management

The TITRATE programme centred on the trial of intensive management. There are two key challenges to overcome when asking patients with moderately active RA to participate in a treatment strategy based on intensive management. First, the treatments have to be effective. Second, patients have to be prepared to take them. The first part of the programme focused on making certain that care was given in a way that patients found acceptable in the context of treating them intensively. Patient involvement in this part of the research was crucial to the success of the programme. As intensive management was taken by patients and they achieved more remissions as a consequence, it is reasonable to conclude that this crucial aspect of patient involvement was successful.

Placing the research in context

Studies of foot health and representation of RA in newspapers were suggested by patients. They helped place the research into context relevant for implementation.

Advice on progress of research

Patients contributed to both the Trial Steering Committee and the Programme Steering Committee. This involvement has proved useful in assessing the progress of the research and in planning how to develop the programme over time. In particular, it was helpful in assessing what is reasonable for patients to be asked to do in respect of the trial and other studies, and also what questions were most relevant to patients.

Publications and dissemination

Patients were involved as co-authors of many TITRATE trial publications and conference presentations. They are also co-authoring the final report.

Presentations

Bahadur S, Mian AN, Scott I, Galloway J, Pollard L, Kingsley GH, Scott DL. Comorbidities and treatment intensity in rheumatoid arthritis. Rheumatology 2015;54:85. https://doi.org/10.1093/rheumatology/kev088.090

Georgopoulou S, Prothero L, Lempp H, Galloway J, Sturt J. Motivational interviewing: relevance in the treatment of rheumatoid arthritis? Rheumatology 2015;54:75. https://doi.org/10.1093/rheumatology/kev379

Matcham F, Mian A, Steer S, Gullick N, Scott DL, Hotopf M, et al. Psychological comorbidity and disease activity scores in rheumatoid arthritis. Rheumatology 2015;54:88. https://doi.org/10.1093/rheumatology/kev088.097

Mian A, Ibrahim F, Scott IC, Bahadur S, Filkova M, Pollard L, et al. Has the relationship between disease activity and disability in rheumatoid arthritis changed? Arthritis Rheumatol 2015;67:2765.

Mian AN, Scott DL, Kingsley GH, Ibrahim F. Impact of achieving low disease activity on general health status. Rheumatology 2015;54:24. https://doi.org/10.1093/rheumatology/kev079.006

Prothero L, Georgopoulou S, Bosworth A, Williams R, Galloway J, Lempp H. A qualitative study to explore patients' and carers' views and expectations about intensive treatment for intermediate rheumatoid arthritis. Rheumatology 2015;54:189. https://doi.org/10.1093/rheumatology/kev091.045

Gullick NJ, Ibrahim F, Mian A, Vincent A, Panayi G, Tom B, et al. Intensive treatment for rheumatoid arthritis reduces disease activity over time. Arthritis Rheumatol 2016;68:2518.

Gullick N, Ibrahim F, Mian A, Vincent A, Scott DL, Tom B, Kirkham B. Intensive treatment for rheumatoid arthritis reduces disease activity over time. Rheumatology 2016;55:i94–95. https://doi.org/10.1093/rheumatology/kew144.008

Gullick N, Ibrahim F, Scott DL, Vincent A, Tom BDM, Kirkham B. The impact of controlling disease activity in rheumatoid arthritis. Rheumatology 2016;55:i97. https://doi.org/10.1093/rheumatology/kew144.013

Hughes CD, Pollard LC, Scott DL. A systematic review of the impact of intensive therapy on remission in rheumatoid arthritis. Rheumatology 2016;55:i100. https://doi.org/10.1093/rheumatology/kew144.021

Matcham F, Scott IC, Ibrahim F, Steer S, Kingsley GH, Scott DL, Hotopf M. Disability and psychological distress in established rheumatoid arthritis: secondary analysis of a clinical trial. Rheumatology 2016;55:88. https://doi.org/10.1093/rheumatology/kew142.007

Prothero L, Barley E, Galloway J, Georgopoulou S, Sturt J. Psychological interventions for rheumatoid arthritis: a systematic review of systematic reviews. Rheumatology 2016;55:i121–2. https://doi.org/10.1093/rheumatology/kes133

Prothero L, Barley E, Galloway J, Georgopoulo S, Sturt J. Psychological interventions for rheumatoid arthritis: a systematic review of reviews. Int J Behav Med 2016;23:70. https://doi.org/10.1016/j.ijnurstu.2018.03.008

Rutherford AI, Scott DL, Subesinghe S, Ibrahim F, Galloway J. The incidence and predictors of flare in a cohort of rheumatoid arthritis patients. Rheumatology 2016;55:i73. https://doi.org/10.1093/rheumatology/kew132

Scott IC, Fowzia I, Lewis CM, Kingsley GH, Scott DL, Strand V. The impact of intensive treatment, inflammation and remission on health-related quality of life in early and established RA. Rheumatology 2016;55:i85. https://doi.org/10.1093/rheumatology/kew141.002

Scott IC, Ibrahim F, Gullick N, Kingsley G, Galloway J, Kirkham B, et al. Rationalising the treatment target in rheumatoid arthritis: defining the optimal 28-joint DAS cut-off to determine good function and normal health-related quality of life. Rheumatology 2016;55:99. https://doi.org/10.1093/rheumatology/kew144.018

Scott I, Ibrahim F, Kirkham B, Gullick N, Kingsley G, Galloway J, et al. Rationalising the treatment target in rheumatoid arthritis. Rheumatology 2016;55:i99. https://doi.org/10.1093/rheumatology/kew144.018

Scott DL. Triple therapy versus biologics: efficacy and cost-effectiveness. Rheumatology 2017;56:9. https://doi.org/10.1093/rheumatology/kex060.040

Scott IC, Ibrahim F, Safi MA, Houssien D, Scott DL. The erythrocyte sedimentation rate dominates 28-joint disease activity scores, but is not associated with post-treatment disability and health-related quality of life. Rheumatology 2017;56:14–12. https://doi.org/10.1093/rheumatology/kex062.232

Prothero L, Sturt J, de Souza S, Lempp H. Patients’ and Practitioners’ Views on Intensive Management for Moderate Rheumatoid Arthritis: A Qualitative Study. 32nd conference of the European Health Psychology Society: Health Psychology Across the Lifespan: Uniting Research, Practice and Policy, Galway, Ireland, 21–25 August 2018.

Baggott R, Scott D, Sturt J, Bosworth A, Parker L, Georgopoulou S, Lempp H. What is the value, impact and role of nurses in rheumatology outpatient care? Rheumatology 2019;58:150. https://doi.org/10.1093/rheumatology/kez108.058

Prothero L, Georgopoulou S, Lempp H, Sturt J. Fidelity Assessment of Motivational Interviewing-Based Treatment Support Delivered by Nurses. 33rd conference of the European Health Psychology Society: Individuals and Professionals: Cooperation to Health, Dubrovnik, Croatia, 3–7 September 2019.