Background The American College of Rheumatology/European League Against Rheumatism remission criteria for rheumatoid arthritis (RA) have been published recently.
Objective To quantify the proportions of patients fulfilling only three of the four Boolean criteria and the relevance of patient global assessment (PGA) in context of remission.
Methods From an observational prospective RA database the first visit of patients, fulfilling just three of the four Boolean criteria was identified. Logistic regression and descriptive analyses were processed, also defining remission by index-based (Simplified Disease Activity Index (SDAI)) definition and comparing outcomes with the evaluator global assessment (EGA).
Results 52% had at least one visit, fulfilling just three criteria (not fulfilled were: PGA 61%; swollen joints 20%; tender joints 13%; C-reactive-protein 7%). 67% of patients not fulfilling the PGA criterion had an EGA≤1 cm, 25% of those fulfilled the SDAI definition. Increased pain (OR=1.28), EGA (OR=1.10) and discrepancy towards higher PGA than EGA (OR=1.28) could explain PGA failure to reach remission.
Conclusions PGA is often the limiting factor for reaching remission; index-based remission showed balancing effects by adjusting for elevated variables in the summative score.
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Over the years different remission criteria for rheumatoid arthritis (RA) have been employed and have led to differences in proportions of patients classified as in remission.1 Recently, a new set of remission criteria has been presented by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR): the index-based criteria defined as a Simplified Disease Activity Index (SDAI) of ≤3.3; and the Boolean-based definition requiring four criteria to be ≤1: patient global assessment (PGA; in cm), swollen and tender joint counts (SJC28, TJC28) and C-reactive protein (CRP; in mg/dl). A remission definition for clinical practice was also proposed, eliminating the CRP—that is, three Boolean criteria, or a Clinical Disease Activity Index (CDAI) level of ≤2.8.2
Although it is generally agreed that the patient perception is necessary in any tool that may be used in studies of RA,3–6 the patient global measurement has been criticised for not being sufficiently accurate for assessing RA disease activity, as it may reflect complaints not directly related to RA disease activity, such as accrued joint damage, muscle wasting, low back pain, fibromyalgia or other.7
Given the recent publication of the ACR/EULAR remission criteria, we used a large outpatient database to investigate if and how the PGA might limit the ability to achieve remission of RA.
We selected all visits from a longitudinal observational dataset of patients with RA regularly attending our outpatient clinic,8 ,9 with complete observations on core set measures. Patients consented to the use of routinely obtained clinical data for subsequent outcomes research, which had also been approved by the local ethics committee. All patient visits with fulfilment of just three of the four Boolean criteria (CRP, SJC, TJC and PGA) were defined as ‘near miss’, as the remaining fourth variable thus becomes the limiting factor for fulfilling the remission definition. PGA was assessed on a 100 mm visual analogue scale using ‘no disease activity’ as anchor at 0 mm and ‘highly active disease’ as anchor at 100 mm. The wording of the question was: ‘How do you estimate your disease activity today?’ (originally in German: ‘Wie schätzen Sie heute Ihre Krankheitsaktivität ein?’).
We selected the first near-miss visit of each patient for further analyses, and investigated how often the near miss was due to failure to reach the CRP, SJC, PGA, or the TJC criterion. We then looked at the proportions of Boolean near-miss patients who achieved index-based (SDAI) remission.
For better characterisation of patients who fail remission because of not meeting the PGA criterion, we conducted a multivariate logistic regression model using ‘PGA>1 despite fulfilling the other three Boolean criteria’ as the dependent, and CRP, morning stiffness, SJC28, TJC28, pain, evaluator global assessment (EGA), intake of non-steroidal anti-inflammatory drugs, analgesics or glucocorticoids as independent variables.
In patients lacking only PGA≤1 cm to fulfil Boolean remission, we investigated the proportion of patients who would fulfil Boolean remission if EGA≤1 cm were used as criterion instead of PGA≤1 cm. We also looked at how the discrepancy between PGA and EGA (calculated by subtracting EGA from PGA) was associated with a PGA near miss of remission: as above, we modelled the probability of being a PGA near miss depending on this difference (PGA−EGA) in a univariate logistic regression model.
Unexplained high PGA may be the result of foot involvement, which is not covered by the 28 joint counts, and often neglected in clinical assessment. The joint count evaluating 32-joint regions includes metatarsophalangeal joints combined as one region and ankles. Joints are assessed by especially trained biometricians. We therefore tested differences in variables and the influence of SJC32 using descriptive statistics and analysis of variance.9
For our analyses 795 patients with RA, who had 8242 visits were identified. Most of the patients were female (80%), positive for anti-citrullinated protein antibodies (79%), and 66% were positive for rheumatoid factor. Mean disease duration was 8 years, when they first presented at our clinic, and a third of our patients was diagnosed within the first 3 months after the first visit. Fifty per cent of the patients had at least 10 visits and in 20%, 20 visits were documented.
The PGA is the most common limiting variable of Boolean-based remission
Among the 795 patients (8242 visits), 411 (52%) fulfilled at least one visit with exactly three of the four required Boolean criteria (table 1). PGA was the major reason for not achieving the remission criteria (n=249/411, 61%; mean PGA=3.6±1.9 cm). SJC, TJC and CRP were much less frequently the limiting factor for not fulfilling the Boolean criteria (table 1). Pain was the most significant predictor of a PGA near miss (OR=1.28; CI 1.17 to 1.40, per unit of increase; p<0.001; figure 1A). EGA was also a significant predictor of a PGA near miss (OR=1.1; CI 1.00 to 1.21, per unit of increase; p=0.046), although with less impact.
When looking at the group of near misses by the PGA criterion, only 13.7% of the patients had a TJC32>1 and 6.4% an SJC32>1, indicating that foot involvement plays only a minor role in explaining unduly high PGA. Considering foot involvement in patients in Boolean remission, we found only one patient who would not be classified as such if the 32-joint assessment were used instead (see supplementary online table S1). An overview of the differing variables between near miss and remission patients can be seen in the supplementary online table S2.
Index-based remission definitions can compensate for some near-miss patients
We found that 43% not fulfilling the CRP criterion in the Boolean definition had an SDAI≤3.3, and 80% had a CDAI≤2.8. The high proportion of CDAI remitters is related to the fact that this index does not include CRP.
However, patients with near misses due to the PGA criterion, achieved SDAI and CDAI remission in only 18% and 17%, respectively. In the SJC near misses by Boolean criteria group, the proportions were 7.5% and 5%, and for the TJC near misses 32% and 21%, respectively (table 1).
Higher patient than physician assessment is responsible for many near misses
When we modified the Boolean criteria by replacing the PGA≤1 cm with the EGA≤1 cm criterion in patients missing the PGA criterion, 166/249 patients (66.7%) would have been classifiable as in remission (table 2). Among those 166 patients, 41 (25%) fulfilled index-based criteria by the SDAI definition and 39 (24%) by the CDAI definition (mean PGA=1.8 cm, mean EGA=0.7 cm). In addition, the probability of being a near miss by PGA increases dramatically, as it becomes discordantly high compared with the evaluator's assessment (OR for each mm increase of the variable ‘PGA−EGA’: 1.28; CI 1.21 to 1.35; p<0.001; figure 1B).
Our study demonstrates that a considerable proportion of patients do not achieve the Boolean-based criteria for remission, because they fail to fulfil the criterion related to the patient's own assessment of disease activity. Conceptually, this is an acceptable situation in the light of patient empowerment by increasing valuation of patient-reported outcomes.10 ,11 Nevertheless, two-thirds of these patients would be evaluated as being in remission if the evaluator global were used instead of the patient global. This indicates that there is a relevant disconnection between these two measures. Discrepancy towards higher patient than physician disease activity evaluation was seen in 24–60% of patients with RA, depending on the definition of concordance (0.5–3 cm).12–14 This is supported by the results of the prediction model, which suggests that as soon as there is a numerical disconnection towards higher patient than physician assessment of disease activity the probability of missing remission ‘just’ because of the PGA increases dramatically.
Eighteen per cent of patients who present as near miss of the Boolean criteria because of failure to reach a PGA≤1 cm, do fulfil the index-based remission criteria, indicating that the index is more tolerant to isolated PGA elevations. Similar findings apply to isolated CRP elevations. This discrepancy between the Boolean and the index-based definitions demonstrate the ‘integrating’ effect of a summative score even in the setting of remission,15 ,16 because slight elevations of certain variables can easily be compensated for by other variables.
Nevertheless, despite using the index, in many cases the patient's self-evaluation of disease activity still remains an issue that—as a practical consequence—interferes with the concept of shared decision-making. It has been shown that pain unrelated to RA disease activity often leads to such disconnection between the patient and physician evaluation.12 ,14 The importance of considering pain is supported by our findings, showing that the probability of being a near miss due to PGA increases to about 75%, even when the pain scores are as low as 20/100 mm.
The management of (non-inflammatory) pain therefore needs to receive adequate focus as it is vital for the perception of RA remission in patients.17 ,18 On the other hand, one might argue that the PGA does not measure what it is supposed to measure. The phrasing of the question is relevant, and when it relates to ‘all the ways your arthritis affects you’,2 then inherently the response may be inaccurate if it is used to capture disease activity. However, PGA and global health seem to be interchangeable when evaluating disease activity by means of composite measures.19 Alternative wording may need to be investigated, which more specifically asks for disease activity.
Further it has to be considered that our results can be strengthened by analyses in larger databases of patients with RA, which also comprise a larger number of patients in remission. Research into the influence of comorbidities on remission frequencies should be enforced. Depressive symptoms and fatigue were shown to be associated with a high PGA.12 ,20 Clinical remission should consider the patient's view and objective disease activity, to which the Boolean criteria adhere.
In summary, we have shown the importance of the PGA in the therapeutic decision-making process for achieving remission by the new ACR/EULAR criteria. This applies to any criteria that involve patient-reported outcomes. As a consequence, doctors need to understand the information that is coming from these measures or, alternatively, need to better inform their patients to obtain measurements that most accurately reflect what they are meant to reflect.
We are indebted to Helga Radner, Michael Reiter and Marion Skobek, for their considerable contributions to the database integrity.
Review history and Supplementary material
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Files in this Data Supplement:
- Data supplement - Online tables
▸ Additional tables are published online only. To view these files please visit the journal online (http://dx.doi.org/10.1136/annrheumdis-2012-201519)
Contributors PS: Study design, data acquisition, data analysis, drafting of manuscript; JSS, DA: Study design, data analysis, drafting of manuscript.
Funding This study was supported through coordination theme 1 (Health) of the European Community's FP7; grant agreement number HEALTH-F2-2008-223404 (Masterswitch).
This is a publication of the Joint and Bone Center for Diagnosis, Research and Therapy of Musculoskeletal Disorders of the Medical University of Vienna.
Competing interests None.
Patient consent Not obtained.
Ethics approval Ethics committee of the Medical University Vienna.
Provenance and peer review Not commissioned; externally peer reviewed.
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