Abstract

Objectives. Current UK management of RA initially employs conventional DMARDs, with biological therapy reserved for DMARD-resistant RA patients with persistently high 28-joint disease activity score (DAS-28). The aim of this study was to examine the effect on patient-reported function of persistently moderate DAS-28 despite modern step-up DMARD therapy in an early arthritis cohort.

Methods. Data were obtained from the Yorkshire Early Arthritis Register, a cohort of early (<12 months) RA patients treated with dose-escalated DMARDs. Change in HAQ exceeding the minimum clinically important difference (MCID) was determined for three values of MCID (0.22, 0.31 and 0.49). Changes in HAQ over Months 6–12 were compared between patients whose DAS-28(ESR) was persistently high (>5.1 at 6- and/or 9-month visits and at the 12-month visit), persistently moderate (>3.2 and ≤5.1) or persistently low (≤3.2).

Results. We selected 194 patients for this analysis. Deteriorating HAQ scores were observed in 10.9% of patients with persistently low DAS-28 compared with 21.4% (persistently moderate DAS-28) and 46.7% (persistently high DAS-28), respectively, for MCID = 0.22; 7.3, 14.3 and 20.0% for MCID = 0.31; 5.5, 10.7 and 11.1% for MCID = 0.49.

Conclusions. A high DAS-28 was generally associated with a greater degree of functional decline, but persistent moderate elevation of DAS-28 was associated with important functional deterioration in 10–21% of early RA patients (depending on choice of MCID) following a modern DMARD protocol. A proportion of patients with persistently moderate DAS-28 may therefore benefit from more aggressive therapy than that allowed by current UK recommendations.

Introduction

Current management of RA in many European countries initially employs conventional DMARD therapy, with introduction of highly effective biological therapy reserved for DMARD-resistant RA with persistently high disease activity [1]. The current UK National Institute for Health and Clinical Excellence (NICE) guidelines recommend that treatment with TNF inhibitors should only be initiated in patients who have active disease, defined as a 28-joint disease activity score (DAS-28) exceeding 5.1 on two occasions at least 1 month apart, following unsuccessful trials of two DMARDs [2]. Such criteria attempt to maximize cost-effective utilization of expensive biologic therapies.

Persistent objectively assessed inflammation does lead to joint damage in RA [3] and an important question remains about how important intermediate clinical levels of inflammation (based on DAS-28) are with respect to disease outcome, especially to patient-reported outcomes such as function [4, 5]. The most commonly used measure of function in RA trials is the HAQ, which also currently underpins health economic assessments of RA therapies. One way of determining meaningful change in HAQ is to explore its minimal clinically important difference (MCID). Published MCID thresholds for the HAQ vary. One study looking at between-patient differences found that MCID was smaller when considering health to be better (−0.22) than worse (0.49) when patients with established disease (median 11 years duration) were asked to rate their health relative to another RA patient with whom they had discussed the severity of their condition during paired interview sessions [6]. Another study looking at within-patient changes [7] derived MCID from the limits of agreement around repeated HAQ measurements in patients who reported no change in health status during the measurement interval, and reported the MCID to be between ±0.31 (based on the 80% limits of agreement) and ±0.48 (95% limits of agreement).

The aim of this study was to examine whether significant loss of function (measured by the HAQ) occurs in RA patients with persistently moderate disease activity (defined as 3.2 < DAS-28 ≤ 5.1), despite conventional DMARD therapy. Given that modern treatment paradigms involve early treatment of RA, an early disease cohort was chosen as the appropriate group in which to explore this hypothesis.

Patients and methods

Patients

Data were taken from the Yorkshire Early Arthritis Register (YEAR), a Yorkshire-wide register that monitors the identification, treatment and outcomes of patients who have been newly diagnosed with RA (disease duration ≤12 months). Treating rheumatologists within YEAR were asked to follow a regionally agreed protocol for RA pharmacotherapy, and this protocol underwent a number of iterative changes since the establishment of YEAR in 1997, with changes reflecting current best practice. In the current study, we included patients from the YEAR C cohort (recruited between 2002 and 2008). The YEAR C therapy protocol recommended initial dose-escalated MTX (up to 20 mg weekly) with subsequent addition of SSZ (2 gm daily) and then HCQ (400 mg) if patients demonstrated poor clinical response. Use of corticosteroids was allowed as per usual practice, with depo-steroid the most frequently used option in the Yorkshire region. Response was based on the treating clinician’s assessment, not a given DAS-28 target.

Ethical approval for YEAR was granted by local research ethics committees: Airedale Local Research Ethics Committee; Barnsley Local Research Ethics Committee; Bradford Local Research Ethics Committee; Calderdale Local Research Ethics Committee; Dewsbury District Hospital Local Research Ethics Committee; Huddersfield Local Research Ethics Committee; Hull & East Riding Local Research Ethics Committee; Leeds HA/United Leeds Teaching Hospitals Local Research Ethics Committee; Harrogate Health Care NHS Trust Local Research Ethics Committee; Northallerton Local Research Ethics Committee; Scarborough & North East Yorkshire Local Research Ethics Committee; York Research Ethics Committee; Wakefield District Research Ethics Committee. All patients gave written informed consent.

For this analysis, we selected all subjects who had four-variable DAS-28(ESR) data available at 6, 9 and 12 months of follow-up, and had HAQ disability index data available at 6 and 12 months. DAS-28(ESR) was used in preference to DAS-28(CRP) based on NICE guidelines and evidence to suggest that DAS-28(CRP) values tend to be lower than DAS-28(ESR).

Disease activity categories

Based on current UK guidance for initiation of biologics [2], we defined the following categories of disease activity:

  • high (>5.1) at 12 months and at least one other visit = persistently high DAS-28;

  • moderate (3.2–5.1) at 12 months and at least one other visit = persistently moderate DAS-28; and

  • low (<3.2) at 12 months and at least one other visit = persistently low DAS-28.

Participants who had, for example, a high DAS-28 at both 6 and 9 months, but moderate DAS-28 at 12 months were categorized as high to moderate DAS-28. Patients with a mixed profile (1 low, 1 moderate, 1 high) were excluded.

Choice of MCID for HAQ

The majority of studies record improvement in HAQ so the figure of 0.22 is familiar to many people as the MCID for HAQ; because we predominantly wanted to look at deterioration we chose to include a more stringent MCID, so we additionally recorded change ±0.31 and ±0.49. These three values of MCID correspond to changes of 2, 3 and 4 points on the 0–24 point summed HAQ scale (0.250, 0.375 and 0.500 on the 0–3 scale, respectively). Patients whose initial scores were too high or too low to allow change exceeding MCID to occur were considered to have exceeded MCID if they showed the maximum amount of change possible, e.g. a patient starting with a score of 0.125 and ending with a score of 0.

Statistical analyses

All statistical analyses were carried out in SPSS 16.0.2 (SPSS Inc., Chicago, IL, USA). Proportions of patients showing changes in HAQ exceeding MCID over Months 6–12 were calculated within groups of subjects categorized according to their DAS-28(ESR) profile at the 6-, 9- and 12-month visits for different values of MCID (0.22, 0.31 and 0.49).

Results

One hundred and ninety-four early RA patients were included in this analysis; demographic and 6-month clinical data are summarized in Table 1. Four patients had a mixed profile of DAS-28 and were excluded from the analysis. Patients excluded from the analysis due to missing data or mixed DAS-28 profile did not differ substantively from those included in terms of age, gender, RF positivity, symptom duration, baseline DAS-28 or baseline HAQ (data not shown). Fourteen patients with low 6-month HAQ scores showed the maximum amount of improvement possible by 12 months; one patient with a high 6-month score deteriorated by the maximum possible amount.

Table 1

Demographic data and 6-month clinical results

  
Baseline demographic and clinical characteristics   
 Age, mean (s.d.) (range), years 194 59.2 (12.1) (28–83) 
 Gender, female, n (%) 194 133 (68.6) 
 Race, Caucasian n (%) 193 186 (96.4) 
 RF positive n (%) 179 129 (72.1) 
 Disease duration, median (interquartile range), months 190 6.3 (4.1–9.1) 
Six-month clinical results   
 TJC28, median (interquartile range) 193a 4 (1–13) 
 SJC28, median (interquartile range) 194 2 (0–5) 
 HAQ, mean (s.d.194 1.068 (0.844) 
 Patient disease activity, 0–100 mm VAS, mean (s.d.193a 45.6 (30.1) 
 ESR, median (interquartile range), mm/h 181a 24 (13–43) 
 CRP, median (interquartile range), mg/l 184a 6 (<5–16) 
 DAS-28(ESR), mean (s.d.180a 4.43 (1.76) 
  
Baseline demographic and clinical characteristics   
 Age, mean (s.d.) (range), years 194 59.2 (12.1) (28–83) 
 Gender, female, n (%) 194 133 (68.6) 
 Race, Caucasian n (%) 193 186 (96.4) 
 RF positive n (%) 179 129 (72.1) 
 Disease duration, median (interquartile range), months 190 6.3 (4.1–9.1) 
Six-month clinical results   
 TJC28, median (interquartile range) 193a 4 (1–13) 
 SJC28, median (interquartile range) 194 2 (0–5) 
 HAQ, mean (s.d.194 1.068 (0.844) 
 Patient disease activity, 0–100 mm VAS, mean (s.d.193a 45.6 (30.1) 
 ESR, median (interquartile range), mm/h 181a 24 (13–43) 
 CRP, median (interquartile range), mg/l 184a 6 (<5–16) 
 DAS-28(ESR), mean (s.d.180a 4.43 (1.76) 

aSome patients with missing 6-month DAS-28 data were in the same DAS-28 category at both 9 and 12 months, and therefore could still be placed into a category of DAS-28 persistence. SJC28: 28-joint swollen joint count; TJC28: 28-joint tender joint count; VAS: visual analogue scale.

There were no substantive differences in age or disease duration at baseline between the three main groups of DAS-28 persistence. Median ages for the persistently low, moderate and high DAS-28 groups were 60, 61, 60 years, respectively, whereas the median disease durations were 6.8, 6.8 and 6.0 months. However, comparatively fewer patients whose disease activity was persistently low were female; 56.4% compared with 75.0% (moderate) and 82.2% (high). Similar proportions were RF positive (63.6, 75.5 and 65.1%, respectively).

Proportions of patients in each category of disease persistence who showed changes in HAQ exceeding different values of MCID are presented in Table 2. The differences in the proportions of patients showing deterioration in HAQ between groups defined as having either persistently moderate DAS-28 or persistently high DAS-28 reduced with increasing MCID; for the most stringent MCID threshold, a greater proportion of those with persistently moderate disease activity deteriorated than did those with persistently high disease activity. Looking only at RF-positive patients, the proportions of patients with persistently low, moderate and high DAS-28 showing change in HAQ exceeding MCID were 14.3, 23.7 and 42.9% for MCID = 0.22; 10.7, 15.8 and 21.4% for MCID = 0.31; 7.1, 13.2 and 10.7% for MCID = 0.49.

Table 2

Proportions of patients in different disease activity categories with HAQ changes according to different MCID values

  Change in HAQ when MCID = 0.22
 
Disease activity Percentage worse (≥0.22) Percentage stable Percentage better (≤−0.22) 
Persistently low 55 10.9 54.5 34.5 
Persistently moderate 56 21.4 33.9 44.6 
Persistently high 45 46.7 33.3 20.0 
Low to high 100.0 0.0 0.0 
Low to moderate 66.7 16.7 16.7 
Moderate to high 62.5 37.5 0.0 
Moderate to low 25.0 25.0 50.0 
High to low 0.0 0.0 100.0 
High to moderate 12 16.7 41.7 41.7 
  Change in HAQ when MCID = 0.22
 
Disease activity Percentage worse (≥0.22) Percentage stable Percentage better (≤−0.22) 
Persistently low 55 10.9 54.5 34.5 
Persistently moderate 56 21.4 33.9 44.6 
Persistently high 45 46.7 33.3 20.0 
Low to high 100.0 0.0 0.0 
Low to moderate 66.7 16.7 16.7 
Moderate to high 62.5 37.5 0.0 
Moderate to low 25.0 25.0 50.0 
High to low 0.0 0.0 100.0 
High to moderate 12 16.7 41.7 41.7 
  Change in HAQ when MCID = 0.31
 
  Percentage worse (≥0.31) Percentage stable Percentage better (≤−0.31) 
Persistently low 55 7.3 60.0 32.7 
Persistently moderate 56 14.3 53.6 32.1 
Persistently high 45 20.0 64.4 15.6 
Low to high 100.0 0.0 0.0 
Low to moderate 50.0 33.3 16.7 
Moderate to high 37.5 62.5 0.0 
Moderate to low 12.5 50.0 37.5 
High to low 0.0 33.3 66.7 
High to moderate 12 16.7 50.0 33.3 
  Change in HAQ when MCID = 0.31
 
  Percentage worse (≥0.31) Percentage stable Percentage better (≤−0.31) 
Persistently low 55 7.3 60.0 32.7 
Persistently moderate 56 14.3 53.6 32.1 
Persistently high 45 20.0 64.4 15.6 
Low to high 100.0 0.0 0.0 
Low to moderate 50.0 33.3 16.7 
Moderate to high 37.5 62.5 0.0 
Moderate to low 12.5 50.0 37.5 
High to low 0.0 33.3 66.7 
High to moderate 12 16.7 50.0 33.3 
  Change in HAQ when MCID = 0.49
 
  Percentage worse (≥0.49) Percentage stable Percentage better (≤−0.49) 
Persistently low 55 5.5 67.3 27.3 
Persistently moderate 56 10.7 60.7 28.6 
Persistently high 45 11.1 73.3 15.6 
Low to high 100.0 0.0 0.0 
Low to moderate 16.7 66.7 16.7 
Moderate to high 37.5 62.5 0.0 
Moderate to low 12.5 50.0 37.5 
High to low 0.0 33.3 66.7 
High to moderate 12 8.3 58.3 33.3 
  Change in HAQ when MCID = 0.49
 
  Percentage worse (≥0.49) Percentage stable Percentage better (≤−0.49) 
Persistently low 55 5.5 67.3 27.3 
Persistently moderate 56 10.7 60.7 28.6 
Persistently high 45 11.1 73.3 15.6 
Low to high 100.0 0.0 0.0 
Low to moderate 16.7 66.7 16.7 
Moderate to high 37.5 62.5 0.0 
Moderate to low 12.5 50.0 37.5 
High to low 0.0 33.3 66.7 
High to moderate 12 8.3 58.3 33.3 

Discussion

This study used a UK early RA cohort to investigate the importance of persistently moderate elevation of DAS-28, in terms of decline in function at 1 year. Using a range of values for the MCID of HAQ, persistently moderate DAS-28 elevation was associated with important functional deterioration in a substantial proportion (13–25%) of patients. Similar proportions of patients with persistently moderate DAS-28 show moderate to large increases in HAQ compared with patients with persistently high DAS-28.

The choice of a real-world RA cohort using a modern treatment protocol was intentional. Clinical trials, although providing much better data capture and drug-usage information, do not reflect real-world use of RA therapies by practising rheumatologists. The YEAR protocol employed did not recommend a targeted or tight-control strategy, as recently recommended [2, 8], reflecting not only practice of several years ago when this protocol was developed, but also in effect reflecting available resources in busy NHS secondary care practices. The YEAR protocol recommended a step-up protocol commencing with MTX, rather than one starting with combination DMARD therapy as has also been recently recommended [2]; however, it is likely that many patients had additional i.m. corticosteroid at the time of first visit to the rheumatologist. We acknowledge the limitation that missing data from the YEAR cohort (a common problem with registries) did limit the number of patients included in this analysis, although the included participants did not differ from patients not included in terms of baseline disease characteristics (data not shown).

There have been improvements in routine management of early RA since the original YEAR protocol was established, and following the introduction of BSR and NICE guidelines [2, 9]. Many patients will now receive initial combination DMARD therapy as well as short-term corticosteroids, and the introduction of treat-to-target tight control with monthly DAS scores should mean reduced time to detection of poor response. However, a significant problem remains in the UK of how to treat people with a moderate DAS who have not entered a low disease activity state after using all the conventional DMARDs.

The HAQ is a measure of activity limitation that incorporates both disease activity and damage constructs [5]. In the early stages of RA, HAQ score is believed to be driven to a greater extent by the burden of inflammation than by joint damage; with increasing disease duration, the HAQ score’s sensitivity to change decreases as irreversible joint damage accumulates [10]. So a potential limitation of this work is that we are demonstrating activity limitation predominantly due to inflammation. However, the HAQ remains a major predictor of subsequent long-term function and, pragmatically, is important in health economic modelling. Regression models and mapping algorithms are used to convert HAQ to health utility values [2]. However, HAQ may not capture all aspects of health-related quality of life (HRQoL); particularly, pain may be under-represented. NICE concludes that although there is a risk that HAQ may underestimate the impact of RA on patients, it remains the best available tool.

We chose a range of putative MCID values for the HAQ based on the literature in this area. MCID may vary depending on where a patient starts on the scale. This problem may be compounded by the fact that the scale in all likelihood does not act in a linear fashion at either extreme [11]. This means that if raw HAQ scores are used, patients who start with low or high HAQ values may show considerable change in true impairment that is nevertheless not deemed to have exceeded MCID. In addition to these concerns, patients starting with low HAQ scores might consider a different amount of change in HAQ to be important than those starting with high scores. Thresholds for improvement and deterioration may differ depending on the starting conditions. They may also depend on the disease duration of cohorts with existing figures largely derived from established RA trials; one study of early RA did suggest an MCID of 0.25 [12].

Recent work from the BSR Biologics Register has demonstrated improvement in HAQ with anti-TNF therapy in both moderate and high baseline DAS-28 groups [13]. Another recent study from a large hospital cohort presented data that suggest our lower value for MCID may be more relevant in clinical practice [14], strengthening the finding that potentially a quarter of patients with persistently moderate DAS-28 have deteriorating function. Clearly, the challenge for the future is to discover poor prognosis biomarkers that identify the subgroup of patients at high risk of functional decline. The current study supports the need for tighter DAS-28 monitoring of patients and suggests that in a UK early RA population, a substantial proportion of patients with persistently moderate DAS-28 would benefit from more aggressive therapy than allowed by current recommendations.

graphic

Acknowledgements

The YEAR Consortium:

Management team: Prof. Paul Emery1, Prof. Philip Conaghan1, Prof. Ann Morgan1, Dr Anne-Maree Keenan1 and Dr Elizabeth Hensor1

Medical staff: Dr Mark Quinn2, Dr Andrew Gough3, Dr Michael Green2,3, Dr Richard Reece4, Dr Lesley Hordon5, Dr Philip Helliwell1,6, Dr Richard Melsom6, Dr Sheelagh Doherty7, Dr Ade Adebajo8, Dr Andrew Harvey9, Dr Steve Jarrett9, Dr Gareth Huson1, Dr Amanda Isdale2, Dr Mike Martin1, Dr Zunaid Karim9, Prof. Dennis McGonagle1,10, Dr Colin Pease1, Dr Sally Cox1, Dr Victoria Bejarano1, Dr Jackie Nam1, Dr Edith Villeneuve1 and Dr Sarah Twigg1

Nursing staff: Claire Brown1, Christine Thomas1, David Pickles1, Alison Hammond1, Beverley Neville3, Alan Fairclough4, Caroline Nunns4, Anne Gill2, Julie Green2, Belinda Rhys-Evans1, Barbara Padwell1, Julie Madden10, Lynda Taylor10, Sally Smith1, Heather King1, Jill Firth6, Jayne Heard7 and Linda Sigsworth6

Support Staff: Diane Corscadden1, Karen Henshaw1, Lubna-Haroon Rashid1, Stephen G. Martin1, James I. Robinson1, Dr Lukasz Kozera1, Sarah Fahy1 and Andrea Paterson1

1Section of Musculoskeletal Disease, LIMM, Leeds, 2York District Hospital, York, 3Harrogate District Hospital, Harrogate, 4Huddersfield Royal Infirmary, Huddersfield, 5Dewsbury District and General Hospital, Dewsbury, 6St Luke’s Hospital, Bradford, 7Hull Royal Infirmary, Hull, 8Barnsley District General Hospital, Barnsley, 9Pinderfields General Hospital, Wakefield and 10Calderdale Royal Hospital, Halifax, UK.

Funding: The YEAR was in part supported by a programme grant from Arthritis Research UK and the NIHR-Leeds Musculoskeletal Biomedical Research Unit. E.M.A.H. and P.G.C. are funded in part by Arthritis Research UK.

Disclosure statement: P.G.C. has done advisory boards, presentations or holds research grants from Abbott, BMS, Centocor, Novartis, Pfizer, Roche and Schering Plough. P.E. has done advisory boards, presentations and holds research grants from Abbott, BMS, Centocor, Novartis, Roche, Schering Plough, UCB and Wyeth. All other authors have declared no conflicts of interest.

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Author notes

*See Acknowledgements for the list of members of the YEAR Consortium.

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